Sung, Jaeyun

Currently available bioinformatics tools to identify BGCs from metagenomic sequencing data are limited in their predictive capability or ease of use to even computationally oriented researchers. We present an automated computational pipeline called TaxiBGC, which predicts experimentally characterized BGCs (and infers their known SMs) in shotgun metagenomes by first considering the microbial species source.

Chemotherapy-induced cognitive impairment (CICI) has emerged as a significant medical problem without therapeutic options. Using the platinum-based chemotherapy cisplatin to model CICI, we revealed robust elevations in the adenosine A 2A receptor (A 2A R) and its downstream effectors, cAMP and CREB, by cisplatin in the adult mouse hippocampus, a critical brain structure for learning and memory. Notably, A 2A R inhibition by the Food and Drug Administration–approved A 2A R antagonist KW-6002 prevented cisplatin-induced impairments in neural progenitor proliferation and dendrite morphogenesis of adult-born neurons, while improving memory and anxiety-like behavior, without affecting tumor growth or cisplatin’s antitumor activity. Collectively, our study identifies A 2A R signaling as a key pathway that can be therapeutically targeted to prevent cisplatin-induced cognitive impairments.

Abstract A key question in human gut microbiome research is what are the robust structural patterns underlying its taxonomic composition. Herein, we use whole metagenomic datasets from healthy human guts to show that such robust patterns do exist, albeit not in the conventional enterotype sense. We first introduce the concept of mixed-membership enterotypes using a network inference approach based on stochastic block models. We find that gut microbiomes across a group of people (hosts) display a nested structure, which has been observed in a number of ecological systems. This finding led us to designate distinct ecological roles to both microbes and hosts: generalists and specialists. Specifically, generalist hosts have microbiomes with most microbial species, while specialist hosts only have generalist microbes. Moreover, specialist microbes are only present in generalist hosts. From the nested structure of microbial taxonomies, we show that these ecological roles of microbes are generally conserved across datasets. Our results show that the taxonomic composition of healthy human gut microbiomes is associated with robustly structured combinations of generalist and specialist species.

ObjectiveTo identify hallmark genes and biomolecular processes in aortitis using high‐throughput gene expression profiling, and to provide a range of potentially new drug targets (genes) and therapeutics from a pharmacogenomic network analysis.MethodsBulk RNA sequencing was performed on surgically resected ascending aortic tissues from inflammatory aneurysms (giant cell arteritis [GCA] with or without polymyalgia rheumatica, n = 8; clinically isolated aortitis [CIA], n = 17) and noninflammatory aneurysms (n = 25) undergoing surgical aortic repair. Differentially expressed genes (DEGs) between the 2 patient groups were identified while controlling for clinical covariates. A protein–protein interaction model, drug–gene target information, and the DEGs were used to construct a pharmacogenomic network for identifying promising drug targets and potentially new treatment strategies in aortitis.ResultsOverall, tissue gene expression patterns were the most associated with disease state than with any other clinical characteristic. We identified 159 and 93 genes that were significantly up‐regulated and down‐regulated, respectively, in inflammatory aortic aneurysms compared to noninflammatory aortic aneurysms. We found that the up‐regulated genes were enriched in immune‐related functions, whereas the down‐regulated genes were enriched in neuronal processes. Notably, gene expression profiles of inflammatory aortic aneurysms from patients with GCA were no different than those from patients with CIA. Finally, our pharmacogenomic network analysis identified genes that could potentially be targeted by immunosuppressive drugs currently approved for other inflammatory diseases.ConclusionWe performed the first global transcriptomics analysis in inflammatory aortic aneurysms from surgically resected aortic tissues. We identified signature genes and biomolecular processes, while finding that CIA may be a limited presentation of GCA. Moreover, our computational network analysis revealed potential novel strategies for pharmacologic interventions and suggests future biomarker discovery directions for the precise diagnosis and treatment of aortitis.

Abstract Problem Prenatal exposure to metabolic dysregulation arising from maternal obesity can have negative health consequences in post‐natal life. To date, the specific effects of maternal obesity on fetal immunity at a cellular level have not been well characterized. Method of Study Using cord blood mononuclear cells (CBMCs) and cord plasma (n = 9/group) isolated from infants born to women with a high body mass index (BMI>25kg/m 2 ) compared to women with a normal BMI (18‐25kg/m 2 ), we evaluated differences in immune cell populations using single‐cell mass cytometry (CyTOF). CBMCs were matched according to potentially confounding variables, such as maternal and gestational age, ethnicity, smoking status, and gravidity. Statistical results were adjusted for fetal sex. Data were analyzed by viSNE and FlowSOM softwares in Cytobank ™ . Results In newborn CBMCs from women with high BMI, we observed changes in frequency and phenotype of immune cell populations, including significant increases in CD4 + T cells and decreases in myeloid cell populations. IL‐12p40 and MDC concentrations were significantly elevated in the high BMI group compared to control. Conclusion This study demonstrates an association between maternal obesity and fetal immunity. Our results warrant following long‐term immunologic outcomes and associated clinical risks in children born to women with a high pre‐pregnancy BMI.

Colorectal adenomas are precursors of CRC. Recently, the gut microbiota, i.e., the collection of microbes residing in our gut, has been recognized as a key player in CRC development. There have been a number of gut microbiota profiling studies for colorectal adenoma and CRC; however, fewer studies have considered the gut metabolome, which serves as the chemical interface between the host and gut microbiota. Here, we conducted a gut metabolome profiling study of colorectal adenoma and CRC and analyzed the metabolomic profiles together with paired microbiota composition profiles. We found several chemical signatures of colorectal adenoma that were associated with some gut microbes and potentially indicative of future CRC. This study highlights potential early-driver metabolites in CRC pathogenesis and guides further targeted experiments and thus provides an important stepping stone toward developing better CRC prevention strategies.

Primary sclerosing cholangitis (PSC) is a pathogenically complex, chronic, fibroinflammatory disorder of the bile ducts without known etiology or effective pharmacotherapy. Emerging in vitro and in vivo evidence support fundamental pathophysiologic mechanisms in PSC centered on enterohepatic circulation. To date, no studies have specifically interrogated the chemical footprint of enterohepatic circulation in PSC. Herein, we evaluated the metabolome and lipidome of portal venous blood and bile obtained at the time of liver transplantation in patients with PSC (n = 7) as compared to individuals with noncholestatic, end-stage liver disease (viral, metabolic, etc. (disease control, DC, n = 19)) and to nondisease controls (NC, living donors, n = 12). Global metabolomic and lipidomic profiling was performed on serum derived from portal venous blood (portal serum) and bile using ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and differential mobility spectroscopy-mass spectroscopy (DMS-MS; complex lipid platform). The Mann–Whitney U test was used to identify metabolites that significantly differed between groups. Principal-component analysis (PCA) showed significant separation of both PSC and DC from NC for both portal serum and bile. Metabolite set enrichment analysis of portal serum and bile demonstrated that the liver-disease cohorts (PSC and DC) exhibited similar enrichment in several metabolite categories compared to NC. Interestingly, the bile in PSC was uniquely enriched for dipeptide and polyamine metabolites. Finally, analysis of patient-matched portal serum and biliary metabolome revealed that these biological fluids were more homogeneous in PSC than in DC or NC, suggesting aberrant bile formation and enterohepatic circulation. In summary, PSC and DC patients exhibited alterations in several metabolites in portal serum and bile, while PSC patients exhibited a unique bile metabolome. These specific alterations in PSC are amenable to hypothesis testing and, potentially, therapeutic pharmacologic manipulation.