Identification and functional characterisation of CRK12:CYC9, a novel cyclin-dependent kinase (CDK)-cyclin complex in Trypanosoma brucei

The protozoan parasite, Trypanosoma brucei, is spread by the tsetse fly and causes trypanosomiasis in humans and animals. Both the life cycle and cell cycle of the parasite are complex. Trypanosomes have eleven cdc2-related kinases (CRKs) and ten cyclins, an unusually large number for a single celled organism. To date, relatively little is known about the function of many of the CRKs and cyclins, and only CRK3 has previously been shown to be cyclin-dependent in vivo. Here we report the identification of a previously uncharacterised CRK:cyclin complex between CRK12 and the putative transcriptional cyclin, CYC9. CRK12:CYC9 interact to form an active protein kinase complex in procyclic and bloodstream T. brucei. Both CRK12 and CYC9 are essential for the proliferation of bloodstream trypanosomes in vitro, and we show that CRK12 is also essential for survival of T. brucei in a mouse model, providing genetic validation of CRK12:CYC9 as a novel drug target for trypanosomiasis. Further, functional characterisation of CRK12 and CYC9 using RNA interference reveals roles for these proteins in endocytosis and cytokinesis, respectively

“Dogged” Search of Fresh Nakhla Surfaces Reveals New Alteration Textures

Special Issue: 74th Annual Meeting of the Meteoritical Society, August 8-12, 2011, London, U.K.International audienceCarbonaceous chondrites are considered as amongst the most primitive Solar System samples available. One of their primitive characteristics is their enrichment in volatile elements.This includes hydrogen, which is present in hydrated and hydroxylated minerals. More precisely, the mineralogy is expected to be dominated by phyllosilicates in the case of CM chondrites, and by Montmorillonite type clays in the case of CI. Here, in order to characterize and quantify the abundance of lowtemperature minerals in carbonaceous chondrites, we performed thermogravimetric analysis of matrix fragments of Tagish Lake, Murchison and Orgueil

The acquisition of asserted, presupposed, and pragmatically implied exhaustivity in Hungarian

The paper reports on three experiments in which the exhaustive interpretation of sentences containing the focus particle csak ‘only’, structural focus constructions, and sentences with neutral intonation and word order were investigated. The results obtained not only reveal the developmental trajectory of the adult-like comprehension of each sentence type, but also contribute to the discussion concerning the semantic or pragmatic nature of their exhaustive meaning component. As the three construction types were judged in different ways on a three-point scale, the findings appear to support the hypothesis according to which exhaustivity is part of the asserted content of sentences with csak ‘only’, it is context-independently presupposed in the case of structural focus, and in certain contexts it can arise as an implicature in the case of neutral utterances, as well

Metal Hydrides Form Halogen Bonds: Measurement of Energetics of Binding

The formation of halogen bonds from iodopentafluorobenzene and 1-iodoperfluorohexane to a series of bis(η5-cyclopentadienyl)metal hydrides (Cp2TaH3, 1; Cp2MH2, M = Mo, 2, M = W, 3; Cp2ReH, 4; Cp2Ta(H)CO, 5; Cp = η5-cyclopentadienyl) is demonstrated by 1H NMR spectroscopy. Interaction enthalpies and entropies for complex 1 with C6F5I and C6F13I are reported (ΔH° = −10.9 ± 0.4 and −11.8 ± 0.3 kJ/mol; ΔS° = −38 ± 2 and −34 ± 2 J/(mol·K), respectively) and found to be stronger than those for 1 with the hydrogen-bond donor indole (ΔH° = −7.3 ± 0.1 kJ/mol, ΔS° = −24 ± 1 J/(mol·K)). For the more reactive complexes 2–5, measurements are limited to determination of their low-temperature (212 K) association constants with C6F5I as 2.9 ± 0.2, 2.5 ± 0.1, <1.5, and 12.5 ± 0.3 M–1, respectively

Glucagon-like peptide-1 and its class B G protein-coupled receptors: A long march to therapeutic successes

Theglucagon-likepeptide (GLP)-1receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) that mediates the action of GLP-1, a peptide hormone secretedfromthreemajor tissues inhumans,enteroendocrine L cells in the distal intestine, a cells in the pancreas, and the central nervous system, which exerts important actions useful in the management of type 2 diabetes mellitus and obesity, including glucose homeostasis and regulation of gastric motility and food intake. Peptidic analogs of GLP-1 have been successfully developed with enhanced bioavailability and pharmacological activity. Physiologic and biochemical studies with truncated, chimeric, and mutated peptides and GLP-1R variants, together with ligand-bound crystal structures of the extracellular domain and the first three-dimensional structures of the 7-helical transmembrane domain of class B GPCRs, have provided the basis for a twodomain-binding mechanism of GLP-1 with its cognate receptor. Although efforts in discovering therapeutically viable nonpeptidicGLP-1R agonists have been hampered, small-moleculemodulators offer complementary chemical tools to peptide analogs to investigate ligand-directed biased cellular signaling of GLP-1R. The integrated pharmacological and structural information of different GLP-1 analogs and homologous receptors give new insights into the molecular determinants of GLP-1R ligand selectivity and functional activity, thereby providing novel opportunities in the design and development of more efficacious agents to treat metabolic disorders

Fruit crops: a summary of research, 1998

Pesticide deposition in orchards: effects of pesticide type, tree canopy, timing, cultivar, and leaf type / Franklin R. Hall, Jane A. Cooper, and David C. Ferree -- The influence of a synthetic foraging attractant, Bee-Scent™, on the number of honey bees visiting apple blossoms and on subsequent fruit production / James E. Tew and David C. Ferree -- The reliability of three traps vs. a single trap for determining population levels of codling moth in commercial northern Ohio apple orchards / Ted W. Gastier -- Evaluation of an empirical model for predicting sooty blotch and flyspeck of apples in Ohio / Michael A. Ellis, Laurence V. Madden, and L. Lee Wilson -- Influence of pesticides and water stress on photosynthesis and transpiration of apple / David C. Ferree, Franklin R. Hall, Charles R. Krause, Bruce R. Roberts, and Ross D. Brazee -- Influence of temporary bending and heading on branch development and flowering of vigorous young apple trees / David C. Ferree and John C. Schmid -- The effect of apple fruit bruising on total returns / Richard C. Funt, Ewen A. Cameron, and Nigel H. Banks -- Yield, berry quality, and economics of mechanical berry harvest in Ohio / Richard C. Funt, Thomas E. Wall, and Joseph C. Scheerens -- Monitoring flower thrips activities in strawberry fields at two Ohio locations / Roger N. Williams, M. Sean Ellis, Dan S. Fickle, and Carl M. Pelland -- Cluster thinning effects on fruit weight, juice quality, and fruit skin characteristics in 'Reliance' grapes / Yu Gao and Garth A. Cahoon -- Effects of various fungicide programs on powdery mildew control, percent berry sugar, yield, and vine vigor of 'Concord' grapes in Ohio / Michael A. Ellis, Laurence V. Madden, L. Lee Wilson, and Gregory R. Johns -- Influence of growth regulators, cropping, and number on replacement trunks of winter-injured 'Vidal Blanc' grapes / David C. Ferree, David M. Scurlock, and Rick Evans -- Effect of new herbicides on tissue-cultured black raspberry plants / Richard C. Funt, Thomas E. Wall, and B. Dale Stokes -- Investigating the relationship between vine vigor and berry set of field-grown 'Seyval Blanc' grapevines / Steven J. McArtney and David C. Ferree -- Summary of Ohio Fruit Growers Society apple cider competition, 1993-1997 / Winston Bash and Diane Mille

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

BioSimulators: a central registry of simulation engines and services for recommending specific tools

Computational models have great potential to accelerate bioscience, bioengineering, and medicine. However, it remains challenging to reproduce and reuse simulations, in part, because the numerous formats and methods for simulating various subsystems and scales remain siloed by different software tools. For example, each tool must be executed through a distinct interface. To help investigators find and use simulation tools, we developed BioSimulators (https://biosimulators.org), a central registry of the capabilities of simulation tools and consistent Python, command-line and containerized interfaces to each version of each tool. The foundation of BioSimulators is standards, such as CellML, SBML, SED-ML and the COMBINE archive format, and validation tools for simulation projects and simulation tools that ensure these standards are used consistently. To help modelers find tools for particular projects, we have also used the registry to develop recommendation services. We anticipate that BioSimulators will help modelers exchange, reproduce, and combine simulations

Proceedings of the Association for Research in Vision and Ophthalmology and Champalimaud Foundation Ocular Oncogenesis and Oncology Conference

Ophthalmic researc