Probing Superatomic Orbitals of Sc-Doped and Undoped Silver Cluster Anions via Photoelectron Angular Anisotropy.

Valence s electrons in alkali- or coinage-metal clusters are conceived to delocalize over the metal frameworks. The electrons occupy so-called superatomic orbitals (SAOs, i.e., 1S, 1P, 1D, 2S, 1F, ...), which provide an essential picture for understanding the size-dependent, unique properties of these metal clusters. While such electronic shells are unambiguously identified in their photoelectron spectra and supported by electronic structure calculations, characterization of SAOs in heteroatom-doped metal clusters has remained elusive as the doping significantly affects its energy levels and even alters the ordering of SAOs. Here, we present a photoelectron imaging study to explore SAOs formed in Sc-doped and undoped silver cluster anions, AgNSc- (N = 15, 16) and AgN- (N = 18, 19). Photoelectron angular distributions from their outermost SAOs are clearly visualized, whose characters are analyzed with the aid of density functional theory calculations. The present methodology enables us to explore not only the quantized energy levels but also the spatial distributions of SAOs formed in various metal cluster anions.

Cyclins in aspergilli: Phylogenetic and functional analyses of group I cyclins.

We have identified the cyclin domain-containing proteins encoded by the genomes of 17 species of Aspergillus as well as 15 members of other genera of filamentous ascomycetes. Phylogenetic analyses reveal that the cyclins fall into three groups, as in other eukaryotic phyla, and, more significantly, that they are remarkably conserved in these fungi. All 32 species examined, for example, have three group I cyclins, cyclins that are particularly important because they regulate the cell cycle, and these are highly conserved. Within the group I cyclins there are three distinct clades, and each fungus has a single member of each clade. These findings are in marked contrast to the yeasts Saccharomyces cerevisiae, Schizosaccharomyces pombe, and Candida albicans, which have more numerous group I cyclins. These results indicate that findings on cyclin function made with a model Aspergillus species, such as A. nidulans, are likely to apply to other Aspergilli and be informative for a broad range of filamentous ascomycetes. In this regard, we note that the functions of only one Aspergillus group I cyclin have been analysed (NimECyclin B of A. nidulans). We have consequently carried out an analysis of the members of the other two clades using A. nidulans as our model. We have found that one of these cyclins, PucA, is essential, but deletion of PucA in a strain carrying a deletion of CdhA, an activator of the anaphase promoting complex/cyclosome (APC/C), is not lethal. These data, coupled with data from heterokaryon rescue experiments, indicate that PucA is an essential G1/S cyclin that is required for the inactivation of the APC/C-CdhA, which, in turn, allows the initiation of the S phase of the cell cycle. Our data also reveal that PucA has additional, non-essential, roles in the cell cycle in interphase. The A. nidulans member of the third clade (AN2137) has not previously been named or analyzed. We designate this gene clbA. ClbA localizes to kinetochores from mid G2 until just prior to chromosomal condensation. Deletion of clbA does not affect viability. However, by using a regulatable promoter system new to Aspergillus, we have found that expression of a version of ClbA in which the destruction box sequences have been removed is lethal and causes a mitotic arrest and a high frequency of non-disjunction. Thus, although ClbA is not essential, its timely destruction is essential for viability, chromosomal disjunction, and successful completion of mitosis.

Preventive effect of renin-angiotensin system inhibitors on new-onset atrial fibrillation in hypertensive patients: a propensity score matching analysis.

It is still controversial whether treatment with renin-angiotensin system (RAS) inhibitors reduces the risk of incident atrial fibrillation (AF). This longitudinal observational study was performed to investigate the confounder-independent effects of RAS inhibitors on new-onset AF in hypertensive patients. Among 1263 consecutive hypertensive patients who underwent echocardiography, 964 eligible patients (mean age, 63 years) were enrolled as the study population. Forty-nine patients developed new-onset AF during the follow-up period (mean: 4.6 years). Kaplan-Meier analysis showed that the cumulative AF event rate was lower in patients receiving RAS inhibitors than in patients without these drugs, but the difference between these two groups was not significant (P=0.057). Since the use of RAS inhibitors was influenced by concomitant diabetes, chronic kidney disease and left ventricular hypertrophy, propensity score matching (1:1) was employed to minimize the influence of selection bias for RAS inhibitors. Clinical and echocardiographic parameters showed no significant differences between the propensity score-matched groups with and without RAS inhibitor therapy (both n=326), but the cumulative AF event rate was significantly lower in the group receiving RAS inhibitors (P=0.013). Univariate and multivariate Cox regression analyses also revealed that RAS inhibitor therapy was associated with a significantly lower risk of new-onset AF during the follow-up period. In conclusion, this propensity score matching study demonstrated that the incidence of new-onset AF was lower in hypertensive patients receiving RAS inhibitor therapy.

Excited-state dynamics of furan studied by sub-20-fs time-resolved photoelectron imaging using 159-nm pulses.

The excited-state dynamics of furan were studied by time-resolved photoelectron imaging using a sub-20-fs deep UV (198 nm) and vacuum UV (159 nm) light source. The 198- and 159-nm pulses produce photoionization signals in both pump-probe and probe-pump pulse sequences. When the 198-nm pulse precedes the 159-nm pulse, it creates the (1)A2(3s) Rydberg and (1)B2(ππ(∗)) valence states, and the former decays exponentially with a time constant of about 20 fs whereas the latter exhibits more complex wave-packet dynamics. When the 159-nm pulse precedes the 198-nm pulse, a wave packet is created on the (1)A1(ππ(∗)) valence state, which rapidly disappears from the observation window owing to structural deformation. The 159-nm photoexcitation also creates the 3s and 3px,y Rydberg states non-adiabatically.

Observation of the wavepacket dynamics on the (1)B2((1)Σ(u)(+)) state of CS2 by sub-20 fs photoelectron imaging using 159 nm probe pulses.

The wavepacket dynamics of CS2 after photoexcitation to the (1)B2((1)Σu(+)) state at 198 nm are studied by time-resolved photoelectron imaging using sub-20 fs 159 nm pulses, which enable single photon ionization from the entire region of the (1)B2 potential energy surface. The time-energy map of the photoelectron intensity reveals vibrational motions along the symmetric stretching and bending coordinates. The time-energy map of the photoelectron anisotropy parameter exhibits time-evolution within single oscillation periods of the ν1 and ν2 modes, which is attributed to variation of the excited state electronic character along these vibrational coordinates. The initially populated (1)B2 state evolves with two time constants of 107 and 394 fs.

Effect of NS-018, a selective JAK2V617F inhibitor, in a murine model of myelofibrosis.

A single somatic mutation, V617F, in Janus kinase 2 (JAK2) is one of the causes of myeloproliferative neoplasms (MPNs), including primary myelofibrosis, and the JAK2V617F mutant kinase is a therapeutic target in MPN. However, inhibition of wild-type (WT) JAK2 can decrease the erythrocyte or platelet (PLT) count. Our selective JAK2 inhibitor, NS-018, suppressed the growth of Ba/F3 cells harboring JAK2V617F more strongly than that of cells harboring WT JAK2. The 4.3-fold JAK2V617F selectivity of NS-018 is higher than the 1.0- to 2.9-fold selectivity of seven existing JAK2 inhibitors. NS-018 also inhibited erythroid colony formation in JAK2V617F transgenic mice at significantly lower concentrations than in WT mice. In keeping with the above results, in a JAK2V617F bone marrow transplantation mouse model with a myelofibrosis-like disease, NS-018 reduced leukocytosis and splenomegaly, improved bone marrow fibrosis and prolonged survival without decreasing the erythrocyte or PLT count in the peripheral blood. By exploring the X-ray co-crystal structure of NS-018 bound to JAK2, we identified unique hydrogen-bonding interactions between NS-018 and Gly993 as a plausible explanation for its JAK2V617F selectivity. These results suggest that NS-018 will have therapeutic benefit for MPN patients through both its efficacy and its reduced hematologic adverse effects.

Efficacy of NS-018, a potent and selective JAK2/Src inhibitor, in primary cells and mouse models of myeloproliferative neoplasms.

Aberrant activation of Janus kinase 2 (JAK2) caused by somatic mutation of JAK2 (JAK2V617F) or the thrombopoietin receptor (MPLW515L) plays an essential role in the pathogenesis of myeloproliferative neoplasms (MPNs), suggesting that inhibition of aberrant JAK2 activation would have a therapeutic benefit. Our novel JAK2 inhibitor, NS-018, was highly active against JAK2 with a 50% inhibition (IC(50)) of <1 n, and had 30-50-fold greater selectivity for JAK2 over other JAK-family kinases, such as JAK1, JAK3 and tyrosine kinase 2. In addition to JAK2, NS-018 inhibited Src-family kinases. NS-018 showed potent antiproliferative activity against cell lines expressing a constitutively activated JAK2 (the JAK2V617F or MPLW515L mutations or the TEL-JAK2 fusion gene; IC(50)=11-120 n), but showed only minimal cytotoxicity against most other hematopoietic cell lines without a constitutively activated JAK2. Furthermore, NS-018 preferentially suppressed in vitro erythropoietin-independent endogenous colony formation from polycythemia vera patients. NS-018 also markedly reduced splenomegaly and prolonged the survival of mice inoculated with Ba/F3 cells harboring JAK2V617F. In addition, NS-018 significantly reduced leukocytosis, hepatosplenomegaly and extramedullary hematopoiesis, improved nutritional status, and prolonged survival in JAK2V617F transgenic mice. These results suggest that NS-018 will be a promising candidate for the treatment of MPNs.

Association of insulin-like growth factor-1 receptor gene polymorphisms with left ventricular mass and geometry in essential hypertension.

Stimulation of insulin-like growth factor (IGF)-1 receptor by IGF-1 and insulin strongly induces cardiomyocyte hypertrophy. In this study, we assessed the hypothesis that genetic variations of the IGF-1 receptor may be linked to the diversity of left ventricular (LV) structure in hypertensive patients. Genotypes in 12 single nucleotide polymorphisms (SNPs) of the IGF-1 receptor gene identified by direct sequencing were determined in 795 Japanese patients with essential hypertension. In echocardiographic examinations, LV mass index (LVMI) and relative wall thickness (RWT) were measured. Among 12 SNPs, promoter -328C>T and intron-13 275124A>C polymorphisms were significantly associated with LV hypertrophy (LVMI> or =125 g m(-2)) and concentric change (RWT> or =0.44), respectively. In allele frequencies, the C allele of -328C>T was related to LV hypertrophy, and the A allele of 275124A>C was related to LV concentric change. In fact, LVMI and prevalence of LV hypertrophy increased in CC genotype of -328C>T. RWT and prevalence of LV concentric change increased in AA genotype of 275124A>C. A multiple logistic regression analysis revealed that the presence of CC genotype of -328C>T or AA genotype of 275124A>C was an independent determinant for LV hypertrophy or concentric change, respectively. Furthermore, the combination of CC of -328C>T and AA of 275124A>C genotypes was significantly associated with abnormal LV geometry, especially concentric hypertrophy. Our findings show that two SNPs of the IGF-1 receptor gene are related to LV hypertrophy in patients with essential hypertension, suggesting that the genetic variation of the IGF-1 receptor may be involved in the diversity of LV structure in hypertensives.

Experimental evaluation of photocrosslinkable chitosan hydrogel as injection solution for endoscopic resection.

BACKGROUND AND STUDY AIMS: Saline as an injection solution for endoscopic resection techniques has several disadvantages such as a short-lasting effect leading to a potentially higher risk of bleeding and perforation. The new substance of photocrosslinkable chitosan hydrogel in a DMEM/F12 medium (PCH) can be converted into an insoluble hydrogel by ultraviolet irradiation for 30 s, and was evaluated in two sets of animal experiments. METHODS: 18 pigs were used in the two parts of the study. First, mucosal resections were done with either PCH or hypertonic saline; the effects of both agents on wound healing were examined endoscopically and histologically. Second, in vivo degradation of PCH was examined using six pig stomachs. RESULT: PCH injection led to a longer-lasting elevation with clearer margins, compared with hypertonic saline, thus enabling precise endoscopic submucosal dissection (ESD) along the margins of the elevated mucosa. The endoscopic appearance after ESD was similar in both groups. PCH biodegradation was completed within 8 weeks according to endoscopic and histologic analyses. CONCLUSION: PCH is a promising agent for submucosal injection prior to various techniques of endoresection. It should be evaluated in clinical trials after biocompatibility testing for PCH is completed.

C-type natriuretic peptide is a Schwann cell-derived factor for development and function of sensory neurones.

Cyclic GMP (cGMP) is known to play important roles for neuronal development and neurite pathfinding. However, the regulatory mechanism that governs the synthesis of cGMP in the nervous system is not well defined. In the present study, we examined the role of C-type natriuretic peptide (CNP), which increases intracellular cGMP upon binding to its receptor, guanylyl cyclase (GC)-B, in the peripheral nervous system. Immunohistochemistry revealed that CNP is demonstrated in Schwann cells, whereas GC-B mRNA is highly expressed in dorsal root ganglion (DRG) neurones. In cultured DRG neurones, GC-B was demonstrated in dendrites of TrkA-positive cells, where it co-exists with cGMP-dependent protein kinase I (cGKI), the major intracellular mediator of cGMP actions. Addition of CNP in the culture medium increased the density of fine neurites, which was accompanied by the increase in phosphorylation of vasodilator-stimulated phosphoprotein, a cGKI substrate. Furthermore, in mice deficient for the CNP gene (CNP-KO), the numbers of TrkA-positive DRG neurones were diminished. Likewise, there were much less cGKI-positive neurones in DRG and cGKI-positive fibres in the dorsal spinal cord of CNP-KO than wild-type mice. Finally, the bone deformity-rescued CNP-KO mice displayed a decreased response to formalin-induced pain compared to wild-type. Taken together, these results suggest that CNP is derived from Schwann cells and plays an important role for the development and function of nociceptive sensory neurones.

Association of single nucleotide polymorphisms in endothelin family genes with the progression of atherosclerosis in patients with essential hypertension.

Endothelin-1 (ET-1) is a potent vasoconstrictive peptide and its activity is mediated by the receptors ET type A (EDNRA) and ET type B (EDNRB). Although ET-1 is thought to play an important role in the development of atherosclerosis, it remains unclear whether polymorphisms of ET-1 family genes, including the ET-1 gene (EDN1), EDNRA, EDNRB and the genes for endothelin converting enzymes 1 and 2 (ECE1 and ECE2), are associated with the progression of atherosclerosis. We investigated the relationship between 11 single nucleotide polymorphisms (SNPs) of ET-1 family genes (including three in EDN1, one in EDNRA, two in EDNRB, four in ECE1 and one in ECE2) and atherosclerotic changes assessed using pulse wave velocity (PWV) and carotid ultrasonography in 630 patients with essential hypertension (EHT). In male subjects, we found significant differences in brachial-ankle PWV (baPWV) in additive and recessive models in EDNRB-rs5351 after Bonferroni correction. Also in male subjects, there were significant differences in mean intima-media thickness (IMT) in additive and recessive models in EDNRA-rs5333 after Bonferroni correction. We found no significant correlation between any SNPs in the ET family genes and baPWV, IMT and Plaque score (PS) in female subjects. Furthermore, after multiple logistic regression analysis, only EDNRB-rs5351 indicated as an independent risk of atherosclerosis in male hypertensive subjects. Of the endothelin-related genes, EDNRB-rs5351 was the most susceptible SNP associated with atherosclerosis in male hypertensives, and the genetic background may be involved in the progression of atherosclerosis in EHT patients.

Reverse white-coat effect as an independent risk for left ventricular concentric hypertrophy in patients with treated essential hypertension.

Recent studies have shown that the converse phenomenon of white-coat hypertension called 'reverse white-coat hypertension' or 'masked hypertension' is associated with poor cardiovascular prognosis. We assessed the hypothesis that this phenomenon may specifically influence left ventricular (LV) structure in treated hypertensive patients. A total of 272 outpatients (mean age, 65 years) with chronically treated essential hypertension and without remarkable white-coat effect were enrolled. Patients were classified into two groups according to office and daytime ambulatory systolic blood pressure (SBP); that is subjects without (Group 1: office SBP > or =daytime SBP, n=149) and with reverse white-coat effect (Group 2: office SBP

Evaluation of intrarenal hemodynamics by Doppler ultrasonography for renoprotective effect of angiotensin receptor blockade.

AIMS: It has been shown that both angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II type 1 receptor blockers (ARB) have renoprotective effects via mechanisms that are independent of blood pressure reduction. The aim of this study was to evaluate the intrarenal hemodynamic change with ARB by renal Doppler ultrasonography (RDU) and to assess the mechanism of ARB in patients with hypertension. METHODS: Thirty hypertensive patients with renal insufficiency caused by glomerular diseases, diabetes and hypertensive nephrosclerosis were included in this study. RDU was performed before and one week after taking ARB. Resistance index (RI) (peak systolic velocity - end diastolic velocity/peak systolic velocity) in the intrarenal segmental artery were calculated, and the amounts of urinary protein or albumin were determined. RESULTS: We defined patients whose microalbuminuria or proteinuria was reduced by greater than 30% by ARB as responders (n = 22) and defined other patients as non-responders (n = 8). There were no significant differences between the responder and non-responder groups in baseline characteristics. RI was significantly improved by ARB in the responder group, but not in the non-responder group. The reduction of RI after ARB treatment was most prominent in patients with hypertensive nephrosclerosis. CONCLUSIONS: Improvement in intrarenal hemodynamics might play an important role in the mechanisms of the renoprotective effect of ARB in patients with hypertension.

Left ventricular diastolic dysfunction in patients with chronic renal failure: impact of diabetes mellitus.

AIMS: Left ventricular (LV) hypertrophy and LV diastolic dysfunction are cardiac changes commonly observed in patients with chronic renal failure (CRF) as well as hypertension. Although the impairment of LV diastolic function in patients with diabetes mellitus has been shown, little is known about the specific effect of diabetes on LV diastolic function in patients with CRF. The present study was designed to investigate the impact of diabetic nephropathy on LV diastolic dysfunction, independent of LV hypertrophy, in CRF patients. METHODS: In 67 patients with non-dialysis CRF as a result of chronic glomerulonephritis (n = 33) or diabetic nephropathy (n = 34), and 134 hypertensive patients with normal renal function, two-dimensional and Doppler echocardiographic examinations were performed, and LV dimension, mass, systolic function, and diastolic function were evaluated. RESULTS: LV mass was increased and LV diastolic dysfunction was advanced in subjects with CRF compared with hypertensive controls. In the comparison of echocardiographic parameters between the two groups of CRF patients, i.e. chronic glomerulonephritis and diabetic nephropathy groups, all indices of LV diastolic function were more deteriorated in the diabetic nephropathy group than in the chronic glomerulonephritis group, although LV structure including hypertrophy and systolic function did not differ between the groups. In a multiple regression analysis, the presence of diabetes (i.e. diabetic nephropathy group) was a significant predictor of LV diastolic dysfunction in CRF subjects, independent of other influencing factors such as age, blood pressure, renal function, anaemia and LV hypertrophy. CONCLUSION: The present findings suggest that LV diastolic dysfunction, independent of LV hypertrophy, is specifically and markedly progressed in patients with CRF as a result of diabetic nephropathy.

Gamma-tubulin localization changes from discrete polar organizers to anastral spindles and phragmoplasts in mitosis of Marchantia polymorpha L.

Unlike the astral mitotic spindle that is organized at discrete centriolar centrosomes, the spindle of land plants is typically anastral and its origin has remained obscure. Gamma tubulin (gamma-tubulin), an important component of the centrosome, has been demonstrated at microtubule-nucleating sites in plant cells. Mitotic spindles of certain hepatics are initiated at distinct acentriolar polar organizers (POs) that appear de novo at the onset of mitosis. Data on the relationship of gamma-tubulin to POs and to microtubule arrays throughout the cell cycle were collected from rapidly dividing cells of Marchantia polymorpha (Bryophyta) that were triple-stained for gamma-tubulin, microtubules, and nuclei. POs at opposite ends of the elongated nucleus in early prophase stain brightly for gamma-tubulin and astral microtubules emanating from them initiate the spindle. As the spindle develops, however, the gamma-tubulin becomes dispersed from the highly concentrated spherical form of the POs to more diffusely organized cups at tips of the fusiform nucleus. By the end of prophase, all astral microtubules have disappeared and the gamma-tubulin is located in several minipoles along the now broad polar regions of the spindle. At metaphase, gamma-tubulin extends into the spindle itself. By telophase, the gamma-tubulin has migrated from distal to proximal surfaces of the sister nuclei and extends into the phragmoplast. Upon completion of cytokinesis, gamma-tubulin appears diminished and surrounds the nuclear envelopes. These data show that gamma-tubulin is only briefly concentrated in the PO, migrates in a cell-cycle-specific manner, and is consistently present at all putative sites of microtubule nucleation.

Inhibitory influences of xanthine oxidase inhibitor and angiotensin I-converting enzyme inhibitor on multinucleated giant cell formation from monocytes by downregulation of adhesion molecules and purinergic receptors.

BACKGROUND: Allopurinol, a xanthine oxidase inhibitor, and captopril, an inhibitor of angiotensin I-converting enzyme, are widely used for hyperuricaemia and hypertension, respectively. There have been reported cases showing that these two agents are effective for the treatment of granulomatous diseases such as sarcoidosis, although the mode of action is not elucidated. OBJECTIVES: We examined the in vitro effects of these agents on the formation of multinucleated giant cells (MGC) from human monocytes by concanavalin A-stimulated mononuclear cell supernatants (conditioned medium). METHODS: We cultured monocytes with conditioned medium and each agent and compared the rate of MGC formation as well as the expression of adhesion molecules and P2X7 receptor, which are involved in MGC formation. RESULTS: The addition of 25 or 100 microg mL(-1) allopurinol or 0.125-1.0 microg mL(-1) captopril inhibited MGC formation. Monocytes treated with these agents exhibited less expression of intercellular adhesion molecular-1 (ICAM-1) than untreated monocytes. The susceptibility of monocytes cultured in conditioned medium for 24 h to 2'-and 3'-o-(4-benzoyl-benzoyl)adenosine triphosphate-mediated cytolysis was significantly lower in monocytes treated with these agents than in untreated monocytes. CONCLUSIONS: Allopurinol and captopril have a therapeutic effect on granulomatous disorders by a direct action on monocyte/macrophage lineage cells partly through downregulation of ICAM-1 and P2X7 receptor.

Diagnostic value of carotid intima-media thickness and plaque score for predicting target organ damage in patients with essential hypertension.

Carotid intima-media thickness (IMT) assessed by ultrasonography is regarded as an early predictor of general arteriosclerosis in patients with essential hypertension. However, the methods of measuring IMT have not been globally standardized, and it remains unclear whether conventional measurement of IMT represents the prevalence of hypertensive target organ damage. In this study, we verified the association between several commonly used carotid ultrasonographical parameters and the severity of hypertensive target organ damage (retinal arteriosclerosis, microalbuminuria, left ventricular hypertrophy (LVH)). Carotid ultrasonography, echocardiography, urinalysis, and funduscopy were performed in 184 patients (64 +/- 12 years, 96 males and 88 females) with various stages of essential hypertension. Carotid arteriosclerosis was assessed using four methodologically different methods: conventional-IMT, maximum-IMT (Max-IMT), Mean-IMT, and Plaque Score (the sum of all plaque thicknesses). Age and all carotid ultrasonographical parameters were significantly associated with albuminuria, retinal arteriosclerosis, and left ventricular mass index. High-sensitivity CRP was significantly correlated with retinopathy and LVH. Carotid parameters in patients with histories of cardiovascular events were significantly greater in those without events. Among all carotid parameters, Max-IMT showed the highest correlation coefficient of the severity of target organ damage, and showed significant association with CRP. Stepwise regression analysis revealed that Max-IMT was the independent factor for predicting target organ damage. Max-IMT is suggested to be the most reliable and simplest parameter for predicting hypertensive target organ damage including microangiopathy in patients with essential hypertension.

Chronic actinic dermatitis developed during phototherapy for psoriasis.

A patient with psoriasis vulgaris had been successfully treated with PUVA and UVB therapy. During maintenance phototherapy, he suddenly became photosensitive and developed eczematous eruption. Minimal response doses to UVB and UVA were extremely low--1.09 mJ/cm2 and 0.3 J/cm2, respectively. No chemical substances were identified as the responsible photosensitizer. The condition was diagnosed as chronic actinic dermatitis (CAD). PUVA therapy was unsatisfactory because it was not possible to administer an adequate dose of UVA. Oral cyclosporine, topical corticosteroid and sunscreen were used with beneficial therapeutic effects on psoriasis and CAD. As far as we know, the development of CAD during phototherapy has not been previously reported.