The Asymmetrical Fe-O-Se Bonds in Fe2O(SeO3)2 Boosting Bifunctional Oxygen Electrocatalytic Performance for Zinc-Air Battery.

Here Fe2O(SeO3)2/Fe3C@NC catalysts with high performance were fabricated for zinc-air batteries (ZABs). The experimental results confirmed that the existence of Fe-O-Se bonds in Fe2O(SeO3)2 crystal phase, and the Fe-O-Se bonds could obviously enhance ORR and OER catalytic performance of Fe2O(SeO3)2/Fe3C@NC. Density functional theoretical calculations (DFT) confirmed that the Fe2O(SeO3)2 in Fe2O(SeO3)2/Fe3C@NC had a higher d-band center of Fe atom and a lower p-orbital coupling degree with its own lattice O atom than Fe2O3, which leads to Fe site of Fe2O(SeO3)2 being more likely to adsorb external oxygen intermediates. The Fe-O-Se bonds in Fe2O(SeO3)2 results in the modification of coordination environment of Fe atoms and optimizes the adsorption energy of Fe site for oxygen intermediates. Compared with Fe2O3/Fe3C@NC, the Fe2O(SeO3)2/Fe3C@NC showed obvious enhancements of ORR/OER catalytic activities with a half-wave potential of 0.91 V for ORR in 0.1 M KOH electrolyte and a low overpotential of 345 mV for OER at 10 mA cm-2 in a 1.0 M KOH electrolyte. The peak power density and specific capacity of Fe2O(SeO3)2/Fe3C@NC-based ZABs are higher than those of Pt/C+RuO2-ZABs. The above results demonstrate that the asymmetrical Fe-O-Se bonds in Fe2O(SeO3)2 plays a key role in improving the bifunctional catalytic activities of ORR/OER for ZABs.

Rising atmospheric carbon dioxide concentrations increase gaps of rice yields between low- and middle-to-high-income countries.

The rising carbon dioxide concentrations are expected to increase future rice yields. However, variations in the CO2 fertilization effect (CFE) between rice subspecies and the influence of concurrent global warming introduce uncertainty in future global rice yield projections. Here we conducted a meta-analysis of rising carbon dioxide field experiments and employed crop modelling to assess future global rice yields for the top 14 rice producing countries. We found a robust parabolic relationship between rice CFE and temperature, with significant variations between rice subspecies. Our projections indicate that global rice production in the 2050s is expected to increase by 50.32 million tonnes (7.6%) due to CFE compared with historical production. Because low-income countries will experience higher temperatures, the gaps (difference of Δyield) between middle-to-high-income and low-income countries are projected to widen from the 2030s to the 2090s under elevated carbon dioxide. These findings underscore the critical role of CFE and emphasize the necessity to increase investments in research and technology for rice producing systems in low-income countries.

Hippocampal transcriptomic analyses reveal the potential antiapoptotic mechanism of a novel anticonvulsant agent Q808 on pentylenetetrazol-induced epilepsy in rats.

Brain apoptosis is one of the main causes of epileptogenesis. The antiapoptotic effect and potential mechanism of Q808, an innovative anticonvulsant chemical, have never been reported. In this study, the seizure stage and latency to reach stage 2 of pentylenetetrazol (PTZ) seizure rat model treated with Q808 were investigated. The morphological change and neuronal apoptosis in the hippocampus were detected by hematoxylin and eosin (HE) and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining, respectively. The hippocampal transcriptomic changes were observed using RNA sequencing (RNA-seq). The expression levels of hub genes were verified by quantitative reverse-transcription PCR (qRT-PCR). Results revealed that Q808 could allay the seizure score and prolong the stage 2 latency in seizure rats. The morphological changes of neurons and the number of apoptotic cells in the DG area were diminished by Q808 treatment. RNA-seq analysis revealed eight hub genes, including Map2k3, Nfs1, Chchd4, Hdac6, Siglec5, Slc35d3, Entpd1, and LOC103690108, and nine hub pathways among the control, PTZ, and Q808 groups. Hub gene Nfs1 was involved in the hub pathway sulfur relay system, and Map2k3 was involved in the eight remaining hub pathways, including Amyotrophic lateral sclerosis, Cellular senescence, Fc epsilon RI signaling pathway, GnRH signaling pathway, Influenza A, Rap1 signaling pathway, TNF signaling pathway, and Toll-like receptor signaling pathway. qRT-PCR confirmed that the mRNA levels of these hub genes were consistent with the RNA-seq results. Our findings might contribute to further studies exploring the new apoptosis mechanism and actions of Q808.

Using new indices to predict metabolism dysfunction-associated fatty liver disease (MAFLD): analysis of the national health and nutrition examination survey database.

BACKGROUND: Metabolism dysfunction-associated fatty liver disease (MAFLD), is the most common chronic liver disease. Few MAFLD predictions are simple and accurate. We examined the predictive performance of the albumin-to-glutamyl transpeptidase ratio (AGTR), plasma atherogenicity index (AIP), and serum uric acid to high-density lipoprotein cholesterol ratio (UHR) for MAFLD to design practical, inexpensive, and reliable models. METHODS: The National Health and Nutrition Examination Survey (NHANES) 2007-2016 cycle dataset, which contained 12,654 participants, was filtered and randomly separated into internal validation and training sets. This study examined the relationships of the AGTR and AIP with MAFLD using binary multifactor logistic regression. We then created a MAFLD predictive model using the training dataset and validated the predictive model performance with the 2017-2018 NHANES and internal datasets. RESULTS: In the total population, the predictive ability (AUC) of the AIP, AGTR, UHR, and the combination of all three for MAFLD showed in the following order: 0.749, 0.773, 0.728 and 0.824. Further subgroup analysis showed that the AGTR (AUC1 = 0.796; AUC2 = 0.690) and the combination of the three measures (AUC1 = 0.863; AUC2 = 0.766) better predicted MAFLD in nondiabetic patients. Joint prediction outperformed the individual measures in predicting MAFLD in the subgroups. Additionally, the model better predicted female MAFLD. Adding waist circumference and or BMI to this model improves predictive performance. CONCLUSION: Our study showed that the AGTR, AIP, and UHR had strong MAFLD predictive value, and their combination can increase MAFLD predictive performance. They also performed better in females.

Does elevated CO2 enhance the arsenic uptake by rice? Yes or maybe: Evidences from FACE experiments.

Elevated CO2 (eCO2) strongly affects rice yield and quality in arsenic (As) paddy soils. However, understanding of the As accumulation in rice under coupled stress of eCO2 and soil As is still limited while data are scarce. It greatly limits the prediction for future rice safety. This study investigated the As uptake by rice grown in different As paddy soils under two CO2 conditions (ambient and ambient +200 µmol mol-1) in the free-air CO2 enrichment (FACE) system. Results showed that eCO2 lowered soil Eh at the tillering stage and caused higher concentrations of dissolved As and Fe2+ in soil pore water. Compared with the control, the increased As transfer abilities in rice straws under eCO2 contributed to the higher As accumulation in rice grains, and their total As concentrations were increased by 10.3-31.2%. Besides, the increased amounts of iron plaque (IP) under eCO2 failed to effectively inhibit the As uptake by rice due to the difference in critical stage between As immobilized by IP (mainly in maturing stage) and uptake by rice roots (about 50% contribution before filling stage). Risk assessments suggest that eCO2 enhanced the human health risks of As intake from rice grains produced in low-As paddy soils (<30 mg kg-1). In order to alleviate the As threats to rice under eCO2, we consider that proper soil drainage before filling stage to improve soil Eh can serve as an effective way to reduce As uptake by rice. Pursuing appropriate rice varieties to reduce the As transfer ability may be the other positive strategy.

Elevated CO2 and temperature under future climate change increase severity of rice sheath blight.

Sheath blight (ShB), caused by Rhizoctonia solani, is one of the major threats to rice (Oryza sativa L.) production. However, it is not clear how the risk of rice ShB will respond to elevated CO2 and temperature under future climate change. Here, we conducted, field experiments of inoculated R. solani under combinations of two CO2 levels (ambient and enriched up to 590 µmol mol-1) and two temperature levels (ambient and increased by 2.0°C) in temperature by free-air CO2 enrichment (T-FACE) system for two cultivars (a susceptible cultivar, Lemont and a resistant cultivar, YSBR1). Results indicate that for the inoculation of plants with R. solani, the vertical length of ShB lesions for cv. Lemont was significantly longer than that for cv. YSBR1 under four CO2 and temperature treatments. The vertical length of ShB lesions was significantly increased by elevated temperature, but not by elevated CO2, for both cultivars. The vertical length of ShB lesions under the combination of elevated CO2 and elevated temperature was increased by 21-38% for cv. Lemont and by -1-6% for cv. YSBR1. A significant increase in MDA level was related to a significant increase in the vertical length of ShB lesions under the combination of elevated CO2 and elevated temperature. Elevated CO2 could not compensate for the negative effect of elevated temperature on yield of both cultivars under future climate change. Rice yield and biomass were further decreased by 2.0-2.5% and 2.9-4.2% by an increase in the severity of ShB under the combination of elevated CO2 and elevated temperature. Thus, reasonable agronomic management practices are required to improve both resistance to ShB disease and grain yield for rice under future climate change.

Effects of elevated CO2 on the Cd uptake by rice in Cd-contaminated paddy soils.

The rising atmospheric CO2 is a major driver for climate change, directly affects rice production. Cadmium (Cd) in paddy soils also serves as a persistent concern. Currently, few studies consider the rice response to coupled stresses of elevated CO2 (eCO2) and soil Cd. Experimental evidence understanding the effects and mechanisms of eCO2 on Cd uptake by rice is lacking yet. In a free-air CO2 enrichment (FACE) system, a 3-year pot experiment was conducted to explore the Cd uptake by rice under two CO2 conditions (ambient and ambient + 200 µmol·mol-1) using combinations of in-situ Cd-contaminated soils and associated rice varieties. Results showed that more low-crystalline Fe oxides (Feh) in iron plaque (IP) were deposited on root surface with the increased dissolved Fe2+ due to lower soil redox status under eCO2. The Cd accumulation in rice was hindered due to more Cd associated with Feh (Feh-Cd) rather than uptake by roots. Taken together, the relative effects of eCO2 on Cd uptake by rice were consistent across years under different Cd-contaminated soils. Our findings will help to better understand the Cd uptake by rice under future climate conditions, and thus push the development of climate-crop-soil models and accurate prediction for food security.

Activated Stellate Cell Paracrine HGF Exacerbated Pancreatic Cancer Cell Ferroptosis Resistance.

As a refractory tumor, pancreatic carcinoma is more vulnerable to ferroptosis, a novel regulated cell death mode. However, the exact role of pancreatic stellate cells (PSCs) in pancreatic cancer ferroptosis is still unclear. Using the coculture system, we revealed that activated PSCs promote pancreatic cancer cell ferroptosis resistance. Mechanistically, activated PSCs secreted HGF, which further activated the HGF receptor, c-MET, in pancreatic cancer cells, prevented lipid peroxidation, and ultimately triggered pancreatic cancer cell ferroptosis resistance in vitro and in vivo. TCGA and GEPIA databases also revealed a strong correlation between c-MET and antiferroptosis indicators. Our study supplied the evidence for the cross-talk between activated PSCs and pancreatic cancer cells in ferroptosis, which suggested a strategy to inhibit PSC paracrine signaling for preventing pancreatic carcinoma ferroptosis resistance.

Disaggregation of Ploidy, Gender, and Genotype Effects on Wood and Fiber Traits in a Diploid and Triploid Hybrid Poplar Family.

Triploid breeding based on unilateral sexual polyploidization is an effective approach for genetic improvement of Populus, which can integrate heterosis and ploidy vigor in an elite variety. However, the phenotypic divergence of unselected allotriploids with the same cross-combination remains poorly understood, and the contributions of ploidy, gender, and genotype effects on phenotypic variation are still unclear. In this study, wood and fiber traits, including basic density (BD), lignin content (LC), fiber length (FL), fiber width (FW), and fiber length/width (FL/W), were measured based on a 10-year-old clonal trial, including full-sib diploid and triploid hybrids of (Populus pseudo-simonii × P. nigra 'Zheyin3#') × P. × beijingensis, and contributions of ploidy, gender, and genotype effects on the variation of these traits, were disaggregated to enhance our understanding of triploid breeding. We found a significant phenotypic variation for all measured traits among genotypes. All the wood and fiber traits studied here underwent strong clonal responses with high repeatabilities (0.55-0.76). The Pearson's correlation analyses based on the best linear unbiased predictors (BLUPs) revealed that BD was significantly positively correlated with FL (r = 0.65, p = 0.030), suggesting that BD could be improved together with FL during triploid breeding. The FL of the triploids was significantly larger than that of the diploids (p < 0.001), suggesting that ploidy strongly affected the variation of FL traits. The difference between females and males was not significant for any measured trait, implying that gender might not be a major factor for variation in these traits. Further analyses of variance components showed that genotype dominantly contributed to the variation of BD, LC, and FW traits (with 54, 62, and 53% contributions, respectively) and ploidy contributed strongly to variation in FL and FL/W (77 and 50%, respectively). The genetic coefficient of variation (CVG) of triploids for each trait was low, suggesting that it is necessary to produce many triploids for selection or to use different Populus species as parents. Our findings provide new insights into the genetic effects of ploidy, gender, and genotype on wood and fiber traits within a full-sib poplar family, enhancing the understanding of the triploid breeding program of Populus.

Curvicladiellapaphiopedili sp. nov. (Hypocreales, Nectriaceae), a new species of orchid (Paphiopedilum sp.) from Guizhou, China.

Background: An asexual fungus, collected from diseased leaves of Paphiopedilum sp. from Guizhou Province, China, and based on the phylogenetic analyses and morphological characters, it was identified as a new species in Curvicladiella. The genus Curvicladiella are recorded for the first time for China. New information: The morphology of Curvicladiellapaphiopedili sp. nov. is characterised by penicillate conidiophores with a stipe, dull, tapering towards the apex, the curved stipe extension and cylindrical conidia. In the phylogenetic analyses of combined cmdA, his3, ITS, LSU, tef1 and tub2 sequence data, this taxon was clustered as sister to Curvicladiellacignea within Nectriaceae.

Lipid metabolism of cancer stem cells.

Cancer stem cells (CSCs), also termed cancer-initiating cells, are a special subset of cells with high self-replicating and self-renewing abilities that can differentiate into various cell types under certain conditions. A number of studies have demonstrated that CSCs have distinct metabolic properties. The reprogramming of energy metabolism enables CSCs to meet the needs of self-renewal and stemness maintenance. Increasing evidence supports the view that alterations in lipid metabolism, including an increase in fatty acid (FA) uptake, de novo lipogenesis, formation of lipid droplets and mitochondrial FA oxidation, are involved in CSC regulation. In the present review, the metabolic characteristics of CSCs, particularly in lipid metabolism, were summarized. In addition, the potential mechanisms of CSC lipid metabolism in treatment resistance were discussed. Given their significance in cancer biology, targeting CSC metabolism may serve an important role in future cancer treatment.

Exogenous HMGB1 Promotes the Proliferation and Metastasis of Pancreatic Cancer Cells.

Background: Exogenous HMGB1 plays a vital role in tumor recurrence, and HMGB1 is ubiquitous in the tumor microenvironment. However, the mechanism of action is still unclear. We investigated the role of exogenous HMGB1 in tumor proliferation and metastasis using human SW1990 and PANC-1 cells after radiotherapy and explored the possible molecular mechanism. Materials and Methods: Residual PANC-1 cells and SW1990 cells were isolated after radiotherapy. The supernatant after radiotherapy was collected. The relative expression of HMGB1 was evaluated by Enzyme Linked Immunosorbent Assay (ELISA). Electron microscope (EMS) was used to collect the images of pancreatic cancer cells pre and post radiotherapy treatment. The proliferation of pancreatic cancer cells which were treated with different radiation doses was measured by Carboxy Fluorescein Succinimidyl Ester (CFSE). The migration rates of pancreatic cancer cells were measured by wound healing assays. Subsequently, the expression of related proteins was detected by Western Blot. In vivo, the subcutaneous pancreatic tumor models of nude mice were established, and therapeutic capabilities were tested. Results: HMGB1 was detected in the supernatant of pancreatic cancer cells after radiotherapy. The results of CFSE showed that exogenous HMGB1 promotes the proliferation and metastasis of pancreatic cancer cells. The western blot results showed activation of p-GSK 3ß and up-regulation of N-CA, Bcl-2, and Ki67 in response to HMGB1 stimulation, while E-CA expression was down-regulated in pancreatic cancer cells in response to HMGB1 stimulation. In vivo, ethyl pyruvate (EP, HMGB1 inhibitor) inhibits the growth of tumors and HMGB1 promotes the proliferation of tumors after radiation. Conclusion: Radiotherapy induces HMGB1 release into the extracellular space. Exogenous HMGB1 promotes the proliferation and metastasis of PANC-1 cells and SW1990 cells by activation of p-GSK 3ß which is mediated by Wnt pathway.

Branched-chain amino acid aminotransferase 2 regulates ferroptotic cell death in cancer cells.

Ferroptosis, a form of iron-dependent cell death driven by cellular metabolism and iron-dependent lipid peroxidation, has been implicated as a tumor-suppressor function for cancer therapy. Recent advance revealed that the sensitivity to ferroptosis is tightly linked to numerous biological processes, including metabolism of amino acid and the biosynthesis of glutathione. Here, by using a high-throughput CRISPR/Cas9-based genetic screen in HepG2 hepatocellular carcinoma cells to search for metabolic proteins inhibiting ferroptosis, we identified a branched-chain amino acid aminotransferase 2 (BCAT2) as a novel suppressor of ferroptosis. Mechanistically, ferroptosis inducers (erastin, sorafenib, and sulfasalazine) activated AMPK/SREBP1 signaling pathway through iron-dependent ferritinophagy, which in turn inhibited BCAT2 transcription. We further confirmed that BCAT2 as the key enzyme mediating the metabolism of sulfur amino acid, regulated intracellular glutamate level, whose activation by ectopic expression specifically antagonize system Xc- inhibition and protected liver and pancreatic cancer cells from ferroptosis in vitro and in vivo. On the contrary, direct inhibition of BCAT2 by RNA interference, or indirect inhibition by blocking system Xc- activity, triggers ferroptosis. Finally, our results demonstrate the synergistic effect of sorafenib and sulfasalazine in downregulating BCAT2 expression and dictating ferroptotic death, where BCAT2 can also be used to predict the responsiveness of cancer cells to ferroptosis-inducing therapies. Collectively, these findings identify a novel role of BCAT2 in ferroptosis, suggesting a potential therapeutic strategy for overcoming sorafenib resistance.

Seasonal variations in the relationship between sun-induced chlorophyll fluorescence and photosynthetic capacity from the leaf to canopy level in a rice crop.

Photosynthetic capacity (leaf maximum carboxylation rate, Vcmax) is a critical parameter for accurately assessing carbon assimilation by plant canopies. Recent studies of sun-induced chlorophyll fluorescence (SIF) have shown potential for estimating Vcmax at the ecosystem level. However, the relationship between SIF and Vcmax at the leaf and canopy levels is still poorly understood. In this study, we investigated the dynamic relationship between SIF and Vcmax and its controlling factors using SIF and CO2 response measurements in a rice paddy. We found that SIF and its yield (SIFy) were strongly correlated with Vcmax during the growing season, although the relationship varied with plant growth stages. After flowering, SIFy showed a stronger relationship with Vcmax than SIF flux at both the leaf and canopy levels. Further analysis suggested that the divergence of the link between SIF and Vcmax from leaf to canopy are the result of changes in canopy structure and leaf physiology, highlighting that these need to be considered when interpreting the SIF signal across spatial scales. Our results provide evidence that remotely sensed SIF observations can be used to track seasonal variations in Vcmax at the leaf and canopy levels.

Ultrasound Elastic Parameters Predict Central Lymph Node Metastasis of Papillary Thyroid Carcinoma.

BACKGROUND: This study aimed to explore the new factors that can predict central lymph node metastasis (CLNM) of papillary thyroid carcinoma (PTC) independently from ultrasound characteristics, elastic parameters, and endocrine indicators. METHODS: A total of 391 patients with PTC undergoing thyroidectomy and prophylactic central lymph node dissection from January 2017 to June 2019 were collected to determine the independent predictors of CLNM by single-factor and multivariate logistic regression analysis. RESULTS: Multivariate logistic regression analysis showed 9 independent predictors of CLNM, age, male, tumors in the middle or lower poles (without tumors in the isthmus), tumors in the isthmus, multiple tumors, and maximum tumor diameter measured by ultrasound, microcalcification, visible surrounding blood flow signal, and the maximum value of elastic modulus (Emax).We used the aforementioned factors to establish a scoring prediction model: predictive score Y(P) = 1/[1 + exp (1.444 + 0.084 ∗ age - 0.834 ∗ men - 0.73 ∗ multifocality - 2.718 ∗ tumors in the isthmus - 0.954 ∗ tumors in the middle or lower poles - 0.086 ∗ tumor maximum diameter - 1.070 ∗ microcalcification - 0.892 ∗ visible surrounding blood flow signal - 0.021 ∗ Emax)]. The area under the curve of the receiver operating characteristic was 0.827. It was found that 0.524 was the highest index of Youden, and the best cutoff value for predicting CLNM. When Y(P)≥0.524, the risk of CLNM in patients with PTC is predicted to be high. Predictive accuracy was 78.5% and 72.4% in the internal validation group and 78.6% in the external validation group. CONCLUSIONS: These data indicate that the scoring prediction model could provide a scientific and quantitative way to predict CLNM in patients with PTC.

Zirconium ion modified melamine sponge for oil and organic solvent cleanup.

Hydrophilic melamine sponge is transferred into hydrophobic melamine sponge by immersing the commercial melamine sponge cubes into zirconium oxychloride aqueous solution and followed by a simple dry process. The hydrophobicity transformation is assigned to the complex bonds constructed by the Zr4+ ions and N atoms, thus reducing the surface polarity. The modified melamine sponge presents excellent absorption capacities toward various oils and organic solvents (70-181 g/g). Its contact angle with water can reach 130° or more, and displays good oil-water selectivity for both heavy oil and light oil. Besides, the sponge has stable chemical properties and good recyclability. This work presents a facile and low-cost method for fabrication of hydrophobic materials that might be used for the cleanup of oil spills.

Highly transparent graphene oxide/cellulose composite film bearing ultraviolet shielding property.

This work investigates the ultraviolet (UV) shielding property of composite films synthesized with graphene oxide (GO) nanosheets and regenerated cellulose. Regenerated cellulose was prepared from ZnCl2/CaCl2/GO solution. The GO sheets presented a homogenous dispersion in the film matrix. The incorporation of GO endows the cellulose films with improved UV shielding capacity. When GO loading reaches 2%, the UVA and UVB blocking percentages are 66.7% and 54.2%, respectively. Moreover, the composite films had excellent visible light transmittance. The resulting films possess promising applications as protective and packing materials.

Endoplasmic reticulum stress, an important factor in the development of Parkinson's disease.

Similar to other types of neuronal degeneration, Parkinson's disease (PD) is characterized by the aggregation of a pathological protein, α-synuclein. The endoplasmic reticulum (ER) is the principal site of protein synthesis, quality control and degradation. Genetic mutants, environmental insults and other factors disturb ER balance and induce the accumulation of misfolded/unfolded proteins, which initiate ER stress and disturb normal cell function. ER stress perturbs Ca2+ homeostasis and initiates the activation of autophagy and inflammasomes, which have been identified as risk factors for the development of PD. However, the mechanisms by which ER stress contributes to the processed of PD pathogenesis and development remain unclear. This review summarizes current knowledge of ER stress and highlights the principal role of ER stress in PD pathogenesis which may help reveal novel sight to illustrate the pathomechanism of PD.

Metal nanoparticle-embedded bacterial cellulose aerogels via swelling-induced adsorption for nitrophenol reduction.

Bacterial cellulose aerogels were chosen as the substrate for supporting and dispersing metal nanoparticles (Cu and Ni). During the catalyst preparation, we found that the swelling-induced adsorption process could control the metal size and dispersion simultaneously. Cu and Ni nanoparticles were confined into the bacterial cellulose network and SEM results demonstrated that Cu particles had a smaller size compared to Ni particles. The metal-loaded catalysts exhibited good catalytic performance in the 4-nitrophenol reduction reaction. The optimal sample (BC-Cu-0.5) prepared with 0.5 wt% CuSO4 solution could complete the reduction process within 8 min. Besides, the BC-Cu-0.5 catalyst showed excellent stability and reusability. This study sheds light on the deposition of metal particles and provides a wider application for bacterial cellulose.

Dedifferentiation process driven by radiotherapy-induced HMGB1/TLR2/YAP/HIF-1α signaling enhances pancreatic cancer stemness.

Differentiated cancer cells reacquiring stem cell traits following radiotherapy may enrich cancer stem cells and accelerate tumor recurrence and metastasis. We are interested in the mechanistic role of dying cells-derived HMGB1 in CD133- pancreatic cancer cells dedifferentiation following radiotherapy. We firstly confirmed that X-ray irradiation induced differentiation of CD133- pancreatic cancer cells, from either sorted from patient samples or established cell lines, into cancer stem-like cells (iCSCs). Using an in vitro coculture model, X-ray irradiation induced dying cells to release HMGB1, which further promoted CD133- pancreatic cancer cells regaining stem cell traits, such as higher sphere forming ability and expressed higher level of stemness-related genes and proteins. Inhibiting the expression and activity of HMGB1 attenuated the dedifferentiation stimulating effect of irradiated, dying cells on C133- pancreatic cancer cells in vitro and in PDX models. Mechanistically, HMGB1 binding with TLR2 receptor functions in a paracrine manner to affect CD133- pancreatic cancer cells dedifferentiation via activating Hippo-YAP pathway and HIF-1α expression in oxygen independent manner in vitro and in vivo. We conclude that X-ray irradiation induces CD133- pancreatic cancer cell dedifferentiation into a CSC phenotype, and inhibiting HMGB1 may be a strategy to prevent CSC enrichment and further pancreatic carcinoma relapse.