Oestrogen-mediated cardioprotection following ischaemia and reperfusion is mimicked by an oestrogen receptor (ER)α agonist and unaffected by an ERβ antagonist

Oestrogen protects the heart from ischaemic injury. The current study aims to characterise two novel oestrogen receptor (ER) ligands, an ERα agonist ERA-45 and an ERβ antagonist ERB-88, and then use them to investigate the roles of ERα and ERβ in mediating the cardioprotection by E from ischaemia–reperfusion injury in the rat. The ER ligands were characterised by gene transactivation assay using ER-transfected Chinese hamster ovary (CHO) cells and in bioavailability studies in vivo. Female rats (n=48) were ovariectomised and implanted with 17β-oestradiol (17βE2) releasing or placebo pellets. ERA-45, ERB-88 or vehicle was administered for 5 days prior to ischaemia–reperfusion studies. Necrosis, neutrophil infiltration (myeloperoxidase activity) and oxidant stress production (electron paramagnetic resonance) from the area-at-risk were measured to assess reperfusion injury. The ERα agonist ERA-45 showed more than 35-fold selectivity for ERα compared with ERβ gene transactivation. In vitro, the ERβ antagonist ERB-88 inhibited transactivation by 17βE2 via ERβ with 46-fold selectivity relative to inhibition via ERα. In vivo, 17βE2 significantly reduced neutrophil infiltration, oxidant stress and necrosis following ischaemia and reperfusion. Cardioprotection by 17βE2 was not inhibited by ERB-88 but was completely reproduced by ERA-45. In conclusion, protection of the rat heart after ischaemia–reperfusion by 17βE2 is achieved through the reduction of cardiomyocyte death, neutrophil infiltration and oxygen-free radical availability.The results of this study indicate that these effects are primarily mediated via activation of ERα

Identifying New Sources of Resistance to Brown Stem Rot in Soybean

Brown stem rot (BSR), caused by the fungus Phialophora gregata f. sp. sojae (Allington & D.W. Chamberlain) W. Gams (syn. Cadophora gregata), causes yield losses up to 38%. Three dominant BSR-resistant genes have been identified: Rbs1, Rbs2, and Rbs3. Additional BSR resistance loci will complement breeding efforts by expanding the soybean [Glycine max (L.) Merr.] genetic base. The objective of this research was to determine if PI 594637, PI 594638B, PI 594650A, and PI 594858B contained novel BSR resistance genes. The accessions were crossed to three genotypes with known BSR resistance genes and populations were developed for allelism studies. A minimum of 60 F2:3 families tracing to individual F2 plants in each population were used, and six seeds from each F2:3 family were tested. Resistant and susceptible controls and parents were also included. The BSR symptoms were assessed under growth chamber conditions 5 wk after inoculation by measuring foliar and stem severities and recovery of P. gregata from stem sections. Allelism tests of F2:3 plants from crosses of PI 594638B, PI 594858B, and PI 594650A with the resistant sources fit a 15:1 ratio, indicating that the resistant gene possessed by each of the PIs was nonallelic to Rbs1, Rbs2, and Rbs3. The three PIs contain at least one novel BSR resistance gene and have the potential to serve as donors to elite germplasm, increasing stability of host resistance to P. gregata. Allelism tests of PI 594637 segregated in a 3:1 ratio and no significant difference was found between PI 594637 and the susceptible controls, indicating that PI 594637 is susceptible to BSR

Progress in Classical and Quantum Variational Principles

We review the development and practical uses of a generalized Maupertuis least action principle in classical mechanics, in which the action is varied under the constraint of fixed mean energy for the trial trajectory. The original Maupertuis (Euler-Lagrange) principle constrains the energy at every point along the trajectory. The generalized Maupertuis principle is equivalent to Hamilton's principle. Reciprocal principles are also derived for both the generalized Maupertuis and the Hamilton principles. The Reciprocal Maupertuis Principle is the classical limit of Schr\"{o}dinger's variational principle of wave mechanics, and is also very useful to solve practical problems in both classical and semiclassical mechanics, in complete analogy with the quantum Rayleigh-Ritz method. Classical, semiclassical and quantum variational calculations are carried out for a number of systems, and the results are compared. Pedagogical as well as research problems are used as examples, which include nonconservative as well as relativistic systems

Pharmacological Analysis of Ionotropic Glutamate Receptor Function in Neuronal Circuits of the Zebrafish Olfactory Bulb

Although synaptic functions of ionotropic glutamate receptors in the olfactory bulb have been studied in vitro, their roles in pattern processing in the intact system remain controversial. We therefore examined the functions of ionotropic glutamate receptors during odor processing in the intact olfactory bulb of zebrafish using pharmacological manipulations. Odor responses of mitral cells and interneurons were recorded by electrophysiology and 2-photon Ca2+ imaging. The combined blockade of AMPA/kainate and NMDA receptors abolished odor-evoked excitation of mitral cells. The blockade of AMPA/kainate receptors alone, in contrast, increased the mean response of mitral cells and decreased the mean response of interneurons. The blockade of NMDA receptors caused little or no change in the mean responses of mitral cells and interneurons. However, antagonists of both receptor types had diverse effects on the magnitude and time course of individual mitral cell and interneuron responses and, thus, changed spatio-temporal activity patterns across neuronal populations. Oscillatory synchronization was abolished or reduced by AMPA/kainate and NMDA receptor antagonists, respectively. These results indicate that (1) interneuron responses depend mainly on AMPA/kainate receptor input during an odor response, (2) interactions among mitral cells and interneurons regulate the total olfactory bulb output activity, (3) AMPA/kainate receptors participate in the synchronization of odor-dependent neuronal ensembles, and (4) ionotropic glutamate receptor-containing synaptic circuits shape odor-specific patterns of olfactory bulb output activity. These mechanisms are likely to be important for the processing of odor-encoding activity patterns in the olfactory bulb

The Future of General Systems Research: Obstacles, Potentials, Case Studies

This paper attempts to provide an evaluative and prescriptive overview of the young field of systems science as exemplified by one of its 'specialties' general systems theory (GST). Subjective observation and some data on seven vital signs are presented to measure the progress of the field over the last two decades. Thirty-three specific obstacles inhibiting current research in systems science are presented. Suggestions for overcoming these obstacles are cited as a prescription for improved progress in the field. A sampling of some of the potential near-term developments that may be expected in the three rather distinct areas of research on systems isomorphics, improvement of systems methodologies, and the utility of systems applications are illustrated with mini-case studies. Throughout, there is an attempt to identify 'key' questions and practical mechanisms that might serve as a stimulus for research. Finally, a set of criteria defining a general theory of systems is suggested and illustrated with a case study. The paper concludes with a projection of the long-term contributions that systems science may make toward a resolution of the growing chasm between high-tech solutions and high-value needs in human systems

Microsecond Isomer at the N=20 Island of Shape Inversion Observed at FRIB

Excited-state spectroscopy from the first Facility for Rare Isotope Beams (FRIB) experiment is reported. A 24(2)-$\mu$s isomer was observed with the FRIB Decay Station initiator (FDSi) through a cascade of 224- and 401-keV $\gamma$ rays in coincidence with $^{32}\textrm{Na}$ nuclei. This is the only known microsecond isomer ($1{\text{ }\mu\text{s}}\leq T_{1/2} < 1\text{ ms}$) in the region. This nucleus is at the heart of the $N=20$ island of shape inversion and is at the crossroads of spherical shell-model, deformed shell-model, and ab initio theories. It can be represented as the coupling of a proton hole and neutron particle to $^{32}\textrm{Mg}$, $^{32}\textrm{Mg}+\pi^{-1} + \nu^{+1}$. This odd-odd coupling and isomer formation provides a sensitive measure of the underlying shape degrees of freedom of $^{32}\textrm{Mg}$, where the onset of spherical-to-deformed shape inversion begins with a low-lying deformed $2^+$ state at 885 keV and a low-lying shape-coexisting $0_2^+$ state at 1058 keV. We suggest two possible explanations for the 625-keV isomer in $^{32}$Na: a $6^-$ spherical shape isomer that decays by $E2$ or a $0^+$ deformed spin isomer that decays by $M2$. The present results and calculations are most consistent with the latter, indicating that the low-lying states are dominated by deformation.Comment: 7 pages, 5 figures, accepted by Physical Review Letter

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Ambient air pollution and thrombosis

Abstract Air pollution is a growing public health concern of global significance. Acute and chronic exposure is known to impair cardiovascular function, exacerbate disease and increase cardiovascular mortality. Several plausible biological mechanisms have been proposed for these associations, however, at present, the pathways are incomplete. A seminal review by the American Heart Association (2010) concluded that the thrombotic effects of particulate air pollution likely contributed to their effects on cardiovascular mortality and morbidity. The aim of the current review is to appraise the newly accumulated scientific evidence (2009–2016) on contribution of haemostasis and thrombosis towards cardiovascular disease induced by exposure to both particulate and gaseous pollutants. Seventy four publications were reviewed in-depth. The weight of evidence suggests that acute exposure to fine particulate matter (PM2.5) induces a shift in the haemostatic balance towards a pro-thrombotic/pro-coagulative state. Insufficient data was available to ascertain if a similar relationship exists for gaseous pollutants, and very few studies have addressed long-term exposure to ambient air pollution. Platelet activation, oxidative stress, interplay between interleukin-6 and tissue factor, all appear to be potentially important mechanisms in pollution-mediated thrombosis, together with an emerging role for circulating microvesicles and epigenetic changes. Overall, the recent literature supports, and arguably strengthens, the contention that air pollution contributes to cardiovascular morbidity by promoting haemostasis. The volume and diversity of the evidence highlights the complexity of the pathophysiologic mechanisms by which air pollution promotes thrombosis; multiple pathways are plausible and it is most likely they act in concert. Future research should address the role gaseous pollutants play in the cardiovascular effects of air pollution mixture and direct comparison of potentially susceptible groups to healthy individuals