Biomedical subjects

T Hara

Publications and source records attributed to T Hara.

At least 19 recordsLinked to original sources

PubMed2006

Modulation of the functional binding sites for TGF-beta on the type II receptor leads to suppression of TGF-beta signaling.

Transforming growth factor-beta (TGF-beta) binds to two different types of serine/threonine kinase receptors termed type II (TbetaR-II) and type I (TbetaR-I). TGF-beta is unable to bind to TbetaR-I in the absence of TbetaR-II, and initiates receptor assembly by binding with high affinity to TbetaR-II. Previous structural analysis of the TGF-beta3-TbetaR-II complex has suggested that two charged amino acid residues, D55 and E142 of TbetaR-II, are binding sites of TGF-beta. In the present study, we have shown that mutations of the amino-acid residues, D55 and E142 of TbetaR-II, resulted in loss of TGF-beta binding and downstream signaling activity. Moreover, we found that 3,5,7,2',4'-pentahydroxyflavone (Morin) inhibits TGF-beta binding to TbetaR-II, and suppresses phosphorylation of Smad2 and expression of a TGF-beta target gene Smad7 induced by TGF-beta. Our findings may thus provide useful information for designing therapeutic agents for various diseases induced by TGF-beta, including advanced cancers.

Amino Acid Sequence↗

PubMed2006

Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation.

The serine protease Omi/HtrA2 was initially regarded as a proapoptotic molecule that proteolyses several proteins to induce cell death. Recent studies, however, indicate that loss of Omi protease activity increases susceptibility to stress-induced cell death. These complicated findings suggest that the protease activity of Omi is involved not only in apoptosis but also in cellular homeostasis. However, the targets which Omi uses to mediate this novel process are unknown. Previously, we showed that WARTS (WTS)/large tumor-suppressor 1 mitotic kinase interacts with the protein/discs-large protein/zonula (PDZ) domain of Omi and promotes its protease activity. We now report that WTS is a substrate for Omi protease activity, thus it is not only a regulator but also a downstream target of this protease. Interaction with Omi PDZ domain is required for WTS to be proteolysed. When caspase-9-deficient mouse embryonic fibroblasts (MEFs) were treated with staurosporine, WTS was proteolysed by activated endogenous Omi without induction of cell death. Therefore, protease activity of Omi and proteolysis of WTS are not necessarily required for cell death. We found that depletion of Omi from HeLa cells results in accelerated cell proliferation despite no significant change in the duration of mitosis. The depletion of WTS showed the same effect on S phase progression. Therefore, WTS proteolytic fragment(s) generated by Omi may act as an inhibitor of G1/S progression. Our data reveal a role for Omi-mediated processing of WTS in negative regulation of cell cycle progression at interphase, suggesting a novel function of Omi other than apoptosis.

Animals↗

PubMed2006

Observation of new states decaying into Lambda(c)(+)Kappa(-)pi(+) and Lambda(c)(+)Kappa(0)/(s)pi(-).

We report the first observation of two charmed strange baryons that decay into Lambda(c)(+)Kappa(-)pi(+). The broader of the two states is measured to have a mass of 2978.5+/-2.1+/-2.0 MeV/c2 and a width of 43.5+/-7.5+/-7.0 MeV/c2. The mass and width of the narrow state are measured to be 3076.7+/-0.9+/-0.5 MeV/c;{2} and 6.2+/-1.2+/-0.8 MeV/c2, respectively. We also perform a search for the isospin partner states that decay into Lambda(c)(+)Kappa(0)/(s)pi(-) and observe a significant signal at the mass of 3082.8+/-1.8+/-1.5 MeV/c2. The data used for this analysis were accumulated at or near the Upsilon(4S) resonance, using the Belle detector at the e+ e- asymmetric-energy collider KEKB. The integrated luminosity of the data sample used is 461.5 fb(-1).

Journal Article↗

PubMed2006

Measurement of D0-->pilnu(Klnu) form factors and absolute branching fractions.

Using a 282 fb-1 data sample collected by the Belle experiment at the KEKB e+e- collider, we study D0 decays to K-l+nu and pi-l+nu final states. The D0 flavor and momentum are tagged through a full reconstruction of the recoiling charm meson and additional mesons from fragmentation. The reconstruction method provides very good resolution in neutrino momentum and in q2=(pl+pnu)2. Normalizing to the total number of D0 tags, we measure the absolute branching fractions to be B(D0-->Klnu)=(3.45+/-0.07stat+/-0.20syst)% and B(D0-->pilnu)=(0.255+/-0.019stat+/-0.016syst)% and the semileptonic form factors (within the modified pole model) f+K(0)=0.695+/-0.007stat+/-0.022syst and f+pi(0)=0.624+/-0.020stat+/-0.030syst.

Journal Article↗

PubMed2006

Evidence for B-->eta'pi and improved measurements for B-->eta'K.

We report evidence for the exclusive two-body charmless hadronic B meson decay B-->eta'pi, and improved measurements of B-->eta'K. The results are obtained from a data sample of 386x10(6) BB pairs collected at the Upsilon(4S) resonance, with the Belle detector at the KEKB asymmetric-energy e+e- collider. We measure B(B+-->eta'pi+)=[1.76(-0.62)(+0.67)(stat)(-0.14)(+0.15)(syst)]x10(-6) and B(B0-->eta'pi0)=[2.79(-0.96)(+1.02)(stat)(-0.34)(+0.25)(syst)]x10(-6). We also find the ratio of B(B+-->eta'K+)/B(B0-->eta'K0)=1.17+/-0.08(stat)+/-0.03(syst) and measure the direct CP asymmetries for the charged modes.

Journal Article↗

PubMed2006

Interferon-gamma enhances superoxide production in human mesangial cells via the JAK-STAT pathway.

Immune reactive cytokines, such as interferon (IFN)-gamma, have multiple effects in glomerulonephritis. Superoxide anions (O(2)(-)), which are associated with the progression of glomerulonephritis, are mainly generated by nicotinamide adenine dinucleotide phosphate (reduced form) NAD(P)H oxidases. We determined the effects of IFN-gamma on O(2)(-) production, phosphorylation of signal transducer and activator of transcription (STAT)-1alpha, and the mRNA and protein expressions of p22phox and Nox1, components of NAD(P)H oxidases, in human mesangial cells (HMCs). Significant increases in O(2)(-) production with IFN-gamma were completely abolished by the flavin-containing enzyme inhibitor, diphenyleneiodonium (10 micromol/l), and the Janus-activated kinase (JAK)2 inhibitor, AG490 (100 micromol/l). Phosphorylated STAT-1alpha was detected after 5 min of IFN-gamma stimulation using Western blot analysis, and binding to the gamma-activating site was observed from 30 min to 4 h, thereafter by electrophoretic mobility shift assay (EMSA). Super-shift analysis in EMSA revealed that the main transcription factor was STAT-1alpha. IFN-gamma significantly increased the expression of p22phox mRNA and protein, although expression was inhibited by AG490. These data suggest that IFN-gamma stimulates O(2)(-) production in HMCs via the JAK-STAT pathway and NAD(P)H oxidase.

Cells, Cultured↗

PubMed2006

Evidence for large direct CP violation in B+/- --> rho(770)0K+/- from analysis of three-body charmless B+/- --> K+/-pi+/-pi+/- decays.

We report results on a Dalitz analysis of three-body charmless B+/- --> K+/-pi+/-pi+/- decay including searches for direct CP violation. We report the first observation of the decay B+/- --> f2(1270)K+/- with a statistical significance above 6sigma. We also observe first evidence for large direct CP violation in the B+/- --> rho(770)0K+/- channel. The results are obtained with a data sample that contains 386 10(6) BB pairs collected at the Y(4s) resonance with the Belle detector at the KEKB asymmetric-energy e+e- collider.

Journal Article↗

PubMed2006

Measurement of forward-backward asymmetry and Wilson coefficients in B --> K*l+l-.

We report the first measurement of the forward-backward asymmetry and the ratios of Wilson coefficients and in A9/A7 and A10/A7 in B --> K*l+l-, where l represents an electron or a muon. We find evidence for the forward-backward asymmetry with a significance of 3.4sigma. The results are obtained from a data sample containing 386 x 10(6) BB pairs that were collected on the Y(4S) resonance with the Belle detector at the KEKB asymmetric-energy e+e- collider.

Journal Article↗

PubMed2006

Observation of b-->dgamma and determination of /Vtd/Vts/.

We report the observation of the flavor-changing neutral current process b-->dgamma using a sample of 386 x 106 B meson pairs accumulated by the Belle detector at the KEKB e+e- collider. We measure branching fractions for the exclusive modes B--->rho-gamma, B0rho0gamma, and B0omegagamma. Assuming that these three modes are related by isospin, we find B(B-->(rho,gamma)gamma)=[Formula: See Text] with a significance of 5.1sigma. This result is used to determine the ratio of Cabibbo-Kobayashi-Maskawa matrix elements /Vtd/Vts/ to be [Formula: See Text].

Journal Article↗

PubMed2006

Improved search for nu(mu) --> nu(e) oscillation in a long-baseline accelerator experiment.

We performed an improved search for nu(mu) --> nu(e) oscillation with the KEK to Kamioka (K2K) long-baseline neutrino oscillation experiment, using the full data sample of 9.2 x 10(19) protons on target. No evidence for a nu(e) appearance signal was found, and we set bounds on the nu(mu) --> nu(e) oscillation parameters. At Deltam(2)=2.8 x 10(-3) eV(2), the best-fit value of the K2Knu(mu) disappearance analysis, we set an upper limit of sin(2)2theta(mue) < 0.13 at a 90% confidence level.

Journal Article↗

PubMed2006

STAT3 activation via interleukin 6 trans-signalling contributes to ileitis in SAMP1/Yit mice.

BACKGROUND AND AIMS: SAMP1/Yit mice spontaneously develops intestinal inflammation. Previously, we demonstrated that the signal transducer and activator of transcription (STAT)-3/suppressor of cytokine signalling (SOCS)-3 pathway is pivotal in human inflammatory bowel disease. In our studies in SAMP1/Yit mice, the aim was to investigate whether STAT3 activation contributes to ileitis and to examine the therapeutic effects of this signal blockade. METHODS: Intestinal expression of phospho-STAT3 in SAMP1/Yit mice and control AKR/J mice was examined by western blotting and immunohistochemistry. SOCS3 and interleukin 6 (IL-6) mRNA were determined by northern blotting and reverse transcription-polymerase chain reaction, respectively. We also examined the effects of intravenously injected hyper-IL-6, an IL-6/soluble IL-6 receptor fusion protein, and of soluble gp130-Fc, a specific inhibitor of soluble IL-6 receptor signalling, on STAT3 phosphorylation and disease severity in SAMP1/Yit mice. RESULTS: Phospho-STAT3 was expressed strongly during the disease course in SAMP1/Yit mice but only transiently in AKR/J mice. Phospho-STAT3 was localised to epithelial and mononuclear cells in the diseased intestine of SAMP1/Yit mice. SOCS3 as well as IL-6 mRNAs were expressed in affected intestine. Administration of hyper-IL-6 caused disease exacerbation and enhancement of STAT3 phosphorylation. In contrast, soluble gp130-Fc administration ameliorated the disease and suppressed STAT3 phosphorylation. CONCLUSION: STAT3 signalling is critical in the development of intestinal inflammation in SAMP1/Yit mice. Blockade of this signalling pathway by soluble gp130-Fc may have therapeutic effects in inflammatory bowel disease.

Animals↗

PubMed2006

Measurement of the branching fraction, polarization, and asymmetry for decays, and determination of the Cabibbo-Kobayashi-Maskawa phase.

We have measured the branching fraction , longitudinal polarization fraction f(L), and CP asymmetry coefficients A and S for B(0) --> rho(+) rho(-) decays with the Belle detector at the KEKB e(+) e(-) collider using 253 Fb(-1) of data. We obtain B = [22.8 +/- 3.8(stat)(+2.3)(-2.6)(syst)] x 10(-6), f(L) = 0.941 (+0.034)(-0.040)(stat) +/- 0.030(syst). A = 0.00 +/- 0.30(stat) +/- 0.09(syst) and S = 0.08 +/- 0.09(syst). These values are used to constrain the Cabibbo-Kobayashi-Maskawa phase ; the solution consistent with the standard model is phi(2) = (88 +/- 17) degrees or 59 degrees < phi(2) < 115 degrees at 90% C.L.

Journal Article↗

PubMed2006

Improved constraints on D0-D0 mixing in D0 --> K+ pi- decays from the Belle detector.

We report the results of a search for D0-D0 mixing in D0 --> K+ pi- decays based on 400 fb(-1) of data accumulated by the Belle detector at KEKB. Both assuming CP conservation and allowing for CP violation, we fit the decay-time distribution for the mixing parameters x and y, as well as for the parameter R(D), the ratio of doubly Cabibbo-suppressed decays to Cabibbo-favored decays. The 95% confidence level region in the (x'2,y') plane is obtained using a frequentist method. Assuming CP conservation, we find x'2 < 0.72 x 10(-3) and -9.9 x 10(-3) < y' < 6.8 x 10(-3) at the 95% confidence level; these are the most stringent constraints on the mixing parameters to date. The no-mixing point (0,0) has a confidence level of 3.9%. Assuming no mixing, we measure R(D) = (0.377 +/- 0.008 +/- 0.005)%.

Journal Article↗

PubMed2006

Semen quality in a Giant Panda (Ailuropoda melanoleuca) in relation to estrus of a nearby resident female panda.

Semen quality was determined in a sexually mature male Giant Panda, electroejaculated 13 times during a 5-year interval, before, during and after estrus of a female Giant Panda housed nearby. Testis volume and plasma testosterone concentrations were also measured. Mean testis volumes were 1223.0 +/- 64.7(S.E.M.)cm3 (before estrus), 1213.2 +/- 218.2 cm3 (during estrus), and 1360.2+/-160.4 cm3 (after estrus). Compared to before and during estrus in the female, testis volume decreased 70 days after estrus and there was no projectile ejaculation. The mean semen volume and sperm count were 2.2+/-0.7 mL and 8.3 +/- 3.1 x 10(8) before estrus, 2.4 +/- 0.9 mL and 5.7 +/- 0.9 x 10(8) during estrus, and 1.3 +/- 0.3 mL and 8.1 +/- 1.7 x 10(8) after estrus, respectively. The semen volume, sperm count, and testis volume markedly differed from 90 days before estrus until 66 days after estrus, whereas no marked differences in sperm motility, sperm viability, and proportion of morphologically abnormal spermatozoa were observed. Plasma testosterone concentrations were elevated both before and during estrus (0.62 +/- 0.23 ng/mL and 0.95 ng/mL), but decreased substantially after estrus (0.20 +/- 0.0 ng/mL). We inferred that spermatogenesis was active in this male panda from approximately 3 months before estrus to 2 months after estrus in the adjacent female.

Animals↗

PubMed2006

Serum levels of 8-isoprostane, a marker of oxidative stress, are elevated in patients with systemic sclerosis.

OBJECTIVE: To determine serum levels and clinical correlation of 8-isoprostane, which is produced in vivo through free radical-catalysed peroxidation of arachidonic acid and reflects oxidative stress, in patients with systemic sclerosis (SSc). METHODS: Serum 8-isoprostane levels from 32 patients with diffuse cutaneous SSc (dSSc) and 25 patients with limited cutaneous SSc (lSSc) were examined by enzyme-linked immunosorbent assay. RESULTS: Serum 8-isoprostane levels were elevated in dSSc and lSSc patients by 75-fold compared with normal controls (n=32). Serum 8-isoprostane levels correlated negatively with pulmonary function, such as percentage vital capacity and diffusion capacity for carbon monoxide, and correlated positively with renal vascular damage determined by colour flow Doppler ultrasonography. Serum 8-isoprostane levels also correlated positively with serum levels of IgG and anti-agalactosyl IgG autoantibody. CONCLUSION: Increased 8-isoprostane levels correlated with the severity of pulmonary fibrosis, the extent of renal vascular damage and immunological abnormalities in SSc, suggesting that enhanced oxidative stress is related to the development of SSc.

Adult↗

PubMed2006

Cytokinesis regulator ECT2 changes its conformation through phosphorylation at Thr-341 in G2/M phase.

The Rho activator ECT2 functions as a key regulator in cytokinesis. ECT2 is phosphorylated during G2/M phase, but the physiological significance of this event is not well known. In this study, we show that phosphorylation of ECT2 at threonine-341 (T341) affects the autoregulatory mechanism of ECT2. In G2/M phase, ECT2 was phosphorylated at T341 most likely by Cyclin B/Cyclin-dependent kinase 1 (Cdk1), and then dephosphorylated before cytokinesis. Depletion of ECT2 by RNA interference (RNAi) efficiently induced multinucleate cells. Expression of the phospho-deficient mutant of ECT2 at T341 suppressed the multinucleation induced by RNAi to ECT2, indicating that ECT2 is biologically active even when it is not phosphorylated at T341. However, the phospho-mimic mutation at T341 weakly stimulates the catalytic activity of ECT2 as detected by serum response element reporter gene assays. As T341 is located at the hinge region of the N-terminal regulatory domain and C-terminal catalytic domain, phosphorylation of T341 may help accessing downstream signaling molecules to further activate ECT2. We found that the phospho-mimic mutation T341D increases binding with itself or the N-terminal half of ECT2. These results suggest a conformational change of ECT2 upon phosphorylation at T341. Therefore, ECT2 activity might be regulated by the phosphorylation status of T341. We propose that T341 phosphorylation by Cyclin B/Cdk1 could be a trigger for further activation of ECT2.

Amino Acid Sequence↗

PubMed2006

Analysis of MxA, IL-4, and IRF-1 genes in Filipino patients with subacute sclerosing panencephalitis.

BACKGROUND: Subacute sclerosing panencephalitis (SSPE) is a chronic and debilitating disease of the central nervous system caused by a latent measles virus infection. Three candidate genes, MxA, IL-4, and IRF-1 genes were shown to be associated with SSPE in Japanese patients. These genes have been suggested to play a role in the establishment of persistent viral infection in the central nervous system. SUBJECTS AND METHODS: Sixty Filipino SSPE patients and 120 healthy control subjects were included in the study. Single nucleotide polymorphisms at promoter regions ( IL-4-590C/T and MXA-88G/T) were screened using PCR-RFLP method. Genotyping was done for GT repeat polymorphism within intron 7 of IRF-1. RESULTS: The TT genotype of MXA, as well as the CT genotype of IL-4, were seen a little more frequently among the SSPE patients as compared to the control subjects. The values though, did not reach statistical significance. IRF-1 analysis did not differ between the two groups. CONCLUSION: Our study failed to demonstrate a significant association between IL-4, MXA, or IRF-1, and SSPE in the Filipino population. Our results might be explained by a greater contribution of environmental factors such as the socio-economic and nutritional factors in the susceptibility of Filipinos to SSPE other than genetic factors.

Adolescent↗

PubMed2006

Novel roles of osteopontin and CXC chemokine ligand 7 in the defence against mycobacterial infection.

Granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced human monocyte-derived macrophage (GM-Mphi) or macrophage CSF (M-CSF)-induced human monocyte-derived Mphi (M-Mphi) are distinct in terms of the resistance to Mycobacterium tuberculosis. To elucidate the role of molecules involved in the functional differences between these Mphis, we investigated the gene expression profiles using microarray. After culture of CD14+ monocytes with CSFs, Mphis were cultured with or without bacillus Calmette-Guérin (BCG) (GM-Mphi-BCG and M-Mphi-BCG). The gene expression profiles from these cells were compared. Chemokines highly expressed in M-Mphis were selected and evaluated for anti-mycobacterial activity and superoxide production. FN1 and FCGR2B were the most up-regulated genes in GM-Mphi and M-Mphi, respectively. After stimulation with BCG, three chemokine genes (Osteopontin (SPP1), CXC chemokine ligand 7 (CXCL7) and CC chemokine ligand 11 (CCL11)) were highly expressed in M-Mphi-BCG when compared to those in GM-Mphi-BCG. A significantly increased resistance to M. tuberculosis H37Ra was observed after the stimulation of GM-Mphi with SPP1 or CXCL7. Superoxide production levels of SPP1- or CXCL7-stimulated GM-Mphis were higher than those of GM-Mphis without stimulation. These results indicate that both SPP1 and CXCL7 might have a role in the resistance against mycobacteria, at least in part, through augmenting reactive oxygen intermediate production in Mphis.

BCG Vaccine↗