Biology subjects

Waller, A.

Publications and source records attributed to Waller, A..

5 recordsLinked to original sources

bioRxiv2026

Pulsed Field Ablation Enables Stromal Manipulation and Tumor Reduction in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense desmoplastic microenvironment that promotes therapeutic resistance and disease progression. Here, we investigated the impact of pulsed field ablation (PFA), a non-thermal electroporation-based therapy, on tumor and stromal remodeling in a syngeneic murine PDAC model. PFA induced rapid apoptotic and necrotic tumor cell death, transient neutrophil infiltration, and durable suppression of tumor growth. Single-cell RNA sequencing following repeated PFA treatments revealed enrichment of a classical secretory tumor cell state associated with complement and stress-response pathways and reduced epithelial-to-mesenchymal transition (EMT) programs. Although overall immune composition was largely unchanged, PFA markedly remodeled the stromal compartment, decreasing SMA-positive activation and shifting cancer-associated fibroblasts (CAFs) from tumor-promoting myofibroblastic CAFs toward Dpp4+ complement-secreting CAFs. This transition was accompanied by increased IL-1 signaling potential, reduced Tgfb1 expression, and diminished tumor cell TGF-{beta} response signatures. Serial PFA treatments further suppressed EMT-associated programs, identifying stromal reprogramming as a potential mechanism through which PFA enhances tumor control.

bioengineering↗

bioRxiv2025

Phylodynamics and genome-wide association studies reveal the expansion of modern Streptococcus canis in Germany

Streptoccocus canis is a leading canine pathogen causing 22.4% of canine streptococcal infections. However, knowledge of factors contributing to S. canis expansion is limited. This study uses population genetics to structure a S. canis dataset of 585 isolates and identify genetic markers contributing to the success of each dominant lineage. The dataset is composed of canine, feline and bovine isolates primarily from Germany collected between the years 1996 and 2021. We performed Multi-Locus Sequence Typing (MLST) for an initial analysis and clustered the population with fastBAPS based on the whole genome. Dated phylogenies were inferred with BEAST and Genome-Wide Association Studies (GWAS) were conducted with Scoary. MLST showed that in Germany there are two dominant groups of canine S. canis, ST43 (n= 75) and ST9 (n= 51), which were grouped into BAPS-6 and BAPS-5, respectively. The BAPS-6 cluster emerged as early as 1988 with major expansion starting around 2010. We showed via GWAS that this cluster is associated with a putative Streptococcus anginosus derived integrative and conjugative element carrying a putative cysteine protease. Furthermore, the BAPS-5 cluster emerged around 1786 with a bovine/feline subcluster appearing around 1879. This subcluster is associated with a variant of the streptococcal lac operon, which appears to have resulted from an exchange with Streptococcus dysgalactiae. We present the largest population genetics study to date for S. canis where we show that its expansion is associated with genetic exchange with other streptococcal species leading to increased pathogenic potential (BAPS-6) or host adaptation (BAPS-5). ImportanceStreptococcus canis is a bacterium which poses considerable threat to the health of dogs through superficial infections. Current research could benefit from understanding the reasons for its expansion and spread into other hosts. We looked at the genomes of 585 S. canis isolates collected during a 25-year period and identified which parts of the population were the most successful. With powerful statistical methods, we found that two groups of S. canis were the most effective: a canine group which had become more pathogenic by acquiring DNA from Streptococcus anginosus, and another group which spread from dogs into cats and cows by acquiring genetic material for lactose consumption from Streptococcus dysgalactiae. For the first time, we link the expansion of major S. canis groups to genetic exchange events with closely related streptococcal species to understand S. canis evolution and spread.

microbiology↗

bioRxiv2020

TIGA: Target illumination GWAS analytics

Genome wide association studies (GWAS) can reveal important genotype-phenotype associations, however, data quality and interpretability issues must be addressed. For drug discovery scientists seeking to prioritize targets based on the available evidence, these issues go beyond the single study. Here, we describe rational ranking, filtering and interpretation of inferred gene-trait associations and data aggregation across studies by leveraging existing curation and harmonization efforts. Each gene-trait association is evaluated for confidence, with scores derived solely from aggregated statistics, linking a protein-coding gene and phenotype. We propose a method for assessing confidence in gene-trait associations from evidence aggregated across studies, including a bibliometric assessment of scientific consensus based on the iCite Relative Citation Ratio, and meanRank scores, to aggregate multivariate evidence. This method, intended for drug target hypothesis generation, scoring and ranking, has been implemented as an analytical pipeline, available as open source, with public datasets of results, and a web application designed for usability by drug discovery scientists, at https://unmtid-shinyapps.net/tiga/.

bioinformatics↗

bioRxiv2018

Gene fitness landscape of group A streptococcus during necrotizing myositis

Necrotizing fasciitis and myositis are devastating infections characterized by high mortality. Group A streptococcus (GAS) is a common cause of these infections, but the molecular pathogenesis is poorly understood. We report a genome-wide analysis using serotype M1 and M28 strains that identified novel GAS genes contributing to necrotizing myositis in nonhuman primates (NHP), a clinically relevant model. Using transposon directed insertion-site sequencing (TraDIS) we identified 126 and 116 GAS genes required for infection by serotype M1 and M28 organisms, respectively. For both M1 and M28 strains, more than 25% of the GAS genes required for necrotizing myositis encode known or putative transporters. Thirteen GAS transporters contributed to both M1 and M28 strain fitness in NHP myositis, including putative importers for amino acids, carbohydrates, and vitamins, and exporters for toxins, quorum sensing peptides, and uncharacterized molecules. Targeted deletion of genes encoding five transporters confirmed that each isogenic mutant strain was significantly impaired in causing necrotizing myositis in NHPs. qRT-PCR analysis showed that these five genes are expressed in infected NHP and human skeletal muscle. Certain substrate-binding lipoproteins of these transporters, such as Spy0271 and Spy1728, were previously documented to be surface-exposed, suggesting that our findings have translational research implications.

microbiology↗

bioRxiv2017

Novel genes required for the fitness of Streptococcus pyogenes in human saliva

Streptococcus pyogenes (group A Streptococcus, or GAS) causes 600 million cases of pharyngitis each year. Despite this considerable disease burden, the molecular mechanisms used by GAS to infect, cause clinical pharyngitis, and persist in the human oropharynx are poorly understood. Saliva is ubiquitous in the human oropharynx and is the first material GAS encounters in the upper respiratory tract. Thus, a fuller understanding of how GAS survives and proliferates in saliva may provide valuable insights into the molecular mechanisms at work in the human oropharynx. We generated a highly saturated transposon insertion mutant library in serotype M1 strain MGAS2221, a strain genetically representative of a pandemic clone that arose in the 1980s and spread globally. The transposon mutant library was exposed to human saliva to screen for GAS genes required for wild-type fitness in this clinically relevant fluid. Using transposon-directed insertion site sequencing (TraDIS), we identified 92 genes required for GAS fitness in saliva. The more prevalent categories represented are genes involved in carbohydrate transport/metabolism, amino acid transport/metabolism, and inorganic ion transport/metabolism. Using six isogenic mutant strains, we confirmed that each of the mutants are significantly impaired for growth or persistence in human saliva ex vivo. Mutants with an inactivated spy0644 (sptA) or spy0646 (sptC) gene have especially severe persistence defects. This study is the first use of TraDIS to study bacterial fitness in human saliva. The new information we obtained is valuable for future translational maneuvers designed to prevent or treat human GAS infections.\n\nIMPORTANCEThe human bacterial pathogen Streptococcus pyogenes (group A streptococcus, GAS) causes more than 600 million cases of pharyngitis annually worldwide, 15 million of which occur in the United States. The human oropharynx is the primary anatomic site for GAS colonization and infection, and saliva is the first material encountered. Using a genome-wide transposon mutant screen, we identified 92 GAS genes required for wild-type fitness in human saliva. Many of the identified genes are involved in carbohydrate transport/metabolism, amino acid transport/metabolism, and inorganic ion transport/metabolism. The new information is potentially valuable for developing novel GAS therapeutics and vaccine research.

microbiology↗