Structure-activity relationships of a novel class of endothelin receptor selective antagonists; 6-carboxy-2-isopropylamino-5,7-diarylcyclopenteno[1,2-b]pyridines

The synthesis and structure-activity relationships of 6-carboxy-2-isopropylamino-5,7-diarylcyclopenteno[1,2-b]pyridine class of ET(A) receptor selective antagonists were described. These derivatives were prepared from the optically active key intermediates (3, 4, 10, and 13). Optimization of the substituent at the 2-position of the bottom 4-methoxyphenyl ring of the lead compound 1 led to identification of 2-hydroxy-1-methylethoxy (2g and h), hydroxyalkyl (2i, m, and p), 3-methoxy-2-methylpropyl (2t and u), N-acetyl-N-methylaminomethyl (2v), and 2-(dimethylcarbamoyl)propyl (2w) derivatives that showed greater than 1000-fold selectivity for the ET(A) receptor over the ET(B) receptor with excellent binding affinity (IC(50)<0.10 nM). Further screening of these compounds by assessing the plasma exposures at 1 h, 4 h, and 8 h after oral administration (3 or 10 mg/kg) in rats led to identification of the hydroxymethyl (2i) and 3-methoxy-2-methylpropyl (2u) derivatives exhibiting good oral bioavailability in rats.     

Therapeutic administration of IL-11 exhibits the postconditioning effects against ischemia-reperfusion injury via STAT3 in the heart

Activation of cardiac STAT3 by IL-6 cytokine family contributes to cardioprotection. Previously, we demonstrated that IL-11, an IL-6 cytokine family, has the therapeutic potential to prevent adverse cardiac remodeling after myocardial infarction; however, it remains to be elucidated whether IL-11 exhibits postconditioning effects. To address the possibility that IL-11 treatment improves clinical outcome of recanalization therapy against acute myocardial infarction, we examined its postconditioning effects on ischemia/reperfusion (I/R) injury. C57BL/6 mice were exposed to ischemia (30 min) and reperfusion (24 h), and IL-11 was intravenously administered at the start of reperfusion. I/R injury mediated the activation of STAT3, which was enhanced by IL-11 administration. IL-11 treatment reduced I/R injury, analyzed by triphenyl tetrazolium chloride staining [PBS, 46.7 ± 14.4%; IL-11 (20 μg/kg), 28.6 ± 7.5% in the ratio of infarct to risk area]. Moreover, echocardiographic and hemodynamic analyses clarified that IL-11 treatment preserved cardiac function after I/R. Terminal deoxynucleotide transferase-mediated dUTP nick-end labeling staining revealed that IL-11 reduced the frequency of apoptotic cardiomyocytes after I/R. Interestingly, IL-11 reduced superoxide production assessed by in situ dihydroethidium fluorescence analysis, accompanied by the increased expression of metallothionein 1 and 2, reactive oxygen species (ROS) scavengers. Importantly, with the use of cardiac-specific STAT3 conditional knockout (STAT3 CKO) mice, it was revealed that cardiac-specific ablation of STAT3 abrogated IL-11-mediated attenuation of I/R injury. Finally, IL-11 failed to suppress the ROS production after I/R in STAT3 CKO mice. IL-11 administration exhibits the postconditioning effects through cardiac STAT3 activation, suggesting that IL-11 has the clinical therapeutic potential to prevent I/R injury in heart.     

Conservation genetics of critically endangered Crepidiastrum grandicollum (Asteraceae) and two closely related woody species of the Bonin Islands,Japan

Crepidiastrum grandicollum is a critically endangered insular endemic herb found only on two oceanic islands of the Bonin Islands in Japan, namely Chichijima Island and Anijima Island. It is explicitly threatened by herbivory pressure from introduced animals. In 2009, a conservation program for C. grandicollum was begun to ensure its future persistence. To provide further information for conservation planning, we investigated the genetic diversity of C. grandicollum using 13 novel microsatellite markers in 55 individuals from four wild populations and an ex situ living collection. Two closely related woody species were also included for interspecific comparison: seven individuals of Crepidiastrum ameristophyllum and 13 of Crepidiastrum linguifolium. The 13 markers were applicable to all three species and identified 129 alleles in total. We found a clear genetic differentiation between C. grandicollum from Anijima Island and Chichijima Island. Crepidiastrum grandicollum also had low expected heterozygosity and allelic richness in populations compared to the two closely related species. Reconstructed divergence history suggested that differentiation between the islands had occurred several thousand generations ago. We suggest separate conservation units for C. grandicollum on Anijima Island and Chichijima Island given the clear (and putatively historical) genetic differentiation, which may result in speciation in the future.

     

Protective Efficacy of Passive Immunization with Monoclonal Antibodies in Animal Models of H5N1 Highly Pathogenic Avian Influenza Virus Infection

Highly pathogenic avian influenza (HPAI) viruses of the H5N1 subtype often cause severe pneumonia and multiple organ failure in humans, with reported case fatality rates of more than 60%. To develop a clinical antibody therapy, we generated a human-mouse chimeric monoclonal antibody (MAb) ch61 that showed strong neutralizing activity against H5N1 HPAI viruses isolated from humans and evaluated its protective potential in mouse and nonhuman primate models of H5N1 HPAI virus infections. Passive immunization with MAb ch61 one day before or after challenge with a lethal dose of the virus completely protected mice, and partial protection was achieved when mice were treated 3 days after the challenge. In a cynomolgus macaque model, reduced viral loads and partial protection against lethal infection were observed in macaques treated with MAb ch61 intravenously one and three days after challenge. Protective effects were also noted in macaques under immunosuppression. Though mutant viruses escaping from neutralization by MAb ch61 were recovered from macaques treated with this MAb alone, combined treatment with MAb ch61 and peramivir reduced the emergence of escape mutants. Our results indicate that antibody therapy might be beneficial in reducing viral loads and delaying disease progression during H5N1 HPAI virus infection in clinical cases and combined treatment with other antiviral compounds should improve the protective effects of antibody therapy against H5N1 HPAI virus infection.     

日本千曲川河中游成年水生昆虫羽化后的沿边扩散与沿岸植被的关系

Adults of aquatic insects emerge fromstreamslive inthe nearby riparian zone where they can select streamsidevegetations as preferred sites in order to(a)completemetamorphosis,(b)rest while awaiting proper swarmingtime,(c)feedin order to produce eggs,or(d)mate toreproduce[1—3].Most adult aquatic insect dispersal studies have fo-cused on quantifying the degree of upstream move-ment[4,5].Some researchers have shown distinct patternsof upstreammovement related to post-mating ovipositionalbehavior…     

Evidence of dominant parasympathetic nervous activity of great cormorants (<Emphasis Type="Italic">Phalacrocorax carbo</Emphasis>)

The characteristics of autonomic nervous activity were examined on captive great cormorants Phalacrocorax carbo hanedae, using a power spectral analysis of heart rate variability. Heart rates were calculated from recordings of the electrocardiograms of the birds via embarked data loggers. We investigated the effects of blockades of the sympathetic or parasympathetic nervous systems using the indices of autonomic nervous activity such as high frequency (0.061–1.5 Hz) component, low frequency (0.02–0.060 Hz) component and the low frequency power component to high frequency power component ratio. Resting heart rate (85.5 ± 6.1 bpm) was lower than the intrinsic heart rate (259.2 ± 15.3 bpm). The heart rate drastically increased after the injection of the parasympathetic nervous blocker, on the other hand it slightly decreased after the injection of the sympathetic nervous blocker. The sympathetic, parasympathetic and net autonomic nervous tones calculated from heart rate with and without blockades were 40.9 ± 27.6, −44.5 ± 7.4 and −29.5 ± 9.0%, respectively. The effect of the parasympathetic nervous blockade on low frequency and high frequency power was greater than that of the sympathetic nervous blockade. Those data suggested that the parasympathetic nervous activity was dominant for great cormorants.     

The MukB-ParC Interaction Affects the Intramolecular,Not Intermolecular,Activities of Topoisomerase IV

Proper chromosome organization is accomplished through binding of proteins such as condensins that shape the DNA and by modulation of chromosome topology by the action of topoisomerases. We found that the interaction between MukB, the bacterial condensin, and ParC, a subunit of topoisomerase IV, enhanced relaxation of negatively supercoiled DNA and knotting by topoisomerase IV, which are intramolecular DNA rearrangements but not decatenation of multiply linked DNA dimers, which is an intermolecular DNA rearrangement required for proper segregation of daughter chromosomes. MukB DNA binding and a specific chiral arrangement of the DNA was required for topoisomerase IV stimulation because relaxation of positively supercoiled DNA was unaffected. This effect could be attributed to a more effective topological reconfiguration of the negatively supercoiled compared with positively supercoiled DNA by MukB. These data suggest that the MukB-ParC interaction may play a role in chromosome organization rather than in separation of daughter chromosomes.