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VUV-CD Imaging of LLPS Proteins
No full textProteins that undergo liquid–liquid phase separation (LLPS), such as (FUS), have been implicated in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) [1, 2]. However, the relationship between phase separation behavior and protein structure remains poorly understood. Clarifying how protein structural properties relate to their droplet state is essential for advancing knowledge of the molecular mechanisms underlying these diseases.Our recent studies using vacuum-ultraviolet circular dichroism (VUV-CD) spectroscopy have demonstrated that the structure of FUS-LC changes in response to LLPS [3]. In the dispersed state, the protein is predominantly disordered, while its β-strand content increases upon phase separation. The emergence and development of amyloid-like β-structures into fibrillar assemblies are believed to contribute to the pathogenesis of neurodegenerative diseases. However, direct evidence linking these structural transitions to disease mechanisms remains lacking. A significant limitation has been the millimeter-scale footprint of the synchrotron radiation beam used for CD measurements, which has hindered quantitative evaluation of structural changes specifically within the droplets.This study analyzed structural changes within FUS droplets using a synchrotron microbeam with a diameter smaller than the droplet size. The droplet state of FUS was reproduced, and scanning measurements were conducted using the newly installed microbeam VUV-CD imaging system at BL12. Protein samples were prepared to remain dispersed at room temperature and to form droplets below 5℃. The droplets were also observed by an optical microscope (Figure). The sample cell was scanned with a VUV beam focused to several tens of micrometers. CD spectra were successfully obtained from regions presumed to be within the droplets. Ongoing experimental trials aim to quantify changes in CD spectral intensity within the droplet phase.The 30th Hiroshima International Symposium on Synchrotron Radiationconference poste
Bladder Preservation Therapy in Combination with Atezolizumab and Radiation Therapy (BPT-ART) for Invasive Bladder Cancer: Final Analysis from a Multicentre, Open-label, Prospective Phase 2 Trial.
No full textRadical cystectomy (RC) is the standard care for muscle-invasive or very high-risk non-muscle-invasive bladder cancer (BC), but optimal management for bladder preservation remains uncertain. In this multicentre, open-label, phase 2 trial, patients with cT1-3 N0 M0 muscle-invasive BC received radiation therapy (RT; 41.4 Gy to the small pelvis and 16.2 Gy to the whole bladder) and atezolizumab (1200 mg) every 3 wk. The primary endpoint was progression-free survival (PFS) at 3 yr. Key secondary endpoints included the clinical complete response (cCR) rate at 24 wk, overall survival (OS), and the bladder-intact recurrence-free rate (BIRFR). From 2019 to 2021, 41 of the 45 patients enrolled received treatment. The median age was 71 yr and most patients (73%) had T2 tumours. At 24 wk, 84% achieved cCR. The 3-yr PFS rate was 70% (95% confidence interval [CI] 54-81%), with the lower limit of the 95% CI exceeding the prespecified threshold of 45%. The 3-yr OS rate was 91% and the 3-yr BIRFR was 89%. Grade ≥3 adverse events occurred in 55% of patients, but no treatment-related deaths were observed. Limitations include the single-arm design and cohort size. Bladder preservation therapy with atezolizumab and RT showed favourable treatment effects with manageable toxicity for patients unfit for or refusing RC.journal articl
Detected Abundances of Nuclei Relative to 26Fe for Elements 14Si through 44Ru with CALET on the International Space Station
No full textThe Calorimetric Electron Telescope (CALET), launched to the International Space Station (ISS) in 2015 August and continuously operating since, measures cosmic-ray (CR) electrons, nuclei, and gamma rays. CALET, with its 27 radiation length deep Total Absorption Calorimeter, measures particle energy and allows for the measurement of spectra, secondary to primary ratios of the more abundant CR nuclei through Ni-28, while the main charge detector can measure ultra-heavy CR nuclei through Ru-44. The results for the abundances of elements from Z = 14 to Z = 44 relative to Fe-26 over 7.5 yr of observation are presented here and compared to previous measurements from ACE-CRIS, SuperTIGER, and HEAO-3.journal articl
4H-SiC中のシリコン空孔形成における電子線照射量と磁気感度の関係
No full text炭化ケイ素(SiC)中の負に帯電したシリコン空孔(Vsi)は、高感度な磁気センシングを可能とする量子センサとして注目されている。我々のこれまでの研究により、高エネルギー電子線照射によってVsiを形成すると、照射量に比例してVsi濃度は増加し、磁気感度もそれに応じて向上することがわかっている(S. Motoki, et al., J. Appl. Phys. 133 (2023) 154402.)。しかし、Vsi濃度が1E17 cm-3を超えるような高濃度条件における磁気感度についてはまだ十分に検討されていない。本研究では、磁気センシングの基本原理である光検出磁気共鳴(ODMR)測定から得られた磁気感度を指標として、電子線照射量との関係を系統的に評価した。2026年第73回応用物理学会春季学術講演会conference presentatio
Benchmarks of iron nuclear data for fusion neutron sources
No full textTo assess the accuracy of iron data in the latest nuclear data libraries, mainly FENDL-3.2b, for accelerator-based fusion neutron source designs, we analyzed the QST/TIARA iron experiment with quasi mono-energy neutrons of 40 and 65 MeV, and the JAEA/FNS iron experiment with DT neutrons, by using the Monte Carlo code MCNP6.2. As the results, we found the following issues: 1) the calculation result with FENDL-3.2b underestimated the measured neutron flux in the continuous energy range (10 - 60 MeV) by 40 % in the TIARA experiment with 65 MeV neutrons, 2) it tended to underestimate the measured neutron flux above 10 MeV by 20 % at a depth of 70 cm and overestimate that below 10 keV by 30 % up to a depth of 40 cm in the FNS experiment. We modified the FENDL-3.2b iron data to investigate these issues and identified underlying remarks: 1) the non-elastic and in- elastic scattering data of 56Fe in FENDL-3.2b underestimated the measured neutron flux above 10 MeV, 2) the (n, np) data of 56Fe in FENDL-3.2b overestimated the measured neutron flux above 10 MeV, and 3) the inelastic scattering and (n,2n) data of 56Fe and the inelastic scattering data of 57Fe in FENDL-3.2b caused the over- estimation of the measured neutron flux below 10 keV. These issues of 56,57Fe in FENDL-3.2b should be improved.journal articl
Theoretical Study of Impurity Effects on Superconductivity in UTe2
No full textThis study investigates the impurity effects on UTe2 within the self-consistent Born approximation using the six-orbital f–d–p model which contains two ranium and tellurium atoms in the minimum unit cell. We analyze the dependence of superconducting transition temperature (Tc) on impurity concentration for various pairing symmetries proposed by experiments and theories. It clarifies that the decrease of Tc significantly depends on which atom sites the impurities reside. Particularly, the analysis shows that the impurity at U-site has a dominant effect on the change of Tc. Then, either the singlet state in the case of magnetic impurities or the triplet states in both nonmagnetic and magnetic impurities are consistent with experiments. Thus, this indicates that elucidating the magnetic properties of impurities (i.e., magnetic or nonmagnetic) is crucial for identifying the pairing symmetry of UTe2.journal articl
191Pt-labeled Trithiol-Hoechst-PSMA: Preliminary evaluation of conjugates designed for delivery to genomic DNA of PSMA-positive cancers
No full textBackground: Several platinum radionuclides, including 191Pt, are promising candidates for DNA-targeted Auger electron radiotherapy; however, effective compound designs are needed for this application. In this study, we developed six novel 191Pt-labeled compounds and evaluated their DNA-targeting properties in PSMA-positive tumors.Results: Six trithiol-Hoechst-PSMA (THP) conjugates that consist of a trithiol ligand for 191Pt labeling, Hoechst33258 for DNA binding, and a PSMA-targeted moiety were synthesized and labeled with 191Pt, achieving radiochemical yields of 60–80%. The six [191Pt]Pt-THP compounds were evaluated for DNA-binding ability and PSMA targeting specificity in vitro, and biodistribution experiments were performed with five of the compounds in mice bearing subcutaneous PSMA-positive and PSMA-negative xenografts. Among them, [191Pt]Pt-THP3-4 and [191Pt]Pt-THP3-8, in which Hoechst33258 is linked on one side of the trithiol ligand via a linear PEG linker and the PSMA-targeting moiety is linked on the other side via a C4 linker, had the best properties. These compounds maintained higher PSMA targeting specificity and DNA-binding ability both in vitro and in vivo than the other [191Pt]Pt-THP compounds, exhibiting similar DNA binding in PSMA-positive PC3 PIP tumors in vivo as in the cultured cells from which the xenograft was derived.Conclusions: This study highlighted the importance of the linkers between the three components (trithiol-Hoechst-PSMA) and demonstrated binding of intravenously administered [191Pt]Pt-THP3-4 and [191Pt]Pt-THP3-8 to DNA in PSMA-positive tumors. Our compound designs and findings could be a useful foundation for DNA-targeted Auger electron cancer therapy, especially with Pt radionuclides.journal articl
Correction and utilization of the washout effect in range-verificationPET for particle therapy
No full textIn charged particle therapy, it is essential to verify the irradiation beam range. Thus, using positron (β+)-emitting nuclideswhich are produced in irradiated tissue, positron emission tomography (PET) has been studied, and clinically applied forin vivo range verification in particle therapy. However, a correction method for the biological washout effect is one ofthe fundamental issues for quantitative verification of the beam range; the irradiation-induced β+-emitting nuclides areaffected by the pathophysiological environment such as blood perfusion. Since the biological washout effect is a tissue-specific phenomenon, extensive basic and clinical research has been conducted for modeling its kinetic process. Althoughconsidered as an undesirable factor in PET-based range validation, on the other hand, the biological washout effect mayprovide unique insights into the vascular status of a tumor and potentially support evaluation of the cancer pathophysiol-ogy. Consequently, this review provides a comprehensive outline of studies of the biological washout effect in particletherapy, focusing on both its correction and potential beneficial utilization.journal articl
Development of galectin-3 targeted radioimmunoligands for cancer theranostics
No full textGalectin-3 is associated with aggression, proliferation, and metastasis in various refractory cancers. Although galectin-3 targeted positron emission tomography (PET) tracers have shown considerable promise for cancer diagnosis, the therapeutic potential of galectin-3-directed radiopharmaceutical therapy for refractory or untreatable malignancies remains largely unexplored. This study aimed to develop novel galectin-3-targeted radioimmunoligands and verify their radiotheranostic potential in multiple tumor models. Two novel galectin-3 targeted monoclonal antibodies (QMAb-1 and QMAb-2) were labeled with both 89Zr and 177Lu. PET/CT imaging of [89Zr]Zr-DFO-QMAb-1 and [89Zr]Zr-DFO-QMAb2 were evaluated in mouse tumor models with varying galectin-3 expression levels. Besides, the therapeutic efficacy of [177Lu]Lu-DTPA-QMAb-1 and [177Lu]Lu-DTPA-QMAb-2 was also investigated.The superior tumor uptake and retention time of [89Zr]Zr-DFO-QMAb-1 was observed. Notably, [89Zr]Zr-DFO-QMAb-1 demonstrated minimal off-target accumulation and rapid clearance from the bloodstream and major organs. Furthermore, [177Lu]Lu-DTPA-QMAb-1 showed potent anti-tumor efficacy without inducing hematotoxicity and major organ damage, highlighting its therapeutic potential and safety profile. This study expands the repertoire of the galectin-3 radiopharmaceutical toolbox by harnessing high affinity mAbs as ligands, offering a new modality for the diagnosis and treatment of galectin-3-positive cancers. In addition, the favorable performance of [89Zr]Zr-DFO-QMAb-1 and [177Lu]LuDTPA-QMAb-1 theranostic pair in triple-negative breast cancer models further supports their clinical application potential across a range of refractory malignancies.journal articl
Specific role of cAMP signaling for clock input pathway from extracellular signals
No full textIn mammalian central clock neurons of the suprachiasmatic nucleus (SCN), cAMP signaling is rhythmically activated by extracellular neuropeptides for amplification of intracellular oscillations. Recent studies revealed that Ca2+, another clock-input signaling, is incorporated into a cell-autonomous oscillation mechanism in various organisms. The study provided a chance for reconsideration of the self-sustained oscillation mechanism of the circadian clock. The present study investigated whether cAMP signaling was involved in the autonomous oscillation of cultured cells. Here, we show that the SCN neurons show clear circadian cAMP rhythms that are sensitive to an adenylyl cyclase inhibitor, MDL-12,330A. On the other hand, no apparent circadian rhythm of cAMP was observed in Rat-1 fibroblasts. Consistently, MDL-12,330A showed no significant effects on circadian oscillation of Per1, Per2, Bmal1 and D-box-dependent transcription. Similarly, no obvious effects of MDL-12,330A on rhythmic gene expression of Per2 and Bmal1 were observed in human U2OS cells. These results showed no significant role of cAMP signaling for cell-autonomous oscillations in cultured cells. In contrast, extracellular activation of cAMP signaling by forskolin caused a phase-shift of transcriptional rhythms of Per2 in Rat-1 fibroblasts. These results indicate that cAMP signaling is specifically involved in the clock input pathway from extracellular signals.journal articl