Understanding the genetic architecture of gene expression traits is key to elucidating the underlying mechanisms of complex traits. Here, for the first time, we perform a systematic survey of the ...heritability and the distribution of effect sizes across all representative tissues in the human body. We find that local h2 can be relatively well characterized with 59% of expressed genes showing significant h2 (FDR < 0.1) in the DGN whole blood cohort. However, current sample sizes (n ≤ 922) do not allow us to compute distal h2. Bayesian Sparse Linear Mixed Model (BSLMM) analysis provides strong evidence that the genetic contribution to local expression traits is dominated by a handful of genetic variants rather than by the collective contribution of a large number of variants each of modest size. In other words, the local architecture of gene expression traits is sparse rather than polygenic across all 40 tissues (from DGN and GTEx) examined. This result is confirmed by the sparsity of optimal performing gene expression predictors via elastic net modeling. To further explore the tissue context specificity, we decompose the expression traits into cross-tissue and tissue-specific components using a novel Orthogonal Tissue Decomposition (OTD) approach. Through a series of simulations we show that the cross-tissue and tissue-specific components are identifiable via OTD. Heritability and sparsity estimates of these derived expression phenotypes show similar characteristics to the original traits. Consistent properties relative to prior GTEx multi-tissue analysis results suggest that these traits reflect the expected biology. Finally, we apply this knowledge to develop prediction models of gene expression traits for all tissues. The prediction models, heritability, and prediction performance R2 for original and decomposed expression phenotypes are made publicly available (https://github.com/hakyimlab/PrediXcan).
Bacteriophages of the Urinary Microbiome Miller-Ensminger, Taylor; Garretto, Andrea; Brenner, Jonathon ...
Journal of bacteriology,
04/2018, Volume:
200, Issue:
7
Journal Article
Peer reviewed
Open access
Bacterial viruses (bacteriophages) play a significant role in microbial community dynamics. Within the human gastrointestinal tract, for instance, associations among bacteriophages (phages), ...microbiota stability, and human health have been discovered. In contrast to the gastrointestinal tract, the phages associated with the urinary microbiota are largely unknown. Preliminary metagenomic surveys of the urinary virome indicate a rich diversity of novel lytic phage sequences at an abundance far outnumbering that of eukaryotic viruses. These surveys, however, exclude the lysogenic phages residing within the bacteria of the bladder. To characterize this phage population, we examined 181 genomes representative of the phylogenetic diversity of bacterial species within the female urinary microbiota and found 457 phage sequences, 226 of which were predicted with high confidence. Phages were prevalent within the bladder bacteria: 86% of the genomes examined contained at least one phage sequence. Most of these phages are novel, exhibiting no discernible sequence homology to sequences in public data repositories. The presence of phages with substantial sequence similarity within the microbiota of different women supports the existence of a core community of phages within the bladder. Furthermore, the observed variation between the phage populations of women with and without overactive bladder symptoms suggests that phages may contribute to urinary health. To complement our bioinformatic analyses, viable phages were cultivated from the bacterial isolates for characterization; a novel coliphage was isolated, which is obligately lytic in the laboratory strain
C. Sequencing of bacterial genomes facilitates a comprehensive cataloguing of the urinary virome and reveals phage-host interactions.
Bacteriophages are abundant within the human body. However, while some niches have been well surveyed, the phage population within the urinary microbiome is largely unknown. Our study is the first survey of the lysogenic phage population within the urinary microbiota. Most notably, the abundance of prophage exceeds that of the bacteria. Furthermore, many of the prophage sequences identified exhibited no recognizable sequence homology to sequences in data repositories. This suggests a rich diversity of uncharacterized phage species present in the bladder. Additionally, we observed a variation in the abundances of phages between bacteria isolated from asymptomatic "healthy" individuals and those with urinary symptoms, thus suggesting that, like phages within the gut, phages within the bladder may contribute to urinary health.
Apocorophium lacustre (Vanhoffen, 1911) is a recent colonizer of freshwater ecosystems in the United States of America and Europe. This species is native primarily to estuarine environments on both ...sides of the North Atlantic, but in the US it has been established in the Gulf of Mexico since at least 1982 and more recently in the Mississippi River Basin. In 2005 it was found in the Dresden Island Pool of the Upper Illinois River, placing it within 100 river kilometers of Lake Michigan, and it is considered a high risk for continuing its spread into the Laurentian Great Lakes. During summer 2015 we conducted what we believe is the only sampling for this species to have taken place upstream of the Dresden Island Pool since 2005. We sampled at 25 sites from the Dresden Island Pool upstream to Lake Michigan, including six Lake Michigan harbors. A. lacustre was found at a single site in the Dresden Island Pool, indicating that the species has not spread over the last decade. This result could occur because of a physical or chemical barrier to further movement, or because our sampling was not sufficient to locate the population. Further sampling, and tests of A. lacustre tolerance to water from different sources, will be required to determine if spread has truly stopped, and if so, the reason for this.
Contemporary DNA sequencing technologies are continuously increasing throughput at ever decreasing costs. Moreover, due to recent advances in sequencing technology new platforms are emerging. As such ...computational challenges persist. The average read length possible has taken a giant leap forward with the PacBio and Nanopore solutions. Regardless of the platform used, impurities within the DNA preparation of the sample - be it from unintentional contaminants or pervasive symbiots - remains an issue. We have developed a new tool, HAsh-MaP-ERadicator (HAMPER), for the detection and removal of non-target, contaminating DNA sequences. Integrating hash-based and mapping-based strategies, HAMPER is both memory and time efficient while maintaining a high level of sensitivity. Moreover, HAMPER was designed for flexibility: reads of any size can be efficiently examined and the user can set parameters specific for the analysis of reads produced by a particular sequencer. To evaluate our method, mock sequencing runs were generated including various contaminating species and with variable rates of mutation revealing a high level of sensitivity and specificity. Reads that are not of interest can quickly be removed using HAMPER thus improving downstream analyses.
Background
We sought to characterize early changes in CD8+ tumor‐infiltrating lymphocytes and tumor transcriptomes after induction cetuximab in a cohort with p16‐positive oropharyngeal cancer on a ...phase II clinical de‐escalation trial.
Methods
Tumor biopsies were obtained before and 1 week after a single cetuximab loading dose in eight patients enrolled in a phase II trial of cetuximab and radiotherapy. Changes in CD8+ tumor‐infiltrating lymphocytes and transcriptomes were assessed.
Results
One week after cetuximab, five patients (62.5%) had an increase in CD8+ cell infiltration with a median (range) fold change of +5.8 (2.5–15.8). Three (37.5%) had unchanged CD8+ cells (median range fold change of −0.85 0.8–1.1). In two patients with evaluable RNA, cetuximab induced rapid tumor transcriptome changes in cellular type 1 interferon signaling and keratinization pathways.
Conclusions
Within 1 week, cetuximab induced measurable changes in pro‐cytotoxic T‐cell signaling and immune content.
Abstract
Sinonasal Undifferentiated Carcinoma (SNUC), a rare and aggressive tumor arising from the sinonasal cavity, remains a difficult-to-treat disease with poor overall survival. There are no ...agreed upon treatment algorithms and research efforts have focused on identifying new genetic mutations for novel targeted therapies. To date, targeted sequencing studies have identified IDH2 and SMARCAB1 as potential SNUC driver alterations, however the molecular alterations found in SMARCAB1 wild type tumors are unknown. Here, using whole exome sequencing, we characterize a series of 7 SNUC tumors and a SNUC cell line and discover recurrent aberrations to the SWI/SNF, MAGE and FAT gene families. We also validate a novel ALK mutation, recurrent ERBB2 copy number amplifications and a previously undescribed PGAP3-SRPK1 gene fusion in the SNUC cell line. Further investigation of the PGAP-SRPK1 fusion gene reveals a change in the active site with loss of three of nine active site residues. Functional studies are ongoing to determine the importance of the PGAP3-SRPK1 gene fusion for oncogenic phenotypes. This discovery extends the need for comprehensive characterization of gene family mutation status in SNUC and supports a need to understand the downstream molecular mechanisms in order to improve therapeutic strategies for this disease.
Citation Format: Erin L. McKean, Andrew C. Birkeland, Molly E. Heft Neal, Aditi Kulkarni, Sue K. Foltin, Brittany M. Jewell, Jonathon B. McHugh, Lawence J. Marentette, John Chad Brenner. Integrative sequencing discovers a novel PGAP3-SRPK1 gene fusion in sinonasal undifferentiated carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1688.
Laser source development for infrared neural stimulation Keller, Matthew D.; Stafford, James W.; Stafford, Ryan C. ...
2013 Saudi International Electronics, Communications and Photonics Conference,
2013-April
Conference Proceeding
Infrared neural stimulation (INS) has emerged as a complementary technology to electrical stimulation with greater precision and no stimulation artifact. Many studies have been performed with ...Lockheed Martin Aculight's (LMA) Capella laser. To explore all optical parameters useful for INS, LMA has produced alternate versions of Capellas operating at a variety of wavelengths, and initial tests indicate their utility. In an effort to begin miniaturizing laser sources for INS, LMA has developed three channel, wearable laser packs for chronic experiments that have been used for up to three months. To even further miniaturize laser sources toward implantable use in humans, LMA has partnered with Vixar, Inc. to develop vertical cavity surface emitting lasers (VCSELs) operating at 1860nm. To date, these devices have produced over 60 mW from a form factor of a few hundred microns, and have shown a clear path toward achieving parameters needed for use in neuroprostheses.
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