The effect of the loss of Lgl1 in murine neural progenitor cells on MAPK signaling and proliferation

Glioblastoma is an incurable, aggressive, and highly invasive type of brain tumor that harbors tumor initiating cells characterized by disrupted polarized cell divisions. A cell polarity gene lethal (2) giant larvae 1 (Lgl1) has been implicated in gliomas and is a tumor suppressor initially identified in Drosophila with roles in proliferation. The loss of Lgl1 in Drosophila activates the MAPK protein kinase JNK and the Ras pathway and therefore its downstream kinase ERK, a transcription factor modulator. Furthermore, when Lgl1 is knocked out in mice, a phenotype similar to glioma is seen. Loss of the human form of Lgl1, Hugl1, and increases in c-Jun, an oncogene and JNK target, has been associated with glioma in humans. Additionally, the protooncogene transcription factor c-Myc is documented in glioma to directly correlate to tumor grade and an increase in an analogous form, d-Myc, in Drosophila has been shown to promote survival of Lgl mutants through a Ras mechanism. Here we sought to determine if the cancer properties associated with loss of Lgl in mice and humans are related to changes in MAPK signaling. To accomplish this, murine neural progenitor cells from the subventricular zone of mice with a Lgl1 knockout were cultured in vitro. These cells were plated adherently and characterized for changes in phosphorylation states of MAPK proteins ERK, JNK and p38 as well as two protooncogene MAPK downstream targets, c-Jun and c-Myc. In addition, to understand if MAPK phosphorylation is related to proliferation we characterized the proliferation rates of these cells in the presence of chemical inhibitors of p38 and ERK’s upstream activating kinase MEK. Differential expression patterns were observed in MAPK proteins and their downstream targets associated with the loss of Lgl1, under standard conditions and with the treatment of DMSO as a drug vehicle control and chemical inhibitors of p38 and MEK. Additionally, it was found that the loss of Lgl1 in neurosphere culture slightly increased growth and under adherent conditions this effect was not seen, however, changes did occur in the presence of p38 and MEK inhibitors. This supports previous data and signifies the importance of MAPK pathway in cancer phenotypes and beginning to characterize the role of the Lgl1 protein in the mouse

A Review of State Procurement and Contracting

Are states effectively managing contracting and procurement activities? Are they striking the right balance between central administrative control and empowerment through delegation? How effective is training and monitoring? How do these practices compare to the principles of best practice? What role will information technology play in the future for procurement and contracting? As part of the Government Performance Project, budget, procurement, and contracting managers in 48 states were surveyed, providing descriptions of their procurement and contracting practices. There are numerous developments that speak to the practical details of contemporary public management. Five key findings are (1) information technology needs are challenging states, with some responding well, but others struggling, (2) in most states staff training needs to be improved, (3) restrictions prohibiting best value purchasing need to be removed, (4) states can learn from and improve practices by partnering with other governments and private organizations, and (5) most states use a hybrid of both centralized and decentralized management structures when it comes to contracting and procurement

Are City Managers Greedy Bureaucrats?

William A. Niskanen\u27s (1971, 1975) theory of bureaucracy has been a source of much debate and research.^ The theory assumes that utility-maximizing bureaucrats will seek to maximize their agency\u27s discretionary budget. A central implication of this theory is that bureaus will supply output inefficiently or in quantities greater than that desired by citizens. The authors test Niskanen\u27s hypothesis by examining the decision of cities to contract out for services. Their premise is that city managers fit the characteristics of the greedy bureaucrat Niskanen describes. If his theory is valid, then city managers should be expected to avoid contracting out because it would expose their discretionary budget and make it more difficult to use for their own purposes

KIC 9406652: An Unusual Cataclysmic Variable in the Kepler Field of View

KIC 9406652 is a remarkable variable star in the Kepler field of view that shows both very rapid oscillations and long term outbursts in its light curve. We present an analysis of the light curve over quarters 1 to 15 and new spectroscopy that indicates that the object is a cataclysmic variable with an orbital period of 6.108 hours. However, an even stronger signal appears in the light curve periodogram for a shorter period of 5.753 hours, and we argue that this corresponds to the modulation of flux from the hot spot region in a tilted, precessing disk surrounding the white dwarf star. We present a preliminary orbital solution from radial velocity measurements of features from the accretion disk and the photosphere of the companion. We use a Doppler tomography algorithm to reconstruct the disk and companion spectra, and we also consider how these components contribute to the object's spectral energy distribution from ultraviolet to infrared wavelengths. This target offers us a remarkable opportunity to investigate disk processes during the high mass transfer stage of evolution in cataclysmic variables.Comment: 31 pages, 13 figures, accepted for Ap

EPIC 219217635: A Doubly Eclipsing Quadruple System Containing an Evolved Binary

We have discovered a doubly eclipsing, bound, quadruple star system in the field of K2 Campaign 7. EPIC 219217635 is a stellar image with $Kp = 12.7$ that contains an eclipsing binary (`EB') with $P_A = 3.59470$ d and a second EB with $P_B = 0.61825$ d. We have obtained followup radial-velocity (`RV') spectroscopy observations, adaptive optics imaging, as well as ground-based photometric observations. From our analysis of all the observations, we derive good estimates for a number of the system parameters. We conclude that (1) both binaries are bound in a quadruple star system; (2) a linear trend to the RV curve of binary A is found over a 2-year interval, corresponding to an acceleration, $\dot \gamma = 0.0024 \pm 0.0007$ cm s$^{-2}$; (3) small irregular variations are seen in the eclipse-timing variations (`ETVs') detected over the same interval; (4) the orbital separation of the quadruple system is probably in the range of 8-25 AU; and (5) the orbital planes of the two binaries must be inclined with respect to each other by at least 25$^\circ$. In addition, we find that binary B is evolved, and the cooler and currently less massive star has transferred much of its envelope to the currently more massive star. We have also demonstrated that the system is sufficiently bright that the eclipses can be followed using small ground-based telescopes, and that this system may be profitably studied over the next decade when the outer orbit of the quadruple is expected to manifest itself in the ETV and/or RV curves.Comment: Accepted for publication in MNRA

Towards delineating functions within the fasciola secreted cathepsin L protease family by integrating in vivo based sub-proteomics and phylogenetics

BACKGROUND: Fasciola hepatica, along with Fasciola gigantica, is the causative agent of fasciolosis, a foodborne zoonotic disease affecting grazing animals and humans worldwide. Pathology is directly related to the release of parasite proteins that facilitate establishment within the host. The dominant components of these excretory-secretory (ES) products are also the most promising vaccine candidates, the cathepsin L (Cat L) protease family. METHODOLOGY/PRINCIPAL FINDINGS: The sub-proteome of Cat L proteases from adult F. hepatica ES products derived from in vitro culture and in vivo from ovine host bile were compared by 2-DE. The individual Cat L proteases were identified by tandem mass spectrometry with the support of an in-house translated liver fluke EST database. The study reveals plasticity within the CL1 clade of Cat L proteases; highlighted by the identification of a novel isoform and CL1 sub-clade, resulting in a new Cat L phylogenetic analysis including representatives from other adult Cat L phylogenetic clades. Additionally, for the first time, mass spectrometry was shown to be sufficiently sensitive to reveal single amino acid polymorphisms in a resolved 2-DE protein spot derived from pooled population samples. CONCLUSIONS/SIGNIFICANCE: We have investigated the sub-proteome at the population level of a vaccine target family using the Cat L proteases from F. hepatica as a case study. We have confirmed that F. hepatica exhibits more plasticity in the expression of the secreted CL1 clade of Cat L proteases at the protein level than previously realised. We recommend that superfamily based vaccine discovery programmes should screen parasite populations from different host populations and, if required, different host species via sub-proteomic assay in order to confirm the relative expression at the protein level prior to the vaccine development phase

Semiclassical Quantization of Effective String Theory and Regge Trajectories

We begin with an effective string theory for long distance QCD, and evaluate the semiclassical expansion of this theory about a classical rotating string solution, taking into account the the dynamics of the boundary of the string. We show that, after renormalization, the zero point energy of the string fluctuations remains finite when the masses of the quarks on the ends of the string approach zero. The theory is then conformally invariant in any spacetime dimension D. For D=26 the energy spectrum of the rotating string formally coincides with that of the open string in classical Bosonic string theory. However, its physical origin is different. It is a semiclassical spectrum of an effective string theory valid only for large values of the angular momentum. For D=4, the first semiclassical correction adds the constant 1/12 to the classical Regge formula.Comment: 65 pages, revtex, 3 figures, added 2 reference

Kepler Eclipsing Binary Stars. VI. Identification of Eclipsing Binaries in the K2 Campaign 0 Data-set

The original {\it Kepler} mission observed and characterized over 2400 eclipsing binaries in addition to its prolific exoplanet detections. Despite the mechanical malfunction and subsequent non-recovery of two reaction wheels used to stabilize the instrument, the {\it Kepler} satellite continues collecting data in its repurposed {\it K2} mission surveying a series of fields along the ecliptic plane. Here we present an analysis of the first full baseline {\it K2} data release: the Campaign 0 data-set. In the 7761 light curves, we have identified a total of 207 eclipsing binaries. Of these, 97 are new discoveries that were not previously identified. Our pixel-level analysis of these objects has also resulted in identification of several false positives (observed targets contaminated by neighboring eclipsing binaries), as well as the serendipitous discovery of two short period exoplanet candidates. We provide catalog cross-matched source identifications, orbital periods, morphologies and ephemerides for these eclipsing systems. We also describe the incorporation of the K2 sample into the Kepler Eclipsing Binary Catalog\footnote{\url{keplerebs.villanova.edu/k2}}, present spectroscopic follow-up observations for a limited selection of nine systems, and discuss prospects for upcoming {\it K2} campaigns.Comment: Accepted for publication in MNRAS. 51 pages [20 figures, 8 tables]. Results available online in the Kepler Eclipsing Binary Star Catalog http://keplerebs.villanova.edu/k

Planet Hunters X: Searching for Nearby Neighbors of 75 Planet and Eclipsing Binary Candidates from the K2 Kepler Extended Mission

We present high-resolution observations of a sample of 75 K2 targets from Campaigns 1-3 using speckle interferometry on the Southern Astrophysical Research (SOAR) telescope and adaptive optics (AO) imaging at the Keck II telescope. The median SOAR $I$-band and Keck $K_s$-band detection limits at 1" were $\Delta m_{I}=4.4$~mag and $\Delta m_{K_s}=6.1$~mag, respectively. This sample includes 37 stars likely to host planets, 32 targets likely to be eclipsing binaries (EBs), and 6 other targets previously labeled as likely planetary false positives. We find nine likely physically bound companion stars within 3" of three candidate transiting exoplanet host stars and six likely EBs. Six of the nine detected companions are new discoveries; one of the six, EPIC 206061524, is associated with a planet candidate. Among the EB candidates, companions were only found near the shortest period ones ($P<3$ days), which is in line with previous results showing high multiplicity near short-period binary stars. This high-resolution data, including both the detected companions and the limits on potential unseen companions, will be useful in future planet vetting and stellar multiplicity rate studies for planets and binaries.Comment: Accepted in A

Planet Hunters. V. A Confirmed Jupiter-Size Planet in the Habitable Zone and 42 Planet Candidates from the Kepler Archive Data

We report the latest Planet Hunter results, including PH2 b, a Jupiter-size (R_PL = 10.12 \pm 0.56 R_E) planet orbiting in the habitable zone of a solar-type star. PH2 b was elevated from candidate status when a series of false positive tests yielded a 99.9% confidence level that transit events detected around the star KIC 12735740 had a planetary origin. Planet Hunter volunteers have also discovered 42 new planet candidates in the Kepler public archive data, of which 33 have at least three transits recorded. Most of these transit candidates have orbital periods longer than 100 days and 20 are potentially located in the habitable zones of their host stars. Nine candidates were detected with only two transit events and the prospective periods are longer than 400 days. The photometric models suggest that these objects have radii that range between Neptune to Jupiter. These detections nearly double the number of gas giant planet candidates orbiting at habitable zone distances. We conducted spectroscopic observations for nine of the brighter targets to improve the stellar parameters and we obtained adaptive optics imaging for four of the stars to search for blended background or foreground stars that could confuse our photometric modeling. We present an iterative analysis method to derive the stellar and planet properties and uncertainties by combining the available spectroscopic parameters, stellar evolution models, and transiting light curve parameters, weighted by the measurement errors. Planet Hunters is a citizen science project that crowd-sources the assessment of NASA Kepler light curves. The discovery of these 43 planet candidates demonstrates the success of citizen scientists at identifying planet candidates, even in longer period orbits with only two or three transit events.Comment: 35 pages, 11 figures, 6 tables, accepted and published on ApJ ApJ, 776, 1