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The female‐specifically expressed response regulator (PdFERR) gene in Populus deltoides, a sex determination gene (an orthologous gene of ARR17 in Populus tremula), was found to promote femaleness in heterologous expression lines of Arabidopsis. None of the genes in the Arabidopsis genome seem to be orthologous to PdFERR. Although originating from two evolutionarily distant plants, the dioecious poplar FERR might promote femaleness in the hermaphroditic Arabidopsis through an evolutionary consistent regulatory pathway. However, there is no molecular evidence to support this viewpoint. In this study, to identify the shared downstream orthologous gene of PdFERR, we used yeast two‐hybrid assay to screen potential interactors of PdFERR in Arabidopsis. We identified the ethylene response factor 96 (AtERF96) and confirmed the interaction via in vivo and in vitro assays. The ERF96 orthologous gene in P. deltoides was also experimentally confirmed to interact with PdFERR. PdFERR could then promote femaleness in poplar or Arabidopsis through interactions with ERF96, which provide a new perspective for understanding the PdFERR gene regulating sex differentiation. [ABSTRACT FROM AUTHOR]

Introduction: Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4–ALK) is identified as an important pathogenic factor in patients with non-small-cell lung cancer (NSCLC) and could induce a stem-like phenotype in NSCLC cells. Crizotinib is commonly used for EML4–ALK+ NSCLC treatment, but its acquired resistance results in tumor recurrence. Long intergenic noncoding RNA, regulator of reprogramming (lincROR) is related to the acquisition and maintenance of self-renewal and stemness features of cancer stem cells. It has been documented that lincROR is implicated in chemoresistance. However, the correlations of lincROR and EML4–ALK in stem cell-like properties and of lincROR and crizotinib resistance in NSCLC cells are yet to be elucidated. Patients and methods: In the present study, we investigated the expression profile of lincROR in EML–ALK NSCLC tissues, and the potential role of lincROR in prognosis was then analyzed. Subsequently, its association with stem cell-like properties of EML–ALK+ NSCLC cells was determined. Furthermore, the correlation of lincROR with crizotinib and the effects of lincROR and crizotinib on cell viability of EML4–ALK+ NSCLC cells were all explored. Results: The results showed that lincROR expression was upregulated in EML4–ALK+ NSCLC tissues relative to EML4–ALK− NSCLC tissues. Low-expressed lincROR was related to a favor-able prognosis of patients with EML–ALK NSCLC. lincROR overexpression could enhance the stemness features of EML–ALK+ NSCLC cells which were repressed by ALK knockdown. Conclusion: We found that lincROR expression was significantly inhibited because of the increased concentration of crizotinib in EML4–ALK+ NSCLC cells. Furthermore, lincROR overexpression increased cell viability of EML4–ALK+ NSCLC cells, which was impaired by crizotinib. Conjointly, these results suggested the important role of lincROR in EML–ALK+NSCLC. lincROR may serve as a potential therapeutic target to overcome chemotherapy resistance in EML–ALK+ NSCLC. [ABSTRACT FROM AUTHOR]

Since the lack of targeted treatment, triple-negative breast cancer (TNBC) has poor outcomes. Histone deacetylase inhibitors (HDACi) blocking the activity of specific HDACs have emerged as cancer therapeutic agents. However, the therapeutic efficiency is still not satisfactory for patients with solid tumor. We thus performed screening for the synergistic agents of Vorinostat (SAHA). The resulting candidate Simvastatin was obtained. The efficacy and mechanism of combination have been studied in TNBC cells. The synergism of SAHA and Simvastatin was evaluated by IC 50 of proliferation and combination index (CI). The antitumor activities of combination were further evaluated in TNBC cells. The pro-apoptotic effects were determined by flow cytometry and Western blot. Autophagosome-lysosome fusion was monitored using confocal microscope. The underlying mechanism was further studied by over-expressing of wild-type or inactive (C205S/C207S) Rab7 in compounds treated cells. The in vivo efficacy was also evaluated in mice. The combination of SAHA and Simvastatin had potent synergism in apoptosis of TNBC cells. It exerted pro-apoptosis effect by compromising the fusion between autophagosome and lysosome. Over-expressing of wild-type, but not inactive Rab7 rescued cells from apoptosis induced by the combinatory treatments. Mevalonate supplementation also decreased the combinatory treatment-induced apoptosis. These results indicate that the combinatory treatment enhances the apoptosis of TNBC cells by interrupting Rab7 prenylation and obstructing autophagosome-lysosome fusion. Combination between SAHA and Simvastatin could also significantly decrease the tumor growth in xenografted mice by inducing apoptosis and inhibiting Rab7 prenylation. Rab7 is a potential target for the combined effects of Simvastatin and SAHA. [ABSTRACT FROM AUTHOR]

• Physiological signals from wearables were investigated for effects of ASMs on autonomic nervous system function. • EDA, HR, and HRV exhibited diurnal rhythms. • High ASM load led to a decrease in HRV, but not in EDA or HR. Patient-generated health data provide a great opportunity for more detailed ambulatory monitoring and more personalized treatments in many diseases. In epilepsy, robust diagnostics applicable to the ambulatory setting are needed as diagnosis and treatment decisions in current clinical practice are primarily reliant on patient self-reports, which are often inaccurate. Recent work using wearable devices has focused on methods to detect and forecast epileptic seizures. Whether wearable device signals may also contain information about the effect of antiseizure medications (ASMs), which may ultimately help to better monitor their efficacy, has not been evaluated yet. Here we systematically investigated the effect of ASMs on different data modalities (electrodermal activity, EDA, heart rate, HR, and heart rate variability, HRV) simultaneously recorded by a wearable device in 48 patients with epilepsy over several days in the epilepsy long-term monitoring unit at a tertiary hospital. All signals exhibited characteristic diurnal variations. HRV, but not HR or EDA-based metrics, were reduced by ASMs. By assessing multiple signals related to the autonomic nervous system simultaneously, our results provide novel insights into the effects of ASMs on the sympathetic and parasympathetic interplay in the setting of epilepsy and indicate the potential of easy-to-wear wearable devices for monitoring ASM action. Future work using longer data may investigate these metrics on multidien cycles and their utility for detecting seizures, assessing seizure risk, or informing treatment interventions. [ABSTRACT FROM AUTHOR]

Key message: LeBAHD56is preferentially expressed in tissues where shikonin and its derivatives are biosynthesized, and it confers shikonin acylation in vivo. Two WRKY transcriptional factors might regulateLeBAHD56’sexpression. Shikonin and its derivatives, found in the roots of Lithospermum erythrorhizon, have extensive application in the field of medicine, cosmetics, and other industries. Prior research has demonstrated that LeBAHD1(LeSAT1) is responsible for the biochemical process of shikonin acylation both in vitro and in vivo. However, with the exception of its documented in vitro biochemical function, there is no in vivo genetic evidence supporting the acylation function of the highly homologous gene of LeSAT1, LeBAHD56(LeSAT2), apart from its reported role. Here, we validated the critical acylation function of LeBAHD56 for shikonin using overexpression (OE) and CRISPR/Cas9-based knockout (KO) strategies. The results showed that the OE lines had a significantly higher ratio of acetylshikonin, isobutyrylshikonin or isovalerylshikonin to shikonin than the control. In contrast, the KO lines had a significantly lower ratio of acetylshikonin, isobutyrylshikonin or isovalerylshikonin to shikonin than controls. As for its detailed expression patterns, we found that LeBAHD56 is preferentially expressed in roots and callus cells, which are the biosynthesis sites for shikonin and its derivatives. In addition, we anticipated that a wide range of putative transcription factors might control its transcription and verified the direct binding of two crucial WRKY members to the LeBAHD56 promoter’s W-box. Our results not only confirmed the in vivo function of LeBAHD56 in shikonin acylation, but also shed light on its transcriptional regulation. [ABSTRACT FROM AUTHOR]

Elucidating the genetic factors underlying long-term biological processes remains challenging since the relevant genes and their effects may vary across different developmental stages. In this study, we carried out a large-scale field trial of the progeny of an F1 full-sib pedigree of Salix suchowensis and measured plant height and ground diameter periodically over a time course of 240 days. With the obtained data, we characterized plant growth rhythms and performed time-sequential analyses of quantitative trait loci underlying the dynamic growth of the plants. The dynamic mapping of quantitative trait loci revealed that stem height and ground diameter were under the control of four quantitative trait loci, and the effects of these quantitative trait loci varied greatly throughout the growth process, in which two quantitative trait loci were found to exert a pleiotropic effect determining the correlation between stem height and ground diameter. The analysis of candidate genes in the target genetic intervals showed that the pleiotropic effect of the two quantitative trait loci arises from the colocalization of genes with independent effects on stem height and ground diameter. Further examination of the expression patterns of the candidate genes indicated that height and circumference growth involve different activities of leaf and cambium tissues. This study provides unprecedented information to help us understand the dynamic growth of plants and presents an applicable strategy for elucidating the genetic mechanism underlying a long-term biological process by using plant growth as an example. [ABSTRACT FROM AUTHOR]

Key message: SbMYC2 functions as a key regulator under JA signaling in enhancing drought tolerance of sorghum through direct activating SbGR1. Drought stress is one of the major threats to crop yield. In response to drought stress, functions of basic helix–loop–helix (bHLH) transcription factors (TFs) have been reported in Arabidopsis and rice, but little is known for sorghum. Here, we characterized the function of SbMYC2, a bHLH TF in sorghum, and found that SbMYC2 responded most significantly to PEG-simulated drought stress and JA treatments. Overexpression of SbMYC2 significantly enhanced drought tolerance in Arabidopsis, rice and sorghum. In addition, it reduced reactive oxygen species (ROS) accumulation and increased chlorophyll content in sorghum leaves. While silencing SbMYC2 by virus-induced gene silencing (VIGS) resulted in compromised drought tolerance of sorghum seedlings. Moreover, SbMYC2 can directly activate the expression of GLUTATHIONE-DISULFIDE REDUCTASE gene SbGR1. SbGR1 silencing led to significantly weakened drought tolerance of sorghum, and higher ROS accumulation and lower chlorophyll content in sorghum leaves were detected. In addition, SbMYC2 can interact with SbJAZs, suppressors of JA signaling, and thus can mediate JA signaling to activate SbGR1, thereby regulating sorghum's tolerance to drought stress. Overall, our findings demonstrate that bHLH TF SbMYC2 plays an important role in sorghum's response to drought stress, thus providing one theoretical basis for genetic enhancement of sorghum and even rice. [ABSTRACT FROM AUTHOR]

Colorectal cancer is a common malignancy and the second leading cause of cancer-related death. Emerging evidence suggests that the Wnt/β-catenin pathway has a significant role in cancer development. Shikonin is one of the main bioactive components of the plant, Lithospermum erythrorhizon, which possesses various biological properties. In this study, we identified a shikonin derivative, E5, as a novel suppressor of colorectal carcinoma that acted by inhibiting cell proliferation and migration, and promoting apoptosis. Mechanistically, the drug activated caspase-dependent pathways, negatively regulating the Wnt/β-catenin pathway, and inhibited epithelial–mesenchymal transition. The findings suggest the potential of β-catenin as a molecular target in colon carcinoma and propose E5 as a promising therapeutic strategy for targeting Wnt/β-catenin [Display omitted] ● A novel thioether shikonin derivative (E5), modified form of shikonin, acts as a novel inhibitor of β-catenin. ● E5 suppressed cancer cell proliferation and migration and promoted cell apoptosis via caspase-dependent pathways. ● E5 can be a drug candidate and has the potential to inhibit Wnt/β-catenin signaling pathway in the colon carcinoma. [ABSTRACT FROM AUTHOR]

In the present meta-analysis, the efficacy and safety of perampanel (PER) for the treatment of adolescents with epilepsy were assessed. Keyword searches were performed in Embase, PubMed, Cochrane Library, Web of Science, EBSCO and CNKI from 1 January 2020 to 10 October 2020. The randomized controlled trials (RCTs) and case-control studies in which PER was compared with other Anti-seizure drugs (ASDs) and/or placebo in children with epilepsy, were considered eligible studies. Odds ratio (OR) with 95% confidence interval (95% CI) for the dichotomous outcome statistic was calculated using a fixed-effects or random-effects model. Three RCTs with a total of 372 adolescents' patients were included in this meta-analysis. Placebo was used as a control in these studies. Compared with placebo, PER showed better efficacy in median seizure frequency reduction from baseline per 28 days (OR = 2.49, 95% CI: 1.25–4.96, p = 0.009) and in responder rate (OR = 1.87, 95% CI: 1.15–3.05, p = 0.01); both were considered statistically increased in PER group. Regarding adverse effects (AEs), significant differences between PER and placebo (OR = 1.47, 95% CI: 0.92–2.41, p = 0.11) were not found, and the most common AEs of PER were dizziness (24.0%), somnolence (15.9%), headache (11.2%), nasopharyngitis (9.7%), upper respiratory tract infection (7.0%) and aggression (7.0%). Based on the results in this study, PER showed better efficacy than placebo therapy in children with epilepsy and the AEs were similar in PER group and placebo group. PER showed good efficacy and a low risk of AEs, and might be a promising medication for the treatment of pediatric epilepsy. In the future, well-designed and large-scale RCTs are necessary to validate the present findings. [ABSTRACT FROM AUTHOR]

3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), as the rate-limiting enzyme in the mevalonate pathway, is essential for the biosynthesis of shikonin in Lithospermum erythrorhizon. However, in the absence of sufficient data, the principles of a genome-wide in-depth evolutionary exploration of HMGR family members in plants, as well as key members related to shikonin biosynthesis, remain unidentified. In this study, 124 HMGRs were identified and characterized from 36 representative plants, including L. erythrorhizon. Vascular plants were found to have more HMGR family genes than nonvascular plants. The phylogenetic tree revealed that during lineage and species diversification, the HMGRs evolved independently and intronless LerHMGRs emerged from multi-intron HMGR in land plants. Among them, Pinus tabuliformis and L. erythrorhizon had the most HMGR gene duplications, with 11 LerHMGRs most likely expanded through WGD/segmental and tandem duplications. In seedling roots and M9 cultured cells/hairy roots, where shikonin biosynthesis occurs, LerHMGR1 and LerHMGR2 were expressed significantly more than other genes. The enzymatic activities of LerHMGR1 and LerHMGR2 further supported their roles in catalyzing the conversion of HMG-CoA to mevalonate. Our findings provide insight into the molecular evolutionary properties and function of the HMGR family in plants and a basis for the genetic improvement of efficiently produced secondary metabolites in L. erythrorhizon. [ABSTRACT FROM AUTHOR]

Summary: The onset of leaf de‐greening and senescence is governed by a complex regulatory network including environmental cues and internal factors such as transcription factors (TFs) and phytohormones, in which ethylene (ET) is one key inducer. However, the detailed mechanism of ET signalling for senescence regulation is still largely unknown.Here, we found that the WRKY TF SbWRKY50 from Sorghum bicolor L., a direct target of the key component ETHYLENE INSENSITIVE 3 in ET signalling, functioned for leaf senescence repression. The clustered regularly interspaced short palindromic repeats/CRISPR‐associated protein9‐edited SbWRKY50 mutant (SbWRKY5O‐KO) of sorghum displayed precocious senescent phenotypes, while SbWRKY50 overexpression delayed age‐dependent and dark‐induced senescence in sorghum.SbWRKY50 negatively regulated chlorophyll degradation through direct binding to the promoters of several chlorophyll catabolic genes. In addition, SbWRKY50 recruited the Polycomb repressive complex 1 through direct interaction with SbBMI1A, to induce histone 2A mono‐ubiquitination accumulation on the chlorophyll catabolic genes for epigenetic silencing and thus delayed leaf senescence. Especially, SbWRKY50 can suppress early steps of chlorophyll catabolic pathway via directly repressing SbNYC1 (NON‐YELLOW COLORING 1). Other senescence‐related hormones could also influence leaf senescence through repression of SbWRKY50.Hence, our work shows that SbWRKY50 is an essential regulator downstream of ET and SbWRKY50 also responds to other phytohormones for senescence regulation in sorghum. [ABSTRACT FROM AUTHOR]

Drought stress severely threatens the yield of cereal crops. Therefore, understanding the molecular mechanism of drought stress response of plants is crucial for developing drought-tolerant cultivars. NAC transcription factors (TFs) play important roles in abiotic stress of plants, but the functions of NAC TFs in sorghum are largely unknown. Here, we characterized a sorghum NAC gene, SbNAC9, and found that SbNAC9 can be highly induced by polyethylene glycol (PEG)-simulated dehydration treatments. We therefore investigated the function of SbNAC9 in drought stress response. Sorghum seedlings overexpressing SbNAC9 showed enhanced drought-stress tolerance with higher chlorophyll content and photochemical efficiency of PSII, stronger root systems, and higher reactive oxygen species (ROS) scavenging capability than wild-type. In contrast, sorghum seedlings with silenced SbNAC9 by virus-induced gene silencing (VIGS) showed weakened drought stress tolerance. Furthermore, SbNAC9 can directly activate a putative peroxidase gene SbC5YQ75 and a putative ABA biosynthesis gene SbNCED3. Silencing SbC5YQ75 and SbNCED3 led to compromised drought tolerance and reduced ABA content of sorghum seedlings, respectively. Therefore, our findings revealed the important role of SbNAC9 in response to drought stress in sorghum and may shed light on genetic improvement of other crop species under drought-stress conditions. [ABSTRACT FROM AUTHOR]

Although it has been frequently suggested that resource partitioning of species coexisting at the same trophic level can be mediated by interactions with species at non-adjacent trophic levels, empirical evidence supporting this claim is scarce. Here we demonstrate that plants may mediate resource partitioning for two parasitoids that share the same herbivorous host. The tephritid fly Tephritis femoralis is the primary pre-dispersal seed predator of two Asteraceae species, Saussurea nigrescens and Anaphalis flavescens, both of which dominate the plant community in the alpine meadows of the Tibetan Plateau. Field surveys and molecular barcoding analyses showed that the identity of the fly's main predator depended on the plant in which the fly developed. Tephritid flies that developed in S. nigrescens were preyed upon mainly by the parasitoid wasp Pteromalus albipennis, while the parasitoid Mesopolobus sp. was the main predator of flies that developed in A. flavescens. Microcosm experiments revealed that P. albipennis could not exploit the host flies within the capitula of A. flavescens due to food limitation (capitula are too small), while Mesopolobus sp. could not exploit the host flies within the capitula of S. nigrescens due to its inability to reach the host with its ovipositor (capitula are too large). Such bottom-up control of plant species traits may facilitate the coexistence of parasitoid wasps sharing a common host in this system. We suggest that interactions between non-adjacent trophic levels may potentially promote species coexistence and diversity in biological communities. [ABSTRACT FROM AUTHOR]

Plant roots significantly influence soil microbial diversity, and soil microorganisms play significant roles in both natural and agricultural ecosystems. Although the genetically modified (GM) crops with enhanced insect and herbicide resistance are thought to have unmatched yield and stress resistance advantages, thorough and in‐depth case studies still need to be carried out in a real‐world setting due to the potential effects of GM plants on soil microbial communities. In this study, three treatments were used: a recipient soybean variety Jack, a triple transgenic soybean line JD321, and the glyphosate‐treated JD321 (JD321G). Three sampling stages (flowering, seed filling and maturing), as well as three host niches of soybean rhizosphere [intact roots (RT), rhizospheric soil (RS) and surrounding soil (SS)] were established. In comparison to Jack, the rhizospheric soil of JD321G had higher urease activity and lower nitrite reductase at the flowering stage. Different treatments and different sampling stages existed no significant effects on the compositions of microbial communities at different taxonomic levels. However, at the genus level, the relative abundance of three plant growth‐promoting fungal genera (i.e. Mortierella, Chaetomium and Pseudombrophila) increased while endophytic bacteria Chryseobacterium and pathogenic bacteria Streptomyces decreased from the inside to the outside of the roots (i.e. RT → RS → SS). Moreover, two bacterial genera, Bradyrhizobium and Ensifer were more abundant in RT than in RS and SS, as well as three species, Agrobacterium radiobacter, Ensifer fredii and Ensifer meliloti, which are closely related to nitrogen‐fixation. Furthermore, five clusters of orthologous groups (COGs) associated to nitrogen‐fixation genes were higher in RT than in RS, whereas only one COG annotated as dinitrogenase iron‐molybdenum cofactor biosynthesis protein was lower. Overall, the results imply that the rhizosphere host niches throughout the soil–plant continuum largely control the composition and function of the root‐associated microbiome of triple transgenic soybean. [ABSTRACT FROM AUTHOR]

Eukaryotic aquaporins share the characteristic of functional multiplicity in transporting distinct substrates and regulating various processes, but the underlying molecular basis for this is largely unknown. Here, we report that the wheat (Triticum aestivum) aquaporin TaPIP2;10 undergoes phosphorylation to promote photosynthesis and productivity and to confer innate immunity against pathogens and a generalist aphid pest. In response to elevated atmospheric CO 2 concentrations, TaPIP2;10 is phosphorylated at the serine residue S280 and thereafter transports CO 2 into wheat cells, resulting in enhanced photosynthesis and increased grain yield. In response to apoplastic H 2 O 2 induced by pathogen or insect attacks, TaPIP2;10 is phosphorylated at S121 and this phosphorylated form transports H 2 O 2 into the cytoplasm, where H 2 O 2 intensifies host defenses, restricting further attacks. Wheat resistance and grain yield could be simultaneously increased by TaPIP2;10 overexpression or by expressing a TaPIP2;10 phosphomimic with aspartic acid substitutions at S121 and S280, thereby improving both crop productivity and immunity. The wheat aquaporin TaPIP2;10 is phosphorylated at the serine residue S280 in response to increased atmospheric CO 2 and thereafter transports CO 2 into wheat cells, resulting in enhanced photosynthesis. In response to apoplastic H 2 O 2 induced by pathogen or insect attacks, TaPIP2;10 is phosphorylated at S121 and thereby transports H 2 O 2 into the cytoplasm, where H 2 O 2 intensifies wheat resistance against further attacks. [ABSTRACT FROM AUTHOR]

(A) The structural maps of pBI121-LeBAHD1/LeSAT1-eGFP overexpression vector and pYLCRISPR/Cas9-LeBAHD1/LeSAT1 knockout vectors. However, not all members of the BAHD acyltransferase gene family could be screened out from the I L. erythrorhizon i genome by only using AAT/SAT amino acid sequences as a query. Identification and Characterization of LeBAHD Genes in L. erythrorhizon Genome In order to have a comprehensive understanding of the characteristics and functions of BAHD family genes in I L. erythrorhizon i , 104 members were initially screened out from the I L. erythrorhizon i genome based on sequences homology and the conserved BAHD superfamily feature domain (Pfam: PF02458). [Extracted from the article]

Aims: This study was conducted to evaluate 35 natural flavonoids for their in vitro susceptibility against E. coli (ATCC 25922), Ps. aeruginosa (ATCC 27853), B. subtilis (ATCC 530) and Staph. aureus (ATCC 6538) in search of a potential broad‐spectrum antibiotic. Methods and Results: Glabridin, a natural isoflavonoid isolated from Glycyrrhiza glabra L., was identified to be highly active with a MIC of 8–16 μg ml−1 against Staph. aureus, B. subtilis and E. coli. By the results of the docking simulation, we located the potential targets of glabridin as DNA gyrase and dihydrofolate reductase (DHFR). The subsequent DNA gyrase inhibition assays (glabridin: IC50 = 0.8516 μmol L−1, ciprofloxacin: IC50 = 0.04697 μmol L−1), DHFR inhibition assays (glabridin: inhibition ratio = 29%, methotrexate: inhibition ratio = 45% under 100 μmol L−1 treatment) and TUNEL confirmed that glabridin acted as DNA gyrase inhibitor and DHFR mild inhibitor, exerting bactericidal activity by blocking bacterial nucleic acid synthesis. CCK‐8 and in silico calculations were also conducted to verify the low cytotoxicity and acceptable druggability of glabridin. Conclusion: These findings suggest that glabridin represents the prototypical member of an exciting structural class of natural antimicrobial agents. Significance and Impact of the Study: This study reports a novel mechanism of bactericidal activity of glabridin against Staph. aureus. [ABSTRACT FROM AUTHOR]

12-Oxophytodienoate reductase (OPR) enzymes in dicots are categorized as flavin mononucleotide (FMN)–dependent oxidoreductases and are divided into two subgroups. Although subgroup II OPRs have been identified as being involved in a critical step in the production of jasmonic acid (JA), the functions of subgroup I OPRs are uncertain. In this study, we cloned a potential subgroup I OPR gene, EpOPR1, from Echium plantagineum using comparative transcriptome analysis. EpOPR1 expression was found to be significantly increased in root samples containing secondary metabolites such as shikonin and its derivatives. Using a transgenic hairy root system, we further explored the role of EpOPR1 in the production of these secondary metabolites. The results indicated that although the chemical profile of EpOPR1 overexpressing hairy roots (OPRO) is similar to that of the empty vector hairy roots (EV), the EpOPR1 overexpressing line considerably increased the yield of acetylshikonin by around two-fold. Our findings shed light on the potential role of subgroup I OPRs in E. plantagineum secondary metabolism regulation. [ABSTRACT FROM AUTHOR]

SUMMARY: Plant aquaporins are a recently noted biological resource with a great potential to improve crop growth and defense traits. Here, we report the functional modulation of the rice (Oryza sativa) aquaporin OsPIP1;3 to enhance rice photosynthesis and grain production and to control bacterial blight and leaf streak, the most devastating worldwide bacterial diseases in the crop. We characterize OsPIP1;3 as a physiologically relevant CO2‐transporting facilitator, which supports 30% of rice photosynthesis on average. This role is nullified by interaction of OsPIP1;3 with the bacterial protein Hpa1, an essential component of the Type III translocon that supports translocation of the bacterial Type III effectors PthXo1 and TALi into rice cells to induce leaf blight and streak, respectively. Hpa1 binding shifts OsPIP1;3 from CO2 transport to effector translocation, aggravates bacterial virulence, and blocks rice photosynthesis. On the contrary, the external application of isolated Hpa1 to rice plants effectively prevents OsPIP1;3 from interaction with Hpa1 secreted by the bacteria that are infecting the plants. Blockage of the OsPIP1;3–Hpa1 interaction reverts OsPIP1;3 from effector translocation to CO2 transport, abrogates bacterial virulence, and meanwhile induces defense responses in rice. These beneficial effects can combine to enhance photosynthesis by 29–30%, reduce bacterial disease by 58–75%, and increase grain yield by 11–34% in different rice varieties investigated in small‐scale field trials conducted during the past years. Our results suggest that crop productivity and immunity can be coordinated by modulating the physiological and pathological functions of a single aquaporin to break the growth–defense tradeoff barrier. [ABSTRACT FROM AUTHOR]

Pipe routing and clamp layout for aeroengine are NP-hard computational problems and complex engineering design processes. Besides space constraints and engineering rules, there are assembly constraints between pipes and clamps, which usually lead to repeatedly modifications between pipe routing and clamp layout designs. In order to solve the problems of assembly constraints and design coupling between them, an integrated optimization method for pipe routing and clamp layout is proposed. To this end, the MOALO (multiobjective ant lion optimizer) algorithm is modified by introducing the levy flight strategy to improve the global search performance and convergence speed, and it is further used as a basic computation tool. The integrated optimization method takes pipe and clamp as a whole system and then solves the Pareto solution set of pipe-clamp layouts by using improved MOALO, where the pipe path, clamp position, and rotation angle are selected as decision variables and are further optimized. Inspired by engineering experience, a clamp-based pipe path mechanism considering regular nodes is established to deal with assembly constraint problem. The proposed method comprehensively considers engineering rules of pipe routing and clamp layout and realizes the overall layout optimization of pipe-clamp system while guaranteeing the assembly constraints between pipes and clamps. Finally, some numerical computations and routing examples are conducted to demonstrate the feasibility and effectiveness of the proposed method. [ABSTRACT FROM AUTHOR]

Shikonin and its derivatives are the main components of traditional Chinese medicine, Zicao. The pharmacological potential of shikonin and its derivatives have been extensively studied. Yet, less is known about the microbial assemblages associated with shikonin producing Borage plants. We studied microbial profiles of two Borage species, Echium plantagineum (EP) and Lithospermum erythrorhizon (LE), to identify the dynamics of microbial colonization pattern within three rhizo-compatments and two distinct soil types. Results of α and β-diversity via PacBio sequencing revealed significantly higher microbial richness and diversity in the natural soil along with a decreasing microbial gradient across rhizosphere to endosphere. Our results displayed genotype and soil type–dependent fine-tuning of microbial profiles. The host plant was found to exert effects on the physical and chemical properties of soil, resulting in reproducibly different micro-biota. Analysis of differentially abundant microbial OTUs displayed Planctomycetes and Bacteroidetes to be specifically enriched in EP and LE rhizosphere while endosphere was mostly prevailed by Cyanobacteria. Network analysis to unfold co-existing microbial species displayed different types of positive and negative interactions within different communities. The data provided here will help to identify microbes associated with different rhizo-compartments of potential host plants. In the future, this might be helpful for manipulating the keystone microbes for ecosystem functioning. [ABSTRACT FROM AUTHOR]

Podophyllotoxin is a potent cytotoxic agent and serves as a useful lead compound for development of anticancer agents. Tubulin is known as an attractive target for drug discovery and cancer therapies. There are few studies on the treatment of breast cancer with podophyllotoxin and its derivatives targeting tubulin. Here, a series of novel aryl 1,3,4‐oxadiazole/1,3,4‐thiadiazole acid podophyllotoxin ester derivatives (D1–D16) were synthesized. Among these compounds, D9 exhibited excellent antiproliferation activity against MCF‐7 cells (IC50=2.46±0.12 μM). Furthermore, D9 caused cell cycle arrest at the G2/M phase and induced cell apoptosis. Confocal microscopy showed that D9 inhibited microtubule polymerization by causing cancer cell growth inhibition. Molecular docking results suggested D9 could bind to the active binding site of tubulin. In a mouse model, compound D9 suppressed malignant growth without causing significant toxicity to normal tissues. Our findings support the utility of D9 as a novel compound for the development of anticancer agent. [ABSTRACT FROM AUTHOR]

Changes in root exudates and rhizospheric microbial functional capacities involved in carbon (C) decomposition and nitrogen (N) transformation of aluminum (Al)-tolerant and Al-sensitive soybean genotypes were investigated under Al stress. Rhizosphere soils were collected from rhizobox systems with two soybean genotypes. A wide range of microbial functional capacities were determined by functional gene arrays. Microbial functional capacities of rhizospheres were distinct between Al-tolerant and Al-sensitive genotypes, which were related to exchangeable Al concentrations. Functional capacities associated with decomposition of chemically recalcitrant C were lower in Al-tolerant than Al-sensitive genotypes, which was negatively correlated with the secretion rate of succinic acid. Microbial functional capacities were higher for nitrification but lower for denitrification in the rhizosphere of Al-tolerant than Al-sensitive genotype, which coincided with higher succinic acid secretion and lower abundance of microbial oxygen stress genes. Soybean biomass increased logarithmically with nitrification capacities. We concluded that exchangeable Al concentrations, root exudation, and microbial C and N cycling capacities were intrinsically linked, which served as a key mechanism for legume genotypes toward enhancing tolerance to Al stress occurring in acid soils. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel series of dual-target benzenesulfonyl shikonin derivative has been designed and synthesized. • Z10 could activate activity of PKM2 and inhibit activity against PDK1 by direct intereaction. • Z10 showed significant anticancer activity in colorectal cancer in comparison with shikonin, PKM2 or PDK1 target agent. • Z10 exhibited lower toxicity than shikonin at 4 μM in vitro and at a dosage of 4.2 mg/kg in vivo. • Z10 could significantly induce apoptosis in colorectal cells and in xenograft mice models. Warburg effect provides energy and material essential for tumor proliferation, the reverse of Warburg effect provides insights into the development of a novel anti-cancer strategy. Pyruvate kinase 2 (PKM2) and pyruvate dehydrogenase kinase 1 (PDK1) are two key enzymes in tumor glucose metabolism pathway that not only contribute to the Warburg effect through accelerating aerobic glycolysis, but also serve as druggable target for colorectal cancer (CRC). Considering that targeting PKM2 or PDK1 alone does not seem to be sufficient to remodel abnormal glucose metabolism and achieve significant antitumor activity, a series of novel benzenesulfonyl shikonin derivatives were designed to regulate PKM2 and PDK1 simultaneously. By means of molecular docking and antiproliferative screen, we found that compound Z10 could act as the combination of PKM2 activator and PDK1 inhibitor, thereby significantly inhibited glycolysis that reshaping tumor metabolism. Moreover, Z10 could inhibit proliferation, migration and induce apoptosis in CRC cell HCT-8. Finally, the in vivo anti-tumor activity of Z10 was evaluated in a colorectal cancer cell xenograft model in nude mice and the results demonstrated that Z10 induced tumor cell apoptosis and inhibited tumor cell proliferation with lower toxicity than shikonin. Our findings indicated that it is feasible to alter tumor energy metabolism through multi-target synergies, and the dual-target benzenesulfonyl shikonin derivative Z10 could be a potential anti-CRC agent. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Cancer cells are continuously challenged by adverse environmental stress and adopt diverse strategies to survive. Hsp70 plays pivotal roles in invasion, migration, drug resistance, and the survival of tumor cells. Hsp70 functions as molecular chaperone to protect tumor cells from stress-induced cell death. Hsp70 acetylation alters its chaperone activity in cell death pathways, but its relevance in the process of cell death and the underlying mechanisms involved are not well understood. In this study, we demonstrated that vincristine induces mitophagy via the disruption of Hsp70 binding with Sirt2, leading to Hsp70 acetylation at K126 and elevated sequestration of Bcl2 by Hsp70 for autophagosome creation. Acetylation at K126 significantly changes the physiological function of Hsp70 compared to acetylation at other sites. It also attenuates the protein folding and renaturation function of Hsp70 by altering the binding co-chaperones. In addition, acetylation at K126 inhibits Hsp70-mediated tumor cell invasion and migration, and the binding of Hsp70 to AIF1 and Apaf1 for promoting mitochondrial-mediated apoptosis. In conclusion, this study describes the molecular mechanism of vincristine induction of cell apoptosis and mitophagy via ablation of Sirt2 induced Hsp70 acetylation at K126 in MDA-MB-231 cells. [ABSTRACT FROM AUTHOR]

There are concerns that the innovation of genetically modified herbicide-tolerant (GMHT) plants, as well as the application of herbicide to such GMHT plants, could have an impact on ecological interactions and unintentionally harm non-targeted organisms. Consequently, we intend to use full-length 16 S rDNA amplicon sequencing to examine changes in the bacterial community in the rhizosphere of GMHT soybean (Z106) harboring 5-enolpyruvylshikimate-3-phosphate synthase and Glyphosate N-acetyltransferase genes and GMHT soybean treated with glyphosate (Z106G). Glyphosate application significantly impacted bacterial alpha diversity (species richness, and Shannon diversity). Permutational multivariate analysis of variance of beta diversity demonstrated that soil compartments and growth stages had a substantial impact on soybean rhizobacterial communities (soil compartments, growth stages, P = 0.001). Community composition revealed that Z106G soils were abundant in Taibaiella and Arthrobacter pascens at maturity, while Chryseobacterium joostei and Stenotrophomonas maltophilia predominated in Z106 soils during flowering. Nitrogen-fixing and phosphate-solubilizing microbes were found in higher proportions in the rhizosphere than in bulk soil, with Sinorhizobium being more abundant in Z106 and Bacillus and Stenotrophomonas being more prevalent in Z106G rhizosphere soils. Collectively, our findings suggest glyphosate application and glyphosate-tolerant soybean as potential regulators of soybean rhizobacterial composition. [Display omitted] • Glyphosate application had an impact on bacterial alpha diversity (species richness, and Shannon diversity). • Sinorhizobium fredii, a nitrogen fixer, was more abundant in the glyphosate-tolerant soybean line. • Neither glyphosate nor transgenic soybean line affected the relative abundance of the pathogenic fungus Fusarium. • Glyphosate spraying and soybean carrying EPSPS and GAT transgenes both positively regulate rhizobacterial composition. [ABSTRACT FROM AUTHOR]

Asparagine (Asn/N)-linked glycans are important for protein folding, trafficking, and endoplasmic reticulum-associated degradation in eukaryotes. The maturation of glycoproteins involves the trimming of mannosyl residues by mannosidases and addition of other sugar molecules to three-branched N-glycans in the Golgi. However, the biological importance of Golgi-mediated mannose trimming is not fully understood. Here, we show that abolishment of two functionally redundant mannosidases, MNS1 and MNS2, responsible for α-1,2-mannose trimming on the A and C branches of plant N-glycans lead to severe root growth inhibition under salt stress conditions in Arabidopsis . In contrast, mutants with defects in the biosynthesis of the oligosaccharide precursor displayed enhanced salt tolerance in the absence of mannose trimming. However, mutation in EBS3 , which is required for the formation of the branched N-glycan precursor, suppressed the salt-sensitive phenotype of mns1 mns2 double mutant. Interestingly, we observed that cellulose biosynthesis was compromised in mns1 mns2 roots under high salinity. Consistently, abundance of a membrane anchored endo-β-1,4-endoglucanase (RSW2/KOR) that plays a key role in cellulose biosynthesis and its mutant variant rsw2-1 were modulated by α-1,2-mannose trimming under salt stress. Overexpression of RSW2 could partially rescue the salt-sensitive phenotype of mns1 mns2 . Taken together, these results suggest that MNS1/2-mediated mannose trimming of N-glycans is crucial in modulating glycoprotein abundance to withstand salt stress in plants. [ABSTRACT FROM AUTHOR]

This study aimed to examine the antiviral effects of shikonin ester ((R)-1-(5, 8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl3-(1H- indol-3-yl) propanoate (PMM-034) against influenza A (H1N1) virus. We investigated PMM-034 anti-H1N1 activity and its effect on caspase 3 gene expression during cellular apoptosis after influenza virus infection in vitro. Neuraminidase (NA) inhibition was assessed in comparison with oseltamivir in the influenza virus standard strains A/PR/8/34 to understand the viral mechanism. MDCK and A549 cells were used to investigate influenza viral infection and the structure-activity relationship between PMM-034 and NA was evaluated by pharmacophore-based docking modeling. The production of viral protein was tested by western blot. A/PR/8/34 induced cell inhibition but this was reduced by PMM-034 to 16 μg/mL and this showed a selective index of 10 mM. PMM-034 inhibited NA in a dose dependent manner, similar to oseltamivir inhibition. A sharp decrease in viral nucleocapsid protein mRNA was observed in infected cells after treatment with PMM-034. Apoptosis of infected A459 cells was inhibited by PMM-034 with decreased caspase 3 levels. ARG 118, ARG 152, ARG 371 and GLU 227 in the binding pocket of NA bound to PMM-034 in the docking model. Taken together, these results suggest PMM-034 shikonin ester blocked H1N1 infection and might be a potential anti-H1N1 drug. [ABSTRACT FROM AUTHOR]

Pyruvate kinase 2 (PKM2) and pyruvate dehydrogenase kinase 1 (PDK1) are two key enzymes in tumor glucose metabolism pathway that not only promote tumor growth and proliferation through accelerating aerobic glycolysis, but also contribute to drug resistance of non-small cell lung cancer (NSCLC). Considering that targeting PKM2 or PDK1 alone seems insufficient to remodel abnormal glucose metabolism to achieve significant antitumor activity, we proposed a "two-step approach" that regulates PKM2 and PDK1 synchronously. Firstly, we found that the combination of ML265 (PKM2 activator) and AZD7545 (PDK1 inhibitor) could synergistically inhibit proliferation and induce apoptosis in H1299 cells. Base on this, we designed a series of novel shikonin (SK) thioether derivatives as PKM2/PDK1 dual-target agents, among which the most potent compound E5 featuring a 2-methyl substitution on the benzene ring exerted significantly increased inhibitory activity toward EGFR mutant NSCLC cell H1975 (IC 50 = 1.51 μmol/L), which was 3 and 17-fold more active than the lead compound SK (IC 50 = 4.56 μmol/L) and the positive control gefitinib (IC 50 = 25.56 μmol/L), respectively. Additionally, E5 also showed good anti-tumor activity in xenografted mouse models, with significantly lower toxicity side effects than SK. Moreover, E5 also inhibited the entry of PKM2 into nucleus to regulate the transcriptional activation of oncogenes, thus restoring the sensitivity of H1975 cell to gefitinib. Collectively, these data demonstrate that E5 , a dual inhibitor of PKM2/PDK1, may be a promising adjunct to gefitinib in the treatment of EGFR-TKIs resistant NSCLC, deserving further investigation. [Display omitted] • A synergistic effect of PKM2 activation and PDK1 inhibition was first demonstrated. • A series of PKM2/PDK1 dual-target shikonin thioether derivatives were developed. • The most active compound E5 significantly inhibit tumor growth in vitro and in vivo. • The most active compound E5 enhance the sensitivity of H1975 cells to gefitinib. [ABSTRACT FROM AUTHOR]

Although arsenite [As(III)] is non-essential and toxic for plants, it is effectively absorbed through various transporters into the roots. Here we identified a calcium-dependent protein kinase (CPK31) response for As(III) tolerance in Arabidopsis. We identified CPK31 as an interacting protein of a nodulin 26-like intrinsic protein (NIP1;1), an aquaporin involved in As(III) uptake. Similarly to the nip1;1 mutants, the loss-of-function mutants of CPK31 improved the tolerance against As(III) but not As(V), and accumulated less As(III) in roots than that of the wild-type plants. The promoter-β-glucuronidase and quantitative Real-Time PCR analysis revealed that CPK31 displayed overlapping expression profiles with NIP1;1 in the roots, suggesting that they might function together in roots. Indeed, the cpk31 nip1;1 double mutants exhibited stronger As(III) tolerance than cpk31 mutants, but similar to nip1;1 mutants, supporting the idea that CPK31 might serve as an upstream regulator of NIP1;1. Furthermore, transient CPK31 overexpression induced by dexamethasone caused the decrease in As(III) tolerance of transgenic Arabidopsis lines. These findings reveal that CPK31 is a key factor in As(III) response in plants. [ABSTRACT FROM AUTHOR]

PDK1 is one of the key enzymes in the glucose metabolism pathway, which is abnormally high expressed in breast cancer tissues and can promote tumor proliferation and metastasis. PDK1 and the PDHC/PDK axis are important targets for regulating glucose metabolism and anti-tumor activity. In this study, we evaluated the anti-tumor activities of a series of semi-synthesized shikonin (SK) derivatives against human breast cancer cells. The anti-proliferation activity of SK derivatives against human breast cancer cell lines was tested by CCK-8 and EdU assay. Flow cytometry was utilized to evaluate cell apoptosis, reactive oxygen species and cell cycle distribution. Cell migration ability was determined by wound healing and trans-well assay. PDK1 targeting effect was confirmed by western bolting, molecular docking, bio-layer interferometry and PDK1 enzyme activity assay. Nude-mouse transplanted tumor model was used to evaluate their anti-tumor effect in vivo. Findings revealed that SK derivatives had good anti-proliferation ability against MDA-MB-231 cell. They induced cell apoptosis by regulating the mitochondrial apoptosis and death receptor pathway. They also inhibited cell migration by suppressing EMT progression. Molecular docking, PDK1 affinity and enzyme activity demonstrated their PDK1 targeting. In vivo antitumor experiment showed that E2 could significantly inhibit tumor growth with lower side-effect on mice than SK. In conclusion, the novel SK derivatives E2 and E5 inhibited tumor glycolysis by targeting PDK1 and ultimately induced apoptosis. Our data demonstrated that E2 would be a good lead compound for the treatment of human TNBC as a novel PDK1 inhibitor. [ABSTRACT FROM AUTHOR]

[Display omitted] • SK and acetyl-SK relieve colonic injuries inAOM / DSS -induced colitis-associated colorectal cancer (CAC) model of C57BL/6J mice. • SK and acetyl-SK remodel the gut microbial communities of CAC mice models. • SK and acetyl-SK rescued the increased Ileibacterium valens and g_norank_f_norank_o_Clostridia_UCG-014 in CAC mice. • SK downregulated the expression of ACTN2, FGG and PKM2 in CAC mice. • SK upregulated the expression of Aldh1a1 and Aldh1b1 which involved in the Wnt/ β -catenin pathway in CAC mice. Colorectal cancer (CRC) and inflammatory bowel disease (IBD) are the most common diseases of human digestive system. Nowadays, the influence of the inflammatory microenvironment on tumorigenesis has become a new direction, and the exploration of relative molecular mechanism will facilitate the discovery and identification of novel potential anti-cancer molecules. Natural shikonin (SK) and acetyl-shikonin (acetyl-SK) was administered to azoxymethane (AOM)/dextran sodium sulphate (DSS)-induced colitis-associated colorectal cancer (CAC) mice model by gavage to investigate their therapeutic effects. Moreover, fresh feces and colon tissues were collected for determining the function of SK and acetyl-SK on the gut microbes and protein expression, respectively. Both SK and acetyl-SK decreased AOM/DSS-induced CAC, and regulated the intestinal flora structure in CAC mouse model. They, especially SK, improved species richness, evenness and diversity of intestinal flora, recovered the upregulated ratio of Firmicutes to Bacteroidota (F/B ratio) which symbolizes gut microbiota dysbiosis. SK and its derivative increased the beneficial bacteria g__norank_f__Muribaculaceae, Lactobacillus, Lachnospiraceae_NK4A136_Group, and reduced those harmful ones including Ileibacterium and Coriobacteriaceae UCG–002. Notably, AOM/DSS caused significant increase in the abundance of Ileibaterium valens and g__norank_f__norank_o__Clostridia_UCG-014 , which were not previously reported in studies of colonic inflammation or cancer, and the disorder was reversed by 20 mg/kg of SK. In our current study, the action of SK and acetyl-SK is dose-dependent, and 20 mg/kg SK exhibited the most effective functions, even better than the positive drug mesalazine. Moreover, differential proteomics and ELISA results showed that SK could recover the increase of pro-inflammatory cytokines (including IL-1β, IL-6 and TNF-α), the upregulation of pyruvate kinase isozyme type M2 (PKM2) and some other proteins (mainly concentrated in transcriptional mis-regulation in cancer and IL-17 signaling pathways), and the downregulation of Aldh1b1-Acc3-Maoa and Μgt2b34-Aldh1a1-Aldh1a7 involved in Wnt/ β -catenin signaling pathway. Our study identified SK and acetyl-SK, especially SK, as potential preventive agents for CAC through regulating both gut microbes and pathways involved in inflammation and cancer such as Wnt/ β -catenin signaling pathway. [ABSTRACT FROM AUTHOR]

Numerous studies have argued that environmental variations may contribute to evolution through the generation of novel heritable variations via meiotic recombination, which plays a crucial role in crop domestication and improvement. Rice is one of the most important staple crops, but no direct estimate of recombination events has yet been made at a fine scale., Here, we address this limitation by sequencing 41 rice individuals with high sequencing coverage and c. 900 000 accurate markers., An average of 33.9 crossover ( c. 4.53 cM Mb−1) and 2.47 non-crossover events were detected per F2 plant, which is similar to the values in Arabidopsis. Although not all samples in the stress treatment group showed an increased number of crossover events, environmental stress increased the recombination rate in c. 28.5% of samples. Interestingly, the crossovers showed a highly uneven distribution among and along chromosomes, with c. 13.9% of the entire genome devoid of crossovers, including 11 of the 12 centromere regions, and c. 0.72% of the genome containing large numbers of crossovers (> 50 cM Mb−1)., The gene ontology ( GO) categories showed that genes clustered within the recombination hot spot regions primarily tended to be involved in responses to environmental stimuli, suggesting that recombination plays an important role for adaptive evolution in rapidly changing environments. [ABSTRACT FROM AUTHOR]

Background and Aims: It has been shown that Faecalibacterium prausnitzii (F. prausnitzii), one of the dominant intestinal bacterial flora, may protect colonic mucosa against the development of inflammation and subsequent inflammatory bowel disease (IBD), with the underlying mechanisms being unclear. Methods: The impacts of F. prausnitzii and its metabolites on IL-23/Th17/IL-17 pathway markers were determined in human monocytes and a rat model of colitis induced by 2,4,6-trinitrobenzene sulfonic acid. F. prausnitzii and its culture medium (containing complete metabolites) were used to treat the rats in vivo, as well as rat splenocytes and human monocytes in vitro. Inflammatory cytokines were measured in colon tissue, plasma and cell culture medium. Results: The culture supernatant of F. prausnitzii increased plasma anti-Th17 cytokines (IL-10 and IL-12)and suppressed IL-17 levels in both plasma and colonic mucosa, with ameliorated colonic colitis lesions. This inhibition of IL-17 release has also been observed in both rat splenocytes and human venous monocytes in vitro. The culture supernatant of F. prausnitzii also suppressed Th17 cell differentiation induced by cytokines (TGF-ß and IL-6) and bone marrow-derived dendritic cells (BMDCs) in vitro. The metabolites of F. prausnitzii in the culture supernatant exert a stronger anti-inflammatory effect than the bacterium itself. F. prausnitzii protected the colon mucosa against the development of IBD by its metabolites, suggesting a promising potential for the use of F. prausnitzii and its metabolic products in the treatment of IBD. [ABSTRACT FROM AUTHOR]

PMMB-302 has an effect on the expression of apoptosis-related proteins such as Bcl2, Bcl-XL, caspase-9, caspase3 and FADD. Moreover, PMMB-302 inhibited expression of telomerase core proteins, dyskerin and NHP2, and telomerase reverse transcriptase RNA. These results suggested that PMMB-302 has tumor suppressive roles in lung cancer cells. [Display omitted] • A small novel molecule modified form of a natural product (shikonin), acts as a novel inhibitor of telomerase. • The small molecule suppresses cancer cell proliferation in vitro via inducing apoptosis and arresting cell cycle at G2/M phase. • This small molecule induces apoptosis in A549 cells through the mitochondrial and death receptor pathways. In this study, a series of novel shikonin N -benzyl matrinic acid ester derivatives (PMMB-299–PMMB-310) were synthesized and tested for their ability to inhibit the proliferation of cancer cells. Compared with shikonin and matrine, some of the ester derivatives were found to exhibit better anti-proliferative activity against seven different cancer cell lines, with less cytotoxicity toward non-cancerous cells. The strongest anti-proliferative activity was exhibited by PMMB-302, which had an IC 50 value of 2.71 μM against A549 cells. The compound caused cell cycle arrest in the G2/M phase and induced apoptosis. Effects on the expression of apoptosis-related molecules such as Bcl2, Bcl-XL, caspase-3, caspase-9 and FADD suggested that PMMB-302 has tumor suppressive roles in lung cancer cells. In addition, PMMB-302 inhibited expression of telomerase core proteins, dyskerin and NHP2, and telomerase reverse transcriptase RNA. Moreover, molecular docking of PMMB-302 was subsequently conducted to determine the probable binding mode with telomerase. Taken together, the results indicate that PMMB-302 acts as a tumor suppressor in lung cancer cells by negatively regulating telomerase expression. [ABSTRACT FROM AUTHOR]

Although magnesium (Mg2+) is the most abundant divalent cation in plant cells, little is known about the mechanism of Mg2+ uptake by plant roots. Here, we report a key function of Magnesium Transport6 (MGT6)/Mitochondrial RNA Splicing2-4 in Mg2+ uptake and low-Mg2+ tolerance in Arabidopsis thaliana. MGT6 is expressed mainly in plant aerial tissues when Mg2+ levels are high in the soil or growth medium. Its expression is highly induced in the roots during Mg2+ deficiency, suggesting a role for MGT6 in response to the low-Mg2+ status in roots. Silencing of MGT6 in transgenic plants by RNA interference (RNAi) resulted in growth retardation under the low-Mg2+ condition, and the phenotype was restored to normal growth after RNAi plants were transferred to Mg2+-sufficient medium. RNAi plants contained lower levels of Mg2+ compared with wild-type plants under low Mg2+ but not under Mg2+-sufficient conditions. Further analysis indicated that MGT6 was localized in the plasma membrane and played a key role in Mg2+ uptake by roots under Mg2+ limitation. We conclude that MGT6 mediates Mg2+ uptake in roots and is required for plant adaptation to a low-Mg2+ environment. [ABSTRACT FROM AUTHOR]

The Orange ( Or) gene is a gene mutation that can increase carotenoid content in plant tissues normally devoid of pigments. It affects plastid division and is involved in the differentiation of proplastids or non-colored plastids into chromoplasts. In this study, the de-etiolation process of the wild type (WT) cauliflower ( Brassica oleracea L. var. botrytis) and Or mutant seedlings was investigated. We analyzed pigment content, plastid development, transcript abundance and protein levels of genes involved in the de-etiolation process. The results showed that Or can increase the carotenoid content in green tissues, although not as effectively as in non-green tissues, and this effect might be caused by the changes in biosynthetic pathway genes at both transcriptional and post-transcriptional levels. There was no significant difference in the plastid development process between the two lines. However, the increased content of antheraxanthin and anthocyanin, and higher expression levels of violaxanthin de- epoxidase gene ( VDE) suggested a stress situation leading to photoinhibition and enhanced photoprotection in the Or mutant. The up-regulated expression levels of the reactive oxygen species (ROS)-induced genes, ZAT10 for salt tolerance zinc finger protein and ASCORBATE PEROXIDASE2 ( APX2), suggested the existence of photo-oxidative stress in the Or mutant. In summary, abovementioned findings provide additional insight into the functions of the Or gene in different tissues and at different developmental stages. [ABSTRACT FROM AUTHOR]

The target of product attributes prediction is to complete the characteristics set for defining a particular product. Most of the existing methods treat the product attributes prediction as a Named-Entity Recognition (NER) problem from the products' affiliated data, such as product title and introduction. However, in a large number of industrial applications of Alibaba, we found that the existing methods are good at concrete attributes extraction (e.g., color, size) but short of abstract attributes extraction (e.g., applicable event). Moreover, these abstract attributes are usually not easy to extract from the products' affiliated data. In this paper, we propose a novel heterogeneous s tar graph a ttention n etwork called "SAN", which incorporates the advantages of multiple information in the e-commerce scene to predict the abstract attributes of products. Specifically, we model the customer interactive behaviors, product title and concrete attributes of a product as a star graph. Then, we extract the node features, node types and graph structure information from the heterogeneous star graph network which consists of n star graphs. By leveraging the parallel multiple attention mechanism, SAN can aggregate features and learn weights of nodes for product representation and abstract attribute prediction. Extensive experimental results of a real-world e-commerce dataset have demonstrated that SAN outperforms state-of-the-art methods significantly for product attributes prediction. These series of solutions are already planned for use in the applications of Alibaba. [ABSTRACT FROM AUTHOR]

• SbNAC2 can be induced by various abiotic stresses. • Silencing of SbNAC2 leads to compromised drought tolerance of sorghum seedlings. • SbNAC2 can directly induce SbAP37 , a stress-response gene, to enhance the stress tolerance of sorghum. • Heterologous expression of SbNAC2 in Arabidopsis and rice enhanced the stress tolerance of the transgenic plants. Major abiotic stresses such as drought and salinity affect the growth and yield of crops. NAC (NAM, ATAF1/2, and CUC2) is a plant-specific gene family that has been demonstrated to contribute to responses and adaption to abiotic stress in plants. The specific NAC transcription factors (TFs) that play important roles in the response to abiotic stress in sorghum are unknown. Here, we characterized a sorghum TF, SbNAC2, that can be strongly induced by abiotic stresses, including polyethylene glycol (PEG)-simulated dehydration stress treatment, salt treatment, and 4 °C chilling. Knockdown of SbNAC2 in sorghum seedlings by virus-induced gene silencing (VIGS) weakened the drought tolerance of plants. Heterologous overexpression of SbNAC2 in Arabidopsis and rice can induce plant antioxidant enzyme activity under abiotic stress conditions. Furthermore, SbNAC2 directly activates the expression of a stress responsive AP2/ERF type TF gene, SbAP37 , by binding to the TTNCGTA motif of its promoter. These results indicate that SbNAC2 functions as a potentially important regulator in response to abiotic stresses and that it may possibly be used for molecular breeding to enhance crop yields under adverse environmental conditions. [ABSTRACT FROM AUTHOR]

Abstract: Aluminum (Al) is one of the limiting factors for crop production in acidic soil. We aimed to demonstrate how the rhizosphere diazotrophic community responds to two contrasting soybean genotypes, BX10 (Al-tolerant) and BD2 (Al-sensitive), under Al stress at different growth stages. The diversity and abundance of nifH gene in the rhizosphere soils were assessed by denaturing gradient gel electrophoresis (DGGE) and real-time PCR. The results indicated that there were differences in the community structure between BX10 and BD2 at three sampling stages, respectively. Phylogenetic analyses revealed that 3 and 16 non-identical sequences were responsive to BX10 and BD2, respectively, during the whole growth periods. Parts of sequences responsive to BD2 were affiliated with Rhizobium sp. and Azospirillum brasilense, which have the potential to promote plant growth. Dominant diazotrophs varied in different growth stages of both soybean genotypes. Higher nifH abundance was observed in BD2 at seedling stage, whereas that was detected in BX10 at flowering and maturity stages. The diazotrophic community is sensitive and responds differentially to different soybean genotypes adapted to Al stress, as demonstrated by the increased quantity of diazotrophs in BX10 and the stimulation of beneficial diazotrophic bacteria in BD2. [Copyright &y& Elsevier]

This study aimed to investigate the correlation between organic acids secreted by two soybeans genotypes, BX10 [aluminum (Al) tolerant] and BD2 (Al sensitive) and rhizosphere microbial communities in acid soil. The organic acids secreted by BX10 and BD2 were significantly different at each growth stage. Both fungi/bacteria and gram-negative bacteria/gram-positive bacteria ratio values were affected by the two soybean genotypes at different growth periods. Compared with BD2, phospholipid fatty acid of BX10 showed higher Shannon diversity at the seedling and flowering stages, but had lower Shannon diversity at the pod-setting stage. Redundancy analysis and canonical correspondence analysis revealed that the organic acids including tartaric acid, lactic acid, and citric acid significantly affected rhizosphere bacterial communities. Sequence analysis indicated that uncultured Acidobacterium, Chloroflexi, and actinomycete enriched in BD2, whereas some uncultured bacteria enriched in BX10. The two soybean genotypes exhibit distinct rhizosphere microbial communities; root organic acid exudates may affect composition of microbial communities of rhizosphere soil: tartaric acid may negatively affect rhizosphere bacteria at the seedling stage, lactic acid may positively affect rhizosphere actinomycetes at the flowering stage, and succinic acid may stimulate fungi at the pod-setting stage. [ABSTRACT FROM AUTHOR]

Abstract: We report the design and characterization of a microarray with 46 short virus-specific oligonucleotides for detecting influenza A virus of 5 subtypes: H1N1, H1N2, H3N2, H5N1, and H9N2. A unique combination of 3 specific modifications was introduced into the microarray assay: (1) short probes of 19 to 27 nucleotides, (2) simple amplification of full-length hemagglutinin and neuraminidase cDNAs with universal primers, and (3) Klenow-mediated labeling and further amplification of the samples before hybridization. The assay correctly and specifically detected and subtyped 11 different influenza A isolates from human, avian, and swine species representing the 5 subtypes. When tested with 225 clinical samples, 20 were detected to be positive using our microarray-based assay, whereas only 10 were positive by the conventional culture method. The entire analysis was completed within 7 h. Thus, these modifications result in a specific, sensitive, and rapid microarray assay and may be used for constructing microarrays for the detection of all influenza subtypes and strains. [Copyright &y& Elsevier]

Seedlings of two soybean genotypes, BX10 [aluminum (Al)-tolerant] and BD2 (Al-sensitive), were treated with Al to evaluate the relative root growth (RRG), callose content, Al-sensitive zone, lipid peroxidation, and the anti-oxidative enzyme activities by histochemical and biochemical assays. Under Al toxicity, the RRG reduction of BD2 was more significant than that of BX10, while callose content displayed a contrary trend. The 2-5 mm zone of root apex was the main Al-sensitive zone for soybeans. The activities of superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and ascorbate peroxidase (APX) were found to be higher in the two genotypes under Al toxicity than that of the controls. The SOD, POD, and CAT activities of BX10; however, were significantly lower than those of BD2. These results implied that producing low quantity of ROS may be one aspect of the Al-tolerant mechanism for soybeans, which in turn helps them adapt to Al stress. [ABSTRACT FROM AUTHOR]

• In children with epilepsy, longer PGES is associated with a higher ictal EDA. • Generalized tonic-clonic seizures with decerebrate posturing are associated with longer PGES and greater ictal EDA. • Semiologic, autonomic, and electrographic seizure characteristics are related. • Results suggest potential applications in monitoring and preventing SUDEP in children. Generalized tonic-clonic seizures (GTCS) are associated with elevated electrodermal activity (EDA) and postictal generalized electroencephalographic suppression (PGES), markers that may indicate sudden unexpected death in epilepsy (SUDEP) risk. This study investigated the association of GTCS semiology, EDA, and PGES in children with epilepsy. Patients admitted to the Boston Children's Hospital long-term video-EEG monitoring unit wore a sensor that records EDA. We selected patients with at least one GTCS and reviewed video-EEGs for semiology, tonic and clonic phase duration, total clinical seizure duration, electrographic onset, offset, and PGES. We grouped patients into three semiology classes: GTCS 1: bilateral symmetric tonic arm extension, GTCS 2: no specific tonic arm extension or flexion, GTCS 3: unilateral or asymmetrical arm extension, tonic arm flexion or posturing that does not fit into GTCS 1 or 2. We analyzed the correlation between semiology, EDA, and PGES, and measured the area under the curve (AUC) of the ictal EDA (seizure onset to one hour after), subtracting baseline EDA (one-hour seizure-free before seizure onset). Using generalized estimating equation (GEE) and linear regression, we analyzed all seizures and single episodes per patient. We included 30 patients (median age 13.8 ± 3.6 years, 46.7% females) and 53 seizures. With GEE, GTCS 1 was associated with longer PGES duration compared to GTCS 2 (Estimate (β) = −26.32 s, 95% Confidence Interval (CI): −36.46 to −16.18, p < 0.001), and the presence of PGES was associated with greater EDA change (β = 429604 μS, 95% CI: 3550.96 to 855657.04, p = 0.048). With single-episode analysis, GTCS 1 had greater EDA change than GTCS 2 ((β = −601339 μS, 95% CI: −1167016.56 to −35661.44, p = 0.047). EDA increased with PGES presence (β = 637500 μS, 95% CI: 183571.84 to 1091428.16, p = 0.01) and duration (β = 16794 μS, 95% CI: 5729.8 to 27858.2, p = 0.006). Patients with GTCS 1 had longer PGES duration compared to GTCS 2 (β = −30.53 s, 95% CI: −44.6 to −16.46, p < 0.001) and GTCS 3 (β = −22.07 s, 95% CI: −38.95 to −5.19, p = 0.016). In children with epilepsy, PGES correlates with greater ictal EDA. GTCS 1 correlated with longer PGES duration and may indirectly correlate with greater ictal EDA. Our study suggests potential applications in monitoring and preventing SUDEP in these patients. [ABSTRACT FROM AUTHOR]

Amphiphilic block copolymers, poly(caprolactone)–poly(ethylene glycol)–poly(lactide) (PCELA), were synthesized by ring opening polymerization of caprolactone and lactide initiated with the hydroxyl groups of poly(ethylene glycol) (PEG). These copolymers could form micelle-like nanoparticles due to their amphiphilic characteristic. From the observation of transmission electron microscopy (TEM), the nanoparticles exhibited a regular spherical shape with core-shell structure. The critical micelle concentrations (CMC) of these nanoparticles in water were decreased as molecular weight of PEG decreased. The particle sizes obtained by dynamic light scattering of these nanoparticles were in the range of 100–200 nm, and increased as the hydrophobic property of the nanoparticles increased. Nimodipine as a model drug was loaded in these nanoparticles to investigate the drug release behavior. It was found that the chemical composition of the nanoparticles was a key factor in controlling nanoparticle size, nanoparticle yields, drug-entrapment efficiency, and drug release behavior. When the PEG content is about 2% (wt), the release profile of PCELA nanoparticles appeared to follow zero-order kinetics. [Copyright &y& Elsevier]

[Display omitted] • A series of novel anilide (dicarboxylic acid) shikonin esters were designed and synthesized as potential antitumor agents. • Representative compound M9 displayed potent anti-proliferative activity in vitro. • M9 could significantly induce apoptosis and arrest cell cycle in G2/M phase on MDA-MB-231 cells. • M9 inhibited the migration of MDA-MB-231 cells through Wnt/β-catenin signaling pathway in vitro. • M9 down-regulates PI3K/Akt/mTOR pathway by targeting Akt, thereby inhibiting cell proliferation and migration. Triple-negative breast cancer (TNBC) has an unfavorable prognosis attribute to its low differentiation, rapid proliferation and high distant metastasis rate. PI3K/Akt/mTOR as an intracellular signaling pathway plays a key role in the cell proliferation, migration, invasion, metabolism and regeneration. In this work, we designed and synthesized a series of anilide (dicarboxylic acid) shikonin esters targeting PI3K/Akt/mTOR signaling pathway, and assessed their antitumor effects. Through three rounds of screening by computer-aided drug design method (CADD), we preliminarily obtained sixteen novel anilide (dicarboxylic acid) shikonin esters and identified them as excellent compounds. CCK-8 assay results demonstrated that compound M9 exhibited better antiproliferative activities against MDA-MB-231, A549 and HeLa cell lines than shikonin (SK), especially for MDA-MB-231 (M9: IC 50 = 4.52 ± 0.28 μM; SK: IC 50 = 7.62 ± 0.26 μM). Moreover, the antiproliferative activity of M9 was better than that of paclitaxel. Further pharmacological studies showed that M9 could induce apoptosis of MDA-MB-231 cells and arrest the cell cycle in G2/M phase. M9 also inhibited the migration of MDA-MB-231 cells by inhibiting Wnt/β-catenin signaling pathway. In addition, western blot results showed that M9 could inhibit cell proliferation and migration by down-regulating PI3K/Akt/mTOR signaling pathway. Finally, a three-dimensional quantitative structure–activity relationship (3D-QSAR) model was also constructed to provide a basis for further development of shikonin derivatives as potential antitumor drugs through structure–activity relationship analysis. To sum up, M9 could be a potential candidate for TNBC therapy. [ABSTRACT FROM AUTHOR]

Background: A key component of the 2009 medical reform in China was the change to family doctor (FD) policy practice. However, this led to an increased workload for primary health-care workers (PHCWs) at community health service centres. Their increasing workload may play a significant role in affecting PHCWs' health. Methods: A questionnaire survey was conducted in Hongkou district of Shanghai amongst PHCWs including family doctors (FDs), family nurses (FNs), public health doctors (PHDs), and other PHCWs in early 2019. Ordered logistic regression models (Models 1 to 3) were performed to explore the differing health status amongst PHCWs, and their respective influential factors were also tested (Models 4 to 7). Results: Five hundred sixty-two valid questionnaires were collected with a response rate of 96.4%. Other PHCWs' (OR = 2.03; 95% CI: 1.163–3.560) and FNs' (OR = 1.98; 95% CI: 1.136–3.452) self-rated health (SRH) were significantly better than that of FDs. In terms of FNs, the OR of SRH for those who strongly perceived the extra workload brought by FD-contracted services was only 12.0% (95% CI: 0.018–0.815) of that of the no-pressure group. Similarly, FNs with stronger work pressure had worse SRH, i.e., compared with "no" pressure, the SRH ORs for "neutral," "strong," and "very strong" evaluations of work pressure were 0.002 (95% CI: 0.000–0.055), 0.001 (95% CI: 0.000–0.033), and 0.000 (95% CI: 0.000–0.006), respectively. Information technology (IT) systems and performance incentives were suggested to improve SRH for FNs, while the former was found to be negatively correlated with other PHCWs. After one unit increase in the PHDs' team/department support, their OR was 10.7 times (95% CI: 1.700–67.352) higher. In addition, policy support had a negative effect on SRH for PHDs. The OR of "good" assessments of cultural environments was 25.98 times (95% CI: 1.391–485.186) higher than that of "very poor" for Other PHCWs. Conclusions: The influences of FD policy practice on FNs' SRH were the most significant amongst PHCWs, rather than FDs' as expected. The significant factors of SRH were varied over different occupational categories, that is team/department support and policy support (though negative) for PHDs, IT system and incentive for FNs, facility and equipment for FDs, and culture environment for other PHCWs respectively. [ABSTRACT FROM AUTHOR]

• SbWRKY30 could respond to various abiotic stresses and phytohormones. • Heterologous overexpression of SbWRKY30 enhances plant drought tolerance in Arabidopsis and rice. • SbWRKY30 confers plant drought stress tolerance by affecting the root architecture. • SbWRKY30 protects plant cells from the damage of active oxygen species by improving ROS scavenging capability. • SbWRKY30 enhances drought stress by directly activating SbRD19 in sorghum. WRKY transcription factors have been suggested to play important roles in response and adaptation to drought stress. However, how sorghum WRKY transcription factors function in drought stress is still unclear. Here, we identify a WRKY transcription factor of sorghum, SbWRKY30, which is induced significantly by drought stress. SbWRKY30 is mainly expressed in sorghum taproot and leaf. SbWRKY30 has transcriptional activation activity and functions in the nucleus. Heterologous expression of SbWRKY30 confers tolerance to drought stress in Arabidopsis (Arabidopsis thaliana) and rice by affecting root architecture. In addition, SbWRKY30 transgenic Arabidopsis and rice plants have higher proline contents and SOD, POD, and CAT activities but lower MDA contents than wild-type plants after drought stress. As a homologous gene of the drought stress-responsive gene RD19 of Arabidopsis , SbRD19 overexpression in Arabidopsis improved the drought tolerance of plants relative to wild-type plants. Further analysis demonstrated that SbWRKY30 could induce SbRD19 expression through binding to the W-box element in the promoter of SbRD19. These results suggest that SbWRKY30 functions as a positive regulator in response to drought stress. Therefore, SbWRKY30 may serve as a promising candidate gene for molecular breeding to generate drought-tolerant crops. [ABSTRACT FROM AUTHOR]