PREX2 contributes to radiation resistance by inhibiting radiotherapy-induced tumor immunogenicity via cGAS/STING/IFNs pathway in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) lacks established biomarkers or molecular targets for predicting or enhancing radiation response. Phosphatidylinositol-3,4,5-triphosphate-dependent Rac exchange factor 2 (PREX2) exhibits intricate implications in tumorigenesis and progression. Nevertheless, the precise role and underlying mechanisms of PREX2 in CRC radioresistance remain unclear. METHODS: RNA-seq was employed to identify differentially expressed genes between radioresistant CRC cell lines and their parental counterparts. PREX2 expression was scrutinized using Western blotting, real-time PCR, and immunohistochemistry. The radioresistant role of PREX2 was assessed through in vitro colony formation assay, apoptosis assay, comet assay, and in vivo xenograft tumor models. The mechanism of PREX2 was elucidated using RNA-seq and Western blotting. Finally, a PREX2 small-molecule inhibitor, designated PREX-in1, was utilized to enhance the efficacy of ionizing radiation (IR) therapy in CRC mouse models. RESULTS: PREX2 emerged as the most significantly upregulated gene in radioresistant CRC cells. It augmented the radioresistant capacity of CRC cells and demonstrated potential as a marker for predicting radioresistance efficacy. Mechanistically, PREX2 facilitated DNA repair by upregulating DNA-PKcs, suppressing radiation-induced immunogenic cell death, and impeding CD8+ T cell infiltration through the cGAS/STING/IFNs pathway. In vivo, the blockade of PREX2 heightened the efficacy of IR therapy. CONCLUSIONS: PREX2 assumes a pivotal role in CRC radiation resistance by inhibiting the cGAS/STING/IFNs pathway, presenting itself as a potential radioresistant biomarker and therapeutic target for effectively overcoming radioresistance in CRC.

Upper bound for permanent orientation of symmetric-top molecule induced by linearly polarized electric fields.

Many symmetric top molecules are among the most important polyatomic molecules. The orientation of a polyatomic molecule is a challenging task, which is at the heart of its quantum control and crucial for many subsequent applications in various fields. Most recent studies focus on the temporary orientation achieved via the quantum revivals. In this study, we reveal the underlying mechanism behind the observed permanent orientation and discuss strategies for a higher degree of permanent orientation. By a careful analysis of symmetry and unitary, it is possible to estimate an upper bound of ⟨⟨cosθ⟩⟩<(2-2)/4≈0.1464 for a molecule in its thermal equilibrium states using a linear field. We show that this bound can be reached for an oblate symmetric-top molecule in the high temperature limit. To demonstrate different possible schemes, we take CHCl3 as an example. Simply with designed microwave fields, one can permanently orient CHCl3 with a degree of ⟨cos θ⟩ ≈ 0.045. We show that this value can be significantly increased by adding one or more pump pulses.

Manipulation of the high-order harmonic generation in monolayer hexagonal boron nitride by two-color laser field.

We theoretically investigate the high-order harmonic generation (HHG) of the monolayer hexagonal boron nitride by two-color laser pulses, based on the ab initio time-dependent density-functional theory. We find that the waveform of the two-color laser field can dramatically control the harmonic spectrum. The two-color laser field can enhance the harmonic radiation more efficiently than the monochromatic pulse laser with the same incident energy. We investigate the influence of incident laser pulse parameters on the harmonic radiation, such as the relative phase of the two-color field, the amplitude ratio between component electric fields, and the laser orientation. We show that the HHG spectrum is controlled by both the electric field and the vector potential. The electronic band structure and the laser-matter energy transfer play an important role in determining the laser polarization for optimal HHG in the hBN crystal. Our work supplies a scheme to manipulate HHGs in two-dimensional materials and provides a potential methodology for the generation of intense extreme-ultraviolet pulses.

Ascorbic acid and hydrocortisone synergistically inhibit septic organ injury via improving oxidative stress and inhibiting inflammation.

BACKGROUND: The current study aimed to investigate the effect of the combination of ascorbic acid (AscA) and hydrocortisone (Hyd) on septic organ injury and its potential mechanism. METHOD: Sepsis was induced in mice by a single intraperitoneal injection of lipopolysaccharides. RESULTS: AscA and Hyd combined showed more effective protection of the injured liver and kidney in septic mice by decreasing alanine aminotransferase, aspartate aminotransferase, serum urea nitrogen, and serum creatinine and ameliorating pathological manifestations than Hyd or AscA alone. AscA showed a mild inhibitory effect on the secretion of proinflammatory cytokines (tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6)). However, Hyd showed a weak regulatory effect on septic oxidative stress markers (malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px)). However, the combination of AscA and Hyd showed a more powerful inhibitory effect on the septic inflammatory response and oxidative stress than Hyd or AscA alone by decreasing TNF-α, IL-1ß, and IL-6 and regulating MDA, SOD, and GSH. In an in vitro study, cotreatment of RAW 264.7 macrophages with Hyd and AscA sharply reduced reactive oxygen species (ROS) generation and synergistically inhibited TNF-α, IL-1ß, and IL-6 secretion, which could be abolished by additional stimulation with the ROS donor 3-nitropropionic acid (3-NP). As expected, cotreatment of macrophages with Hyd and AscA synergistically inhibited the activation of p38 MAPK and p-p65, and the effect could be reversed by additional stimulation with 3-NP. CONCLUSIONS: AscA and Hyd synergistically protect the kidney and liver from injury by inhibiting the inflammatory response and oxidative stress. The powerful inhibitory effects of AscA on oxidative stress contribute to the synergistic anti-inflammatory action.

Baseline Sensitivity and Control Efficacy of Two Quinone Outside Inhibitor Fungicides, Azoxystrobin and Pyraclostrobin, Against Ustilaginoidea virens.

Rice false smut caused by the filamentous fungus Ustilaginoidea virens is a devastating grain disease in rice. Fungicides have been an important measure for the control of this disease. In this study, baseline sensitivities of 179 isolates of U. virens to the quinone outside inhibitor (QoI) fungicides azoxystrobin and pyraclostrobin were established. The distribution of the 50% effective concentration (EC50) values of each fungicide was unimodal. The frequency distribution of logarithmically transformed EC50 values fit or fit closer to a normal distribution. The ranges of EC50 values for azoxystrobin and pyraclostrobin were 0.001 to 0.864 and 0.001 to 0.569 µg/ml, with means and standard errors of the mean values of 0.203 ± 0.012 and 0.079 ± 0.006 µg/ml, respectively. There was a statistically significant and moderately positive correlation (n = 100, r = 0.469, P = 0.001) in sensitivity between these two fungicides. No cross-resistance was found between azoxystrobin, pyraclostrobin, and carbendazim or sterol demethylation inhibitor fungicides. Each fungicide had a significantly higher mean preventive efficacy compared with its curative efficacy. Field assays showed that the control efficacy of pyraclostrobin against rice false smut was greater than that of azoxystrobin. Pyraclostrobin had the best control of rice false smut in three rice varieties, with the control efficacy ranging from 81.5 to 95.5%, whereas azoxystrobin decreased the disease index by 64.1 to 69.2% under the same conditions. These results provide us a reference point in the management of U. virens and future QoI fungicide resistance monitoring programs.

Nanosheet-Facilitated Spray Delivery of dsRNAs Represents a Potential Tool to Control Rhizoctonia solani Infection.

Rhizoctonia solani is one of the important pathogenic fungi causing several serious crop diseases, such as maize and rice sheath blight. Current methods used to control the disease mainly depend on spraying fungicides because there is no immunity or high resistance available in crops. Spraying double-strand RNA (dsRNA) for induced-gene silencing (SIGS) is a new potentially sustainable and environmentally friendly tool to control plant diseases. Here, we found that fluorescein-labelled EGFP-dsRNA could be absorbed by R. solani in co-incubation. Furthermore, three dsRNAs, each targeting one of pathogenicity-related genes, RsPG1, RsCATA, and RsCRZ1, significantly downregulated the transcript levels of the target genes after co-incubation, leading to a significant reduction in the pathogenicity of the fungus. Only the spray of RsCRZ1 dsRNA, but not RsPG1 or RsCATA dsRNA, affected fungal sclerotium formation. dsRNA stability on leaf surfaces and its efficiency in entering leaf cells were significantly improved when dsRNAs were loaded on layered double hydroxide (LDH) nanosheets. Notably, the RsCRZ1-dsRNA-LDH approach showed stronger and more lasting effects than using RsCRZ1-dsRNA alone in controlling pathogen development. Together, this study provides a new potential method to control crop diseases caused by R. solani.

Two-Electron Interference in Strong-Field Ionization of He by a Short Intense Extreme Ultraviolet Laser Pulse.

Double ionization of helium by a single intense (above 10^{18} W/cm^{2}) linearly polarized extreme ultraviolet laser pulse is studied by numerically solving the full-dimensional time-dependent Schrödinger equation. For the laser intensities well beyond the perturbative limit, novel gridlike interference fringes are found in the correlated energy spectrum of the two photoelectrons. The interference can be traced to the multitude of two-electron wave packets emitted at different ionization times. A semianalytical model for the dressed two-photon double ionization is shown to qualitatively account for the interference patterns in the joint energy spectrum. Similar signatures of interferences between transient induced time-delayed ionization bursts are expected for other atomic and molecular multielectron systems.

Photon Momentum Transfer in Single-Photon Double Ionization of Helium.

We theoretically and experimentally investigate the photon momentum transfer in single-photon double ionization of helium at various large photon energies. We find that the forward shifts of the momenta along the light propagation of the two photoelectrons are roughly proportional to their fraction of the excess energy. The mean value of the forward momentum is about 8/5 of the electron energy divided by the speed of light. This holds for fast and slow electrons despite the fact that the energy sharing is highly asymmetric and the slow electron is known to be ejected by secondary processes of shake off and knockout rather than directly taking its energy from the photon. The biggest deviations from this rule are found for the region of equal energy sharing where the quasifree mechanism dominates double ionization.

Proposal for Measuring Electron Displacement Induced by a Short Laser Pulse.

In laser-matter interaction, most previous studies have focused on the change of the electron momentum induced by the external fields. Here, we theoretically investigate the electron displacement induced by an ultrashort pulse, whose precise waveform is hard to determine experimentally. We propose and numerically demonstrate a scheme to accurately measure the electron displacement using a ruler formed by the interfering spirals in the photoelectron momentum distribution generated by two oppositely circularly polarized pulses. The scheme is robust against the focusing volume effects and the jitter of the carrier envelope phase of the two circular pulses. The ability to measure the electron displacement by an arbitrary pulse may pave the way to quantitative control of the charge migration in matter on the scale of Ångström.

Accurate in situ Measurement of Ellipticity Based on Subcycle Ionization Dynamics.

Elliptically polarized laser pulses (EPLPs) are widely applied in many fields of ultrafast sciences, but the ellipticity (ϵ) has never been in situ measured in the interaction zone of the laser focus. In this Letter, we propose and realize a robust scheme to retrieve the ϵ by temporally overlapping two identical counterrotating EPLPs. The combined linearly electric field is coherently controlled to ionize Xe atoms by varying the phase delay between the two EPLPs. The electron spectra of the above-threshold ionization and the ion yield are sensitively modulated by the phase delay. We demonstrate that these modulations can be used to accurately determine ϵ of the EPLP. We show that the present method is highly reliable and is applicable in a wide range of laser parameters. The accurate retrieval of ϵ offers a better characterization of a laser pulse, promising a more delicate and quantitative control of the subcycle dynamics in many strong field processes.

[Modulation effect of Acanthopanax senticosus polysaccharides through inflammatory cytokines in protecting immunological liver-injured mice].

The aim of this paper was to discuss the protective effect and mechanism of Acanthopanax senticosus polysaccharides( ASPs) on immunological liver injury caused by conanavalin A( Con A). BALB/c mice were randomly divided into seven groups: control group,model group( Con A),low-,medium-,and high-dose( 36. 25,72. 5,145 mg·kg~(-1)) ASPs groups,bifendate( 200 mg·kg~(-1),positive drug) group and pyrrolidinedithiocarbamate( PDTC,NF-κB inhibitor,200 mg·kg~(-1)) group. ASPs groups and bifendate group were given with corresponding drugs by ig administration once daily for 7 d. Control group,model group and PDTC group were given with normal saline by ig administration once daily for 7 d. After the last ig administration,PDTC was given in DTC group by iv administration( 200 mg·kg~(-1)); 0. 5 h after that,Con A( 20 mg·kg~(-1)) was injected via the tail vein to induce immunological liver injury in all the mice except normal control group. The mice were killed 8 h later and their liver tissues were collected for histopathological examination. The contents of nitric oxide( NO),superoxide dismutase( SOD),malondialdehyde( MDA),reduced glutathione( GSHPX),interleukin( IL-1ß) and tumor necrosis factor( TNF-α) in liver tissues were detected by kit assay. Western blot method was used to detect TNF-α,intercellular cell adhesion molecule-1( ICAM-1),inducible nitric oxide synthase( i NOS) and nuclear factor( NF-κB) protein expression in liver tissues. As compared with model group,ASPs not only could reduce the activity of MDA,NO,IL-1ß and TNF-α,but also increase the content of GSH-PX and SOD; at the same time,the protein expression levels of TNF-α,ICAM-1,i NOS and NF-κB were reduced in liver tissues; in addition,inflammatory cell infiltration was alleviated,hepatocyte cytoplasm was loose and swollen,and nuclear condensation and staining were improved. ASPs has a protective effect on immunological liver injury,and the mechanism may be associated with regulating secretion of inflammatory cytokines and the expression of adhesion factor through NF-κB signaling pathway.

Correction to: CBFA2T2 is associated with a cancer stem cell state in renal cell carcinoma.

[This corrects the article DOI: 10.1186/s12935-017-0473-z.].

Synthesis and application of imidazolium-based ionic liquids as extraction solvent for pretreatment of triazole fungicides in water samples.

Five novel ionic liquids (ILs), 1,3-dibutylimidazolium bromide [BBMIm][Br], 1-pentyl-3-butylimidazolium bromide [BPMIm][Br], 1-hexyl-3-butylimidazolium bromide [BHMIm][Br], 1,1'-(butane-1,4-diyl)bis(3-butylimidazolium) bromide [C4(BMIm)2][Br2], and 1,1'-(butane-1,4-diyl)bis(3-methylimidazolium) bromide [C4(MIm)2][Br2], were prepared and used in situ to react with bis(trifluoromethane)sulfonamide lithium salt to extract the myclobutanil, tebuconazole, cyproconazole, and prothioconazole from water samples. The results showed that mono-cationic ILs had much better recovery than dicationic ILs, and mono-imidazolium IL bearing butyl groups at N-1 and N-3 sites had the best recovery. When the length of the alkyl substituent group was more than four carbons at N-3 site, the recovery decreased with increase of alkyl chain length of 1-butylimidazolium IL. The extraction efficiency order of triazoles from high to low was [BBMIm][Br], [BPMIm][Br], [BHMIm][Br], [BMIm][Br] (1-butyl-3-methylimidazolium bromide), [C4(BMIm)2]Br2, [C4(MIm)2]Br2. An in situ ionic liquid dispersive liquid-liquid microextraction combined with ultrasmall superparamagnetic Fe3O4 was established as a pretreatment method for enrichment of triazole fungicides in water samples by using the synthetic [BBMIm][Br] as the cationic IL and used to detect analytes followed by high-performance liquid chromatography. Under the optimized conditions, the proposed method showed a good linearity within a range of 5-250 µg L-1, with the determination coefficient (r2) varying from 0.998 to 0.999. High mean enrichment factors were achieved ranging from 187 to 323, and the recoveries of the target analytes from real water samples at spiking levels of 10.0, 20.0, and 50.0 µg L-1 were between 70.1% and 115.0%. The limits of detection for the analytes were 0.74-1.44 µg L-1, and the intra-day relative standard deviations varied from 5.23% to 8.65%. The proposed method can be further applied to analyze and monitor pesticides in other related samples. Graphical Abstract The scheme of the in-situ DLLME method for the determination of triazoles using the imidazolium-based ionic liquids.

CBFA2T2 is associated with a cancer stem cell state in renal cell carcinoma.

BACKGROUND: Renal cell carcinoma (RCC) is the most common kidney cancer, accounting for approximately 80-90% of all primary kidney cancer. Treatment for patients with advanced RCC remains unsatisfactory. Rare cancer stem cells (CSCs) are proposed to be responsible for failure of current treatment. METHODS: OncoLnc was used as a tool for interactively exploring survival correlations. Gene manipulation and expression analysis were carried out using siRNA, RT-PCR and Western blotting. Wound healing and invasion assays were used for phenotypical characterization. Aldefluor assay and FACS sorting Sphere culture were used to determine the "stemness" of CSCs. Co-Immunoprecipitation (Co-IP) was used to examine the interaction between OCT4 and CBFA2T2. Student's t-test and Chi square test was used to analyze statistical significance. RESULTS: CBFA2T2 expression can significantly predict the survival of RCC patients. Knocking-down of CBFA2T2 can inhibit cell migration and invasion in RCC cells in vitro, and reduce ALDHhigh CSCs populations. CBFA2T2 expression is necessary for sphere-forming ability and cancer stem cells marker expression in RCC cell lines. CONCLUSIONS: Our data suggest that CBFA2T2 expression correlates with aggressive characteristics of RCC and CBFA2T2 is required for maintenance of "stemness" through regulation of stem cells factors, thereby highlighting CBFA2T2 as a potential therapeutic target for RCC treatment.

The Statistical Determinants of the Speed of Motor Learning.

It has recently been suggested that movement variability directly increases the speed of motor learning. Here we use computational modeling of motor adaptation to show that variability can have a broad range of effects on learning, both negative and positive. Experimentally, we also find contributing and decelerating effects. Lastly, through a meta-analysis of published papers, we verify that across a wide range of experiments, movement variability has no statistical relation with learning rate. While motor learning is a complex process that can be modeled, further research is needed to understand the relative importance of the involved factors.

Short-term efficacy and safety of low-intensity extracorporeal shock wave therapy in erectile dysfunction: a systematic review and meta-analysis.

AIM: The role of low-intensity extracorporeal shock wave therapy (LI-ESWT) in erectile dysfunction (ED) is not clearly determined. The purpose of this study is to investigate the short-term efficacy and safety of LI-ESWT for ED patients. MATERIALS AND METHODS: Relevant studies were searched in Medline, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), WANFANG and VIP databases. Effective rate in terms of International Index of Erectile Function-Erectile Function Domain (IIEF-EF) and Erectile Hardness Score (EHS) at about 1month after LI-ESWT was extracted from eligible studies for meta-analysis to calculate risk ratio (RR) of effective treatment in ED patients treated by LI-ESWT compared to those receiving sham-treatment. RESULTS: Overall fifteen studies were included in the review, of which four randomized controlled trials (RCTs) were for meta-analysis. Effective treatment was 8.31 [95% confidence interval (CI): 3.88-17.78] times more effective in the LI-ESWT group (n=176) than in the sham-treatment group (n=101) at about 1 month after the intervention in terms of EHS, while it was 2.50 (95% CI: 0.74-8.45) times more in the treatment group (n=121) than in the control group (n=89) in terms of IIEF-EF. Nine-week protocol with energy density of 0.09mJ/mm2 and 1500 pluses seemed to have better therapeutic effect than five-week protocol. No significant adverse event was reported. CONCLUSION: LI-ESWT, as a noninvasive treatment, has potential short-term therapeutic effect on patients with organic ED irrespective of sensitivity to PDE5is. Owing to the limited number and quality of the studies, more large-scale, well-designed and long-term follow-up time studies are needed to confirm our analysis.

Virtual Sequential Picture for Nonsequential Two-Photon Double Ionization of Helium.

By using a model based on the second-order time-dependent perturbation theory, we show that the nonsequential two-photon double ionization of He can be understood in a virtual sequential picture: to excite the final double continuum state |k_{1},k_{2}⟩ by absorbing two photons from the ground state |1s^{2},^{1}S_{0}⟩, the single continuum states |1s,k_{1}⟩ and |1s,k_{2}⟩ serve as the dominant intermediate states. This virtual sequential picture is verified by the perfect agreement of the total ionization cross section, respectively, calculated by this model and by the sophisticated numerical solution to the full-dimensional time-dependent Schrödinger equation. This model, without the consideration of the electron correlation in the final double continuum state, works well for a wide range of laser parameters extending from the nonsequential to the sequential regime. The present Letter demonstrates that the electron correlation in the final double continuum state is not important in evaluating the total cross section, while it is indispensable for an accurate computation of a triply differential cross section. In addition, the virtual sequential picture bridges the sequential and nonsequential two-photon double ionization and reveals connections and distinctions between them.

Nonadiabatic Electron Dynamics in Orthogonal Two-Color Laser Fields with Comparable Intensities.

We theoretically investigate the nonadiabatic subcycle electron dynamics in orthogonally polarized two-color laser fields with comparable intensities. The photoelectron dynamics is simulated by exact solution to the 3D time-dependent Schrödinger equation, and also by two other semiclassical methods, i.e., the quantum trajectory Monte Carlo simulation and the Coulomb-corrected strong field approximation. Through these methods, we identify the underlying mechanisms of the subcycle electron dynamics and find that both the nonadiabatic effects and the Coulomb potential play very important roles. The contribution of the nonadiabatic effects manifest in two aspects, i.e., the nonadiabatic ionization rate and the nonzero initial velocities at the tunneling exit. The Coulomb potential has a different impact on the electrons' trajectories for different relative phases between the two pulses.

Resistance to niclosamide in Oncomelania hupensis, the intermediate host of Schistosoma japonicum: should we be worried?

As the currently only available molluscicide, niclosamide has been widely used for snail control for over 2 decades in China. There is therefore a concern about the emergence of niclosamide-resistant snail populations following repeated, extensive use of the chemical. The purpose of this study was to investigate the likelihood of niclosamide resistance in Oncomelania hupensis in China. Active adult O. hupensis snails derived from 20 counties of 10 schistosomiasis-endemic provinces of China, of 10 snails in each drug concentration, were immersed in solutions of 1, 0.5, 0.25, 0.125, 0.063, 0.032, 0.016 and 0.008 mg L-1 of a 50% wettable powder of niclosamide ethanolamine salt (WPN) for 24 and 48 h at 25 °C, and the median lethal concentration (LC50) was estimated. Then, the 24- and 48-h WPN LC50 values were compared with those determined in the same sampling sites in 2002. The results indicated that the 24- and 48-h WPN LC50 values for O. hupensis were not significantly different from those determined in 2002 (P = 0.202 and 0.796, respectively). It is concluded that the current sensitivity of O. hupensis to niclosamide has not changed after more than 2 decades of repeated, extensive application in the main endemic foci of China, and there is no evidence of resistance to niclosamide detected in O. hupensis.