Genetic Signatures for \u3cem\u3eHelicobacter pylori\u3c/em\u3e Strains of West African Origin

Helicobacter pylori is a genetically diverse bacterial species that colonizes the stomach in about half of the human population. Most persons colonized by H. pylori remain asymptomatic, but the presence of this organism is a risk factor for gastric cancer. Multiple populations and subpopulations of H. pylori with distinct geographic distributions are recognized. Genetic differences among these populations might be a factor underlying geographic variation in gastric cancer incidence. Relatively little is known about the genomic features of African H. pylori strains compared to other populations of strains. In this study, we first analyzed the genomes of H. pylori strains from seven globally distributed populations or subpopulations and identified encoded proteins that exhibited the highest levels of sequence divergence. These included secreted proteins, an LPS glycosyltransferase, fucosyltransferases, proteins involved in molybdopterin biosynthesis, and Clp protease adaptor (ClpS). Among proteins encoded by the cag pathogenicity island, CagA and CagQ exhibited the highest levels of sequence diversity. We then identified proteins in strains of Western African origin (classified as hspWAfrica by MLST analysis) with sequences that were highly divergent compared to those in other populations of strains. These included ATP-dependent Clp protease, ClpS, and proteins of unknown function. Three of the divergent proteins sequences identified in West African strains were characterized by distinct insertions or deletions up to 8 amino acids in length. These polymorphisms in rapidly evolving proteins represent robust genetic signatures for H. pylori strains of West African origin

Stimulating TAM-mediated anti-tumor immunity with mannose-decorated nanoparticles in ovarian cancer

BACKGROUND: Current cancer immunotherapies have made tremendous impacts but generally lack high response rates, especially in ovarian cancer. New therapies are needed to provide increased benefits. One understudied approach is to target the large population of immunosuppressive tumor-associated macrophages (TAMs). Using inducible transgenic mice, we recently reported that upregulating nuclear factor-kappaB (NF-κB) signaling in TAMs promotes the M1, anti-tumor phenotype and limits ovarian cancer progression. We also developed a mannose-decorated polymeric nanoparticle system (MnNPs) to preferentially deliver siRNA payloads to M2, pro-tumor macrophages in vitro. In this study, we tested a translational strategy to repolarize ovarian TAMs via MnNPs loaded with siRNA targeting the inhibitor of NF-κB alpha (IκBα) using mouse models of ovarian cancer. METHODS: We evaluated treatment with MnNPs loaded with IκBα siRNA (IκBα-MnNPs) or scrambled siRNA in syngeneic ovarian cancer models. ID8 tumors in C57Bl/6 mice were used to evaluate consecutive-day treatment of late-stage disease while TBR5 tumors in FVB mice were used to evaluate repetitive treatments in a faster-developing disease model. MnNPs were evaluated for biodistribution and therapeutic efficacy in both models. RESULTS: Stimulation of NF-κB activity and repolarization to an M1 phenotype via IκBα-MnNP treatment was confirmed using cultured luciferase-reporter macrophages. Delivery of MnNPs with fluorescent payloads (Cy5-MnNPs) to macrophages in the solid tumors and ascites was confirmed in both tumor models. A three consecutive-day treatment of IκBα-MnNPs in the ID8 model validated a shift towards M1 macrophage polarization in vivo. A clear therapeutic effect was observed with biweekly treatments over 2-3 weeks in the TBR5 model where significantly reduced tumor burden was accompanied by changes in immune cell composition, indicative of reduced immunosuppressive tumor microenvironment. No evidence of toxicity associated with MnNP treatment was observed in either model. CONCLUSIONS: In mouse models of ovarian cancer, MnNPs were preferentially associated with macrophages in ascites fluid and solid tumors. Evidence of macrophage repolarization, increased inflammatory cues, and reduced tumor burden in IκBα-MnNP-treated mice indicate beneficial outcomes in models of established disease. We have provided evidence of a targeted, TAM-directed approach to increase anti-tumor immunity in ovarian cancer with strong translational potential for future clinical studies

Generalization of Signal Point Target Code

Detecting and correcting errors occurring in the transmitted data through a channel is a task of great importance in digital communication. In Error Correction Coding (ECC), some redundant data is added with the original data while transmitting. By exploiting the properties of the redundant data, the errors occurring in the data from the transmission can be detected and corrected. In this thesis, a new coding algorithm named Signal Point Target Code has been studied and various properties of the proposed code have been extended. Signal Point Target Code (SPTC) uses a predefined shape within a given signal constellation to generate a parity symbol. In this thesis, the relation between the employed shape and the performance of the proposed code have been studied and an extension of the SPTC are presented. This research presents simulation results to compare the performances of the proposed codes. The results have been simulated using different programming languages, and a comparison between those programming languages is provided. The performance of the codes are analyzed and possible future research areas have been indicated

Sequence alignments of three proteins encoded by strains of diverse geographic origins.

<p>A) Amino acid sequence alignment of a portion of the translated gene region of A) HP0408, B) HP1051, and C) HP1053 in a comparison of seven, globally distributed strains. The HP0408 alignment corresponds to the amino-terminus, and the other two alignments correspond to internal sequences.</p

Examples of proteins that exhibit high levels of sequence diversity among geographically dispersed populations of <i>H</i>. <i>pylori</i>.

<p>Examples of proteins that exhibit high levels of sequence diversity among geographically dispersed populations of <i>H</i>. <i>pylori</i>.</p

Sequence alignments of three proteins encoded by strains of diverse geographic origins.

<p>A) Amino acid sequence alignment of a portion of the translated gene region of A) HP0408, B) HP1051, and C) HP1053 in a comparison of seven, globally distributed strains. The HP0408 alignment corresponds to the amino-terminus, and the other two alignments correspond to internal sequences.</p

Sequence diversity among <i>cag</i> pathogenicity island proteins from African and European strains.

<p>Sequence diversity among <i>cag</i> pathogenicity island proteins from African and European strains.</p

Proteins that exhibit high levels of sequence diversity when comparing hspWAfrica and hpEurope strains.

<p>Proteins that exhibit high levels of sequence diversity when comparing hspWAfrica and hpEurope strains.</p

Signatures of positive selection in genes encoding proteins with divergent sequences.

<p>Signatures of positive selection in genes encoding proteins with divergent sequences.</p

Sequence alignments of three proteins exhibiting high levels of sequence divergence when comparing hpEurope and hspWAfrica strains.

<p>A) Amino acid sequence alignment of proteins encoded by A) HP0408, B) HP1051, and C) HP1053. The HP0408 alignment corresponds to the amino-terminus, and the other two alignments correspond to internal sequences. For each protein, the first eight lines are sequences from hpEurope strains and the last eight lines are sequences from hspWAfrica strains.</p