Impact of Two-Body Currents on Magnetic Dipole Moments of Nuclei.

We investigate the effects of two-body currents on magnetic dipole moments of medium-mass and heavy nuclei using the valence-space in-medium similarity renormalization group with chiral effective field theory interactions and currents. Focusing on near doubly magic nuclei from oxygen to bismuth, we have found that the leading two-body currents globally improve the agreement with experimental magnetic moments. Moreover, our results show the importance of multishell effects for ^{41}Ca, which suggest that the Z=N=20 gap in ^{40}Ca is not as robust as in ^{48}Ca. The increasing contribution of two-body currents in heavier systems is explained by the operator structure of the center-of-mass dependent Sachs term.

Ab Initio Uncertainty Quantification of Neutrinoless Double-Beta Decay in

The observation of neutrinoless double-beta (0νßß) decay would offer proof of lepton number violation, demonstrating that neutrinos are Majorana particles, while also helping us understand why there is more matter than antimatter in the Universe. If the decay is driven by the exchange of the three known light neutrinos, a discovery would, in addition, link the observed decay rate to the neutrino mass scale through a theoretical quantity known as the nuclear matrix element (NME). Accurate values of the NMEs for all nuclei considered for use in 0νßß experiments are therefore crucial for designing and interpreting those experiments. Here, we report the first comprehensive ab initio uncertainty quantification of the 0νßß-decay NME, in the key nucleus ^{76}Ge. Our method employs nuclear strong and weak interactions derived within chiral effective field theory and recently developed many-body emulators. Our result, with a conservative treatment of uncertainty, is an NME of 2.60_{-1.36}^{+1.28}, which, together with the best-existing half-life sensitivity and phase-space factor, sets an upper limit for effective neutrino mass of 187_{-62}^{+205} meV. The result is important for designing next-generation germanium detectors aiming to cover the entire inverted hierarchy region of neutrino masses.

Isomeric Excitation Energy for

The excitation energy of the 1/2^{-} isomer in ^{99}In at N=50 is measured to be 671(37) keV and the mass uncertainty of the 9/2^{+} ground state is significantly reduced using the ISOLTRAP mass spectrometer at ISOLDE/CERN. The measurements exploit a major improvement in the resolution of the multireflection time-of-flight mass spectrometer. The results reveal an intriguing constancy of the 1/2^{-} isomer excitation energies in neutron-deficient indium that persists down to the N=50 shell closure, even when all neutrons are removed from the valence shell. This trend is used to test large-scale shell model, ab initio, and density functional theory calculations. The models have difficulties describing both the isomer excitation energies and ground-state electromagnetic moments along the indium chain.

Microsecond Isomer at the N=20 Island of Shape Inversion Observed at FRIB.

Excited-state spectroscopy from the first experiment at the Facility for Rare Isotope Beams (FRIB) is reported. A 24(2)-µs isomer was observed with the FRIB Decay Station initiator (FDSi) through a cascade of 224- and 401-keV γ rays in coincidence with ^{32}Na nuclei. This is the only known microsecond isomer (1 µs≤T_{1/2}<1 ms) in the region. This nucleus is at the heart of the N=20 island of shape inversion and is at the crossroads of the spherical shell-model, deformed shell-model, and ab initio theories. It can be represented as the coupling of a proton hole and neutron particle to ^{32}Mg, ^{32}Mg+π^{-1}+ν^{+1}. This odd-odd coupling and isomer formation provides a sensitive measure of the underlying shape degrees of freedom of ^{32}Mg, where the onset of spherical-to-deformed shape inversion begins with a low-lying deformed 2^{+} state at 885 keV and a low-lying shape-coexisting 0_{2}^{+} state at 1058 keV. We suggest two possible explanations for the 625-keV isomer in ^{32}Na: a 6^{-} spherical shape isomer that decays by E2 or a 0^{+} deformed spin isomer that decays by M2. The present results and calculations are most consistent with the latter, indicating that the low-lying states are dominated by deformation.

Anti-A and anti-B titers, age, gender, biochemical parameters, and body mass index in Japanese blood donors.

It has been reported that anti-A and anti-B (ABO antibody) titers decrease with age, but little is known about the association between ABO antibody titers and physiologic/biochemical parameters such as body mass index (BMI), gamma-glutamyl transpeptidase (GGT), and total cholesterol (T-Cho). We investigated the present situation of ABO antibody titers among healthy blood donors in Japan and the physiologic/biochemical factors that may be associated with changes in ABO antibody titers. Plasma from 7450 Japanese blood donors was tested for ABO antibody titers using ABO reverse typing reagents by an automated microplate system; donor samples were classified into low, middle, and high titers according to the agglutination results obtained with diluted plasma samples. Multivariate regression analysis was performed to analyze the association between ABO antibody titers and age, gender, biochemical parameters (alanine transaminase [ALT], GGT, globulin, T-Cho, and glycosylated albumin [GA]), and BMI according to the ABO blood groups. A significant correlation between ABO antibody titers and age/gender, except for gender in anti-A of blood group B donors, was observed. BMI showed significant but negative correlations with anti-A and anti-B (ß = -0.085 and -0.062, respectively; p < 0.01) in blood group O donors. In addition, significant but negative correlations between GGT and T-Cho with anti-B of blood group A donors (ß = -0.055 and -0.047, respectively; p < 0.05) were observed. Although differences existed among the ABO blood groups, ABO antibody titers seem to be associated with physiologic and biochemical parameters of healthy individuals.

High-Precision Spectroscopy of

The excited states of unstable ^{20}O were investigated via γ-ray spectroscopy following the ^{19}O(d,p)^{20}O reaction at 8 AMeV. By exploiting the Doppler shift attenuation method, the lifetimes of the 2_{2}^{+} and 3_{1}^{+} states were firmly established. From the γ-ray branching and E2/M1 mixing ratios for transitions deexciting the 2_{2}^{+} and 3_{1}^{+} states, the B(E2) and B(M1) were determined. Various chiral effective field theory Hamiltonians, describing the nuclear properties beyond ground states, along with a standard USDB interaction, were compared with the experimentally obtained data. Such a comparison for a large set of γ-ray transition probabilities with the valence space in medium similarity renormalization group ab initio calculations was performed for the first time in a nucleus far from stability. It was shown that the ab initio approaches using chiral effective field theory forces are challenged by detailed high-precision spectroscopic properties of nuclei. The reduced transition probabilities were found to be a very constraining test of the performance of the ab initio models.

Proton Distribution Radii of

The root mean square radii of the proton density distribution in ^{16-24}O derived from measurements of charge changing cross sections with a carbon target at ∼900A MeV together with the matter radii portray thick neutron skin for ^{22-24}O despite ^{22,24}O being doubly magic. Imprints of the shell closures at N=14 and 16 are reflected in local minima of their proton radii that provide evidence for the tensor interaction causing them. The radii agree with ab initio calculations employing the chiral NNLO_{sat} interaction, though skin thickness predictions are challenged. Shell model predictions agree well with the data.

Nuclear moments of indium isotopes reveal abrupt change at magic number 82.

In spite of the high-density and strongly correlated nature of the atomic nucleus, experimental and theoretical evidence suggests that around particular 'magic' numbers of nucleons, nuclear properties are governed by a single unpaired nucleon1,2. A microscopic understanding of the extent of this behaviour and its evolution in neutron-rich nuclei remains an open question in nuclear physics3-5. The indium isotopes are considered a textbook example of this phenomenon6, in which the constancy of their electromagnetic properties indicated that a single unpaired proton hole can provide the identity of a complex many-nucleon system6,7. Here we present precision laser spectroscopy measurements performed to investigate the validity of this simple single-particle picture. Observation of an abrupt change in the dipole moment at N = 82 indicates that, whereas the single-particle picture indeed dominates at neutron magic number N = 82 (refs. 2,8), it does not for previously studied isotopes. To investigate the microscopic origin of these observations, our work provides a combined effort with developments in two complementary nuclear many-body methods: ab initio valence-space in-medium similarity renormalization group and density functional theory (DFT). We find that the inclusion of time-symmetry-breaking mean fields is essential for a correct description of nuclear magnetic properties, which were previously poorly constrained. These experimental and theoretical findings are key to understanding how seemingly simple single-particle phenomena naturally emerge from complex interactions among protons and neutrons.

Ab Initio Structure Factors for Spin-Dependent Dark Matter Direct Detection.

We present converged ab initio calculations of structure factors for elastic spin-dependent WIMP scattering off all nuclei used in dark matter direct-detection searches: ^{19}F, ^{23}Na, ^{27}Al, ^{29}Si, ^{73}Ge, ^{127}I, and ^{129,131}Xe. From a set of established two- and three-nucleon interactions derived within chiral effective field theory, we construct consistent WIMP-nucleon currents at the one-body level, including effects from axial-vector two-body currents. We then apply the in-medium similarity renormalization group to construct effective valence-space Hamiltonians and consistently transformed operators of nuclear responses. Combining the recent advances of natural orbitals with three-nucleon forces expressed in large spaces, we obtain basis-space converged structure factors even in heavy nuclei. Generally results are consistent with previous calculations but large uncertainties in ^{127}I highlight the need for further study.

Nuclear Charge Radii of the Nickel Isotopes

Collinear laser spectroscopy is performed on the nickel isotopes ^{58-68,70}Ni, using a time-resolved photon counting system. From the measured isotope shifts, nuclear charge radii R_{c} are extracted and compared to theoretical results. Three ab initio approaches all employ, among others, the chiral interaction NNLO_{sat}, which allows an assessment of their accuracy. We find agreement with experiment in differential radii δ⟨r_{c}^{2}⟩ for all employed ab initio methods and interactions, while the absolute radii are consistent with data only for NNLO_{sat}. Within nuclear density functional theory, the Skyrme functional SV-min matches experiment more closely than the Fayans functional Fy(Δr,HFB).

Ab Initio Neutrinoless Double-Beta Decay Matrix Elements for

We calculate basis-space converged neutrinoless ßß-decay nuclear matrix elements for the lightest candidates: ^{48}Ca, ^{76}Ge, and ^{82}Se. Starting from initial two- and three-nucleon forces, we apply the ab initio in-medium similarity renormalization group to construct valence-space Hamiltonians and consistently transformed ßß-decay operators. We find that the tensor component is non-negligible in ^{76}Ge and ^{82}Se, and the resulting nuclear matrix elements are overall 25%-45% smaller than those obtained from the phenomenological shell model. While a final matrix element with uncertainties still requires substantial developments, this work nevertheless opens a path toward a true first-principles calculation of neutrinoless ßß decay in all nuclei relevant for ongoing large-scale searches.

Precision Mass Measurements of Neutron-Rich Scandium Isotopes Refine the Evolution of N=32 and N=34 Shell Closures.

We report high-precision mass measurements of ^{50-55}Sc isotopes performed at the LEBIT facility at NSCL and at the TITAN facility at TRIUMF. Our results provide a substantial reduction of their uncertainties and indicate significant deviations, up to 0.7 MeV, from the previously recommended mass values for ^{53-55}Sc. The results of this work provide an important update to the description of emerging closed-shell phenomena at neutron numbers N=32 and N=34 above proton-magic Z=20. In particular, they finally enable a complete and precise characterization of the trends in ground state binding energies along the N=32 isotone, confirming that the empirical neutron shell gap energies peak at the doubly magic ^{52}Ca. Moreover, our data, combined with other recent measurements, do not support the existence of a closed neutron shell in ^{55}Sc at N=34. The results were compared to predictions from both ab initio and phenomenological nuclear theories, which all had success describing N=32 neutron shell gap energies but were highly disparate in the description of the N=34 isotone.

The efficacy of eribulin mesylate for patients with cutaneous angiosarcoma previously treated with taxane: a multicentre prospective observational study.

BACKGROUND: Taxanes are the current first-line treatment for advanced cutaneous angiosarcoma (CAS) for patients who are considered difficult to treat with doxorubicin owing to advanced age or comorbidity. However, no effective second-line therapy for such patients has been established. METHODS: We designed a single-arm prospective observational study of eribulin mesylate (ERB) administered at a dose of 1·4 mg m-2 on days 1 and 8 in a 21-day cycle. Patients with advanced CAS who were previously treated with a taxane and were scheduled to begin ERB treatment were enrolled. The primary endpoint was overall survival (OS) and the secondary endpoints were response rate (RR), progression-free survival (PFS) and toxicity assessment. RESULTS: We enrolled a total of 25 patients. The median OS and PFS were 8·6 months and 3·0 months, respectively. The best overall RR was 20% (five of 25). In total, 16 grade 3/4 severe adverse events (SAEs) occurred; however, all patients recovered. Patients who achieved partial response or stable disease as best response had longer OS than those with progressive disease (median OS not reached and 3·3 months, respectively; P < 0·001). Patients who did not experience SAEs showed longer OS than those who did (median OS 18·8 months and 7·5 months, respectively; P < 0·05). Patients with distant metastasis had shorter median OS than those with locoregional disease, but without statistically significant difference. CONCLUSIONS: ERB showed a promising RR and is a potential candidate for second-line treatment for patients with CAS, after treatment with taxanes. However, owing to the occurrence of SAEs in over half of the participants, caution should be exercised regarding ERB use in elderly patients. What is already known about this topic? Taxanes are the current first-line treatment for patients with advanced cutaneous angiosarcoma (CAS) who are considered difficult to treat with doxorubicin owing to advanced age or comorbidity. No effective therapy for taxane-resistant CAS has been established thus far. Eribulin suppresses microtubule polymerization and elicits an antitumour effect similar to that of taxanes. What does this study add? In our single-arm prospective observational study to evaluate the efficacy of eribulin for treating patients with advanced CAS who previously received taxanes, the median overall survival and progression-free survival were 8·6 and 3·0 months, respectively. Response rates at weeks 7, 13 and 25 were 20%, 17% and 14%, respectively. Although 16 grade 3/4 severe adverse events occurred, all patients recovered. Eribulin showed a promising response rate and is a potential candidate for second-line treatment in CAS after taxane treatment. Linked Comment: Smrke and Benson. Br J Dermatol 2020; 183:797-798.

Hydroxychloroquine modulates elevated expression of S100 proteins in systemic lupus erythematosus.

OBJECTIVES: We investigated the effect of hydroxychloroquine (HCQ) on S100A8 and S100A9 serum levels in systemic lupus erythematosus (SLE) patients with low disease activity receiving immunosuppressants. METHODS: SELENA-SLEDAI, Cutaneous Lupus Erythematous Disease Area and Severity Index (CLASI) and serum levels of complement factors, anti-dsDNA antibodies, and white blood cell, lymphocyte, and platelet counts were used to evaluate disease activity, cutaneous disease activity, and immunological activity, respectively. Serum S100A8 and S100A9 were measured at HCQ administration and after 3 or 6 months using ELISA. RESULTS: S100A8 and S100A9 serum levels were elevated at baseline and the magnitude of decrease from baseline at 3 and 6 months after HCQ administration was greater in patients with renal involvement than in those without (baseline: S100A8, p = 0.034; S100A9, p = 0.0084; decrease: S100A8, p = 0.049; S100A9, p = 0.023). S100 modulation was observed in patients with (n = 17; S100A8, p = 0.0011; S100A9, p = 0.0002) and without renal involvement (n = 20; S100A8, p = 0.0056; S100A9, p = 0.0012), and was more apparent in patients with improved CLASI activity scores (improved: S100A8, p = 0.013; S100A9, p = 0.0032; unimproved: S100A8, p = 0.055; S100A9, p = 0.055). No associations were observed for immunological biomarkers. CONCLUSION: HCQ may improve organ involvement in SLE by modulating S100 protein levels, especially in patients with renal or skin involvement.

Successful treatment of toxoplasmic encephalitis diagnosed early by polymerase chain reaction after allogeneic hematopoietic stem cell transplantation: two case reports and review of the literature.

Toxoplasmic encephalitis represents a rare, but often fatal infection after allogeneic hematopoietic stem cell transplantation. Polymerase chain reaction (PCR)-based preemptive therapy is considered promising for this disease, but is not routinely applied, especially in low seroprevalence countries including Japan. We encountered 2 cases of toxoplasmic encephalitis after transplantation that were successfully treated. The diagnosis of toxoplasmic encephalitis in these cases was confirmed by PCR testing when neurological symptoms were observed. Both patients received pyrimethamine and sulfadiazine treatments within 2 weeks of the development of neurological symptoms, and remained free of recurrence for 32 and 12 months. These results emphasized the importance of the PCR test and immediate treatment after diagnosis for the management of toxoplasmic encephalitis.

The real impact of telaprevir dosage on the antiviral and side effects of telaprevir, pegylated interferon and ribavirin therapy for chronic hepatitis C patients with HCV genotype 1.

Triple therapy with telaprevir, pegylated interferon and ribavirin has been reported to improve antiviral efficacy but have potentially severe adverse effects in patients with chronic hepatitis C. To avoid the severe effects of telaprevir, lowering the dose has been suggested. However, impact of dosage changes on antiviral and adverse effects remains unclear. One hundred and sixty-six Japanese patients with HCV genotype 1 were treated with triple therapy. The drug exposure of each medication was calculated by averaging the dose actually taken. The overall SVR rate was 82%. The telaprevir discontinuation rate was 26%. The factors associated with discontinuation were an older age (≥65 y.o.) and a higher average dose during treatment. The telaprevir discontinuation rates were 42%, 25% and 14% in patients at ≥35, 25-35 and <25 mg/kg/day of telaprevir and 58% in older patients at ≥35 mg/kg/day of TVR. The factors associated with SVR were treatment-naïve, relapse to previous treatment, higher average telaprevir dose during treatment and completion of treatment. The SVR rate was higher, at 91%, in patients at 25-35 mg/kg/day of telaprevir than the 71% and 78% observed in those at <25 and ≥35 mg/kg/day of drug. In Japanese patients, a mean telaprevir dose of 25-35 mg/kg/day during treatment can augment its efficacy in triple therapy for patients with HCV genotype 1.

Risk factors for hepatocellular carcinoma in hepatitis C patients with normal alanine aminotransferase treated with pegylated interferon and ribavirin.

Pegylated interferon (Peg-IFN) plus ribavirin combination therapy is effective in patients with hepatitis C virus (HCV) infection and normal alanine aminotransferase levels (NALT). However, it remains unclear whether the risk of hepatocellular carcinoma (HCC) incidence is actually reduced in virological responders. In this study, HCC incidence was examined for 809 patients with NALT (ALT ≤ 40 IU/mL) treated with Peg-IFN alpha-2b and ribavirin for a mean observation period of 36.2 ± 16.5 months. The risk factors for HCC incidence were analysed by Kaplan-Meier method and Cox proportional hazards model. On multivariate analysis among NALT patients, the risk of HCC incidence was significantly reduced in patients with sustained virological response (SVR) or relapse compared with those showing nonresponse (NR) (SVR vs NR, hazard ratio (HR): 0.16, P = 0.009, relapse vs NR, HR: 0.11, P = 0.037). Other risk factors were older age (≥65 years vs <60 years, HR: 6.0, P = 0.032, 60-64 vs <60 years, HR: 3.2, P = 0.212) and male gender (HR: 3.9, P = 0.031). Among 176 patients with PNALT (ALT ≤ 30 IU/mL), only one patient developed HCC and no significant risk factors associated with HCC development were found. In conclusion, antiviral therapy for NALT patients with HCV infection can lower the HCC incidence in responders, particularly for aged and male patients. The indication of antiviral therapy for PNALT (ALT ≤ 30 IU/mL) patients should be carefully determined.

Mcl-1 and Bcl-xL regulate Bak/Bax-dependent apoptosis of the megakaryocytic lineage at multistages.

Anti-apoptotic Bcl-2 family proteins, which inhibit the mitochondrial pathway of apoptosis, are involved in the survival of various hematopoietic lineages and are often dysregulated in hematopoietic malignancies. However, their involvement in the megakaryocytic lineage is not well understood. In the present paper, we describe the crucial anti-apoptotic role of Mcl-1 and Bcl-xL in this lineage at multistages. The megakaryocytic lineage-specific deletion of both, in sharp contrast to only one of them, caused apoptotic loss of mature megakaryocytes in the fetal liver and systemic hemorrhage, leading to embryonic lethality. ABT-737, a Bcl-xL/Bcl-2/Bcl-w inhibitor, only caused thrombocytopenia in adult wild-type mice, but further induced massive mature megakaryocyte apoptosis in the Mcl-1 knockout mice, leading to severe hemorrhagic anemia. All these phenotypes were fully restored if Bak and Bax, downstream apoptosis executioners, were also deficient. In-vitro study revealed that the Jak pathway maintained Mcl-1 and Bcl-xL expression levels, preventing megakaryoblastic cell apoptosis. Similarly, both were involved in reticulated platelet survival, whereas platelet survival was dependent on Bcl-xL due to rapid proteasomal degradation of Mcl-1. In conclusion, Mcl-1 and Bcl-xL regulate the survival of the megakaryocytic lineage, which is critically important for preventing lethal or severe hemorrhage in both developing and adult mice.

Plasma membrane-associated sialidase (NEU3) regulates progression of prostate cancer to androgen-independent growth through modulation of androgen receptor signaling.

Prostate cancers generally become androgen-independent and resistant to hormone therapy with progression. To understand the underlying mechanisms and facilitate the development of novel treatments for androgen-independent prostate cancer, we have investigated plasma membrane-associated sialidase (NEU3), the key enzyme for ganglioside hydrolysis participating in transmembrane signaling. We have discovered NEU3 to be upregulated in human prostate cancer compared with non-cancerous tissue, correlating with the Gleason score. NEU3 silencing with siRNA in prostate cancer PC-3 and LNCaP cells resulted in increased expression of differentiation markers and in cell apoptosis, but decrease in Bcl-2 as well as a progression-related transcription factor, early growth response gene (EGR-1). In androgen-sensitive LNCaP cells, forced overexpression of NEU3 significantly induced expression of EGR-1, androgen receptor (AR) and PSA both with and without androgen, the cells becoming sensitive to androgen. The NEU3-mediated induction was abrogated by inhibitors for PI-3 kinase and MAP kinase and more specifically by their silencing in the absence of androgen, being confirmed by increased phosphorylation of AKT and ERK1/2 in NEU3 overexpressing cells. NEU3 siRNA introduction caused reduction of cell growth of an androgen-independent PC-3 cells in culture and of transplanted tumors in nude mice. These data suggest that NEU3 regulates tumor progression through AR signaling, and thus be a potential tool for diagnosis and therapy of androgen-independent prostate cancer.