8 research outputs found
Discovering collectively informative descriptors from high-throughput experiments
Get PDF<p>Abstract</p> <p>Background</p> <p>Improvements in high-throughput technology and its increasing use have led to the generation of many highly complex datasets that often address similar biological questions. Combining information from these studies can increase the reliability and generalizability of results and also yield new insights that guide future research.</p> <p>Results</p> <p>This paper describes a novel algorithm called BLANKET for symmetric analysis of two experiments that assess informativeness of descriptors. The experiments are required to be related only in that their descriptor sets intersect substantially and their definitions of case and control are consistent. From resulting lists of n descriptors ranked by informativeness, BLANKET determines <b>shortlists </b>of descriptors from each experiment, generally of different lengths p and q. For any pair of shortlists, four numbers are evident: the number of descriptors appearing in both shortlists, in exactly one shortlist, or in neither shortlist. From the associated contingency table, BLANKET computes Right Fisher Exact Test (RFET) values used as scores over a plane of possible pairs of shortlist lengths <abbrgrp><abbr bid="B1">1</abbr><abbr bid="B2">2</abbr></abbrgrp>. BLANKET then chooses a pair or pairs with RFET score less than a threshold; the threshold depends upon n and shortlist length limits and represents a quality of intersection achieved by less than 5% of random lists.</p> <p>Conclusions</p> <p>Researchers seek within a universe of descriptors some minimal subset that collectively and efficiently predicts experimental outcomes. Ideally, any smaller subset should be insufficient for reliable prediction and any larger subset should have little additional accuracy. As a method, BLANKET is easy to conceptualize and presents only moderate computational complexity. Many existing databases could be mined using BLANKET to suggest optimal sets of predictive descriptors.</p
Analysis of Apoptotic Cell Clearance by Microglia in Zebrafish Mutants Lacking \u3cem\u3eHavcr1\u3c/em\u3e, a Putative Phosphatidylserine Receptor
No full textThe retina is made functional by complex interactions of various cell types unique to the central nervous system. While neurons and glia are well appreciated in this context, the microglia, a lesser understood cell type, has emerged as an important player. Microglia are resident phagocytes that colonize the central nervous system (brain and retina) early in vertebrate development. Recent work indicates that microglia have a variety of functions in development and homeostasis, but the genes and pathways that are involved, and therefore molecular mechanisms, are poorly understood. A well-described function of microglia is the phagocytic clearance of apoptotic cells during normal development as well as in contexts of tissue damage or degeneration. However, the genes required for this function remain to be fully elucidated. Recent transcriptome analysis published by our lab has shown zebrafish microglia express high levels of the gene havcr1. Sequence and genomic comparisons indicate havcr1 is a receptor for Phosphatidylserine (PS), which is exposed on the surface of dying cells. Therefore, we hypothesize that havcr1 has a function in the recognition and clearance of apoptotic cells by microglia. We propose to use the zebrafish to reveal the function of havcr1 in the vertebrate retina, by the following objectives: (1) Demonstrate that microglia express havcr1 using in situ hybridization, and (2) Determine if clearance of apoptotic cells during development is reduced in havcr1 mutants. This work will increase mechanistic understanding of apoptotic cell clearance by microglia and will provide a novel genetic tool for future experiments
Effects of Selected Modulators of RXR Receptors on Microglial Apolipoprotein Expression During Early CNS Development
No full textThe apolipoprotein genes are clustered within a chromosomal region in vertebrates called the apolipoprotein gene cluster. Of these genes, APOE and APOC1 are genetically associated with human neurodegenerative disease. In addition, these two genes and are considered to be part of a set of “Disease-Associated Microglia” genes, which are genes upregulated in microglial cells in contexts of neurodegeneration. Zebrafish orthologs of human APOE and APOC1 are apoeb and apoc1.
Microglia are resident macrophages in the central nervous system (CNS) of vertebrates. In our transcriptome analysis of sorted zebrafish microglia, apoc1 was our top hit of the microglia-enriched genes (1). This was interesting to us because Apoe expression by microglia is well appreciated, but Apoc1 expression by microglia has not been well-examined.
Interestingly, Gosselin et al. 2017 (2) showed RNA-seq that APOC1 is highly expressed by human microglia with comparatively lower expression by mouse microglia. This indicates that zebrafish are a justified model organism to study regulation and function of this gene.
PPAR//RXR and LXR/RXR receptors have been shown to regulate expression of the apolipoprotein gene cluster in other macrophages, but a similar role in microglia in an in vivo system has not been studied.
The zebrafish allows us to use a pharmacological approach to modulate PPAR, LXR, and RXR activity by immersion of fish in compounds during early development.
This allowed us to examine the role of these particular nuclear hormone receptors in regulation of microglial expression of apoc1 and apoeb during development of the central nervous system in a vertebrate animal
Causes of Noncompliance with International Law: A Field Experiment on Anonymous Incorporation
No full text20110302 into the Experiments on Governance and Politics Registry once that registry was begun at e-gap.org. Of those interventions registered, we report on the FATF, Premium, Corruption, and Terrorism conditions in this article. All other interventions outlined in the registered document are reported in other work. In our registration, we indicated that we would report results dichotomously as compliant or noncompliant, given a response. We still report response and nonresponse followed by a compliance level, but we expanded the set of possible types of compliance (nonresponse, noncompliance, partial compliance, compliance, and refusal). Presenting the information this way is more precise and is also consistent with the registry document because the fuller set of outcomes contains all information the dichotomized measures capture (se
