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Chemical biology, an integration of multiple fields When the Nobel Prizes were first created in 1901 to honor major progress in various domains of human knowledge, the awards for scientific [...]

Human metabolic incorporation of nonhuman sialic acid (Sia) N-glycolylneuraminic acid into endogenous glycans generates inflammation via preexisting antibodies, which likely contributes to red meat-induced atherosclerosis acceleration. Exploring whether this mechanism affects atherosclerosis in end-stage renal disease (ESRD), we instead found serum accumulation of 2-keto-3-deoxy-D-glycero-D-galacto-2-nonulosonic acid (Kdn), a Sia prominently expressed in cold-blooded vertebrates. In patients with ESRD, levels of the Kdn precursor mannose also increased, but within a normal range. Mannose ingestion by healthy volunteers raised the levels of urinary mannose and Kdn. Kdn production pathways remained conserved in mammals but were diminished by an M42T substitution in a key biosynthetic enzyme, N-acetylneuraminate synthase. Remarkably, reversion to the ancestral methionine then occurred independently in 2 lineages, including humans. However, mammalian glycan databases contain no Kdn-glycans. We hypothesize that the potential toxicity of excess mannose in mammals is partly buffered by conversion to free Kdn. Thus, mammals probably conserve Kdn biosynthesis and modulate it in a lineage-specific manner, not for glycosylation, but to control physiological mannose intermediates and metabolites. However, human cells can be forced to express Kdn-glycans via genetic mutations enhancing Kdn utilization, or by transfection with fish enzymes producing cytidine monophosphate-Kdn (CMP-Kdn). Antibodies against Kdn-glycans occur in pooled human immunoglobulins. Pathological conditions that elevate Kdn levels could therefore result in antibody-mediated inflammatory pathologies., Introduction Sialic acids (Sias) are a diverse family of 9-carbon backbone monosaccharides found in glycosidic linkage to outer tips of the glycan forest that covers all vertebrate cells and most [...]

Cystic fibrosis (CF) disrupts respiratory host defenses, allowing bacterial infection, inflammation, and mucus accumulation to progressively destroy the lungs. Our previous studies revealed that mucus with abnormal behavior impaired mucociliary transport in newborn CF piglets prior to the onset of secondary manifestations. To further investigate mucus abnormalities, here we studied airway surface liquid (ASL) collected from newborn piglets and ASL on cultured airway epithelia. Fluorescence recovery after photobleaching revealed that the viscosity of CF ASL was increased relative to that of non- CF ASL. CF ASL had a reduced pH, which was necessary and sufficient for genotype-dependent viscosity differences. The increased viscosity of CF ASL was not explained by pH-independent changes in HC[O.sub.3.sup.-] concentration, altered glycosylation, additional pH-induced disulfide bond formation, increased percentage of nonvolatile material, or increased sulfation. Treating acidic ASL with hypertonic saline or heparin largely reversed the increased viscosity, suggesting that acidic pH influences mucin electrostatic interactions. These findings link loss of cystic fibrosis transmembrane conductance regulator-dependent alkalinization to abnormal CF ASL. In addition, we found that increasing [Ca.sup.2+] concentrations elevated ASL viscosity, in part, independently of pH. The results suggest that increasing pH, reducing [Ca.sup.2*] concentration, and/or altering electrostatic interactions in ASL might benefit early CF., Introduction Cystic fibrosis (CF) is a life-shortening disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel (1-3). Lung disease is the major [...]

This position statement originated from a working group meeting convened on April 15, 2015, by the NHLBI and incorporates follow-up contributions by the participants as well as other thought leaders subsequently consulted, who together represent research fields relevant to all branches of the NIH. The group was deliberately composed not only of individuals with a current research emphasis in the glycosciences, but also of many experts from other fields, who evinced a strong interest in being involved in the discussions. The original goal was to discuss the value of creating centers of excellence for training the next generation of biomedical investigators in the glycosciences. A broader theme that emerged was the urgent need to bring the glycosciences back into the mainstream of biology by integrating relevant education into the curricula of medical, graduate, and postgraduate training programs, thus generating a critical sustainable workforce that can advance the much- needed translation of glycosciences into a more complete understanding of biology and the enhanced practice of medicine., Background and current status Every living cell in nature that has emerged from more than 3 billion years of biological evolution is composed of nucleic acids, proteins, lipids, metabolites, and [...]

The breakdown and release of hyaluronan (HA) from the extracellular matrix has been hypothesized to act as an endogenous signal of injury. To test this hypothesis, we generated mice that conditionally overexpressed human hyaluronidase 1 (HYAL1). Mice expressing HYAL1 in skin either during early development or by inducible transient expression exhibited extensive HA degradation, yet displayed no evidence of spontaneous inflammation. Further, HYAL1 expression activated migration and promoted loss of DCs from the skin. We subsequently determined that induction of HYAL1 expression prior to topical antigen application resulted in a lack of an antigenic response due to the depletion of DCs from the skin. In contrast, induction of HYAL1 expression concurrent with antigen exposure accelerated allergic sensitization. Administration of HA tetrasaccharides, before or simultaneously with antigen application, recapitulated phenotypes observed in HYAL1-expressing animals, suggesting that the generation of small HA fragments, rather than the loss of large HA molecules, promotes DC migration and subsequent modification of allergic responses. Furthermore, mice lacking TLR4 did not exhibit HA-associated phenotypes, indicating that TLR4 mediates these responses. This study provides direct evidence that HA breakdown controls the capacity of the skin to present antigen. These events may influence DC function in injury or disease and have potential to be exploited therapeutically for modification of allergic responses., Introduction The early inflammatory response to tissue injury has been proposed to involve recognition of components of damaged cells by pattern recognition receptors, such as TLRs (1). These dead cell [...]

President Horwitz, Members of the AAP, Ladies and Gentlemen: it is a great pleasure and a very special honor to present the prestigious Kober Medal to Stuart Kornfeld, the very [...]

Presents a study which evaluated various chemically-modified heparin derivatives for their ability to block P- and L-selectin-dependent interactions with sialylated, fucosylated ligands in vitro and to block inflammation in mice. Methods; Results and discussion.

Cystic fibrosis (CF) disrupts respiratory host defenses, allowing bacterial infection, inflammation, and mucus accumulation to progressively destroy the lungs. Our previous studies revealed that mucus with abnormal behavior impaired mucociliary transport in newborn CF piglets prior to the onset of secondary manifestations. To further investigate mucus abnormalities, here we studied airway surface liquid (ASL) collected from newborn piglets and ASL on cultured airway epithelia. Fluorescence recovery after photobleaching revealed that the viscosity of CF ASL was increased relative to that of non-CF ASL. CF ASL had a reduced pH, which was necessary and sufficient for genotype-dependent viscosity differences. The increased viscosity of CF ASL was not explained by pH-independent changes in HCO3- concentration, altered glycosylation, additional pH-induced disulfide bond formation, increased percentage of nonvolatile material, or increased sulfation. Treating acidic ASL with hypertonic saline or heparin largely reversed the increased viscosity, suggesting that acidic pH influences mucin electrostatic interactions. These findings link loss of cystic fibrosis transmembrane conductance regulator-dependent alkalinization to abnormal CF ASL. In addition, we found that increasing Ca2+ concentrations elevated ASL viscosity, in part, independently of pH. The results suggest that increasing pH, reducing Ca2+ concentration, and/or altering electrostatic interactions in ASL might benefit early CF. [ABSTRACT FROM AUTHOR]

Carcinomas are common in humans but rare among closely related "great apes." Plausible explanations, including human-specific genomic alterations affecting the biology of sialic acids, are proposed, but causality remains unproven. Here, an integrated evolutionary genetics-phenome-transcriptome approach studied the role of SIGLEC12 gene (encoding Siglec-XII) in epithelial transformation and cancer. Exogenous expression of the protein in cell lines and genetically engineered mice recapitulated approximately 30% of the human population in whom the protein is expressed in a form that cannot bind ligand because of a fixed, homozygous, human-universal missense mutation. Siglec-XII-null cells/mice recapitulated the remaining approximately 70% of the human population in whom an additional polymorphic frameshift mutation eliminates the entire protein. Siglec-XII expression drove several pro-oncogenic phenotypes in cell lines and increased tumor burden in mice challenged with chemical carcinogen and inflammation. Transcriptomic studies yielded a 29-gene signature of Siglec-XII-positive disease and when used as a computational tool for navigating human data sets, pinpointed with surprising precision that SIGLEC12 expression (model) recapitulates a very specific type of colorectal carcinomas (disease) that is associated with mismatch-repair defects and inflammation, disproportionately affects European Americans, and carries a favorable prognosis. They revealed a hitherto-unknown evolutionary genetic mechanism for an ethnic/environmental predisposition of carcinogenesis.