Inhibitory action of a macrolide antibiotic, roxithromycin, on co-stimulatory molecule expressions in vitro and in vivo.

OBJECTIVE: The influence of a macrolide antibiotic, roxithromycin (RXM), on co-stimulatory molecule expression was examined in vitro and in vivo. MATERIALS AND METHODS: Spleen cells obtained from BALB/c mice 10 days after immunization with 8.0 microg of hemocyanin absorbed to 4.0 mg of aluminum hydroxide were cultured in the presence of 100.0 microg/ml of hemocyanin and various concentrations of RXM. We first examined the influence of RXM on cell activation by examining the proliferative response of cells and cytokine production. We also examined the influence of RXM on co-stimulatory molecule (CD40, CD80 and CD86) expressions on cultured splenic B-lymphocytes induced by in vitro antigenic stimulation using flow cytometry. In the second part of experiments, non-immunized and immunized mice were treated orally with 2.5 mg/kg of RXM once a day for 4 or 8 weeks. Splenic B lymphocytes were obtained from these mice 24 h after antigenic challenge, and co-stimulatory molecule expressions were examined by flow cytometer. RESULTS: Cell activation induced by in vitro antigenic stimulation was suppressed by RXM when cells were cultured in the presence of more than 5.0 microg/ml of the agent. Addition of RXM at a concentration of 5.0 microg/ml into cell cultures also suppressed co-stimulatory molecule (CD40, CD80 and CD86) expressions on splenic B lymphocytes, which was enhanced by antigenic stimulation in vitro. Oral RXM administration for 4 weeks clearly suppressed the enhancement of CD40 and CD86 (but not CD80) expressions on splenic B lymphocytes induced by antigenic stimulation in vivo. This suppressive activity of RXM on co-stimulatory molecule (CD40 and CD86) expressions was further strengthened by the treatment of mice for 8 weeks. Long-term treatment with oral RXM also suppressed CD80 expressions, which was not suppressed by 4-week treatment. CONCLUSION: The present results suggest that RXM exerts its immunomodulating effects through suppression of both cell activation and co-stimulatory molecule expressions induced by antigenic stimulation. These suppressive activities of RXM might contribute, in part, to the therapeutic mode of action of RXM on inflammatory diseases

High-resolution measurement of the time-modulated orbital electron capture and of the β+\beta^+ decay of hydrogen-like 142^{142}Pm60+^{60+} ions

The periodic time modulations, found recently in the two-body orbital electron-capture (EC) decay of both, hydrogen-like $^{140}$Pr$^{58+}$ and $^{142}$Pm$^{60+}$ ions, with periods near to 7s and amplitudes of about 20%, were re-investigated for the case of $^{142}$Pm$^{60+}$ by using a 245 MHz resonator cavity with a much improved sensitivity and time resolution. We observed that the exponential EC decay is modulated with a period $T = 7.11(11)$s, in accordance with a modulation period $T = 7.12(11)$ s as obtained from simultaneous observations with a capacitive pick-up, employed also in the previous experiments. The modulation amplitudes amount to $a_R = 0.107(24)$ and $a_P = 0.134(27)$ for the 245 MHz resonator and the capacitive pick-up, respectively. These new results corroborate for both detectors {\it exactly} our previous findings of modulation periods near to 7s, though with {\it distinctly smaller} amplitudes. Also the three-body $\beta^+$ decays have been analyzed. For a supposed modulation period near to 7s we found an amplitude $a = 0.027(27)$, compatible with $a = 0$ and in agreement with the preliminary result $a = 0.030(30)$ of our previous experiment. These observations could point at weak interaction as origin of the observed 7s-modulation of the EC decay. Furthermore, the data suggest that interference terms occur in the two-body EC decay, although the neutrinos are not directly observed.Comment: In memoriam of Prof. Paul Kienle, 9 pages, 1 table, 5 figures Phys. Lett. B (2013) onlin

A putative lipase gene EXTRA GLUME1 regulates both empty-glume fate and spikelet development in rice

Recent studies have shown that molecular control of inner floral organ identity appears to be largely conserved between monocots and dicots, but little is known regarding the molecular mechanism underlying development of the monocot outer floral organ, a unique floral structure in grasses. In this study, we report the cloning of the rice EXTRA GLUME1 (EG1) gene, a putative lipase gene that specifies empty-glume fate and floral meristem determinacy. In addition to affecting the identity and number of empty glumes, mutations in EG1 caused ectopic floral organs to be formed at each organ whorl or in extra ectopic whorls. Iterative glume-like structures or new floral organ primordia were formed in the presumptive region of the carpel, resulting in an indeterminate floral meristem. EG1 is expressed strongly in inflorescence primordia and weakly in developing floral primordia. We also found that the floral meristem and organ identity gene OsLHS1 showed altered expression with respect to both pattern and levels in the eg1 mutant, and is probably responsible for the pleiotropic floral defects in eg1. As a putative class III lipase that functionally differs from any known plant lipase, EG1 reveals a novel pathway that regulates rice empty-glume fate and spikelet development

First application of mass measurement with the Rare-RI Ring reveals the solar r-process abundance trend at A=122 and A=123

The Rare-RI Ring (R3) is a recently commissioned cyclotron-like storage ring mass spectrometer dedicated to mass measurements of exotic nuclei far from stability at Radioactive Isotope Beam Factory (RIBF) in RIKEN. The first application of mass measurement using the R3 mass spectrometer at RIBF is reported. Rare isotopes produced at RIBF, $^{127}$Sn, $^{126}$In, $^{125}$Cd, $^{124}$Ag, $^{123}$Pd, were injected in R3. Masses of $^{126}$In, $^{125}$Cd, and $^{123}$Pd were measured whereby the mass uncertainty of $^{123}$Pd was improved. This is the first reported measurement with a new storage ring mass spectrometery technique realized at a heavy-ion cyclotron and employing individual injection of the pre-identified rare nuclei. The latter is essential for the future mass measurements of the rarest isotopes produced at RIBF. The impact of the new $^{123}$Pd result on the solar $r$-process abundances in a neutron star merger event is investigated by performing reaction network calculations of 20 trajectories with varying electron fraction $Y_e$. It is found that the neutron capture cross section on $^{123}$Pd increases by a factor of 2.2 and $\beta$-delayed neutron emission probability, $P_\mathrm{1n}$, of $^{123}$Rh increases by 14\%. The neutron capture cross section on $^{122}$Pd decreases by a factor of 2.6 leading to pileup of material at $A=122$, thus reproducing the trend of the solar $r$-process abundances. The trend of the two-neutron separation energies (S$_\mathrm{2n}$) was investigated for the Pd isotopic chain. The new mass measurement with improved uncertainty excludes large changes of the S$_\mathrm{2n}$ value at $N=77$. Such large increase of the S$_\mathrm{2n}$ values before $N=82$ was proposed as an alternative to the quenching of the $N=82$ shell gap to reproduce $r$-process abundances in the mass region of $A=112-124$

Efficacy and safety of once-monthly pasireotide in Cushing's disease: A 12 month clinical trial

© 2017 Elsevier Ltd. Background: Cushing's disease is a rare debilitating endocrine disorder for which few prospective interventional studies have been done. We report results of the first phase 3 trial assessing long-acting intramuscular pasireotide in patients with Cushing's disease. Methods: In this phase 3 clinical trial we recruited patients aged 18 years or older with persistent, recurrent, or de-novo (non-surgical candidates) Cushing's disease who had a mean urinary free cortisol (mUFC) concentration (from three 24 h samples) of 1·5-5·0 times the upper limit of normal (ULN), a normal or greater than normal morning plasma adrenocorticotropic hormone concentration, and a pituitary source of Cushing's syndrome, from 57 sites across 19 countries. Exclusion criteria included previous pasireotide treatment, mitotane therapy within 6 months, and pituitary irradiation within 10 years. We randomly allocated patients 1:1 (block size of four) using an interactive-response-technology system to intramuscular pasireotide 10 mg or 30 mg every 4 weeks for 12 months (in the core phase). We stratified randomisation by screening mUFC concentration (1·5 to < 2·0 × ULN and 2·0-5·0 × ULN). The dose could be uptitrated (from 10 mg to 30 mg or from 30 mg to 40 mg) at month 4 if the mUFC concentration was greater than 1·5 × ULN, and at month 7, month 9, or month 12 if the mUFC concentration was greater than 1·0 × ULN. Investigators, patients, site personnel, and those assessing outcomes were masked to dose group allocation. The primary endpoint was the proportion of patients in each group with an mUFC concentration of less than or equal to the ULN at month 7. Efficacy analyses were based on intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01374906. Findings: Between Dec 28, 2011, and Dec 9, 2014, we randomly allocated 150 patients to receive pasireotide 10 mg (74 [49%] patients) or 30 mg (76 [51%] patients). The primary efficacy endpoint was met by 31 (41·9% [95% CI 30·5-53·9]) of 74 patients in the 10 mg group and 31 (40·8% [29·7-52·7] ) of 76 in the 30 mg group. The most common adverse events were hyperglycaemia (36 [49%] in the 10 mg group and 36 [47%] in the 30 mg group), diarrhoea (26 [35%] and 33 [43%] ), cholelithiasis (15 [20%] and 34 [45%] ), diabetes mellitus (14 [19%] and 18 [24%] ), and nausea (15 [20%] and 16 [21%] ). Serious adverse events suspected to be study drug related were reported in eight (11%) patients in the 10 mg group and four (5%) in the 30 mg group. Two (3%) patients in the 30 mg group died during the study (pulmonary artery thrombosis and cardiorespiratory failure); neither death was judged to be related to the study drug. Interpretation: Long-acting pasireotide normalised mUFC concentration in about 40% of patients with Cushing's disease at month 7 and had a similar safety profile to that of twice-daily subcutaneous pasireotide. Long-acting pasireotide is an efficacious treatment option for some patients with Cushing's disease who have persistent or recurrent disease after initial surgery or are not surgical candidates, and provides a convenient monthly administration schedule. Funding: Novartis Pharma AG

Towards molecular breeding of reproductive traits in cereal crops

The transition from vegetative to reproductive phase, flowering per se, floral organ development, panicle structure and morphology, meiosis, pollination and fertilization, cytoplasmic male sterility (CMS) and fertility restoration, and grain development are the main reproductive traits. Unlocking their genetic insights will enable plant breeders to manipulate these traits in cereal germplasm enhancement. Multiple genes or quantitative trait loci (QTLs) affecting flowering (phase transition, photoperiod and vernalization, flowering per se), panicle morphology and grain development have been cloned, and gene expression research has provided new information about the nature of complex genetic networks involved in the expression of these traits. Molecular biology is also facilitating the identification of diverse CMS sources in hybrid breeding. Few Rf (fertility restorer) genes have been cloned in maize, rice and sorghum. DNA markers are now used to assess the genetic purity of hybrids and their parental lines, and to pyramid Rf or tms (thermosensitive male sterility) genes in rice. Transgene(s) can be used to create de novo CMS trait in cereals. The understanding of reproductive biology facilitated by functional genomics will allow a better manipulation of genes by crop breeders and their potential use across species through genetic transformation

Ferrocene-containing [1]-, [2]-, [3]- and [4]rotaxanes synthesized from a common precursor

The Cu-catalyzed reaction of a dialkylammonium, having ferrocenyl and hexynyl end groups, FcCH2NH2CH2C6H4–4-O(CH2)4CCH]PF6 (Fc = Fe(C5H4)(C5H5)), with a crown ether having an azidemethyl side-arm yields a [1]rotaxane composed of a single molecule. The crystal structure of the [1]rotaxane suggests an arrangement where the 1,4-phenylene ring is tilted at 22° close to the catechol ring rather than in a parallel alignment. Another dialkylammonium with ferrocenyl and alkynyl terminal groups, [FcCH2NH2CH2C6H4–4-O(CH2)4CCH]PF6, reacts with aromatic compounds with one to three azide groups in the presence of dibenzo[24]crown-8-ether (DB24C8) and [Cu(MeCN)4]PF6 catalyst, to afford the corresponding [2]–[4]rotaxanes. The products contain DB24C8 molecules as the cyclic components which are bound to the ammonium group of the axle component with NH⋯O hydrogen bonding. The [3]rotaxane having two triazole groups on the axle component reacts with PdCl2(MeCN)2 to yield mono- and di-palladium complexes with different conformations of the axle component