A miRNA Host Response Signature Accurately Discriminates Acute Respiratory Infection Etiologies

Background: Acute respiratory infections (ARIs) are the leading indication for antibacterial prescriptions despite a viral etiology in the majority of cases. The lack of available diagnostics to discriminate viral and bacterial etiologies contributes to this discordance. Recent efforts have focused on the host response as a source for novel diagnostic targets although none have explored the ability of host-derived microRNAs (miRNA) to discriminate between these etiologies.Methods: In this study, we compared host-derived miRNAs and mRNAs from human H3N2 influenza challenge subjects to those from patients with Streptococcus pneumoniae pneumonia. Sparse logistic regression models were used to generate miRNA signatures diagnostic of ARI etiologies. Generalized linear modeling of mRNAs to identify differentially expressed (DE) genes allowed analysis of potential miRNA:mRNA relationships. High likelihood miRNA:mRNA interactions were examined using binding target prediction and negative correlation to further explore potential changes in pathway regulation in response to infection.Results: The resultant miRNA signatures were highly accurate in discriminating ARI etiologies. Mean accuracy was 100% [88.8–100; 95% Confidence Interval (CI)] in discriminating the healthy state from S. pneumoniae pneumonia and 91.3% (72.0–98.9; 95% CI) in discriminating S. pneumoniae pneumonia from influenza infection. Subsequent differential mRNA gene expression analysis revealed alterations in regulatory networks consistent with known biology including immune cell activation and host response to viral infection. Negative correlation network analysis of miRNA:mRNA interactions revealed connections to pathways with known immunobiology such as interferon regulation and MAP kinase signaling.Conclusion: We have developed novel human host-response miRNA signatures for bacterial and viral ARI etiologies. miRNA host response signatures reveal accurate discrimination between S. pneumoniae pneumonia and influenza etiologies for ARI and integrated analyses of the host-pathogen interface are consistent with expected biology. These results highlight the differential miRNA host response to bacterial and viral etiologies of ARI, offering new opportunities to distinguish these entities

Phylogeny-Aware Analysis of Metagenome Community Ecology Based on Matched Reference Genomes while Bypassing Taxonomy

We introduce the operational genomic unit (OGU) method, a metagenome analysis strategy that directly exploits sequence alignment hits to individual reference genomes as the minimum unit for assessing the diversity of microbial communities and their relevance to environmental factors. This approach is independent of taxonomic classification, granting the possibility of maximal resolution of community composition, and organizes features into an accurate hierarchy using a phylogenomic tree. The outputs are suitable for contemporary analytical protocols for community ecology, differential abundance, and supervised learning while supporting phylogenetic methods, such as UniFrac and phylofactorization, that are seldom applied to shotgun metagenomics despite being prevalent in 16S rRNA gene amplicon studies. As demonstrated in two real-world case studies, the OGU method produces biologically meaningful patterns from microbiome data sets. Such patterns further remain detectable at very low metagenomic sequencing depths. Compared with taxonomic unit-based analyses implemented in currently adopted metagenomics tools, and the analysis of 16S rRNA gene amplicon sequence variants, this method shows superiority in informing biologically relevant insights, including stronger correlation with body environment and host sex on the Human Microbiome Project data set and more accurate prediction of human age by the gut microbiomes of Finnish individuals included in the FINRISK 2002 cohort. We provide Woltka, a bioinformatics tool to implement this method, with full integration with the QIIME 2 package and the Qiita web platform, to facilitate adoption of the OGU method in future metagenomics studies. IMPORTANCE Shotgun metagenomics is a powerful, yet computationally challenging, technique compared to 16S rRNA gene amplicon sequencing for decoding the composition and structure of microbial communities. Current analyses of metagenomic data are primarily based on taxonomic classification, which is limited in feature resolution. To solve these challenges, we introduce operational genomic units (OGUs), which are the individual reference genomes derived from sequence alignment results, without further assigning them taxonomy. The OGU method advances current read-based metagenomics in two dimensions: (i) providing maximal resolution of community composition and (ii) permitting use of phylogeny-aware tools. Our analysis of real-world data sets shows that it is advantageous over currently adopted metagenomic analysis methods and the finest-grained 16S rRNA analysis methods in predicting biological traits. We thus propose the adoption of OGUs as an effective practice in metagenomic studies.Peer reviewe

Phylogeny-Aware Analysis of Metagenome Community Ecology Based on Matched Reference Genomes while Bypassing Taxonomy

We introduce the operational genomic unit (OGU) method, a metagenome analysis strategy that directly exploits sequence alignment hits to individual reference genomes as the minimum unit for assessing the diversity of microbial communities and their relevance to environmental factors. This approach is independent of taxonomic classification, granting the possibility of maximal resolution of community composition, and organizes features into an accurate hierarchy using a phylogenomic tree. The outputs are suitable for contemporary analytical protocols for community ecology, differential abundance, and supervised learning while supporting phylogenetic methods, such as UniFrac and phylofactorization, that are seldom applied to shotgun metagenomics despite being prevalent in 16S rRNA gene amplicon studies. As demonstrated in two real-world case studies, the OGU method produces biologically meaningful patterns from microbiome data sets. Such patterns further remain detectable at very low metagenomic sequencing depths. Compared with taxonomic unit-based analyses implemented in currently adopted metagenomics tools, and the analysis of 16S rRNA gene amplicon sequence variants, this method shows superiority in informing biologically relevant insights, including stronger correlation with body environment and host sex on the Human Microbiome Project data set and more accurate prediction of human age by the gut microbiomes of Finnish individuals included in the FINRISK 2002 cohort. We provide Woltka, a bioinformatics tool to implement this method, with full integration with the QIIME 2 package and the Qiita web platform, to facilitate adoption of the OGU method in future metagenomics studies.IMPORTANCE Shotgun metagenomics is a powerful, yet computationally challenging, technique compared to 16S rRNA gene amplicon sequencing for decoding the composition and structure of microbial communities. Current analyses of metagenomic data are primarily based on taxonomic classification, which is limited in feature resolution. To solve these challenges, we introduce operational genomic units (OGUs), which are the individual reference genomes derived from sequence alignment results, without further assigning them taxonomy. The OGU method advances current read-based metagenomics in two dimensions: (i) providing maximal resolution of community composition and (ii) permitting use of phylogeny-aware tools. Our analysis of real-world data sets shows that it is advantageous over currently adopted metagenomic analysis methods and the finest-grained 16S rRNA analysis methods in predicting biological traits. We thus propose the adoption of OGUs as an effective practice in metagenomic studies.</p

A comparison of biodegradation caused by Teredinidae (Mollusca:Bivalvia), Limnoriidae (Crustacea:Isopoda), and C. terebans (Crustacea:Amphipoda) across 4 shipwreck sites in the English Channel

The need to protect underwater cultural heritage from biodegradation is paramount, however with many sites needing funding and support, it is hard to prioritise, thus the ability to identify high risk sites is crucial to ensure resources are best placed. In doing so a clear understanding of environmental conditions acting upon a site and abundance and composition of species present is essential to this identification. Therefore, the aim of this study was to assess the rate of biodegradation on four underwater cultural heritage sites in different marine environments by placing a series of wooden test panels in direct contact with the exposed structure on the sites. Upon recovery, test panels were photographed, X-rayed, and wood boring and sessile fouling species were identified and counted. The damage attributed to each species was recorded with CAD software. Results indicated a significant difference between sites, with HMS Invincible having the highest abundance of marine wood borers and the highest rate of surface area and volume degradation; whilst vestigial evidence of marine wood borers was found on the London, it would appear the environmental conditions had significantly impeded their survival. The study indicated further factors such as sediment type and coverage, availability of wood and the proximity of other colonised sites were also determining factors controlling the abundance of marine wood borers and the rate of biodegradation

Herbivore regulation of plant abundance in aquatic ecosystems.

Herbivory is a fundamental process that controls primary producer abundance and regulates energy and nutrient flows to higher trophic levels. Despite the recent proliferation of small-scale studies on herbivore effects on aquatic plants, there remains limited understanding of the factors that control consumer regulation of vascular plants in aquatic ecosystems. Our current knowledge of the regulation of primary producers has hindered efforts to understand the structure and functioning of aquatic ecosystems, and to manage such ecosystems effectively. We conducted a global meta-analysis of the outcomes of plant-herbivore interactions using a data set comprised of 326 values from 163 studies, in order to test two mechanistic hypotheses: first, that greater negative changes in plant abundance would be associated with higher herbivore biomass densities; second, that the magnitude of changes in plant abundance would vary with herbivore taxonomic identity. We found evidence that plant abundance declined with increased herbivore density, with plants eliminated at high densities. Significant between-taxa differences in impact were detected, with insects associated with smaller reductions in plant abundance than all other taxa. Similarly, birds caused smaller reductions in plant abundance than echinoderms, fish, or molluscs. Furthermore, larger reductions in plant abundance were detected for fish relative to crustaceans. We found a positive relationship between herbivore species richness and change in plant abundance, with the strongest reductions in plant abundance reported for low herbivore species richness, suggesting that greater herbivore diversity may protect against large reductions in plant abundance. Finally, we found that herbivore-plant nativeness was a key factor affecting the magnitude of herbivore impacts on plant abundance across a wide range of species assemblages. Assemblages comprised of invasive herbivores and native plant assemblages were associated with greater reductions in plant abundance compared with invasive herbivores and invasive plants, native herbivores and invasive plants, native herbivores and mixed-nativeness plants, and native herbivores and native plants. By contrast, assemblages comprised of native herbivores and invasive plants were associated with lower reductions in plant abundance compared with both mixed-nativeness herbivores and native plants, and native herbivores and native plants. However, the effects of herbivore-plant nativeness on changes in plant abundance were reduced at high herbivore densities. Our mean reductions in aquatic plant abundance are greater than those reported in the literature for terrestrial plants, but lower than aquatic algae. Our findings highlight the need for a substantial shift in how biologists incorporate plant-herbivore interactions into theories of aquatic ecosystem structure and functioning. Currently, the failure to incorporate top-down effects continues to hinder our capacity to understand and manage the ecological dynamics of habitats that contain aquatic plants

Reuniting philosophy and science to advance cancer research

Cancers rely on multiple, heterogeneous processes at different scales, pertaining to many biomedical fields. Therefore, understanding cancer is necessarily an interdisciplinary task that requires placing specialised experimental and clinical research into a broader conceptual, theoretical, and methodological framework. Without such a framework, oncology will collect piecemeal results, with scant dialogue between the different scientific communities studying cancer. We argue that one important way forward in service of a more successful dialogue is through greater integration of applied sciences (experimental and clinical) with conceptual and theoretical approaches, informed by philosophical methods. By way of illustration, we explore six central themes: (i) the role of mutations in cancer; (ii) the clonal evolution of cancer cells; (iii) the relationship between cancer and multicellularity; (iv) the tumour microenvironment; (v) the immune system; and (vi) stem cells. In each case, we examine open questions in the scientific literature through a philosophical methodology and show the benefit of such a synergy for the scientific and medical understanding of cancer

Comprehensive characterization of the cancer microbiome and its immuno-oncology interface

By all measures of genetic diversity or species abundance, life is primarily microbial. However, decades of cancer genomics have treated human tumors as sterile entities. The central argument of this thesis is that this sterility assumption is unfounded, unnecessary, and harmful for the future of cancer care. In Chapter 1, I comprehensively outline the literature landscape of cancer-associated microbes and their impact on each stage of the clinical cancer care cycle. I demonstrate that the majority of known cancer “hallmarks” are impacted by microbial mechanisms that act proximal and distal to tumors. I further summarize microbial impacts on cancer into an “immuno-oncology-microbiome” (IOM) axis and critically review the landscape of intratumoral and intracellular bacteria. In Chapter 2, I then argue (i) how microbiome-augmented cancer diagnostics directly benefit from the microbiome’s diversity and (ii) how the intratumoral microbiome necessitates a redefinition of cancer clonal evolution as a multi-species process. Evaluating multi-species clonal evolution, in turn, impacts how the field should model therapeutic resistance and metastasis. In Chapter 3, I present the largest to-date analysis of microbes in cancer, covering ~18,000 samples across 33 cancer types and more than 10,000 patients. Critically, I find microbial DNA and RNA is present in every major human cancer. I further show that these microbial compositions are cancer type-specific and that a patient’s cancer type is predictable solely on the basis of microbial nucleic acids found in cancer tissues, whole blood, or plasma, thereby concluding that microbial nucleic acids comprise a novel class of cancer diagnostics. In Chapter 4, I explore fungal constituents of the cancer microbiome, finding fungal DNA and RNA across most types of human cancers, and demonstrate that these fungal ecologies are also cancer type-specific. I also characterize fungal-bacterial-immune co-occurrences, revealing distinct immune responses, associations with patient survival, and multi-domain intratumoral ecologies. Collectively, these chapters and analyses comprehensively characterize the existence of the cancer microbiome, its immuno-oncology interface, and its utility for improving cancer diagnostics, prognostics, and therapeutics

Theism and the justification of first principles in Thomas Reid’s epistemology.

The role of theism in Thomas Reid’s epistemology remains an unresolved question. Opinions range from outright denials that theism has any relevance to Reid’s epistemology to claims that Reid’s epistemology depends upon theism in a dogmatic or a viciously circular manner. This dissertation attempts to bring some order to this interpretive fray by answering the following question: What role or roles does theism play in Reid’s epistemology, particularly in relation to the epistemic justification of first principles? Chapters 2-4 lay the foundation for answering this question and clarify some terminology. Chapter 2 distinguishes key senses in which Reid uses the terms “principle” and “first principle.” Chapter 3 argues for a novel interpretation of common sense and the principles of common sense. This interpretation avoids a number of objections to Reid’s principles of common sense. Chapter 4 considers the initial externalist justification of Reid’s first principles. It shows Reid has a surprisingly well-developed proper-functionalism and brings to light several overlooked elements of his epistemology. Chapters 5-8 argue theism can and does play various important and philosophically respectable roles in Reid’s epistemology, particularly in relation to the justification of first principles. Chapter 5 argues that even on the standard foundationalist interpretation of Reid’s epistemology, theism can and does boost the justification of first principles. Chapter 6 shows Reid’s epistemology is not a form of simple foundationalism but contains coherentist elements. This enables theism further to boost the justification of first principles. Chapter 7 reveals that Reid’s epistemology contains different kinds or levels of knowledge, and shows that theism enables the highest form of knowledge, which I call scientia. Chapter 8 argues that within Reid’s epistemology theism helps protect and preserve the justification of first principles.Ph.D

Redrawing therapeutic boundaries: microbiota and cancer

The unexpected roles of the microbiota in cancer challenge explanations of carcinogenesis that focus on tumor-intrinsic properties. Most tumors contain bacteria and viruses, and the host's proximal and distal microbiota influence both cancer incidence and therapeutic responsiveness. Continuing the history of cancer-microbe research, these findings raise a key question: to what extent is the microbiota relevant for clinical oncology? We approach this by critically evaluating three issues: how the microbiota provides a predictive biomarker of cancer growth and therapeutic responsiveness, the microbiota's causal role(s) in cancer development, and how therapeutic manipulations of the microbiota improve patient outcomes in cancer. Clarifying the conceptual and empirical aspects of the cancer-associated microbiota can orient future research and guide its implementation in clinical oncology