Cascadia Journal of Biomedical Research - Articles

Birzu, G., Subrahmaniam Muralidharan, H., Goudeau, D., Malmstrom, R., Fisher, D., Bhaya, D.

Bacterial species often undergo rampant recombination yet maintain cohesive genomic identity. Ecological differences can generate recombination barriers between species and sustain genomic clusters in the short term. But can these forces prevent genomic mixing during long-term coevolution? Cyanobacteria in Yellowstone hot springs comprise several diverse species that have coevolved for hundreds of thousands of years, providing a rare natural experiment. By analyzing more than 300 single-cell genomes, we show that despite each species forming a distinct genomic cluster, much of the diversity within species is the result of hybridization driven by selection, which has mixed their ancestral genotypes. This widespread mixing is contrary to the prevailing view that ecological barriers can maintain cohesive bacterial species and highlights the importance of hybridization as a source of genomic diversity.

He, J., Wang, K., Shu, W., Hu, W., Duan, J.

Objectives: To evaluate the efficacy of intensive care unit ventilators versus dedicated noninvasive ventilators when used for noninvasive ventilation. Methods: This was a secondary analysis of data from a multicenter prospective observational study. Eligible patients were recruited from 17 hospitals in China between September 2017 and September 2021. Inclusion criteria were restricted to those receiving noninvasive ventilation for acute hypoxemic respiratory failure. The type of ventilator used was determined at the discretion of the treating clinicians. The primary objective was to compare clinical outcomes between intensive care unit ventilators and dedicated noninvasive ventilation ventilators for noninvasive ventilation delivery. Key outcomes included noninvasive ventilation failure rate, 28-day mortality, intensive care unit length of stay, and hospital length of stay. Results: A total of 2054 patients were enrolled, with 5% (n = 103) receiving noninvasive ventilation via intensive care unit ventilators and 95% (n = 1951) via dedicated noninvasive ventilation ventilators. No significant difference was observed in the overall noninvasive ventilation failure rate between the two groups (46% versus 38%, p = 0.15). However, the median time from noninvasive ventilation initiation to endotracheal intubation was shorter in the intensive care unit ventilator group (9 h, interquartile range: 3–25) compared with the dedicated noninvasive ventilation ventilator group (21 h, interquartile range: 6–65). The 28-day cumulative incidence of noninvasive ventilation failure was significantly higher in the intensive care unit ventilator group (log-rank test p = 0.01; crude hazard ratio = 1.43, 95% confidence interval: 1.06–1.91; adjusted hazard ratio = 1.41, 95% confidence interval: 1.04–1.93). No significant difference was found in 28-day mortality between the groups (16% versus 17%, p = 0.79). The 28-day cumulative incidence of mortality also did not differ (log-rank test p = 0.65; crude hazard ratio = 0.84, 95% confidence interval: 0.52–1.34; adjusted hazard ratio = 0.95, 95% confidence interval: 0.58–1.55). Conclusions: The use of intensive care unit ventilators for noninvasive ventilation is uncommon in China. Based on low-level evidence, intensive care unit ventilators are not associated with a difference in mortality compared with dedicated noninvasive ventilation ventilators, but are linked to earlier endotracheal intubation.

Salminen, S., Collado, M., Endo, A., Hill, C., Lebeer, S., Quigley, E., Sanders, M., Shamir, R., Swann, J., Szajewska, H., Vinderola, G.

In 2019, the International Scientific Association for Probiotics and Prebiotics (ISAPP) convened a panel of experts specializing in nutrition, microbial physiology, gastroenterology, paediatrics, food science and microbiology to review the definition and scope of postbiotics. The term ‘postbiotics’ is increasingly found in the scientific literature and on commercial products, yet is inconsistently used and lacks a clear definition. The purpose of this panel was to consider the scientific, commercial and regulatory parameters encompassing this emerging term, propose a useful definition and thereby establish a foundation for future developments. The panel defined a postbiotic as a “preparation of inanimate microorganisms and/or their components that confers a health benefit on the host”. Effective postbiotics must contain inactivated microbial cells or cell components, with or without metabolites, that contribute to observed health benefits. The panel also discussed existing evidence of health-promoting effects of postbiotics, potential mechanisms of action, levels of evidence required to meet the stated definition, safety and implications for stakeholders. The panel determined that a definition of postbiotics is useful so that scientists, clinical triallists, industry, regulators and consumers have common ground for future activity in this area. A generally accepted definition will hopefully lead to regulatory clarity and promote innovation and the development of new postbiotic products.

Wen, H., Zheng, S., Zhu, X., Wang, L., Chen, D.

Renal cell carcinoma (RCC) is a highly vascularized and immunogenic malignancy with a complex tumor microenvironment (TME) that shapes disease progression and therapeutic resistance. Despite advances in immune checkpoint inhibitors (ICIs) and targeted therapies, clinical responses remain heterogeneous, underscoring the need for a deeper understanding of RCC immunobiology. This review comprehensively examines the immunosuppressive TME of RCC, emphasizing the roles of cytotoxic and immunosuppressive immune cells, carcinoma-associated fibroblasts (CAFs), abnormal vasculature, and extracellular matrix (ECM) remodeling in fostering immune evasion. This review summarized emerging biomarkers—including PD-L1 expression, tumor mutational burden (TMB), gene mutations, and immune-based subtypes—that may predict ICI response. Furthermore, we evaluate current immunotherapeutic strategies, such as ICIs, combination therapies, and novel approaches targeting immunosuppressive cells and metabolic pathways. While combination therapies have improved outcomes, challenges like toxicity and resistance persist, necessitating biomarker-driven patient stratification and optimized treatment sequencing. Future directions should focus on deciphering TME heterogeneity and developing precision immunotherapy strategies to enhance clinical efficacy in RCC.

Birzu, G., Subrahmaniam Muralidharan, H., Goudeau, D., Malmstrom, R., Fisher, D., Bhaya, D.

Bacterial species often undergo rampant recombination yet maintain cohesive genomic identity. Ecological differences can generate recombination barriers between species and sustain genomic clusters in the short term. But can these forces prevent genomic mixing during long-term coevolution? Cyanobacteria in Yellowstone hot springs comprise several diverse species that have coevolved for hundreds of thousands of years, providing a rare natural experiment. By analyzing more than 300 single-cell genomes, we show that despite each species forming a distinct genomic cluster, much of the diversity within species is the result of hybridization driven by selection, which has mixed their ancestral genotypes. This widespread mixing is contrary to the prevailing view that ecological barriers can maintain cohesive bacterial species and highlights the importance of hybridization as a source of genomic diversity.

Jin, S., Guerrero-Juarez, C., Zhang, L., Chang, I., Ramos, R., Kuan, C., Myung, P., Plikus, M., Nie, Q.

Understanding global communications among cells requires accurate representation of cell-cell signaling links and effective systems-level analyses of those links. We construct a database of interactions among ligands, receptors and their cofactors that accurately represent known heteromeric molecular complexes. We then develop CellChat, a tool that is able to quantitatively infer and analyze intercellular communication networks from single-cell RNA-sequencing (scRNA-seq) data. CellChat predicts major signaling inputs and outputs for cells and how those cells and signals coordinate for functions using network analysis and pattern recognition approaches. Through manifold learning and quantitative contrasts, CellChat classifies signaling pathways and delineates conserved and context-specific pathways across different datasets. Applying CellChat to mouse and human skin datasets shows its ability to extract complex signaling patterns. Our versatile and easy-to-use toolkit CellChat and a web-based Explorer (http://www.cellchat.org/) will help discover novel intercellular communications and build cell-cell communication atlases in diverse tissues.

Nair, V., Kim, H., Johansson, L., Mukherjee, S., Mwangi, A.

Renal cell carcinoma (RCC) is a highly vascularized and immunogenic malignancy with a complex tumor microenvironment (TME) that shapes disease progression and therapeutic resistance. Despite advances in immune checkpoint inhibitors (ICIs) and targeted therapies, clinical responses remain heterogeneous, underscoring the need for a deeper understanding of RCC immunobiology. This review comprehensively examines the immunosuppressive TME of RCC, emphasizing the roles of cytotoxic and immunosuppressive immune cells, carcinoma-associated fibroblasts (CAFs), abnormal vasculature, and extracellular matrix (ECM) remodeling in fostering immune evasion. This review summarized emerging biomarkers—including PD-L1 expression, tumor mutational burden (TMB), gene mutations, and immune-based subtypes—that may predict ICI response. Furthermore, we evaluate current immunotherapeutic strategies, such as ICIs, combination therapies, and novel approaches targeting immunosuppressive cells and metabolic pathways. While combination therapies have improved outcomes, challenges like toxicity and resistance persist, necessitating biomarker-driven patient stratification and optimized treatment sequencing. Future directions should focus on deciphering TME heterogeneity and developing precision immunotherapy strategies to enhance clinical efficacy in RCC.

McQuarrie, D., Stephens, F., Ferguson, A., Arnold, R., Civetta, A., Soller, M.

Seminal fluid proteins (Sfps) are essential for reproductive success and evolve fast on average, possibly driven by post-copulatory sexual selection (PCSS) originating from sperm competition and cryptic female choice. Counterintuitively, however, the coding region only in few Sfps evolves adaptively. Hence, additional genomic and functional factors must play a role in Sfp evolution independent of the protein coding region. To shed light on drivers of Sfp evolution we focus on those Sfps predominantly expressed in male accessory glands of Drosophila to examine their evolution in the tissue which produces the majority of Sfps. Unlike the testis, the accessory glands are known to develop normally in hybrids, allowing us to control for cellular environment differences arising during speciation. Here, we identify hotspots of rapid evolution in accessory gland protein genes (Acp) promoters, driven by base changes and insertions/deletions (indels). We further show that changes in promoter sequences are accompanied by gene expression divergence among closely related species. Using hybrids, we demonstrate that species-specific expression divergence is maintained for some Acps, while others exhibit dominance of one allele. These results indicate that regulatory evolution, rather than genome background variation, drives Acp expression changes and promotes their rapid evolution.

McQuarrie, D., Stephens, F., Ferguson, A., Arnold, R., Civetta, A., Soller, M.

Seminal fluid proteins (Sfps) are essential for reproductive success and evolve fast on average, possibly driven by post-copulatory sexual selection (PCSS) originating from sperm competition and cryptic female choice. Counterintuitively, however, the coding region only in few Sfps evolves adaptively. Hence, additional genomic and functional factors must play a role in Sfp evolution independent of the protein coding region. To shed light on drivers of Sfp evolution we focus on those Sfps predominantly expressed in male accessory glands of Drosophila to examine their evolution in the tissue which produces the majority of Sfps. Unlike the testis, the accessory glands are known to develop normally in hybrids, allowing us to control for cellular environment differences arising during speciation. Here, we identify hotspots of rapid evolution in accessory gland protein genes (Acp) promoters, driven by base changes and insertions/deletions (indels). We further show that changes in promoter sequences are accompanied by gene expression divergence among closely related species. Using hybrids, we demonstrate that species-specific expression divergence is maintained for some Acps, while others exhibit dominance of one allele. These results indicate that regulatory evolution, rather than genome background variation, drives Acp expression changes and promotes their rapid evolution.