Biology subjects

Dogan, O.

Publications and source records attributed to Dogan, O..

3 recordsLinked to original sources

bioRxiv2021

Protein scaffold-based multimerization of soluble ACE2 efficiently blocks SARS-CoV-2 infection in vitro

Soluble ACE2 (sACE2) decoy receptors are promising agents to inhibit SARS-CoV-2, as their efficiency is less likely to be affected by common escape mutations in viral proteins. However, their success may be limited by their relatively poor potency. To address this challenge, we developed a large decoy library of sACE2 fusion proteins, generated with several protease inhibitors or multimerization tags. Among these decoys, multimeric sACE2 consisting of SunTag or MoonTag systems, which were originally utilized for signal amplification or gene activation systems, were extremely effective in neutralizing SARS-CoV-2 in pseudoviral systems and in clinical isolates. These novel sACE2 fusion proteins exhibited greater than 100-fold SARS-CoV-2 neutralization efficiency, compared to monomeric sACE2. SunTag or MoonTag in combination with a more potent version of sACE2, which has multiple point mutations for greater binding (v1), achieved near complete neutralization at a sub-nanomolar range, comparable with clinical monoclonal antibodies. Pseudoviruses bearing mutant versions of Spike, alpha, beta, gamma or delta variants, were also neutralized efficiently with SunTag or MoonTag fused sACE2(v1). Finally, therapeutic treatment of sACE2(v1)-MoonTag provided protection against SARS-CoV-2 infection in an in vivo mouse model. Overall, we suggest that the superior activity of the sACE2-SunTag or sACE2-MoonTag fusions is due to the greater occupancy of the multimeric sACE2 receptors on Spike protein as compared to monomeric sACE2. Therefore, these highly potent multimeric sACE2 decoy receptors may offer a promising treatment approach against SARS-CoV-2 infections. One Sentence SummaryMultimerization of sACE2 markedly enhanced the neutralization of SARS-CoV-2 by blocking multiple viral spike proteins simultaneously.

molecular biology↗

bioRxiv2020

The de novo genome of the "Spanish" slug Arion vulgaris Moquin-Tandon, 1855 (Gastropoda: Panpulmonata): massive expansion of transposable elements in a major pest species

BackgroundThe "Spanish" slug, Arion vulgaris Moquin-Tandon, 1855, is considered to be among the 100 worst pest species in Europe. It is common and invasive to at least northern and eastern parts of Europe, probably benefitting from climate change and the modern human lifestyle. The origin and expansion of this species, the mechanisms behind its outstanding adaptive success and ability to outcompete other land slugs are worth to be explored on a genomic level. However, a high-quality chromosome-level genome is still lacking. FindingsThe final assembly of A. vulgaris was obtained by combining short reads, linked reads, Nanopore long reads, and Hi-C data. The genome assembly size is 1.54 Gb with a contig N50 length of 8.6 Mb. We found a recent expansion of transposable elements (TEs) which results in repetitive sequences accounting for more than 75% of the A. vulgaris genome, which is the highest among all known gastropod species. We identified 32,518 protein coding genes, and 2,763 species specific genes were functionally enriched in response to stimuli, nervous system and reproduction. With 1,237 single-copy orthologs from A. vulgaris and other related mollusks with whole-genome data available, we reconstructed the phylogenetic relationships of gastropods and estimated the divergence time of stylommatophoran land snails (Achatina) and Arion slugs at around 126 million years ago, and confirmed the whole genome duplication event shared by them. ConclusionsTo our knowledge, the A. vulgaris genome is the first land slug genome assembly published to date. The high-quality genomic data will provide valuable genetic resources for further phylogeographic studies of A. vulgaris origin and expansion, invasiveness, as well as molluscan aquatic-land transition and shell formation.

genomics↗

bioRxiv2019

The role of iron uptake systems in the pathogenesis of colistin-resistant hypervirulent K. pneumoniae infections

Here we proposed the hypothesis that hypervirulent colistin resistant K.pneumoniae (ColR-Kp) exhibit high number of virulence factors and have enhanced survival capacity against neutrophil activity.\n\nWe studied virulence genes of ColR-Kp isolates and neutrophil response in 142 patients with invasive infections.\n\nThe patients infected with hypervirulent ST101 and ST395 ColR-Kp had higher 30-day mortality (58%, p=0.005 and 75%, p=0.003, respectively. The yersiniabactin biosynthesis gene (ybtS) and ferric uptake operon associated gene (kfu) were significantly higher in ST101 (99%, p=<0.001) and in ST395 (94%, p<0.012). Being in ICU (OR: 7.9; CI: 1.43-55.98; p=0.024), kfu (OR:27.0; CI:5.67-179.65; p<0.001) and ST101 (OR: 17.2; CI: 2.45-350.40; p=0.01) were found to be predictors of 30-day mortality. The uptake of kfu+-ybtS+ ColR-Kp by neutrophils was significantly higher than kfu--ybtS- ColR-Kp (78% vs 65%, p<0.001). However, kfu+-ybtS+ ColR-Kp were more resistant to the killing activity of neutrophils than negative ones (7.90 vs 4.22; p=0.001). The kfu+-ybtS+ ColR-Kp stimulated excessive NET formation while the NETs against kfu--ybtS- ColR-Kp were weak and rare.\n\nIron uptake systems enhance successful survival of K.pneumoniae against neutrophil phagocytic defense, and stimulate excessive NET formation. The drugs targeted to iron uptake systems would be a promising approach for treatment of hypervirulent K.pneumoniae infections.

microbiology↗