Browsing by Author "Zhang, Sheng"
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Item Change Point Modeling of Covid-19 Data in the United States(Society of Statistics, Computer and Applications (SSCA), 2020-07-28) Zhang, Sheng; Xu, Ziyue; Peng, Hanxiang; Mathematical Sciences, School of ScienceTo simultaneously model the change point and the possibly nonlinear relationship in the Covid-19 data of the US, a continuous second-order free knot spline model was proposed. Using the least squares method, the change point of the daily new cases against the total confirmed cases up to the previous day was estimated to be 04 April 2020. Before the point, the daily new cases were proportional to the total cases with a ratio of 0.287, suggesting that each patient had 28.7% chance to infect another person every day. After the point, however, such ratio was no longer maintained and the daily new cases were decreasing slowly. At the individual state level, it was found that most states had change points. Before its change point for each state, the daily new cases were still proportional to the total cases. And all the ratios were about the same except for New York State in which the ratio was much higher (probably due to its high population density and heavy usage of public transportation). But after the points, different states had different patterns. One interesting observation was that the change point of one state was about 3 weeks lagged behind the state declaration of emergency. This might suggest that there was a lag period, which could help identify possible causes for the second wave. In the end, consistency and asymptotic normality of the estimates were briefly discussed where the criterion functions are continuous but not differentiable (irregular).Item Defects in IL-2R Signaling Contribute to Diminished Maintenance of FOXP3 Expression in CD4+CD25+ Regulatory T-Cells of Type 1 Diabetic Subjects(American Diabetes Association, 2010-02) Long, S. Alice; Cerosaletti, Karen; Bollyky, Paul L.; Tatum, Megan; Shilling, Heather; Zhang, Sheng; Zhang, Zhong-Yin; Pihoker, Catherine; Sanda, Srinath; Greenbaum, Carla; Buckner, Jane H.; Biochemistry and Molecular Biology, School of MedicineOBJECTIVE In humans, multiple genes in the interleukin (IL)-2/IL-2 receptor (IL-2R) pathway are associated with type 1 diabetes. However, no link between IL-2 responsiveness and CD4+CD25+FOXP3+ regulatory T-cells (Tregs) has been demonstrated in type 1 diabetic subjects despite the role of these IL-2–dependent cells in controlling autoimmunity. Here, we address whether altered IL-2 responsiveness impacts persistence of FOXP3 expression in Tregs of type 1 diabetic subjects. RESEARCH DESIGN AND METHODS Persistence of Tregs was assessed by culturing sorted CD4+CD25hi natural Tregs with IL-2 and measuring FOXP3 expression over time by flow cytometry for control and type 1 diabetic populations. The effects of IL-2 on FOXP3 induction were assessed 48 h after activation of CD4+CD25− T-cells with anti-CD3 antibody. Cytokine receptor expression and signaling upon exposure to IL-2, IL-7, and IL-15 were determined by flow cytometry and Western blot analysis. RESULTS Maintenance of FOXP3 expression in CD4+CD25+ Tregs of type 1 diabetic subjects was diminished in the presence of IL-2, but not IL-7. Impaired responsiveness was not linked to altered expression of the IL-2R complex. Instead, IL-2R signaling was reduced in Tregs and total CD4+ T-cells of type 1 diabetic subjects. In some individuals, decreased signal transducer and activator of transcription 5 phosphorylation correlated with significantly higher expression of protein tyrosine phosphatase N2, a negative regulator of IL-2R signaling. CONCLUSIONS Aberrant IL-2R signaling in CD4+ T-cells of type 1 diabetic subjects contributes to decreased persistence of FOXP3 expression that may impact establishment of tolerance. These findings suggest novel targets for treatment of type 1 diabetes within the IL-2R pathway and suggest that an altered IL-2R signaling signature may be a biomarker for type 1 diabetes.Item First-generation structure-activity relationship studies of 2,3,4,9-tetrahydro-1H-carbazol-1-amines as CpxA phosphatase inhibitors(Elsevier, 2019-07) Li, Yangxiong; Gardner, Jessi J.; Fortney, Katherine R.; Leus, Inga V.; Bonifay, Vincent; Zgurskaya, Helen I.; Pletnev, Alexandre A.; Zhang, Sheng; Zhang, Zhong-Yin; Gribble, Gordon W.; Spinola, Stanley M.; Duerfeldt, Adam S.; Microbiology and Immunology, School of MedicineGenetic activation of the bacterial two-component signal transduction system, CpxRA, abolishes the virulence of a number of pathogens in human and murine infection models. Recently, 2,3,4,9-tetrahydro-1H-carbazol-1-amines were shown to activate the CpxRA system by inhibiting the phosphatase activity of CpxA. Herein we report the initial structure-activity relationships of this scaffold by focusing on three approaches 1) A-ring substitution, 2) B-ring deconstruction to provide N-arylated amino acid derivatives, and 3) C-ring elimination to give 2-ethylamino substituted indoles. These studies demonstrate that the A-ring is amenable to functionalization and provides a promising avenue for continued optimization of this chemotype. Further investigations revealed that the C-ring is not necessary for activity, although it likely provides conformational constraint that is beneficial to potency, and that the (R) stereochemistry is required at the primary amine. Simplification of the scaffold through deconstruction of the B-ring led to inactive compounds, highlighting the importance of the indole core. A new lead compound 26 was identified, which manifests a ∼30-fold improvement in CpxA phosphatase inhibition over the initial hit. Comparison of amino and des-amino derivatives in bacterial strains differing in membrane permeability and efflux capabilities demonstrate that the amine is required not only for target engagement but also for permeation and accumulation in Escherichia coli.Item Molecular Basis of Gain-of-Function LEOPARD Syndrome-Associated SHP2 Mutations(American Chemical Society, 2014-07-01) Yu, Zhi-Hong; Zhang, Ruo-Yu; Walls, Chad D.; Chen, Lan; Zhang, Sheng; Wu, Li; Liu, Sijiu; Zhang, Zhong-Yin; Department of Biochemistry & Molecular Biology, IU School of MedicineThe Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP2) is a critical signal transducer downstream of growth factors that promotes the activation of the RAS-ERK1/2 cascade. In its basal state, SHP2 exists in an autoinhibited closed conformation because of an intramolecular interaction between its N-SH2 and protein tyrosine phosphatase (PTP) domains. Binding to pTyr ligands present on growth factor receptors and adaptor proteins with its N-SH2 domain localizes SHP2 to its substrates and frees the active site from allosteric inhibition. Germline mutations in SHP2 are known to cause both Noonan syndrome (NS) and LEOPARD syndrome (LS), two clinically similar autosomal dominant developmental disorders. NS-associated SHP2 mutants display elevated phosphatase activity, while LS-associated SHP2 mutants exhibit reduced catalytic activity. A conundrum in how clinically similar diseases result from mutations to SHP2 that have opposite effects on this enzyme’s catalytic functionality exists. Here we report a comprehensive investigation of the kinetic, structural, dynamic, and biochemical signaling properties of the wild type as well as all reported LS-associated SHP2 mutants. The results reveal that LS-causing mutations not only affect SHP2 phosphatase activity but also induce a weakening of the intramolecular interaction between the N-SH2 and PTP domains, leading to mutants that are more readily activated by competing pTyr ligands. Our data also indicate that the residual phosphatase activity associated with the LS SHP2 mutant is required for enhanced ERK1/2 activation. Consequently, catalytically impaired SHP2 mutants could display gain-of-function properties because of their ability to localize to the vicinity of substrates for longer periods of time, thereby affording the opportunity for prolonged substrate turnover and sustained RAS-ERK1/2 activation.Item Novel anticancer agents based on targeting the trimer interface of the PRL phosphatase(AACR Publications, 2016-08-15) Bai, Yunpeng; Yu, Zhi-Hong; Liu, Sijiu; Zhang, Lujuan; Zhang, Ruo-Yu; Zeng, Li-Fan; Zhang, Sheng; Zhang, Zhong-Yin; Biochemistry and Molecular Biology, School of MedicinePRL oncoproteins are phosphatases overexpressed in numerous types of human cancer. Elevated levels of PRL associate with metastasis and poor clinical outcomes. In principle, PRL phosphatases offer appealing therapeutic targets, but they remain underexplored due to the lack of specific chemical probes. In this study, we address this issue by exploiting a unique property of PRL phosphatases, namely, that they may function as homotrimers. Starting from a sequential structure-based virtual screening and medicinal chemistry strategy, we identified Cmpd-43 and several analogs which disrupt PRL1 trimerization. Biochemical and structural analyses demonstrate that Cmpd-43 and its close analogs directly bind the PRL1 trimer interface and obstruct PRL1 trimerization. Cmpd-43 also specifically blocks the PRL1-induced cell proliferation and migration through attenuation of both ERK1/2 and Akt activity. Importantly, Cmpd-43 exerted potent anticancer activity both in vitro and in vivo in a murine xenograft model of melanoma. Our results validate a trimerization-dependent signaling mechanism for PRL and offer proof-of-concept for trimerization inhibitors as candidate therapeutics to treat PRL-driven cancersItem Pre-Treatment and During-Treatment Weight Trajectories in Black and White Women(Elsevier, 2022) Schneider-Worthington, Camille R.; Kinsey, Amber W.; Tan, Fei; Zhang, Sheng; Borgatti, Alena; Davis, Andrea; Dutton, Gareth R.; Mathematical Sciences, School of ScienceIntroduction: Black participants often lose less weight than White participants in response to behavioral weight-loss interventions. Many participants experience significant pretreatment weight fluctuations (between baseline measurement and treatment initiation), which have been associated with treatment outcomes. Pretreatment weight gain has been shown to be more prevalent among Black participants and may contribute to racial differences in treatment responses. The purpose of this study was to (1) examine the associations between pretreatment weight change and treatment outcomes and (2) examine racial differences in pretreatment weight change and weight loss among Black and White participants. Methods: Participants were Black and White women (n=153, 60% Black) enrolled in a 4-month weight loss program. Weight changes occurring during the pretreatment period (41 ± 14 days) were categorized as weight stable (±1.15% of baseline weight), weight gain (≥+1.15%), or weight loss (≤-1.15%). Recruitment and data collection occurred from 2011 to 2015; statistical analyses were performed in 2021. Results: During the pretreatment period, most participants (56%) remained weight stable. Pretreatment weight trajectories did not differ by race (p=0.481). At 4-months, those who lost weight before treatment experienced 2.63% greater weight loss than those who were weight stable (p<0.005), whereas those who gained weight before treatment experienced 1.91% less weight loss (p<0.01). Conclusions: Pretreatment weight changes can impact weight outcomes after initial treatment, although no differences between Black and White participants were observed. Future studies should consider the influence of pretreatment weight change on long-term outcomes (e.g., weight loss maintenance) along with potential racial differences in these associations.Item Sample Size Determination for Subsampling in the Analysis of Big Data, Multiplicative Models for Confidence Intervals and Free-Knot Changepoint Models(2024-05) Zhang, Sheng; Peng, Hanxiang; Tan, Fei; Sarkar, Jyoti; Boukai, BenThe dissertation consists of three parts. Motivated by subsampling in the analysis of Big Data and by data-splitting in machine learning, sample size determination for multidimensional parameters is presented in the first part. In the second part, we propose a novel approach to the construction of confidence intervals based on improved concentration inequalities. We provide the missing factor for the tail probability of a random variable which generalizes Talagrand’s (1995) result of the missing factor in Hoeffding’s inequalities. We give the procedure for constructing confidence intervals and illustrate it with simulations. In the third part, we study irregular change-point models using free-knot splines. The consistency and asymptotic normality of the least squares estimators are proved for the irregular models in which the linear spline is not differentiable. Simulations are carried out to explore the numerical properties of the proposed models. The results are used to analyze the US Covid-19 data.Item SHP2 phosphatase as a novel therapeutic target for melanoma treatment(Impact Journals, 2016-11-08) Zhang, Ruo-Yu; Yu, Zhi-Hong; Zeng, Lifan; Zhang, Sheng; Bai, Yunpeng; Miao, Jinmin; Chen, Lan; Xie, Jingwu; Zhang, Zhong-Yin; Department of Biochemistry & Molecular Biology, IU School of MedicineMelanoma ranks among the most aggressive and deadly human cancers. Although a number of targeted therapies are available, they are effective only in a subset of patients and the emergence of drug resistance often reduces durable responses. Thus there is an urgent need to identify new therapeutic targets and develop more potent pharmacological agents for melanoma treatment. Herein we report that SHP2 levels are frequently elevated in melanoma, and high SHP2 expression is significantly associated with more metastatic phenotype and poorer prognosis. We show that SHP2 promotes melanoma cell viability, motility, and anchorage-independent growth, through activation of both ERK1/2 and AKT signaling pathways. We demonstrate that SHP2 inhibitor 11a-1 effectively blocks SHP2-mediated ERK1/2 and AKT activation and attenuates melanoma cell viability, migration and colony formation. Most importantly, SHP2 inhibitor 11a-1 suppresses xenografted melanoma tumor growth, as a result of reduced tumor cell proliferation and enhanced tumor cell apoptosis. Taken together, our data reveal SHP2 as a novel target for melanoma and suggest SHP2 inhibitors as potential novel therapeutic agents for melanoma treatment.Item Small Molecule Inhibitors Target the Tissue Transglutaminase and Fibronectin Interaction(Public Library of Science, 2014-02-20) Yakubov, Bakhtiyor; Chen, Lan; Belkin, Alexey M.; Zhang, Sheng; Chelladurai, Bhadrani; Zhang, Zhong-Yin; Matei, Daniela; Medicine, School of MedicineTissue transglutaminase (TG2) mediates protein crosslinking through generation of ε-(γ-glutamyl) lysine isopeptide bonds and promotes cell adhesion through interaction with fibronectin (FN) and integrins. Cell adhesion to the peritoneal matrix regulated by TG2 facilitates ovarian cancer dissemination. Therefore, disruption of the TG2-FN complex by small molecules may inhibit cell adhesion and metastasis. A novel high throughput screening (HTS) assay based on AlphaLISA™ technology was developed to measure the formation of a complex between His-TG2 and the biotinylated FN fragment that binds TG2 and to discover small molecules that inhibit this protein-protein interaction. Several hits were identified from 10,000 compounds screened. The top candidates selected based on >70% inhibition of the TG2/FN complex formation were confirmed by using ELISA and bioassays measuring cell adhesion, migration, invasion, and proliferation. In conclusion, the AlphaLISA bead format assay measuring the TG2-FN interaction is robust and suitable for HTS of small molecules. One compound identified from the screen (TG53) potently inhibited ovarian cancer cell adhesion to FN, cell migration, and invasion and could be further developed as a potential inhibitor for ovarian cancer dissemination.Item Small Molecules Target the Interaction between Tissue Transglutaminase and Fibronectin(American Association for Cancer Research, 2019-06-01) Sima, Livia Elena; Yakubov, Bakhtiyor; Zhang, Sheng; Condello, Salvatore; Grigorescu, Arabela A.; Nwani, Nkechiyere G.; Chen, Lan; Schiltz, Gary E.; Arvanitis, Constandina; Zhang, Zhong-Yin; Matei, Daniela; Medicine, School of MedicineTissue transglutaminase (TG2) is a multi-functional protein, with enzymatic, GTP-ase and scaffold properties. TG2 interacts with fibronectin (FN) through its N-terminus domain, stabilizing integrin complexes, which regulate cell adhesion to the matrix. Through this mechanism, TG2 participates in key steps involved in metastasis in ovarian and other cancers. High throughput screening identified several small molecule inhibitors (SMIs) for the TG2/FN complex. Rational medicinal chemistry optimization of the hit compound (TG53) led to second generation analogues (MT1–6). ELISA demonstrated that these analogues blocked TG2/FN interaction and bio-layer interferometry (BLI) showed that the SMIs bound to TG2. The compounds also potently inhibited cancer cell adhesion to FN and decreased outside-in signaling mediated through the focal adhesion kinase (FAK). Blockade of TG2/FN interaction by the small molecules caused membrane ruffling, delaying the formation of stable focal contacts and mature adhesions points and disrupted organization of the actin cytoskeleton. In an in vivo model measuring intraperitoneal (ip) dissemination, MT4 and MT6 inhibited the adhesion of ovarian cancer (OC) cells to the peritoneum. Pre-treatment with MT4 also sensitized OC cells to paclitaxel. The data support continued optimization of the new class of SMIs that block the TG2/FN complex at the interface between cancer cells and the tumor niche.