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Shikonin has been reported to regulate caudal-type homeobox 2 (CDX2)-mediated intestinal epithelial cell (IEC) differentiation, and ferroptosis has been identified a critical event during this process. However, the exact role of ferroptosis in shikonin-induced IEC differentiation remains unclear. Accordingly, the aim of this study was to elucidate the involvement of ferroptosis in CDX2-mediated IEC differentiation induced by shikonin. Real-time polymerase chain reaction, western blotting, luciferase assay, immunoprecipitation, and chromatin immunoprecipitation were used to reveal the mechanism underlying shikonin-modulated ferroptosis-dependent IEC differentiation in HT-29 and Caco-2 cells. Shikonin treatment reduced ferroptosis in IECs, as evidenced by the increased expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 (cationic amino acid transporter) member 11, which enhanced CDX2 expression and improved IEC barrier function. Mechanistically, shikonin activated the protein kinase A (PKA)/cAMP-responsive element-binding protein (CREB) signaling cascade, promoting CREB binding to the GPX4 promoter and initiating GPX4 transactivation. GPX4 inhibition reversed the effects of shikonin on CDX2 expression. Endogenous pyruvate kinase isozyme M2 interacted with phosphodiesterase 4; this interaction was disrupted by shikonin, leading to the activation of PKA/CREB signaling. The findings of this study indicate that a low dose of shikonin improves IEC barrier function through GPX4-mediated inhibition of ferroptosis, highlighting its potential as a therapeutic agent for intestinal mucosal injury.

Social entrepreneurship (SE) is often viewed as an effective means to promote social well-being (SWB). However, how SE emerges from a country’s institutional and social context, and consequently, how the institutional and social embeddedness of SE influences the level of SWB in a particular country, remains unanswered. This study, utilizing fuzzy set qualitative comparative analysis (fsQCA), addresses these questions by exploring, (1) the configurations of institutional and social capital conditions that lead to high prevalence rates of different types of SE activities in a country, and (2) the configurations of such institutionally and socially embedded SE activities that deliver high level of SWB in a country. It advances the SE literature by revealing the embeddedness and configurational nature of SE. Specifically, multiple equifinal configurations of socio-political conditions can lead to high prevalence rates of not-for-profit SE and hybrid SE. Moreover, this study finds that while both not-for-profit SE and hybrid SE can facilitate SWB by interacting with socio-political conditions, they do so through different mechanisms.

Background Cardiovascular disease (CVD), one of the most common comorbidities of coronavirus disease 2019 (COVID-19), has been suspected to be associated with adverse outcomes in COVID-19 patients, but their correlation remains controversial. Method This is a quantitative meta-analysis on the basis of adjusted effect estimates. PubMed, Web of Science, MedRxiv, Scopus, Elsevier ScienceDirect, Cochrane Library and EMBASE were searched comprehensively to obtain a complete data source up to January 7, 2021. Pooled effects (hazard ratio (HR), odds ratio (OR)) and the 95% confidence intervals (CIs) were estimated to evaluate the risk of the adverse outcomes in COVID-19 patients with CVD. Heterogeneity was assessed by Cochran’s Q-statistic, I 2 test, and meta-regression. In addition, we also provided the prediction interval, which was helpful for assessing whether the variation across studies was clinically significant. The robustness of the results was evaluated by sensitivity analysis. Publication bias was assessed by Begg’s test, Egger’s test, and trim-and-fill method. Result Our results revealed that COVID-19 patients with pre-existing CVD tended more to adverse outcomes on the basis of 203 eligible studies with 24,032,712 cases (pooled ORs = 1.41, 95% CIs: 1.32-1.51, prediction interval: 0.84-2.39; pooled HRs = 1.34, 95% CIs: 1.23-1.46, prediction interval: 0.82-2.21). Further subgroup analyses stratified by age, the proportion of males, study design, disease types, sample size, region and disease outcomes also showed that pre-existing CVD was significantly associated with adverse outcomes among COVID-19 patients. Conclusion Our findings demonstrated that pre-existing CVD was an independent risk factor associated with adverse outcomes among COVID-19 patients.

Although inoculation of COVID-19 vaccines has rolled out globally, there is still a critical need for safe and effective vaccines to ensure fair and equitable supply for all countries. Here, we report on the development of a highly efficacious mRNA vaccine, SW0123 that is composed of sequence-modified mRNA encoding the full-length SARS-CoV-2 Spike protein packaged in core–shell structured lipopolyplex (LPP) nanoparticles. SW0123 is easy to produce using a large-scale microfluidics-based apparatus. The unique core–shell structured nanoparticle facilitates vaccine uptake and demonstrates a high colloidal stability, and a desirable biodistribution pattern with low liver targeting effect upon intramuscular administration. Extensive evaluations in mice and nonhuman primates revealed strong immunogenicity of SW0123, represented by induction of Th1-polarized T cell responses and high levels of antibodies that were capable of neutralizing not only the wild-type SARS-CoV-2, but also a panel of variants including D614G and N501Y variants. In addition, SW0123 conferred effective protection in both mice and non-human primates upon SARS-CoV-2 challenge. Taken together, SW0123 is a promising vaccine candidate that holds prospects for further evaluation in humans.

Lilies are economically important monocots known for their ornamental flowers, bulbs, and large genomes. The absence of their genomic information has impeded evolutionary studies and genome-based breeding efforts. Here, we present reference genomes for Lilium sargentiae (lily, 35.66 Gb) and Gloriosa superba (flame lily, 5.09 Gb). The giant lily genome is shaped by recent long terminal repeat retroelements. Phylogenetic analysis reveals diverse, independent origins of lily cultivars. Gene families involved in sucrose and starch metabolism are significantly expanded in the lily genome. Key homologs of XTH22 , SOC1 , and AP1/FUL -like genes regulate the development, bud growth transition, and floral bud growth transition of lily bulbs. Colchicine biosynthetic gene clusters are identified in G. superba but are absent in L. sargentiae , highlighting independent colchicine evolution in Colchicaceae. These genomic insights enhance understanding of Liliales evolution, providing a foundation for future breeding and molecular research. Lilies are perennial plants with ornamental flowers and large genomes. The authors assemble genomes of two Liliales species, analyze lily phylogeny, flower and stem development (bulbs in lilies, rhizomes in flame lilies), bulb growth transitions, and colchicine biosynthesis.

Sexual dysfunction is common in males with chronic kidney disease (CKD), but yet the prevalence and specific relationship between CKD and sexual dysfunction, especially premature ejaculation (PE), remain to be investigated in China; This study aims to examine the prevalence and association between CKD and sexual dysfunction in male patients in China; In this cross-sectional, non-interventional, observational study conducted at a single center. 72 male patients with CKD were enrolled. Data collection included socio-demographic information, assessments via the 5-item version of the International Index of Erectile Function (IIEF-5), the Chinese version of the Premature Ejaculation Diagnostic Tool, the Patient Health Quentionnnaire-9 and the General Anxiety Disorder-7. Data analysis was performed using R version 3.5.2 and SPSS software version 25.0; Among the 72 CKD patients, 56.9% experienced erectile dysfunction and 29.2% had PE. Various factors including estimated Glomerular Filtration Rate, Albumin-to-Creatinine Ratio, psychological aspects, medication use were found to be associated with sexual dysfunction in these CKD patients; Sexual dysfunction is prevalent in males with CKD and is, influenced by multiple factors. It is important for clinicians to focus on sexual dysfunction in this patient group and further investigate its underlying mechanisms.

Malus hupehensis, as an apple rootstock, is an economically important tree species popular due to its excellent fruit yield and stress resistance. Nitrogen is one of the critical limiting factors of plant growth and fruit yield, so it is crucial to explore new methods to improve nitrogen use efficiency. Melatonin and dopamine, as multifunctional metabolites, play numerous physiological roles in plants. We analyzed the effects of exogenous melatonin and dopamine treatments on the growth, root system architecture, nitrogen absorption, and metabolism of M. hupehensis when seedlings were exposed to nitrate-deficient conditions. Under low nitrate stress, plant growth slowed, and chlorophyll contents and 15 NO 3 – accumulation decreased significantly. However, the application of 0.1 μmol/L melatonin or 100 μmol/L exogenous dopamine significantly reduced the inhibition attributable to low nitrate levels during the ensuing period of stress treatment, and the effect of dopamine was more obvious. In addition to modifying the root system architecture of nitrate-deficient plants, exogenous melatonin and dopamine also changed the uptake, transport, and distribution of 15 NO 3 – . Furthermore, both exogenous melatonin and dopamine enhanced tolerance to low nitrate stress by maintaining the activity of enzymes (NR, NiR, GS, Fd-GOGAT, and NADH-GOGAT) and the transcription levels of related genes involved in leaf and root nitrogen metabolism. We also found that exogenous melatonin and dopamine promoted the expression of nitrate transporter genes ( NRT1.1 , NRT2.4 , NRT2.5 , and NRT2.7 ) in nitrate-deficient plant leaves and roots. Our results suggest that both exogenous melatonin and dopamine can mitigate low nitrate stress by changing the root system architecture, promoting the absorption of nitrate, and regulating the expression of genes related to nitrogen transport and metabolism. However, according to a comprehensive analysis of the results, exogenous dopamine plays a more significant role than melatonin in improving plant nitrogen use efficiency.

PurposeWaterlogging poses a severe threat to the worldwide apple industry, but systematic research on the mechanisms of waterlogging resistance in apples is lacking. The roles of melatonin and dopamine in waterlogging in apples are also not understood.MethodsWe performed a glass container experiment to investigate the effects of exogenous melatonin and dopamine on N uptake and utilization of M. hupehensis under waterlogging stress, and the rhizosphere microbial community.ResultsUnder waterlogging stress, melatonin and dopamine enhanced the antioxidant enzyme system and reduced reactive oxygen species (ROS) levels in plants. Importantly, melatonin and dopamine regulated the expression of genes related to N transport (NRTs, AMTs, and NLPs) and N metabolism enzymes (NR, NiR, GS, NADH-GOGAT, and Fd-GOGAT), and promoted the uptake and utilization of N in plants under waterlogging stress. Additionally, using 16S/ITS sequencing technology, we revealed for the first time the regulatory effects of melatonin and dopamine on the rhizosphere microbial community in apples under waterlogging stress. We identified the key flora (e.g., Hydrogenophaga, Flavobacterium, and Preussia) regulated by melatonin and dopamine, and effects on plant N absorption and growth, by analyzing differences in the abundance of bacteria and fungi at the order and genus levels, and identified correlations with plant growth and development.ConclusionsOur results show that melatonin and dopamine effectively reduce ROS, promote N uptake and utilization, and regulate specific microbial communities, thus alleviating the inhibitory effects of waterlogging stress on the growth and development of apple plants.

Human papillomavirus (HPV)-16 infection may be related to non-smoking associated lung cancer. Our previous studies have found that HPV-16 oncoproteins promoted angiogenesis via enhancing hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and interleukin-8 (IL-8) expression in non-small cell lung cancer (NSCLC) cells. In this study, we further investigated the roles of PI3K/Akt and c-Jun signaling pathways in it. Human NSCLC cell lines, A549 and NCI-H460, were stably transfected with pEGFP-16 E6 or E7 plasmids. Western blotting was performed to analyze the expression of HIF-1α, p-Akt, p-P70S6K, p-P85S6K, p-mTOR, p-JNK, and p-c-Jun proteins. VEGF and IL-8 protein secretion and mRNA levels were determined by ELISA and Real-time PCR, respectively. The in vitro angiogenesis was observed by human umbilical vein endothelial cells (HUVECs) tube formation assay. Co-immunoprecipitation was performed to analyze the interaction between c-Jun and HIF-1α. HPV-16 E6 and E7 oncoproteins promoted the activation of Akt, P70S6K, P85S6K, mTOR, JNK, and c-Jun. LY294002, a PI3K inhibitor, inhibited HPV-16 oncoprotein-induced activation of Akt, P70S6K, and P85S6K, expression of HIF-1α, VEGF, and IL-8, and in vitro angiogenesis. c-Jun knockdown by specific siRNA abolished HPV-16 oncoprotein-induced HIF-1α, VEGF, and IL-8 expression and in vitro angiogenesis. Additionally, HPV-16 oncoproteins promoted HIF-1α protein stability via blocking proteasome degradation pathway, but c-Jun knockdown abrogated this effect. Furthermore, HPV-16 oncoproteins increased the quantity of c-Jun binding to HIF-1α. PI3K/Akt signaling pathway and c-Jun are involved in HPV-16 oncoprotein-induced HIF-1α, VEGF, and IL-8 expression and in vitro angiogenesis. Moreover, HPV-16 oncoproteins promoted HIF-1α protein stability possibly through enhancing the interaction between c-Jun and HIF-1α, thus making a contribution to angiogenesis in NSCLC cells.

[This corrects the article DOI: 10.1371/journal.pone.0103440.].