TopDom: an efficient and deterministic method for identifying topological domains in genomes.

Genome-wide proximity ligation assays allow the identification of chromatin contacts at unprecedented resolution. Several studies reveal that mammalian chromosomes are composed of topological domains (TDs) in sub-mega base resolution, which appear to be conserved across cell types and to some extent even between organisms. Identifying topological domains is now an important step toward understanding the structure and functions of spatial genome organization. However, current methods for TD identification demand extensive computational resources, require careful tuning and/or encounter inconsistencies in results. In this work, we propose an efficient and deterministic method, TopDom, to identify TDs, along with a set of statistical methods for evaluating their quality. TopDom is much more efficient than existing methods and depends on just one intuitive parameter, a window size, for which we provide easy-to-implement optimization guidelines. TopDom also identifies more and higher quality TDs than the popular directional index algorithm. The TDs identified by TopDom provide strong support for the cross-tissue TD conservation. Finally, our analysis reveals that the locations of housekeeping genes are closely associated with cross-tissue conserved TDs. The software package and source codes of TopDom are available athttp://zhoulab.usc.edu/TopDom/.

Potent antibody lineage against malaria transmission elicited by human vaccination with Pfs25.

Transmission-blocking vaccines have the potential to be key contributors to malaria elimination. Such vaccines elicit antibodies that inhibit parasites during their development in Anopheles mosquitoes, thus breaking the cycle of transmission. To date, characterization of humoral responses to Plasmodium falciparum transmission-blocking vaccine candidate Pfs25 has largely been conducted in pre-clinical models. Here, we present molecular analyses of human antibody responses generated in a clinical trial evaluating Pfs25 vaccination. From a collection of monoclonal antibodies with transmission-blocking activity, we identify the most potent transmission-blocking antibody yet described against Pfs25; 2544. The interactions of 2544 and three other antibodies with Pfs25 are analyzed by crystallography to understand structural requirements for elicitation of human transmission-blocking responses. Our analyses provide insights into Pfs25 immunogenicity and epitope potency, and detail an affinity maturation pathway for a potent transmission-blocking antibody in humans. Our findings can be employed to guide the design of improved malaria transmission-blocking vaccines.

Producing genome structure populations with the dynamic and automated PGS software.

Chromosome conformation capture technologies such as Hi-C are widely used to investigate the spatial organization of genomes. Because genome structures can vary considerably between individual cells of a population, interpreting ensemble-averaged Hi-C data can be challenging, in particular for long-range and interchromosomal interactions. We pioneered a probabilistic approach for the generation of a population of distinct diploid 3D genome structures consistent with all the chromatin-chromatin interaction probabilities from Hi-C experiments. Each structure in the population is a physical model of the genome in 3D. Analysis of these models yields new insights into the causes and the functional properties of the genome's organization in space and time. We provide a user-friendly software package, called PGS, which runs on local machines (for practice runs) and high-performance computing platforms. PGS takes a genome-wide Hi-C contact frequency matrix, along with information about genome segmentation, and produces an ensemble of 3D genome structures entirely consistent with the input. The software automatically generates an analysis report, and provides tools to extract and analyze the 3D coordinates of specific domains. Basic Linux command-line knowledge is sufficient for using this software. A typical running time of the pipeline is ∼3 d with 300 cores on a computer cluster to generate a population of 1,000 diploid genome structures at topological-associated domain (TAD)-level resolution.

Electrodiagnosis support system for localizing neural injury in an upper limb.

Needle electromyography (EMG) is used for the diagnosis of a neural injury in patients with a cervical/lumbar radiculopathy, plexopathy, peripheral neuropathy, or myopathy. Needle EMG is a particularly invasive test and thus it is important to minimize the pain during inspections. In this paper, we introduce the Electrodiagnosis Support System (ESS), which is a clinical decision support system specialized for neural injury diagnosis in the upper limb. ESS can guide users through the diagnosis process and assist them in making the optimal decision for minimizing unnecessary inspections and as an educational tool for medical trainees. ESS provides a graphical user interface that visualizes the neural structure of the upper limb, through which users input the results of needle EMG tests and retrieve diagnosis results. We validated the accuracy of the system using the diagnosis records of 133 real patients.

A cube framework for incorporating inter-gene information into biological data mining.

Large volumes of microarray data are registered daily in public repositories such as SMD (Belkin and Niyogi, 2003) and GEO (Ashburner et al., 2000). Such repositories have quickly become a community resource. However, due to the inherent heterogeneity of the microarray experiments, the data generated from different experiments could not be directly integrated and hence the resources have not been fully utilised. To address this problem, we propose a new microarray integration framework that achieves high-quality integration through exploiting invariant features such as relative information among genes. We also show how the proposed approach generalises the previous frameworks.