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The aberration-corrected scanning transmission electron microscope (STEM) has emerged as a key tool for atomic resolution characterization of materials, allowing the use of imaging modes such as Z -contrast and spectroscopic mapping. The STEM has not been regarded as optimal for the phase-contrast imaging necessary for efficient imaging of light materials. Here, recent developments in fast electron detectors and data processing capability is shown to enable electron ptychography, to extend the capability of the STEM by allowing quantitative phase images to be formed simultaneously with incoherent signals. We demonstrate this capability as a practical tool for imaging complex structures containing light and heavy elements, and use it to solve the structure of a beam-sensitive carbon nanostructure. The contrast of the phase image contrast is maximized through the post-acquisition correction of lens aberrations. The compensation of defocus aberrations is also used for the measurement of three-dimensional sample information through post-acquisition optical sectioning. The use of ptychography with electrons has been limited. Here, Yang et al . demonstrate that the combination of Z-contrast and phase imaging reveals the structure of complex nanomaterials. This practical tool can be used to solve the structure of a beam-sensitive carbon nanostructure at atomic-resolution.

Malignant mesothelioma (MM) shows frequent inactivation of the neurofibromatosis type 2 ( NF2 ) –tumor-suppressor gene. Recent studies have documented that the Hippo signaling pathway, a downstream cascade of Merlin (a product of NF2 ), has a key role in organ size control and carcinogenesis by regulating cell proliferation and apoptosis. We previously reported that MMs show overexpression of Yes-associated protein (YAP) transcriptional coactivator, the main downstream effector of the Hippo signaling pathway, which results from the inactivation of NF2 , LATS2 and/or SAV1 genes (the latter two encoding core components of the mammalian Hippo pathway) or amplification of YAP itself. However, the detailed roles of YAP remain unclear, especially the target genes of YAP that enhance MM cell growth and survival. Here, we demonstrated that YAP-knockdown inhibited cell motility, invasion and anchorage-independent growth as well as cell proliferation of MM cells in vitro . We analyzed genes commonly regulated by YAP in three MM cell lines with constitutive YAP-activation, and found that the major subsets of YAP-upregulating genes encode cell cycle regulators. Among them, YAP directly induced the transcription of CCND1 and FOXM1 , in cooperation with TEAD transcription factor. We also found that knockdown of CCND1 and FOXM1 suppressed MM cell proliferation, although the inhibitory effects were less evident than those of YAP knockdown. These results indicate that constitutive YAP activation in MM cells promotes cell cycle progression giving more aggressive phenotypes to MM cells.

Aluminum alloy is widely used in aircraft structural components. The high cutting force in the conventional machining often causes the burr formation in the machined parts. To overcome the problems, machining method with low cutting force are recommended. In this study, we attempted to mechanize the manual drilling (soft-machining) to establish a new drilling method with a small probability of burr generation. The thrust force in manual drilling is less than one-tenth of that in CNC machining. A total of more than 200 holes were drilled with the same drill at 35 to 110N of applied load. In the drilling of single plate, burr formation is related to the inclination of the drill exit surfaces. Even in the drilling of stacked plates, the soft-machining can drill the through holes at the specified points in all conditions. In the soft-machining, the level of load P[N] becomes an important parameter to minimize the damage generation and it may be a mandatory to adjust the load to the minimum level required for cutting and tool feed. Applying soft machining to robotic drilling may solve vibration problem.

Background:Peritenon extensor tendon inflammation (PTI) patterns of Metacarpophalangeal (MCP) joints detected by ultrasound (US) are demonstrating to be enthesitis-related lesion and considered to be functional enthesitis of peripheral spondylarthritis (SpA), especially psoriatic arthritis (PsA). PTI patterns can also be observed in early rheumatoid arthritis (RA) and other connective tissue diseases (CTDs), however the frequency of PTI pattern in MCP joints in those diseases and their clinical characteristics are not clear.Objectives:The aim of this study is to clarify the prevalence and characteristics of newly diagnosed patients with rheumatic and musculoskeletal diseases who have peritenon extensor tendon inflammation.Methods:This was a prospective cohort study in patients with newly diagnosed rheumatic and musculoskeletal diseases with clinical swelling of at least one of the MCP joints. Demographic, clinical, and laboratory data were collected from their charts. All patients were assessed for 28 joints and the 6 entheses included in the MASEI index (bilateral triceps, quadriceps, proximal and distal patellar, Achilles tendons, and proximal insertion of plantar aponeurosis) with US examinations performed by certificated rheumatological sonographers who were blinded to clinical data. PTIs were defined as hypoechoic image surrounding the extensor digitorum tendon with or without PD signal and synovitis based on the OMERACT definition. All data analysis in this research was carried out through JMP version 17.Results:A total of 323 patients with newly diagnosed rheumatic and musculoskeletal disease were recruited. Their final diagnosis were 245 patients with RA, 45 patients with CTDs including systemic lupus erythematosus (SLE), Sjogren syndrome, mixed connective tissue disease (MCTD), polymyositis/dermatomyositis (PM/DM) and Behcet disease, and 27 with SpA. Among them, PTIs of MCP joints were observed in 82 patients (25.4%). The mean age was 53.8 years old and 70% were female. Serum CRP levels were similar among the three groups. The positivity of PTI pattern were significantly higher in patients with SpA (n=21, 76.9%) and CTDs (n=35, 77.8%) than that in RA (n=24, 10.9%). Comparison of other findings detected with US in those patients with PTI patterns between three disease groups revealed that enthesitis were more frequent in patients with CTD and SpA than RA (RA vs CTD vs SpA; 17% vs 34% vs 57%, respectively), while the prevalence of synovitis and tenosynovitis were comparable. In the CTD group, SLE (40.0%), Sjogren (45.7%), and PM/DM (11.4%) accounted for all but one patient with CTDs with PTI patterns. In each CTD, (82.3%) with SLE, 16 (72.1%) with Sjogren syndrome, and 4 (30.8%) with PM/DM showed PTI pattens in the US.Conclusion:We found that PTI pattern on MCP Joints is also observed frequently in patients with CTDs as well as SpA. Combination of other sites of enthesitis and serological test are useful to distinguish patients with positive PTIs among patients with RA, CTDs, and SpA.REFERENCES:[1] Gutierrez M, Filippucci E, Salaffi F, Di Geso L, Grassi W. Differential diagnosis between rheumatoid arthritis and psoriatic arthritis: the value of ultrasound findings at metacarpophalangeal joints level. Ann Rheum Dis 2011;70:1111–4.[2] Filippou G, Di Sabatino V, Adinolfi A, Bertoldi I, Picerno V, Biasi G, et al. No enthesis should be overlooked when psoriatic arthritis is suspected: enthesitis of the extensor digitorum tendons. J Rheumatol 2013;40:335.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:Methotrexate (MTX) is widely used as an anchor drug in the treatment of rheumatoid arthritis (RA) because of its established efficacy. However, a part of patients shows poor response regardless of MTX dose escalation or experience adverse events, which can be partly ascribed to the difference in MTX metabolism. Intracellular MTX-polyglutamates (PGs) concentrations, active form of MTX metabolites, are associated with improvement in clinically assessed disease activity. In recent years, musculoskeletal ultrasonography (MSUS) has been increasingly used to assess synovitis sensitively, however, the association of increased MTX-PG concentrations and synovitis on MSUS has not been clarified.Objectives:To investigate the relationship of MTX-PG levels with effectiveness of MTX detected with MSUS in MTX-naïve patients with RA.Methods:We prospectively enrolled 79 patients in this analysis from the MAGIK study, which was a 76-week cohort study measuring MTX-PG concentrations in patients with RA. Among them, twenty-six patients were completely assessed for 40 joints of MSUS at baseline, week 12, and week 36 after MTX initiation. Patients who started biological agents within 36-week were excluded, resulting in 14 patients included in the analyses. Erythrocyte MTX-PG levels were measured by mass spectrometry. The associations of MTX-PG concentrations with disease activity including DAS28 and grayscale (GS)/power doppler signal (PD) score of MSUS were analysed.Results:Characteristics of patients included in the analysis were following: a median age was 65 years, 85.7% were female, and a median DAS28 of 4.03 (Table 1). The mean concentrations of total MTX-PG levels were elevated with MTX dose escalation, while MTX-PG3 concentrations showed a slow, delayed increase after 12-week. The mean number of swollen joints by examination at baseline and week 36 were 3.07 and 0.88, respectively, while the mean number of GS-positive joints and PD-positive joints with MSUS were 4.79 and 3.79 at baseline and 2.17 and 1.08 at week 36, respectively. Linear regression analysis revealed no relationship between MTX-PG concentrations and the changes in DAS28, swollen/tender joint counts, and serum CRP levels. In contrast, higher MTX-PG3 and total MTX-PG concentrations at 24-week were significantly associated with greater improvement in the number of PD-positive joint detected with MSUS at 36-week (r=0.66, p=0.0133 and r=0.69, p=0.0088, respectively) and total MSUS scores of 40 and 28 joints at 36-week, especially in the total PD score (Table 2).Conclusion:In patients with RA treated with MTX monotherapy, sufficient MTX-PG3 and total MTXPG concentration can lead to future improvement in joint inflammation detected sensitively with MSUS.REFERENCES:[1] Takahashi C, et al. RMD Open. 2017;3(1):e000363.Acknowledgements:NIL.Disclosure of Interests:None declared.

The muon linac has been developed at J-PARC to accelerate muons from thermal energy (25 meV) to 212 MeV using electrostatic extraction and four different types of radio-frequency cavities: RFQ, IH-DTL, DAW-CCL, and disk-loaded structures. Although some of the technologies employed were relatively novel, most proof-of-principle demonstrations have been successfully completed through prototype testing and actual production. Based on these experiences, it has become possible to propose a shorter or more efficient schematic design derived from the current design. In this poster, the new schematic design will be presented.

Malignant mesothelioma (MM) is one of the most aggressive neoplasms usually associated with asbestos exposure and is highly refractory to current therapeutic modalities. MMs show frequent activation of a transcriptional coactivator Yes-associated protein (YAP), which is attributed to the neurofibromatosis type 2 (NF2)–Hippo pathway dysfunction, leading to deregulated cell proliferation and acquisition of a malignant phenotype. However, the whole mechanism of disordered YAP activation in MMs has not yet been well clarified. In the present study, we investigated various components of the NF2-Hippo pathway, and eventually found that MM cells frequently showed downregulation of LIM-domain protein AJUBA, a binding partner of large tumor suppressor type 2 (LATS2), which is one of the last-step kinases of the NF2-Hippo pathway. Although loss of AJUBA expression was independent of the alteration status of other Hippo pathway components, MM cell lines with AJUBA inactivation showed a more dephosphorylated (activated) level of YAP. Immunohistochemical analysis showed frequent downregulation of AJUBA in primary MMs, which was associated with YAP constitutive activation. We found that AJUBA transduction into MM cells significantly suppressed promoter activities of YAP-target genes, and the suppression of YAP activity by AJUBA was remarkably canceled by knockdown of LATS2. In connection with these results, transduction of AJUBA-expressing lentivirus significantly inhibited the proliferation and anchorage-independent growth of the MM cells that harbored ordinary LATS family expression. Taken together, our findings indicate that AJUBA negatively regulates YAP activity through the LATS family, and inactivation of AJUBA is a novel key mechanism in MM cell proliferation.

Signal transducer and activator of transcription-3 (STAT3) is constitutively activated in a variety of cancer types, including malignant gliomas. STAT3 is activated by phosphorylation of a tyrosine residue, after which it dimerizes and translocates into the nucleus. There it regulates the expression of several genes responsible for proliferation and survival at the transcriptional level. A selective inhibitor of STAT3 phosphorylation, AG490, has been shown to inhibit growth and induce apoptosis in some cancer cell types. However, although AG490 routinely shows in vitro anticancer activity, it has not consistently demonstrated an in vivo anticancer effect in animal models. Here, we have tested WP1066, a novel inhibitor structurally related to AG490 but significantly more potent and active, against human malignant glioma U87-MG and U373-MG cells in vitro and in vivo . IC 50 values for WP1066 were 5.6  μ M in U87-MG cells and 3.7  μ M in U373-MG cells, which represents 18-fold and eightfold increases in potency, respectively, over that of AG490. WP1066 activated Bax, suppressed the expression of c- myc , Bcl-X L and Mcl-1 , and induced apoptosis. Systemic intraperitoneal administration of WP1066 in mice significantly ( P <0.001) inhibited the growth of subcutaneous malignant glioma xenografts during the 30-day follow-up period. Immunohistochemical analysis of the excised tumors revealed that phosphorylated STAT3 levels in the WP1066 treatment group remained inhibited at 3 weeks after the final WP1066 injection, whereas tumors from the control group expressed high levels of phosphorylated STAT3. We conclude that WP1066 holds promise as a therapeutic agent against malignant gliomas.

We have developed a non-destructive technique to observe Li in an electrode and metallic Li deposition on an anode using muonic x-rays. With high intent negative muon beam at J-PARC, we have attempted operando measurements of Li and metallic Li deposition in LIBs for the first time. Both increase and decrease of Li in a cathode during charging and discharging processes were observed. We also observed significant increase of muonic x-rays of Li with cycles, which may correspond to the degradation of charge capacity with the cycles.

Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive cancer with a poor prognosis. Although microRNA (miRNA) transcripts have a crucial role in carcinogenesis and development, little information is known regarding the aberrant DNA methylation of miRNAs in PDAC. Using methylated DNA immunoprecipitation-chip analysis, we found that miR-615-5p was hypermethylated in its putative promoter region, which silenced its expression in PDAC cell lines. In addition, the overexpression of miR-615-5p in pancreatic cancer cells suppressed cell proliferation, migration and invasion. Insulin-like growth factor 2 (IGF2) is an imprinted gene, and its abnormal expression contributes to tumor growth. Here, we identified IGF2 as a target of miR-615-5p using a luciferase reporter assay. IGF2 upregulation in PDAC tissues was not correlated with a loss of imprinting but was inversely correlated with miR-615-5p downregulation. In addition, miR-615-5p suppressed pancreatic cancer cell proliferation, migration and invasion by directly targeting IGF2, and this effect could be reversed by co-transfection with IGF2. Furthermore, the stable overexpression of miR-615-5p inhibited tumor growth in vivo and was correlated with IGF2 expression. Using RNA sequencing, we further identified miR-615-5p as potentially targeting other genes, such as the proto-oncogene JUNB , and interfering with the insulin signaling pathway. Taken together, our results demonstrate that miR-615-5p was abnormally downregulated in PDAC cells due to promoter hypermethylation, which limited its inhibition of IGF2 and other target genes, thereby contributing to tumor growth, invasion and migration. These data demonstrate a novel and important role of miR-615-5p as a tumor suppressor in PDAC.