다중혈관 관상동맥 환자에서 y-문합을 이용하여 양쪽 내흉동맥만을 사용한 우회술의 조기 성적

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.

Bacterial vaginosis (BV) is a condition of the vaginal microbiome in which there are lower levels of “healthy” Lactobacillus species and an outgrowth of diverse anaerobic bacteria. BV is associated with increased risk of infection by the bacterium Neisseria gonorrhoeae - the causative agent of gonorrhea. Here we test if one known facet of BV - the presence of bacterial cytolysins – leads to the mobilization of specific intracellular contents that aid in gonococcal virulence. We cloned and expressed recombinant vaginolysin (VLY), a cytolysin produced by the BV-associated bacterium Gardnerella, verifying that it liberates the contents of red blood cells and cervical epithelial (HeLa) cells while vector control preparations made in parallel did not. We tested if VLY mediates a well-known virulence mechanism of gonococcus – the molecular mimicry of host glycans. To evade host immunity, N. gonorrhoeae caps its surface lipooligosaccharide (LOS) with α2-3-linked sialic acid. To do this, gonococci must scavenge an intermediate metabolite made and used inside host cells. Flow-cytometry based lectin-binding assays showed that, compared to controls, gonococci exposed to vaginolysin-liberated contents of HeLa cells displayed greater sialic acid capping of their LOS. This higher level of bacterial sialylation was accompanied by increased binding of the complement regulatory protein Factor H, and greater resistance to complement attack. Together these results suggest that cytolytic activities present during BV may enhance the ability of N. gonorrhoeae to capture intracellular metabolites and evade host immunity via glycan molecular mimicry.

/pdf/gardnerella-vaginolysin-potentiates-glycan-molecular-mimicry-2x1775gg.pdf

Gardnerella vaginolysin potentiates glycan molecular mimicry by Neisseria gonorrhoeae

User-friendly bioorthogonal reactions click to explore glycan functions in complex biological systems

Short Title: Preeclampsia Effects on Basal Plate Gene Expression

Vertebrate sialic acids (Sias) display much diversity in modifications, linkages and underlying glycans. Slide microarrays allow high-throughput analysis of sialoglycan-protein interactions. The preceding paper used ~150 structurally-defined sialyltrisaccharides with various Sias and modified forms at non-reducing ends, to compare pentameric sialoglycan-recognizing bacterial toxin B subunits. Unlike the poor correlation between B subunits and species phylogeny, there is stronger correlation with Sia types prominently expressed in susceptible species. Further supporting this pattern we report a B subunit(YenB) from Yersinia enterocolitica (broad host range) recognizing almost all sialoglycans in the microarray, including 4-O-acetylated-Sias not recognized by a Y.pestis orthologue(YpeB). Differential Sia-binding patterns were also observed with phylogenetically-related B subunits from Escherichia coli(SubB), Salmonella Typhi(PltB), S. Typhimurium(ArtB), extra-intestinal E. coli(EcPltB), Vibrio cholera(CtxB), and cholera family homologue of E. coli(EcxB). Given library size, data sorting and analysis posed a challenge. We devised a 9-digit code for trisaccharides with terminal Sias and underlying two monosaccharides assigned from the non-reducing end, with three digits assigning a monosaccharide, its modifications, and linkage. This code allows logical sorting, motif searching of results, and optimizes printing. While we developed the system for the >113,000 possible linear sialyltrisaccharides, we note that a biantennary N-glycan with two terminal sialoglycan trisaccharides could have >1010 potential combinations and a triantennary N-glycan with three terminal sequences, >1015 potential combinations. While all possibilities likely do not exist in nature, sialoglycans encode enormous diversity. Thus, while glycomic approaches address these challenges, naturally-occurring toxin B subunits are simpler tools to track the dynamic sialome in biological systems.

https://biorxiv.org/content/10.1101/2021.05.28.446191v1.full.pdf

Sialoglycan microarray encoding reveals differential sialoglycan binding of phylogenetically-related bacterial AB5 toxin B subunits

Late-onset Alzheimers Disease (LOAD) pathology is rare in our closest living evolutionary relatives (chimpanzees), which also express much lower microglial levels of CD33(Siglec-3)-a myelomonocytic receptor inhibiting innate immune reactivity by extracellular V-set domain recognition of sialic acid(Sia)-containing "self-associated molecular patterns" (SAMPs). We earlier showed that V-set domain-deficient CD33-variant allele, protective against LOAD, is derived and specific to hominin-lineage. We now report that CD33 also harbors multiple hominin-specific V-set domain mutations and explore selection forces that may have favored such genomic changes. N-glycolylneuraminic acid (Neu5Gc), the preferred Sia-ligand of ancestral CD33 is absent in humans, due to hominin-specific, fixed loss-of-function mutation in CMAH, which generates CMP-Neu5Gc from its precursor, CMP-N-acetylneuraminic acid (Neu5Ac). Extensive mutational analysis and MD-simulations indicate that fixed change in amino acid 21 of hominin V-set domain and conformational changes related to His45 corrected for Neu5Gc-loss by switching to Neu5Ac-recognition. Considering immune-evasive "molecular mimicry" of SAMPs by pathogens, we found that human-specific pathogens Neisseria gonorrhoeae and Group B Streptococcus (affecting fertility and fetuses/neonates respectively) selectively bind huCD33 and this binding is significantly impacted by amino acid 21 modification. Alongside LOAD-protective CD33 alleles, humans harbor additional, derived, population-universal, cognition-protective variants absent in "great ape" genomes. Interestingly, 11 of 13 SNPs in these human genes (including CD33), that protect the cognitive health of elderly populations, are not shared by genomes of archaic hominins: Neanderthals and Denisovans. Finally, we present a plausible evolutionary scenario to compile, correlate and comprehend existing knowledge about huCD33 evolution and suggest that grandmothering emerged in humans.

https://www.biorxiv.org/content/biorxiv/early/2021/11/26/2021.11.26.470088.full.pdf

Ajit Varki

Papers

Gardnerella vaginolysin potentiates glycan molecular mimicry by Neisseria gonorrhoeae

User-friendly bioorthogonal reactions click to explore glycan functions in complex biological systems

Short Title: Preeclampsia Effects on Basal Plate Gene Expression

Sialoglycan microarray encoding reveals differential sialoglycan binding of phylogenetically-related bacterial AB5 toxin B subunits

Evolution of Human-specific Alleles Protecting Cognitive Function of Grandmothers