Information-based methods for predicting gene function from systematic gene knock-downs

<p>Abstract</p> <p>Background</p> <p>The rapid annotation of genes on a genome-wide scale is now possible for several organisms using high-throughput RNA interference assays to knock down the expression of a specific gene. To date, dozens of RNA interference phenotypes have been recorded for the nematode <it>Caenorhabditis elegans</it>. Although previous studies have demonstrated the merit of using knock-down phenotypes to predict gene function, it is unclear how the data can be used most effectively. An open question is how to optimally make use of phenotypic observations, possibly in combination with other functional genomics datasets, to identify genes that share a common role.</p> <p>Results</p> <p>We compared several methods for detecting gene-gene functional similarity from phenotypic knock-down profiles. We found that information-based measures, which explicitly incorporate a phenotype's genomic frequency when calculating gene-gene similarity, outperform non-information-based methods. We report the presence of newly predicted modules identified from an integrated functional network containing phenotypic congruency links derived from an information-based measure. One such module is a set of genes predicted to play a role in regulating body morphology based on their multiply-supported interactions with members of the TGF-<it>β </it>signaling pathway.</p> <p>Conclusion</p> <p>Information-based metrics significantly improve the comparison of phenotypic knock-down profiles, based upon their ability to enhance gene function prediction and identify novel functional modules.</p

Capecitabine as Salvage Treatment for Lymphoepithelioma-Like Carcinoma of Lung

AbstractLymphoepithelioma-like carcinoma (LELC) of lung has previously demonstrated good clinical response to 5-fluorouracil containing chemotherapy regimen, similar to the observation in undifferentiated nasopharyngeal carcinoma. Capecitabine, which is converted into active 5-fluorouracil within tumor cells, has been found effective in colorectal, breast, and recently nasopharyngeal carcinomas. We report our experience in five patients with advanced or metastatic LELC of lung who were treated with single agent capecitabine as salvage chemotherapy. The finding of disease control in three of five patients, especially with exceptionally durable stable disease (14.8 months) in one patient, suggests the potential clinical activity of capecitabine in LELC of lung. Future studies on capecitabine-containing chemotherapy regimens in LELC of lung are warranted

Shear wave pulse compression for dynamic elastography using phase-sensitive optical coherence tomography

Assessing the biomechanical properties of soft tissue provides clinically valuable information to supplement conventional structural imaging. In the previous studies, we introduced a dynamic elastography technique based on phase-sensitive optical coherence tomography (PhS-OCT) to characterize submillimetric structures such as skin layers or ocular tissues. Here, we propose to implement a pulse compression technique for shear wave elastography. We performed shear wave pulse compression in tissue-mimicking phantoms. Using a mechanical actuator to generate broadband frequency-modulated vibrations (1 to 5 kHz), induced displacements were detected at an equivalent frame rate of 47 kHz using a PhS-OCT. The recorded signal was digitally compressed to a broadband pulse. Stiffness maps were then reconstructed from spatially localized estimates of the local shear wave speed. We demonstrate that a simple pulse compression scheme can increase shear wave detection signal-to-noise ratio ([Formula: see text] gain) and reduce artifacts in reconstructing stiffness maps of heterogeneous media

Heme Oxygenase-1 Expression Affects Murine Abdominal Aortic Aneurysm Progression.

Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme degradation, is a cytoprotective enzyme upregulated in the vasculature by increased flow and inflammatory stimuli. Human genetic data suggest that a diminished HO-1 expression may predispose one to abdominal aortic aneurysm (AAA) development. In addition, heme is known to strongly induce HO-1 expression. Utilizing the porcine pancreatic elastase (PPE) model of AAA induction in HO-1 heterozygous (HO-1+/-, HO-1 Het) mice, we found that a deficiency in HO-1 leads to augmented AAA development. Peritoneal macrophages from HO-1+/- mice showed increased gene expression of pro-inflammatory cytokines, including MCP-1, TNF-alpha, IL-1-beta, and IL-6, but decreased expression of anti-inflammatory cytokines IL-10 and TGF-beta. Furthermore, treatment with heme returned AAA progression in HO-1 Het mice to a wild-type profile. Using a second murine AAA model (Ang II-ApoE-/-), we showed that low doses of the HMG-CoA reductase inhibitor rosuvastatin can induce HO-1 expression in aortic tissue and suppress AAA progression in the absence of lipid lowering. Our results support those studies that suggest that pleiotropic statin effects might be beneficial in AAA, possibly through the upregulation of HO-1. Specific targeted therapies designed to induce HO-1 could become an adjunctive therapeutic strategy for the prevention of AAA disease

Heterogeneity in Surface Sensing Suggests a Division of Labor in Pseudomonas aeruginosa Populations

The second messenger signaling molecule cyclic diguanylate monophosphate (c-di-GMP) drives the transition between planktonic and biofilm growth in many bacterial species. Pseudomonas aeruginosa has two surface sensing systems that produce c-di-GMP in response to surface adherence. Current thinking in the field is that once cells attach to a surface, they uniformly respond by producing c-di-GMP. Here, we describe how the Wsp system generates heterogeneity in surface sensing, resulting in two physiologically distinct subpopulations of cells. One subpopulation has elevated c-di-GMP and produces biofilm matrix, serving as the founders of initial microcolonies. The other subpopulation has low c-di-GMP and engages in surface motility, allowing for exploration of the surface. We also show that this heterogeneity strongly correlates to surface behavior for descendent cells. Together, our results suggest that after surface attachment, P. aeruginosa engages in a division of labor that persists across generations, accelerating early biofilm formation and surface exploration

Long-Range Exciton Diffusion in Two-Dimensional Assemblies of Cesium Lead Bromide Perovskite Nanocrystals

F\"orster Resonant Energy Transfer (FRET)-mediated exciton diffusion through artificial nanoscale building block assemblies could be used as a new optoelectronic design element to transport energy. However, so far nanocrystal (NC) systems supported only diffusion length of 30 nm, which are too small to be useful in devices. Here, we demonstrate a FRET-mediated exciton diffusion length of 200 nm with 0.5 cm2/s diffusivity through an ordered, two-dimensional assembly of cesium lead bromide perovskite nanocrystals (PNC). Exciton diffusion was directly measured via steady-state and time-resolved photoluminescence (PL) microscopy, with physical modeling providing deeper insight into the transport process. This exceptionally efficient exciton transport is facilitated by PNCs high PL quantum yield, large absorption cross-section, and high polarizability, together with minimal energetic and geometric disorder of the assembly. This FRET-mediated exciton diffusion length matches perovskites optical absorption depth, opening the possibility to design new optoelectronic device architectures with improved performances, and providing insight into the high conversion efficiencies of PNC-based optoelectronic devices

Tailored versus generic knowledge brokering to integrate mood management into smoking cessation interventions in primary care settings : Protocol for a cluster randomized controlled trial

Background: Both tobacco smoking and depression are major public health problems associated with high morbidity and mortality. In addition, individuals with depression are almost twice as likely to smoke and less likely to achieve smoking cessation. In the Smoking Treatment for Ontario Patients program, an established smoking cessation program in Ontario, Canada, 38% of smokers in primary care settings have current or past depression with 6-month quit rates that are significantly lower than those without depression (33% versus 40%, P<.001). Integrating self-help mood management (eg, relaxation exercises and mood monitoring) with smoking cessation treatment increases long-term quit rates by 12%-20%. However, integration in real-world settings has not been reported. It is unclear which knowledge translation strategy would be more effective for motivating clinicians to provide resources on mood management to eligible patients. Objective: The objectives of this study are to investigate the following comparisons among depressed smokers enrolled in a smoking cessation program: 1) the effectiveness of generalized, exclusively email-based prompts versus a personalized knowledge broker in implementing mood management interventions; 2) the effectiveness of the two knowledge translation strategies on smoking quit rates; and 3) the incremental costs of the two knowledge translation strategies on the implementation of mood management interventions. Methods: The study design is a cluster randomized controlled trial of Family Health Teams participating in the Smoking Treatment for Ontario Patients program. Family Health Teams will be randomly allocated 1:1 to receive either generalized messages (related to depression and smoking) exclusively via email (group A) or be assigned a knowledge broker who provides personalized support through phone- and email-based check-ins (group B). The primary outcome, measured at the site level, is the proportion of eligible baseline visits that result in the provision of the mood management intervention to eligible patients. Results: Recruitment for the primary outcome of this study will be completed in 2018/2019. Results will be reported in 2019/2020. Conclusions: This study will address the knowledge gap in the implementation strategies (ie, email-based prompts versus a knowledge broker) of mood management interventions for smokers with depression in primary care settings. Trial Registration: ClinicalTrials.gov NCT03130998; https://clinicaltrials.gov/ct2/show/NCT03130998 (Archived on WebCite at www.webcitation.org/6ylyS6RTe)