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Jason LIu

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Papers by Jason LIu

Epigenome-based Splicing Prediction using a Recurrent Neural Network

Alternative RNA splicing provides an important means to expand metazoan transcriptome diversity. ... more Alternative RNA splicing provides an important means to expand metazoan transcriptome diversity. Contrary to what was accepted previously, splicing is now thought to predominantly take place during transcription. Motivated by emerging data showing the physical proximity of the spliceosome to Pol II, we surveyed the effect of epigenetic context on co-transcriptional splicing. In particular, we observed that splicing factors were not necessarily enriched at exon junctions and that most epigenetic signatures had a distinctly asymmetric profile around known splice sites. Given this, we tried to build an interpretable model that mimics the physical layout of splicing regulation where the chromatin context progressively changes as the Pol II moves along the guide DNA. We used a recurrent-neural-network architecture to predict the inclusion of a spliced exon based on adjacent epigenetic signals, and we showed that distinct spatio-temporal features of these signals were key determinants of ...

format_quoteA new RNN-based computational approach was proposed to model epigenetic influences on co-transcriptional splicing.format_quote

Carbon chain shape selectivity by the mouse olfactory receptor OR-I7

Organic & biomolecular chemistry, Jan 23, 2018

The rodent OR-I7 is an olfactory receptor exemplar activated by aliphatic aldehydes such as octan... more The rodent OR-I7 is an olfactory receptor exemplar activated by aliphatic aldehydes such as octanal. Normal alkanals shorter than heptanal bind OR-I7 without activating it and hence function as antagonists in vitro. We report a series of aldehydes designed to probe the structural requirements for aliphatic ligand chains too short to meet the minimum approximate 6.9 Å length requirement for receptor activation. Experiments using recombinant mouse OR-I7 expressed in heterologous cells show that in the context of short aldehyde antagonists, OR-I7 prefers binding aliphatic chains without branches, though a single methyl on carbon-3 is permitted. The receptor can accommodate a surprisingly large number of carbons (e.g. ten in adamantyl) as long as the carbons are part of a conformationally constrained ring system. A rhodopsin-based homology model of mouse OR-I7 docked with the new antagonists suggests that small alkyl branches on the alkyl chain sterically interfere with the hydrophobic ...

format_quoteAn aliphatic carbon chain of at least five carbons is essential for antagonist binding to OR-I7, alongside an aldehyde group.format_quote

Proceedings of the 2006 Winter Simulation Conference

Proceedings of the 2006 Winter Simulation Conference, 2006

In this paper, we discuss the design and use of an objectoriented framework for simulating multi-... more In this paper, we discuss the design and use of an objectoriented framework for simulating multi-echelon inventory systems. We present a context for how the framework can be used through its application on two examples. In addition, we describe the design by examining the major conceptual artifacts within the object-oriented model. The framework is built on a Java Simulation Library (JSL) and permits easy modeling and execution of simulation models. The results and discussion indicate the flexibility and power of modeling with the framework. In addition, we summarize our future research efforts to model complex supply chains.

A High-Density Subthreshold SRAM with Data-Independent Bitline Leakage and Virtual Ground Replica Scheme

2007 IEEE International Solid-State Circuits Conference. Digest of Technical Papers, 2007

Robust high-density subthreshold SRAMs are indispensable for emerging ultra-low power application... more Robust high-density subthreshold SRAMs are indispensable for emerging ultra-low power applications such as implantable devices, medical instruments, and wireless sensor networks. Conventional 6T SRAMs in the subthreshold region fail to deliver the density and yield requirements due to the reduced static noise margin (SNM), poor writability, limited number of cells per bitline, and reduced bitline sensing margin. 8T and 10T SRAM cells have been proposed to improve the SNM by decoupling the SRAM cell nodes from the bitline and hence making the read mode SNM equal to the hold mode SNM . This paper introduces various circuit techniques for designing robust high-density subthreshold SRAMs: (i) decoupled cell for read margin improvement, (ii) utilizing reverse short channel effect (RSCE) for write margin improvement, (iii) eliminating data-dependent bitline leakage to enable long bitlines, (iv) virtual ground replica scheme for improved bitline sensing margin, (v) writeback scheme for data preservation during write, and (vi) optimal gate sizing based on subthreshold logical effort.

An 8T Subthreshold SRAM Cell Utilizing Reverse Short Channel Effect for Write Margin and Read Performance Improvement

2007 IEEE Custom Integrated Circuits Conference, 2007

Guardian Function of Mitsugumin 53 in Cell Membrane Repair and Metabolic Syndrome

Biophysical Journal, 2015

isolated mitochondria. Accordingly, we hypothesized that downstream respiratory inhibition by sph... more isolated mitochondria. Accordingly, we hypothesized that downstream respiratory inhibition by sphingosine leads to increased formation of O 2 radicals after reperfusion, which by themselves have only a moderately harmful effect. However when Fe 2D redistributes from lysosomes into mitochondria during ischemia, Fenton chemistry occurs after reperfusion, leading to formation of highly reactive OH radicals, potent inducers of the mitochondrial permeability transition pore and cell death. This hypothesis was directly tested using bafilomycin, which induces the release of Fe 2D from lysosomes with subsequent uptake into mitochondria. Indeed, bafilomycin potentiated sphingosine-induced cell death. The data highlight a novel mechanism mediating I/R injury, which involves sphingosine accumulation and uptake of lysosomal iron into mitochondria during ischemia, leading to respiratory chain inhibition, irondependent oxidative stress, mitochondrial permeability transition and cell death after reperfusion. DK073336, DK037034 and 14.Z50.31.0028 (JJL) and NS083544 (TIG).

Propagation direction reversal of ionization zones in the transition between high and low current magnetron sputtering

Applied Physics Letters, 2014

Past research has revealed the propagation of dense, asymmetric ionization zones in both high and... more Past research has revealed the propagation of dense, asymmetric ionization zones in both high and low current magnetron discharges. Here we report about the direction reversal of ionization zone propagation as observed with fast cameras. At high currents, zones move in the × direction with velocities of 10 3 to 10 4 m/s. However at lower currents, ionization zones are observed to move in the opposite, the − × direction, with velocities ~ 10 3 m/s. It is proposed that the direction reversal is associated with the local balance of ionization and supply of neutrals in the ionization zone. Previous research on high current magnetron sputtering (MS) discharges, especially high power impulse magnetron sputtering (HiPIMS), has revealed a plasma that is rich in structure, featuring self-organized patterns 1,2,3,4 , plasma flares 3,5 , and azimuthally asymmetric particle jets 6,7. The high discharge currents suggest that waves and instabilities play a critical role in the formation of these phenomena 8,9. The most prominent features are drifting regions of enhanced excitation and ionization. Fast imaging of HiPIMS plasma has shown evidence of the presence of

Preferential gene expression in the limbus of the vervet monkey

Molecular vision, 2008

To elucidate the unique molecular factors and biological processes that are differentially expres... more To elucidate the unique molecular factors and biological processes that are differentially expressed in the limbal stem cell microenvironment by comparing directly to that of its immediate adjacent structures, the cornea and conjunctiva. Total RNA was isolated and amplified from the limbus, cornea, and conjunctiva. A gene expression profile of each tissue type was obtained by using microarray technique. The transcripts in which the expression level was at least twofold higher than that in the other two tissue types were identified. The expression levels of selected genes were confirmed by quantitative reverse transcription polymerase chain reaction (QRT-PCR). Protein expression of selected genes were confirmed by an immunohistochemistry study in normal human ocular tissue. There were 186 preferentially overexpressed transcripts in the limbus in direct comparison to that in the cornea and conjunctiva. Many signature genes in the cornea and conjunctiva were among the preferentially ex...

Effect of Electromechanical Stimulation on the Maturation of Myotubes on Aligned Electrospun Fibers

Cellular and molecular bioengineering, 2008

Tissue engineering may provide an alternative to cell injection as a therapeutic solution for myo... more Tissue engineering may provide an alternative to cell injection as a therapeutic solution for myocardial infarction. A tissue-engineered muscle patch may offer better host integration and higher functional performance. This study examined the differentiation of skeletal myoblasts on aligned electrospun polyurethane (PU) fibers and in the presence of electromechanical stimulation. Skeletal myoblasts cultured on aligned PU fibers showed more pronounced elongation, better alignment, higher level of transient receptor potential cation channel-1 (TRPC-1) expression, upregulation of contractile proteins and higher percentage of striated myotubes compared to those cultured on random PU fibers and film. The resulting tissue constructs generated tetanus forces of 1.1 mN with a 10-ms time to tetanus. Additional mechanical, electrical, or synchronized electromechanical stimuli applied to myoblasts cultured on PU fibers increased the percentage of striated myotubes from 70 to 85% under optimal ...

Candidate disease gene prediction using Gentrepid: application to a genome-wide association study on coronary artery disease

Molecular genetics & genomic medicine, 2014

Current single-locus-based analyses and candidate disease gene prediction methodologies used in g... more Current single-locus-based analyses and candidate disease gene prediction methodologies used in genome-wide association studies (GWAS) do not capitalize on the wealth of the underlying genetic data, nor functional data available from molecular biology. Here, we analyzed GWAS data from the Wellcome Trust Case Control Consortium (WTCCC) on coronary artery disease (CAD). Gentrepid uses a multiple-locus-based approach, drawing on protein pathway- or domain-based data to make predictions. Known disease genes may be used as additional information (seeded method) or predictions can be based entirely on GWAS single nucleotide polymorphisms (SNPs) (ab initio method). We looked in detail at specific predictions made by Gentrepid for CAD and compared these with known genetic data and the scientific literature. Gentrepid was able to extract known disease genes from the candidate search space and predict plausible novel disease genes from both known and novel WTCCC-implicated loci. The disease g...

Maspin expression in prostate tumor elicits host anti-tumor immunity

Oncotarget, Jan 30, 2014

The goal of the current study is to examine the biological effects of epithelial-specific tumor s... more The goal of the current study is to examine the biological effects of epithelial-specific tumor suppressor maspin on tumor host immune response. Accumulated evidence demonstrates an anti-tumor effect of maspin on tumor growth, invasion and metastasis. The molecular mechanism underlying these biological functions of maspin is thought to be through histone deacetylase inhibition, key to the maintenance of differentiated epithelial phenotype. Since tumor-driven stromal reactivities co-evolve in tumor progression and metastasis, it is not surprising that maspin expression in tumor cells inhibits extracellular matrix degradation, increases fibrosis and blocks hypoxia-induced angiogenesis. Using the athymic nude mouse model capable of supporting the growth and progression of xenogeneic human prostate cancer cells, we further demonstrate that maspin expression in tumor cells elicits neutrophil- and B cells-dependent host tumor immunogenicity. Specifically, mice bearing maspin-expressing tu...

format_quoteThe study utilized an athymic nude mouse model to establish maspin's role in host immune responses against human cancer cells.format_quote

Parallel Discrete-Event Simulation

Wiley Encyclopedia of Operations Research and Management Science, 2011

Parallel discrete-event simulation (PDES), sometimes simply referred to as parallel simulation, i... more Parallel discrete-event simulation (PDES), sometimes simply referred to as parallel simulation, is concerned with the execution of discrete-event simulation on parallel computers. PDES has been recognized as a challenging field of research bridging modeling and simulation, and high-performance computing. By exploiting the potential parallelism in a simulation model, PDES can overcome the limitations imposed by sequential simulation, both in the execution time and the memory space. It has been demonstrated to be a viable technique for solving large-scale complex models. In this article, we provide a brief overview of the current state of PDES, identify its fundamental challenges, and discuss existing principal solutions resulting from three decades of intensive research in this field. Further, we report specific research advances in high-performance modeling and simulation of large-scale computer networks as an exemplar of typical PDES applications. Keywords: parallel simulation; PDES; conservative synchronization; optimistic synchronization; network simulation

Circuit techniques for ultra-low power subthreshold SRAMs

2008 IEEE International Symposium on Circuits and Systems, 2008

Figure 1. (a) Worst case SNM scenario. (b) SNM simulation results.

Conformational changes in redox pairs of protein structures

Protein Science, 2009

Disulfides are conventionally viewed as structurally stabilizing elements in proteins but emergin... more Disulfides are conventionally viewed as structurally stabilizing elements in proteins but emerging evidence suggests two disulfide subproteomes exist. One group mediates the well known role of structural stabilization. A second redox-active group are best known for their catalytic functions but are increasingly being recognized for their roles in regulation of protein function. Redox-active disulfides are, by their very nature, more susceptible to reduction than structural disulfides; and conversely, the Cys pairs that form them are more susceptible to oxidation. In this study, we searched for potentially redox-active Cys Pairs by scanning the Protein Data Bank for structures of proteins in alternate redox states. The PDB contains over 1134 unique redox pairs of proteins, many of which exhibit conformational differences between alternate redox states. Several classes of structural changes were observed, proteins that exhibit: disulfide oxidation following expulsion of metals such as zinc; major reorganisation of the polypeptide backbone in association with disulfide redox-activity; order/disorder transitions; and changes in quaternary structure. Based on evidence gathered supporting disulfide redox activity, we propose disulfides present in alternate redox states are likely to have physiologically relevant redox activity.

Hyperactive Neuroendocrine Secretion Causes Size, Feeding, and Metabolic Defects of C. elegans Bardet-Biedl Syndrome Mutants

PLoS Biology, 2011

Bardet-Biedl syndrome, BBS, is a rare autosomal recessive disorder with clinical presentations in... more Bardet-Biedl syndrome, BBS, is a rare autosomal recessive disorder with clinical presentations including polydactyly, retinopathy, hyperphagia, obesity, short stature, cognitive impairment, and developmental delays. Disruptions of BBS proteins in a variety of organisms impair cilia formation and function and the multi-organ defects of BBS have been attributed to deficiencies in various cilia-associated signaling pathways. In C. elegans, bbs genes are expressed exclusively in the sixty ciliated sensory neurons of these animals and bbs mutants exhibit sensory defects as well as body size, feeding, and metabolic abnormalities. Here we show that in contrast to many other cilia-defective mutants, C. elegans bbs mutants exhibit increased release of dense-core vesicles and organism-wide phenotypes associated with enhanced activities of insulin, neuropeptide, and biogenic amine signaling pathways. We show that the altered body size, feeding, and metabolic abnormalities of bbs mutants can be corrected to wild-type levels by abrogating the enhanced secretion of dense-core vesicles without concomitant correction of ciliary defects. These findings expand the role of BBS proteins to the regulation of dense-core-vesicle exocytosis and suggest that some features of Bardet-Biedl Syndrome may be caused by excessive neuroendocrine secretion.

format_quoteBardet-Biedl Syndrome involves mutations in at least 14 genes, with seven forming a complex called the BBSome, crucial for ciliary function.format_quote

Analysis of protein sequence and interaction data for candidate disease gene prediction

Nucleic Acids Research, 2006

Linkage analysis is a successful procedure to associate diseases with specific genomic regions. T... more Linkage analysis is a successful procedure to associate diseases with specific genomic regions. These regions are often large, containing hundreds of genes, which make experimental methods employed to identify the disease gene arduous and expensive. We present two methods to prioritize candidates for further experimental study: Common Pathway Scanning (CPS) and Common Module Profiling (CMP). CPS is based on the assumption that common phenotypes are associated with dysfunction in proteins that participate in the same complex or pathway. CPS applies network data derived from protein-protein interaction (PPI) and pathway databases to identify relationships between genes. CMP identifies likely candidates using a domain-dependent sequence similarity approach, based on the hypothesis that disruption of genes of similar function will lead to the same phenotype. Both algorithms use two forms of input data: known disease genes or multiple disease loci. When using known disease genes as input, our combined methods have a sensitivity of 0.52 and a specificity of 0.97 and reduce the candidate list by 13-fold. Using multiple loci, our methods successfully identify disease genes for all benchmark diseases with a sensitivity of 0.84 and a specificity of 0.63. Our combined approach prioritizes good candidates and will accelerate the disease gene discovery process.

Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function

Nature Genetics, 2011

on Air Pollution and Lung Disease in adults; the TwinsUK-II study. * Total number of individuals ... more on Air Pollution and Lung Disease in adults; the TwinsUK-II study. * Total number of individuals with both genotype and phenotype data and which were included in the analyses described in this paper. Study N Total N male N female Age range (y) at FEV 1 /FVC measurement Mean age, y (s.d.) Mean FEV 1 , L (s.d.) Mean FVC, L (s.d.) Mean FEV 1 /FVC (s.d.) N neversmoker s N eversmoker s Genomic inflation factor (λ) FEV 1 Genomic inflation factor (λ) FEV 1 /FVC Stage 1: GWAS Eversmoker s Neversmokers Eversmoker s Neversmokers AGES 1689 686 66-95 42 , but candidate gene studies reporting its association to COPD susceptibility have not provided consistent and conclusive evidence 43 and suggest publication bias. BAT1-BAT5 are HLA-B associated transcripts. MICA and MICB encode the MHC class I chain-related proteins A and B

A whole-organism screen identifies new regulators of fat storage

Nature Chemical Biology, 2011

The regulation of energy homeostasis integrates diverse biological processes ranging from behavio... more The regulation of energy homeostasis integrates diverse biological processes ranging from behavior to metabolism and is linked fundamentally to numerous disease states. To identify new molecules that can bypass homeostatic compensatory mechanisms of energy balance in intact animals, we screened for small molecule modulators of C. elegans fat content. We report on several molecules that modulate fat storage without obvious deleterious effects on feeding, growth, and reproduction. A subset of these compounds also altered fat storage in mammalian and insect cell culture. We found that one of the newly identified compounds exerts its effects in C. elegans through a pathway that requires novel functions of an AMP-activated kinase catalytic subunit and a transcription factor previously unassociated with fat regulation. Thus, our strategy identifies small molecules that are effective within the context of intact animals and reveals relationships between new pathways that operate across phyla to influence energy homeostasis. Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Multiple targets of miR-302 and miR-372 promote reprogramming of human fibroblasts to induced pluripotent stem cells

Nature Biotechnology, 2011

format_quoteThe human ESCC miRNAs hsa-miR-302b and hsa-miR-372 enhance the reprogramming of somatic cells to iPSCs by repressing multiple target genes.format_quote

Primary Glioblastomas Express Mesenchymal Stem-Like Properties

Molecular Cancer Research, 2006

Glioblastoma is the most common and aggressive primary brain cancer. Recent isolation and charact... more Glioblastoma is the most common and aggressive primary brain cancer. Recent isolation and characterization of brain tumor-initiating cells supports the concept that transformed neural stem cells may seed glioblastoma. We previously identified a wide array of mesenchymal tissue transcripts overexpressed in a broad set of primary glioblastoma (de novo) tumors but not in secondary glioblastoma (derived from lower-grade) tumors, low-grade astrocytomas, or normal brain tissues. Here, we extend this observation and show that a subset of primary glioblastoma tumors and their derived tumor lines express cellular and molecular markers that are associated with mesenchymal stem cells (MSC) and that glioblastoma cell cultures can be induced to differentiate into multiple mesenchymal lineage-like cell types. These findings suggest either that a subset of primary glioblastomas derive from transformed stem cells containing MSC-like properties and retain partial phenotypic aspects of a MSC nature i...