Fast Approximate Shortest Hyperpaths for Inferring Pathways in Cell Signaling Hypergraphs

Cell signaling pathways, which are a series of reactions that start at receptors and end at transcription factors, are basic to systems biology. Properly modeling the reactions in such pathways requires directed hypergraphs, where an edge is now directed between two sets of vertices. Inferring a pathway by the most parsimonious series of reactions then corresponds to finding a shortest hyperpath in a directed hypergraph, which is NP-complete. The state of the art for shortest hyperpaths in cell-signaling hypergraphs solves a mixed-integer linear program to find an optimal hyperpath that is restricted to be acyclic, and offers no efficiency guarantees. We present for the first time a heuristic for general shortest hyperpaths that properly handles cycles, and is guaranteed to be efficient. Its accuracy is demonstrated through exhaustive experiments on all instances from the standard NCI-PID and Reactome pathway databases, which show the heuristic finds a hyperpath that matches the state-of-the-art mixed-integer linear program on over 99% of all instances that are acyclic. On instances where only cyclic hyperpaths exist, the heuristic surpasses the state-of-the-art, which finds no solution; on every such cyclic instance, enumerating all possible hyperpaths shows that the solution found by the heuristic is in fact optimal

The design and evaluation of grazing incidence relay optics

X-ray astronomy, both solar and celestial, has many needs for high spatial resolution observations which have to be performed with electronic detectors. If the resolution is not to be detector limited, plate scales in excess of 25 microns arc/sec, corresponding to focal lengths greater than 5 m, are required. In situations where the physical size is restricted, the problem can be solved by the use of grazing incidence relay optics. A system was developed which employs externally polished hyperboloid-hyperboloid surfaces to be used in conjunction with a Wolter-Schwarzschild primary. The secondary is located in front of the primary focus and provides a magnification of 4, while the system has a plate scale of 28 microns arc/sec and a length of 1.9 m. The design, tolerance specification, fabrication and performance at visible and X-ray wavelengths of this optical system are described

The Neuroinflammatory Response in ALS: The Roles of Microglia and T Cells

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by upper and lower motoneuron death. Mutations in the gene for superoxide dismutase 1 (SOD1) cause a familial form of ALS and have been used to develop transgenic mice which overexpress human mutant SOD1 (mSOD) and these mice exhibit a motoneuron disease which is pathologically and phenotypically similar to ALS. Neuroinflammation is a pathological hallmark of many neurodegenerative diseases including ALS and is typified by the activation and proliferation of microglia and the infiltration of T cells into the brain and spinal cord. Although the neuroinflammatory response has been considered a consequence of neuronal dysfunction and death, evidence indicates that manipulation of this response can alter disease progression. Previously viewed as deleterious to neuronal survival, recent reports suggest a trophic role for activated microglia in the mSOD mouse during the early stages of disease that is dependent on instructive signals from infiltrating T cells. However, at advanced stages of disease, activated microglia acquire increased neurotoxic potential, warranting further investigation into factors capable of skewing microglial activation towards a neurotrophic phenotype as a means of therapeutic intervention in ALS

Cibenzoline for treatment of ventricular arrhythmias: A double-blind placebo-controlled study

Cibenzoline, a new class I antiarrhythmic drug, was administered to 24 patients with frequent (> 30/h) premature ventricular complexes. Three patients discontinued the medication because of epigastric distress before repeat ambulatory electrocardiography. Of the remaining 21 patients, 13 responded to 130 mg twice daily by more than 75% suppression of premature ventricular complex frequency and 6 additional patients responded to 160 mg twice daily during an open-label titration phase. Events of ventricular tachycardia (≥3 beats) were totally suppressed in 9 of 10 patients and markedly diminished in the 1 remaining patient. During a doubleblind placebo-controlled crossover phase in 16 patients (21 patients minus 2 nonresponders and 3 who developed side effects), cibenzoline suppressed the number of premature ventricular complexes per 24 hours (4,075 ± 868 to 1,758 ± 1,089, p = 0.02), the number of events of ventricular tachycardia (31 ± 30 to 2 ± 0, p = 0.01) and the number of premature ventricular complex pairs (61 ± 28 to 25 ± 21, p = 0.01). Cibenzoline plasma concentration was 59 to 421 ng/ml in responders and higher (387,758 and 852 ng/ml, respectively) in the three subjects with side effects (right bundle branch block in one, hypotension in one, gastrointestinal upset and central nervous system complaints in one). Cibenzoline plasma concentration correlated with PR interval (r = 0.55, p = 0.0106) and corrected QT interval (r = 0.58, p = 0.0054). Further clinical investigation of this new antiarrhythmic agent is needed

Characterisation of Bombyx mori odorant-binding proteins reveals that a general odorant-binding protein discriminates between sex pheromone components

In many insect species, odorant-binding proteins (OBPs) are thought to be responsible for the transport of pheromones and other semiochemicals across the sensillum lymph to the olfactory receptors (ORs) within the antennal sensilla. In the silkworm Bombyx mori, the OBPs are subdivided into three main subfamilies; pheromone-binding proteins (PBPs), general odorant-binding proteins (GOBPs) and antennal-binding proteins (ABPs). We used the MotifSearch algorithm to search for genes encoding putative OBPs in B. mori and found 13, many fewer than are found in the genomes of fruit flies and mosquitoes. The 13 genes include seven new ABP-like OBPs as well as the previously identified PBPs (three), GOBPs (two) and ABPx. Quantitative examination of transcript levels showed that BmorPBP1, BmorGOBP1, BmorGOBP2 and BmorABPx are expressed at very high levels in the antennae and so could be involved in olfaction. A new two-phase binding assay, along with other established assays, showed that BmorPBP1, BmorPBP2, BmorGOBP2 and BmorABPx all bind to the B. mori sex pheromone component (10E,12Z)-hexadecadien-1-ol (bombykol). BmorPBP1, BmorPBP2 and BmorABPx also bind the pheromone component (10E,12Z)-hexadecadienal (bombykal) equally well, whereas BmorGOBP2 can discriminate between bombykol and bombykal. X-ray structures show that when bombykol is bound to BmorGOBP2 it adopts a different conformation from that found when it binds to BmorPBP1. Binding to BmorGOBP2 involves hydrogen bonding to Arg110 rather than to Ser56 as found for BmorPBP1

Betriebswirtschaftliche Ziele und Effekte einer familienbewussten Personalpolitik

Die Analyse betriebswirtschaftlicher Ziele und Effekte einer familienbewussten Personalpolitik stellt vor dem Hintergrund eines nicht zuletzt demografiebedingten Bedeutungszuwachses der betrieblichen Familienpolitik ein zentrales Forschungsdesiderat dar. Vor der konzeptionellen Folie eines Input-Output Modells wird in vorliegendem Arbeitspapier zunächst gezeigt, dass mit dem berufundfamilie-Index ein dienliches Instrument zur Quantifizierung betrieblichen Familienbewusstseins vorliegt, es jedoch bisher an einer Systematik fehlt, welche die Output-Seite konsistent erfasst. Diese Forschungslücke wird im ersten Teil vorliegender Arbeit geschlossen, indem theoretische Ansätze und metaanalytische Befunde hinsichtlich der Ziele familienbewusster Personalpolitik in einem Zielsystem konzentriert werden. In dessen Zentrum stehen Mitarbeiterbindung und Mitarbeitergewinnung als überlagernde Ziele, welche hinsichtlich aktueller Beschäftigter in Wirkungsbeziehungen zu deren Arbeitszufriedenheit und Motivation, zu Fehlzeiten, Humankapitalakkumulation, Kundenbindung, Kostensenkung und Mitarbeiterproduktivität stehen; hinsichtlich potenzieller Mitarbeiter lassen sich die Wirkungsbeziehungen in Bezug auf den Bewerberpool, die Bewerberqualität sowie die Senkung von Opportunitätskosten unbesetzter Stellen beschreiben. Aufbauend auf dieser Systematik wird im zweiten Teil der Arbeit ein empirisches Forschungsdesign entwickelt und in einer Betriebsstättenbefragung in Deutschland (n=1.001) angewandt. Quantitative Datenanalysen zeigen einerseits, dass familienbewusste Personalpolitik bei allen beschriebenen Zielbereichen einen signifikant positiven Beitrag leistet. Andererseits führen Untersuchungen der Wirkungsintensität familienbewusster Personalpolitik zu dem Ergebnis, dass Unternehmen mit einem hohen betrieblichen Familienbewusstsein die beschriebenen Ziele zum Teil deutlich besser erreichen als die Vergleichsgruppe nicht familienbewusster Unternehmen.Due to the increasing relevance of demographic developments for human resources management, the analysis of goals and effects of corporate family-consciousness has become a central field of research. The concept of an input/output analysis presented in the paper shows that the berufundfamilie-index offers a quantification of corporate family-consciousness but also reveals that the output has not yet been conceptualized consistently. The first part of this paper closes this gap of research by issuing a system of goals of corporate family-consciousness. Central goals are employee loyalty and recruiting. With regard to current employees these goals relate to job satisfaction and motivation, absenteeism, accumulation of human capital, customer loyalty, cost reduction and efficiency of labour. With regard to potential employees they relate to the pool and quality of applicants as well as to the reduction of opportunity costs caused by vacancies. The second part of the paper describes the survey of 1001 companies in Germany based on the construction mentioned before. It shows that corporate family-consciousness significantly contributes to achieving the goals. Furthermore it proves that the more family-conscious a company is, the better the goals mentioned can be achieved. The empirical findings indicate that family friendly human resources management constitutes an important parameter in managerial decision making

Feature-based inheritance networks for computational lexicons

The virtues of viewing the lexicon as an inheritance network are its succinctness and its tendency to highlight significant clusters of linguistic properties. From its succinctness follow two practical advantages, namely its ease of maintenance and modification. In this paper we present a feature-based foundation for lexical inheritance. We argue that the feature-based foundation is both more economical and expressively more powerful than non-feature-based systems. It is more economical because it employs only mechanisms already assumed to be present elsewhere in the grammar (viz., in the feature system), and it is more expressive because feature systems are more expressive than other mechanisms used in expressing lexical inheritance (cf. DATR). The lexicon furthermore allows the use of default unification, based on the ideas of default unification, defined by Bouma. These claims are buttressed in sections sketching the opportunities for lexical description in feature-based lexicons in two central lexical topics, inflection and derivation. Briefly, we argue that the central notion of paradigm may be defined in feature structures, and that it may be more satisfactorily (in fact, immediately) linked to the syntactic information in this fashion. Our discussion of derivation is more programmatic; but here, too, we argue that feature structures of a suitably rich sort provide a foundation for the definition of lexical rules. We illustrate theoretical claims in application to German lexis. This work is currently under implementation in a natural language understanding effort (DISCO) at the German Artiffical Intelligence Center (Deutsches Forschungszentrum für Künstliche Intelligenz)

Myelosuppressive Conditioning Using Busulfan Enables Bone Marrow Cell Accumulation in the Spinal Cord of a Mouse Model of Amyotrophic Lateral Sclerosis

Myeloablative preconditioning using irradiation is the most commonly used technique to generate rodents having chimeric bone marrow, employed for the study of bone marrow-derived cell accumulation in the healthy and diseased central nervous system. However, irradiation has been shown to alter the blood-brain barrier, potentially creating confounding artefacts. To better study the potential of bone marrow-derived cells to function as treatment vehicles for neurodegenerative diseases alternative preconditioning regimens must be developed. We treated transgenic mice that over-express human mutant superoxide dismutase 1, a model of amyotrophic lateral sclerosis, with busulfan to determine whether this commonly used chemotherapeutic leads to stable chimerism and promotes the entry of bone marrow-derived cells into spinal cord. Intraperitoneal treatment with busulfan at 60 mg/kg or 80 mg/kg followed by intravenous injection of green fluorescent protein-expressing bone marrow resulted in sustained levels of chimerism (~80%). Bone marrow-derived cells accumulated in the lumbar spinal cord of diseased mice at advanced stages of pathology at both doses, with limited numbers of bone marrow derived cells observed in the spinal cords of similarly treated, age-matched controls; the majority of bone marrow-derived cells in spinal cord immunolabelled for macrophage antigens. Comparatively, significantly greater numbers of bone marrow-derived cells were observed in lumbar spinal cord following irradiative myeloablation. These results demonstrate bone marrow-derived cell accumulation in diseased spinal cord is possible without irradiative preconditioning

Reduction of dynatomic curves

The dynatomic modular curves parametrize polynomial maps together with a point of period $n$. It is known that the dynatomic curves $Y_1(n)$ are smooth and irreducible in characteristic 0 for families of polynomial maps of the form $f_c(z) = z^m +c$ where $m\geq 2$. In the present paper, we build on the work of Morton to partially characterize the primes $p$ for which the reduction modulo $p$ of $Y_1(n)$ remains smooth and/or irreducible. As an application, we give new examples of good reduction of $Y_1(n)$ for several primes dividing the ramification discriminant when $n=7,8,11$. The proofs involve arithmetic and complex dynamics, reduction theory for curves, ramification theory, and the combinatorics of the Mandelbrot set