The water lily genome and the early evolution of flowering plants.

Water lilies belong to the angiosperm order Nymphaeales. Amborellales, Nymphaeales and Austrobaileyales together form the so-called ANA-grade of angiosperms, which are extant representatives of lineages that diverged the earliest from the lineage leading to the extant mesangiosperms1-3. Here we report the 409-megabase genome sequence of the blue-petal water lily (Nymphaea colorata). Our phylogenomic analyses support Amborellales and Nymphaeales as successive sister lineages to all other extant angiosperms. The N. colorata genome and 19 other water lily transcriptomes reveal a Nymphaealean whole-genome duplication event, which is shared by Nymphaeaceae and possibly Cabombaceae. Among the genes retained from this whole-genome duplication are homologues of genes that regulate flowering transition and flower development. The broad expression of homologues of floral ABCE genes in N. colorata might support a similarly broadly active ancestral ABCE model of floral organ determination in early angiosperms. Water lilies have evolved attractive floral scents and colours, which are features shared with mesangiosperms, and we identified their putative biosynthetic genes in N. colorata. The chemical compounds and biosynthetic genes behind floral scents suggest that they have evolved in parallel to those in mesangiosperms. Because of its unique phylogenetic position, the N. colorata genome sheds light on the early evolution of angiosperms.

High-flux and bright betatron X-ray source generated from femtosecond laser pulse interaction with sub-critical density plasma.

Recent progress on betatron X-ray source enables the exploration of new physics in fundamental science; however, the application range is still limited by the source flux and brightness. In this Letter, we show the generation of more than 1 × 1012 photons (energy > 1 keV) with a peak brightness of 7.8 × 1022 photons/(s mm2 mrad2) at 0.1% bandwidth (BW) at 10 keV, driven by a femtosecond laser pulse of ≈5.5 J and a sub-critical density plasma (SCDP). The source flux is more than two orders of magnitude higher than that from typical laser wakefield electron acceleration. This method to produce high-flux and bright X-ray source would open a wide range of applications.

CXCL5 Promotes Acetaminophen-Induced Hepatotoxicity by Activating Kupffer Cells.

Kupffer cells (KCs) play a key part in the pathological process of acetaminophen (APAP)-induced acute liver injury (ALI), the leading cause of acute liver failure in the world. CXC motif chemokine ligand 5 (CXCL5) exerts proinflammatory effects in acute respiratory distress syndrome and arthritis. In the current study, we aim to reveal the effects of CXCL5 on the activation of KCs and the role of CXCL5 in the pathogenesis of APAP-induced hepatotoxicity. The in vivo study, conducted on mice intraperitoneally injected with APAP (300 mg/kg) to establish the ALI model and then treated with Anti-CXCL5 mAb at 30 min and 12 h after the APAP challenge, showed that CXCL5 expression significantly increased in injured livers, and Anti-CXCL5 mAb mitigated the degree of APAP-evoked ALI in mice which was proven through biochemicals and histological examination. Also, neutralization of CXCL5 had no significant effect on APAP metabolism in the liver but exhibited anti-inflammatory effects and ameliorated hepatocellular death in the injured liver. The in vitro data displayed that recombinant mouse CXCL5 treatment promoted APAP-induced cellular toxicity in primary hepatocytes co-cultured with KCs, compared with single-cultured hepatocytes. Consistent with the result, we found that the Anti-CXCL5 mAb gradient decreased LPS-induced expression of inflammatory cytokines in single-cultured KCs. Therefore, CXCL5 could stimulate KCs to produce inflammatory mediators, therefore damaging hepatocytes from APAP toxicity.

High-efficiency water-window x-ray generation from nanowire array targets irradiated with femtosecond laser pulses.

We demonstrate the high-efficiency generation of water-window soft x-ray emissions from polyethylene nanowire array targets irradiated by femtosecond laser pulses at the intensity of 4×1019 W/cm2. The experimental results indicate more than one order of magnitude enhancement of the water-window x-ray emissions from the nanowire array targets compared to the planar targets. The highest energy conversion efficiency from laser to water-window x-rays is measured as 0.5%/sr, which comes from the targets with the longest nanowires. Supported by particle-in-cell simulations and atomic kinetic codes, the physics that leads to the high conversion efficiency is discussed.

High-efficiency generation of narrowband soft x rays from carbon nanotube foams irradiated by relativistic femtosecond lasers.

A number of applications require x rays of both high flux and narrow bandwidth. In this work, we experimentally demonstrate the high-efficiency generation of narrowband soft x rays from carbon nanotube foams irradiated by a femtosecond laser pulse at an intensity of 1019W/cm2. The building blocks of the foam, single-walled carbon nanotube bundles with diameters smaller than the laser skin length can be volumetrically heated and fully ionized on a femtosecond time scale. The three-dimensional network structure of the foam permits deep penetration and drastic absorption of the laser pulse, and results in bright line emissions without prominent Stark broadening. A single-shot yield of 3×1014photons in the carbon Lyα line at 3.37 nm was measured with a bandwidth of 0.013 nm.

Near-diffraction-limited laser focusing with a near-critical density plasma lens.

In this Letter, we investigate the feasibility of focusing relativistic laser pulses toward diffraction limit by near-critical density plasma lenses. A theoretical model is developed to estimate the focal length of the plasma lens. Particle-in-cell simulations with various pulse parameters, such as pulse duration, beam waist, and intensity, are performed to show the robustness of plasma lenses. The results prove that the near-critical density plasma lenses can be deployed to obtain higher laser peak intensities with sub-wavelength focal spots in experiments.

The cold responsive mechanism of the paper mulberry: decreased photosynthesis capacity and increased starch accumulation.

BACKGROUND: Most studies on the paper mulberry are mainly focused on the medicated and pharmacology, fiber quality, leaves feed development, little is known about its mechanism of adaptability to abiotic stress. Physiological measurement, transcriptomics and proteomic analysis were employed to understand its response to cold stress in this study. METHODS: The second to fourth fully expanded leaves from up to down were harvested at different stress time points forthe transmission electron microscope (TEM) observation. Physiological characteristics measurement included the relative electrolyte leakage (REL), SOD activity assay, soluble sugar content, and Chlorophyll fluorescence parameter measurement. For screening of differentially expressed genes, the expression level of every transcript in each sample was calculated by quantifying the number of Illumina reads. To identify the differentially expressed protein, leaves of plants under 0, 6, 12, 24, 48 and 72 h cold stress wereharvested for proteomic analysis. Finally, real time PCR was used to verify the DEG results of the RNA-seq and the proteomics data. RESULTS: Results showed that at the beginning of cold stress, respiratory metabolism was decreased and the transportation and hydrolysis of photosynthetic products was inhibited, leading to an accumulation of starch in the chloroplasts. Total of 5800 unigenes and 38 proteins were affected, including the repressed expression of photosynthesis and the enhanced expression in signal transduction, stress defense pathway as well as secondary metabolism. Although the transcriptional level of a large number of genes has been restored after 12 h, sustained cold stress brought more serious injury to the leaf cells, including the sharp rise of the relative electrolyte leakage, the declined Fv/Fm value, swelled chloroplast and the disintegrated membrane system. CONCLUSION: The starch accumulation and the photoinhibition might be the main adaptive mechanism of the paper mulberry responded to cold stress. Most of important, enhancing the transport and hydrolysis of photosynthetic products could be the potential targets for improving the cold tolerance of the paper mulberry.

The large-scale investigation of gene expression in Leymus chinensis stigmas provides a valuable resource for understanding the mechanisms of poaceae self-incompatibility.

BACKGROUND: Many Poaceae species show a gametophytic self-incompatibility (GSI) system, which is controlled by at least two independent and multiallelic loci, S and Z. Until currently, the gene products for S and Z were unknown. Grass SI plant stigmas discriminate between pollen grains that land on its surface and support compatible pollen tube growth and penetration into the stigma, whereas recognizing incompatible pollen and thus inhibiting pollination behaviors. Leymus chinensis (Trin.) Tzvel. (sheepgrass) is a Poaceae SI species. A comprehensive analysis of sheepgrass stigma transcriptome may provide valuable information for understanding the mechanism of pollen-stigma interactions and grass SI. RESULTS: The transcript abundance profiles of mature stigmas, mature ovaries and leaves were examined using high-throughput next generation sequencing technology. A comparative transcriptomic analysis of these tissues identified 1,025 specifically or preferentially expressed genes in sheepgrass stigmas. These genes contained a significant proportion of genes predicted to function in cell-cell communication and signal transduction. We identified 111 putative transcription factors (TFs) genes and the most abundant groups were MYB, C2H2, C3H, FAR1, MADS. Comparative analysis of the sheepgrass, rice and Arabidopsis stigma-specific or preferential datasets showed broad similarities and some differences in the proportion of genes in the Gene Ontology (GO) functional categories. Potential SI candidate genes identified in other grasses were also detected in the sheepgrass stigma-specific or preferential dataset. Quantitative real-time PCR experiments validated the expression pattern of stigma preferential genes including homologous grass SI candidate genes. CONCLUSIONS: This study represents the first large-scale investigation of gene expression in the stigmas of an SI grass species. We uncovered many notable genes that are potentially involved in pollen-stigma interactions and SI mechanisms, including genes encoding receptor-like protein kinases (RLK), CBL (calcineurin B-like proteins) interacting protein kinases, calcium-dependent protein kinase, expansins, pectinesterase, peroxidases and various transcription factors. The availability of a pool of stigma-specific or preferential genes for L. chinensis offers an opportunity to elucidate the mechanisms of SI in Poaceae.

Differential proteomic analysis of grapevine leaves by iTRAQ reveals responses to heat stress and subsequent recovery.

BACKGROUND: High temperature is a major environmental factor limiting grape yield and affecting berry quality. Thermotolerance includes the direct response to heat stress and the ability to recover from heat stress. To better understand the mechanism of the thermotolerance of Vitis, we combined a physiological analysis with iTRAQ-based proteomics of Vitis vinifera cv Cabernet Sauvignon, subjected to 43°C for 6 h, and then followed by recovery at 25/18°C. RESULTS: High temperature increased the concentrations of TBARS and inhibited electronic transport in photosynthesis apparatus, indicating that grape leaves were damaged by heat stress. However, these physiological changes rapidly returned to control levels during the subsequent recovery phase from heat stress. One hundred and seventy-four proteins were differentially expressed under heat stress and/or during the recovery phase, in comparison to unstressed controls, respectively. Stress and recovery conditions shared 42 proteins, while 113 and 103 proteins were respectively identified under heat stress and recovery conditions alone. Based on MapMan ontology, functional categories for these dysregulated proteins included mainly photosynthesis (about 20%), proteins (13%), and stress (8%). The subcellular localization using TargetP showed most proteins were located in the chloroplasts (34%), secretory pathways (8%) and mitochondrion (3%). CONCLUSION: On the basis of these findings, we proposed that some proteins related to electron transport chain of photosynthesis, antioxidant enzymes, HSPs and other stress response proteins, and glycolysis may play key roles in enhancing grapevine adaptation to and recovery capacity from heat stress. These results provide a better understanding of the proteins involved in, and mechanisms of thermotolerance in grapevines.

Exogenous Methyl Jasmonate (MeJA) Improves 'Ruixue' Apple Fruit Quality by Regulating Cell Wall Metabolism.

'Ruixue' apples were used as the test material to study the effect of 10 µM methyl jasmonate (MeJA) on the quality and cell wall metabolism of apples after 18 d of storage. The results showed that MeJA significantly decreased the respiratory rate, reduced the titratable acid content and maintained a high soluble solids content. MeJA has been shown to suppress the activities and gene expressions of WSP, CSP, ISP, and cellulose in contrast to the control group, thereby maintaining a lower cell permeability and higher exocarp firmness. MeJA significantly decreased the expression of MdACS, MdACO, MdPL, Mdgal, and MdPG genes in the apple exocarp when compared to the control group. In addition, the overexpression of MdPL18 increased the content of cell wall polysaccharides such as WSP and CSP, enhanced cell wall-degrading enzyme activities, and accelerated fruit ripening and softening, whereas silencing MdPL18 did the opposite. Together, these results demonstrate that exogenous MeJA maintains the Ruixue apple fruit quality by regulating the metabolism of cell wall substances.

Generation of attosecond gigawatt soft x-ray pulses through coherent Thomson backscattering.

Collision between relativistic electron sheets and counterpropagating laser pulses is recognized as a promising way to produce intense attosecond x rays through coherent Thomson backscattering (TBS). In a double-layer scheme, the electrons in an ultrathin solid foil are first pushed out by an intense laser driver and then interact with the laser reflected off a second foil to form a high-density relativistic electron sheet with vanishing transverse momentum. However, the repulsion between these concentrated electrons can increase the thickness of the layer, reducing both its density and subsequently the coherent TBS. Here, we present a systematic study on the evolution of the flying electron layer and find that its resulting thickness is determined by the interplay between the intrinsic space-charge expansion and the velocity compression induced by the drive laser. How the laser driver, the target areal density, the reflector, and the collision laser intensity affect the properties of the produced x rays is explored. Multidimensional particle-in-cell simulations indicate that employing this scheme in the nonlinear regime has the potential to stably produce soft x rays with several gigawatt peak power in hundreds of terawatt ultrafast laser facilities. The pulse duration can be tuned to tens of attoseconds. This compact and intense attosecond x-ray source may have broad applications in attosecond science.

A Novel Dose Rate Optimization Method to Maximize Ultrahigh-Dose-Rate Coverage of Critical Organs at Risk Without Compromising Dosimetry Metrics in Proton Pencil Beam Scanning FLASH Radiation Therapy.

PURPOSE: This study aimed to investigate a dose rate optimization framework based on the spot-scanning patterns to improve ultrahigh-dose-rate coverage of critical organs at risk (OARs) for proton pencil beam scanning (PBS) FLASH radiation therapy (ultrahigh dose-rate (often referred to as >40 Gy per second) delivery) and present implementation of a genetic algorithm (GA) method for spot sequence optimization to achieve PBS FLASH dose rate optimization under relatively low nozzle beam currents. METHODS AND MATERIALS: First, a multifield FLASH plan was developed to meet all the dosimetric goals and optimal FLASH dose rate coverage by considering the deliverable minimum monitor unit constraint. Then, a GA method was implemented into the in-house treatment platform to maximize the dose rate by exploring the best spot delivery sequence. A phantom study was performed to evaluate the effectiveness of the dose rate optimization. Then, 10 consecutive plans for patients with lung cancer previously treated using PBS intensity-modulated proton therapy were optimized using 45 GyRBE in 3 fractions for both transmission and Bragg peak FLASH radiation therapy for further validation. The spot delivery sequence of each treatment field was optimized using this GA. The ultrahigh-dose-rate-volume histogram and dose rate coverage V40GyRBE/s were investigated to assess the efficacy of dose rate optimization quantitatively. RESULTS: Using a relatively low monitor unit/spot of 150, corresponding to a nozzle beam current of 65 nA, the FLASH dose rate ratio V40GyRBE/s of the OAR contour of the core was increased from 0% to ∼60% in the phantom study. In the patients with lung cancer, the ultrahigh-dose-rate coverage V40GyRBE/s was improved from 15.2%, 15.5%, 17.6%, and 16.0% before the delivery sequence optimization to 31.8%, 43.5%, 47.6%, and 30.5% after delivery sequence optimization in the lungs-GTV (gross tumor volume), spinal cord, esophagus, and heart (for all, P < .001). When the beam current increased to 130 nA, V40GyRBE/s was improved from 45.1%, 47.1%, 51.2%, and 51.4% to 65.3%, 83.5%, 88.1%, and 69.4% (P < .05). The averaged V40GyRBE/s for the target and OARs increased from 12.9% to 41.6% and 46.3% to 77.5% for 65 and 130 nA, respectively, showing significant improvements based on a clinical proton system. After optimizing the dose rate for the Bragg peak FLASH technique with a beam current of 340 nA, the V40GyRBE/s values for the lung GTV, spinal cord, esophagus, and heart were increased by 8.9%, 15.8%, 22%, and 20.8%, respectively. CONCLUSIONS: An optimal plan quality can be maintained as the spot delivery sequence optimization is a separate independent process after the plan optimization. Both the phantom and patient results demonstrated that novel spot delivery sequence optimization can effectively improve the ultrahigh-dose-rate coverage for critical OARs, which can potentially be applied in clinical practice for better OARs-sparing efficacy.

Advanced Terahertz Refractive Sensing And Fingerprint Recognition Through Metasurface-Excited Surface Waves.

High-sensitive metasurface-based sensors are essential for effective substance detection and insightful bio-interaction studies, which compress light in subwavelength volumes to enhance light-matter interactions. However, current methods to improve sensing performance always focus on optimizing near-field response of individual meta-atom, and fingerprint recognition for bio-substances necessitates several pixelated metasurfaces to establish a quasi-continuous spectrum. Here, a novel sensing strategy is proposed to achieve Terahertz (THz) refractive sensing, and fingerprint recognition based on surface waves (SWs). Leveraging the long-range transmission, strong confinement, and interface sensitivity of SWs, a metasurface-supporting SWs excitation and propagation is experimentally verified to achieve sensing integrations. Through wide-band information collection of SWs, the proposed sensor not only facilitates refractive sensing up to 215.5°/RIU, but also enables the simultaneous resolution of multiple fingerprint information within a continuous spectrum. By covering 5 µm thickness of polyimide, quartz and silicon nitride layers, the maximum phase change of 91.1°, 101.8°, and 126.4° is experimentally obtained within THz band, respectively. Thus, this strategy broadens the research scope of metasurface-excited SWs and introduces a novel paradigm for ultrasensitive sensing functions.

Giant isolated half-cycle attosecond pulses generated in coherent bremsstrahlung emission regime.

Giant half-cycle attosecond pulse generation in the coherent bremsstrahlung emission regime is proposed for laser pulses with normal incidence on a double-foil target, where the first foil is transparent and the second foil is opaque. The presence of the second opaque target contributes to the formation of a relativistic flying electron sheet (RFES) from the first foil target. After the RFES has passed through the second opaque target, it is decelerated sharply, and bremsstrahlung emission occurs, which results in the generation of an isolated half-cycle attosecond pulse having an intensity of ∼1.4×10^{22}W/cm^{2} and a duration of 3.6 as. The generation mechanism does not require extra filters and may open a regime of nonlinear attosecond science.

Sappanone A Alleviates the Severity of Carbon Tetrachloride-Induced Liver Fibrosis in Mice.

Liver fibrosis is a major challenge to global health because of its various complications, including cirrhosis and hepatocarcinoma, while no effective treatment is available for it. Sappanone A (SA) is a homoisoflavonoid extracted from the heartwood of Caesalpinia sappan Linn. with anti-inflammatory and antioxidant properties. However, the effects of SA on hepatic fibrosis remain unknown. This study aimed to investigate the protective effects of SA on carbon tetrachloride (CCl4)-induced liver fibrosis in mice. To establish a liver fibrosis model, mice were treated intraperitoneally (i.p.) with CCl4 for 4 weeks. SA (25, 50, and 100 mg/kg body weight) was i.p. injected every other day during the same period. Our data indicated that SA decreased liver injury, fibrotic responses, and inflammation due to CCl4 exposure. Consistently, SA reduced oxidative stress and its-mediated hepatocyte death in fibrotic livers. Of note, SA could not directly affect the activation of hepatic stellate cells. Mechanistically, SA treatment lessened oxidative stress-triggered cell death in hepatocytes after CCl4 exposure. SA down-regulated the expression of M1 macrophage polarization markers (CD86 and iNOS) and up-regulated the expression of M2 macrophage polarization markers (CD163, IL-10, and Arg1) in livers and macrophages. Meanwhile, SA induced the activation of peroxisome proliferator-activated receptor gamma (PPARγ). However, decreased inflammatory responses and the trend of M2 macrophage polarization provided by SA were substantially abolished by SR202 (a PPARγ inhibitor) treatment in macrophages. Additionally, SA treatment promoted fibrosis regression. Taken together, our findings revealed that treatment with SA alleviated CCl4-induced fibrotic liver in mice through suppression of oxidative stress-mediated hepatocyte death and promotion of M2 macrophage polarization via PPARγ. Thus, SA might pave the way for a new hepatoprotective agent to treat liver fibrosis.

CXCL5 promotes lipotoxicity of hepatocytes through upregulating NLRP3/Caspase-1/IL-1ß signaling in Kupffer cells and exacerbates nonalcoholic steatohepatitis in mice.

Immune-inflammatory responses play a key role in the development of nonalcoholic steatohepatitis (NASH). Previous studies have demonstrated that CXC motif chemokine ligand 5 (CXCL5) correlates positively with obesity and type 2 diabetes. This study is to explore the functional role of CXCL5 in the pathogenesis of NASH. To establish a NASH model, mice were fed with methionine-and choline-deficient high-fat diet for 6 weeks and anti-CXCL5 mAb was injected during the same period. An in vitro NASH model was established by treating palmitic acid (PA), using a trans-well co-culture system of mouse primary hepatocytes and Kupffer cells (KCs), and recombinant mouse (rm) CXCL5 was treated after PA administration. Our data showed that hepatic CXCL5 levels were highly expressed in the NASH mouse model. CXCL5 neutralization significantly alleviated the severity of NASH livers, demonstrated by pathological analysis, decreased biochemicals, and inflammation. Besides, neutralizing CXCL5 reduced lipid accumulation, cell death, and fibrosis in injured livers. In vitro, rmCXCL5 could not affect the activation of hepatic stellate cells. Also, rmCXCL5 exacerbated PA-induced hepatotoxicity and lipid deposition in hepatocytes co-cultured with KCs rather than in single-cultured hepatocytes. Mechanistically, rmCXCL5 not only promoted NOD-like receptor pyrin domain-containing protein 3 (NLRP3) expression, Cleaved caspase-1 expression, and interleukin 1 beta (IL-1ß) secretion in single-cultured and co-cultured KCs but also increased lipid deposition in co-cultured hepatocytes. In addition, MCC950, an inhibitor of NLRP3, almost abolished the effects of rmCXCL5 on PA-treated co-culture system. Therefore, CXCL5 could exacerbate NASH by promoting lipotoxicity of hepatocytes via upregulating NLRP3/Caspase-1/IL-1ß signaling in KCs.

Genome resources for the elite bread wheat cultivar Aikang 58 and mining of elite homeologous haplotypes for accelerating wheat improvement.

Despite recent progress in crop genomics studies, the genomic changes brought about by modern breeding selection are still poorly understood, thus hampering genomics-assisted breeding, especially in polyploid crops with compound genomes such as common wheat (Triticum aestivum). In this work, we constructed genome resources for the modern elite common wheat variety Aikang 58 (AK58). Comparative genomics between AK58 and the landrace cultivar Chinese Spring (CS) shed light on genomic changes that occurred through recent varietal improvement. We also explored subgenome diploidization and divergence in common wheat and developed a homoeologous locus-based genome-wide association study (HGWAS) approach, which was more effective than single homoeolog-based GWAS in unraveling agronomic trait-associated loci. A total of 123 major HGWAS loci were detected using a genetic population derived from AK58 and CS. Elite homoeologous haplotypes (HHs), formed by combinations of subgenomic homoeologs of the associated loci, were found in both parents and progeny, and many could substantially improve wheat yield and related traits. We built a website where users can download genome assembly sequence and annotation data for AK58, perform blast analysis, and run JBrowse. Our work enriches genome resources for wheat, provides new insights into genomic changes during modern wheat improvement, and suggests that efficient mining of elite HHs can make a substantial contribution to genomics-assisted breeding in common wheat and other polyploid crops.

Ultrahigh-amplitude isolated attosecond pulses generated by a two-color laser pulse interacting with a microstructured target.

A unique electron nanobunching mechanism using a two-color laser pulse interacting with a microstructured foil is proposed for directly generating ultraintense isolated attosecond pulses in the transmission direction without requiring extra filters and gating techniques. The unique nanobunching mechanism ensures that only one electron sheet contributes to the transmitted radiation. Accordingly, the generated attosecond pulses are unipolar and have durations at the full width at half-maximum about 5 attoseconds. The emitted ultrahigh-amplitude isolated attosecond pulses have intensities of up to ∼10^{21}W/cm^{2}, which are beyond the limitations of weak attosecond pulses generated by gas harmonics sources and may open a new regime of nonlinear attosecond studies. Unipolar pulses can be useful for probing ultrafast electron dynamics in matter via asymmetric manipulation.

A Novel Prognostic Four-Gene Signature of Breast Cancer Identified by Integrated Bioinformatics Analysis.

Molecular analysis facilitates the prediction of overall survival (OS) of breast cancer and decision-making of the treatment plan. The current study was designed to identify new prognostic genes for breast cancer and construct an effective prognostic signature with integrated bioinformatics analysis. Differentially expressed genes in breast cancer samples from The Cancer Genome Atlas (TCGA) dataset were filtered by univariate Cox regression analysis. The prognostic model was optimized by the Akaike information criterion and further validated using the TCGA dataset (n = 1014) and Gene Expression Omnibus (GEO) dataset (n = 307). The correlation between the risk score and clinical information was assessed by univariate and multivariate Cox regression analyses. Functional pathways in relation to high-risk and low-risk groups were analyzed using gene set enrichment analysis (GSEA). Four prognostic genes (EXOC6, GPC6, PCK2, and NFATC2) were screened and used to construct a prognostic model, which showed robust performance in classifying the high-risk and low-risk groups. The risk score was significantly related to clinical features and OS. We identified 19 functional pathways significantly associated with the risk score. This study constructed a new prognostic model with a high prediction performance for breast cancer. The four-gene prognostic signature could serve as an effective tool to predict prognosis and assist the management of breast cancer patients.

Sappanone A ameliorates acetaminophen-induced acute liver injury in mice.

Sappanone A (SA), a homoisoflavonoid compound extracted from the heartwood of Caesalpinia sappan Linn., exerts anti-inflammatory and antioxidant activities. However, the effects of SA on acetaminophen (APAP) overdose-induced acute liver injury (ALI) have not been determined yet. This study aims to explore the protective effects of SA and the potential mechanisms of action. Mice were pretreated with SA (25, 50, and 100 mg/kg) by intraperitoneal (i.p.) injection for seven days prior to APAP (300 mg/kg, i.p.) administration. At 12 h after APAP injection, serum and liver samples were collected. Primary murine hepatocytes were used to investigate the underlying mechanisms. SA pretreatment dose-dependently attenuated APAP-induced ALI, as validated by reduced serum alanine/aspartate aminotransferase levels, histopathologic lesions, and oxidative stress. Consistently, pretreatment with SA reduced the formation of APAP protein adducts in damaged livers of mice. Mechanistically, SA could facilitate the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and thus promote cellular glutathione (GSH) synthesis. The hepatoprotective outcomes provided by SA were significantly abolished by treatment with ML385, a Nrf2 inhibitor. Besides, anti-inflammatory property of SA reduced inflammatory reaction in injured livers of mice. Of note, posttreatment with SA reveals significant therapeutic influences against APAP-induced ALI in mice. Collectively, our findings demonstrated that pretreated-SA ameliorated APAP-mediated ALI in mice, at least in part, by reducing the generation of APAP protein adducts via Nrf2-enhanced GSH synthesis, and by diminishing hepatic inflammation. Therefore, SA could be a potential hepatoprotective agent for treating ALI.