Abstract
Protein dynamics is central to all biological processes, including signal transduction, cellular regulation and biological catalysis. Among them, in-depth exploration of ligand-driven ...protein dynamics contributes to an optimal understanding of protein function, which is particularly relevant to drug discovery. Hence, a wide range of computational tools have been designed to investigate the important dynamic information in proteins. However, performing and analyzing protein dynamics is still challenging due to the complicated operation steps, giving rise to great difficulty, especially for nonexperts. Moreover, there is a lack of web protocol to provide online facility to investigate and visualize ligand-driven protein dynamics. To this end, in this study, we integrated several bioinformatic tools to develop a protocol, named Ligand and Receptor Molecular Dynamics (LARMD, http://chemyang.ccnu.edu.cn/ccb/server/LARMD/ and http://agroda.gzu.edu.cn:9999/ccb/server/LARMD/), for profiling ligand-driven protein dynamics. To be specific, estrogen receptor (ER) was used as a case to reveal ERβ-selective mechanism, which plays a vital role in the treatment of inflammatory diseases and many types of cancers in clinical practice. Two different residues (Ile373/Met421 and Met336/Leu384) in the pocket of ERβ/ERα were the significant determinants for selectivity, especially Met336 of ERβ. The helix H8, helix H11 and H7-H8 loop influenced the migration of selective agonist (WAY-244). These computational results were consistent with the experimental results. Therefore, LARMD provides a user-friendly online protocol to study the dynamic property of protein and to design new ligand or site-directed mutagenesis.
•Transfer learning enhances PK prediction models by leveraging relevant knowledge transfer.•Transfer learning categorizes into three types based on domain and tasks.•Diverse toolkits offer ...user-friendly approaches to deploy transfer learning effectively.•Several case studies exhibit the process and outcomes of transfer learning in PK prediction.
Accurate assessment of pharmacokinetic (PK) properties is crucial for selecting optimal candidates and avoiding downstream failures. Transfer learning is an innovative machine learning approach enabling high-throughput prediction with limited data. Recently, transfer learning methods showed promise in predicting ADME/PK parameters. Given the prolific growth of research on transfer learning for PK prediction, a comprehensive review of its advantages and challenges is imperative. This study explores the fundamentals, classifications, toolkits and applications of various transfer learning techniques for PK prediction, demonstrating their utility through three practical case studies. This work will serve as a reference for drug design researchers.
We prepared novel Fe3O4 magnetic nanoparticles (MNPs) modified with 3-aminopropyltriethoxysilane (APS) and copolymers of acrylic acid (AA) and crotonic acid (CA). The MNPs were characterized by ...transmission electron microscopy, X-ray diffraction, infra-red spectra and thermogravimetric analysis. We explored the ability of the MNPs for removing heavy metal ions (Cd2+, Zn2+, Pb2+ and Cu2+) from aqueous solution. We investigated the adsorption capacity of Fe3O4@APS@AA-co-CA at different pH in solution and metal ion uptake capacity as a function of contact time and metal ion concentration. Moreover, adsorption isotherms, kinetics and thermodynamics were studied to understand the mechanism of the synthesized MNPs adsorbing metal ions. In addition, we evaluated the effect of background electrolytes on the adsorption. Furthermore, we explored desorption and reuse of MNPs. Fe3O4@APS@AA-co-CA MNPs are excellent for removal of heavy metal ions such as Cd2+, Zn2+, Pb2+ and Cu2+ from aqueous solution. Furthermore, the MNPs could efficiently remove the metal ions with high maximum adsorption capacity at pH 5.5 and could be used as a reusable adsorbent with convenient conditions.
Necroptosis is a type of programmed necrosis regulated by receptor interacting protein kinase 1 （RIP1） and RIP3. Necroptosis is found to be accompanied by an overproduction of reactive oxygen species ...（ROS）, but the role of ROS in regulation of necroptosis remains elusive. In this study, we investigated how shikonin, a necroptosis inducer for cancer cells, regulated the signaling leading to necroptosis in glinoma cells in vitro. Treatment with shikonin （2-10 pmol/L） dose-dependently triggered necrosis and induced overproduction of intracellular ROS in rat C6 and human SHG-44, U87 and U251 glioma cell lines. Moreover, shikonin treatment dose- dependently upregulated the levels of RIP1 and RIP3 and reinforced their interaction in the glioma cells. Pretreatment with the specific RIP1 inhibitor Nec-1 （100 pmol/L） or the specific RIP3 inhibitor GSK-872 （5 pmol/L） not only prevented shikonin-induced glioma cell necrosis but also significantly mitigated the levels of intraceliular ROS and mitochondrial superoxide. Mitigation of ROS with MnTBAP （40 pmol/L）, which was a cleaner of mitochondrial superoxide, attenuated shikonin-induced glioma cell necrosis, whereas increasing ROS levels with rotenone, which improved the mitochondrial generation of superoxide, significantly augmented shikonin-caused glioma cell necrosis. Furthermore, pretreatment with MnTBAP prevented the shikonin-induced upregulation of RIP1 and RIP3 expression and their interaction while pretreatment with rotenone reinforced these effects. These findings suggest that ROS is not only an executioner of shikonin-induced glioma cell necrosis but also a regulator of RIP1 and RIP3 expression and necrosome assembly.
Parkinson’s disease (PD) is one of the most common age-related neurodegenerative diseases. Inhibition of monoamine oxidase-B (MAO-B), which is mainly found in the glial cells of the brain, may lead ...to an elevated level of dopamine (DA) in patients. MAO-B inhibitors have been used extensively for patients with PD. However, the discovery of the selective MAO-B inhibitor is still a challenge. In this study, a computational strategy was designed for the rapid discovery of selective MAO-B inhibitors. A series of (S)-2-(benzylamino)propanamide derivatives were designed. In vitro biological evaluations revealed that (S)-1-(4-((3-fluorobenzyl)oxy)benzyl)azetidine-2-carboxamide (C3) was more potent and selective than safinamide, a promising drug for regulating MAO-B. Further studies revealed that the selectivity mechanism of C3 was due to the steric clash caused by the residue difference of Phe208 (MAO-A) and Ile199 (MAO-B). Animal studies showed that compound C3 could inhibit cerebral MAO-B activity and alleviate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neuronal loss.
Past assessments of coupled climate models have indicated that precipitation extremes are expected to intensify over Southeast Asia (SEA) under the global warming. Here, we use outputs from 15 ...climate models from the Coupled Model Intercomparison Project Phase 6 (CMIP6) to evaluate projected changes in precipitation extremes for SEA at the end of the 21st century. The results suggest that CMIP6 multi-model ensemble medians show better performances in characterizing precipitation extremes than individual models. Projected changes in precipitation extremes linked to rising greenhouse gas (GHG) emissions (represented by the latest proposed Shared Socioeconomic Pathways) increase significantly over the Indochina Peninsula and the Maritime Continent. Substantial changes in the number of very heavy precipitation days (R20mm) and the intensity of daily precipitation (SDII) indicate that such locally heavy rainfall is likely to occur over a short time and that more precipitation extremes over SEA are probable in a warmer future. This is consistent with projections from the Coordinated Regional Downscaling Experiment and CMIP5 models. The present study reveals the high sensitivity of the precipitation extremes over SEA, and highlights the importance of constrained anthropogenic GHG emissions in an ambitious mitigation scenario.
Phosphorus (P) is a vital element in biological molecules, and one of the main limiting elements for biomass production as plant-available P represents only a small fraction of total soil P. ...Increasing global food demand and modern agricultural consumption of P fertilizers could lead to excessive inputs of inorganic P in intensively managed croplands, consequently rising P losses and ongoing eutrophication of surface waters. Despite phosphate solubilizing microorganisms (PSMs) are widely accepted as eco-friendly P fertilizers for increasing agricultural productivity, a comprehensive and deeper understanding of the role of PSMs in P geochemical processes for managing P deficiency has received inadequate attention. In this review, we summarize the basic P forms and their geochemical and biological cycles in soil systems, how PSMs mediate soil P biogeochemical cycles, and the metabolic and enzymatic mechanisms behind these processes. We also highlight the important roles of PSMs in the biogeochemical P cycle and provide perspectives on several environmental issues to prioritize in future PSM applications.
Oral lichen planus (OLP) is a T cell–mediated chronic inflammatory disease with uncertain aetiology. Exosomes are nanosized particles with biological capacities. Here, we aimed to study the effects ...of T cell–derived exosomes (T‐exos) on the pathogenesis of OLP and its mechanism. T‐exos were incubated with Jurkat cells for 48 hours, and 26 cytokines in the supernatant were measured by luminex assay. The expression of macrophage inflammatory protein (MIP)‐1α/β was detected using immunohistochemistry and ELISA; that of CCR1/3/5 on peripheral T cells was determined by flow cytometry. Transwell assay was performed to investigate the chemotactic effect of MIP‐1α/β, and cells in the lower chambers were examinated by flow cytometry. As a result, OLP T‐exos elevated the production of MIP‐1α/β, which were highly expressed in OLP tissues and plasma. CCR1/5 were markedly expressed on OLP peripheral T cells, and the majority of CCR1/5+ T cells were CD8+ T cells. Besides, MIP‐1α/β promoted the migration of OLP mononuclear cells, while inhibiting CCR1/5 significantly decreased the trafficking of mononuclear cells, especially that of CD8+ T cells. Conclusively, OLP T‐exos‐induced MIP‐1α/β may drive the trafficking of CD8+ T cells after binding with CCR1/5 in OLP, contributing to the development of OLP.
Herein, we report an unprecedented skeletal rearrangement reaction of tetrahydro‐β‐carbolines enabled by copper‐catalyzed single‐electron oxidative oxygenation, in which H2O and O2 act as oxygen ...sources to generate a unique 2‐hydroxyl‐3‐peroxide indoline intermediate. The synthetic reactivity of 2‐hydroxyl‐3‐peroxide indoline species was demonstrated by a unique multi‐step bond cleavage and formation cascade. Using a readily available copper catalyst under open‐air conditions, highly important yet synthetically difficult spiropyrrolidone‐(3,1‐benzoxazine) products were obtained in a single operation. The synthetic utility of this methodology is demonstrated by the efficient synthesis of the natural products donaxanine and chimonamidine, as well as the 3‐hydroxyl‐pyrroloindoline scaffold, in just one or two steps.
An unprecedented oxygenative skeletal rearrangement reaction of tetrahydro‐β‐carbolines (THβCs) was developed under mild conditions enabled by copper‐catalyzed single‐electron transfer oxidation, in which H2O and O2 act as oxygen sources to generate a unique 2‐hydroxyl‐3‐peroxide indoline intermediate. The process involves a multistep sequence to enable the transformation of THβCs to donaxanine‐type heterocycles in an efficient manner.
Summary
In eukaryotes, mechanisms such as alternative splicing (AS) and alternative translation initiation (ATI) contribute to organismal protein diversity. Specifically, splicing factors play ...crucial roles in responses to environment and development cues; however, the underlying mechanisms are not well investigated in plants. Here, we report the parallel employment of short‐read RNA sequencing, single molecule long‐read sequencing and proteomic identification to unravel AS isoforms and previously unannotated proteins in response to abscisic acid (ABA) treatment. Combining the data from the two sequencing methods, approximately 83.4% of intron‐containing genes were alternatively spliced. Two AS types, which are referred to as alternative first exon (AFE) and alternative last exon (ALE), were more abundant than intron retention (IR); however, by contrast to AS events detected under normal conditions, differentially expressed AS isoforms were more likely to be translated. ABA extensively affects the AS pattern, indicated by the increasing number of non‐conventional splicing sites. This work also identified thousands of unannotated peptides and proteins by ATI based on mass spectrometry and a virtual peptide library deduced from both strands of coding regions within the Arabidopsis genome. The results enhance our understanding of AS and alternative translation mechanisms under normal conditions, and in response to ABA treatment.
Significance Statement
In this study, a customized analytical pipeline was developed to study transcriptional and translational changes during the abscisic acid response in plants. Using single molecule long‐read sequencing and short‐read RNA sequencing, we identified numerous alternative spliced (AS) transcripts in Arabidopsis and characterized two new AS types. Proteomic identification indicates differentially expressed AS events were more likely to undergo protein translation. The entire workflow is applicable for other plant species.
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