Inhibiting dopamine reuptake blocks the induction of long-term potentiation and depression in the lateral entorhinal cortex of awake rats

Synaptic plasticity in olfactory inputs to the lateral entorhinal cortex may result in lasting changes in the processing of olfactory stimuli. Changes in dopaminergic tone can have strong effects on basal evoked synaptic responses in the superficial layers of the entorhinal cortex, and the current study investigated whether dopamine may modulate the induction of long-term potentiation (LTP) and depression (LTD) in piriform cortex inputs to layer II of the lateral entorhinal cortex in awake rats. Groups of animals were pretreated with either saline or the selective dopamine reuptake inhibitor GBR12909 prior to low or high frequency stimulation to induce LTD or LTP. In saline-treated groups, synaptic responses were potentiated to 122.4 ± 6.4% of baseline levels following LTP induction, and were reduced to 84.5 ± 4.9% following induction of LTD. Changes in synaptic responses were maintained for up to 60 min and returned to baseline levels within 24 h. In contrast, induction of both LTP and LTD was blocked in rats pretreated with GBR12909. Dopaminergic suppression of synaptic plasticity in the entorhinal cortex may serve to restrain activity-dependent plasticity during reward-relevant behavioral states or during processing of novel stimuli

Flower Iridescence Increases Object Detection in the Insect Visual System without Compromising Object Identity.

Iridescence is a form of structural coloration, produced by a range of structures, in which hue is dependent on viewing angle [1-4]. One of these structures, the diffraction grating, is found both in animals (for example, beetles [2]) and in plants (on the petals of some animal pollinated flowers [5]). The behavioral impacts of floral iridescence and its potential ecological significance are unknown [6-9]. Animal-pollinated flowers are described as "sensory billboards" [10], with many floral features contributing to a conspicuous display that filters prospective pollinators. Yet floral iridescence is more subtle to the human eye than that of many animal displays because the floral diffraction grating is not perfectly regular [5-9]. This presents a puzzle: if the function of petals is to attract pollinators, then flowers might be expected to optimize iridescence to increase showiness. On the other hand, pollinators memorize floral colors as consistent advertisements of reward quality, and iridescence might corrupt flower color identity. Here we tested the trade-off between flower detectability and recognition, requiring bumblebees (Bombus terrestris) to identify artificial flowers that varied in pigmentation and degree of iridescence. We find that iridescence does increase target detectability but that "perfect" iridescence (produced by an artificial diffraction grating) corrupts target identity and bees make many mistakes. However, "imperfect" floral iridescence does not lead to mistaken target identity, while still benefitting flower detectability. We hypothesize that similar trade-offs might be found in the many naturally "imperfect" iridescence-producing structures found in animal-animal, as well as other plant-animal, interactions.We thank Divykriti Chopra, Matthew Dorling, Lucy Sandbach and James Philpott for assistance with experiments, and Edwige Moyroud for helpful discussions. We thank James Foster for assistance with measurement of flight arena light level measurements. HW is supported by ERC Starting Grant 260920. AR was supported by a BBSRC doctoral training grant studentship. LC is supported by a Royal Society Wolfson Research Merit Award and ERC Advanced Grant 339347.This is the author accepted manuscript. It is currently embargoed pending publication

Coordinated regulation of transcription by CcpA and the \u3ci\u3eStaphylococcus aureus\u3c/i\u3e twocomponent system HptRS

The success of Staphylococcus aureus as a pathogen is due in part to its ability to adapt to changing environmental conditions using signal transduction pathways, such as metaboliteresponsive regulators and two-component systems. S. aureus has a two-component system encoded by the gene pair sav0224 (hptS) and sav0223 (hptR) that regulate the hexose phosphate transport (uhpT) system in response to extracellular glucose-6-phosphate. Glycolytic intermediates such as glucose-6-phosphate are important carbon sources that also modulate the activity of the global metabolite-responsive transcriptional regulator CcpA. Because uhpT has a putative CcpA binding site in its promoter and it is regulated by HptR, it was hypothesized the regulons of CcpA and HptR might intersect. To determine if the regulatory domains of CcpA and HptRS overlap, ccpA was deleted in strains SA564 and SA564- ΔhptRS and growth, metabolic, proteomic, and transcriptional differences were assessed. As expected, CcpA represses hptS and hptR in a glucose dependent manner; however, upon CcpA derepression, the HptRS system functions as a transcriptional activator of metabolic genes within the CcpA regulon. Importantly, inactivation of ccpA and hptRS altered sensitivity to fosfomycin and ampicillin in the absence of exogenous glucose-6-phosphate, indicating that both CcpA and HptRS modulate antibiotic susceptibility

Development of a model for marburgvirus based on severe-combined immunodeficiency mice

The filoviruses, Ebola (EBOV) and Marburg (MARV), cause a lethal hemorrhagic fever. Human isolates of MARV are not lethal to immmunocompetent adult mice and, to date, there are no reports of a mouse-adapted MARV model. Previously, a uniformly lethal EBOV-Zaire mouse-adapted virus was developed by performing 9 sequential passages in progressively older mice (suckling to adult). Evaluation of this model identified many similarities between infection in mice and nonhuman primates, including viral tropism for antigen-presenting cells, high viral titers in the spleen and liver, and an equivalent mean time to death. Existence of the EBOV mouse model has increased our understanding of host responses to filovirus infections and likely has accelerated the development of countermeasures, as it is one of the only hemorrhagic fever viruses that has multiple candidate vaccines and therapeutics. Here, we demonstrate that serially passaging liver homogenates from MARV-infected severe combined immunodeficient (scid) mice was highly successful in reducing the time to death in scid mice from 50–70 days to 7–10 days after MARV-Ci67, -Musoke, or -Ravn challenge. We performed serial sampling studies to characterize the pathology of these scid mouse-adapted MARV strains. These scid mouse-adapted MARV models appear to have many similar properties as the MARV models previously developed in guinea pigs and nonhuman primates. Also, as shown here, the scid-adapted MARV mouse models can be used to evaluate the efficacy of candidate antiviral therapeutic molecules, such as phosphorodiamidate morpholino oligomers or antibodies

Planet Hunters. VIII. Characterization of 41 Long-Period Exoplanet Candidates from Kepler Archival Data

The census of exoplanets is incomplete for orbital distances larger than 1 AU. Here, we present 41 long-period planet candidates in 38 systems identified by Planet Hunters based on Kepler archival data (Q0-Q17). Among them, 17 exhibit only one transit, 14 have two visible transits and 10 have more than three visible transits. For planet candidates with only one visible transit, we estimate their orbital periods based on transit duration and host star properties. The majority of the planet candidates in this work (75%) have orbital periods that correspond to distances of 1-3 AU from their host stars. We conduct follow-up imaging and spectroscopic observations to validate and characterize planet host stars. In total, we obtain adaptive optics images for 33 stars to search for possible blending sources. Six stars have stellar companions within 4". We obtain high-resolution spectra for 6 stars to determine their physical properties. Stellar properties for other stars are obtained from the NASA Exoplanet Archive and the Kepler Stellar Catalog by Huber et al. (2014). We validate 7 planet candidates that have planet confidence over 0.997 (3-{\sigma} level). These validated planets include 3 single-transit planets (KIC-3558849b, KIC-5951458b, and KIC-8540376c), 3 planets with double transits (KIC-8540376b, KIC-9663113b, and KIC-10525077b), and 1 planet with 4 transits (KIC-5437945b). This work provides assessment regarding the existence of planets at wide separations and the associated false positive rate for transiting observation (17%-33%). More than half of the long-period planets with at least three transits in this paper exhibit transit timing variations up to 41 hours, which suggest additional components that dynamically interact with the transiting planet candidates. The nature of these components can be determined by follow-up radial velocity and transit observations.Comment: Published on ApJ, 815, 127 Notations of validated planets are changed in accordance with naming convention of NASA Exoplanet Archiv

Gaussian Fluctuations of Eigenvalues in Wigner Random Matrices

We study the fluctuations of eigenvalues from a class of Wigner random matrices that generalize the Gaussian orthogonal ensemble. We begin by considering an $n \times n$ matrix from the Gaussian orthogonal ensemble (GOE) or Gaussian symplectic ensemble (GSE) and let $x_k$ denote eigenvalue number $k$. Under the condition that both $k$ and $n-k$ tend to infinity with $n$, we show that $x_k$ is normally distributed in the limit. We also consider the joint limit distribution of $m$ eigenvalues from the GOE or GSE with similar conditions on the indices. The result is an $m$-dimensional normal distribution. Using a recent universality result by Tao and Vu, we extend our results to a class of Wigner real symmetric matrices with non-Gaussian entries that have an exponentially decaying distribution and whose first four moments match the Gaussian moments.Comment: 21 pages, to appear, J. Stat. Phys. References and other corrections suggested by the referees have been incorporate

Mechanism of double-base lesion bypass catalyzed by a Y-family DNA polymerase

As a widely used anticancer drug, cis-diamminedichloroplatinum(II) (cisplatin) reacts with adjacent purine bases in DNA to form predominantly cis-[Pt(NH3)2{d(GpG)-N7(1),-N7(2)}] intrastrand cross-links. Drug resistance, one of the major limitations of cisplatin therapy, is partially due to the inherent ability of human Y-family DNA polymerases to perform translesion synthesis in the presence of DNA-distorting damage such as cisplatin–DNA adducts. To better understand the mechanistic basis of translesion synthesis contributing to cisplatin resistance, this study investigated the bypass of a single, site-specifically placed cisplatin-d(GpG) adduct by a model Y-family DNA polymerase, Sulfolobus solfataricus DNA polymerase IV (Dpo4). Dpo4 was able to bypass this double-base lesion, although, the incorporation efficiency of dCTP opposite the first and second cross-linked guanine bases was decreased by 72- and 860-fold, respectively. Moreover, the fidelity at the lesion decreased up to two orders of magnitude. The cisplatin-d(GpG) adduct affected six downstream nucleotide incorporations, but interestingly the fidelity was essentially unaltered. Biphasic kinetic analysis supported a universal kinetic mechanism for the bypass of DNA lesions catalyzed by various translesion DNA polymerases. In conclusion, if human Y-family DNA polymerases adhere to this bypass mechanism, then translesion synthesis by these error-prone enzymes is likely accountable for cisplatin resistance observed in cancer patients

Emerging Infectious Disease leads to Rapid Population Decline of Common British Birds

Emerging infectious diseases are increasingly cited as threats to wildlife, livestock and humans alike. They can threaten geographically isolated or critically endangered wildlife populations; however, relatively few studies have clearly demonstrated the extent to which emerging diseases can impact populations of common wildlife species. Here, we report the impact of an emerging protozoal disease on British populations of greenfinch Carduelis chloris and chaffinch Fringilla coelebs, two of the most common birds in Britain. Morphological and molecular analyses showed this to be due to Trichomonas gallinae. Trichomonosis emerged as a novel fatal disease of finches in Britain in 2005 and rapidly became epidemic within greenfinch, and to a lesser extent chaffinch, populations in 2006. By 2007, breeding populations of greenfinches and chaffinches in the geographic region of highest disease incidence had decreased by 35% and 21% respectively, representing mortality in excess of half a million birds. In contrast, declines were less pronounced or absent in these species in regions where the disease was found in intermediate or low incidence. Also, populations of dunnock Prunella modularis, which similarly feeds in gardens, but in which T. gallinae was rarely recorded, did not decline. This is the first trichomonosis epidemic reported in the scientific literature to negatively impact populations of free-ranging non-columbiform species, and such levels of mortality and decline due to an emerging infectious disease are unprecedented in British wild bird populations. This disease emergence event demonstrates the potential for a protozoan parasite to jump avian host taxonomic groups with dramatic effect over a short time period

Subacromial decompression surgery for adults with shoulder pain : a clinical practice guideline

Clinical question Do adults with atraumatic shoulder pain for more than 3 months diagnosed as subacromial pain syndrome (SAPS), also labelled as rotator cuff disease, benefit from subacromial decompression surgery? This guideline builds on to two recent high quality trials of shoulder surgery. Current practice SAPS is the common diagnosis for shoulder pain with several first line treatment options, including analgesia, exercises, and injections. Surgeons frequently perform arthroscopic subacromial decompression for prolonged symptoms, with guidelines providing conflicting recommendations. Recommendation The guideline panel makes a strong recommendation against surgery. How this guideline was created A guideline panel including patients, clinicians, and methodologists produced this recommendation in adherence with standards for trustworthy guidelines and the GRADE system. The recommendation is based on two linked systematic reviews on (a) the benefits and harms of subacromial decompression surgery and (b) the minimally important differences for patient reported outcome measures. Recommendations are made actionable for clinicians and their patients through visual overviews. These provide the relative and absolute benefits and harms of surgery in multilayered evidence summaries and decision aids available in MAGIC (www.magicapp.org) to support shared decisions and adaptation. The evidence Surgery did not provide important improvements in pain, function, or quality of life compared with placebo surgery or other options. Frozen shoulder may be more common with surgery. Understanding the recommendation The panel concluded that almost all informed patients would choose to avoid surgery because there is no benefit but there are harms and it is burdensome. Subacromial decompression surgery should not be offered to patients with SAPS. However, there is substantial uncertainty in what alternative treatment is best.Peer reviewe