Self-Consistent Picture of the Mass Ejection from a One Second Long Binary Neutron Star Merger Leaving a Short-Lived Remnant in a General-Relativistic Neutrino-Radiation Magnetohydrodynamic Simulation.

We perform a general-relativistic neutrino-radiation magnetohydrodynamic simulation of a one second-long binary neutron star merger on the Japanese supercomputer Fugaku using about 85 million CPU hours with 20 736 CPUs. We consider an asymmetric binary neutron star merger with masses of 1.2M_{⊙} and 1.5M_{⊙} and a "soft" equation of state SFHo. It results in a short-lived remnant with the lifetime of ≈0.017 s, and subsequent massive torus formation with the mass of ≈0.05M_{⊙} after the remnant collapses to a black hole. For the first time, we find that after the dynamical mass ejection, which drives the fast tail and mildly relativistic components, the postmerger mass ejection from the massive torus takes place due to the magnetorotational instability-driven turbulent viscosity in a single simulation and the two ejecta components are seen in the distributions of the electron fraction and velocity with distinct features.

Effects of root morphology, respiration and carboxylate exudation on carbon economy in two non-mycorrhizal lupines under phosphorus deficiency.

Under phosphorus (P) deficiency, Lupinus albus develops cluster roots that allow efficient P acquisition, while L. angustifolius without cluster roots also grows well. Both species are non-mycorrhizal. We quantitatively examined the carbon budgets to investigate the different strategies of these species. Biomass allocation, respiratory rates, protein amounts and carboxylate exudation rates were examined in hydroponically-grown plants treated with low (1 µM; P1) or high (100 µM; P100) P. At P1, L. albus formed cluster roots, and L. angustifolius increased biomass allocation to the roots. The respiratory rates of the roots were faster in L. albus than in L. angustifolius. The protein amounts of the non-phosphorylating alternative oxidase and uncoupling protein were greater in the cluster roots of L. albus at P1 than in the roots at P100, but similar between the P treatments in L. angustifolius roots. At P1, L. albus exuded carboxylates at a faster rate than L. angustifolius. The carbon budgets at P1 were surprisingly similar between the two species, which is attributed to the contrasting root growth and development strategies. L. albus developed cluster roots with rapid respiratory and carboxylate exudation rates, while L. angustifolius developed a larger root system with slow respiratory and exudation rates.

Effects of Neutron-Star Dynamic Tides on Gravitational Waveforms within the Effective-One-Body Approach.

Extracting the unique information on ultradense nuclear matter from the gravitational waves emitted by merging neutron-star binaries requires robust theoretical models of the signal. We develop a novel effective-one-body waveform model that includes, for the first time, dynamic (instead of only adiabatic) tides of the neutron star as well as the merger signal for neutron-star-black-hole binaries. We demonstrate the importance of the dynamic tides by comparing our model against new numerical-relativity simulations of nonspinning neutron-star-black-hole binaries spanning more than 24 gravitational-wave cycles, and to other existing numerical simulations for double neutron-star systems. Furthermore, we derive an effective description that makes explicit the dependence of matter effects on two key parameters: tidal deformability and fundamental oscillation frequency.

LIL3, a light-harvesting-like protein, plays an essential role in chlorophyll and tocopherol biosynthesis.

The light-harvesting chlorophyll-binding (LHC) proteins are major constituents of eukaryotic photosynthetic machinery. In plants, six different groups of proteins, LHC-like proteins, share a conserved motif with LHC. Although the evolution of LHC and LHC-like proteins is proposed to be a key for the diversification of modern photosynthetic eukaryotes, our knowledge of the evolution and functions of LHC-like proteins is still limited. In this study, we aimed to understand specifically the function of one type of LHC-like proteins, LIL3 proteins, by analyzing Arabidopsis mutants lacking them. The Arabidopsis genome contains two gene copies for LIL3, LIL3:1 and LIL3:2. In the lil3:1/lil3:2 double mutant, the majority of chlorophyll molecules are conjugated with an unsaturated geranylgeraniol side chain. This mutant is also deficient in α-tocopherol. These results indicate that reduction of both the geranylgeraniol side chain of chlorophyll and geranylgeranyl pyrophosphate, which is also an essential intermediate of tocopherol biosynthesis, is compromised in the lil3 mutants. We found that the content of geranylgeranyl reductase responsible for these reactions was severely reduced in the lil3 double mutant, whereas the mRNA level for this enzyme was not significantly changed. We demonstrated an interaction of geranylgeranyl reductase with both LIL3 isoforms by using a split ubiquitin assay, bimolecular fluorescence complementation, and combined blue-native and SDS polyacrylamide gel electrophoresis. We propose that LIL3 is functionally involved in chlorophyll and tocopherol biosynthesis by stabilizing geranylgeranyl reductase.

NAD-dependent histone deacetylase, SIRT1, plays essential roles in the maintenance of hematopoietic stem cells.

Sir2 has been shown to be essential for transcriptional silencing and longevity provided by calorie restriction in Saccharomyces cerevisiae and Caenorhabditis elegans. In this study, we investigated the role for its mammalian homologue, SIRT1, in hematopoietic cells. SIRT1 inhibitor, nicotinamide (NA), promoted and its activator, resveratrol, inhibited the differentiation of murine bone marrow c-Kit(high)Sca-1(+)Lineage(-) (KSL) cells during the culture system ex vivo. To further clarify the roles of SIRT1 in hematopoietic cells, we isolated KSL cells from fetal liver of SIRT1 knockout (KO) mice and cultured them for 5days, because SIRT1 KO mice die shortly after the delivery. In agreement with the results from the experiments using NA and resveratrol, KSL cells isolated from SIRT1 KO mice more apparently differentiated and lost the KSL phenotype than those from wild-type (WT) mice. Furthermore, in each of colony assay, replating assay, or serial transplantation assay, SIRT1 KO KSL cells lost earlier the characteristics of stem cells than WT KSL cells. In addition, we found that SIRT1 maintains prematurity of hematopoietic cells through ROS elimination, FOXO activation, and p53 inhibition. These results suggest that SIRT1 suppresses differentiation of hematopoietic stem/progenitor cells and contributes to the maintenance of stem cell pool.

BCR-ABL but not JAK2 V617F inhibits erythropoiesis through the Ras signal by inducing p21CIP1/WAF1.

BCR-ABL is a causative tyrosine kinase (TK) of chronic myelogenous leukemia (CML). In CML patients, although myeloid cells are remarkably proliferating, erythroid cells are rather decreased and anemia is commonly observed. This phenotype is quite different from that observed in polycythemia vera (PV) caused by JAK2 V617F, whereas both oncogenic TKs activate common downstream molecules at the level of hematopoietic stem cells (HSCs). To clarify this mechanism, we investigated the effects of BCR-ABL and JAK2 V617F on erythropoiesis. Enforced expression of BCR-ABL but not of JAK2 V617F in murine LSK (Lineage(-)Sca-1(hi)CD117(hi)) cells inhibited the development of erythroid cells. Among several signaling molecules downstream of BCR-ABL, an active mutant of N-Ras (N-RasE12) but not of STAT5 or phosphatidylinositol 3-kinase (PI3-K) inhibited erythropoiesis, while N-RasE12 enhanced the development of myeloid cells. BCR-ABL activated Ras signal more intensely than JAK2 V617F, and inhibition of Ras by manumycin A, a farnesyltransferase inhibitor, ameliorated erythroid colony formation of CML cells. As for the mechanisms of Ras-induced suppression of erythropoiesis, we found that GATA-1, an erythroid-specific transcription factor, blocked Ras-mediated mitogenic signaling at the level of MEK through the direct interaction. Furthermore, enforced expression of N-RasE12 in LSK cells derived from p53-, p16(INK4a)/p19(ARF)-, and p21(CIP1/WAF1)-null/wild-type mice revealed that suppressed erythroid cell growth by N-RasE12 was restored only by p21(CIP1/WAF1) deficiency, indicating that a cyclin-dependent kinase (CDK) inhibitor, p21(CIP1/WAF1), plays crucial roles in Ras-induced suppression of erythropoiesis. These data would, at least partly, explain why respective oncogenic TKs cause different disease phenotypes.

Distinct responses of the mitochondrial respiratory chain to long- and short-term high-light environments in Arabidopsis thaliana.

In order to ensure the cooperative function with the photosynthetic system, the mitochondrial respiratory chain needs to flexibly acclimate to a fluctuating light environment. The non-phosphorylating alternative oxidase (AOX) is a notable respiratory component that may support a cellular redox homeostasis under high-light (HL) conditions. Here we report the distinct acclimatory manner of the respiratory chain to long- and short-term HL conditions and the crucial function of AOX in Arabidopsis thaliana leaves. Plants grown under HL conditions (HL plants) possessed a larger ubiquinone (UQ) pool and a higher amount of cytochrome c oxidase than plants grown under low light conditions (LL plants). These responses in HL plants may be functional for efficient ATP production and sustain the fast plant growth. When LL plants were exposed to short-term HL stress (sHL), the UQ reduction level was transiently elevated. In the wild-type plant, the UQ pool was re-oxidized concomitantly with an up-regulation of AOX. On the other hand, the UQ reduction level of the AOX-deficient aox1a mutant remained high. Furthermore, the plastoquinone pool was also more reduced in the aox1a mutant under such conditions. These results suggest that AOX plays an important role in rapid acclimation of the respiratory chain to sHL, which may support efficient photosynthetic performance.

A murine model for induction of long-term immunologic tolerance to factor VIII does not require persistent detectable levels of plasma factor VIII and involves contributions from Foxp3+ T regulatory cells.

Under certain instances, factor VIII (FVIII) stimulates an immune response, and the resulting neutralizing antibodies present a significant clinical challenge. Immunotherapies to re-establish or induce long-term tolerance would be beneficial, and an in-depth knowledge of mechanisms involved in tolerance induction is essential to develop immune-modulating strategies. We have developed a murine model system for studying mechanisms involved in induction of immunologic tolerance to FVIII in hemophilia A mice. We used lentiviral vectors to deliver the canine FVIII transgene to neonatal hemophilic mice and demonstrated that induction of long-term FVIII tolerance could be achieved. Hemophilia A mice are capable of mounting a robust immune response to FVIII after neonatal gene transfer, and tolerance induction is dependent on the route of delivery and type of promoter used. High-level expression of FVIII was not required for tolerance induction and, indeed, tolerance developed in some animals without evidence of detectable plasma FVIII. Tolerance to FVIII could be adoptively transferred to naive hemophilia recipient mice, and FVIII-stimulated splenocytes isolated from tolerized mice expressed increased levels of interleukin-10 and decreased levels of interleukin-6 and interferon-gamma. Finally, induction of FVIII tolerance mediated by this protocol is associated with a FVIII-expandable population of CD4(+)CD25(+)Foxp3(+) regulatory T cells.

Gravitational waves and neutrino emission from the merger of binary neutron stars.

Numerical simulations for the merger of binary neutron stars are performed in full general relativity incorporating a finite-temperature (Shen's) equation of state (EOS) and neutrino cooling for the first time. It is found that for this stiff EOS, a hypermassive neutron star (HMNS) with a long lifetime (≫10 ms) is the outcome for the total mass ≲3.0M(⊙). It is shown that the typical total neutrino luminosity of the HMNS is ∼3-8×10(53) erg/s and the effective amplitude of gravitational waves from the HMNS is 4-6×10(-22) at f=2.1-2.5 kHz for a source distance of 100 Mpc. We also present the neutrino luminosity curve when a black hole is formed for the first time.

Effects of hyperons in binary neutron star mergers.

Numerical simulations for the merger of binary neutron stars are performed in full general relativity incorporating both nucleonic and hyperonic finite-temperature equations of state (EOS) and neutrino cooling. It is found that even for the hyperonic EOS, a hypermassive neutron star is first formed after the merger for the typical total mass ≈2.7M(⊙), and subsequently collapses to a black hole (BH). It is shown that hyperons play a substantial role in the postmerger dynamics, torus formation around the BH, and emission of gravitational waves (GWs). In particular, the existence of hyperons is imprinted in GWs. Therefore, GW observations will provide a potential opportunity to explore the composition of neutron star matter.

Gravitational waves from the Papaloizou-Pringle instability in black-hole-torus systems.

Black hole (BH)-torus systems are promising candidates for the central engine of γ-ray bursts (GRBs), and also possible outcomes of the collapse of supermassive stars to supermassive black holes (SMBHs). By three-dimensional general relativistic numerical simulations, we show that an m = 1 nonaxisymmetric instability grows for a wide range of self-gravitating tori orbiting BHs. The resulting nonaxisymmetric structure persists for a time scale much longer than the dynamical one, becoming a strong emitter of large amplitude, quasiperiodic gravitational waves. Our results indicate that both, the central engine of GRBs and newly formed SMBHs, can be strong gravitational wave sources observable by forthcoming ground-based and spacecraft detectors.

Coalescence of Black Hole-Neutron Star Binaries.

We review the current status of general relativistic studies for the coalescence of black hole-neutron star (BH-NS) binaries. First, procedures for a solution of BH-NS binaries in quasi-equilibrium circular orbits and the numerical results, such as quasi-equilibrium sequence and mass-shedding limit, of the high-precision computation, are summarized. Then, the current status of numerical-relativity simulations for the merger of BH-NS binaries is described. We summarize our understanding for the merger and/or tidal disruption processes, the criterion for tidal disruption, the properties of the remnant formed after the tidal disruption, gravitational waveform, and gravitational-wave spectrum.

Simultaneous determination of in vivo plastoquinone and ubiquinone redox states by HPLC-based analysis.

For a better understanding of the metabolic interaction between chloroplasts and mitochondria, it is important to analyze the in vivo redox states of the electron transport chains in both organelles at the same time. For this purpose, we devised an HPLC-based measurement system simultaneously analyzing plastoquinone (PQ) and ubiquinone (UQ) contents and redox states. Using this system, we discovered that, in addition to PQ, the reduction levels of UQ were elevated under high-light conditions. We also provide direct evidence that mitochondrial alternative oxidase contributes to alleviate UQ over-reduction under such conditions.

De novo biosynthesis of fatty acids plays critical roles in the response of the photosynthetic machinery to low temperature in Arabidopsis.

The Arabidopsis thaliana kas3 mutant was isolated based on the hypersensitivity of PSII to low temperature using a Chl fluorescence imaging technique. Chl content was lower in kas3 seedlings cultured at 23 degrees C than in the wild type, but PSII activity was only mildly affected. However, after the chilling treatment at 4 degrees C for 7 d, PSII activity was severely impaired in kas3. PSII was more sensitive to light at 4 degrees C in the presence of lincomycin, suggesting that the kas3 mutation accelerates at least the PSII photodamage. The kas3 mutation causes an amino acid alteration in 3-ketoacyl-ACP synthase III (KasIII), leading to the partial loss of the de novo synthesis pathway for fatty acids in plastids. Consequently, the total fatty acid level was reduced to 75% of the wild-type level in kas3 at 23 degrees C and was further reduced to 60% at 4 degrees C. The composition of fatty acids was also slightly affected in kas3 at both 4 and 23 degrees C. Consistent with the results of the electron transport analysis, the chilling treatment also destabilized PsaA and cytochrome (Cyt) f and D1 in kas3. An analysis of double mutants with pgr1 conditionally defective in Cyt b(6)f activity and with var2 defective in FtsH protease suggested that the kas3 mutation has pleiotropic effects on chloroplast function, probably impacting both the Cyt b(6)f activity and translation in chloroplasts at 23 degrees C. The full activity of KasIII is required for the biogenesis of the intact electron transport machinery in thylakoid membranes and is especially important for the process of responding to low temperature.

Influence of self-gravity on the runaway instability of black-hole-torus systems.

Results from the first fully general relativistic numerical simulations in axisymmetry of a system formed by a black hole surrounded by a self-gravitating torus in equilibrium are presented, aiming to assess the influence of the torus self-gravity on the onset of the runaway instability. We consider several models with varying torus-to-black-hole mass ratio and angular momentum distribution orbiting in equilibrium around a nonrotating black hole. The tori are perturbed to induce the mass transfer towards the black hole. Our numerical simulations show that all models exhibit a persistent phase of axisymmetric oscillations around their equilibria for several dynamical time scales without the appearance of the runaway instability, indicating that the self-gravity of the torus does not play a critical role favoring the onset of the instability, at least during the first few dynamical time scales.

Exploring binary-neutron-star-merger scenario of short-gamma-ray bursts by gravitational-wave observation.

We elucidate the feature of gravitational waves (GWs) from a binary-neutron-star merger collapsing to a black hole by general relativistic simulation. We show that GW spectrum imprints the coalescence dynamics, formation process of disk, equation of state for neutron stars, total masses, and mass ratio. A formation mechanism of the central engine of short-gamma-ray bursts, which are likely to be composed of a black hole and surrounding disk, therefore could be constrained by GW observation.

HbA1c adjusted by erythrocyte creatine is a useful glycemic control indicator in patients with hemolysis.

OBJECTIVES: HbA1c shows low in patients with hemolysis, whereas glycated albumin (GA) is not affected by hemolysis. Therefore, the GA/HbA1c ratio reflects hemolysis in diabetic patients with hemolysis. Erythrocyte creatine (EC) is an indicator of hemolysis that reflects the mean erythrocyte age. The aim of this study was to examine whether HbA1c adjusted by EC accurately reflected glycemic control in patients with hemolysis. MATERIALS AND METHODS: A total of 238 individuals, consisting of 131 diabetic patients and 107 non-diabetic subjects, and consisting of 42 patients with hemolysis, and 196 subjects without hemolysis were selected for the study. HbA1c expressed in the IFCC units (iA1c) as well as in the NGSP units (A1C) were used. From the fact that EC and the GA/iA1c ratio showed a significant positive correlation, a formula for iA1c adjusted by EC (ECadj-iA1c) was created from a regression equation between EC and the GA/iA1c ratio. RESULTS: Significant correlations were observed between the GA/iA1c ratio and various hemolytic indicators but not between the GA/ECadj-iA1c ratio and those hemolytic indicators. The GA/iA1c ratio in individuals with hemolysis was significantly higher than in individuals without hemolysis, while no significant differences were observed in the GA/ECadj-iA1c ratio between the groups. Further, iA1c concentrations in non-diabetic patients with hemolysis were significantly lower than in the non-diabetic subjects without hemolysis, whereas ECadj-iA1c and GA concentrations showed no significant difference between the two groups. CONCLUSIONS: These results suggested that ECadj-iA1c accurately reflected glycemic control in patients with hemolysis.

Successful in vivo propagation of factor IX-producing hepatocytes in mice: potential for cell-based therapy in haemophilia B.

Cell-based therapies using isolated hepatocytes have been proposed to be an attractive application in the treatment of haemophilia B due to the normal production of coagulation factor IX (FIX) in these particular cells. Current cell culture technologies have largely failed to provide adequate isolated hepatocytes, so the present studies were designed to examine a new approach to efficiently proliferate hepatocytes that can retain normal biological function, including the ability to synthesize coagulation factors like FIX. Canine or human primary hepatocytes were transplanted into urokinase-type plasminogen activator-severe combined immunodeficiency (uPA/SCID) transgenic mice. Both donor hepatocytes from canines and humans were found to progressively proliferate in the recipient mouse livers as evidenced by a sharp increase in the circulating blood levels of species-specific albumin, which was correlated with the production and release of canine and human FIX antigen levels into the plasma. Histological examination confirmed that the transplanted canine and human hepatocytes were able to proliferate and occupy >80% of the host livers. In addition, the transplanted hepatocytes demonstrated strong cytoplasmic staining for human FIX, and the secreted coagulation factor IX was found to be haemostatically competent using specific procoagulant assays. In all, the results from the present study indicated that developments based on this technology could provide sufficient FIX-producing hepatocytes for cell-based therapy for haemophilia B.

Ex vivo gene therapy for hemophilia A that enhances safe delivery and sustained in vivo factor VIII expression from lentivirally engineered endothelial progenitors.

Novel therapeutic strategies for hemophilia must be at least as effective as current treatments and demonstrate long-term safety. To date, several small clinical trials of hemophilia gene transfer have failed to show the promise of preclinical evaluations. Therefore, we wanted to develop and evaluate the feasibility of a novel ex vivo gene transfer strategy whereby cells derived from progenitor cells are engineered to express factor VIII (FVIII) and then implanted subcutaneously to act as a depot for FVIII expression. Circulating blood outgrowth endothelial cells (BOECs) were isolated from canine and murine blood and transduced with a lentiviral vector encoding the canine FVIII transgene. To enhance safety, these cells were implanted subcutaneously in a Matrigel scaffold, and the efficacy of this strategy was compared with i.v. delivery of engineered BOECs in nonhemophilic nonobese diabetic/severe combined immunodeficiency mice. Therapeutic levels of FVIII persisted for 15 weeks, and these levels of stable expression were extended to 20 weeks when the cytomegalovirus promoter was replaced with the thrombomodulin regulatory element. Subsequent studies in immunocompetent hemophilic mice, pretreated with tolerizing doses of FVIII or with transient immunosuppression, showed therapeutic FVIII expression for 27 weeks before the eventual return to baseline levels. This loss of transgene expression appears to be due to the disappearance of the implanted cells. The animals treated with either of the two tolerizing regimens did not develop anti-FVIII antibodies. Biodistribution analysis demonstrated that BOECs were retained inside the subcutaneous implants. These results indicate, for the first time, that genetically modified endothelial progenitor cells implanted in a subcutaneous scaffold can provide sustained therapeutic levels of FVIII and are a promising and safe treatment modality for hemophilia A. Disclosure of potential conflicts of interest is found at the end of this article.