Evaluation of plasma nucleosome concentrations in dogs with a variety of common cancers and in healthy dogs.

BACKGROUND: Cell free DNA, in the form of nucleosomes, is released into circulation during apoptosis and necrosis in a variety of diseases. They are small fragments of chromosomes that are composed of DNA wrapped around a histone core made of four duplicate histone proteins forming an octamer. The nucleosome compartment is a relatively uninvestigated area of circulating tumor biomarkers in dogs. The objectives of this study were to quantify and better characterize nucleosome concentrations in 528 dogs with various common malignancies and compare them to 134 healthy dogs. RESULTS: The sensitivity of increased circulating nucleosome concentrations for the detection of cancer in all dogs was 49.8% with a specificity of 97% with an area under the curve of 68.74%. The top 4 malignancies detected by the test included lymphoma, hemangiosarcoma, histiocytic sarcoma and malignant melanoma. The malignancies least likely to be detected were soft tissue sarcomas, osteosarcoma and mast cell tumors. CONCLUSIONS: A variety of tumor types may cause increased nucleosome concentrations in dogs. Tumors of hematopoietic origin are most likely to cause elevations and local tumors such as soft tissue sarcomas are least likely to cause elevations in plasma nucleosome concentrations.

Seed production and storage for endangered Morus boninensis using an ex-situ living collection.

Meaningful conservation techniques for the endangered Morus boninensis require seed production and storage, since in situ purebred seed production is infrequent in Ogasawara Islands (World Natural Heritage Site) in Japan. Ex situ living M. boninensis specimens produced seeds by open- and artificial-pollination in a greenhouse. Seed desiccation tolerance and storage characteristics were examined. Open-pollinated seeds were dried at 75, 33 and 8% relative humidity (RH) for 5 days then cryopreserved at -170 °C. Artificially pollinated seeds were dried at 8% RH then stored cryogenically at -170 °C and in freezers at -80 or -20 °C for 6 months. Germination rates were compared among seeds before and after drying and storage. Germination rates of undried seeds were 83% for open-pollinated seeds and 65% for artificially pollinated seeds. M. boninensis seeds exhibited the characteristic high desiccation tolerance of orthodox seeds and maintained a high germination rate after drying to a moisture content of approximately 4%. Cryopreservation of open-pollinated dry seeds with moisture contents of ca. 12, 7 and 4% maintained germination rates, while cryopreservation of undried seeds (moisture content ca. 44%) resulted in no germinability. Cryogenic and freezer storage of artificially pollinated dry seeds for 6 months resulted in maintenance of germination rates comparable to undried seeds before storage. Seed production was enabled by ex situ M. boninensis collection. The present study also developed a method for low temperature seed storage. Ex situ living tree collection represents a feasible seed resource for reintroduction and restoration programmes for M. boninensis.

Mapping of a New Deformation Region around

We performed the first direct mass measurements of neutron-rich scandium, titanium, and vanadium isotopes around the neutron number 40 at the RIKEN RI Beam Factory using the time-of-flight magnetic-rigidity technique. The atomic mass excesses of ^{58-60}Sc, ^{60-62}Ti, and ^{62-64}V were measured for the first time. The experimental results show that the two-neutron separation energies in the vicinity of ^{62}Ti increase compared to neighboring nuclei. This shows that the masses of Ti isotopes near N=40 are affected by the Jahn-Teller effect. Therefore, a development of Jahn-Teller stabilization appears below the Cr isotopes, and the systematics in Sc, Ti, and V isotopes suggest that ^{62}Ti is located close to the peak of the Jahn-Teller effect.

Sequential Nature of (p,3p) Two-Proton Knockout from Neutron-Rich Nuclei.

Twenty-one two-proton knockout (p,3p) cross sections were measured from neutron-rich nuclei at ∼250 MeV/nucleon in inverse kinematics. The angular distribution of the three emitted protons was determined for the first time, demonstrating that the (p,3p) kinematics are consistent with two sequential proton-proton collisions within the projectile nucleus. Ratios of (p,3p) over (p,2p) inclusive cross sections follow the trend of other many-nucleon removal reactions, further reinforcing the sequential nature of (p,3p) in neutron-rich nuclei.

Fragmentation of Single-Particle Strength around the Doubly Magic Nucleus

Spectroscopic factors of neutron-hole and proton-hole states in ^{131}Sn and ^{131}In, respectively, were measured using one-nucleon removal reactions from doubly magic ^{132}Sn at relativistic energies. For ^{131}In, a 2910(50)-keV γ ray was observed for the first time and tentatively assigned to a decay from a 5/2^{-} state at 3275(50) keV to the known 1/2^{-} level at 365 keV. The spectroscopic factors determined for this new excited state and three other single-hole states provide first evidence for a strong fragmentation of single-hole strength in ^{131}Sn and ^{131}In. The experimental results are compared to theoretical calculations based on the relativistic particle-vibration coupling model and to experimental information for single-hole states in the stable doubly magic nucleus ^{208}Pb.

78Ni revealed as a doubly magic stronghold against nuclear deformation.

Nuclear magic numbers correspond to fully occupied energy shells of protons or neutrons inside atomic nuclei. Doubly magic nuclei, with magic numbers for both protons and neutrons, are spherical and extremely rare across the nuclear landscape. Although the sequence of magic numbers is well established for stable nuclei, experimental evidence has revealed modifications for nuclei with a large asymmetry between proton and neutron numbers. Here we provide a spectroscopic study of the doubly magic nucleus 78Ni, which contains fourteen neutrons more than the heaviest stable nickel isotope. We provide direct evidence of its doubly magic nature, which is also predicted by ab initio calculations based on chiral effective-field theory interactions and the quasi-particle random-phase approximation. Our results also indicate the breakdown of the neutron magic number 50 and proton magic number 28 beyond this stronghold, caused by a competing deformed structure. State-of-the-art phenomenological shell-model calculations reproduce this shape coexistence, predicting a rapid transition from spherical to deformed ground states, with 78Ni as the turning point.

Prominence of Pairing in Inclusive (p,2p) and (p,pn) Cross Sections from Neutron-Rich Nuclei.

Fifty-five inclusive single nucleon-removal cross sections from medium mass neutron-rich nuclei impinging on a hydrogen target at ∼250 MeV/nucleon are measured at the RIKEN Radioactive Isotope Beam Factory. Systematically higher cross sections are found for proton removal from nuclei with an even number of protons as compared to odd-proton number projectiles for a given neutron separation energy. Neutron removal cross sections display no even-odd splitting, contrary to nuclear cascade model predictions. Both effects are understood through simple considerations of neutron separation energies and bound state level densities originating in pairing correlations in the daughter nuclei. These conclusions are supported by comparison with semimicroscopic model predictions, highlighting the enhanced role of low-lying level densities in nucleon-removal cross sections from loosely bound nuclei.

Erratum: Persistence of the Z=28 Shell Gap Around

This corrects the article DOI: 10.1103/PhysRevLett.119.192501.

Magic Nature of Neutrons in

We perform the first direct mass measurements of neutron-rich calcium isotopes beyond neutron number 34 at the RIKEN Radioactive Isotope Beam Factory by using the time-of-flight magnetic-rigidity technique. The atomic mass excesses of ^{55-57}Ca are determined for the first time to be -18650(160), -13510(250), and -7370(990) keV, respectively. We examine the emergence of neutron magicity at N=34 based on the new atomic masses. The new masses provide experimental evidence for the appearance of a sizable energy gap between the neutron 2p_{1/2} and 1f_{5/2} orbitals in ^{54}Ca, comparable to the gap between the neutron 2p_{3/2} and 2p_{1/2} orbitals in ^{52}Ca. For the ^{56}Ca nucleus, an open-shell property in neutrons is suggested.

Persistence of the Z=28 Shell Gap Around

In-beam γ-ray spectroscopy of ^{79}Cu is performed at the Radioactive Isotope Beam Factory of RIKEN. The nucleus of interest is produced through proton knockout from a ^{80}Zn beam at 270 MeV/nucleon. The level scheme up to 4.6 MeV is established for the first time and the results are compared to Monte Carlo shell-model calculations. We do not observe significant knockout feeding to the excited states below 2.2 MeV, which indicates that the Z=28 gap at N=50 remains large. The results show that the ^{79}Cu nucleus can be described in terms of a valence proton outside a ^{78}Ni core, implying the magic character of the latter.

CXorf48 is a potential therapeutic target for achieving treatment-free remission in CML patients.

Although the introduction of tyrosine kinase inhibitors (TKIs) has improved overall survival of patients with chronic myeloid leukemia (CML), about half of the patients eventually relapse after cessation of TKIs. In contrast, the remainder of the patients maintain molecular remission without TKIs, indicating that the patients' immune system could control proliferation of TKI-resistant leukemic stem cells (LSCs). However, the precise mechanism of immunity against CML-LSCs is not fully understood. We have identified a novel immune target, CXorf48, expressed in LSCs of CML patients. Cytotoxic T cells (CTLs) induced by the epitope peptide derived from CXorf48 recognized CD34+CD38- cells obtained from the bone marrow of CML patients. We detected CXorf48-specific CTLs in the peripheral blood mononuclear cells from CML patients who have discontinued imatinib after maintaining complete molecular remission for more than 2 years. Significantly, the relapse rate of CXorf48-specific CTL-negative patients was 63.6%, compared to 0% in CXorf48-specific CTL-positive patients. These results indicate that CXorf48 could be a promising therapeutic target of LSCs for immunotherapy to obtain durable treatment-free remission in CML patients.

Brown adipose tissue is involved in diet-induced thermogenesis and whole-body fat utilization in healthy humans.

BACKGROUND/OBJECTIVES: Brown adipose tissue (BAT) is a potential therapeutic target against obesity and diabetes through thermogenesis and substrate disposal with cold exposure. The role of BAT in energy metabolism under thermoneutral conditions, however, remains controversial. We assessed the contribution of BAT to energy expenditure (EE), particularly diet-induced thermogenesis (DIT), and substrate utilization in human adults. METHODS: In this cross-sectional study, BAT activity was evaluated in 21 men using 18F-fluoro-2-deoxy-D-glucose positron emission tomography combined with computed tomography (18F-FDG-PET/CT) after cold exposure (19 °C). The subjects were divided into BAT-positive (n=13) and BAT-negative (n=8) groups according to the 18F-FDG-PET/CT findings. Twenty-four hour EE, DIT and respiratory quotient were measured using a whole-room indirect calorimeter at 27 °C. RESULTS: Body composition, blood metabolites and 24-h EE did not differ between groups. DIT (%), calculated as DIT divided by total energy intake, however, was significantly higher in the BAT-positive group (BAT-positive: 9.7±2.5%, BAT-negative: 6.5±4.0%, P=0.03). The 24-h respiratory quotient was significantly lower (P=0.03) in the BAT-positive group (0.861±0.027) than in the BAT-negative group (0.889±0.024). CONCLUSION: DIT and fat utilization were higher in BAT-positive subjects compared to BAT-negative subjects, suggesting that BAT has a physiologic role in energy metabolism.

Emerging treatments in neurogastroenterology: Acotiamade, a novel treatment option for functional dyspepsia.

BACKGROUND: Acotiamide hydrochloride (Z-338) is a new therapeutic agent for functional dyspepsia (FD). In 2013, the use of acotiamide was approved by the Japanese health insurance system. PURPOSE: The aim of this review is to summarize the present staus of basic and clinical approach to acotiamide for the treatment of functional dyspepsia. The agent inhibits acetylcholinesterase in vitro and enhances muscle motility ex vivo. In phase-II studies, 100 mg three times daily (t.i.d.) was determined to be the optimal dose for the treatment of FD. In phase-III studies, overall treatment efficacy (OTE) was significantly better in the acotiamide group (52.2%) than in the placebo group (34.8%). However, the mechanism of its efficacy needs to be further elucidated. Acotiamide effectively improved FD symptoms, particularly postprandial distress syndrome symptoms, without causing major adverse effects.

The combined associations of social participation and support with self-rated health and dietary satisfaction in men with spinal cord injury.

STUDY DESIGN: Cross-sectional study. OBJECTIVES: (1) To examine the association between social participation (SP) and social support (SS) with self-rated health and dietary satisfaction and (2) to explore the joint association and interactions of SP and SS with self-rated health and dietary satisfaction in community-dwelling adult men with spinal cord injury. SETTING: Members of the Spinal Injuries Japan organization. METHODS: We sent questionnaires to 2731 registered members of Spinal Injuries Japan via mail. Responses from 625 men aged ⩾40 years were analyzed. Respondents were categorized into four groups: SP/sufficient SS, SP/insufficient SS, no SP/sufficient SS and no SP/insufficient SS. Logistic regression analysis was used to examine the odds ratios for self-rated health and dietary satisfaction according to the SP/SS categories. RESULTS: Relative to participants in the no SP/insufficient SS category, those in the SP/sufficient SS group demonstrated significantly better self-rated health and dietary satisfaction after adjusting for sociodemographic variables. There was no interaction between SP and SS in self-rated health or dietary satisfaction. SP was associated with high self-rated health without SS, and sufficient SS was associated with high dietary satisfaction without SP. CONCLUSIONS: Relative to other groups, participants with SP/sufficient SS demonstrated higher self-rated health and dietary satisfaction. Sufficient SS was associated with high dietary satisfaction without SP. This study suggested the importance of addressing aspects of both SP and SS using self-rated health and dietary satisfaction as outcome measures in health promotion programs.

Extension of the N=40 Island of Inversion towards N=50: Spectroscopy of (66)Cr, (70,72)Fe.

We report on the measurement of the first 2(+) and 4(+) states of (66)Cr and (70,72)Fe via in-beam γ-ray spectroscopy. The nuclei of interest were produced by (p,2p) reactions at incident energies of 260 MeV/nucleon. The experiment was performed at the Radioactive Isotope Beam Factory, RIKEN, using the DALI 2γ-ray detector array and the novel MINOS device, a thick liquid hydrogen target combined with a vertex tracker. A low-energy plateau of 2(1)(+) and 4(1)(+) energies as a function of the neutron number was observed for N≥38 and N≥40 for even-even Cr and Fe isotopes, respectively. State-of-the-art shell model calculations with a modified Lenzi-Nowacki-Poves-Sieja (LNPS) interaction in the pfg(9/2)d(5/2) valence space reproduce the observations. Interpretation within the shell model shows an extension of the island of inversion at N=40 for more neutron-rich isotopes towards N=50.

Reflecting microscope system with a 0.99 numerical aperture designed for three-dimensional fluorescence imaging of individual molecules at cryogenic temperatures.

We have developed a cryogenic fluorescence microscope system, the core of which is a reflecting objective that consists of spherical and aspherical mirrors. The use of an aspherical mirror allows the reflecting objective to have a numerical aperture (NA) of up to 0.99, which is close to the maximum possible NA of 1.03 in superfluid helium. The performance of the system at a temperature of 1.7 K was tested by recording a three-dimensional fluorescence image of individual quantum dots using excitation wavelengths (λex) of 532 nm and 635 nm. At 1.7 K, the microscope worked with achromatic and nearly diffraction-limited performance. The 1/e(2) radius (Γ) of the point spread function of the reflecting objective in the lateral (xy) direction was 0.212 ± 0.008 µm at λex = 532 nm and was less than 1.2 times the simulated value for a perfectly polished objective. The radius Γ in the axial (z) direction was 0.91 ± 0.04 µm at λex = 532 nm and was less than 1.4 times the simulated value of Γ. The chromatic aberrations between the two wavelengths were one order of magnitude smaller than Γ in each direction.

Low-Lying Structure of (50)Ar and the N=32 Subshell Closure.

The low-lying structure of the neutron-rich nucleus (50)Ar has been investigated at the Radioactive Isotope Beam Factory using in-beam γ-ray spectroscopy with (9)Be((54)Ca,(50)Ar+γ)X, (9)Be((55)Sc,(50)Ar+γ)X, and (9)Be((56)Ti,(50)Ar+γ)X multinucleon removal reactions at ∼220 MeV/u. A γ-ray peak at 1178(18) keV is reported and assigned as the transition from the first 2(+) state to the 0(+) ground state. A weaker, tentative line at 1582(38) keV is suggested as the 4(1)(+)→2(1)(+) transition. The experimental results are compared to large-scale shell-model calculations performed in the sdpf model space using the SDPF-MU effective interaction with modifications based on recent experimental data for exotic calcium and potassium isotopes. The modified Hamiltonian provides a satisfactory description of the new experimental results for (50)Ar and, more generally, reproduces the energy systematics of low-lying states in neutron-rich Ar isotopes rather well. The shell-model calculations indicate that the N=32 subshell gap in (50)Ar is similar in magnitude to those in (52)Ca and (54)Ti and, notably, predict an N=34 subshell closure in (52)Ar that is larger than the one recently reported in (54)Ca.

The Impact of c-Fos/Activator Protein-1 Inhibition on Allogeneic Pancreatic Islet Transplantation.

Unpreventable allograft rejection is one of the main problems in pancreatic islet transplantation (PIT). Therefore, it is imperative to develop a more effective immunosuppressive strategy. The blockade of transcription factors has been a central part of T cell-depleting immunosuppressive therapies, as typified by the use of calcineurin inhibitors. The inhibition of activator protein-1 (AP-1) offers a novel strategy for immunosuppression in PIT, although to date, no reports on the effects of AP-1 inhibition are available. In this study, we investigated the immunosuppressive effects of T-5224, a c-Fos/AP-1-selective inhibitor, on murine T cells activated by αCD3+αCD28 mAbs. T-5224 inhibited proliferation, CD25 up-regulation, and the production of IL-2 and interferon-γ. In addition, T-5224 blocked the nuclear translocation of c-Fos/AP-1 in activated murine T cells. In BALB/c (H-2(d) )-to-C57BL/6J (H-2(b) ) mouse PIT, the 2-week administration of T-5224 prolonged survival of 600 islet allografts in a dose-dependent manner. When combined with a 2-week low-dose tacrolimus, the T-5224 treatment markedly prolonged allograft survival to over 300 days, while the efficacy was indeterminate when transplanted islet allograft mass was reduced to 300. We conclude that the c-Fos/AP-1 inhibition by T-5224 is a potentially attractive strategy for allogeneic PIT.

Monocyte CD64 expression as a novel biomarker for the disease activity of systemic lupus erythematosus.

OBJECTIVE: Interferon alpha (IFN-α) is a key cytokine associated with systemic lupus erythematosus (SLE). IFN-α induces the expression of CD64 on monocytes (mCD64). Although enhanced mCD64 expression has been reported in patients with SLE, it has never been assessed quantitatively. The aim of this study was to investigate whether or not mCD64 expression correlates with SLE disease activity. METHODS: The mCD64 expression levels were assessed quantitatively in 40 patients with active or inactive SLE by using flow cytometry. The mCD64 expression levels were subsequently compared with the SLE disease activity index (SLEDAI) and levels of existing SLE activity biomarkers, such as anti-DNA antibody, complements, and so on. RESULTS: The mCD64 expression was significantly higher in active disease than in inactive disease SLE (median molecules/cell, interquartile range: 34,648, 8174-24,932 and 20,865, 6357-21,503, respectively; p < 0.001). The levels of mCD64 expression strongly correlated with SLEDAI (r = 0.68, p < 0.001). CONCLUSION: The mCD64 expression is a simple and useful biomarker for evaluating disease activity in patients with SLE.

Differences in female reproductive success between female and hermaphrodite individuals in the subdioecious shrub Eurya japonica (Theaceae).

Subdioecy is thought to occupy a transitional position in the gynodioecy-dioecy pathway, explaining one of the evolutionary routes from hermaphroditism to dioecy. Quantifying any female reproductive advantage of females versus hermaphrodites is fundamental to examining the spectrum between subdioecy and dioecy; however, this is challenging, as multiple interacting factors, such as pollen limitation and resource availability, affect plant reproduction. We compared the female reproductive success of females and hermaphrodites via a field experiment in which we hand-pollinated individuals of the subdioecious shrub Eurya japonica of similar size growing under similar light conditions. Effects of pollen limitation and seed quality were also evaluated through comparing the results of hand- and natural-pollination treatments and performing additional laboratory and greenhouse experiments. Overall, females had higher fruit set and produced heavier fruit and more seeds than hermaphrodites, and these results were more pronounced for hand-pollinated than for natural-pollinated plants of both sexes. We also found that seeds naturally produced by females had a higher mean germination rate. These results indicate that females had a pronounced advantage in female reproductive success under conditions of no pollen limitation. The sexual difference in the degree of pollen limitation suggests a pollinator-mediated interaction, whereas the higher female reproductive success of females even under natural conditions implies that E. japonica is a good model species for elucidating the later stages of the gynodioecy-dioecy pathway.