9-(trans-2',trans-3'-Dihydroxycyclopent-4'-Enyl)-Adenine and -3-Deazaadenine: Analogs of Neplanocin A Which Retain Potent Antiviral Activity but Exhibit Reduced Cytotoxicity

Two synthetic analogs of neplanocin A, which were shown in a separate study to be inhibitors of S-adenosylhomocysteine hydrolase and devoid of substrate activity with adenosine kinase, were found in this study to inhibit vaccinia virus replication in murine L929 cells but to have reduced cytotoxicity compared with that of the parent compound. These results confirm that S-adenosylhomocysteine hydrolase is the molecular target which mediates the antiviral effects of neplanocin A and that transformation by cellular adenosine kinase mediates its cytotoxic properties.This work was supported by Public Health Service research grant GM-29332 from the National Institutes of Health

Broad-Spectrum Antiviral Activities of Neplanocin A, 3-Deazaneplanocin A, and Their 5'-Nor Derivatives

The neplanocin A analogs, 3-deazaneplanocin A, 9-(trans-2',trans-3'-dihydroxycyclopent-4'-enyl)adenine (DHCA), and 9-(trans-2',trans-3'-dihydroxycyclopent-4'-enyl)-3-deazaadenine (DHCDA), all potent inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase, were studied for their broad-spectrum antiviral potential. 3-Deazaneplanocin A, DHCA, and DHCDA proved specifically effective against vesicular stomatitis virus, vaccinia virus, parainfluenza virus, reovirus, and rotavirus. Their selectivity was greater than that of neplanocin A, particularly against vesicular stomatitis virus and rotavirus. As could be expected from adenosine analogs that are directly targeted at AdoHcy hydrolase, 3-deazaneplanocin A, DHCA, and DHCDA were fully active in adenosine kinase-deficient cells, implying that their activity did not depend on phosphorylation by adenosine kinase. None of the AdoHcy hydrolase inhibitors showed selective activity against human immunodeficiency virus (type 1). 3-Deazaneplanocin A at a dose of 0.5 mg/kg per day conferred marked protection against a lethal infection of newborn mice with vesicular stomatitis virus.This work was supported by the Belgian Fonds voor Geneeskundig Wetenschappelijk Onderzoek (project no. 3.0040.83) and the Belgian Geconcerteerde Onderzoeksacties (project no. 85/90-79). We thank Anita Van Lierde, Frieda De Meyer, Ria Van Berwaer, Ann Absillis, Etsuko Nitanai, and Willy Zeegers for excellent technical assistance and Christiane Callebaut for fine editorial help

Broadband Alfvénic excitation correlated to turbulence level in the Wendelstein 7-X stellarator plasmas

During the first operational phase (OP1) of the Wendelstein 7-X (W7-X) stellarator, poloidal magnetic field fluctuations, $\dot{B}_{\theta}$, were measured in several different plasma scenarios with a system of Mirnov coils. In the spectrograms, multiple frequency bands close together in frequency are observed below f = 600 kHz. Furthermore, a dominant feature is the appearance of a frequency band with the highest spectral amplitude centred between $f = 180-220$ kHz. The fluctuations are observed from the beginning of most W7-X plasmas of OP1, which were often operated solely with electron cyclotron resonance heating. The fluctuations show characteristics known from Alfvén waves and possibly Alfvén eigenmodes (AEs). However, the fast particle drive from heating sources, which is generally a driver necessary for the appearance of AEs in magnetic confinement plasmas, is absent in most of the analysed experiments. A characterization of the Alfvénic fluctuations measured during OP1 plasmas is possible using a newly developed tracking algorithm. In this paper, we extensively survey the different spectral properties of the fluctuations in correlation with plasma parameters and discuss possible driving mechanisms. The correlation studies of the dynamics of the possible ellipticity induced AEs indicate that Alfvén activity in the frequency interval between $f = 100-450$ kHz could be excited due to an interaction with turbulence, or profile effects also affecting the turbulence amplitude

Occurrence and greater intensity of estrus in recipient lactating dairy cows improve pregnancy per embryo transfer.

The aim of this study was to determine the association between occurrence and intensity of estrous expression with pregnancy success in recipient lactating dairy cows subjected to embryo transfer (ET). Two observational studies were conducted. Holstein cows were synchronized using the same timed ET protocol, based on estradiol and progesterone in both experiments. At 9 d after the end of the timed ET protocol only animals that had ovulated were implanted with a 7-d embryo [experiment 1 (Exp. 1); n = 1,401 ET events from 1,045 cows, and experiment 2 (Exp. 2); n = 1,147 ET events from 657 cows]. Embryos were produced in vivo (Exp. 1 and Exp. 2) and in vitro (only Exp. 2), then transferred to recipient cows as fresh or frozen-thawed. Pregnancy was confirmed at 29 and 58 d after the end of timed ET protocol. In Exp. 1, animals had their estrous expression monitored through a tail chalk applied on the tail head of the cows and evaluated daily for chalk removal (no estrus: 100% of chalk remaining; estrus: <50% of chalk remaining). In Exp. 2, cows were continuously monitored by a leg-mounted automated activity monitor. Estrous expression was quantified using the relative increase in physical activity at estrus in relation to the days before estrus. Estrous expression was classified as no estrus [<100% relative increase in activity (RI)], weak intensity (100-299% RI), and strong intensity (≥300% RI). Data were analyzed by analysis of variance using mixed linear regression models (GLIMMIX) in SAS (SAS Institute Inc.). A total of 65.2% (914/1,401) and 89.2% (1,019/1,142) of cows from Exp. 1 and Exp. 2, respectively, displayed estrus at the end of the ovulation synchronization protocol. In Exp. 1, cows expressing estrus before to ET had greater pregnancy per ET than those that did not [41.0 ± 2.3% (381/914) vs. 31.5 ± 2.9% (151/487), respectively]. Similarly, in Exp. 2, cows classified in the strong intensity group had greater pregnancy per ET compared with cows in the weak intensity and no estrus groups [41.3 ± 2.2% (213/571) vs. 32.7 ± 2.7% (115/353) vs. 11.3 ± 3.5% (26/218), respectively]. There was no effect of ET type on pregnancy per ET in Exp. 1. However, in Exp. 2, cows that received an in vivo-produced embryo, either fresh or frozen, had greater pregnancy per ET compared with cows that received in vitro-produced embryo. Cows receiving embryos in the early blastocyst and blastocyst stage had greater fertility compared with cows receiving embryos in the morula stage. There was an interaction between the occurrence of estrus and the stage of embryo development on pregnancy per ET, cows which displayed estrus and received a morula or early blastocyst had greater pregnancy per ET than cows that did not display estrus. In conclusion, the occurrence and the intensity of estrous expression improved pregnancy per ET in recipient lactating dairy cows and thus could be used as a tool to assist in the decision making of reproduction strategies in dairy farms

Zeros of the i.i.d. Gaussian power series: a conformally invariant determinantal process

Consider the zero set of the random power series f(z)=sum a_n z^n with i.i.d. complex Gaussian coefficients a_n. We show that these zeros form a determinantal process: more precisely, their joint intensity can be written as a minor of the Bergman kernel. We show that the number of zeros of f in a disk of radius r about the origin has the same distribution as the sum of independent {0,1}-valued random variables X_k, where P(X_k=1)=r^{2k}. Moreover, the set of absolute values of the zeros of f has the same distribution as the set {U_k^{1/2k}} where the U_k are i.i.d. random variables uniform in [0,1]. The repulsion between zeros can be studied via a dynamic version where the coefficients perform Brownian motion; we show that this dynamics is conformally invariant.Comment: 37 pages, 2 figures, updated proof

Regeneration versus scarring in vertebrate appendages and heart

Injuries to complex human organs, such as the limbs and the heart, result in pathological conditions, for which we often lack adequate treatments. While modern regenerative approaches are based on the transplantation of stem cell-derived cells, natural regeneration in lower vertebrates, such as zebrafish and newts, relies predominantly on the intrinsic plasticity of mature tissues. This property involves local activation of the remaining material at the site of injury to promote cell division, cell migration and complete reproduction of the missing structure. It remains an unresolved question why adult mammals are not equally competent to reactivate morphogenetic programmes. Although organ regeneration depends strongly on the proliferative properties of cells in the injured tissue, it is apparent that various organismic factors, such as innervation, vascularization, hormones, metabolism and the immune system, can affect this process. Here, we focus on a correlation between the regenerative capacity and cellular specialization in the context of functional demands, as illustrated by appendages and heart in diverse vertebrates. Elucidation of the differences between homologous regenerative and non-regenerative tissues from various animal models is essential for understanding the applicability of lessons learned from the study of regenerative biology to clinical strategies for the treatment of injured human organs

Somatic Accumulation of GluA1-AMPA Receptors Leads to Selective Cognitive Impairments in Mice

© 2018 Bannerman, Borchardt, Jensen, Rozov, Haj-Yasein, Burnashev, Zamanillo, Bus, Grube, Adelmann, Rawlins and Sprengel. The GluA1 subunit of the L-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) plays a crucial, but highly selective, role in cognitive function. Here we analyzed AMPAR expression, AMPAR distribution and spatial learning in mice (Gria1R/R), expressing the “trafficking compromised” GluA1(Q600R) point mutation. Our analysis revealed somatic accumulation and reduction of GluA1(Q600R) and GluA2, but only slightly reduced CA1 synaptic localization in hippocampi of adult Gria1R/R mice. These immunohistological changes were accompanied by a strong reduction of somatic AMPAR currents in CA1, and a reduction of plasticity (short-term and long-term potentiation, STP and LTP, respectively) in the CA1 subfield following tetanic and theta-burst stimulation. Nevertheless, spatial reference memory acquisition in the Morris water-maze and on an appetitive Y-maze task was unaffected in Gria1R/R mice. In contrast, spatial working/short-term memory during both spontaneous and rewarded alternation tasks was dramatically impaired. These findings identify the GluA1(Q600R) mutation as a loss of function mutation that provides independent evidence for the selective role of GluA1 in the expression of short-term memory