Ernestine Lee

G protein-coupled receptors

The invention provides human G-protein coupled receptors (GCREC) and polynucleotides which identify and encode GCREC. The invention also provides expression vectors, host cells, antibodies, agonists, and antagonists. The invention also provides methods for diagnosing, treating, or preventing disorders associated with aberrant expression of GCREC.

Discovery of a cytokine and its receptor by functional screening of the extracellular proteome.

To understand the system of secreted proteins and receptors involved in cell-cell signaling, we produced a comprehensive set of recombinant secreted proteins and the extracellular domains of transmembrane proteins, which constitute most of the protein components of the extracellular space. Each protein was tested in a suite of assays that measured metabolic, growth, or transcriptional responses in diverse cell types. The pattern of responses across assays was analyzed for the degree of functional selectivity of each protein. One of the highly selective proteins was a previously undescribed ligand, designated interleukin-34 (IL-34), which stimulates monocyte viability but does not affect responses in a wide spectrum of other assays. In a separate functional screen, we used a collection of extracellular domains of transmembrane proteins to discover the receptor for IL-34, which was a known cytokine receptor, colony-stimulating factor 1 (also called macrophage colony-stimulating factor) receptor. This systematic approach is thus useful for discovering new ligands and receptors and assessing the functional selectivity of extracellular regulatory proteins.

Formation of Kuiper-belt binaries through multiple chaotic scattering encounters with low-mass intruders

The discovery that many trans-Neptunian objects exist in pairs, or binaries, is proving invaluable for shedding light on the formation, evolution and structure of the outer Solar system. Based on recent systematic searches it has been estimated that up to 10 per cent of Kuiper-belt objects might be binaries. However, all examples discovered to date are unusual, as compared with near-Earth and main-belt asteroid binaries, for their mass ratios of the order of unity and their large, eccentric orbits. In this article we propose a common dynamical origin for these compositional and orbital properties based on four-body simulations in the Hill approximation. Our calculations suggest that binaries are produced through the following chain of events. Initially, long-lived quasi-bound binaries form by two bodies getting entangled in thin layers of dynamical chaos produced by solar tides within the Hill sphere. Next, energy transfer through gravitational scattering with a low-mass intruder nudges the binary into a nearby non-chaotic, stable zone of phase space. Finally, the binary hardens (loses energy) through a series of relatively gentle gravitational scattering encounters with further intruders. This produces binary orbits that are well fitted by Kepler ellipses. Dynamically, the overall process is strongly favoured if the original quasi-bound binary contains comparable masses. We propose a simplified model of chaotic scattering to explain these results. Our findings suggest that the observed preference for roughly equal-mass ratio binaries is probably a real effect; that is, it is not primarily due to an observational bias for widely separated, comparably bright objects. Nevertheless, we predict that a sizeable population of very unequal-mass Kuiper-belt binaries is probably awaiting discovery.

Intracellular signaling molecules

Various embodiments of the invention provide human intracellular signaling molecules (INTSIG) and polynucleotides which identify and encode INTSIG. Embodiments of the invention also provide expression vectors, host cells, antibodies, agonists, and antagonists. Other embodiments provide methods for diagnosing, treating, or preventing disorders associated with aberrant expression of INTSIG.

Production of trans-Neptunian binaries through chaos-assisted capture

The recent discovery of binary objects in the Kuiper Belt opens an invaluable window into past and present conditions in the trans-Neptunian part of the Solar System. For example, knowledge of how these objects formed can be used to impose constraints on planetary formation theories. We have recently proposed a binary object formation model based on the notion of chaosassisted capture (CAC). In this model two potential binary partners may become trapped for long times inside chaotic layers within their mutual Hill sphere. The binary may then be captured permanently through gravitational scattering with a third ‘intruder’ body. The creation of binaries having similarly sized partners is an ab initio prediction of the model which also predicts large binary semimajor axes and moderately eccentric mutual orbits similar to those observed. Here we present a more detailed analysis with calculations performed in the spatial (three-dimensional) three- and four-body Hill approximations. It is assumed that the potential binary partners are initially following heliocentric Keplerian orbits and that their relative motion becomes perturbed as these objects undergo close encounters. First, the mass, velocity and orbital element distributions which favour binary formation are identified in the circular and elliptical Hill limits. We then consider intruder scattering to the circular Hill four-body problem and find that the CAC mechanism is consistent with observed, apparently randomly distributed, binary mutual orbit inclinations. It also predicts asymmetric distributions of retrograde versus prograde orbits. The time-delay induced by chaos on particle transport through the Hill sphere is analogous to the formation of a resonance in a chemical reaction. Implications for binary formation rates are considered and the ‘fine-tuning’ problem recently identified by Noll et al. is also addressed.

Deorphanization of the human leukocyte tyrosine kinase (LTK) receptor by a signaling screen of the extracellular proteome

Significance Secreted factors and their cell-surface receptors play important roles in the communication between cells in normal and pathological conditions. There are many transmembrane receptor-like proteins whose ligands have not been identified (also known as orphan receptors). Knowledge of the ligand should help in understanding the biological role of the receptor. We used a strategy of screening the extracellular proteome, one protein at a time, to identify ligands for such receptors. We discovered the ligands for the orphan receptor leukocyte tyrosine kinase. To our knowledge, this is the first case in which secreted factor ligands were identified for an orphan receptor with this technique. This approach is especially valuable when little is known about the ligand. There are many transmembrane receptor-like proteins whose ligands have not been identified. A strategy for finding ligands when little is known about their tissue source is to screen each extracellular protein individually expressed in an array format by using a sensitive functional readout. Taking this approach, we have screened a large collection (3,191 proteins) of extracellular proteins for their ability to activate signaling of an orphan receptor, leukocyte tyrosine kinase (LTK). Only two related secreted factors, FAM150A and FAM150B (family with sequence similarity 150 member A and member B), stimulated LTK phosphorylation. FAM150A binds LTK extracellular domain with high affinity (KD = 28 pM). FAM150A stimulates LTK phosphorylation in a ligand-dependent manner. This strategy provides an efficient approach for identifying functional ligands for other orphan receptors.

Core-induced stabilization and autoionization of molecular Rydberg states

Abstract Stabilization of molecular Rydberg states through interaction with the core is demonstrated. Core rotation is shown to provide a mechanism for recent, unexplained, experimental observations that long-living Rydberg states, under ZEKE conditions, exist both below and above the ionization threshold.

Controlling feature selection in random forests of decision trees using a genetic algorithm: classification of class I MHC peptides.

Feature selection is an important challenge in many classification problems, especially if the number of features greatly exceeds the number of examples available. We have developed a procedure--GenForest--which controls feature selection in random forests of decision trees by using a genetic algorithm. This approach was tested through our entry into the Comparative Evaluation of Prediction Algorithms 2006 (CoEPrA) competition (accessible online at: http://www.coepra.org). CoEPrA was a modeling competition organized to provide an objective testing for various classification and regression algorithms via the process of blind prediction. In the competition GenForest ranked 10/23, 5/16 and 9/16 on CoEPrA classification problems 1, 3 and 4, respectively, which involved the classification of type I MHC nonapeptides i.e. peptides containing nine amino acids. These problems each involved the classification of different sets of nonapeptides. Associated with each amino acid was a set of 643 features for a total of 5787 features per peptide. The method, its application to the CoEPrA datasets, and its performance in the competition are described.

G-protein coupled receptors

G-Protein-coupled receptors mediate many of the hypnotic and analgesic actions of the drugs employed in anesthesia. Notably, opioid agonists represent the most successful and efficacious class of analgesic agents employed over the last century. Also, major clinical advances have been made by the study of alpha(2) adrenoceptor agonists, which possess both hypnotic and analgesic qualities that are being increasingly exploited in both anesthetic and critical care settings. Furthermore orexin, gamma-aminobutyric acid (GABA) (B), and muscarinic cholinergic receptors have been identified as potential anesthetic targets; clinical exploitation of ligands at these receptors may lead to important advances in anesthetic pharmacology. In this review we discuss the relevant molecular and neural network pharmacology of anesthetic agents acting at G-protein-coupled receptors.

Magnetic field stabilization of Rydberg, Gaussian wave packets in a circularly polarized microwave field

Abstract The dynamics of a hydrogen atom subjected simultaneously to a circularly polarized microwave field and a magnetic field perpendicular to the plane of polarization are investigated. Stability analysis of the flow and numerical simulations reveal that the magnetic field can have the effect of stabilizing Gaussian wavepackets prepared at a global equilibrium point — a maximum — against dispersion and spreading.