SnoopCGH: software for visualizing comparative genomic hybridization data.

Unlabelled: Array-based comparative genomic hybridization (CGH) technology is used to discover and validate genomic structural variation, including copy number variants, insertions, deletions and other structural variants (SVs). The visualization and summarization of the array CGH data outputs, potentially across many samples, is an important process in the identification and analysis of SVs. We have developed a software tool for SV analysis using data from array CGH technologies, which is also amenable to short-read sequence data.

Reoperation for intracranial hypertension in TWIST1-confirmed Saethre-Chotzen syndrome: a 15-year review.

Background: Saethre-Chotzen syndrome is a syndromic craniosynostosis defined by a genetic mutation affecting the TWIST1 gene on chromosome 7p21. It is typically associated with unicoronal or bicoronal synostosis, eyelid ptosis, dysmorphic external ears, and other variable facial and limb abnormalities. Surgical management of the craniosynostosis addresses the calvarial deformity and may relieve or reduce the risk of intracranial hypertension.

Stem cell states, fates, and the rules of attraction.

Understanding cell-fate decisions in stem cell populations is a major goal of modern biology. Stem and progenitor cell populations are often heterogeneous, which may reflect stem cell subsets that express subtly different properties, including different propensities for lineage selection upon differentiation, yet remain able to interconvert. We discuss these properties with examples both from the hematopoietic and embryonic stem cell (ESC) systems.

The congenital dyserythropoietic anemias.

The congenital dyserythropoietic anemias (CDAs) are a heterogeneous group of hereditary disorders that seem to be restricted to the erythroid lineage. They are characterized by morphologic abnormalities of erythroid precursors in the bone marrow, resulting in ineffective erythropoiesis and a suboptimal reticulocyte response. As with many rare disorders, cases of CDA are often misdiagnosed, which may lead to inappropriate management.

Implications of a vertex bulge following modified strip craniectomy for sagittal synostosis.

Background: Modified strip craniectomy is a common treatment for early isolated sagittal synostosis. The authors assessed the significance of the development of a progressive vertex bulge following strip craniectomy as a predictor of raised intracranial pressure or multiple suture synostosis.

Methods: All cases of sagittal synostosis treated by modified strip craniectomy (removal of the sagittal suture with lateral barrel staving) at the authors' institution were reviewed.

Single-molecule level analysis of the subunit composition of the T cell receptor on live T cells.

The T cell receptor (TCR) expressed on most T cells is a protein complex consisting of TCRalphabeta heterodimers that bind antigen and cluster of differentiation (CD) 3epsilondelta, epsilongamma, and zetazeta dimers that initiate signaling. A long-standing controversy concerns whether there is one, or more than one, alphabeta heterodimer per complex. We used a form of single-molecule spectroscopy to investigate this question on live T cell hybridomas.

A closer look at CD1d molecules: new horizons in studying NKT cells.

Recent findings have highlighted the ability of invariant natural killer T (iNKT) cells to recognize microbe-derived glycolipids and have demonstrated the role of these cells in several disease states, from autoimmune disease to cancer. It has also become clear that iNKT cells can rapidly mature dendritic cells and licence them to prime antigen-specific T- and B-cell responses. The use of CD1d tetramers to monitor iNKT cell frequency and phenotype has moved the field forward at a fast pace.

Harnessing NKT cells for therapeutic applications.

Activation of NKT cells leads to the maturation of dendritic cells and efficiently assists priming of antigen-specific immune responses. The lack of polymorphism of CDld molecules and the evolutionary conservation of NKT cell responses highlight the important role of these cells in bridging innate and adaptive immune responses and advocate the value of harnessing this system in clinical settings. Compounds capable of fine tuning NKT cell activation should be actively exploited as potent adjuvants in vaccination strategies or as immunomodulators of autoimmune diseases.

Developmental impact of leukemic fusion genes on stem cell fate.

Stem and progenitor cells present attractive targets for transformation by leukemia-associated fusion genes generated by chromosomal translocation. The mechanism by which these fusion genes corrupt the transcriptional programs of these cellular compartments remains largely unknown. We have sought to gain insight into these issues through expressing TEL-AML1 and TEL-TRKC fusion genes in murine stem cells and recording effects on cell behavior in a transplant setting.

Antiangiogenic activity of a domain deletion mutant of tissue plasminogen activator containing kringle 2.

Objective: The thrombolytic therapy drug, Reteplase, is a domain deletion mutant of tissue plasminogen activator (tPA), comprising the kringle 2 and protease (K2P) domains. Some kringle domains of hemostatic proteins are antiangiogenic and promote apoptosis. The objective of this study was to investigate whether K2P is an angiogenesis inhibitor because of the presence of kringle 2.

Hypoxia-inducible factors and hypoxic cell death in tumour physiology.

Hypoxic up-regulation of hypoxia-inducible factors (HIFs) during tumourigenesis presents an interesting paradox with respect to their role in tumour growth. Hypoxia-inducible factor 1 (HIF-1) plays a key role in the adaptive response to hypoxia, trans-activating many genes whose protein products are involved in pathways of angiogenesis, glucose metabolism and cell proliferation, thus facilitating tumour progression. However, it is also emerging that up-regulation of HIF-1 trans-activates anti-proliferative and pro-apoptotic genes (such as BNIP3, NIX and IGFBP3).

UGT1A1 variation and gallstone formation in sickle cell disease.

Pigment gallstones are a common clinical complication of sickle cell (SS) disease. Genetic variation in the promoter of uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1) underlies Gilbert syndrome, a chronic form of unconjugated hyperbilirubinemia, and appears to be a risk factor for gallstone formation. We investigated the association between UGT1A1 (TA)(n) genotype, hyperbilirubinemia, and gallstones in a sample of Jamaicans with SS disease.

Generation of CD1 tetramers as a tool to monitor glycolipid-specific T cells.

CD1 molecules are beta(2)m-associated HLA class-I-like glycoproteins which have the unique ability to present glycolipid and phospholipid antigens to specific T lymphocytes. To study the biology of CD1 and its role in human disease we developed novel techniques for generation of recombinant CD1/lipid complexes by in vitro refolding. Fluorescent tetrameric complexes made from soluble recombinant CD1d/alpha-galactosylceramide complexes allowed highly sensitive and specific ex vivo and in vitro detection and functional characterization of novel human T-lymphocyte populations.

Signature Tagged Mutagenesis of Haemophilus influenzae identifies genes required for in vivo survival.

The pathogenic bacterium Haemophilus influenzae causes meningitis, epiglottitis, pneumonia, otitis media and other infections. To further understand the genetic basis of invasive disease and to inform about the bacterium's requirements in an in vivo environment, we analysed a library of 1632 insertional Tn1545 -Delta3 transposon mutants for their capacity to cause systemic infection in an animal model. We identified 25 genes that are potentially essential for H.

Immunotherapy of colorectal cancer.

Over the last decade, there has been a rapid expansion in the field of tumour immunology. There is now convincing evidence that both the cellular and humoral arms of the immune system are capable of interacting with tumour cells. The most significant advances have been in our understanding of cellular responses and the complex events that lead to T-lymphocyte activation, as well as in the identification of tumour antigens recognised by T-lymphocytes.

MHC/peptide tetramer-based studies of T cell function.

Direct visualization and quantification of antigen-specific T cells using major histocompatibility complex (MHC)/peptide tetramer technology offers a powerful means to study specific T cell populations of interest. In combination with functional assays, this technology has already provided many new insights into several long-standing immunological concepts in basic science as well as clinical settings.

Structure of human CD1b with bound ligands at 2.3 A, a maze for alkyl chains.

The human genome encodes five nonpolymorphic major histocompatibility complex class I-like glycoproteins, CD1a to CD1e, that present lipid antigens for specific recognition by T lymphocytes. Using single alkyl chain detergents, we developed a protocol to generate recombinant human CD1b-lipid complexes. We present here the crystal structures of CD1b in complex with either phosphatidylinositol or ganglioside GM2 at 2.

Regulation of hypoxia-inducible factor is preserved in the absence of a functioning mitochondrial respiratory chain.

Hypoxia-inducible factor (HIF) mediates a large number of transcriptional responses to hypoxia and has an important role in processes that include angiogenesis and erythropoiesis. The HIF DNA binding complex consists of 2 basic-helix-loop-helix PAS proteins designated alpha and beta subunits. Regulation occurs principally through the alpha subunits, which are stabilized and activated in hypoxia.