Like all organisms on the planet, environmental microbes are subject to the forces of molecular evolution. Metagenomic sequencing provides a means to access the DNA sequence of uncultured microbes. By combining DNA sequencing of microbial communities with evolutionary modeling and phylogenetic analysis we might obtain new insights into microbiology and also provide a basis for practical tools such as forensic pathogen detection. In this work we present an approach to leverage phylogenetic analysis of metagenomic sequence data to conduct several types of analysis. First, we present a method to conduct phylogeny-driven Bayesian hypothesis tests for the presence of an organism in a sample. Second, we present a means to compare community structure across a collection of many samples and develop direct associations between the abundance of certain organisms and sample metadata. Third, we apply new tools to analyze the phylogenetic diversity of microbial communities and again demonstrate how this can be associated to sample metadata. These analyses are implemented in an open source software pipeline called PhyloSift. As a pipeline, PhyloSift incorporates several other programs including LAST, HMMER, and pplacer to automate phylogenetic analysis of protein coding and RNA sequences in metagenomic datasets generated by modern sequencing platforms (e.g., Illumina, 454).

Pediatric non-Hodgkin lymphoma (NHL) includes over 30 histologies (many with subtypes), with approximately 800 cases per year in the United States. Improvements in survival in NHL over the past 5 decades align with the overall success of the cooperative trial model with dramatic improvements in outcomes. As an example, survival for advanced Burkitt lymphoma is now >95%. Major remaining challenges include survival for relapsed and refractory disease and long-term morbidity in NHL survivors. Langerhans cell histiocytosis (LCH) was added to the NHL Committee portfolio in recognition of LCH as a neoplastic disorder and the tremendous unmet need for improved outcomes. The goal of the Children Oncology Group NHL Committee is to identify optimal cures for every child and young adult with NHL (and LCH). Further advances will require creative solutions, including engineering study groups to combine rare populations, biology-based eligibility, alternative endpoints, facilitating international collaborations, and coordinated correlative biology.

Preventing the biogenesis of disease-relevant proteins is an attractive therapeutic strategy, but attempts to target essential protein biogenesis factors have been hampered by excessive toxicity. Here we describe KZR-8445, a cyclic depsipeptide that targets the Sec61 translocon and selectively disrupts secretory and membrane protein biogenesis in a signal peptide-dependent manner. KZR-8445 potently inhibits the secretion of pro-inflammatory cytokines in primary immune cells and is highly efficacious in a mouse model of rheumatoid arthritis. A cryogenic electron microscopy structure reveals that KZR-8445 occupies the fully opened Se61 lateral gate and blocks access to the lumenal plug domain. KZR-8445 binding stabilizes the lateral gate helices in a manner that traps select signal peptides in the Sec61 channel and prevents their movement into the lipid bilayer. Our results establish a framework for the structure-guided discovery of novel therapeutics that selectively modulate Sec61-mediated protein biogenesis.