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Radioresistance limits the efficacy of radiotherapy against triple-negative breast cancer (TNBC). Epithelial-to-mesenchymal transition (EMT) is closely related to tumor radioresistance. In this work, we attempted to identify the key EMT-related transcription factor(s) that can induce radioresistance in TNBC cells. A set of 44 EMT transcription factors were analyzed in parental and radioresistant TNBC cell lines. The function of FOXQ1, a differentially expressed transcription factor, was determined in TNBC radioresistance. FOXQ1-interacting proteins were identified by co-immunoprecipitation and mass spectrometry. Compared with parental cells, FOXQ1 was significantly upregulated in radioresistant TNBC cells. Silencing of FOXQ1 increased the radiosensitiviy of radioresistant TNBC cells both in vitro and in vivo. FOXQ1 associated with a nuclear isoform of RAPH1 (named RAPH1-i3) in radioresistant TNBC cells. Overexpression of RAPH1-i3 enhanced TNBC cell proliferation and migration, and most interestingly, induced radioresistance in parental TNBC cells when co-expressed with FOXQ1. Mechanistically, co-expression of RAPH1-i3 and FOXQ1 activated the STAT3 signaling pathway and increased the expression of CCND1, MCL1, Bcl-XL, MMP2, and MMP9. Depletion of RAPH1-i3 impaired the radioresistance of radioresistant TNBC cells. Additionally, RAPH1-i3 upregulation was associated with advanced tumor stage and reduced disease-free survival in TNBC patients. These results collectively show that RAPH1-i3 interacts with FOXQ1 to promote TNBC progression and radioresistance via activation of STAT3 signaling. RAPH1-i3 and FOXQ1 may represent therapeutic targets for overcoming the radioresistance of TNBC.

ZEB1 (a positive enhancer) and KLF5 (a negative silencer) affect transcription factors and play inherently conserved roles in tumorigenesis and multidrug resistance. In humans, the rs2295080T-allele at the mTOR promoter locus has been associated with human cancer risk; however, the 63 bp spacing of another SNP rs2295079 has not been identified. Here, we discovered, for the first time, that rs2295079 (-78C/G) and rs2295080 (-141G/T) formed linkage haplotypes, with Ht1 (-78C/-141G) and Ht2 (-78G/-141T) being dominant, which were associated with distinct susceptibility to breast cancer, response to paclitaxel, and clinical outcomes in breast cancer. At the cellular level, compared with Ht1, Ht2 exhibits a much stronger effect on promoting mTOR expression, leading to enhanced tumor cell growth and strengthened resistance to PTX treatment. Mechanistically, the -141T allele of Ht2 creates a novel ZEB1-binding site; meanwhile, the -78C allele of Ht1 exists as an emerging KLF5-binding site, which synergistically induces promote/inhibit mTOR expression, cell proliferation, and excretion of cytotoxic drugs through the ZEB1/KLF5–mTOR–CCND1/ABCB1 cascade, thereby affecting the response to paclitaxel treatment in vivo and in vitro. Our results suggest the existence of a ZEB1/KLF5–mTOR–CCND1/ABCB1 axis in human cells that could be involved in paclitaxel response pathways and functionally regulate interindividualized breast cancer susceptibility and prognosis.Implications:This study highlights the function of haplotypes of mTOR -78C/-141G and -78G/-141T, in affecting breast cancer susceptibility and paclitaxel response regulated by ZEB1/KLF5–mTOR–CCND1/ABCB1 axis.

Table S1. Frequencies of mTOR promoter polymorphisms in patients with breast cancer and healthy controls Table S2. Frequency distribution of mTOR haplotypes and their associations with the risk of developing breast cancer Table S3. Association of mTOR haplotypes with clinicopathological parameters in patients with breast cancer Table S4. Association of mTOR polymorphisms with clinicopathological parameters in patients with breast cancer Table S5. Association of mTOR polymorphisms with therapeutic response to neoadjuvant chemotherapy (n=131) Figure S1. The impact of forced expression of pcmTOR-Ht1 or pcmTOR-Ht2 on cell proliferation and cell cycle and chemoresistance to PTX in MCF7/PTX cells. Figure S2. Plasma concentration of PTX detection by using UPLC-MS/MS method.

A new generation of high-gradient normal conducting 1.3 GHz RF gun with 1% duty factor was developed to provide a high-quality electron source for superconducting linac driven free-electron lasers like FLASH and European XFEL. Compared to the Gun4 series, Gun5 aims for a ~50% longer RF pulse length (RF pulse duration of up to 1 ms at 10 Hz repetition rate) combined with high gradients (up to ~60 MV/m at the cathode). In addition to the improved cell geometry and cooling concept, the new cavity is equipped with an RF probe to measure and control the amplitude and phase of the RF field inside the gun. The first characterization of Gun5.1 included measurements of RF amplitude and phase stability (pulse-to-pulse and along 1 ms RF pulse). The dark current was measured at various peak power levels. The results of this characterization will be reported.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. TNBC is enriched with breast cancer stem cells (BCSCs), which are responsible for cancer initiation, cancer progression and worse prognosis. Our previous study found that HES1 was overexpressed and promoted invasion in TNBC. However, the role of HES1 in modulating BCSC stemness of TNBC remains unclear. Here, we found that HES1 upregulates Slug both in transcriptional level and in protein level. HES1 also has a positive correlation with Slug expression in 150 TNBC patient samples. TNBC patients with high HES1 and Slug levels show worse prognosis in both progression-free survival and overall survival analyses. Survival analyses indicate that the effects of HES1 on survival prognosis may depend on Slug. Furthermore, we reveal that HES1 is a novel transcriptional activator for Slug through acting directly on its promoter. Meanwhile, HES1 knockdown reduces BCSC self-renewal, BCSC population, and cancer cell proliferation in TNBC, whereas overexpression of Slug restores the oncogenic function of HES1, both in vitro and in vivo, suggesting that HES1 performs its oncogenic role through upregulating Slug. Taken together, HES1 promotes BCSC stemness properties via targeting Slug, highlighting that HES1 might be a novel candidate for BCSC stemness regulation in TNBC and providing new clues for identifying promising prognostic biomarkers and therapeutic targets of TNBC.

Purpose Glioblastoma (GBM) is the most lethal primary cancer in adult central nervous system, and new strategies are desperately needed. The secretory pathway kinase or kinase-like proteins (SPKKPs) have been shown to mediate multiple physiological functions by phosphorylating extracellular proteins and proteoglycans. However, their roles in cancers, especially GBM, remain poorly defined. Methods The least absolute shrinkage and selection operator (LASSO) regression was employed for establishing the SPKKPs signature for IDH wild type (wt) GBM prognosis. Integrative analyses with multiple datasets were employed to identify the core member of this gene family in glioma. The receiver operator characteristic (ROC) curves and immunohistochemistry were further used for evaluating its association with progressive malignancy in glioma and GBM patients' survival, respectively. Gene set enrichment analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to interpret its functions in GBM, which were further verified in vitro. Results A SPKKPs classifier was constructed with 3 genes of this family. This signature could effectively distinguish IDH wt GBM survival. Family with sequence similarity 20 C (FAM20C) was further identified as the core member of this family in glioma. Elevated FAM20C expression was not only closely correlated with glioma malignancy progression and the mesenchymal subtype of GBM but also indicated unfavorable survival of GBM patients. FAM20C was also found to be associated with the disrupted immune response in GBM microenvironment and was required for the migration of glioma and immune cells. Conclusion These data indicate that the potential of FAM20C serving as a predictive molecule and a therapeutic target for GBM.

In order to research the method of strength empirical correlation between conventional small punch test (SPT) and uniaxial tensile test, a series of austenitic stainless steel including pre-strained SUS304 have been tested in this study. The conventional SPT is conducted on a small disc-shaped specimen whose edge is firmly gripped by a die, and the specimen is deformed by a punch. The method of empirical correlation between SPT and uniaxial tensile test is a direct way to obtain the mechanical properties of materials. Through establishing the strength empirical correlation, it can achieve to calculate the strength of material by SPT which is nondestructive to equipments. However, the per-strained steels have never been tested in this method. This study is to fill that gap and to obtain the empirical correlation between SPT and uniaxial tensile test with pre-strained steel. In this study, a series of austenitic stainless steel including SUS304 after different levels of pre-strain were tested successively by uniaxial tensile test and SPT. It is found that the tensile strength obtained from uniaxial tensile test increases with the increasing levels of pre-strain. However, the maximum load obtained from prestrained SPT specimen does not increase with the increasing levels of pre-strain. It is contradictory to the linear relation between maximum load and tensile strength. According to the analysis of conventional discshaped SPT specimen, the directions of maximum load obtained from SPT and tensile strength from tensile test are not uniform. It results in the non-linearity between the maximum load and the tensile strength with pre-strained steel, and it indicates the pre-strained steel cannot be applied to the conventional disc-shaped SPT specimen. Furthermore, the prestrained steel is a typical kind of anisotropic material. Therefore, extending to anisotropic material, the conventional disc-shaped SPT specimen is not suitable for the method of strength empirical correlation.

Grape downy mildew (Plasmopara viticola) is one of the most destructive diseases of grapevine worldwide. In order to better understand the cellular processes involved in resistance to downy mildew, leaves of Vitis vinifera cv. ‘Centennial Seedless’ (susceptible) and Vitis labrusca×Vitis riparia cv. ‘Beta’ (resistant) were inoculated with Plasmopara viticola, and were used in the Illumina HiSeq™2000 platform for deep transcriptome sequencing. We performed transcriptome analysis and identified a total of 1091 differentially expressed genes (DEGs) in the disease-resistant cultivar and 849 in the susceptible cultivar. To increase understanding of the DEGs, the datasets were analyzed using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genome (KEGG) database. Most of them were found to be associated with plant–pathogen interaction, flavonoid synthesis, phenylpropanoid synthesis metabolism and phytohormone signal transduction. Moreover, transcription factors ERF, MYB, WRKY, and bHLH associated with disease resistance were screened. A total of 196 genes were identified as the candidate resistant genes. The expression of 18 differentially expressed genes was detected by RT-qPCR. Finally, the pattern of differentially expressed genes was consistent with the result of transcriptome sequencing. The present study identified several candidate resistance genes and signal transduction pathways that may contribute to downy mildew resistance in grapes.

Proceedings of the 31st International Linear Accelerator Conference, LINAC2022, Liverpool, UK 31st Linear Accelerator Conference, LINAC22, Liverpool, United Kingdom, 28 Aug 2022 - 2 Sep 2022; JACoW Publishing, Geneva, Switzerland 699-702 (2022). doi:10.18429/JACoW-LINAC2022-THPOJO03, A new generation of normal conducting 1.3GHz RF gun was developed to provide a high-quality electron source for superconducting linac driven free-electron lasers like FLASH and European XFEL. Compared to the Gun4 series, Gun5 aims for a 50% increase of the duration of the RF pulse (up to 1 ms at 10 Hz repetition rate) combined with high gradients (up to ~60 MV/m at the cathode). In addition to the improved impedance, the new cavity is equipped with an RF probe to measure and control the amplitude and phase of the RF field inside the gun. The first prototype of the new RF gun was manufactured at DESY and installed at the Photo Injector Test facility at DESY in Zeuthen (PITZ) in October 2021. In mid-October 2021 the RF conditioning began, aiming for achieving the aforementioned RF parameters. The conditioning procedure involves a slow gradual increase in repetition rate, RF pulse duration and peak power while carefully monitoring vacuum conditions and signals from interlock sensors. The results of RF conditioning will be reported., Published by JACoW Publishing, Geneva, Switzerland

The High Energy Photon Source (HEPS) is a synchrotron radiation source of ultrahigh brightness and under construction in China. Its accelerator system is comprised of a 6-GeV storage ring, a full energy booster, a 500-MeV Linac and three transfer lines. The Linac is a S-band normal conducting electron linear accelerator with available bunch charge up to 10 nC. The Linac installation has been finished at the end of May this year. The system joint debugging and device conditioning of the accelerating units, the power supplies, et al., are in progress. The beam commissioning will start in September 2022. This paper presents the status of the HEPS Linac and detailed introduction of the beam commissioning simulations and preparations., Proceedings of the 13th International Particle Accelerator Conference, IPAC2022, Bangkok, Thailand

Proceedings of the 13th International Particle Accelerator Conference, IPAC2022, Bangkok, Thailand 13th International Particle Accelerator Conference, IPAC'22, Bangkok, Thailand, 12 Jun 2022 - 17 Jun 2022; JACoW Publishing, Geneva, Switzerland 310-312 (2022). doi:10.18429/JACOW-IPAC2022-MOPOPT029, The longitudinal phase space characteristics of space-charge dominated electron beams are keys to achieving bunch compression for the accelerator-based THz source at the Photo Injector Test facility at DESY in Zeuthen (PITZ). Such a THz source is proposed as a prototype for an accelerator-based THz source for pump-probe experiments at the European XFEL. A start-to-end simulation has suggested the settings of the phase of booster linear accelerator manipulating longitudinal beam characteristics to optimize the performance of the THz FEL. Although beam diagnostics after compression at PITZ are limited, the longitudinal beam characteristics as a function of the booster phase have been measured and compared with the corresponding simulations. The benchmark involves measurements of longitudinal phase space distribution for bunch charges up to 2 nC. The measurement technique assigned uses 50-um slits to achieve higher momentum and time resolution (1.8 keV/c and 0.5 ps, respectively)., Published by JACoW Publishing, Geneva, Switzerland

Biofuel cell (BFC) is a kind of bio-cell based on biological enzymes. The enzyme as a catalyst can interconvert renewable and sustainable energy into each other more rapidly, such as the biochemical energy in glucose and ethanol into electrical energy. In this work, artificial blood vessel and fuel cell are based on polyaniline/thermoplastic polyurethane (PANI/TPU) fiber membrane with an average fiber diameter of 1300 nm, a film thickness of 167μm, and a permeability of 18.4 mm s-1. The PANI/TPU fiber membrane was prepared by electrospinning and followedin situpolymerization. The membrane has good flexibility and mechanical properties, and can be stretched up to 200%. The advantages of good hydrophilicity, biocompatibility and high porosity make it possible to efficiently load glucose oxidase and laccase. The prepared BFC can stably output a voltage of 50 mV in simulated blood, and the output electrical signal changes significantly with the change of glucose concentration, which may be used in implantable devices or blood glucose monitoring.

ZEB1 (a positive enhancer) and KLF5 (a negative silencer) affect transcription factors and play inherently conserved roles in tumorigenesis and multidrug resistance. In humans, the rs2295080T-allele at the mTOR promoter locus has been associated with human cancer risk; however, the 63 bp spacing of another SNP rs2295079 has not been identified. Here, we discovered, for the first time, that rs2295079 (-78C/G) and rs2295080 (-141G/T) formed linkage haplotypes, with Ht1 (-78C/-141G) and Ht2 (-78G/-141T) being dominant, which were associated with distinct susceptibility to breast cancer, response to paclitaxel, and clinical outcomes in breast cancer. At the cellular level, compared with Ht1, Ht2 exhibits a much stronger effect on promoting mTOR expression, leading to enhanced tumor cell growth and strengthened resistance to PTX treatment. Mechanistically, the -141T allele of Ht2 creates a novel ZEB1-binding site; meanwhile, the -78C allele of Ht1 exists as an emerging KLF5-binding site, which synergistically induces promote/inhibit mTOR expression, cell proliferation, and excretion of cytotoxic drugs through the ZEB1/KLF5–mTOR–CCND1/ABCB1 cascade, thereby affecting the response to paclitaxel treatment in vivo and in vitro. Our results suggest the existence of a ZEB1/KLF5–mTOR–CCND1/ABCB1 axis in human cells that could be involved in paclitaxel response pathways and functionally regulate interindividualized breast cancer susceptibility and prognosis. Implications: This study highlights the function of haplotypes of mTOR -78C/-141G and -78G/-141T, in affecting breast cancer susceptibility and paclitaxel response regulated by ZEB1/KLF5–mTOR–CCND1/ABCB1 axis.

Rate of area reduction is an important mechanical characterization to appraise the plasticity of metals, which is always obtained from the uniaxial tensile test. A methodology is proposed to determine the area reduction rate by continuous ball indentation test technique. The continuum damage accumulation theory has been adopted in this work to identify the failure point in the indentation. According to this theory, the damage is accumulated in the material during the test with voids nucleating and growing, which can be divided into two stages due to the variation in the degree of constraint. The turning point between two stages can be identified as the failure point where the material beneath the indenter collapses. The corresponding indentation depth of this point can be obtained and used to estimate the area reduction rate. The local strain limit criterion proposed in the ASME VIII-2 2007 alternative rules is also adopted in this research to convert the multiaxial strain of indentation test to uniaxial strain of tensile test. This method can be useful in engineering practice to evaluate the material degradation under severe working condition due to the non-destructive nature of ball indentation test. In order to validate the method, spherical indentation test is performed on ferritic steel 16MnR and B16, then the results are compared with that got from the traditional uniaxial tensile test.

JR-curve is one of an important index to characterize the fracture properties of metal materials. It is usually determined by multi-sample unloading method and single-sample unloading compliance method recommended by standard methods; In consideration of the similarity between the continuous ball indentation method and the single-sample unloading compliance method, The JR-curve is obtained by using the empirical correlation between effective elastic modulus ED of the continuous ball indentation and the unloading compliance C for single simple in this article. The calculation conducted by the correlation formula of the extension length of crack with unloading compliance C. However, results indicate that the fracture toughness J0.05 obtained by empirical correlation of load-depth curve of continuous spherical indentation is still quite different from those given by the standard test.

Fracture toughness empirical correlation between SPT(Small Punch Test) with non-crack sample and standard fracture toughness test has been established in recent years. In order to compensate the imperfection of empirical correlation, such as absence theoretical basis, poor repeatability and universality, in this paper, an O-type pre-cracked sample was adopted to evaluate fracture toughness. The mechanical model of the sample is in compliance with plane strain condition in the direction of crack propagation. In this paper a determination procedure was studied and established, and the J-integral of steel Q345R was calculated using the procedure.

Tumor metastasis is a complex and multistep process and its exact molecular mechanisms remain unclear. We attempted to find novel microRNAs (miRNAs) contributing to the migration and invasion of breast cancer cells. In this study, we found that the expression of miR-487a was higher in MDA-MB-231breast cancer cells with high metastasis ability than MCF-7 breast cancer cells with low metastasis ability and the treatment with transforming growth factor β1 (TGF-β1) significantly increased the expression of miR-487a in MCF-7 and MDA-MB-231 breast cancer cells. Subsequently, we found that the transfection of miR-487a inhibitor significantly decreased the expression of vimentin, a mesenchymal marker, while increased the expression of E-cadherin, an epithelial marker, in both MCF-7 cells and MDA-MB-231 cells. Also, the inactivation of miR-487a inhibited the migration and invasion of breast cancer cells. Furthermore, our findings demonstrated that miR-487a directly targeted the MAGI2 involved in the stability of PTEN. The down-regulation of miR-487a increased the expression of p-PTEN and PTEN, and reduced the expression of p-AKT in both cell lines. In addition, the results showed that NF-kappaB (p65) significantly increased the miR-487a promoter activity and expression, and TGF-β1 induced the increased miR-487a promoter activity via p65 in MCF-7 cells and MDA-MB-231 cells. Moreover, we further confirmed the expression of miR-487a was positively correlated with the lymph nodes metastasis and negatively correlated with the expression of MAGI2 in human breast cancer tissues. Overall, our results suggested that miR-487a could promote the TGF-β1-induced EMT, the migration and invasion of breast cancer cells by directly targeting MAGI2.

Photocathode Physics for Photoinjectors Workshop, California, DESY, USA, 10 Nov 2021 - 12 Nov 2021

12th International Particle Accelerator Conference, IPAC'21, Campinas, Brazil, 24 May 2021 - 28 May 2021; doi:10.18429/JACOW-IPAC2021-WEPAB115, The need for carrier-envelope-phase (CEP) stable THz pump pulses is recognized at many pump-probe experiments at the European XFEL. At the Photo Injector Test Facility at DESY in Zeuthen (PITZ), a proof-of-principle experiment of an accelerator-based THz FEL source is in preparation. Since the CEP stability of FEL pulses is not guaranteed in the SASE regime, a seeding scheme is needed. A common scheme for seeding is to drive the microbunching process with external laser pulses, which are power-limited in the THz range. Alternatively, a pre-bunched beam, generated for example by applying a temporally modulated photocathode laser pulse, can be used to drive the FEL. The beam dynamics with such a seeding method are studied with ASTRA tracking code simulations with space-charge forces as well as experimentally. The results of these studies are shown and discussed.