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Abstract In Earth and planetary science, Pb isotopic composition is well known to play a key role in deciphering the origin and evolution of materials because they provide unique chronological and/or indigenous regional information as a radiogenic daughter nuclide from U and Th. To determine such an isotopic composition, mass spectrometers have been widely used over several decades, which requires a destructive/consuming treatment such as sputtering, laser ablation and thermal ionization. Here, we first report the non-destructive Pb isotopic measurement of natural galena (PbS) using the energy shift of muon-induced characteristic X-rays. The observed Pb isotopic composition of the natural galena is in good agreement with that obtained by conventional mass spectrometry. Such a muon-based Pb isotopic analysis method is expected to be applied to identify the production area of archaeological artefacts (e.g. bronze products), where non-destructive analysis is highly desirable compared to conventional mass spectrometry.

Introduction: Inherited bone marrow failure syndrome (IBMFS) is characterized by a heterogeneous group of disorders with marked cytopenia in one hematopoietic cell lineage. Aldehyde Degradation Deficiency Syndrome (ADDS) is one of the newly discovered IBMFS, caused by a combined deficiency of ADH5 and ALDH2, which are important for the degradation of endogenously produced formaldehyde. Here, we utilized recent technological advances in data-independent proteomic analysis to establish a diagnostic testing for IBMFS, including ADDS. Methods: We performed a multi-omics analysis of in-depth proteomic analysis, targeted capture DNA sequencing, and RNA sequencing among patients with IBMFS. Results: In-depth non-targeted proteomic analysis was performed on 74 samples obtained from 60 patients with IBMFS and 14 healthy controls. We identified eight independent proteomic clusters (C1-C8), with ribosome pathway-related proteins specifically downregulated in C1 and C2, enriched for Diamond-Blackfan anemia and Schwachman-Diamond syndrome, respectively. In the 74 samples, four patients with ADDS showed significantly reduced ADH5 protein expression, whereas the remaining samples showed normal expression. To provide a large-scale rapid screening system in a practical clinical setting, targeted proteomic analysis was performed using a small panel, including ADH5 proteins, in a developmental cohort of 417 samples with hematological malignancies and healthy controls. ADH5 protein expression levels were significantly reduced in ADDS, and its sensitivity and specificity values were 100.0% and 97.5%, respectively. Conclusions: We have performed the first integrated multi-omics analysis for IBMFS, and demonstrated that clinical applications of targeted proteomic assays would be useful in diagnosing for IBMFS, including ADDS.

Abstract Background Autologous hematopoietic stem cell transplantation (AHSCT) treats patients with severe and progressive systemic sclerosis (SSc). However, basic mechanisms associated with the therapeutic efficacy of the procedure are not entirely understood. We aimed to evaluate how AHSCT affects skin fibrosis in SSc patients. Methods Clinical data, serum, and skin samples from 39 SSc patients who underwent AHSCT were retrospectively evaluated. Skin biopsies were analyzed by immunohistochemistry with anti-MMP-1, -MMP-2, -MMP-3, -MMP-9, -TIMP-1, -α-SMA, -TGF-β, and -NF-κB p65 antibodies, and stained with hematoxylin and eosin and picrosirius red to assess skin thickness and collagen density, respectively. Serum samples were evaluated by Multiplex Assay for COL1A1, COL4A1, FGF-1, MMP-1, MMP-3, MMP-12, MMP-13, PDGF-AA, PDGF-BB, S100A9, and TIMP-1 levels and compared to healthy controls. Results After AHSCT, SSc patients showed clinical improvement in skin involvement, assessed by modified Rodnan’s skin score (mRSS). Histologically, collagen density and skin thickness decreased after AHSCT. Immunohistochemical analyses showed increased expression of MMP-2, MMP-3, MMP-9, and TIMP-1 after AHSCT, whereas expression of NF-κB p65 decreased. At baseline, serum levels of COL4A1 and S100A9 were higher than in healthy controls. Serum levels of S100A9 normalized after AHCST in SSc patients compared to controls. Serum levels of PDGF-AA, PDGF-BB, TIMP-1, and MMP-1 decreased, while COL1A1 increased after AHSCT in SSc patients. No changes were detected in MMP-3, MMP-12, MMP-13, and FGF-1 serum levels after AHSCT. Conclusions Our results suggest that the therapeutic effects of AHSCT on skin fibrosis are related to changes in molecules associated with connective tissue maintenance and inflammation in SSc.

Systemic sclerosis (SSc) is a chronic autoimmune disease that includes fibrosis, diffuse vasculopathy, inflammation, and autoimmunity. Autologous hematopoietic stem cell transplantation (auto-HSCT) is considered for patients with severe and progressive SSc. In recent decades, knowledge about patient management and clinical outcomes after auto-HSCT has significantly improved. Mechanistic studies have contributed to increasing the comprehension of how profound and long-lasting are the modifications to the immune system induced by transplantation. This review revisits the immune monitoring studies after auto-HSCT for SSc patients and how they relate to clinical outcomes. This understanding is essential to further improve clinical applications of auto-HSCT and enhance patient outcomes.

Objective: Autologous hematopoietic stem cell transplantation (AHSCT) is a therapeutic option for patients with severe and progressive systemic sclerosis (SSc). Here, we aimed to investigate how AHSCT affects the vasculopathy of SSc patients. Methods: Twenty-seven SSc patients were retrospectively assessed, before and after AHSCT, for vessel morphology (nailfold capillaroscopy), skin expression of endothelial markers and serum levels of markers of inflammation, angiogenesis and endothelial activation. Skin biopsies were analyzed by immunohistochemistry (IHC) for expression of CD31, VE-cadherin, E-selectin, angiopoietin-1 (Ang1), angiopoietin-2 (Ang2), Tie-2, vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor 2 (VEGFR2), and endothelin-1 before and 12 months post-AHSCT. Serum samples from SSc patients were assessed before and up to 36 months after AHSCT for IL-6, von Willebrand factor (vWF), CXC Motif Chemokine Ligand 8 (CXCL8), Endothelin-1, epidermal growth factor (EGF), VEGFA, Pentraxin-3, Intercellular Adhesion Molecule 1 (ICAM-1), E-selectin, P-selectin, Thrombomodulin and IL-18 levels, and compared to healthy control samples. Results: On nailfold capillaroscopy, the number of capillaries increased at 1 year, while giant capillaries decreased at 6 months and 1 year after AHSCT. In the skin biopsies, expression of E-selectin notably decreased and Ang1 increased after AHSCT. At baseline, all vascular markers evaluated in the serum were significantly higher in SSc patients when compared to healthy controls, except for ICAM-1. When compared at different time points after AHSCT, Thrombomodulin, Pentraxin-3, vWF, and IL-18 levels remained generally stable at high levels until 36 months after AHSCT. Conclusion: Our results suggest that AHSCT contributes to improvements of the vessel morphology and dermal microvasculopathy, but does not normalize elevated levels of serum vascular markers in SSc patients. Additional vascular therapeutic approaches might contribute to more effectively treat the endothelial injury.

In electron accelerator facilities, radio frequencies for a linac accelerator and a circular accelerator including a booster synchrotron ring and a storage ring are completely different. In order to improve the beam transmission efficiency from a linac to a circular accelerator, and to make the beam intensity constant, both rf's are generally synchronized. This method is well known and uses a common subharmonic frequency of around 10 MHz. The rf's used are generated by using a frequency multiplier from the common frequency, and they are continuously generated. We paid attention to the fact that the electron beam from a linac accelerator is always pulsed, and the rf of the linac requires only a moment during beam emission and acceleration. Taking this fact into account, we invented a new synchronization method for the rf's of both the linac and the circular accelerators. The new method is explained by describing a concrete example at the synchrotron radiation facility, SPring-8 (Super Photon ring 8 GeV). A 2856 MHz rf for the linac is generated by 508.58 MHz rf of the storage ring for a short duration of about 290 μs. Thus, the phase difference between the two rf's is automatically fixed. This method can be applied to any combination of arbitrary different rf's.

In this paper we analyse tiebreak results from some tennis players in order to investigate whether we are able to identify a non-aleatory distribution of the points in this crucial moment of the game. We compared the observed results with a binomial distribution considering that the probabilities of winning or losing a point are equal. Using a χ2 test we found that, excepting some players, the greatest part of the results agrees with our hypothesis that the points in tiebreaks are merely aleatory.