Darrell Conklin

Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function.

Cytokines are important in the regulation of haematopoiesis and immune responses, and can influence lymphocyte development. Here we have identified a class I cytokine receptor that is selectively expressed in lymphoid tissues and is capable of signal transduction. The full-length receptor was expressed in BaF3 cells, which created a functional assay for ligand detection and cloning. Conditioned media from activated human CD3+ T cells supported proliferation of the assay cell line. We constructed a complementary DNA expression library from activated human CD3+ T cells, and identified a cytokine with a four-helix-bundle structure using functional cloning. This cytokine is most closely related to IL2 and IL15, and has been designated IL21 with the receptor designated IL21R. In vitro assays suggest that IL21 has a role in the proliferation and maturation of natural killer (NK) cell populations from bone marrow, in the proliferation of mature B-cell populations co-stimulated with anti-CD40, and in the proliferation of T cells co-stimulated with anti-CD3.

Interleukin 20: discovery, receptor identification, and role in epidermal function.

A structural, profile-based algorithm was used to identify interleukin 20 (IL-20), a novel IL-10 homolog. Chromosomal localization of IL-20 led to the discovery of an IL-10 family cytokine cluster. Overexpression of IL-20 in transgenic (TG) mice causes neonatal lethality with skin abnormalities including aberrant epidermal differentiation. Recombinant IL-20 protein stimulates a signal transduction pathway through STAT3 in a keratinocyte cell line, demonstrating a direct action of this ligand. An IL-20 receptor was identified as a heterodimer of two orphan class II cytokine receptor subunits. Both receptor subunits are expressed in skin and are dramatically upregulated in psoriatic skin. Taken together, these results demonstrate a role in epidermal function and psoriasis for IL-20, a novel cytokine identified solely by bioinformatics analysis.

A novel mammalian receptor for the evolutionarily conserved type II GnRH.

Mammalian gonadotropin-releasing hormone (GnRH I: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) stimulates pituitary gonadotropin secretion, which in turn stimulates the gonads. Whereas a hypothalamic form of GnRH of variable structure (designated type I) had been shown to regulate reproduction through a cognate type I receptor, it has recently become evident that most vertebrates have one or two other forms of GnRH. One of these, designated type II GnRH (GnRH II: pGlu-His-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH2), is conserved from fish to man and is widely distributed in the brain, suggesting important neuromodulatory functions such as regulating K+ channels and stimulating sexual arousal. We now report the cloning of a type II GnRH receptor from marmoset cDNA. The receptor has only 41% identity with the type I receptor and, unlike the type I receptor, has a carboxyl-terminal tail. The receptor is highly selective for GnRH II. As with the type I receptor, it couples to Gαq/11 and also activates extracellular signal-regulated kinase (ERK1/2) but differs in activating p38 mitogen activated protein (MAP) kinase. The type II receptor is more widely distributed than the type I receptor and is expressed throughout the brain, including areas associated with sexual arousal, and in diverse non-neural and reproductive tissues, suggesting a variety of functions. Surprisingly, the type II receptor is expressed in the majority of gonadotropes. The presence of two GnRH receptors in gonadotropes, together with the differences in their signaling, suggests different roles in gonadotrope functioning.

Multiple viewpoint systems for music prediction

Abstract This paper examines the prediction and generation of music using a multiple viewpoint system, a collection of independent views of the musical surface each of which models a specific type of musical phenomena. Both the general style and a particular piece are modeled using dual short‐term and long‐term theories, and the model is created using machine learning techniques on a corpus of musical examples. The models are used for analysis and prediction, and we conjecture that highly predictive theories will also generate original, acceptable, works. Although the quality of the works generated is hard to quantify objectively, the predictive power of models can be measured by the notion of entropy, or unpredictability. Highly predictive theories will produce low‐entropy estimates of a musical language. The methods developed are applied to the Bach chorale melodies. Multiple‐viewpoint systems are learned from a sample of 95 chorales, estimates of entropy are produced, and a predictive theory is used to...

Identification of INSL6, a New Member of the Insulin Family That Is Expressed in the Testis of the Human and Rat

Abstract A new member of the insulin gene family (INSL6) was identified from an Expressed Sequence Tag database through a search for proteins containing the insulin family B-chain cysteine motif. Human and rat INSL6 encoded polypeptides of 213 and 188 amino acids, respectively. These orthologous sequences contained the B-chain, C-peptide, and A-chain motif found in other members of the insulin family. Human INSL6 was 43% identical to human relaxin H2 in the B- and A-chain regions. As with other family members, human and rat INSL6 had predicted dibasic sequences at the junction of the C-peptide and A-chain. Human INSL6 sequence had an additional dibasic site near the C-terminus of the A-chain. The presence of a single basic residue at the predicted junction of the B-chain and C-peptide suggests that multiple prohormone convertases are required to produce the fully mature hormone. INSL6 was found to be expressed at high levels in the testis as determined by Northern blot analysis and specifically within the seminiferous tubules in spermatocytes and round spermatids as detected by in situ hybridization analysis. Radiation hybrid mapping placed the human INSL6 locus at chromosome 9p24 near the placenta insulin-like homologue INSL4 and the autosomal testis-determining factor (TDFA) locus.

Representation and Discovery of Vertical Patterns in Music

The automated discovery of recurrent patterns in music is a fundamental task in computational music analysis. This paper describes a new method for discovering patterns in the vertical and horizontal dimensions of polyphonic music. A formal representation of music objects is used to structure the musical surface, and several ideas for viewing pieces as successions of vertical structures are examined. A knowledge representation method is used to view pieces as sequences of relationships between music objects, and a pattern discovery algorithm is applied using this view of the Bach chorale harmonizations to find significant recurrent patterns. The method finds a small set of vertical patterns that occur in a large number of pieces in the corpus. Most of these patterns represent specific voice leading formulae within cadences.

Discovery of distinctive patterns in music

This paper proposes a new view of pattern discovery in music: inductive querying a corpus for maximally general distinctive patterns. A pattern is distinctive if it is over-represented with respect to an anticorpus, and maximally general distinctive if no subsuming pattern is also distinctive. An algorithm for maximally general distinctive pattern discovery is presented and applied to folk song melodies from three geographic regions, and to chord sequences from three music genres. Distinctive patterns are applicable to a wide range of music analysis tasks where an anticorpus can be defined and contrasted with an analysis corpus.

Methods for combining statistical models of music

The paper concerns the use of multiple viewpoint representation schemes for prediction with statistical models of monophonic music. We present an experimental comparison of the performance of two techniques for combining predictions within the multiple viewpoint framework. The results demonstrate that a new technique based on a weighted geometric mean outperforms existing techniques. This finding is discussed in terms of previous research in machine learning.

Structure motif discovery and mining the PDB

MOTIVATION Many of the most interesting functional and evolutionary relationships among proteins are so ancient that they cannot be reliably detected through sequence analysis and are apparent only through a comparison of the tertiary structures. The conserved features can often be described as structural motifs consisting of a few single residues or Secondary Structure (SS) elements. Confidence in such motifs is greatly boosted when they are found in more than a pair of proteins. RESULTS We describe an algorithm for the automatic discovery of recurring patterns in protein structures. The patterns consist of individual residues having a defined order along the proteins backbone that come close together in the structure and whose spatial conformations are similar. The residues in a pattern need not be close in the proteins sequence. The work described in this paper builds on an earlier reported algorithm for motif discovery. This paper describes a significant improvement of the algorithm which makes it very efficient. The improved efficiency allows us to use it for doing unsupervised learning of patterns occurring in small subsets in a large set of structures, a non-redundant subset of the Protein Data Bank (PDB) database of all known protein structures.

Molecular cloning, chromosome mapping and characterization of UBQLN3 a testis-specific gene that contains an ubiquitin-like domain.

The sequence of the ubiquitin protein is highly conserved between species and has facilitated the cloning of numerous ubiquitin-like proteins. In the present study, we report the cloning of the cDNA for human ubiquilin 3 (UBQLN3). The deduced amino acid sequence of UBQLN3 contains a UBQ domain (ubiquitin-like) in the amino terminus as well as two highly conserved domains found in several recently cloned ubiquitin-like proteins. One of these domains, termed the NP domain, is a highly conserved 93 amino acid region present in UBQLN3 and several ubiquitin-like proteins. The last conserved domain is the UBA domain (ubiquitin-associated) found in a variety of proteins of the ubiquination pathway. The human UBQLN3 gene was mapped to the 11p15 region of chromosome 11. Northern blot analysis of multiple human and mouse tissues demonstrated UBQLN3 mRNA expression specifically in testis.