A pan-cancer single-cell panorama of human natural killer cells.

Natural killer (NK) cells play indispensable roles in innate immune responses against tumor progression. To depict their phenotypic and functional diversities in the tumor microenvironment, we perform integrative single-cell RNA sequencing analyses on NK cells from 716 patients with cancer, covering 24 cancer types. We observed heterogeneity in NK cell composition in a tumor-type-specific manner. Notably, we have identified a group of tumor-associated NK cells that are enriched in tumors, show impaired anti-tumor functions, and are associated with unfavorable prognosis and resistance to immunotherapy. Specific myeloid cell subpopulations, in particular LAMP3+ dendritic cells, appear to mediate the regulation of NK cell anti-tumor immunity. Our study provides insights into NK-cell-based cancer immunity and highlights potential clinical utilities of NK cell subsets as therapeutic targets.

Cancer-associated fibroblast-associated gene IGFBP2 promotes glioma progression through induction of M2 macrophage polarization.

We elucidated the molecular mechanism of cancer-associated fibroblast (CAF)-associated gene insulin-like growth factor binding protein-2 (IGFBP2)-induced M2 macrophage polarization in the tumor microenvironment involved in glioma progression. The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) provided bulk RNA-sequencing datasets, ESTIMATE scores for glioma stromal cells, and overall survival-clinicopathological correlation analyses. TIMER provided CAF abundance in the TCGA glioma-related dataset, differential gene analysis was performed for high- and low-CAF groups, and weighted gene coexpression network analysis identified CAF-related genes. Univariate and multifactorial cyclooxygenase (COX) regression analyses created the CAF risk models single sample gene set enrichment analysis, CIBERSORT, and GSE84465. Mice were implanted with gliomas, and Western blot and RT-quantitative PCR showed IGFBP2 in tumor tissues. Adeno-associated virus (AAV) decreased IGFBP2, flow cytometry measured M1 and M2 macrophage ratios, and immunohistochemistry detected markers. TCGA and CGGA transcriptome data showed malignant gliomas had higher stromal cell scores and worse prognoses. Low- and high-CAF TCGA gliomas were detected, and differential expression, WGCNA, and multifactorial COX identified 132 CAF-related genes and seven high-risk genes (CPQ, EFEMP2, IGFBP2, RAB42, TNFRSF12A, and VASN). Neither CAF risk score, grade, nor 1p/19q affected glioma prognosis. CAF only enriched EFEMP2 and IGFBP2. Gene Expression Profiling Interactive Analysis compared EFEMP2 and IGFBP2 expression in normal brain tissue and gliomas. Low-grade glioma and malignant glioblastoma highly expressed IGFBP2 and EFEMP2. GSEA raised IGFBP2. CIBERSORT linked M2 macrophage infiltration to TCGA glioma immune cell subpopulation IGFBP2 expression. IGFBP2 knockdown stopped mouse glioma and M2 macrophage polarization. CAF plays a procarcinogenic role in glioma, and the CAF-related gene IGFBP2 could promote glioma progression by inducing M2 macrophage polarization.NEW & NOTEWORTHY The cancer-associated fibroblast (CAF)-related gene insulin-like growth factor binding protein-2 (IGFBP2) is highly expressed in gliomas and is associated with poor prognosis. CAF-related gene IGFBP2 promotes glioma progression by inducing polarization of M2 macrophages. This study provides a new basis for an in-depth investigation of the functional mechanisms of the glioma tumor microenvironment and the search for key genes involved in immune regulation in CAF.

P75NTR+CD64+ neutrophils promote sepsis-induced acute lung injury.

Patients suffering from sepsis-induced acute lung injury (ALI) exhibit a high mortality rate, and their prognosis is closely associated with infiltration of neutrophils into the lungs. In this study, we found a significant elevation of CD64+ neutrophils, which highly expressed p75 neurotrophin receptor (p75NTR) in peripheral blood of mice and patients with sepsis-induced ALI. p75NTR+CD64+ neutrophils were also abundantly expressed in the lung of ALI mice induced by lipopolysaccharide. Conditional knock-out of the myeloid lineage's p75NTR gene improved the survival rates, attenuated lung tissue inflammation, reduced neutrophil infiltration and enhanced the phagocytic functions of CD64+ neutrophils. In vitro, p75NTR+CD64+ neutrophils exhibited an upregulation and compromised phagocytic activity in blood samples of ALI patients. Blocking p75NTR activity by soluble p75NTR extracellular domain peptide (p75ECD-Fc) boosted CD64+ neutrophils phagocytic activity and reduced inflammatory cytokine production via regulation of the NF-κB activity. The findings strongly indicate that p75NTR+CD64+ neutrophils are a novel pathogenic neutrophil subpopulation promoting sepsis-induced ALI.

Metabolomics analysis reveals the metabolite profiles of Rheum tanguticum grown under different altitudinal gradients.

BACKGROUND: Plant growth and quality are often affected by environmental factors, including geographical location, climate, and soil. In this study, we describe the effect of altitudinal differences on the growth and active ingredients in Rheum tanguticum Maxim. ex Balf. (R. tanguticum), a traditional Chinese medicinal herb known for its laxative properties. RESULTS: The results showed that plants grown at lower altitudes had better growth performances than those in higher altitude areas. The yield varied by 2.45-23.68 times with altitude, reaching a maximum of 102.01 t/ha. In addition, total anthraquinone and total sennoside contents decreased with increasing altitude, whereas total tannins increased with increasing altitude. The total anthraquinone content of the indicator compound reached 5.15% at five experimental sites, which exceeded the Chinese Pharmacopoeia standard by 70.87%. The content of the other two categories of active ingredients reached a maximum value of 0.94% (total sennosides) and 2.65% (total tannins). Redundancy analysis revealed that annual rainfall, annual average temperature, annual sunshine hours, and pH significantly affected growth and active ingredients. Moreover, key metabolites, such as flavonoids, amino acids and their derivatives, phenolic acids, lipids, and terpenes, were differentially expressed between samples from low- and high-altitude cultivation areas. These metabolites were enriched in the flavonoid and flavonol biosynthetic pathway and the monoterpene biosynthetic pathway. CONCLUSIONS: These results suggest that high anthraquinone content was observed in the lowest-latitude cultivation area due to low rainfall and alkaline soil pH. Key metabolites were significantly upregulated in high-latitude cultivation areas. These results provide a scientific basis for quality control and the systematic cultivation of R. tanguticum.

Transformed pupil-function misalignment calibration strategy for Fourier ptychographic microscopy.

Fourier ptychographic microscopy (FPM) is an enabling quantitative phase imaging technique with both high-resolution (HR) and wide field-of-view (FOV), which can surpass the diffraction limit of the objective lens by employing an LED array to provide angular-varying illumination. The precise illumination angles are critical to ensure exact reconstruction, while it's difficult to separate actual positional parameters in conventional algorithmic self-calibration approaches due to the mixing of multiple systematic error sources. In this paper, we report a pupil-function-based strategy for independently calibrating the position of LED array. We first deduce the relationship between positional deviation and pupil function in the Fourier domain through a common iterative route. Then, we propose a judgment criterion to determine the misalignment situations, which is based on the arrangement of LED array in the spatial domain. By combining the mapping of complex domains, we can accurately solve the spatial positional parameters concerning the LED array through a boundary-finding scheme. Relevant simulations and experiments demonstrate the proposed method is accessible to precisely correct the positional misalignment of LED array. The approach based on the pupil function is expected to provide valuable insights for precise position correction in the field of microscopy.

Global miRNA profiling reveals key molecules that contribute to different chronic lymphocytic leukemia incidences in Asian and Western populations.

It has been known for decades that the incidence of chronic lymphocytic leukemia (CLL) is significantly lower in Asia than in Western countries, but the reason responsible for this difference still remains a major knowledge gap. Using GeneChip® miRNA array to analyze the global microRNA expression in B lymphocytes from Asian and Western CLL patients and healthy individuals, we have identified microRNA with CLL-promoting or suppressive functions that are differentially expressed in Asian and Western individuals. In particular, miR-4485 is upregulated in CLL patients of both ethnic groups, and its expression is significantly lower in Asian healthy individuals. Genetic silencing of miR-4485 in CLL cells suppresses leukemia cell growth, whereas ectopic expression of miR-4485 promotes cell proliferation. Mechanistically, miR-4485 exerts its CLL-promoting activity by inhibiting the expression of TGR5 and activating the ERK1/2 pathway. In contrast, miR-138, miR-181a, miR- 181c, miR-181d, and miR-363 with tumor-suppressive function are highly expressed in Asian healthy individuals. Our study suggests that differential expression of several important microRNA with pro- or anti-CLL functions in Asian and Western B lymphocytes likely contributes to the difference in CLL incidence between the two ethnic groups, and that miR-4485 and its downstream molecule TGR5 could be potential therapeutic targets.

Whole-genome DNA methylation profiling revealed epigenetic regulation of NF-κB signaling pathway involved in response to Vibrio alginolyticus infection in the Pacific oyster, Crassostrea gigas.

DNA methylation, an essential epigenetic alteration, is tightly linked to a variety of biological processes, such as immune response. To identify the epigenetic regulatory mechanism in Pacific oyster (Crassostrea gigas), whole-genome bisulfite sequencing (WGBS) was conducted on C. gigas at 0 h, 6 h, and 48 h after infection with Vibrio alginolyticus. At 6 h and 48 h, a total of 11,502 and 14,196 differentially methylated regions (DMRs) were identified (p<0.05, FDR<0.001) compared to 0 h, respectively. Gene ontology (GO) analysis showed that differentially methylated genes (DMGs) were significantly enriched in various biological pathways including immunity, cytoskeleton, epigenetic modification, and metabolic processes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that transcription machinery (ko03021) is one of the most important pathways. Integrated transcriptome and methylome analyses allowed the identification of 167 and 379 DMG-related DEGs at 6 h and 48 h, respectively. These genes were significantly enriched in immune-related pathways, including nuclear factor kappa B (NF-κB) signaling pathway (ko04064) and tumor necrosis factor (TNF) signaling pathway (ko04668). Interestingly, it's observed that the NF-κB pathway could be activated jointly by TNF Receptor Associated Factor 2 (TRAF2) and Baculoviral IAP Repeat Containing 3 (BIRC3, the homolog of human BIRC2) which were regulated by DNA methylation in response to the challenge posed by V. alginolyticus infection. Through this study, we provided insightful information about the epigenetic regulation of immunity-related genes in the C. gigas, which will be valuable for the understanding of the innate immune system modulation and defense mechanism against bacterial infection in invertebrates.

Double-Network Organohydrogels Toughened by Solvent Exchange.

Double-network hydrogels based on calcium alginate are extensively exploited. Unfortunately, their low strength and unstable constitution to open environments limit their application potential. Herein, a new type of double-network organohydrogel (OHG) is proposed. By solvent exchange, a stable physical network is established based on dimethyl sulfoxide (DMSO)-alginate in the presence of a polyacrylamide network. The DMSO content endows tunable mechanical properties, with a maximum tensile strength of ≈1.7 MPa. Importantly, the OHG shows much better environmental stability compared to the conventional double-network hydrogels. Due to the reversible association of hydrogen bonds, the OHG possesses some unique properties, including free-shapeability, shape-memory, and self-adhesion, that offers several promising ways to utilize alginate-based gels for wide applications.

m6A facilitates hippocampus-dependent learning and memory through YTHDF1.

N6-methyladenosine (m6A), the most prevalent internal RNA modification on mammalian messenger RNAs, regulates the fates and functions of modified transcripts through m6A-specific binding proteins1-5. In the nervous system, m6A is abundant and modulates various neural functions6-11. Whereas m6A marks groups of mRNAs for coordinated degradation in various physiological processes12-15, the relevance of m6A for mRNA translation in vivo remains largely unknown. Here we show that, through its binding protein YTHDF1, m6A promotes protein translation of target transcripts in response to neuronal stimuli in the adult mouse hippocampus, thereby facilitating learning and memory. Mice with genetic deletion of Ythdf1 show learning and memory defects as well as impaired hippocampal synaptic transmission and long-term potentiation. Re-expression of YTHDF1 in the hippocampus of adult Ythdf1-knockout mice rescues the behavioural and synaptic defects, whereas hippocampus-specific acute knockdown of Ythdf1 or Mettl3, which encodes the catalytic component of the m6A methyltransferase complex, recapitulates the hippocampal deficiency. Transcriptome-wide mapping of YTHDF1-binding sites and m6A sites on hippocampal mRNAs identified key neuronal genes. Nascent protein labelling and tether reporter assays in hippocampal neurons showed that YTHDF1 enhances protein synthesis in a neuronal-stimulus-dependent manner. In summary, YTHDF1 facilitates translation of m6A-methylated neuronal mRNAs in response to neuronal stimulation, and this process contributes to learning and memory.

FHL3 promotes the formation of fast glycolytic muscle fibers by interacting with YY1 and muscle glycolytic metabolism.

The proportions of the various muscle fiber types are important in the regulation of skeletal muscle metabolism, as well as animal meat production. Four-and-a-half LIM domain protein 3 (FHL3) is highly expressed in fast glycolytic muscle fibers and differentially regulates the expression of myosin heavy chain (MyHC) isoforms at the cellular level. Whether FHL3 regulates the transformation of muscle fiber types in vivo and the regulatory mechanism is unclear. In this study, muscle-specific FHL3 transgenic mice were generated by random integration, and lentivirus-mediated gene knockdown or overexpression in muscles of mice or pigs was conducted. Functional analysis showed that overexpression of FHL3 in muscles significantly increased the proportion of fast-twitch myofibers and muscle mass but decreased muscle succinate dehydrogenase (SDH) activity and whole-body oxygen consumption. Lentivirus-mediated FHL3 knockdown in muscles significantly decreased muscle mass and the proportion of fast-twitch myofibers. Mechanistically, FHL3 directly interacted with the Yin yang 1 (YY1) DNA-binding domain, repressed the binding of YY1 to the fast glycolytic MyHC2b gene regulatory region, and thereby promoted MyHC2b expression. FHL3 also competed with EZH2 to bind the repression domain of YY1 and reduced H3K27me3 enrichment in the MyHC2b regulatory region. Moreover, FHL3 overexpression reduced glucose tolerance by affecting muscle glycolytic metabolism, and its mRNA expression in muscle was positively associated with hemoglobin A1c (HbA1c) in patients with type 2 diabetes. Therefore, FHL3 is a novel potential target gene for the treatment of muscle metabolism-related diseases and improvement of animal meat production.

Long noncoding RNA lncMREF promotes myogenic differentiation and muscle regeneration by interacting with the Smarca5/p300 complex.

Long noncoding RNAs (lncRNAs) play important roles in the spatial and temporal regulation of muscle development and regeneration. Nevertheless, the determination of their biological functions and mechanisms underlying muscle regeneration remains challenging. Here, we identified a lncRNA named lncMREF (lncRNA muscle regeneration enhancement factor) as a conserved positive regulator of muscle regeneration among mice, pigs and humans. Functional studies demonstrated that lncMREF, which is mainly expressed in differentiated muscle satellite cells, promotes myogenic differentiation and muscle regeneration. Mechanistically, lncMREF interacts with Smarca5 to promote chromatin accessibility when muscle satellite cells are activated and start to differentiate, thereby facilitating genomic binding of p300/CBP/H3K27ac to upregulate the expression of myogenic regulators, such as MyoD and cell differentiation. Our results unravel a novel temporal-specific epigenetic regulation during muscle regeneration and reveal that lncMREF/Smarca5-mediated epigenetic programming is responsible for muscle cell differentiation, which provides new insights into the regulatory mechanism of muscle regeneration.

Dissipation behaviours, residues, and health risk of six herbicides in sugar beets under field conditions.

This study established a residue detection method based on the QuEChERS pre-treatment method and combined it with high-performance liquid chromatography-tandem mass spectrometry to test six herbicides (metamitron, clopyralid, desmedipham, phenmedipham, ethofumesate, and haloxyfop-p-methyl) in sugar beet plants, soil, and roots. The degradation dynamics and terminal residues of each herbicide in sugar beets were analysed. Finally, the dietary risks of various herbicides in sugar beets were evaluated based on the dietary structure of Chinese people, and the risk quotient values were below 100%. Using this detection method, all reagents exhibited good linearity (0.9724 ≤ R2 ≤ 0.9998), The limit of quantification (LOQ) ranged from 0.01 to 0.05 mg/L, the matrix effect ranged from -1.2% to -50%, the addition recovery rate ranged from 77.00% to 103.48%, and the relative standard deviation ranged from 1.61% to 16.17%; therefore, all indicators of this method met the residue detection standards. Under field conditions, the half-lives (t1/2) ranged about 0.65 ∼ 2.96 d and 0.38 ∼ 27.59 d in sugar beet plants and soil, respectively. All herbicides were easily degraded in sugar beet plants and soil (t1/2 < 30 d). The terminal residue amounts in the beet plants, soil, and roots ranged from < LOQ to 0.243 mg/kg. The dietary risk assessment of each pesticide was conducted based on the residual median of the terminal residues and the highest residual values on the edible part of the beetroot. The chronic exposure risk quotient (RQc) and acute exposure risk quotient (RQa) values were < 100%, indicating that the residue of each pesticide in beetroot posed low risks to consumers in China at the recommended dosage.

Clarification of the molecular mechanisms underlying glyphosate-induced major depressive disorder: a network toxicology approach.

Major depressive disorder (MDD) is predicted to become the second most common cause of disability in the near future. Exposure to glyphosate (Gly)-based herbicides has been linked to the onset of MDD. However, the underlying mechanisms remain unclear. The aim of this study was to investigate the potential molecular mechanisms of MDD induced by Gly using network toxicology approach. The MDD dataset GSE76826 from the Gene Expression Omnibus database was referenced to identify differentially expressed genes (DEGs) in peripheral blood leukocytes of MDD patients and controls. The potential intersection targets of Gly-induced MDD were screened by network toxicology. The intersection targets were used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and to construct protein-protein interaction networks. The binding potentials of hub targets with Gly were validated by molecular docking. In total, 1216 DEGs associated with Gly-induced MDD were identified. Subsequent network pharmacology further refined the search to 43 targets. GO and KEGG enrichment analyses revealed multiple signaling pathways involved in GLY-induced MDD. Six potential core targets (CD40, FOXO3, FOS, IL6, TP53, and VEGFA) were identified. Finally, molecular docking demonstrated that Gly exhibited strong binding affinity to the core targets. The results of this study identified potential molecular mechanisms underlying Gly induced MDD and provided new insights for prevention and treatment.

Exoskeleton rehabilitation robot training for balance and lower limb function in sub-acute stroke patients: a pilot, randomized controlled trial.

PURPOSE: This pilot study aimed to investigate the effects of REX exoskeleton rehabilitation robot training on the balance and lower limb function in patients with sub-acute stroke. METHODS: This was a pilot, single-blind, randomized controlled trial. Twenty-four patients with sub-acute stroke (with the course of disease ranging from 3 weeks to 3 months) were randomized into two groups, including a robot group and a control group. Patients in control group received upright bed rehabilitation (n = 12) and those in robot group received exoskeleton rehabilitation robot training (n = 12). The frequency of training in both groups was once a day (60 min each) for 5 days a week for a total of 4 weeks. Besides, the two groups were evaluated before, 2 weeks after and 4 weeks after the intervention, respectively. The primary assessment index was the Berg Balance Scale (BBS), whereas the secondary assessment indexes included the Fugl-Meyer Lower Extremity Motor Function Scale (FMA-LE), the Posture Assessment Scale for Stroke Patients (PASS), the Activities of Daily Living Scale (Modified Barthel Index, MBI), the Tecnobody Balance Tester, and lower extremity muscle surface electromyography (sEMG). RESULTS: The robot group showed significant improvements (P < 0.05) in the primary efficacy index BBS, as well as the secondary efficacy indexes PASS, FMA-LE, MBI, Tecnobody Balance Tester, and sEMG of the lower limb muscles. Besides, there were a significant differences in BBS, PASS, static eye-opening area or dynamic stability limit evaluation indexes between the robotic and control groups (P < 0.05). CONCLUSIONS: This is the first study to investigate the effectiveness of the REX exoskeleton rehabilitation robot in the rehabilitation of patients with stroke. According to our results, the REX exoskeleton rehabilitation robot demonstrated superior potential efficacy in promoting the early recovery of balance and motor functions in patients with sub-acute stroke. Future large-scale randomized controlled studies and follow-up assessments are needed to validate the current findings. CLINICAL TRIALS REGISTRATION: URL: https://www.chictr.org.cn/index.html.Unique identifier: ChiCTR2300068398.

Dialysis bag-microalgae photobioreactor: Novel strategy for enhanced bioresource production and wastewater purification.

Cultivating microalgae in wastewater offers various advantages, but it still faces limitations such as bacteria and other impurities in wastewater affecting the growth and purity of microalgae, difficulty in microalgae harvesting, and extracellular products of microalgae affecting effluent quality. In this study, a novel dialysis bag-microalgae photobioreactor (Db-PBR) was developed to achieve wastewater purification and purer bioresource recovery by culturing microalgae in a dialysis bag. The dialysis bag in the Db-PBR effectively captured the microalgae cells and promoted their lipid accumulation, leading to higher biomass (1.53 times of the control) and lipid production (2.50 times of the control). During the stable operation stage of Db-PBR, the average soluble microbial products (SMP) content outside the dialysis bag was 25.83 mg L-1, which was significantly lower than that inside the dialysis bag (185.63 mg L-1), indicating that the dialysis bag effectively intercepted the SMP secreted by microalgae. As a result, the concentration of dissolved organic carbon (DOC) in Db-PBR effluent was significantly lower than that of traditional photobioreactor. Furthermore, benefiting from the dialysis bag in the reactor effectively intercepted the microorganisms in wastewater, significantly improving the purity of the cultured microalgae biomass, which is beneficial for the development of high-value microalgae products.

Leveraging a disulfidptosis-related signature to predict the prognosis and immunotherapy effectiveness of cutaneous melanoma based on machine learning.

BACKGROUND: Disulfidptosis is a recently discovered programmed cell death pathway. However, the exact molecular mechanism of disulfidptosis in cutaneous melanoma remains unclear. METHODS: In this study, clustering analysis was performed using data from public databases to construct a prognostic model, which was subsequently externally validated. The biological functions of the model genes were then investigated through various experimental techniques, including qRT-PCR, Western blotting, CCK-8 assay, wound healing assay, and Transwell assay. RESULTS: We constructed a signature using cutaneous melanoma (CM) data, which accurately predicts the overall survival (OS) of patients. The predictive value of this signature for prognosis and immune therapy response was validated using multiple external datasets. High-risk CM subgroups may exhibit decreased survival rates, alterations in the tumor microenvironment (TME), and increased tumor mutation burden. We initially verified the expression levels of five optimum disulfidptosis-related genes (ODRGs) in normal tissues and CM. The expression levels of these genes were further confirmed in HaCaT cells and three melanoma cell lines using qPCR and protein blotting analysis. HLA-DQA1 emerged as the gene with the highest regression coefficient in our risk model, highlighting its role in CM. Mechanistically, HLA-DQA1 demonstrated the ability to suppress CM cell growth, proliferation, and migration. CONCLUSION: In this study, a novel signature related to disulfidptosis was constructed, which accurately predicts the survival rate and treatment sensitivity of CM patients. Additionally, HLA-DQA1 is expected to be a feasible therapeutic target for effective clinical treatment of CM.

A core root bacteria contribute to plant growth and anisodine accumulation of Anisodus tanguticus.

BACKGROUND: Although it is well recognized that core root microorganisms contribute to plant health and productivity, little is known about their role to the accumulation of secondary metabolites. The roots of Anisodus tanguticus, a traditional herbal medication utilized by Tibetan medicine, are rich in tropane alkaloids. We collected wild A. tanguticus populations throughout a 1500 km transect on the Qinghai-Tibetan Plateau. RESULTS: Our results showed that despite sampling at a distance of 1500 km, the root of A. tanguticus selectively recruits core root bacteria. We obtained 102 root bacterial core OTUs, and although their number only accounted for 2.99% of the total, their relative abundance accounted for 73% of the total. Spearman correlation and random forest analyses revealed that the composition of core root microbiomes was related to anisodine contents, aboveground biomass and nitrogen contents of Anisodus tanguticus. Among them, the main role is played by Rhizobacter, Variovorax, Polaromonas, and Mycobacterium genus that are significantly enriched in roots. Functional prediction by FAPROTAX showed that nitrogen-cycling microorganisms and pathogenic bacteria are strongly associated with anisodine contents, aboveground biomass and nitrogen contents of Anisodus tanguticus. CONCLUSIONS: Our findings show that the root selectively recruits core root bacteria and revealed that the core microbiomes and microbial functions potentially contributed to the anisodine contents, aboveground biomass and nitrogen contents of the plant. This work may increase our understanding of the interactions between microorganisms and plants and improve our ability to manage root microbiota to promote sustainable production of herbal medicines.

Ectopic expression of Camellia oleifera Abel. gibberellin 20-oxidase gene increased plant height and promoted secondary cell walls deposition in Arabidopsis.

MAIN CONCLUSION: Ectopic expression of Camellia oleifera Abel. gibberellin 20-oxidase 1 caused a taller phenotype, promoted secondary cell wall deposition, leaf enlargement, and early flowering, and reduced chlorophyll and anthocyanin accumulation and seed enlargement phenotype in Arabidopsis. Plant height and secondary cell wall (SCW) deposition are important plant traits. Gibberellins (GAs) play important roles in regulating plant height and SCWs deposition. Gibberellin 20-oxidase (GA20ox) is an important enzyme involved in GA biosynthesis. In the present study, we identified a GA synthesis gene in Camellia oleifera. The total length of the CoGA20ox1 gene sequence was 1146 bp, encoding 381 amino acids. Transgenic plants with CoGA20ox1 had a taller phenotype; a seed enlargement phenotype; promoted SCWs deposition, leaf enlargement, and early flowering; and reduced chlorophyll and anthocyanin accumulation. Genetic analysis showed that the mutant ga20ox1-3 Arabidopsis partially rescued the phenotype of CoGA20ox1 overexpression plants. The results showed that CoGA20ox1 participates in the growth and development of C. oleifera. The morphological changes in CoGA20ox1 overexpressed plants provide a theoretical basis for further exploration of GA biosynthesis and analysis of the molecular mechanism in C. oleifera.

Plasma protein binding prediction focusing on residue-level features and circularity of cyclic peptides by deep learning.

MOTIVATION: In recent years, cyclic peptide drugs have been receiving increasing attention because they can target proteins that are difficult to be tackled by conventional small-molecule drugs or antibody drugs. Plasma protein binding rate (%PPB) is a significant pharmacokinetic property of a compound in drug discovery and design. However, due to structural differences, previous computational prediction methods developed for small-molecule compounds cannot be successfully applied to cyclic peptides, and methods for predicting the PPB rate of cyclic peptides with high accuracy are not yet available. RESULTS: Cyclic peptides are larger than small molecules, and their local structures have a considerable impact on PPB; thus, molecular descriptors expressing residue-level local features of cyclic peptides, instead of those expressing the entire molecule, as well as the circularity of the cyclic peptides should be considered. Therefore, we developed a prediction method named CycPeptPPB using deep learning that considers both factors. First, the macrocycle ring of cyclic peptides was decomposed residue by residue. The residue-based descriptors were arranged according to the sequence information of the cyclic peptide. Furthermore, the circular data augmentation method was used, and the circular convolution method CyclicConv was devised to express the cyclic structure. CycPeptPPB exhibited excellent performance, with mean absolute error (MAE) of 4.79% and correlation coefficient (R) of 0.92 for the public drug dataset, compared to the prediction performance of the existing PPB rate prediction software (MAE=15.08%, R=0.63). AVAILABILITY AND IMPLEMENTATION: The data underlying this article are available in the online supplementary material. The source code of CycPeptPPB is available at https://github.com/akiyamalab/cycpeptppb. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

CycPeptMPDB: A Comprehensive Database of Membrane Permeability of Cyclic Peptides.

Recently, cyclic peptides have been considered breakthrough drugs because they can interact with "undruggable" targets such as intracellular protein-protein interactions. Membrane permeability is an essential indicator of oral bioavailability and intracellular targeting, and the development of membrane-permeable peptides is a bottleneck in cyclic peptide drug discovery. Although many experimental data on membrane permeability of cyclic peptides have been reported, a comprehensive database is not yet available. A comprehensive membrane permeability database is essential for developing computational methods for cyclic peptide drug design. In this study, we constructed CycPeptMPDB, the first web-accessible database of cyclic peptide membrane permeability. We collected information on a total of 7334 cyclic peptides, including the structure and experimentally measured membrane permeability, from 45 published papers and 2 patents from pharmaceutical companies. To unambiguously represent cyclic peptides larger than small molecules, we used the hierarchical editing language for macromolecules notation to generate a uniform sequence representation of peptides. In addition to data storage, CycPeptMPDB provides several supporting functions such as online data visualization, data analysis, and downloading. CycPeptMPDB is expected to be a valuable platform to support membrane permeability research on cyclic peptides. CycPeptMPDB can be freely accessed at http://cycpeptmpdb.com.