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Background: Hypoxia is an important clinical feature of glioblastoma (GBM), which regulates a variety of tumor processes and is inseparable from radiotherapy. Accumulating evidence suggests that long non-coding RNAs (lncRNAs) are strongly associated with survival outcomes in GBM patients and modulate hypoxia-induced tumor processes. Therefore, the aim of this study was to establish a hypoxia-associated lncRNAs (HALs) prognostic model to predict survival outcomes in GBM. Material and Methods: LncRNAs in GBM samples were extracted from The Cancer Genome Atlas database. Hypoxia-related genes were downloaded from the Molecular Signature Database. Co-expression analysis of differentially expressed lncRNAs and hypoxia-related genes in GBM samples was performed to determine HALs. Six optimal lncRNAs were selected for building HALs models by univariate Cox regression analysis. Results: The prediction model has a good predictive effect on the prognosis of GBM patients. Meanwhile, LINC00957 among the six lncRNAs was selected and subjected to pan-cancer landscape analysis. Conclusion: Taken together, our findings suggest that the HALs assessment model can be used to predict the prognosis of GBM patients. In addition, LINC00957 included in the model may be a useful target to study the mechanism of cancer development and design individualized treatment strategies.

County school education has a profound impact on social class upgrading in China’s rural areas, where teachers are the core actors in this field yet have not been paid enough attention. This study, through ethnography, focuses on county teachers as subjective actors who are embedded in the background of Chinese educational bureaucratic management mode and educational marketization. Under a pressure of college enrolment rates and students’ quality degrading in county high schools, the teachers are facing the situation of being managed both mentally and physically. Teachers’ mind has been highly influenced by Daily Performance, College Entrance Examination Quality Assessment and Title Evaluation Systems. Meanwhile, they have to obey the systems of Punching-in and Homework Review Registration & Supervision to maintain physical presence. However, without hope, these lead to the loss of professional passion of teachers, and teachers show a state of negative emotional labor.

Arabidopsis cryptochrome 1 (CRY1) is an important blue light photoreceptor that promotes photomorphogenesis under blue light. The blue light photoreceptors CRY2 and phototropin 1, and the red/far-red light photoreceptors phytochromes B and A undergo degradation in response to blue and red light, respectively. This study investigated whether and how CRY1 might undergo degradation in response to high-intensity blue light (HBL). We demonstrated that CRY1 is ubiquitinated and degraded through the 26S proteasome pathway in response to HBL. We found that the E3 ubiquitin ligase constitutive photomorphogenic 1 (COP1) is involved in mediating HBL-induced ubiquitination and degradation of CRY1. We also found that the E3 ubiquitin ligases LRBs physically interact with CRY1 and are also involved in mediating CRY1 ubiquitination and degradation in response to HBL. We further demonstrated that blue-light inhibitor of cryptochromes 1 interacts with CRY1 in a blue-light-dependent manner to inhibit CRY1 dimerization/oligomerization, leading to the repression of HBL-induced degradation of CRY1. Our findings indicate that the regulation of CRY1 stability in HBL is coordinated by COP1 and LRBs, which provides a mechanism by which CRY1 attenuates its own signaling and optimizes photomorphogenesis under HBL.

Empirical data from a qualitative study of tourism industry by a local development zone in a China county is analysed in the context of the theories of McDonaldization, consumer society, and postem...

Brassinosteroids (BR) play diverse roles in the regulation of plant growth and development. BR promotes plant growth by triggering cell division and expansion. However, the effect of exogenous BR application on the leaf size and expansion of tobacco is unknown. Tobacco seedlings are treated with different concentrations of exogenous 2,4-epibrassinolide (EBL) [control (CK, 0 mol L(−1)), T1 (0.5 × 10(−7) mol L(−1)), and T2 (0.5 × 10(−4) mol L(−1))]. The results show that T1 has 17.29% and T2 has 25.99% more leaf area than control. The epidermal cell area is increased by 24.40% and 17.13% while the number of epidermal cells is 7.06% and 21.06% higher in T1 and T2, respectively, relative to control. So the exogenous EBL application improves the leaf area by increasing cell numbers and cell area. The endogenous BR (7.5 times and 68.4 times), auxin (IAA) (4.03% and 25.29%), and gibberellin (GA(3)) contents (84.42% and 91.76%) are higher in T1 and T2, respectively, in comparison with control. Additionally, NtBRI1, NtBIN2, and NtBES1 are upregulated showing that the brassinosteroid signaling pathway is activated. Furthermore, the expression of the key biosynthesis-related genes of BR (NtDWF4), IAA (NtYUCCA6), and GA(3) (NtGA3ox-2) are all upregulated under EBL application. Finally, the exogenous EBL application also upregulated the expression of cell growth-related genes (NtCYCD3;1, NtARGOS, NtGRF5, NtGRF8, and NtXTH). The results reveal that the EBL application increases the leaf size and expansion by promoting the cell expansion and division through higher BR, IAA, and GA(3) contents along with the upregulation of cell growth-related genes. The results of the study provide a scientific basis for the effect of EBL on tobacco leaf growth at morphological, anatomical, biochemical, and molecular levels. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12298-021-00971-x.

Teachers face a high degree of risk when disciplining students in contemporary China. Under the guidance of risk society theory, based on a qualitative study of teachers at a county town high school in Southwest China, this paper finds that, in the context of shifting responsibility for education from family to school and inequal risk distribution system in school, teachers become a primary risk taker. The culture of the teacher as a service provider with unlimited responsibilities and the institution of “No Accident” in daily management supported by schools and local government is constructing the sense of risk in teachers. The consequences of risky events are unbearable for teachers in most cases, so they have to adopt limited discipline strategies with a focus on risk avoidance. Reconceptualizing cooperative family–school relations and constructing a reasonable risk allocation mechanism in school would be the keys to eliminating teachers’ conception of discipline risk.

Sugar is involved in initiating leaf senescence. However, its regulatory role, especially as a signal in the senescence process, is unclear. Therefore, this study was designed to illustrate how sugar stimulates the onset of leaf senescence and controls sugar homeostasis through the T6P-SnRK (sucrose non-fermenting (SNF)-related kinase) and HXK (hexokinase) signaling pathways. We used a leaf disc system detached from fully expanded leaves of Nicotiana tabacum cv. K326 and designed a time-course study (days 3, 5, 7, and 9) with exogenously gradient concentrations (0, 30, 60, 90, 120, and 150 mM) of sucrose (Suc) treatment to identify how Suc application affects sugar metabolism and induces senescence. Our results revealed that early decreases of Fv/Fm and increases in electrolyte leakage responded to Suc on day 3. Furthermore, a substantial increase in lipid peroxidation and up-regulated expression of senescence marker genes (NtSAG12) (except 60 mM on day 3) responded sequentially by day 5. The glucose, G6P, and HXK contents were first induced by Suc on day 3 and then repressed from day 5 to day 7. However, exogenous Suc treatment significantly improved the TPS content and the subsequent precursor T6P from day 3 to day 7. Following exogenous Suc treatments, the transcript level of NtSnRK1 was markedly down-regulated from day 3 to day 7. On the other hand, a linear regression analysis demonstrated that the T6P-NtSnRK1 signaling pathway was strongly associated with senescence initiation, and was accompanied by membrane degradation and NtCP1/NtSAG12 up-regulation by day 3. The T6P-NtSnRK1 signaling pathway experienced membrane and chloroplast degradation by day 5. HXK functioned as a metabolic enzyme promoting Glc-G6P and as a Glc sensor, accelerating the initiation of senescence through the HXK-dependent pathway by repressing PSII by day 3 and the senescence process through the Glycolytic pathway by day 7. These physiological, biochemical, and molecular analyses demonstrate that exogenous Suc regulates T6P accumulation, inducing senescence through the NtSnRK signaling pathway. These results illustrate the role of Suc and the transition of the sugar signaling pathway during the progression of senescence initiation.

Background Thymocyte selection‐associated high mobility group box (TOX) plays a crucial role on the development of innate immunity and tumor microenvironment. This study aims to explore the prognostic potential of TOX and comprehensively analyze the correlations between TOX, immune infiltration, and T cells function in diverse cancers particularly lung adenocarcinoma (LUAD). Methods TIMER was used to analyze TOX expression in different cancers. Potential prognostic value of TOX was evaluated by the PrognoScan, Kaplan‐Meier Plotter, and GEPIA2. The relationships between TOX, immune infiltration, and related gene marker sets were analyzed by TIMER and GEPIA2. Single‐cell RNA‐seq for T cells in LUAD was analyzed to further investigate the correlations between TOX expression and different T cells populations. Results TOX downregulates in most of the cancer types and correlates with poor prognosis in LUAD. TOX shows significant impacts on survival of LUAD with early stage, ever‐smoking, or low‐TMB status. Increased TOX expression positively correlates with high immune infiltration levels in most of the immune cells and functional T cells including exhausted T cells. Moreover, multiple key genes of exhausted T cells comprising PD‐1, TIM‐3, TIGHT, and CXCL13 have remarkable interaction with TOX. Specifically, TOX is observed with high enrichment in exhausted CD4+ and CD8+ T cells populations in single‐cell RNA‐seq analysis for LUAD. Conclusion TOX is a prognosis‐related biomarker for multiple cancer types especially LUAD. Increased TOX expression significantly increase immune infiltration levels in most of the immune cells comprising CD8+ T cells, CD4+ T cells, mast cells, and functional T cells. Moreover, we verified that TOX highly correlates with exhausted T cells and is probable a critical regulator promoted T cells exhaustion in LUAD. Detection of TOX expression could help to predict prognosis and regulating TOX expression in exhausted T cells may offer a novel strategy in maximizing immunotherapy efficacy for LUAD., In this study, we identified TOX is a prognosis‐related biomarker for multiple cancer types especially lung adenocarcinoma and correlate with immune infiltration levels in most of immune cells and functional T cells. Meanwhile, TOX is observed with high enrichment in exhausted CD4+ and CD8+ T cells populations in single‐cell RNA‐seq analysis. Our findings suggested that detecting expression level of TOX may help to predict prognosis and regulating TOX expression in exhausted T cells may provide a potential strategy in maximizing immunotherapy efficacy for lung adenocarcinoma patients.

Due to its great convenience for inspection of pipelines under special conditions, leakage localization with a single acoustic emission (AE) sensor has attracted increasing attention. However, the reported study achieves a good accuracy of leakage localization only for short source-to-sensor distance. In this work, an improved method for pipeline leakage localization with a single sensor is proposed based on modal acoustic emission and empirical mode decomposition with Hilbert transform (EMD-HT). The pipeline is considered as a cylindrical shell to compute the velocity dispersion curves of different guided wave modes. A criterion to select the specific wave modes for leakage localization is presented with the consideration of frequency matching, dispersive properties, and the modes’ confusing possibilities. Integrating the empirical mode decomposition (EMD) with wavelet transform (WT), the framework of the proposed method is developed. A number of field experiments were performed on a steel pipe with a continuous leakage source. The results show that using the proposed method, a maximum relative leakage localization error of 7.32% for the source-to-sensor distances from 0 to 33 meters (m) can be achieved, which is much improved than those of the reported method. With the capacity of precisely locating the leakage source within the range of 33m for each side of the sensor, the proposed method provides a promising way to make the AE technique more suitable for in-situ inspection of pipelines.

Purpose: The efficacy of PD-1/PD-L1 checkpoint blockade immunotherapy in recurrence glioblastoma remains unclear. The aim of this meta-analysis is to access the survival outcomes of immunotherapy in these patients.Methods: A comprehensive electronic literature search of PubMed, Web of Science, Embase and Cochrane Library was conducted up to August 22, 2021. The main evaluation data were the overall survival (OS) rate at 12 months and the progression-free survival (PFS) rate at 6 months. The secondary evaluation data was the incidence of serious adverse events(grade 3 or greater AEs). The study was performed using R“meta” package.Results: Seven studies met the inclusion criteria, which totally contained 343 participants. The 12-month OS in recurrent GBM were 40% (95% CI: 89.2% -95.1%), while the 6-month PFS 16.0% (95%CI 9%–23%). The overall incidence of adverse reactions is approximately 25% [0.13; 0.40], the toxicity of immunotherapy was acceptable.Conclusions: Compared with survival data for BEV (bevacizumab) /BPC(best physician's choice chemotherapy) treatment, immunotherapy seemed to improve overall survival and progression-free survival, Meanwhile, the toxicity of immunotherapy was tolerable. Further randomised controlled clinical studies are needed to confirm these findings. And also suggests that the earlier we apply anti-PD-1/PDL-1 immunotherapy to patients with relapsed glioblastoma, the greater the benefit may be.

This study is aimed at summarizing and analyzing the epidemiological characteristics and prognostic risk factors of patients with a pelvic fracture with perineal injury. The clinical data of 153 patients with pelvic fracture with perineal injury treated in our hospital from January 2012 to June 2021 were analyzed retrospectively. The data of sex, age, injury mechanism, pelvic fracture type, shock index (SI), perineal wound depth, concomitant injury, total hospital stay, and death were collected by the electronic medical record system. Among the 153 patients, there were 94 males and 59 females, with an average age of (43.2 ± 16.8) years. The cases were mainly concentrated into two age groups: 20–29 years old and 50–59 years old. In a year, pelvic fractures were mainly concentrated in 1–2 months and 11–12 months. In terms of injury time, there were mainly two periods of time in a day: 10 : 00～12 : 00 and 15 : 00～18 : 00. The MOTS-RTS scores of the patients in the undead group and the dead group were (7.12 ± 1.52), (2.69 ± 0.96), ISS scores were (27.36 ± 15.84), (61.32 ± 7.08), GCS scores were (12.84 ± 3.69), (4.13 ± 1.25), APACH II scores were (12.87 ± 8.84), (32.41 ± 6.98), and SOFA scores were (6.68 ± 5.87), (17.12 ± 3.12). The MOTS-RTS and GCS scores of the nondeath group were significantly higher, while the ISS score, APACH II score, SOFA score, and shock index were significantly lower. The overall mortality rate of 153 patients was 13.7%. The average area of perineal trauma in undead and dead patients was (54.5 ± 113.52) cm2 and (262.63 ± 300.84) cm2, respectively. The average depth of perineal trauma was (9.63 ± 7.22) cm and (16.23 ± 10.13) cm, respectively. The larger the area of perineal injury and the deeper the depth of perineal trauma, the worse their prognosis. Cox multivariate analysis showed that complications, MOTS-RTS score, ISS score, GCS score, perineal trauma area, and perineal trauma depth were independent risk factors affecting the prognosis of patients with pelvic fracture with perineal injury. Most of the patients with pelvic fracture complicated with perineal injury are 20–29 years old and 50–59 years old. The more serious the perineal injury is, the higher the mortality is. The main causes of death are refractory hemorrhagic shock and infection.

Glioma is the most common malignancy of the nervous system with high mortality rates. The MS4A family members have been reported as potential prognostic biomarkers in several cancers; however, the relationship between the MS4A family and glioma has not been clearly confirmed. In our study, we explored the prognostic value of MS4As as well as their potential pro-cancer mechanisms of glioma. Using bioinformatics analysis methods based on the data from public databases, we found that the expression of MS4A4A, MS4A4E, MS4A6A, MS4A7, TMEM176A, and TMEM176B was significantly overexpressed in glioma tissues compared with that of normal tissues. The Kaplan–Meier method and Cox proportional hazards models revealed that high levels of MS4As can be associated with a poorer prognosis; TMEM176A, TMEM176B, age, WHO grade, and IDH status were identified as independent prognostic factors. Enrichment analysis predicted that MS4As were related to tumor-related pathways and immune response, which might regulate the process of MS4As promoting tumorigenesis. Additionally, we analyzed the correlations of MS4A expression with immune cells and immune inhibitory molecules. Finally, data from the cell culture suggested that knockdown of the TMEM176B gene contributes to the decreased proliferation and migration of glioma cells. In conclusion, MS4A4A, MS4A4E, MS4A6A, MS4A7, TMEM176A, and TMEM176B may act as potential diagnostic or prognostic biomarkers in glioma and play a role in forming the immune microenvironment in gliomas.

Secondary wall-associated NAC (SWN) genes are a subgroup of NAC (NAM, ATAF, and CUC) transcription factors (TF) that play a key role in regulating secondary cell wall biosynthesis in plants. However, this gene family has not been systematically characterized, and their potential roles in response to hormones are unknown in Nicotiana tabacum. In this study, a total of 40 SWN genes, of which 12 from Nicotiana tomentosiformis, 13 from Nicotiana sylvestris, and 15 from Nicotiana tabacum, were successfully identified. The 15 SWNs from Nicotiana tabacum were further classified into three groups, namely, vascular-related NAC domain genes (NtVNDs), NAC secondary wall thickening promoting factor genes (NtNSTs), and secondary wall-associated NAC domain genes (NtSNDs). The protein characteristic, gene structure, and chromosomal location of 15 NtSWNs (also named Nt1 to Nt15) were also analyzed. The NtVND and NtNST group genes had five conserved subdomains in their N-terminal regions and a motif (LP[Q/x] L[E/x] S[P/A]) in their diverged C- terminal regions. Some hormones, dark and low-temperature related cis-acting elements, were significantly enriched in the promoters of NtSWN genes. A comprehensive expression profile analysis revealed that Nt4 and Nt12 might play a role in vein development. Others might be important for stem development. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) revealed that in the NtNST group, genes such as Nt7, Nt8, and Nt13 were more sensitive than the genes in NtVND and NtSND groups under abiotic stress conditions. A transactivation assay further suggested that Nt7, Nt8, and Nt13 showed a significant transactivation activity. Overall, SWN genes were finally identified and characterized in diploid and tetraploid tobacco, revealing new insights into their evolution, variation, and homology relationships. Transcriptome, cis-acting element, qRT-PCR, and transactivation assay analysis indicated the roles in hormonal and stress responses, which provided further resources in molecular mechanism and genetic improvement.

Phytochrome B (phyB), the primary red light photoreceptor, promotes photomorphogenesis in Arabidopsis by interacting with the basic helix-loop-helix transcriptional factor PIF3 and inducing its phosphorylation and degradation. Heterotrimeric G proteins are known to regulate various developmental processes in plants and animals. In Arabidopsis, the G-protein β subunit AGB1 is known to repress photomorphogenesis. However, whether and how phyB and AGB1 coordinately regulate photomorphogenesis are largely unknown. Here we show that phyB physically interacts with AGB1 in a red light-dependent manner and that AGB1 interacts directly with PIF3. Moreover, we demonstrate that the AGB1-PIF3 interaction inhibits the association of PIF3 with phyB, leading to reduced phosphorylation and degradation of PIF3, whereas the phyB-AGB1 interaction represses the association of PIF3 with AGB1, resulting in enhanced phosphorylation and degradation of PIF3. Our results suggest that phyB and AGB1 antagonistically regulate PIF3 stability by dynamically interacting with each other and PIF3. This dynamic mechanism may allow plants to balance phyB and G-protein signaling to optimize photomorphogenesis.

Cryptochromes are blue light photoreceptors that mediate various light responses in plants and mammals. In Arabidopsis (Arabidopsis thaliana), cryptochrome 1 (CRY1) mediates blue light-induced photomorphogenesis, which is characterized by reduced hypocotyl elongation and enhanced anthocyanin production, whereas gibberellin (GA) signaling mediated by the GA receptor GA-INSENSITIVE DWARF1 (GID1) and DELLA proteins promotes hypocotyl elongation and inhibits anthocyanin accumulation. Whether CRY1 control of photomorphogenesis involves regulation of GA signaling is largely unknown. Here, we show that CRY1 signaling involves the inhibition of GA signaling through repression of GA-induced degradation of DELLA proteins. CRY1 physically interacts with DELLA proteins in a blue light-dependent manner, leading to their dissociation from SLEEPY1 (SLY1) and the inhibition of their ubiquitination. Moreover, CRY1 interacts directly with GID1 in a blue light-dependent but GA-independent manner, leading to the inhibition of the interaction between GID1 with DELLA proteins. These findings suggest that CRY1 controls photomorphogenesis through inhibition of GA-induced degradation of DELLA proteins and GA signaling, which is mediated by CRY1 inhibition of the interactions of DELLA proteins with GID1 and SCFSLY1, respectively.

Cadmium (Cd) is known as one of the most hazardous elements in the environment and a persistent soil constraint toxic to all flora and fauna. In this study, we conducted physiological, biochemical, and transcriptomic analyses of Nicotiana rustica (N. rustica) and Nicotiana tabacum (N. tabacum) treated with CdCl2 to know the underlying molecular mechanisms of Cd accumulation. As a result, N. rustica had more dry weight than N. tabacum. Additionally, N. rustica accumulated higher Cd concentration (69.65 times), Cd2+ influx (1.32-fold), glutathione S-transferases (GST) enzyme activity (2.54 times), GSH/GSSG (oxidized form of GSH) ratio, increase of superoxide dismutase and CAT and a lower H2 O2 and superoxide (O2 •- ) accumulation in their roots than N. tabacum. Cd mainly distributed in the cytoplasm of both species and N. rustica had a significant proportion in the cell wall. Furthermore, the transcriptomic analysis revealed 173 and 710 differentially expressed genes (DEGs) between control and Cd-stressed plants in the leaves and roots of N. rustica, while 576 and 1543 DEGs were found in the leaves and roots of N. tabacum, respectively. In N. rustica, phenylpropanoid biosynthesis and phenylalanine metabolism were the most enriched pathways, while GSH metabolism, ATP-binding cassette transporters and phenylpropanoid biosynthesis were the most enriched in N. tabacum. Finally, we found that DEGs related to metal influx, sequestration, remobilization, and chelation were responsible for Cd accumulation. These results indicated that N. rustica accumulated higher Cd content than N. tabacum, suggesting that each species utilized different response mechanism under the same Cd stress conditions. The DEGs identified in this study might lead to the identification of genes or pathways related to Cd regulation. This study identifies important regulators related to Cd accumulation.

BackgroundBefore the introduction of the chemotherapeutic agent methotrexate, radiotherapy (RT) and steroids have been the sole, first-line treatment of primary central nervous system lymphoma (PCNSL). With the application of methotrexate, the role of RT in the treatment of PCNSL has been challenged. MethodsWe performed observation analysis on 2,486 PCNSL patients between 1988 and 2016 from the Surveillance, Epidemiology and End Results (SEER) database. Propensity score matching (PSM) was employed to ensure well-balanced characteristics of two groups of patients who received RT and those who did not receive it. Two randomized controlled trials (RCTs) were pooled to further evaluate the role of consolidation whole-brain radiotherapy (WBRT) in PCNSL. To clarify whether WBRT is necessary for PCNSL, 27 relapsed patients who attained complete response (CR), partial response (PR) or stable disease (SD) during or after first-line treatment without WBRT for newly diagnosed PCNSL in our institution was retrospectively analyzed; the pattern and location of relapse was identified. ResultsAfter matching, there was no statistical difference on survival between the two groups. In patients did not received chemotherapy, RT significantly improved the survival of patients who undergone biopsy (All P < .0001) or subtotal resection (All P < .0001). In particular, RT helped improve survival for patients with other infectious and parasitic diseases including HIV (OIPDH). Pool-analysis shown the better progression free survival (PFS) of patients with WBRT arm compared with no WBRT arm in per-protocol (PP) population (HR 0.71, 95% CI 0.52 to 0.98). In the 27 relapse patients, 17 (63%) had new measurable enhancing lesions at relapse at a spatially distinct site, the remote recurrence after CR was 9/11 (82%), and after PR was 8/15 (53%). Single lesion occurred remote recurrence was 11/13 (85%), while multiple lesions were 7/14 (50%). We also established a novel prediction model with excellent performance to estimate the potential benefit from RT with respect to the end point of overall survival. ConclusionsRT is still an important method in the treatment of PCNSL, which cannot be removed. More precise studies should be carried out to perfect the treatment strategies of the disease.

Tumor-derived exosomes (exo) could modulate the biological behaviors of human umbilical vein endothelial cells (HUVECs). Here, the role of microRNA (miR)-10a-5p-modified gastric cancer (GC) cells-derived exo for HUVECs was studied. GC tissue specimens were collected, and miR-10a-5p and zinc finger MYND-type containing 11 (ZMYND11) levels were determined. HUVECs interfered with ZMYND11 or miR-10a-5p-related oligonucleotides. Exo was extracted from GC cells (HGC-27 exo), and miR-10a-5p mimic-modified HGC-27 exo were co-cultured with HUVECs. HUVECs viability, migration and angiogenesis were evaluated, and miR-10a-5p/ZMYND11 crosstalk was explored. It was observed that GC patients had raised miR-10a-5p and reduced ZMYND11, and miR-10a-5p negatively mediated ZMYND11 expression. Suppression of miR-10a-5p or overexpression of ZMYND11 inhibited viability, migration and tube formation ability of HUVECs. Notably, miR-10a-5p mimic-modified HGC-27 exo enhanced the viability, migration and tube formation ability of HUVECs, but this effect was impaired after up-regulating ZMYND11. In summary, miR-10a-5p from GC cells-derived exo enhances viability and migration of HUVECs by suppressing ZMYND11., Graphical abstract

To improve the capability of radar detection in a time-varying maritime environment, an algorithm was proposed and analyzed in this paper that can be applied to determine the shape and scale parameters of the K-distributed model using the radar parameters and environmental information under the context of K-distributed sea clutter, and improved the original algorithm to improve the accuracy of the parameter estimation algorithm. Furthermore, a CFAR detector capable of identifying the characteristics of sea clutter distribution was developed. It can estimate the parameters of K-distributed model for sea clutter in real time using both radar parameters and environmental perception information, thus improving the accuracy of clutter background estimation. When the false alarm rate reaches a certain level, the adaptive threshold factor can be obtained for the CFAR detector proposed in this paper, thus improving the effectiveness of control on the CFAR detector. As suggested by the simulation results, the proposed method outperforms the CFAR detector with fixed parameters in the capability of detection and robustness under the context of K-distributed clutter.

OBJECTIVE: To explore the protective effect of vitamin E (VE) against radiation injury of hippocampal neurons in mice and explore the possible mechanism. METHODS: Cultured HT-22 and U251 cells with or without exposure to 8 Gy irradiation were treated with VE (200 μmol/L for 24 h), ferroptosis inhibitor (ferrostatin-1, 5 μmol/L for 24 h), apoptosis inhibitor (ZVAD-FMK, 2 μmol/L), or necroptosis inhibitor (100 μmol/L). MTT assay was used to evaluate the cell viability after the treatments, and reduced glutathione (GSH), malondialdehyde (MDA), lipid reactive oxygen species (lipid ROS), and intracellular iron ion levels were detected for assessment of ferroptosis. The mice exposed to 16 Gy irradiation with or without vitamin E (500 U/kg) treatment for 6 weeks were assessed for behavioral changes and cognitive functions using Morris water maze test. RESULTS: Treatment with VE significantly promoted the cell survival following irradiation in HT-22 cells (P < 0.05) but not in U251 cells (P > 0.05). Ferrostatin-1, but not ZVAD or the necroptosis inhibitor, promoted the survival of HT-22 cells following the irradiation. Exposure to irradiation significantly increased ferroptosis-related oxidative stress level in HT-22 cells, manifested by decreased GSH level and increased MDA, lipid ROS and intracellular iron ion levels (P < 0.05); treatment with VE and ferrostatin-1 both obviously reversed radiation-induced ferroptosis-related oxidative stress in the cells (P < 0.05). In Morris water maze test, the mice with radiation exposure showed obviously increased exploration time and distance (P < 0.05), which were significantly decreased after treatment with VE (P < 0.05). CONCLUSION: Vitamin E reduces radiation injury by inhibiting ferroptosis in the hippocampal neurons in mice.

The efficacy of hypofractionated radiotherapy (HFRT) in glioblastoma (GBM) without age restrictions remains unclear. The aim of this meta-analysis is to access the survival outcomes of HFRT in these patients.A comprehensive electronic literature search of PubMed, Web of Science and Cochrane Library was conducted up to June 1, 2020. The main evaluation data were the overall survival (OS) rate at 12 months and 24 months and the progression-free survival (PFS) rate at 6 and 12 months. The secondary evaluation data was the incidence of radionecrosis and adverse events. The study was performed using R "meta" package.Eleven studies met the inclusion criteria, which totally contained 484 participants. The 12-month OS and 24-month OS rate of HFRT in GBM were 71.3% and 34.8%, while the 6-month PFS and 12-month rate were 74.0% and 40.8%. Compared to low-BED (biological equivalent dose) schedules (78Gy), high-BED schedules may increase survival benefit both in PFS-6 (P=0.003) and PFS-12 (P=0.011), while the difference did not show on OS. Different dose per fraction had no significant effect on both OS and PFS. Incidence of radionecrosis was 14.2%. Although the overall incidence of adverse reactions cannot be quantified, the toxicity of HFRT was acceptable.Compared with survival data for standard treatment, HFRT seemed to improve overall survival and progression-free survival, while high BED schedules may future increase benefit on PFS. Meanwhile, the toxicity of HFRT was tolerable. Further randomised controlled clinical studies are needed to confirm these findings.

Cryptochromes are photolyase-like, blue-light (BL) photoreceptors found in various organisms. Arabidopsis (Arabidopsis thaliana) cryptochromes (CRYs; CRY1, and CRY2) mediate many light responses including photoperiodic floral initiation. Cryptochromes interact with COP1 and SPA1, causing the stabilization of CONSTANS (CO) and promotion of FLOWERING LOCUS T (FT) transcription and flowering. The AP2-like transcriptional factor TOE1 negatively regulates FT expression and flowering by indirectly inhibiting CO transcriptional activation activity and directly binding to FT. Here, we demonstrate that CRY1 and CRY2 physically interact with TOE1 and TOE2 in a BL-dependent manner in flowering regulation. Genetic studies showed that mutation of TOE1 and TOE2 partially suppresses the late-flowering phenotype of cry1 cry2 mutant plants. BL-triggered interactions of CRY2 with TOE1 and TOE2 promote the dissociation of TOE1 and TOE2 from CO, resulting in alleviation of their inhibition of CO transcriptional activity and enhanced transcription of FT. Furthermore, we show that CRY2 represses TOE1 binding to the regulatory element within the Block E enhancer of FT. These results reveal that TOE1 and TOE2 act as downstream components of CRY2, thus partially mediating CRY2 regulation of photoperiodic flowering through modulation of CO activity and FT transcription.

A good smart contract can provide safe and reliable services to efficiently solve real-world problems. However, smart contracts written by developers create potential security vulnerabilities and can result in huge economic losses. Therein, detecting potential vulnerabilities in smart contracts plays an important role in maintaining the security of the blockchain. There are a series of schemes work on finding bugs in smart contracts, such as Oyente and ContractFuzzer, etc. However, existing solutions only address several types of security vulnerabilities on a single platform. In this paper, we propose a general framework to detect potential vulnerabilities of smart contracts. In order to abstract the execution logic of smart contracts, we need to convert them into control flow graphs. We use the Ullmann algorithm to discover vulnerabilities from these graphs. Also, we give a running example to illustrate how our framework can be used to detect the reentrancy problems written by solidity.

Cryptochromes (CRYs) are blue light photoreceptors that mediate a variety of light responses in plants and animals, including photomorphogenesis, flowering, and circadian rhythms. The signaling mechanism by which Arabidopsis thaliana cryptochromes CRY1 and CRY2 promote photomorphogenesis involves direct interactions with COP1, a RING motif-containing E3 ubiquitin ligase, and its enhancer SPA1. Brassinosteroid (BR) is a key phytohormone involved in the repression of photomorphogenesis, and here, we show that the signaling mechanism of Arabidopsis CRY1 involves the inhibition of BR signaling. CRY1 and CRY2 physically interact with BES1-INTERACTING MYC-LIKE1 (BIM1), a basic helix-loop-helix protein. BIM1, in turn, interacts with and enhances the activity of BRI1-EMS SUPPRESSOR1 (BES1), a master transcription factor in the BR signaling pathway. In addition, CRY1 and CRY2 interact specifically with dephosphorylated BES1, the physiologically active form of BES1 that is activated by BR in a blue light-dependent manner. The CRY1-BES1 interaction leads to both the inhibition of BES1 DNA binding activity and the repression of its target gene expression. Our study suggests that the blue light-dependent, BR-induced interaction of CRY1 with BES1 is a tightly regulated mechanism by which plants optimize photomorphogenesis according to the availability of external light and internal BR signals.

Loss of hair cells occurs after radiotherapy, which is a major treatment modality for head and neck cancers. In the lateral line neuromasts of zebrafish, hair cells regenerate rapidly from supporting cells after damage from ototoxins. To investigate hair cell regeneration after radiation damage, zebrafish larvae were exposed to radiation, and hair cells were counted and cell proliferation was detected in neuromasts. After irradiation exposure, cell proliferation was inhibited in neuromasts and the number of supporting cells remained stable. There was a gradual loss of hair cells in lateral line neuromasts, which was not followed by regeneration. An activator of Wnt signaling (1-azakenpaullone) promoted robust regeneration of hair cells in irradiated neuromasts. By the quantitative real-time PCR and immunofluorescence, dkk2, an inhibitory Wnt ligand, was identified upregulated in irradiated neuromasts. Accelerating the death process of irradiated hair cells by treatment with neomycin also restored the regenerative capacity of neuromasts. However, a proportion of the new hair cells died within several days after forced regeneration and baseline activity of proliferation in supporting cells remained unimproved. In conclusion, these findings suggested that radiation suppressed hair cell regeneration in zebrafish lateral line neuromasts through inhibition of Wnt signaling in supporting cells possibly by secreting anti-proliferation factors like dkk2. Maintaining a healthy supporting cell pool is vital for regeneration of hair cells.

Arabidopsis CRY1 and phyB are the primary blue and red light photoreceptors mediating blue and red light inhibition of hypocotyl elongation, respectively. Auxin is a pivotal phytohormone involved in promoting hypocotyl elongation. CRY1 and phyB interact with and stabilize auxin/indole acetic acid proteins (Aux/IAAs) to inhibit auxin signaling. The present study investigated whether photoreceptors might interact directly with Auxin Response Factors (ARFs) to regulate auxin signaling. Protein-protein interaction studies demonstrated that CRY1 and phyB interact physically with ARF6 and ARF8 through their N-terminal domains in a blue and red light-dependent manner, respectively. Moreover, the N-terminal DNA-binding domain of ARF6 and ARF8 is involved in mediating their interactions with CRY1. Genetic studies showed that ARF6 and ARF8 act partially downstream from CRY1 and PHYB to regulate hypocotyl elongation under blue and red light, respectively. Chromatin immunoprecipitation-PCR assays demonstrated that CRY1 and phyB mediate blue and red light repression of the DNA-binding activity of ARF6 and ARF6-target gene expression, respectively. Altogether, the results herein suggest that the direct repression of auxin-responsive gene expression mediated by the interactions of CRY1 and phyB with ARFs constitutes a new layer of the regulatory mechanisms by which light inhibits auxin-induced hypocotyl elongation.

Purpose Although increasing evidence has shown that long noncoding RNAs play an important regulatory role in carcinogenesis and tumor progression, little is known about the role of small nucleolar RNA host gene 18 (SNHG18) in cancer. The goal of this study was to investigate the expression of SNHG18 and its clinical significance in glioma. Methods and Materials Differences in the lncRNA expression profile between M059K and M059J cells were assessed by lncRNA expression microarray analysis. The expression and localization of SNHG18 in glioma cells or tissues was evaluated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH), respectively. the clinical associations of SNHG18 in glioma was evaluated by qRT-PCR, ISH and immunohistochemistry. The role of SNHG18 in glioma radiosensitivity was evaluated by colony formation assays, immunofluorescence, Western blot and tumor growth inhibition study. Results The present study investigated the clinical associations of SNHG18 and its role in glioma. Our results showed that the expression of SNHG18 was remarkably upregulated in clinical glioma tissues compared with normal brain tissues. SNHG18 expression was associated with the clinical tumor grade and correlated negatively with isocitrate dehydrogenase 1 mutation. In addition, knockdown of SNHG18 with short hairpin RNA suppressed the radioresistance of glioma cells, and transgenic expression of SNHG18 had the opposite effect. Furthermore, xenograft tumors grown from cells with SNHG18 deletion were more radiosensitive than tumors grown from control cells. Further studies revealed that SNHG18 promotes radioresistance by inhibiting semaphorin 5A and that inhibition of semaphorin 5A expression abrogated the radiosensitizing effect caused by SNHG18 deletion. Conclusions Our findings provide new insights into the role of SNHG18 in glioma and suggest its potential as a target for glioma therapy.

Proper timing of flowering is essential for reproduction of plants. Although it is well known that both light and gibberellin (GA) signaling play critical roles in promoting flowering in Arabidopsis thaliana, whether and how they are integrated to regulate flowering remain largely unknown. Here, we show through biochemical studies that DELLA proteins physically interact with CONSTANS (CO). Furthermore, the interaction of CO with NF-YB2 is inhibited by the DELLA protein, RGA. Our findings suggest that regulation of flowering by GA signaling in leaves under long days is mediated, at least in part, through repression of DELLA proteins on CO, providing a molecular link between DELLA proteins, key components in GA signaling pathway, and CO, a critical flowering activator in photoperiod signaling pathway.

Based on the effective radiological responses, bevacizumab (BEV) has been widely used in the treatment of recurrent high-grade glioma. Although the current standard dose is 5 mg/kg/week, the optimal dosage of BEV is controversial, as few dose-response studies have been performed in recent years. Therefore, we conducted a meta-analysis to explore the value of reduced-dose bevacizumab versus standard-dose bevacizumab in recurrent high-grade glioma treatment.Three major electronic databases (PubMed, EMBASE and the Cochrane Library) were searched for eligible documents published before February 2020. Literature on low-dose bevacizumab versus conventional dose in progressive high-grade glioma was included, and the endpoints of eligible researches should be progression-free survival (PFS) and overall survival (OS). All available data were collected and then analyzed with Stata software.Four cohort studies were evaluated, including 552 patients (reduced-dose BEV group: 257, standard-dose BEV group: 295). Low dose BEV seems to slightly improve survival compared to conventional dose as HR1 indicates a protective effect, but no significant differences in OS (HR 0.77; 95 % CI 0.53-1.10; P = 0.151) and PFS (HR 0.66; 95 % CI 0.37-1.20; P = 0.175) were found between the two groups in this study.Reduced-dose bevacizumab schedule resulted in similar OS and PFS to standard-dose bevacizumab in recurrent high-grade glioma, with less side effects and less cost of treatment. Therefore, low-dose bevacizumab represents a promising therapeutic option for recurrent high-grade glioma patients. Further prospective randomized trials are needed to confirm our results.

The immobilization strategy of cell-specific aptamers is of great importance for studying the interaction between a cell and its aptamer. However, because of the difficulty of studying living cell, there have not been any systematic reports about the effect of immobilization strategies on the binding ability of an immobilized aptamer to its target cell. Because atomic force spectroscopy (AFM) could not only be suitable for the investigation of living cell under physiological conditions but also obtains information reflecting the intrinsic properties of individuals, the effect of immobilization strategies on the interaction of aptamer/human hepatocarcinoma cell Bel-7404 was successively evaluated using AFM here. Two different immobilization methods, including polyethylene glycol immobilization method and glutaraldehyde immobilization method were used, and the factors, such as aptamer orientation, oligodeoxythymidine spacers and dodecyl spacers, were investigated. Binding events measured by AFM showed that a similar unbinding force was obtained regardless of the change of the aptamer orientation, the immobilization method, and spacers, implying that the biophysical characteristics of the aptamer at the molecular level remain undisturbed. However, it showed that the immobilization orientation, immobilization method, and spacers could alter the binding probability of aptamer/Bel-7404 cell. Presumably, these factors may affect the accessibility of the aptamer toward its target cell. These results may provide valuable information for aptamer sensor platforms including ultrasensitive biosensor design.

The effects of medicine on the biomolecular interaction have been given increasing attention in biochemistry and affinity-based analytics since the environment in vivo is complex especially for the patients. Herein, myoglobin, a biomarker of acute myocardial infarction, was used as a model, and the medicine effects on the interactions of myoglobin/aptamer and myoglobin/antibody were systematically investigated using atomic force microscopy (AFM) for the first time. The results showed that the average binding force and the binding probability of myoglobin/aptamer almost remained unchanged after myoglobin-modified gold substrate was incubated with promazine, amoxicillin, aspirin, and sodium penicillin, respectively. These parameters were changed for myoglobin/antibody after the myoglobin-modified gold substrate was treated with these medicines. For promazine and amoxicillin, they resulted in the change of binding force distribution of myoglobin/antibody (i.e., from unimodal distribution to bimodal distribution) and the increase of binding probability; for aspirin, it only resulted in the change of the binding force distribution, and for sodium penicillin, it resulted in the increase of the average binding force and the binding probability. These results may be attributed to the different interaction modes and binding sites between myoglobin/aptamer and myoglobin/antibody, the different structures between aptamer and antibody, and the effects of medicines on the conformations of myoglobin. These findings could enrich our understanding of medicine effects on the interactions of aptamer and antibody to their target proteins. Moreover, this work will lay a good foundation for better research and extensive applications of biomolecular interaction, especially in the design of biosensors in complex systems.

Light is a key environmental cue that inhibits hypocotyl cell elongation through the blue and red/far-red light photoreceptors cryptochrome- and phytochrome-mediated pathways in Arabidopsis. In contrast, as a pivotal endogenous phytohormone auxin promotes hypocotyl elongation through the auxin receptors TIR1/AFBs-mediated degradation of AUX/IAA proteins (AUX/IAAs). However, the molecular mechanisms underlying the antagonistic interaction of light and auxin signaling remain unclear. Here, we report that light inhibits auxin signaling through stabilization of AUX/IAAs by blue and red light-dependent interactions of cryptochrome 1 (CRY1) and phytochrome B with AUX/IAAs, respectively. Blue light-triggered interactions of CRY1 with AUX/IAAs inhibit the associations of TIR1 with AUX/IAAs, leading to the repression of auxin-induced degradation of these proteins. Our results indicate that photoreceptors share AUX/IAAs with auxin receptors as the same direct downstream signaling components. We propose that antagonistic regulation of AUX/IAA protein stability by photoreceptors and auxin receptors allows plants to balance light and auxin signals to optimize their growth.

Effects of medicine on the biomolecular interaction have been given extensive attention in biochemistry and biomedicine because of the complexity of the environment in vivo and the increasing opportunity of exposure to medicine. Herein, the effect of lidocaine on the interactions of C-reactive protein (CRP) with its aptamer and antibody under different temperature was investigated through dynamic force spectroscopy (DFS). The results revealed that lidocaine could reduce the binding probabilities and binding affinities of the CRP-aptamer and the CRP-antibody. An interesting discovery was that lidocaine had differential influences on the dynamic force spectra of the CRP-aptamer and the CRP-antibody. The energy landscape of the CRP-aptamer turned from two activation barriers to one after the treatment of lidocaine, while the one activation barrier in energy landscape of the CRP-antibody almost remained unchanged. In addition, similar results were obtained for 25 and 37 °C. In accordance with the result of molecular docking, the reduction of binding probabilities might be due to the binding of lidocaine on CRP. Additionally, the alteration of the dissociation pathway of the CRP-aptamer and the change of binding affinities might be caused by the conformational change of CRP, which was verified through synchronous fluorescence spectroscopy. Furthermore, differential effects of lidocaine on the interactions of CRP-aptamer and CRP-antibody might be attributed to the different dissociation processes and binding sites of the CRP-aptamer and the CRP-antibody and different structures of the aptamer and the antibody. This work indicated that DFS provided information for further research and comprehensive applications of biomolecular interaction, especially in the design of biosensors in complex systems.

The renin-angiotensin system (RAS) is a principal determinant of arterial blood pressure and fluid and electrolyte balance. RAS component dysregulation was recently found in some malignancies and correlated with poor patient outcomes. However, the exact mechanism of local RAS activation in tumors is still unclear. Here, we find that the local angiotensin II predominantly exists in the hypoxic regions of tumor formed by nasopharyngeal carcinoma CNE2 cells and breast cancer MDA-MB-231 cells, where these tumor cells autocrinely produce angiotensin II by a chymase-dependent rather than an angiotensin converting enzyme-dependent mechanism. We further demonstrate in nasopharyngeal carcinoma CNE2 and 5–8F cells that this chymase-dependent effect is mediated by increased levels of lactate, a by-product of glycolytic metabolism. Finally, we show that the enhanced angiotensin II plays an important role in the intracellular accumulation of HIF-1α of hypoxic nasopharyngeal carcinoma cells and mediates the radiation-resistant phenotype of these nasopharyngeal carcinoma cells. Thus, our findings reveal the critical role of hypoxia in producing local angiotensin II by a lactate-chymase-dependent mechanism and highlight the importance of local angiotensin II in regulating radioresistance of hypoxic tumor cells.

Radioresistance is a major challenge during the treatment of breast cancer. A further understanding of the mechanisms of radioresistance could provide strategies to address this challenge. In our study, we compared the expression of miR-200c in four distinct breast cancer cell lines: two representative basal cancer cells (MDA-MB-231 and BT549) vs. two representative luminal cancer cells (MCF-7 and BT474). The results revealed practically lower expression of miR-200c in the two basal cancer cell lines and higher expression of miR-200c in luminal cancer cells compared to the normal breast epithelial cell line MCF-10A. Ectopic expression of miR-200c in MDA-MB-231 cells inhibited irradiation-induced autophagy and sensitized the breast cancer cells to irradiation. We also identified UBQLN1 as a direct functional target of miR-200c involved in irradiation-induced autophagy and radioresistance. In 35 human breast cancer tissue samples, we detected an inverse correlation between the expression of miR-200c vs. UBQLN1 and LC3. These results indicate that the identified miR-200c/UBQLN1-mediated autophagy pathway may help to elucidate radioresistance in human breast cancer and might represent a therapeutic strategy.