Browsing by Author "Wang, L"

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Open Access
Analysis of oxygen/glucose-deprivation-induced changes in SUMO3 conjugation using SILAC-based quantitative proteomics.
(Journal of proteome research, 2012-02) Yang, W; Thompson, JW; Wang, Z; Wang, L; Sheng, H; Foster, MW; Moseley, MA; Paschen, W
Transient cerebral ischemia dramatically activates small ubiquitin-like modifier (SUMO2/3) conjugation. In cells exposed to 6 h of transient oxygen/glucose deprivation (OGD), a model of ischemia, SUMOylation increases profoundly between 0 and 30 min following re-oxygenation. To elucidate the effect of transient OGD on SUMO conjugation of target proteins, we exposed neuroblastoma B35 cells expressing HA-SUMO3 to transient OGD and used stable isotope labeling with amino acids in cell culture (SILAC) to quantify OGD-induced changes in levels of specific SUMOylated proteins. Lysates from control and OGD-treated cells were mixed equally, and HA-tagged proteins were immunoprecipitated and analyzed by 1D-SDS-PAGE-LC-MS/MS. We identified 188 putative SUMO3-conjugated proteins, including numerous transcription factors and coregulators, and PIAS2 and PIAS4 SUMO ligases, of which 22 were increased or decreased more than ±2-fold. In addition to SUMO3, the levels of protein-conjugated SUMO1 and SUMO2, as well as ubiquitin, were all increased. Importantly, protein ubiquitination induced by OGD was completely blocked by gene silencing of SUMO2/3. Collectively, these results suggest several mechanisms for OGD-modulated SUMOylation, point to a number of signaling pathways that may be targets of SUMO-based signaling and recovery from ischemic stress, and demonstrate a tightly controlled crosstalk between the SUMO and ubiquitin conjugation pathways.
Open Access
Complexity of randomized algorithms for underdamped Langevin dynamics
Cao, Y; Lu, J; Wang, L
We establish an information complexity lower bound of randomized algorithms for simulating underdamped Langevin dynamics. More specifically, we prove that the worst $L^2$ strong error is of order $\Omega(\sqrt{d}\, N^{-3/2})$, for solving a family of $d$-dimensional underdamped Langevin dynamics, by any randomized algorithm with only $N$ queries to $\nabla U$, the driving Brownian motion and its weighted integration, respectively. The lower bound we establish matches the upper bound for the randomized midpoint method recently proposed by Shen and Lee [NIPS 2019], in terms of both parameters $N$ and $d$.
Open Access
CPAG: software for leveraging pleiotropy in GWAS to reveal similarity between human traits links plasma fatty acids and intestinal inflammation.
(Genome Biol, 2015-09-15) Wang, L; Oehlers, SH; Espenschied, ST; Rawls, JF; Tobin, DM; Ko, DC
Meta-analyses of genome-wide association studies (GWAS) have demonstrated that the same genetic variants can be associated with multiple diseases and other complex traits. We present software called CPAG (Cross-Phenotype Analysis of GWAS) to look for similarities between 700 traits, build trees with informative clusters, and highlight underlying pathways. Clusters are consistent with pre-defined groups and literature-based validation but also reveal novel connections. We report similarity between plasma palmitoleic acid and Crohn's disease and find that specific fatty acids exacerbate enterocolitis in zebrafish. CPAG will become increasingly powerful as more genetic variants are uncovered, leading to a deeper understanding of complex traits. CPAG is freely available at www.sourceforge.net/projects/CPAG/.
Open Access
Cross-cultural differences of the non-motor symptoms studied by the traditional Chinese version of the International Parkinson and Movement Disorder Society–unified Parkinson’s disease rating scale
(Movement Disorders Clinical Practice, 2017) Yu, RL; Wu, RM; Chan, AYY; Mok, V; Wu, YR; Tilley, BC; Luo, S; Wang, L; LaPelle, NR; Stebbins, GT; others
Open Access
Gender-, age-, and race/ethnicity-based differential item functioning analysis of the movement disorder society–sponsored revision of the Unified Parkinson’s disease rating scale
(Movement Disorders, 2016) Goetz, CG; Liu, Y; Stebbins, GT; Wang, L; Tilley, BC; Teresi, JA; Merkitch, D; Luo, S
Open Access
Generalized Bregman Divergence and Gradient of Mutual Information for Vector Poisson Channels
(2013 IEEE INTERNATIONAL SYMPOSIUM ON INFORMATION THEORY PROCEEDINGS (ISIT), 2013) Wang, L; Rodrigues, M; Carin, L
Open Access
Handling missing values in the MDS-UPDRS
(Movement Disorders, 2015) Goetz, CG; Luo, S; Wang, L; Tilley, BC; LaPelle, NR; Stebbins, GT
Open Access
Human genetic and metabolite variation reveals that methylthioadenosine is a prognostic biomarker and an inflammatory regulator in sepsis
(Science Advances, 2017-03-08) Wang, L; Ko, ER; Gilchrist, JJ; Pittman, KJ; Rautanen, A; Pirinen, M; Thompson, JW; Dubois, LG; Langley, RJ; Jaslow, SL; Salinas, RE; Rouse, DC; Moseley, MA; Mwarumba, S; Njuguna, P; Mturi, N; Williams, TN; Scott, JAG; Hill, AVS; Woods, CW; Ginsburg, GS; Tsalik, EL; Ko, DC
Sepsis is a deleterious inflammatory response to infection with high mortality. Reliable sepsis biomarkers could improve diagnosis, prognosis, and treatment. Integration of human genetics, patient metabolite and cytokine measurements, and testing in a mouse model demonstrate that the methionine salvage pathway is a regulator of sepsis that can accurately predict prognosis in patients. Pathway-based genome-wide association analysis of nontyphoidal Salmonella bacteremia showed a strong enrichment for single-nucleotide polymorphisms near the components of the methionine salvage pathway. Measurement of the pathway’s substrate, methylthioadenosine (MTA), in two cohorts of sepsis patients demonstrated increased plasma MTA in nonsurvivors. Plasma MTA was correlated with levels of inflammatory cytokines, indicating that elevated MTA marks a subset of patients with excessive inflammation. A machine-learning model combining MTA and other variables yielded approximately 80% accuracy (area under the curve) in predicting death. Furthermore, mice infected with Salmonella had prolonged survival when MTA was administered before infection, suggesting that manipulating MTA levels could regulate the severity of the inflammatory response. Our results demonstrate how combining genetic data, biomolecule measurements, and animal models can shape our understanding of disease and lead to new biomarkers for patient stratification and potential therapeutic targeting.
Open Access
Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol
(Proceedings of the National Academy of Sciences, 2017-08-21) Alvarez, MI; Glover, LC; Luo, P; Wang, L; Theusch, E; Oehlers, SH; Walton, EM; Tram, TTB; Kuang, Y; Rotter, JI; McClean, CM; Chinh, NT; Medina, MW; Tobin, DM; Dunstan, SJ; Ko, DC
Risk, severity, and outcome of infection depend on the interplay of pathogen virulence and host susceptibility. Systematic identification of genetic susceptibility to infection is being undertaken through genome-wide association studies, but how to expeditiously move from genetic differences to functional mechanisms is unclear. Here, we use genetic association of molecular, cellular, and human disease traits and experimental validation to demonstrate that genetic variation affects expression of VAC14, a phosphoinositide-regulating protein, to influence susceptibility to Salmonella enterica serovar Typhi (S. Typhi) infection. Decreased VAC14 expression increased plasma membrane cholesterol, facilitating Salmonella docking and invasion. This increased susceptibility at the cellular level manifests as increased susceptibility to typhoid fever in a Vietnamese population. Furthermore, treating zebrafish with a cholesterol-lowering agent, ezetimibe, reduced susceptibility to S. Typhi. Thus, coupling multiple genetic association studies with mechanistic dissection revealed how VAC14 regulates Salmonella invasion and typhoid fever susceptibility and may open doors to new prophylactic/therapeutic approaches.
Open Access
Human uterine leiomyoma-derived fibroblasts stimulate uterine leiomyoma cell proliferation and collagen type I production, and activate RTKs and TGF beta receptor signaling in coculture.
(Cell Commun Signal, 2010-06-10) Moore, AB; Yu, L; Swartz, CD; Zheng, X; Wang, L; Castro, L; Kissling, GE; Walmer, DK; Robboy, SJ; Dixon, D
BACKGROUND: Uterine leiomyomas (fibroids) are benign smooth muscle tumors that often contain an excessive extracellular matrix (ECM). In the present study, we investigated the interactions between human uterine leiomyoma (UtLM) cells and uterine leiomyoma-derived fibroblasts (FB), and their importance in cell growth and ECM protein production using a coculture system. RESULTS: We found enhanced cell proliferation, and elevated levels of ECM collagen type I and insulin-like growth factor-binding protein-3 after coculturing. There was also increased secretion of vascular endothelial growth factor, epidermal growth factor, fibroblast growth factor-2, and platelet derived growth factor A and B in the media of UtLM cells cocultured with FB. Protein arrays revealed increased phosphorylated receptor tyrosine kinases (RTKs) of the above growth factor ligands, and immunoblots showed elevated levels of the RTK downstream effector, phospho-mitogen activated protein kinase 44/42 in cocultured UtLM cells. There was also increased secretion of transforming growth factor-beta 1 and 3, and immunoprecipitated transforming growth factor-beta receptor I from cocultured UtLM cells showed elevated phosphoserine expression. The downstream effectors phospho-small mothers against decapentaplegic -2 and -3 protein (SMAD) levels were also increased in cocultured UtLM cells. However, none of the above effects were seen in normal myometrial cells cocultured with FB. The soluble factors released by tumor-derived fibroblasts and/or UtLM cells, and activation of the growth factor receptors and their pathways stimulated the proliferation of UtLM cells and enhanced the production of ECM proteins. CONCLUSIONS: These data support the importance of interactions between fibroid tumor cells and ECM fibroblasts in vivo, and the role of growth factors, and ECM proteins in the pathogenesis of uterine fibroids.
Open Access
Independent Spanish validation of the Unified Dyskinesia rating scale
(Movement Disorders Clinical Practice, 2014) Cubo, E; Goetz, CG; Stebbins, GT; LaPelle, NR; Tilley, BC; Wang, L; Luo, S
Open Access
MDS-sponsored scale translation program: process, format, and clinimetric testing plan for the MDS-UPDRS and UDysRS
(Movement Disorders Clinical Practice, 2014) Goetz, CG; Stebbins, GT; Wang, L; LaPelle, NR; Luo, S; Tilley, BC
Open Access
Neuropeptide Y gene polymorphisms confer risk of early-onset atherosclerosis.
(PLoS Genet, 2009-01) Shah, SH; Freedman, NJ; Zhang, L; Crosslin, DR; Stone, DH; Haynes, C; Johnson, J; Nelson, S; Wang, L; Connelly, JJ; Muehlbauer, M; Ginsburg, GS; Crossman, DC; Jones, CJ; Vance, J; Sketch, MH; Granger, CB; Newgard, CB; Gregory, SG; Goldschmidt Clermont, PJ; Kraus, WE; Hauser, ER
Neuropeptide Y (NPY) is a strong candidate gene for coronary artery disease (CAD). We have previously identified genetic linkage to familial CAD in the genomic region of NPY. We performed follow-up genetic, biostatistical, and functional analysis of NPY in early-onset CAD. In familial CAD (GENECARD, N = 420 families), we found increased microsatellite linkage to chromosome 7p14 (OSA LOD = 4.2, p = 0.004) in 97 earliest age-of-onset families. Tagged NPY SNPs demonstrated linkage to CAD of a 6-SNP block (LOD = 1.58-2.72), family-based association of this block with CAD (p = 0.02), and stronger linkage to CAD in the earliest age-of-onset families. Association of this 6-SNP block with CAD was validated in: (a) 556 non-familial early-onset CAD cases and 256 controls (OR 1.46-1.65, p = 0.01-0.05), showing stronger association in youngest cases (OR 1.84-2.20, p = 0.0004-0.09); and (b) GENECARD probands versus non-familial controls (OR 1.79-2.06, p = 0.003-0.02). A promoter SNP (rs16147) within this 6-SNP block was associated with higher plasma NPY levels (p = 0.04). To assess a causal role of NPY in atherosclerosis, we applied the NPY1-receptor-antagonist BIBP-3226 adventitially to endothelium-denuded carotid arteries of apolipoprotein E-deficient mice; treatment reduced atherosclerotic neointimal area by 50% (p = 0.03). Thus, NPY variants associate with atherosclerosis in two independent datasets (with strong age-of-onset effects) and show allele-specific expression with NPY levels, while NPY receptor antagonism reduces atherosclerosis in mice. We conclude that NPY contributes to atherosclerosis pathogenesis.
Open Access
Numerical methods for stochastic differential equations based on Gaussian mixture
Li, L; Lu, J; Mattingly, JC; Wang, L
We develop in this work a numerical method for stochastic differential equations (SDEs) with weak second order accuracy based on Gaussian mixture. Unlike the conventional higher order schemes for SDEs based on It\^o-Taylor expansion and iterated It\^o integrals, the proposed scheme approximates the probability measure $\mu(X^{n+1}|X^n=x_n)$ by a mixture of Gaussians. The solution at next time step $X^{n+1}$ is then drawn from the Gaussian mixture with complexity linear in the dimension $d$. This provides a new general strategy to construct efficient high weak order numerical schemes for SDEs.
Open Access
Official Japanese version of the Movement Disorder Society-unified Parkinson's disease rating scale: validation against the original English version
(Movement Disorders Clinical Practice, 2014) Kashihara, K; Tomoyoshi, T; Mizuno, Y; Kikuchi, S; Kuno, S; Hasegawa, K; Hattori, N; Mochizuki, H; Mori, H; Murata, M; Nomoto, M; Takahashi, R; Takeda, A; Tsuboi, Y; Ugawa, Y; Yamanmoto, M; Yokochi, F; Yoshii, F; Stebbins, GT; Tilley, BC; Luo, S; Wang, L; LaPelle, NR; Goetz, CG