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抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Recent data have expanded the concept that inflammation is a critical component of tumour progression. Many cancers arise from sites of infection, chronic irritation and inflammation. It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration. In addition, tumour cells have co-opted some of the signalling molecules of the innate immune system, such as selectins, chemokines and their receptors for invasion, migration and metastasis. These insights are fostering new anti-inflammatory therapeutic approaches to cancer development.

Inflammation and cancer

Statistical method for testing the neutral mutation hypothesis by DNA polymorphism.

Integrins: versatility, modulation, and signaling in cell adhesion.

Heparin in Cancer: Role of Selectin Interactions

/pdf/omics-account-for-the-dark-matter-of-biology-3r4x6df8dd.pdf

Omics: Account for the 'dark matter' of biology.

It was six men of Indostan

To learning much inclined,

Who went to see the Elephant

(Though all of them were blind),

That each by observation

Might satisfy his mind… .

—John Godfrey Saxe, based on an Indian fable

https://www.pnas.org/content/pnas/99/2/543.full.pdf

Six blind men and the elephant--the many faces of heparan sulfate.

In the preceding article (Manzi,A.E., Norgard-Sumnicht,K., Argade,S., Marth,J.D., van Halbeek,H. and Varki.A. [2000] GLYCOBIOLOGY:, 10, 669-688), we reported a comprehensive approach for the extraction, fractionation, and isolation of all of the major classes of sugar chains (glycans) from vertebrate tissues. Here we apply this "Glycan Isolation Protocol" to a variety of cultured mammalian cell lines, including two wild-type Chinese hamster ovary (CHO) cell lines and some of their genetically modified variants that were predicted or known to have defined abnormalities in the biosynthesis of one or more classes of glycans. We also use this approach to characterize clone 489, a new derivative of the GAG-deficient CHO clone pgsA-745, in which sulfation has been restored by transfection of a wild-type CHO cDNA library. By metabolically labeling the cell lines with [6-(3)H]glucosamine we were able to monitor the recovery of all major classes of glycans. The results allow us to reach several conclusions: first, the protocol described in the preceding paper is further validated by finding good recovery of total radioactivity and appropriate distribution of label in the correct glycan classes in the fractions from a variety of cell lines; second, the amount of radioactivity recovered in free glycosylphosphatidylinositol (GPI) lipids is remarkably high when compared to that found in GPI anchors, with the former being the dominant form in some cells; third, cells with known genetic mutations in specific glycosylation pathways are shown to have the expected changes in the distribution of recovered radioactivity in the appropriate fractions; fourth, the N- and O- glycans recovered via the protocol are of adequate quality to demonstrate marked differences in their structural profiles and/or content; fifth, the protocol can pick up unexpected differences of glycan classes not predicted to be affected by the primary defect; finally, the reappearance of sulfation in the novel clone 489 is not due to restoration of GAG sulfation, but rather due to the new expression of sulfation in the fraction enriched in N- and O-linked glycopeptides. These results demonstrate the power of this comprehensive approach for the concurrent exploration and profiling of the different major classes of glycans in cells.

/pdf/exploring-the-outcome-of-genetic-modifications-of-2zyu51o67y.pdf

Exploring the outcome of genetic modifications of glycosylation in cultured cell lines by concurrent isolation of the major classes of vertebrate glycans

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.

/pdf/evolutionary-conservation-of-human-ketodeoxynonulosonic-acid-3vzdftdz5o.pdf

Ajit Varki

Papers

Heparin in Cancer: Role of Selectin Interactions

Omics: Account for the 'dark matter' of biology.

Six blind men and the elephant--the many faces of heparan sulfate.

Exploring the outcome of genetic modifications of glycosylation in cultured cell lines by concurrent isolation of the major classes of vertebrate glycans

Evolutionary conservation of human ketodeoxynonulosonic acid production is independent of sialoglycan biosynthesis.