Amyloid β peptide (Aβ) has been implicated in Alzheimer's disease (AD) as an initiator of the pathological cascades. Several lines of compelling evidence have supported major roles of Aβ‐degrading ...enzyme neprilysin in the pathogenesis of sporadic AD. Here, we have shown a substantial reduction of cerebrospinal fluid (CSF) neprilysin activity (CSF‐NEP) in patients with AD‐converted mild cognitive impairment and early AD as compared with age‐matched control subjects. The altered CSF‐NEP likely reflects changes in neuronal neprilysin, since transfer of neprilysin from brain tissue into CSF was demonstrated by injecting neprilysin‐carrying viral vector into the brains of neprilysin‐deficient mice. Interestingly, CSF‐NEP showed an elevation with the progression of AD. Along with a close association of CSF‐NEP with CSF tau proteins, this finding suggests that presynaptically located neprilysin can be released into CSF as a consequence of synaptic disruption. The impact of neuronal damages on CSF‐NEP was further demonstrated by a prominent increase of CSF‐NEP in rats exhibiting kainate‐induced neurodegeneration. Our results unequivocally indicate significance of CSF‐NEP as a biochemical indicator to pursue a pathological process that involves decreased neprilysin activity and Aβ‐induced synaptic toxicity, and the support the potential benefits of neprilysin up‐regulation in ameliorating neuropathology in prodromal and early AD. Ann Neurol 2005;57:832–842
A member of the Forkhead transcription factor family, FKHRL1, lies downstream of the phosphatidylinositol 3-kinase-Akt activation pathway in cytokine signaling. Because the phosphatidylinositol ...3-kinase-Akt activation pathway is required for BCR-ABL-mediated transformation and survival signaling in chronic myelogenous leukemia (CML), in this study we examined the involvement of FKHRL1 in the BCR-ABL-mediated signaling pathway. FKHRL1 was constitutively phosphorylated in BCR-ABL-expressing cell lines KCL22 and KU812, and its phosphorylation was inhibited by treatment with STI571, a specific inhibitor of BCR-ABL tyrosine kinase. Concomitantly, STI571 induced cell cycle arrest at the G(0)/G(1) phase, accompanied by up-regulation of a cyclin-dependent kinase inhibitor p27/Kip1 in KCL22 cells. In addition, FKHRL1 was constitutively phosphorylated in the TF-1/bcr-abl cell line ectopically expressing BCR-ABL but not in the parent TF-1 cell line. Considering several lines of evidence that phosphorylated FKHRL1 has lost transcriptional activity and that p27/Kip1 expression is positively regulated by dephosphorylated "active" FKHRL1, BCR-ABL may down-regulate p27/Kip1 expression via the loss of FKHRL1 function as a transcription factor. To demonstrate this hypothesis, we generated a tamoxifen-inducible "active FKHRL1" FKHRL1-TM (a triple mutant of FKHRL1, in which all three Akt phosphorylation sites have been mutated), estrogen receptor system in the KCL22 cell line. The addition of tamoxifen inhibited the cell growth indicating that overexpression of FKHRL1 in the nucleus antagonized deregulated proliferation of CML cells. Collectively, FKHRL1 regulates the expression of p27/Kip1 as a downstream molecule of BCR-ABL signaling in CML cells. BCR-ABL-induced loss of FKHRL1 function may be involved in oncogenic transformation of CML partially via the down-regulation of p27/Kip1 proteins.
This study examined the effects of the inulin-type fructans known as fructo-oligosaccharide (FOS) and inulin on the growth and persistence of Lactobacillus plantarum No. 14 (LP14) in the gut. ...Cultivation in medium that contained either FOS or inulin revealed that both fructans supported the growth of LP14. Fecal recovery of viable L. plantarum at 24 and 30 h following administration of LP14 were highest in mice fed inulin, followed by mice fed FOS and the control diet. However, neither of the fructans prolonged the appearance of LP14 in the gut. Cultivation in fecal extract medium prepared from mice fed each of the test diets showed higher growth of LP14 in the mice fed fructans. Histological analysis following fluorescein-stained LP14 administration showed that LP14 was largely localized to the luminal contents. These results suggest that inulin-type fructans support the growth of LP14 in the luminal contents only during their passage through the gut.
Angle-resolved photoemission spectroscopy (ARPES) is used to study the electronic structure of an HfC (111) surface. A sharp peak is observed at 0.37
eV below the Fermi level in normal-emission ...spectra. From the analysis of the photon energy dependence of the spectra and a crude test using oxygen adsorption, the initial state of the peak is determined to be a surface state. The two-dimensional band structure of the surface state is measured it is found to have a dispersion having a minimum at the
Γ
̄
point.
Cross sections for midrapidity production of direct photons in p+p collisions at the Relativistic Heavy Ion Collider (RHIC) are reported for transverse momenta of 3 < p(T)< 16 GeV/c. Next-to-leading ...order perturbative QCD (pQCD) describes the data well for p(T)> 5 GeV/c, where the uncertainties of the measurement and theory are comparable. We also report on the effect of requiring the photons to be isolated from parton jet energy. The observed fraction of isolated photons is well described by pQCD for p(T)> 7 GeV/c.
Thrombopoietin (TPO), an essential factor for megakaryopoiesis and thrombopoiesis, works as a survival factor for megakaryocytic lineage cells. However, little is known about the molecular mechanism ...in detail. We show here that TPO supports the survival of TPO-dependent leukemia cell line UT-7/TPO and normal megakaryocytic progenitors via the induction of Bcl-xL, an anti-apoptotic member of the Bcl-2 family. We further analyzed the signal transduction pathways required for TPO-induced Bcl-xL gene expression. A reporter assay with various lengths of Bcl-x gene promoter revealed that both Stat- and nuclear factor κB-binding sites are prerequisites for TPO-induced promoter activity. Consistent with these results, TPO induced the binding of Stat5 and subunits of nuclear factor κB, p50, and c-Rel to the Bcl-x gene promoter. AG490, a specific inhibitor for Jak2, and LY294002, a specific inhibitor for phosphatidylinositol (PI) 3-kinase, reduced the protein level of Bcl-xL in UT-7/TPO cells, accompanied by an increase in the ratio of apoptotic cells. Interestingly, LY294002 enhanced the TPO-induced DNA binding activity of Stat5 without affecting the Jak2 activation and tyrosine phosphorylation of Stat5. Concomitantly, confocal microscopy revealed that LY294002 clearly inhibited the nuclear export of Stat5, suggesting that PI 3-kinase regulates the subcellular localization of Stat5. Taken together, our results suggest that both Jak-Stat and PI 3-kinase activation pathways regulate the TPO-induced survival of megakaryocytic cells via Bcl-xL gene expression. In addition, our data suggest possible cross-talk between these two signaling pathways.
The Three Gorge Reservoir (TGR) is the largest reservoir in China and its water quality is an important health concern, we have determined the concentrations of PCDDs/PCDFs and PCBs in the water ...samples collected at three seasons: August 2004, January 2005 and August 2005. The results showed that the average WHO-TEQ of total dioxins-like compounds (PCDDs/PCDFs
+
PCBs) was 0.06558
pg
l
−1, ranged from 0.0008 to 0.32439
pg
l
−1, which are much lower than other reported water sources. The main dioxins (PCDDs/PCDFs) are hepta- and octa-chlorinated dibenzo-
p-dioxins (CDDs) and chlorinated dibenzofurans (CDFs). Since the levels of dioxins may change after the last water-store stage, the present study provides important data to compare the water quality in the TGR in the future.
An 81-year-old male appealed against a feeling of dyspnea, and consulted the hospital. The giant tumor discovered in the thorax and it was enlarging gradually for 7 years. The tumor shadow with a ...diameter of about 15 cm was noted in right lower lung field on the chest X-ray. A definite diagnosis was not obtained by the needle biopsy. The tumor was found to exist between upper lobe and lower lobe and pressed lower lobe at surgery. The tumor was completely excised with partial resection of the collapsed lower lobe. The tumor was 1,050 g in weight and 18 cm in maximum diameter. Pathological examination showed the irregular and plan-like arrangement of the spindle-shape cell. Immunohistochemical study revealed positive findings for bcl-2 and CD34, negative findings for desmin, ketatin, and alpha-actin. The tumor was diagnosed as malignant solitary fibrous tumor of the pleura due to highly atypical nuclear finding with an abundant nuclear fission or histology.
We present measurements of the cross section and double-helicity asymmetry A_{LL} of direct-photon production in pover →+pover → collisions at sqrts=510 GeV. The measurements have been performed at ...midrapidity (|η|<0.25) with the PHENIX detector at the Relativistic Heavy Ion Collider. At relativistic energies, direct photons are dominantly produced from the initial quark-gluon hard scattering and do not interact via the strong force at leading order. Therefore, at sqrts=510 GeV, where leading-order-effects dominate, these measurements provide clean and direct access to the gluon helicity in the polarized proton in the gluon-momentum-fraction range 0.02<x<0.08, with direct sensitivity to the sign of the gluon contribution.
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