Search

We present the first search for the pair production of dark particles $X$ via $K_L^0\to XX$ with $X$ decaying into two photons using the data collected by the KOTO experiment. No signal was observed in the mass range of 40 - 110 MeV/c$^2$ and 210 - 240 MeV/c$^2$. This sets upper limits on the branching fractions as $\mathcal{B}(K_L^0 \to XX)$ $

Combined experimental and modeling studies of the magnetocaloric effect, ultrasound, and magnetostriction were performed on single-crystal samples of the spin-dimer system Sr$_3$Cr$_2$O$_8$ in large magnetic fields, to probe the spin-correlated regime in the proximity of the field-induced XY-type antiferromagnetic order also referred to as a Bose-Einstein condensate of magnons. The magnetocaloric effect, measured under adiabatic conditions, reveals details of the field-temperature ($H,T$) phase diagram, a dome characterized by critical magnetic fields $H_{c1}$ = 30.4 T, $H_{c2}$ = 62 T, and a single maximum ordering temperature $T_{{\rm max}}(45~$T$)\simeq$8 K. The sample temperature was observed to drop significantly as the magnetic field is increased, even for initial temperatures above $T_{{\rm max}}$, indicating a significant magnetic entropy associated to the field-induced closure of the spin gap. The ultrasound and magnetostriction experiments probe the coupling between the lattice degrees of freedom and the magnetism in Sr$_3$Cr$_2$O$_8$. Our experimental results are qualitatively reproduced by a minimalistic phenomenological model of the exchange-striction by which sound waves renormalize the effective exchange couplings., Comment: 9 pages, 14 figures

The rare decay $K_L \!\to\! ��^0 ��\overline��$ was studied with the dataset taken at the J-PARC KOTO experiment in 2016, 2017, and 2018. With a single event sensitivity of $( 7.20 \pm 0.05_{\rm stat} \pm 0.66_{\rm syst} ) \times 10^{-10}$, three candidate events were observed in the signal region. After unveiling them, contaminations from $K^{\pm}$ and scattered $K_L$ decays were studied, and the total number of background events was estimated to be $1.22 \pm 0.26$. We conclude that the number of observed events is statistically consistent with the background expectation. For this dataset, we set an upper limit of $4.9 \times 10^{-9}$ on the branching fraction of $K_L \!\to\! ��^0 ��\overline��$ at the 90% confidence level., 6 pages, 5 figures; published version, no change in the results. Fig. 2 and Fig. 4 were revised. In Fig. 5, the plot of the $P_{t}$ versus ${Z_{\mathrm{vtx}}}$ of the beam-halo $K_L\!\to\!2\gamma$ background events was added as Fig. 5 (b)

We report the first search for the $K_L \to ��^0 ��$ decay, which is forbidden by Lorentz invariance, using the data from 2016 to 2018 at the J-PARC KOTO experiment. With a single event sensitivity of $(7.1\pm 0.3_{\rm stat.} \pm 1.6_{\rm syst.})\times 10^{-8}$, no candidate event was observed in the signal region. The upper limit on the branching fraction was set to be $1.7\times 10^{-7}$ at the 90\% confidence level.

In antiferromagnets, the interplay of spin frustration and spin-lattice coupling has been extensively studied as the source of complex spin patterns and exotic magnetism. Here, we demonstrate that, although neglected in the past, the spin-lattice coupling is essential to ferrimagnetic spinels as well. We performed ultrahigh-field magnetization measurements up to 110 T on a Yafet-Kittel ferrimagnetic spinel, MnCr$_2$S$_4$, which was complemented by measurements of magnetostriction and sound velocities up to 60 T. Classical Monte Carlo calculations were performed to identify the complex high-field spin structures. Our minimal model incorporating spin-lattice coupling accounts for the experimental results and corroborates the complete phase diagram, including two new high-field phase transitions at 75 and 85 T. Magnetoelastic coupling induces striking effects: An extremely robust magnetization plateau is embedded between two unconventional spin-asymmetric phases. Ferrimagnetic spinels provide a new platform to study asymmetric and multiferroic phases stabilized by spin-lattice coupling., Comment: 9 pages, 7 figures

The acoustic properties of liquid oxygen have been studied up to 90 T by means of the ultrasound pulse-echo technique. A monotonic decrease of the sound velocity and an asymptotic increase of the acoustic attenuation are observed by applying magnetic fields. An unusually large acoustic attenuation, that becomes 20 times as large as the zero-field value, cannot be explained by the classical theory. These results indicate strong fluctuations of antiferromagnetically coupled local structures. We point out that the observed fluctuations are a precursor of a liquid-liquid transition, from a low-susceptibility to a high-susceptibility liquid, which is characterized by a local-structure rearrangement., Comment: 5 pages, 3 figures

We searched for the $CP$-violating rare decay of neutral kaon, $K_{L} \to \pi^0 \nu \overline{\nu}$, in data from the first 100 hours of physics running in 2013 of the J-PARC KOTO experiment. One candidate event was observed while $0.34\pm0.16$ background events were expected. We set an upper limit of $5.1\times10^{-8}$ for the branching fraction at the 90\% confidence level (C.L.). An upper limit of $3.7\times10^{-8}$ at the 90\% C.L. for the $K_{L} \to \pi^{0} X^{0}$decay was also set for the first time, where $X^{0}$ is an invisible particle with a mass of 135 MeV/$c^{2}$.

Purpose Systemic and local immune environments in human biliary atresia (BA) were analyzed. Methods Plasma concentrations of 19 inflammatory components in 16 preoperative BA patients (median age, 51 days), 13 normal controls (NCs) (44 days), and 15 cholestatic controls (CC) (23 days) were measured using flow cytometry, and compared according to post-Kasai outcomes in BA patients. Hepatic mRNA levels of representative helper T (Th) cell cytokines and forkhead box protein 3 (FoxP3) quantified by real-time reverse transcription polymerase chain reaction were compared between BA and non-BA. Results No significant differences were observed between BA and control in serum Th1, Th2, or macrophage markers, while soluble cellular adhesion molecule (CAM) levels were significantly higher in BA (p Conclusions A skewed bias toward specific Th-oriented immunity was not demonstrated in either the systemic or local environment in the early stage of human BA, with patient prognoses not necessarily revealed by preoperative plasma inflammatory component levels. CAM and regulatory T cell roles and functions warrant further investigation.

We searched for the $CP$-violating rare decay of neutral kaon, $K_{L} \to ��^0 ��\overline��$, in data from the first 100 hours of physics running in 2013 of the J-PARC KOTO experiment. One candidate event was observed while $0.34\pm0.16$ background events were expected. We set an upper limit of $5.1\times10^{-8}$ for the branching fraction at the 90\% confidence level (C.L.). An upper limit of $3.7\times10^{-8}$ at the 90\% C.L. for the $K_{L} \to ��^{0} X^{0}$decay was also set for the first time, where $X^{0}$ is an invisible particle with a mass of 135 MeV/$c^{2}$., 11 pages, 5 figures, to be published in PTEP

Objectives: Prostate biopsy is considered a common procedure for the diagnosis of prostate cancer, with few major complications. There are some reports on complications, voiding function, and health-related quality of life (HRQOL) after prostate biopsy, but the association between prostate biopsy and erectile function, anxiety, and depression has been only sparsely investigated. With the aim of improving patient counseling and informed consent, we prospectively evaluated HRQOL outcomes, including sexual function and mental health, after prostate biopsy. Methods: In total, 207 patients who underwent initial prostate needle biopsy were evaluated. All patients completed the following measurements before and 2-4 weeks after the procedure: Medical Outcomes Study Short- Form 8 (SF-8), Expanded Prostate Cancer Index Composite (EPIC), International Prostate Symptom Score (IPSS), International Index of Erectile Function-5 (IIEF-5), and Self-Rating Depression Scale (SDS). Results: No significant differences were evident between baseline and post biopsy scores for SF-8. The EPIC scores for the general urinary domain and all its subscales dropped significantly, and the scores for the general sexual domain and its function decreased significantly after biopsy. Positive correlations between function and bother subscales within domains, including urinary and bowel components were high, but no positive correlation was observed between sexual function and bother. The IPSS was not significantly increased, but the QOL score was significantly decreased after biopsy. A significant difference between baseline and post biopsy was noted for the IIEF-5 score, and in particular, patients who were initially potent significantly developed erectile dysfunction (ED) after biopsy. The SDS score was significantly different between baseline and post biopsy, and patients aged 73 years or older showed clinically significant depression after the procedure. Conclusion: Based on these data, urologists should pay attention not only to physical and short-lasting complications related to the biopsy procedure but also to HRQOL, including sexual function and mental health after prostate biopsy.

Evidence of the $K^+\to��^+��\bar����$ decay was searched for using E949 experimental data with an exposure of $1.70\times 10^{12}$ stopped kaons. The data sample is dominated by the backgrond process $K^+\to��^+��_����$. An upper limit on the decay rate $��(K^+\to��^+��\bar����)< 2.4\times 10^{-6}��(K^+\to all)$ at 90% confidence level was set assuming the Standard Model muon spectrum. The data are presented in such a way as to allow calculation of rates for any assumed $��^+$ spectrum., 7 pages, 5 figures

5R-l-Erythro-5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor for tyrosine hydroxylase (TH). Recently, a type of dopa-responsive dystonia (DRD) (DYT5, Segawa’s disease) was revealed to be caused by dominant mutations of the gene encoding GTP cyclohydrolase I (GCHI), which is the rate-limiting enzyme of BH4 biosynthesis. In order to probe the role of BH4 in vivo, we established BH4-depleted mice by disrupting the 6-pyruvoyltetrahydropterin synthase (PTS) gene (Pts−/−) and rescued them by introducing human PTS cDNA under the control of the human dopamine β-hydroxylase (DBH) promoter (Pts−/−-DPS). The Pts−/−-DPS mice developed hyperphenylalaninemia. Interestingly, tyrosine hydroxylase protein was dramatically reduced in the dopaminergic nerve terminals of these mice, and they developed abnormal posture and motor disturbance. We propose that the biochemical and pathologic changes of Pts−/−-DPS mice are caused by mechanisms common to human DRD, and understanding these mechanisms could give us insight into other movement disorders. Keywords:: tetrahydrobiopterin, dystonia, tyrosine hydroxylase, striatum, dopamine

Dopa-responsive dystonia (DRD) is a hereditary dystonia characterized by a childhood onset of fixed dystonic posture with a dramatic and sustained response to relatively low doses of levodopa. DRD is thought to result from striatal dopamine deficiency due to a reduced synthesis and activity of tyrosine hydroxylase (TH), the synthetic enzyme for dopamine. The mechanisms underlying the genesis of dystonia in DRD present a challenge to models of basal ganglia movement control, given that striatal dopamine deficiency is the hallmark of Parkinson's disease. We report here behavioral and anatomical observations on a transgenic mouse model for DRD in which the gene for 6-pyruvoyl-tetrahydropterin synthase is targeted to render selective dysfunction of TH synthesis in the striatum. Mutant mice exhibited motor deficits phenotypically resembling symptoms of human DRD and manifested a major depletion of TH labeling in the striatum, with a marked posterior-to-anterior gradient resulting in near total loss caudally. Strikingly, within the regions of remaining TH staining in the striatum, there was a greater loss of TH labeling in striosomes than in the surrounding matrix. The predominant loss of TH expression in striosomes occurred during the early postnatal period, when motor symptoms first appeared. We suggest that the differential striosome-matrix pattern of dopamine loss could be a key to identifying the mechanisms underlying the genesis of dystonia in DRD.

Sepiapterin reductase (SPR) is an enzyme that acts in the third and final step of tetrahydrobiopterin (BH4) biosynthesis. The human Spr gene locates within the region of 2.5MB mapped to PARK3, an autosomal dominant form of familial Parkinson's diseases. In order to explore the role of SPR in the metabolism of BH4, we produced and analyzed Spr-deficient mice. Most of Spr-null mice survived beyond two weeks. Whereas the BH4 contents in the homozygous mutant mice were greatly decreased than those in wild-type and heterozygous mice, the substantial amounts of BH4 were remained even 17 days after delivery. Spr-null mice exhibited severe monoamine deficiencies and a tremor-like phenotype after weaning. The amount of TH protein in the brain of Spr-null mice was less than 10% of wild-type, while TH protein in the adrenal, phenylalanine hydroxylase protein in the liver, and nNOS in the brain were not altered. These data suggest an essential role of SPR in the biosynthesis of BH4, and that the SPR gene could be a candidate gene for PARK3.

One of the possibly mutated genes in DOPA-responsive dystonia (DRD, Segawa's disease) is the gene encoding GTP cyclohydrolase I, which is the rate-limiting enzyme for tetrahydrobiopterin (BH4) biosynthesis. Based on our findings on 6-pyruvoyltetrahydropterin synthase (PTS) gene-disrupted (Pts(-/-)) mice, we suggested that the amount of tyrosine hydroxylase (TH) protein in dopaminergic nerve terminals is regulated by the intracellular concentration of BH4. In this present work, we rescued Pts(-/-) mice by transgenic introduction of human PTS cDNA under the control of the dopamine beta-hydroxylase promoter to examine regional differences in the sensitivity of dopaminergic neurons to BH4-insufficiency. The DPS-rescued (Pts(-/-), DPS) mice showed severe hyperphenylalaninemia. Human PTS was efficiently expressed in noradrenergic regions but only in a small number of dopaminergic neurons. Biopterin and dopamine contents, and TH activity in the striatum were poorly restored compared with those in the midbrain. TH-immunoreactivity in the lateral region of the striatum was far weaker than that in the medial region or in the nucleus accumbens. We concluded that dopaminergic nerve terminals projecting to the lateral region of the striatum are the most sensitive to BH4-insufficiency. Biochemical and pathological changes in DPS-rescued mice were similar to those in human malignant hyperphenylalaninemia and DRD.

Tetrahydrobiopterin (BH4) acts as an essential cofactor for the enzymatic activity of nitric oxide (NO) synthases. Biosynthesis of the cofactor BH4 starts from GTP and requires 3 enzymatic steps, which include GTP cyclohydrolase I (GCH I) catalysis of the first and rate-limiting step. In this study we examined the effects of cGMP on GCH I activity in human umbilical vein endothelial cells under inflammatory conditions. Exogenous application of the cGMP analogue 8-bromo-cGMP markedly inhibited GCH I activity in the short term, whereas an cAMP analogue had no effect on GCH I activity under the same condition. NO donors, NOR3 and sodium nitroprusside, elevated the intracellular cGMP level and reduced GCH I activity in the short term. This inhibition of GCH I activity was obliterated in the presence of an NO trapper carboxy-PTIO. NO donors had no effect on GCH I mRNA expression in the short term. Moreover, cycloheximide did not alter the inhibition by NO donors of GCH I activity. These findings suggest that stimulation of the cGMP signaling cascade down-regulates GCH I activity through post translational modification of the GCH I enzyme.

A full-length cDNA clone for GTP cyclohydrolase I (EC 3.5.4.16) was isolated from a Tetrahymena pyriformis cDNA library by plaque hybridization. The nucleotide sequence determination revealed that the length of the cDNA insert was 1516 bp. The coding region encoded a protein of 223 amino acid residues with a calculated molecular mass of 25 416 Da. The deduced amino acid sequence of Tetrahymena GTP cyclohydrolase I showed sequence identity with that of Escherichia coli (55%). The identity of T. pyriformis GTP cyclohydrolase I with sequences of Dictyostelium discoideum , Saccharomyces cerevisiae , Drosophila melanogaster , mouse, rat, and human enzymes was less marked and was 30, 30, 25, 28, 28, and 27%, respectively. RNA blot analysis showed a single mRNA species of 2.1 kb in this protozoan. The mRNA level of GTP cyclohydrolase I increased during synchronous cell division induced by intermittent heat treatment. The results suggest that the mRNA expression is associated with the cell cycle of T. pyriformis .

Mechanosensitive (MS) channels of small (MscS) and large (MscL) conductance are the major players in the protection of bacterial cells against hypoosmotic shock. Although a great deal is known about structure and function of these channels, much less is known about how membrane lipids may influence their mechanosensitivity and function. In this study, we use liposome coreconstitution to examine the effects of different types of lipids on MscS and MscL mechano-sensitivity simultaneously using the patch-clamp technique and confocal microscopy. Fluorescence lifetime imaging (FLIM)-FRET microscopy demonstrated that coreconstitution of MscS and MscL led to clustering of these channels causing a significant increase in the MscS activation threshold. Furthermore, the MscL/MscS threshold ratio dramatically decreased in thinner compared with thicker bilayers and upon addition of cholesterol, known to affect the bilayer thickness, stiffness and pressure profile. In contrast, application of micromolar concentrations of lysophosphatidylcholine (LPC) led to an increase of the MscL/MscS threshold ratio. These data suggest that differences in hydrophobic mismatch and bilayer stiffness, change in transbilayer pressure profile, and close proximity of MscL and MscS affect the structural dynamics of both channels to a different extent. Our findings may have far-reaching implications for other types of ion channels and membrane proteins that, like MscL and MscS, may coexist in multiple molecular complexes and, consequently, have their activation characteristics significantly affected by changes in the lipid environment and their proximity to each other.

In order to evaluate the effect of specific immune response on prognosis in acute leukemia, we investigated the correlation between the lysis of autologous tumor cells (ATC) by lymphocytes and prognosis. Peripheral mononuclear cells (PMC) from most patients with acute leukemia in complete remission (CR) do not exhibit cytotoxic activity against fresh-frozen ATC, although they have adequate cytotoxic activity against K562 cells. When the large granular lymphocyte (LGL) fraction was used in this study, we observed lysis of ATC in 17 (43.6%) of 39 patients with acute leukemia (12 (42.9%) of the 28 patients with acute myelogenous leukemia (AML) and 5 (45.5%) of the 11 patients with acute lymphocytic leukemia (ALL)). With regard to prognosis, the lytic activity of the LGL fraction did not reflect the duration of CR. The median CR duration in AML patients was 13 months for the lysis-positive group and 11 months for the lysis-negative group. No significant correlation was also found between lytic activity of the LGL fraction and overall survival in each patient. However, the lysis-positive group tended to have a longer survival, the median overall survival being 48 months for the lysis-positive group vs 12 months for the lysis-negative group. The prolonging of overall survival in the lysis-positive group was attributed to a high rate of induction of second remissions in this group. Long-term patient survival in the two groups did not differ.

The rare decay K0(L) --> pi0 pi0 nu nu-bar was studied with the E391a detector at the KEK 12-GeV proton synchrotron. Based on 9.4 x 10^9 K0L decays, an upper limit of 8.1 x 10^{-7} was obtained for the branching fraction at 90% confidence level. We also set a limit on the K0(L) --> pi0 pi0 X (X --> invisible particles) process; the limit on the branching fraction varied from 7.0 x 10^{-7} to 4.0 x 10^{-5} for the mass of X ranging from 50 MeV/c^2 to 200 MeV/c^2., 5 pages, 5 figures

We performed a search for the decay $K_L^0 \rightarrow 3��$ with the E391a detector at KEK. In the data accumulated in 2005, no event was observed in the signal region. Based on the assumption of $K_L^0 \rightarrow 3��$ proceeding via parity-violation, we obtained the single event sensitivity to be $(3.23\pm0.14)\times10^{-8}$, and set an upper limit on the branching ratio to be $7.4\times10^{-8}$ at the 90% confidence level. This is a factor of 3.2 improvement compared to the previous results. The results of $K_L^0 \rightarrow 3��$ proceeding via parity-conservation were also presented in this paper.

Thirty-two patients with advanced non-Hodgkin's lymphoma (NHL) with aggressive histologic findings were treated with cyclophosphamide, doxorubicin, methotrexate with leucovorin rescue, bleomycin, vincristine, etoposide, ifosfamide, and prednisolone (CAMBO-VIP), in which presumably non-cross-resistant myelosuppressive and nonmyelosuppressive agents were administered during alternate weeks for 12 weeks. To ensure the high-dose intensity of the protocol, dose reduction and delay in treatment were minimized. Three patients were treated inadequately. Twenty-six (89.7%) of 29 evaluable patients had a complete response, and three had a good partial response. Relapse occurred in four patients, with a median follow-up of 29 months. The actuarial overall survival and disease-free survival were estimated to be 87.6% and 75.9%, respectively. The CAMBO-VIP treatment was well tolerated; myelosuppression was severe but transient and caused no serious infections. Side effects that affected dose intensity were oral ulceration, occurring in 28 patients, and blister formation under the thickened skin of palms and/or soles, followed by desquamation (5 patients). Hepatic toxicity was generally mild to moderate; it was severe in one patient. A 12-week regimen of CAMBO-VIP was effective for advanced NHL with aggressive histologic findings.

Experiment E949 at Brookhaven National Laboratory has observed three new events consistent with the decay K+ => pi+,nu,nubar in the pion momentum region 140 < P_pi < 199 MeV/c in an exposure of 1.71e12 stopped kaons with an estimated total background of 0.93+-0.17(stat.)+0.32-0.24(syst.) events. This brings the total number of observed K+ => pi+,nu,nubar events to seven. Combining this observation with previous results, assuming the pion spectrum predicted by the standard model, results in a branching ratio of (1.73+1.15-1.05)e-10. An interpretation of the results for alternative models of the decay K^ => pi+,nothing is also presented., Submitted to Phys.Rev. D

We performed a search for a light pseudoscalar particle $X$ in the decay $K_L^0->pi0pi0X$, $X->����$ with the E391a detector at KEK. Such a particle with a mass of 214.3 MeV/$c^2$ was suggested by the HyperCP experiment. We found no evidence for $X$ and set an upper limit on the product branching ratio for $K_L^0->pi0pi0X$, $X->����$ of $2.4 \times 10^{-7}$ at the 90% confidence level. Upper limits on the branching ratios in the mass region of $X$ from 194.3 to 219.3 MeV/$c^2$ are also presented., 5 pages, 5 figures

Cell penetrating peptides (CPPs) have drawn attention as carriers for intracellular drug delivery. It is commonly believed that TAT peptide is the best carrier among the existing CPPs due to its high translocational activity. Despite considerable research, the cellular uptake mechanism of TAT peptide remains unclear. Additionally, the transduction efficiency of TAT peptide is insufficient for use in intracellular therapy. In this study, we attempted to identify novel CPPs from a random 18mer peptide library using a phage display system. To isolate novel CPPs more effectively, PSIF (protein synthesis inhibition factor) was used with the screening system. Consequently, we isolated 7 novel CPPs from the library and determined by flow cytometry and confocal laser microscopy that these CPPs were taken up into cells. Once the cellular uptake pathway of these CPPs has been determined, it may be possible to use them for intracellular therapy.

We performed cytogenetic studies in a patient with treatment-related acute leukemia (t-AL) to identify the associated chromosomal changes. Metaphase analysis revealed a t(3;21)(q26;q22) translocation. Acute promyelocytic leukemia (APL) had been diagnosed 4 years earlier and the patient had received intensive induction chemotherapy and sequential post-induction therapy that included agents that targeted DNA-topoisomerase II (topo II). This case suggests an association between previous therapy with topo II inhibitors and development of t-AL associated with a balanced aberration involving the 3q26 and 21q22 bands.

We studied the effects of cAMP on cytokine (interferon-gamma plus tumor necrosis factor-alpha)-induced stimulation of tetrahydrobiopterin (BH4) synthesis in human umbilical vein endothelial cells (HUVEC). The cytokine mixture caused a marked increase in the biosynthesis and release of BH4 by HUVEC. Dibutyryl-cAMP produced a dose-dependent inhibition of this cytokine-induced stimulation of synthesis and release of BH4 by these cells. 8-Bromo-cAMP also caused a significant inhibition, although the effects were less marked than those of dibutyryl-cAMP. Both forskolin and the stable analog of prostacyclin, iloprost, caused cAMP accumulation and a concomitant diminution of the cytokine-induced BH4 synthesis in HUVEC. Dibutyryl-cAMP and iloprost also significantly inhibited the cytokine-induced stimulation of GTP cyclohydrolase I (GCHI) activity and mRNA production. We concluded that the suppression by the cAMP messenger system of cytokine-induced stimulation of synthesis and release of BH4 by HUVEC can be attributed to the inhibition of the activity of GCHI, the rate-limiting enzyme in BH4 biosynthetic pathway, in HUVEC. The data also suggest that the cAMP-mediated reduction in the GCHI mRNA level may at least partially explain the decline in GCHI activity. It is reasoned that under inflammatory conditions, cAMP-elevating agents such as prostacyclin exert regulatory effects on circulation by inhibiting cytokine-induced synthesis and release of BH4 by HUVEC.

Nurr1 is a member of the nuclear receptor superfamily of transcription factors that is expressed predominantly in the central nervous system, including developing dopaminergic neurons. Recently, it was demonstrated that Nurr1 is critical for midbrain dopaminergic cell differentiation. In order to investigate a possible relation of Nurr1 with the pathogenesis of Parkinson's disease or other neuropsychiatric disorders, we have cloned and characterized the human Nurr1 gene. The gene exists as a single copy in the human genome and comprises eight exons spanning 8kb. We determined the complete nucleotide sequence and flanking regions of the gene. Potential regulatory regions included consensus binding sites for NF-kappaB, CREB, and Sp1. Isolation of human Nurr1 cDNAs from fetal brain suggested the presence of a new splicing variant of Nurr1 in the human brain.

This paper deals with particle formation by homogeneous nucleation in a system containing seed particles. A model of homogeneous nucleation previously developed by the present authors1 is here extended to include the effect of the presence of seed particles. To this end, the cell model upon which the original model was based has been modified to account for the random distribution of the interparticle distances in the medium. Liquid-phase experiments, in which particles have been generated by a chemical reduction method with varying number concentrations of seed particles and generation rates of precursor monomers, have confirmed the validity of the model. The proposed model enables determination of the operating conditions where 1) homogeneous nucleation is predominant, 2) particle growth is predominant, and 3) homogeneous nucleation and particle growth coexist.

We report on results of a search for the decay mode K_L -> pi^0 gamma e^+ e^- conducted by the E162 experiment at KEK. We observed no events and set a 90% confidence level upper limit of Br(K_L -> pi^0 gamma e^+ e^-)< 7.1x10^{-7} for its branching ratio. This is the first published experimental result on this decay mode., 10 pages, 4 figures, submitted to Physics Letters B

The response of human acute myelogenous leukemia (AML) cells to four different hematopoietic growth factors (granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 beta (IL-1beta), interleukin-3 (IL-3), and stem cell factor (SCF)) and the relationship of the proliferative response of the AML cells to treatment outcome were studied. Proliferative responses were analyzed in 79 patients with de novo AML and 19 patients with AML arising from myelodysplastic syndrome (MDS). In de novo AML, a positive proliferative response (stimulation index2) was seen in 65 to 75% of cases. AML cells arising from MDS had a much higher incidence of proliferative response to each growth factor (79 to 90%) and a much higher level of 3H-TdR incorporation. The relationship to treatment outcome was evaluated in 79 patients with de novo AML. The patients whose leukemic cells had a positive proliferative response to any growth factor, especially IL-3 and SCF, had a poorer outcome, ie a lower complete remission (CR) rate, shorter CR duration, and shorter survival. The outcome was particularly poor in patients whose leukemic cells had proliferative responses to all four or any of the growth factors, compared to patients whose leukemic cells had no response. This increased response may be a marker of poor prognosis in patients with AML.

We report on results of an experimental search for the K_L -> pi^+ pi^- e^+ e^- decay mode. We found 13.5 +- 4.0 events and determined its branching ratio to be (4.4 +- 1.3(stat) +- 0.5(syst))*10^{-7}. The result agrees well with the theoretical prediction., 9 pages, 6 eps-figures, LaTeX2e, graphicx package, submitted to Physics Letters B

Rapid carcinogenicity tests were done with transgenic (Tg) mice human prototype c-HRAS gene, namely BALB/cByJ x C57BL/6JF1-TgN(HRAS)2 or CB6F1-HRAS2 mice. The studies were conducted as the first step in the evaluation of the CB6F1-HRAS2 mouse as a model for the rapid carcinogenicity testing system. Results of short-term tests of various genotoxic carcinogens indicated that CB6F1-HRAS2 mice are more susceptible to these carcinogens than control non-Tg mice. According to the first-step evaluation studies, more rapid onset and a higher incidence of more malignant tumors can be expected with a higher probability after treatment with various genotoxic carcinogens in the CB6F1-HRAS2 mice than in control non-Tg mice. The CB6F1-HRAS2 mouse seems to be a promising candidate as an animal model for the development of a rapid carcinogenicity testing system.

Recently, the sequential changes from adenoma to adenocarcinoma have been well studied in human colorectal carcinogenesis. To study the precise clonal changes from colorectal polyps to cancer, we have established an experimental system to maintain human colorectal polyps in severe combined immunodeficient (SCID) mice that have been improved by the selective inbreeding of C.B17-scid/scid homozygous male and female showing undetectable serum IgG and IgM (1 microgram/ml). Two of two solitary polyps from two nonhereditary colon polyp patients, four of five colon polyps from two Peutz-Jeghers' syndrome patients and one polypoid lesion from a familial polyposis coli (FAP) patient grew very slowly but steadily, at approximately one-tenth the rate of their malignant form, (i.e., adenocarcinoma), in the improved SCID mice and were maintained for a long period (more than 2 years), over several mouse generations. However, two polyps from FAP and Peutz-Jeghers' syndrome patients could not be transplanted further because of microinfection at the transplanted site due to incomplete sterilization of original human tumors prior to surgical operation (endoscopic polypectomy). Transplanted colon polyps had a semitransparent, soft and sticky appearance, with cells containing large amounts of mucin. Malignant transformation of human colon polyp to adenocarcinoma has not been observed during the maintenance period (about 2 years) in SCID mice. In the consecutively maintained human colon polyps, however, K-ras mutations were detected at codon 12, while these mutations were not found in their original polyps in the patients.

A B-cell lymphoma cell line, designated KML-1, was established from pleural effusion of a patient with non-Hodgkin's lymphoma of large-cell type. The lymphoma arose in the pelvis and ran an aggressive clinical course. Chromosome analysis of the cell line exhibited a complex karyotype including the loss of chromosome 18. To evaluate the molecular events in the cell line that may be associated with the development of the lymphoma, we investigated the expression and/or alterations of several classes of human genes, including oncogenes, tumor suppressor genes, and cytokine genes. The expression of the DCC (deleted in colorectal cancer) gene, located on the chromosome 18q21, was extremely reduced in KML-1 cell line, as compared with that in a normal spleen tissue and other 4 lymphoma cell lines by the reverse transcription-polymerase-chain-reaction (RT-PCR) method. This finding suggests that inactivation of the DCC gene might play a role in the pathogenesis of the case of lymphoma.

Although the existence of three different cDNA forms of human GTP cyclohydrolase I (GCH I) have been reported (Togari et al., 1992), the full-length sequence of any human GCH I cDNA involving poly (A) tail has not yet been documented. In the present study, we first isolated a full-length cDNA clone encoding human GCH I type 1 from human pheochromocytoma cDNA library. The length of the cDNA insert was 2,921 base pairs including poly (A) tail. RNA blot analysis showed a single niRNA species of 4.0kb in human pheochromocytoma tissue.

We evaluated the in vitro proliferative response to exogenous IL-1 beta in terms of tritiated thymidine (3H-TdR) incorporation in leukemic cells obtained from 119 patients with various types of acute leukemia. The content of IL-1 beta in leukemic cells was measured by enzyme-amplified sensitivity immunoassay. We observed a significant proliferative response to exogenous IL-1 beta in leukemic cells from 27/66 patients with de novo AML, 1/29 patients with ALL, 2/3 patients with AUL, 8/12 patients with AML arising from MDS, 4/7 patients with myeloid crisis of CML, and 0/4 patients with lymphoid crisis of CML. Proliferation was marked in myeloid leukemic cells of a more premature stem cell origin. There were no significant differences in proliferative responses among the different FAB classes of de novo AML. The IL-1 beta content of leukemic cells was low in patients with lymphoid leukemia, but there was no significant difference among the various types of myeloid leukemia. There was no correlation between the proliferative response to exogenous IL-1 beta and the IL-1 beta content of leukemic cells. When we correlated the proliferative response to exogenous IL-1 beta with treatment outcome in patients with de novo AML, we found the rate of complete remission (CR) to be lower in those with a high proliferative response. We noted a longer duration of CR (p = 0.07) and of survival (p0.05) in patients with a low proliferative response. Thus, a high proliferative response to IL-1 beta in the cells of AML patients may indicate a poor prognosis.

Inoculation of M. leprae were made into the both hind feet at a dose of 4.8 x 10(6) bacilli per foot in order to determine the susceptibility to M. leprae of SCID mice which is severely deficient in both T- and B cell immunity. SCID mice was found to have an extremely high susceptibility to M. leprae, and the progress of infection observed in the SCID mice were shown a rapid systemic spread of infection at the all over the tissues as well as the growth of the leprosy bacilli at the site of inoculation. Therefore, SCID mice can be used as a suitable multibacillary model for the study of leprosy.

A functional defect (respiratory distress), in addition to morphological defects, was induced in the offspring of male ICR mice treated with ethylnitrosourea (ENU) before mating. ENU (100 and 50 micrograms/g) was injected intraperitoneally into adult male ICR mice that were then mated with untreated females. After the cesarian operation on the 18th day of gestation, fetuses were resuscitated. In the apneic fetuses showing respiratory distress, the lung was collapsed and the ductus arteriosus was not closed. The incidence of fetuses showing respiratory distress was significantly increased with the high dose (100 micrograms/g) of ENU, and it was higher after spermatogonial exposure than after postmeiotic exposure. There was no linearity in the dose-response relationship at the lower dose (50 micrograms/g), as was the case with the specific-locus mutation. The frequency per microgram ENU of fetuses showing respiratory distress was 3.7 X 10(-4) for spermatogonial treatment (calculated at a dose of 100 micrograms/g), the value being about 10-20 times higher than that of ordinary mutations in mice. About half of the fetuses showing respiratory distress often had specific anomalies (dwarfism and gigantic thymus), but the remainder showed no morphological changes. Spermatogonial treatment produced a zero or very low incidence of translocations in the meiotic configurations of primary spermatocytes. G-band analysis of the affected F1 fetuses also revealed no visible chromosomal abnormalities (there could be small deletions or inversions) except that trisomy 19 was found in a dwarf fetus.

Quantitative trait loci (QTLs) for a number of agronomically important traits of perennial ryegrass (Lolium perenne L.) were identified using a reference molecular marker-based genetic map. Replicated phenotypic data was obtained for a number of field-assessed morphological and developmental traits as well as the winter hardiness-associated characters of winter survival and electrical conductivity. Marker-trait association analysis was performed using a number of methods, and a high degree of congruence was observed between the respective results. QTLs were detected for morphological traits such as plant height, tiller size, leaf length, leaf width, fresh weight at harvest, plant type, spikelet number per spike and spike length, as well as the developmental traits of heading date and degree of aftermath heading. A number of traits were significantly correlated, and coincident QTL locations were identified. No significant QTLs for winter survival in the field were identified. However, a QTL for electrical conductivity corresponding to frost tolerance was located close to a heading date QTL in a region that may show conserved synteny with chromosomal regions associated with both winter hardiness and flowering time variation in cereals. The QTL analysis of multiple phenotypic traits provides the basis for marker assisted selection (MAS) of important agronomic characters, allowing genetic improvement of yield, quality and adaptation in perennial ryegrass breeding.

Twelve patients with subacute thyroiditis were divided into two groups and treated with prednisolone or salicylate. The initially elevated T4, T3, free T4 (FT4), free T3 (FT3) and erythrocyte sedimentation rate (ESR) were reduced during the early phase within about 4 weeks in both groups. The serum levels of thyroglobulin (Tg) were elevated in both groups treated with salicylate and prednisolone (252 +/- SD 117 ng/ml and 233 +/- SD 157 ng/ml, respectively) at initial examination. The serum level of Tg declined during the early phase with prednisolone treatment, and it reached normal values at the end of the early phase (17 +/- SD 15 ng/ml). With salicylate treatment, the decline of levels of Tg was delayed and it was elevated (80 +/- SD 34 ng/ml) despite normal levels of thyroid hormones and ESR at the end of early phase. The serum level of Tg at the end of the early phase of prednisolone treated was significantly lower than that of salicylate treatment (P less than 0.01). It is suggested that the effect of prednisolone on rapid decrease of Tg may be related to its inhibitory action of intrathyroid hydrolysis.