Deciphering recursive polyploidization in Lamiales and reconstructing their chromosome evolutionary trajectories.

Lamiales is an order of core eudicots with abundant diversity, and many Lamiales plants have important medicinal and ornamental values. Here, we comparatively reanalyzed 11 Lamiales species with well-assembled genome sequences and found evidence that Lamiales plants, in addition to a hexaploidization or whole-genome triplication (WGT) shared by core eudicots, experienced further polyploidization events, establishing new groups in the order. Notably, we identified a whole-genome duplication (WGD) occurred just before the split of Scrophulariaceae from the other Lamiales families, such as Acanthaceae, Bignoniaceae, and Lamiaceae, suggesting its likely being the causal reason for the establishment and fast divergence of these families. We also found that a WGT occurred ∼68 to 78 million years ago (Mya), near the split of Oleaceae from the other Lamiales families, implying that it may have caused their fast divergence and the establishment of the Oleaceae family. Then, by exploring and distinguishing intra- and intergenomic chromosomal homology due to recursive polyploidization and speciation, respectively, we inferred that the Lamiales ancestral cell karyotype had 11 proto-chromosomes. We reconstructed the evolutionary trajectories from these proto-chromosomes to form the extant chromosomes in each Lamiales plant under study. We must note that most of the inferred 11 proto-chromosomes, duplicated during a WGD thereafter, have been well preserved in jacaranda (Jacaranda mimosifolia) genome, showing the credibility of the present inference implementing a telomere-centric chromosome repatterning model. These efforts are important to understand genome repatterning after recursive polyploidization, especially shedding light on the origin of new plant groups and angiosperm cell karyotype evolution.

RIP3 orchestrates oxidative stress and pyroptosis in doxorubicin-induced cardiotoxicity through regulation of AKT/Nrf2 signaling cascade.

This study was designed to explore the role of RIP3 in DOX-induced cardiotoxicity and its underlying molecular mechanisms. Our results demonstrate that RIP3 exacerbates DOX-induced cardiotoxicity through promoting oxidative stress and pyroptosis by regulating the AKT/Nuclear factor erythroid 2-related factor 2 (Nrf2) signal pathway. Inhibition of RIP3 using GSK-872 attenuated DOX-induced cardiac remodeling and contractile dysfunction. Moreover, using GSK-872 in vivo, the results revealed that inhibition of RIP3 alleviated DOX-induced cardiotoxicity by the resulting inhibition of oxidative stress and pyroptosis. In addition, inhibition of RIP3 increased the protein levels of AKT and Nrf2 in DOX-treated mouse hearts. Furthermore, the AKT inhibitor LY294002 lessened RIP3 reduction-offered protection against DOX-induced H9c2 cell injury by moderating oxidative stress and pyroptosis. Taken together, these data demonstrate that RIP3 activation orchestrates DOX-induced cardiotoxicity through elevated oxidative stress and pyroptosis in an AKT/Nrf2-dependent manner. Those findings highlight the clinical relevance and therapeutic potential of targeting RIP3 for the treatment of DOX-induced cardiotoxicity.

Characterization of the ADP-ß-D-manno-heptose biosynthetic enzymes from two pathogenic Vibrio strains.

ADP-activated ß-D-manno-heptoses (ADP-ß-D-manno-heptoses) are precursors for the biosynthesis of the inner core of lipopolysaccharide in Gram-negative bacteria. Recently, ADP-D-glycero-ß-D-manno-heptose (ADP-D,D-manno-heptose) and its C-6'' epimer, ADP-L-glycero-ß-D-manno-heptose (ADP-L,D-manno-heptose), were identified as potent pathogen-associated molecular patterns (PAMPs) that can trigger robust innate immune responses. Although the production of ADP-D,D-manno-heptose has been studied in several different pathogenic Gram-negative bacteria, current knowledge of ADP-ß-D-manno-heptose biosynthesis in Vibrio strains remains limited. Here, we characterized the biosynthetic enzymes of ADP-D,D-manno-heptose and the epimerase that converts it to ADP-L,D-manno-heptose from Vibrio cholerae (the causative agent of pandemic cholera) and Vibrio parahaemolyticus (non-cholera pathogen causing vibriosis with clinical manifestations of gastroenteritis and wound infections) in comparison with their isozymes from Escherichia coli. Moreover, we discovered that ß-D-mannose 1-phosphate, but not α-D-mannose 1-phosphate, could be activated to its ADP form by the nucleotidyltransferase domains of bifunctional kinase/nucleotidyltransferases HldEVC (from V. cholerae) and HldEVP (from V. parahaemolyticus). Kinetic analyses of the nucleotidyltransferase domains of HldEVC and HldEVP together with the E. coli-derived HldEEC were thus carried out using ß-D-mannose 1-phosphate as a mimic sugar substrate. Overall, our works suggest that V. cholerae and V. parahaemolyticus are capable of synthesizing ADP-ß-D-manno-heptoses and lay a foundation for further physiological function explorations on manno-heptose metabolism in Vibrio strains. KEY POINTS: • Vibrio strains adopt the same biosynthetic pathway as E. coli in synthesizing ADP-ß-D-manno-heptoses. • HldEs from two Vibrio strains and E. coli could activate ß-D-mannose 1-phosphate to ADP-ß-D-mannose. • Comparable nucleotidyltransfer efficiencies were observed in the kinetic studies of HldEs.

MarkovHC: Markov hierarchical clustering for the topological structure of high-dimensional single-cell omics data with transition pathway and critical point detection.

Clustering cells and depicting the lineage relationship among cell subpopulations are fundamental tasks in single-cell omics studies. However, existing analytical methods face challenges in stratifying cells, tracking cellular trajectories, and identifying critical points of cell transitions. To overcome these, we proposed a novel Markov hierarchical clustering algorithm (MarkovHC), a topological clustering method that leverages the metastability of exponentially perturbed Markov chains for systematically reconstructing the cellular landscape. Briefly, MarkovHC starts with local connectivity and density derived from the input and outputs a hierarchical structure for the data. We firstly benchmarked MarkovHC on five simulated datasets and ten public single-cell datasets with known labels. Then, we used MarkovHC to investigate the multi-level architectures and transition processes during human embryo preimplantation development and gastric cancer procession. MarkovHC found heterogeneous cell states and sub-cell types in lineage-specific progenitor cells and revealed the most possible transition paths and critical points in the cellular processes. These results demonstrated MarkovHC's effectiveness in facilitating the stratification of cells, identification of cell populations, and characterization of cellular trajectories and critical points.

DAZL regulates proliferation of human primordial germ cells by direct binding to precursor miRNAs and enhances DICER processing activity.

Understanding the molecular and cellular mechanisms of human primordial germ cells (hPGCs) is essential in studying infertility and germ cell tumorigenesis. Many RNA-binding proteins (RBPs) and non-coding RNAs are specifically expressed and functional during hPGC developments. However, the roles and regulatory mechanisms of these RBPs and non-coding RNAs, such as microRNAs (miRNAs), in hPGCs remain elusive. In this study, we reported a new regulatory function of DAZL, a germ cell-specific RBP, in miRNA biogenesis and cell proliferation. First, DAZL co-localized with miRNA let-7a in human PGCs and up-regulated the levels of >100 mature miRNAs, including eight out of nine let-7 family, miR21, miR22, miR125, miR10 and miR199. Purified DAZL directly bound to the loops of precursor miRNAs with sequence specificity of GUU. The binding of DAZL to the precursor miRNA increased the maturation of miRNA by enhancing the cleavage activity of DICER. Furthermore, cell proliferation assay and cell cycle analysis confirmed that DAZL inhibited the proliferation of in vitro PGCs by promoting the maturation of these miRNAs. Evidently, the mature miRNAs up-regulated by DAZL silenced cell proliferation regulators including TRIM71. Moreover, DAZL inhibited germline tumor cell proliferation and teratoma formation. These results demonstrate that DAZL regulates hPGC proliferation by enhancing miRNA processing.

Two-dimensional fractal nanocrystals templating for substantial performance enhancement of polyamide nanofiltration membrane.

In this study, we report the emergence of two-dimensional (2D) branching fractal structures (BFS) in the nanoconfinement between the active and the support layer of a thin-film-composite polyamide (TFC-PA) nanofiltration membrane. These BFS are crystal dendrites of NaCl formed when salts are either added to the piperazine solution during the interfacial polymerization process or introduced to the nascently formed TFC-PA membrane before drying. The NaCl dosing concentration and the curing temperature have an impact on the size of the BFS but not on the fractal dimension (∼1.76). The BFS can be removed from the TFC-PA membranes by simply dissolving the crystal dendrites in deionized water, and the resulting TFC-PA membranes have substantially higher water fluxes (three- to fourfold) without compromised solute rejection. The flux enhancement is believed to be attributable to the distributed reduction in physical binding between the PA active layer and the support layer, caused by the exertion of crystallization pressure when the BFS formed. This reduced physical binding leads to an increase in the effective area for water transport, which, in turn, results in higher water flux. The BFS-templating method, which includes the interesting characteristics of 2D crystal dendrites, represents a facile, low-cost, and highly practical method of enhancing the performance of the TFC-PA nanofiltration membrane without having to alter the existing infrastructure of membrane fabrication.

Laser hemorrhoidoplasty vs. rubber band ligation: a randomized trial comparing 2 mini-invasive treatment for grade II hemorrhoids.

PURPOSE: As a minimally invasive procedure, laser hemorrhoidoplasty (LHP) can not only relieve the symptoms of hemorrhoids, but also protect the anal cushion structure. This study aimed to investigate the clinical efficacy of LHP in the treatment of grade II hemorrhoids. METHODS: A total of 70 patients with grade II hemorrhoids were randomly assigned to receive LHP or Rubber Band Ligation (RBL) (n = 35 per group) in 2019 from a single center. The postoperative pain, bleeding, feeling of anal distension(local falling, swelling, foreign body sensation, stool) and postoperative recurrence rate were compared between the two groups. RESULTS: The postoperative pain, bleeding, and feeling of anal distension in the LHP group were improved significantly as compared with the RBL group within 2 weeks after surgery (P < 0.01). Both methods can relieve the symptoms of grade II hemorrhoids. There was no difference in the recurrence rate between the two groups at 1 year after surgery (P > 0.05). The patients in LHP group took less time to return to normal activities (P < 0.001). CONCLUSIONS: As a minimally invasive treatment, LHP is easy and not traumatic and results in mild postoperative pain and few complications. It is an ideal choice for grade II hemorrhoids.

An effective and considerable treatment of pilonidal sinus disease by laser ablation.

The treatment of sacrococcygeal pilonidal disease (SPD) is still challenging. Although many non-surgical and surgical methods exist, no consensus has been reached on the best treatment. This study aimed to evaluate the efficacy of laser ablation using 1470-nm radial diode laser fiber in treating SPD. We retrospectively studied the data of our 48 patients who operated on this technique between March 2019 and July 2022. All patients were treated with laser ablation using 1470-nm radial diode laser fiber. The healing rate and recurrence rate, demographic and surgical data, postoperative pain, complications (wound infection, wound bleeding), the time of returning to regular work and life, and the time of wound healing were recorded. Postoperative pain was measured based on the visual analog scale (VAS) score. Postoperative follow-up was performed in the outpatient clinic every 1 week for 1 month. Among the 48 patients, 41 males and 7 females, with a mean age of 27.7 years (range 14-42), the healing rate was 100%, and the average healing time was 28.3 ± 5.5 days. Mean operative time was 15.5 ± 3.3 min. The recurrence rate was 2.1%. One patient relapsed 3 months after the operation. The patient underwent laser ablation again, and the sinus tract was closed. The median visual analog scale (VAS) score on the day of operation was 0(0,2). The median VAS score on the first, third, seventh, and fourteenth day after operation was 0(0,2), 0(0,1), 0(0,1), and 0(0,0), respectively. There was no wound infection or bleeding after the operation. The mean time to normal work/life was 7.1 ± 3.2 days. Almost all the patients felt very satisfied with the operation. Laser ablation using 1470-nm radial diode laser fiber is effective in SPD treatment. It is associated with minor wounds and mild postoperative pain. It is a simple, safe, and minimally invasive technique and its clinical application for acute and chronic SPD in the absence of abscess is promising.

Regional Thermal Radiation Characteristics of FY Satellite Remote Sensing Based on Big Data Analysis.

It is of great significance to study the thermal radiation anomalies of earthquake swarms in the same area in terms of selecting abnormal characteristic determination parameters, optimizing and determining the processing model, and understanding the abnormal machine. In this paper, we investigated short-term and long-term thermal radiation anomalies induced by earthquake swarms in Iran and Pakistan between 2007 and 2016. The anomalies were extracted from infrared remote sensing black body temperature data from the China Geostationary Meteorological Satellites (FY-2C/2E/2F/2G) using the multiscale time-frequency relative power spectrum (MS T-FRPS) method. By analyzing and summarizing the thermal radiation anomalies of series earthquake groups with consistency law through a stable and reliable MS T-FRPS method, we first obtained the relationship between anomalies and ShakeMaps from USGS and proposed the anomaly regional indicator (ARI) to determine seismic anomalies and the magnitude decision factor (MDF) to determine seismic magnitude. In addition, we explored the following discussions: earthquake impact on regional thermal radiation background and the relationship between thermal anomalies and earthquake magnitude and the like. Future research directions using the MS T-FRPS method to characterize regional thermal radiation anomalies induced by strong earthquakes could help improve the accuracy of earthquake magnitude determination.

Gut Microbiota Combined with Metabolomics Reveal the Mechanisms of Sika Deer Antler Protein on Cisplatin-Induced Hepatorenal Injury in Mice.

Cisplatin is a widely used antineoplastic drug, though its adverse effects, particularly its hepatorenal toxicity, limit its long-term application. Sika deer antler is a valuable traditional Chinese medicine (TCM) documented to possess the capacity for tonifying the kidney and regulating the liver, of which the sika deer antler protein is an important active ingredient. In this study, two protein fractions, SVPr1 and SVPr2, of sika deer antler were purified and administered to mice treated with cisplatin, and serum metabolome and fecal microbiota were measured using ultrahigh-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) and 16S rRNA gene sequencing. SVPr1 and SVPr2 significantly ameliorated cisplatin-induced liver and kidney injury and reduced mitochondrial dysfunction, oxidative stress, inflammatory response, and apoptosis. In addition, SVPr1 and SVPr2 impacted the gut microbiota structure of mice, significantly increasing the relative abundances of Lactobacillus, which deserves to be scrutinized. Moreover, SVPr1 and SVPr2 antagonism of cisplatin-induced hepatorenal injury may be related to the regulation of lysine degradation, tryptophan metabolism, and riboflavin metabolism pathways, significantly altering the levels of L-saccharopine, L-lysine, L-kynurenine, 3-methylindole, xanthurenic acid, riboflavin, and D-ribulose-5-phosphate. A correlation between the differential metabolites and Lactobacillus was identified. These findings increased the knowledge of the gut microbiota-metabolites axis mediated by SVPr1 and SVPr2, and may be able to contribute to the development of new therapeutic strategies for the simultaneous prevention and treatment of liver and kidney injury from cisplatin treatment.

CaMKII orchestrates endoplasmic reticulum stress and apoptosis in doxorubicin-induced cardiotoxicity by regulating the IRE1α/XBP1s pathway.

Doxorubicin (Dox), an anthracycline antibiotic with potent antitumor effects, has limited clinical applications due to cumulative cardiotoxicity. Ca2+ /calmodulin-dependent protein kinase II (CaMKII) is implicated in the pathological progression of Dox-induced cardiotoxicity. This study examined the hypothesis that CaMKII exacerbates Dox-induced cardiotoxicity by promoting endoplasmic reticulum stress and apoptosis through regulation of the inositol-requiring enzyme 1α (IRE1α)/spliced X-box binding protein 1 (XBP1s) pathway. Our results demonstrated that CaMKII activation and IRE1α/XBP1s pathway were involved in Dox-treated hearts. CaMKII inhibition with KN-93 ameliorated Dox-induced cardiac dysfunction and pathological myocardial changes. In addition, CaMKII inhibition prevented Dox-induced endoplasmic reticulum stress and apoptosis. Moreover, CaMKII inhibition increased the expression of IRE1α and XBP1s in Dox-treated hearts. The IRE1α inhibitor 4µ8C blocked the protective effect of CaMKII inhibition against Dox-induced cardiotoxicity. Mechanistically, 4µ8C prevented the effects of CaMKII inhibition on Dox-induced endoplasmic reticulum stress and apoptosis by inhibiting the expression of IRE1α and XBP1s. Additionally, treatment with rhADAMTS13 decreased the protein level of thrombospondin 1 (TSP1) and the phosphorylation of CaMKII in Dox-treated human AC16 cardiomyocytes. Taken together, these results demonstrate that the ADAMTS13-TSP1 axis regulates CaMKII activation and exacerbates Dox-induced cardiotoxicity by triggering endoplasmic reticulum stress and apoptosis by inhibiting the IRE1α/XBP1s pathway.

A data-driven method to learn a jump diffusion process from aggregate biological gene expression data.

Dynamic models of gene expression are urgently required. In this paper, we describe the time evolution of gene expression by learning a jump diffusion process to model the biological process directly. Our algorithm needs aggregate gene expression data as input and outputs the parameters of the jump diffusion process. The learned jump diffusion process can predict population distributions of gene expression at any developmental stage, obtain long-time trajectories for individual cells, and offer a novel approach to computing RNA velocity. Moreover, it studies biological systems from a stochastic dynamic perspective. Gene expression data at a time point, which is a snapshot of a cellular process, is treated as an empirical marginal distribution of a stochastic process. The Wasserstein distance between the empirical distribution and predicted distribution by the jump diffusion process is minimized to learn the dynamics. For the learned jump diffusion process, its trajectories correspond to the development process of cells, the stochasticity determines the heterogeneity of cells, its instantaneous rate of state change can be taken as "RNA velocity", and the changes in scales and orientations of clusters can be noticed too. We demonstrate that our method can recover the underlying nonlinear dynamics better compared to previous parametric models and the diffusion processes driven by Brownian motion for both synthetic and real world datasets. Our method is also robust to perturbations of data because the computation involves only population expectations.

Conversion between 100-million-year-old duplicated genes contributes to rice subspecies divergence.

BACKGROUND: Duplicated gene pairs produced by ancient polyploidy maintain high sequence similarity over a long period of time and may result from illegitimate recombination between homeologous chromosomes. The genomes of Asian cultivated rice Oryza sativa ssp. indica (XI) and Oryza sativa ssp. japonica (GJ) have recently been updated, providing new opportunities for investigating ongoing gene conversion events and their impact on genome evolution. RESULTS: Using comparative genomics and phylogenetic analyses, we evaluated gene conversion rates between duplicated genes produced by polyploidization 100 million years ago (mya) in GJ and XI. At least 5.19-5.77% of genes duplicated across the three rice genomes were affected by whole-gene conversion after the divergence of GJ and XI at ~ 0.4 mya, with more (7.77-9.53%) showing conversion of only portions of genes. Independently converted duplicates surviving in the genomes of different subspecies often use the same donor genes. The ongoing gene conversion frequency was higher near chromosome termini, with a single pair of homoeologous chromosomes, 11 and 12, in each rice genome being most affected. Notably, ongoing gene conversion has maintained similarity between very ancient duplicates, provided opportunities for further gene conversion, and accelerated rice divergence. Chromosome rearrangements after polyploidization are associated with ongoing gene conversion events, and they directly restrict recombination and inhibit duplicated gene conversion between homeologous regions. Furthermore, we found that the converted genes tended to have more similar expression patterns than nonconverted duplicates. Gene conversion affects biological functions associated with multiple genes, such as catalytic activity, implying opportunities for interaction among members of large gene families, such as NBS-LRR disease-resistance genes, contributing to the occurrence of the gene conversion. CONCLUSION: Duplicated genes in rice subspecies generated by grass polyploidization ~ 100 mya remain affected by gene conversion at high frequency, with important implications for the divergence of rice subspecies.

Recursive Paleohexaploidization Shaped the Durian Genome.

The durian (Durio zibethinus) genome has recently become available, and analysis of this genome reveals two paleopolyploidization events previously inferred as shared with cotton (Gossypium spp.). Here, we reanalyzed the durian genome in comparison with other well-characterized genomes. We found that durian and cotton were actually affected by different polyploidization events: hexaploidization in durian ∼19-21 million years ago (mya) and decaploidization in cotton ∼13-14 mya. Previous interpretations of shared polyploidization events may have resulted from the elevated evolutionary rates in cotton genes due to the decaploidization and insufficient consideration of the complexity of plant genomes. The decaploidization elevated evolutionary rates of cotton genes by ∼64% compared to durian and explained a previous ∼4-fold over dating of the event. In contrast, the hexaploidization in durian did not prominently elevate gene evolutionary rates, likely due to its long generation time. Moreover, divergent evolutionary rates probably explain 98.4% of reconstructed phylogenetic trees of homologous genes being incongruent with expected topology. The findings provide further insight into the roles played by polypoidization in the evolution of genomes and genes, and they suggest revisiting existing reconstructed phylogenetic trees.

Pose Filter-Based Ensemble Learning Enables Discovery of Orally Active, Nonsteroidal Farnesoid X Receptor Agonists.

Farnesoid X receptor (FXR) agonists can reverse dysregulated bile acid metabolism, and thus, they are potential therapeutics to prevent and treat nonalcoholic fatty liver disease. The low success rate of FXR agonists' R&D and the side effects of clinical candidates such as obeticholic acid make it urgent to discover new chemotypes. Unfortunately, structure-based virtual screening (SBVS) that can speed up drug discovery has rarely been reported with success for FXR, which was likely hindered by the failure in addressing protein flexibility. To address this issue, we devised human FXR (hFXR)-specific ensemble learning models based on pose filters from 24 agonist-bound hFXR crystal structures and coupled them to traditional SBVS approaches of the FRED docking plus Chemgauss4 scoring function. It turned out that the hFXR-specific pose filter ensemble (PFE) was able to improve ligand enrichment significantly, which rendered 3RUT-based SBVS with its PFE the ideal approach for FXR agonist discovery. By screening of the Specs chemical library and in vitro FXR transactivation bioassay, we identified a new class of FXR agonists with compound XJ034 as the representative, which would have been missed if the PFE was not coupled. Following that, we performed in-depth biological studies which demonstrated that XJ034 resulted in a downtrend of intracellular triglyceride in vitro, significantly decreased the serum/liver TG in high fat diet-induced C57BL/6J obese mice, and more importantly, showed metabolic stabilities in both plasma and liver microsomes. To provide insight into further structure-based lead optimization, we solved the crystal structure of hFXR complexed with compound XJ034, uncovering a unique hydrogen bond between compound XJ034 and residue Y375. The current work highlights the power of our pose filter-based ensemble learning approach in terms of scaffold hopping and provides a promising lead compound for further development.

Reconstruction of evolutionary trajectories of chromosomes unraveled independent genomic repatterning between Triticeae and Brachypodium.

BACKGROUND: After polyploidization, a genome may experience large-scale genome-repatterning, featuring wide-spread DNA rearrangement and loss, and often chromosome number reduction. Grasses share a common tetraploidization, after which the originally doubled chromosome numbers reduced to different chromosome numbers among them. A telomere-centric reduction model was proposed previously to explain chromosome number reduction. With Brachpodium as an intermediate linking different major lineages of grasses and a model plant of the Pooideae plants, we wonder whether it mediated the evolution from ancestral grass karyotype to Triticeae karyotype. RESULTS: By inferring the homology among Triticeae, rice, and Brachpodium chromosomes, we reconstructed the evolutionary trajectories of the Triticeae chromosomes. By performing comparative genomics analysis with rice as a reference, we reconstructed the evolutionary trajectories of Pooideae plants, including Ae. Tauschii (2n = 14, DD), barley (2n = 14), Triticum turgidum (2n = 4x = 28, AABB), and Brachypodium (2n = 10). Their extant Pooidea and Brachypodium chromosomes were independently produced after sequential nested chromosome fusions in the last tens of millions of years, respectively, after their split from rice. More frequently than would be expected by chance, in Brachypodium, the 'invading' and 'invaded' chromosomes are homoeologs, originating from duplication of a common ancestral chromosome, that is, with more extensive DNA-level correspondence to one another than random chromosomes, nested chromosome fusion events between homoeologs account for three of seven cases in Brachypodium (P-value≈0.00078). However, this phenomenon was not observed during the formation of other Pooideae chromosomes. CONCLUSIONS: Notably, we found that the Brachypodium chromosomes formed through exclusively distinctive trajectories from those of Pooideae plants, and were well explained by the telomere-centric model. Our work will contribute to understanding the structural and functional innovation of chromosomes in different Pooideae lineages and beyond.

An Overlooked Paleotetraploidization in Cucurbitaceae.

Cucurbitaceae plants are of considerable biological and economic importance, and genomes of cucumber, watermelon, and melon have been sequenced. However, a comparative genomics exploration of their genome structures and evolution has not been available. Here, we aimed at performing a hierarchical inference of genomic homology resulted from recursive paleopolyploidizations. Unexpectedly, we found that, shortly after a core-eudicot-common hexaploidy, a cucurbit-common tetraploidization (CCT) occurred, overlooked by previous reports. Moreover, we characterized gene loss (and retention) after these respective events, which were significantly unbalanced between inferred subgenomes, and between plants after their split. The inference of a dominant subgenome and a sensitive one suggested an allotetraploid nature of the CCT. Besides, we found divergent evolutionary rates among cucurbits, and after doing rate correction, we dated the CCT to be 90-102 Ma, likely common to all Cucurbitaceae plants, showing its important role in the establishment of the plant family.

TPP-related mitochondrial targeting copper (II) complex induces p53-dependent apoptosis in hepatoma cells through ROS-mediated activation of Drp1.

BACKGROUND: In recent years, copper complexes have gradually become the focus of potential anticancer drugs due to their available redox properties and low toxicity. In this study, a novel mitochondrion-targeting copper (II) complex, [Cu (ttpy-tpp)Br2] Br (simplified as CTB), is first synthesized by our group. CTB with tri-phenyl-phosphine (TPP), a targeting and lipophilic group, can cross the cytoplasmic and mitochondrial membranes of tumor cells. The present study aims to investigate how CTB affects mitochondrial functions and exerts its anti-tumor activity in hepatoma cells. METHODS: Multiple molecular experiments including Flow cytometry, Western blot, Immunofluorescence, Tracker staining, Transmission Electron Microscopy and Molecular docking simulation were used to elucidate the underlying mechanisms. Human hepatoma cells were subcutaneously injected into right armpit of male nude mice for evaluating the effects of CTB in vivo. RESULTS: CTB induced apoptosis via collapse of mitochondrial membrane potential (MMP), ROS production, Bax mitochondrial aggregation as well as cytochrome c release, indicating that CTB-induced apoptosis was associated with mitochondrial pathway in human hepatoma cells. Mechanistic study revealed that ROS-related mitochondrial translocation of p53 was involved in CTB-mediated apoptosis. Simultaneously, elevated mitochondrial Drp1 levels were also observed, and interruption of Drp1 activation played critical role in p53-dependent apoptosis. CTB also strongly suppressed the growth of liver cancer xenografts in vivo. CONCLUSION: In human hepatoma cells, CTB primarily induces mitochondrial dysfunction and promotes accumulation of ROS, leading to activation of Drp1. These stimulation signals accelerate mitochondrial accumulation of p53 and lead to the eventual apoptosis. Our research shows that CTB merits further evaluation as a chemotherapeutic agent for the treatment of Hepatocellular carcinoma (HCC).

Genomic, expressional, protein-protein interactional analysis of Trihelix transcription factor genes in Setaria italia and inference of their evolutionary trajectory.

BACKGROUND: Trihelix transcription factors (TTF) play important roles in plant growth and response to adversity stress. Until now, genome-wide identification and analysis of this gene family in foxtail millet has not been available. Here, we identified TTF genes in the foxtail millet and its grass relatives, and characterized their functional domains. RESULTS: As to sequence divergence, TTF genes were previously divided into five subfamilies, I-V. We found that Trihelix family members in foxtail millet and other grasses mostly preserved their ancestral chromosomal locations during millions of years' evolution. Six amino acid sites of the SIP1 subfamily possibly were likely subjected to significant positive selection. Highest expression level was observed in the spica, with the SIP1 subfamily having highest expression level. As to the origination and expansion of the gene family, notably we showed that a subgroup of subfamily IV was the oldest, and therefore was separated to define a new subfamily O. Overtime, starting from the subfamily O, certain genes evolved to form subfamilies III and I, and later from subfamily I to develop subfamilies II and V. The oldest gene, Si1g016284, has the most structural changes, and a high expression in different tissues. What's more interesting is that it may have bridge the interaction with different proteins. CONCLUSIONS: By performing phylogenetic analysis using non-plant species, notably we showed that a subgroup of subfamily IV was the oldest, and therefore was separated to define a new subfamily O. Starting from the subfamily O, certain genes evolved to form other subfamilies. Our work will contribute to understanding the structural and functional innovation of Trihelix transcription factor, and the evolutionary trajectory.