Signature Search Method Development and Application in Drug Discovery

This dissertation is about the development of gene expression signature (GES) search methods and their application in drug discovery, specifically for promoting healthy aging. GES searching is a powerful technology facilitating the identification of drugs for treating diseases and drug repurposing. This is achieved by identifying drugs in GES databases inducing signatures similar to query GESs obtained from diseased samples or drug treatments. The new connections are useful for developing pharmacological interventions. This dissertation is divided into the following three components. First, I developed the signatureSearch R/Bioconductor package that integrates existing and novel methods for GES searching and functional enrichment analysis (FEA). Subsequently, I tested the performance of different GES search methods. They represent the first systematic performance tests of these methods in the field. Second, I applied signatureSearch to the human healthy aging field to reveal insights into longevity associated (LA) drugs and their targets by searching the Integrated Network-based Cellular Signatures (LINCS) database. For this, I assessed the performance of LINCS drugs, inducing GESs representative for their mechanism of action (MOA), by computing for each MOA a recall score based on the GES similarity of the corresponding drugs. The obtained recall scores were used to prioritize LA drugs in the downstream discovery. LA MOA categories along with the corresponding drugs were identified by querying LINCS with GESs of drugs present in LINCS and DrugAge, and scoring the enrichment of each MOA. The corresponding LA pathways were identified via global mapping of targets of LA drugs and MOA categories. Next, I searched LINCS with the GESs from 11 well-studied LA drugs and one longevity phenotype. To identify LA pathways, the targets of the newly identified LA drugs were used for FEA. The results from the three steps were integrated and then interrogated with a combinatorial approach to select the most reliable set of LA drugs and targets. Collectively, this study identified a list of drugs, targets and pathways useful for pharmacological lifespan extension strategies. Third, I developed several data packages to incorporate in signatureSearch detailed annotations of drugs and targets from different community databases

Understanding the Regional Integration Process from the Perspective of Agglomeration and Urban Networks: Case Study in Central China

Previously, urban planning approaches have tended to convert local agglomeration into network connections to advance urban development. However, is this successful experience learned from developed counties appropriate for developing countries? Scholars hold different opinions on this debate. To answer this question, we need to examine the effects of urban agglomeration in developing countries with a quantitative method. In this paper, we introduced a method of examining network connections from a geospatial perspective to explore the practice and spatial consequences of regional integration using a new concept of “coupling distance” based on metal valence bond theory. Then we applied this method to conduct an empirical case study of the urban agglomeration in the middle reaches of the Yangtze River region in China. We found that: (1) the real integration scale of the investigated urban areas was less than one-fourth the planned area, as most of interactions between cities are local, although we see the positive facilitation of urban networks on cross-provincial integration. (2) In terms of spatial consequences, the study area demonstrated phenomena of “agglomeration shadows”, “enclaves” and “inverse integration”. Specifically, these “agglomeration shadows” were all in their province’s geometric centers, which seemed to have suffered a “central position curse”. (3) Both “enclaves” and “inverse integration” call for a readjustment of government-led regional integration planning. Differently, the former has a positive attitude towards integration while the latter holds the opposite attitude. This study hopes to provide operationalizing methods and guidelines for planners and decision makers in the field of regional integration planning

signatureSearch: environment for gene expression signature searching and functional interpretation

signatureSearch is an R/Bioconductor package that integrates a suite of existing and novel algorithms into an analysis environment for gene expression signature (GES) searching combined with functional enrichment analysis (FEA) and visualization methods to facilitate the interpretation of the search results. In a typical GES search (GESS), a query GES is searched against a database of GESs obtained from large numbers of measurements, such as different genetic backgrounds, disease states and drug perturbations. Database matches sharing correlated signatures with the query indicate related cellular responses frequently governed by connected mechanisms, such as drugs mimicking the expression responses of a disease. To identify which processes are predominantly modulated in the GESS results, we developed specialized FEA methods combined with drug-target network visualization tools. The provided analysis tools are useful for studying the effects of genetic, chemical and environmental perturbations on biological systems, as well as searching single cell GES databases to identify novel network connections or cell types. The signatureSearch software is unique in that it provides access to an integrated environment for GESS/FEA routines that includes several novel search and enrichment methods, efficient data structures, and access to pre-built GES databases, and allowing users to work with custom databases

Streamlined Mesoporous Silica Nanoparticles with Tunable Curvature from Interfacial Dynamic-Migration Strategy for Nanomotors

Streamlined architectures with a low fluid-resistance coefficient have been receiving great attention in various fields. However, it is still a great challenge to synthesize streamlined architecture with tunable surface curvature at the nanoscale. Herein, we report a facile interfacial dynamic migration strategy for the synthesis of streamlined mesoporous nanotadpoles with varied architectures. These tadpole-like nanoparticles possess a big streamlined head and a slender tail, which exhibit large inner cavities (75–170 nm), high surface areas (424–488 m2 g–1), and uniform mesopore sizes (2.4–3.2 nm). The head curvature of the streamlined mesoporous nanoparticles can be well-tuned from ∼2.96 × 10–2 to ∼5.56 × 10–2 nm–1, and the tail length can also be regulated from ∼30 to ∼650 nm. By selectively loading the Fe3O4 catalyst in the cavity of the streamlined silica nanotadpoles, the H2O2-driven mesoporous nanomotors were designed. The mesoporous nanomotors with optimized structural parameters exhibit outstanding directionality and a diffusion coefficient of 8.15 μm2 s–1Scopu

High-throughput small molecule screening reveals Nrf2-dependent and -independent pathways of cellular stress resistance.

Aging is the dominant risk factor for most chronic diseases. Development of antiaging interventions offers the promise of preventing many such illnesses simultaneously. Cellular stress resistance is an evolutionarily conserved feature of longevity. Here, we identify compounds that induced resistance to the superoxide generator paraquat (PQ), the heavy metal cadmium (Cd), and the DNA alkylator methyl methanesulfonate (MMS). Some rescue compounds conferred resistance to a single stressor, while others provoked multiplex resistance. Induction of stress resistance in fibroblasts was predictive of longevity extension in a published large-scale longevity screen in Caenorhabditis elegans, although not in testing performed in worms and flies with a more restricted set of compounds. Transcriptomic analysis and genetic studies implicated Nrf2/SKN-1 signaling in stress resistance provided by two protective compounds, cardamonin and AEG 3482. Small molecules identified in this work may represent attractive tools to elucidate mechanisms of stress resistance in mammalian cells

High-throughput small molecule screening reveals Nrf2-dependent and -independent pathways of cellular stress resistance

Aging is the dominant risk factor for most chronic diseases. Development of antiaging interventions offers the promise of preventing many such illnesses simultaneously. Cellular stress resistance is an evolutionarily conserved feature of longevity. Here, we identify compounds that induced resistance to the superoxide generator paraquat (PQ), the heavy metal cadmium (Cd), and the DNA alkylator methyl methanesulfonate (MMS). Some rescue compounds conferred resistance to a single stressor, while others provoked multiplex resistance. Induction of stress resistance in fibroblasts was predictive of longevity extension in a published large-scale longevity screen in , although not in testing performed in worms and flies with a more restricted set of compounds. Transcriptomic analysis and genetic studies implicated Nrf2/SKN-1 signaling in stress resistance provided by two protective compounds, cardamonin and AEG 3482. Small molecules identified in this work may represent attractive tools to elucidate mechanisms of stress resistance in mammalian cells