Browsing by Author "Chen, Chen"
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Item Open Access Emi2-mediated inhibition of E2-substrate ubiquitin transfer by the anaphase-promoting complex/cyclosome through a D-box-independent mechanism.(Mol Biol Cell, 2010-08-01) Tang, Wanli; Wu, Judy Qiju; Chen, Chen; Yang, Chih-Sheng; Guo, Jessie Yanxiang; Freel, Christopher D; Kornbluth, SallyVertebrate eggs are arrested at Metaphase II by Emi2, the meiotic anaphase-promoting complex/cyclosome (APC/C) inhibitor. Although the importance of Emi2 during oocyte maturation has been widely recognized and its regulation extensively studied, its mechanism of action remained elusive. Many APC/C inhibitors have been reported to act as pseudosubstrates, inhibiting the APC/C by preventing substrate binding. Here we show that a previously identified zinc-binding region is critical for the function of Emi2, whereas the D-box is largely dispensable. We further demonstrate that instead of acting through a "pseudosubstrate" mechanism as previously hypothesized, Emi2 can inhibit Cdc20-dependent activation of the APC/C substoichiometrically, blocking ubiquitin transfer from the ubiquitin-charged E2 to the substrate. These findings provide a novel mechanism of APC/C inhibition wherein the final step of ubiquitin transfer is targeted and raise the interesting possibility that APC/C is inhibited by Emi2 in a catalytic manner.Item Restricted Genomic signatures of near-extinction and rebirth of the crested ibis and other endangered bird species(GENOME BIOLOGY, 2014) Li, Shengbin; Li, Bo; Cheng, Cheng; Xiong, Zijun; Liu, Qingbo; Lai, Jianghua; Carey, Hannah V; Zhang, Qiong; Zheng, Haibo; Wei, Shuguang; Zhang, Hongbo; Chang, Liao; Liu, Shiping; Zhang, Shanxin; Yu, Bing; Zeng, Xiaofan; Hou, Yong; Nie, Wenhui; Guo, Youmin; Chen, Teng; Han, Jiuqiang; Wang, Jian; Wang, Jun; Chen, Chen; Liu, Jiankang; Stambrook, Peter J; Xu, Ming; Zhang, Guojie; Gilbert, M Thomas P; Yang, Huanming; Jarvis, Erich D; Yu, Jun; Yan, JianqunBACKGROUND: Nearly one-quarter of all avian species is either threatened or nearly threatened. Of these, 73 species are currently being rescued from going extinct in wildlife sanctuaries. One of the previously most critically-endangered is the crested ibis, Nipponia nippon. Once widespread across North-East Asia, by 1981 only seven individuals from two breeding pairs remained in the wild. The recovering crested ibis populations thus provide an excellent example for conservation genomics since every individual bird has been recruited for genomic and demographic studies. RESULTS: Using high-quality genome sequences of multiple crested ibis individuals, its thriving co-habitant, the little egret, Egretta garzetta, and the recently sequenced genomes of 41 other avian species that are under various degrees of survival threats, including the bald eagle, we carry out comparative analyses for genomic signatures of near extinction events in association with environmental and behavioral attributes of species. We confirm that both loss of genetic diversity and enrichment of deleterious mutations of protein-coding genes contribute to the major genetic defects of the endangered species. We further identify that genetic inbreeding and loss-of-function genes in the crested ibis may all constitute genetic susceptibility to other factors including long-term climate change, over-hunting, and agrochemical overuse. We also establish a genome-wide DNA identification platform for molecular breeding and conservation practices, to facilitate sustainable recovery of endangered species. CONCLUSIONS: These findings demonstrate common genomic signatures of population decline across avian species and pave a way for further effort in saving endangered species and enhancing conservation genomic efforts.Item Open Access Performance Analysis in Large-Scale Stochastic Dynamic Programs(2020) Chen, ChenThis dissertation studies approximations to large-scale stochastic dynamic programs, with an emphasis on applications in revenue management and operations.
Many sequential decision problems from a wide variety of fields can be formulated as stochastic dynamic programs, with optimal policies characterized by the corresponding Bellman equations. However, many such formulations suffer from the so-called “curse of dimensionality”: the number of possible states grows exponentially with the size of the problem, rendering finding an optimal solution impossible when the problem size is large. This forces us to design and analyze suboptimal heuristic policies. In this dissertation, we study two duality techniques --- information relaxations and Lagrangian relaxations --- for analyzing the sub-optimality of heuristic policies in particular applications. These performance bounds in turn imply asymptotic optimality of the heuristic policies for specific “large” regimes in which the “curse of dimensionality” is especially relevant.
The information relaxation duality approach relaxes non-anticipativity constraints by considering a decision maker who has access to the outcomes of future uncertainties before making decisions and adds a penalty that punishes violations of the non-anticipativity onstraints. With a “perfect” information relaxation, the decision maker has access to all future uncertainties, and the problem then reduces to solving a deterministic problem for each outcome. As an application, we consider the classic problem of non-preemptively scheduling a set of jobs on machines with stochastic job processing times and the weighted sum of expected completion time objective. Scheduling problems have a deep and well-developed literature in both operations research and computer science, and many varieties of scheduling problems arise in a broad range of applications. Over the past several decades, research in the stochastic scheduling literature has been focused on the case when processing times are identical across machines, and far less is known about the case with specialized (or “unrelated”) machines --- i.e., each job’s processing distribution may vary across machines. Using a perfect information relaxation duality approach in which all processing times are revealed before scheduling jobs and a penalty that appropriately compensates for this additional information, we explicitly characterize the performance loss of a simple static routing policy relative to an optimal adaptive, non-anticipative scheduling policy. Our result implies that a static routing policy is asymptotically optimal in the regime of many jobs relative to the number of machines.
The second part of the dissertation focuses on Lagrangian relaxations, which decompose a problem into simpler subproblems by moving “complicated” constraints to the objective using Lagrangian dual variables. As an application, we study the problem of dynamic pricing of resources that relocate over a network of locations. Customers with private willingness-to-pay sequentially request to relocate a resource from one location to another, and a revenue-maximizing service provider sets a price for each request. This problem can be formulated as an infinite horizon stochastic dynamic program, but is quite difficult to solve, as optimal pricing policies may depend on the locations of all resources in the network. We first focus on networks with a hub-and-spoke structure, and we develop a dynamic pricing policy and a performance bound based on a Lagrangian relaxation of the capacity constraint that the number of resources at the hub being nonnegative. This relaxation decomposes the problem over spokes and is thus far easier to solve than the original problem. We analyze the performance of the Lagrangian-based policy and focus on a supply-constrained large network regime in which the number of spokes (n) and the number of resources grow at the same rate. We show that the Lagrangian policy loses no more than O(\sqrt{ln n/n}) in performance compared to an optimal policy, thus implying asymptotic optimality as n grows large. Using the same methodology, we also show that no static policy is asymptotically optimal in the large network regime. Finally, we extend the approach to general networks (i.e., multiple, interconnected hubs and spoke-to-spoke connections) and to incorporate relocation times, and we observe strong empirical performance of the policies and bounds on extensive numerical examples, including examples based on data from the ride-hailing company RideAustin.
Item Open Access Regulation of DNA Double Strand Break Response(2014) Chen, ChenTo ensure genomic integrity, dividing cells implement multiple checkpoint pathways during the course of the cell cycle. In response to DNA damage, cells may either halt the progression of the cycle (cell cycle arrest) or undergo apoptosis. This choice depends on the extent of damage and the cell's capacity for DNA repair. Cell cycle arrest induced by double-stranded DNA breaks relies on the activation of the ataxia-telangiectasia (ATM) protein kinase, which phosphorylates cell cycle effectors (e.g., Chk2 and p53) to inhibit cell cycle progression. ATM is an S/T-Q directed kinase that is critical for the cellular response to double-stranded DNA breaks. Following DNA damage, ATM is activated and recruited to sites of DNA damage by the MRN protein complex (Mre11-Rad50-Nbs1 proteins) where ATM phosphorylates multiple substrates to trigger a cell cycle arrest. In cancer cells, this regulation may be faulty and cell division may proceed even in the presence of damaged DNA. We show here that the RSK kinase, often elevated in cancers, can suppress DSB-induced ATM activation in both Xenopus egg extracts and human tumor cell lines. In analyzing each step in ATM activation, we have found that RSK disrupts the binding of the MRN complex to DSB DNA. RSK can directly phosphorylate the Mre11 protein at Ser 676 both in vitro and in intact cells and can thereby inhibit loading of Mre11 onto DSB DNA. Accordingly, mutation of Ser 676 to Ala can reverse inhibition of the DSB response by RSK. Collectively, these data point to Mre11 as an important locus of RSK-mediated checkpoint inhibition acting upstream of ATM activation.
The phosphorylation of Mre11 on Ser 676 is antagonized by phosphatases. Here, we screened for phosphatases that target this site and identified PP5 as a candidate. This finding is consistent with the fact that PP5 is required for the ATM-mediated DNA damage response, indicating that PP5 may promote DSB-induced, ATM-dependent DNA damage response by targeting Mre11 upstream of ATM.
Item Open Access Suppression of DNA-damage checkpoint signaling by Rsk-mediated phosphorylation of Mre11.(Proc Natl Acad Sci U S A, 2013-12-17) Chen, Chen; Zhang, Liguo; Huang, Nai-Jia; Huang, Bofu; Kornbluth, SallyAtaxia telangiectasia mutant (ATM) is an S/T-Q-directed kinase that is critical for the cellular response to double-stranded breaks (DSBs) in DNA. Following DNA damage, ATM is activated and recruited by the MRN protein complex [meiotic recombination 11 (Mre11)/DNA repair protein Rad50/Nijmegen breakage syndrome 1 proteins] to sites of DNA damage where ATM phosphorylates multiple substrates to trigger cell-cycle arrest. In cancer cells, this regulation may be faulty, and cell division may proceed even in the presence of damaged DNA. We show here that the ribosomal s6 kinase (Rsk), often elevated in cancers, can suppress DSB-induced ATM activation in both Xenopus egg extracts and human tumor cell lines. In analyzing each step in ATM activation, we have found that Rsk targets loading of MRN complex components onto DNA at DSB sites. Rsk can phosphorylate the Mre11 protein directly at S676 both in vitro and in intact cells and thereby can inhibit the binding of Mre11 to DNA with DSBs. Accordingly, mutation of S676 to Ala can reverse inhibition of the response to DSBs by Rsk. Collectively, these data point to Mre11 as an important locus of Rsk-mediated checkpoint inhibition acting upstream of ATM activation.Item Open Access The Trim39 ubiquitin ligase inhibits APC/CCdh1-mediated degradation of the Bax activator MOAP-1.(J Cell Biol, 2012-04-30) Huang, Nai-Jia; Zhang, Liguo; Tang, Wanli; Chen, Chen; Yang, Chih-Sheng; Kornbluth, SallyProapoptotic Bcl-2 family members, such as Bax, promote release of cytochrome c from mitochondria, leading to caspase activation and cell death. It was previously reported that modulator of apoptosis protein 1 (MOAP-1), an enhancer of Bax activation induced by DNA damage, is stabilized by Trim39, a protein of unknown function. In this paper, we show that MOAP-1 is a novel substrate of the anaphase-promoting complex (APC/C(Cdh1)) ubiquitin ligase. The influence of Trim39 on MOAP-1 levels stems from the ability of Trim39 (a RING domain E3 ligase) to directly inhibit APC/C(Cdh1)-mediated protein ubiquitylation. Accordingly, small interfering ribonucleic acid-mediated knockdown of Cdh1 stabilized MOAP-1, thereby enhancing etoposide-induced Bax activation and apoptosis. These data identify Trim39 as a novel APC/C regulator and provide an unexpected link between the APC/C and apoptotic regulation via MOAP-1.Item Open Access Ubiquitylation of p53 by the APC/C inhibitor Trim39.(Proc Natl Acad Sci U S A, 2012-12-18) Zhang, Liguo; Huang, Nai-Jia; Chen, Chen; Tang, Wanli; Kornbluth, SallyTripartite motif 39 (Trim39) is a RING domain-containing E3 ubiquitin ligase able to inhibit the anaphase-promoting complex (APC/C) directly. Through analysis of Trim39 function in p53-positive and p53-negative cells, we have found, surprisingly, that p53-positive cells lacking Trim39 could not traverse the G1/S transition. This effect did not result from disinhibition of the APC/C. Moreover, although Trim39 loss inhibited etoposide-induced apoptosis in p53-negative cells, apoptosis was enhanced by Trim39 knockdown in p53-positive cells. Furthermore, we show here that the Trim39 can directly bind and ubiquitylate p53 in vitro and in vivo, leading to p53 degradation. Depletion of Trim39 significantly increased p53 protein levels and cell growth retardation in multiple cell lines. We found that the relative importance of Trim39 and the well-characterized p53-directed E3 ligase, murine double minute 2 (MDM2), varied between cell types. In cells that were relatively insensitive to the MDM2 inhibitor, nutlin-3a, apoptosis could be markedly enhanced by siRNA directed against Trim39. As such, Trim39 may serve as a potential therapeutic target in tumors with WT p53 when MDM2 inhibition is insufficient to elevate p53 levels and apoptosis.Item Open Access Video capsule endoscopy for upper gastrointestinal hemorrhage in the emergency department: A systematic review and meta-analysis.(The American journal of emergency medicine, 2020-06) Shah, Nidhi; Chen, Chen; Montano, Nataly; Cave, David; Siegel, Rebecca; Gentile, Nina T; Limkakeng, Alexander T; Kumar, Anita B; Ma, Yan; Meltzer, Andrew COBJECTIVE:The assessment of the severity of upper gastrointestinal hemorrhage in emergency department (ED) patients is difficult to assess with commonly available diagnostic tools. Small studies have shown that video capsule endoscopy (VCE) is a promising risk-stratification method and may be better than current clinical decision rules such as the Rockall score and the Glasgow Blatchford score. This review aims to assess the accuracy of VCE to detect active upper gastrointestinal hemorrhage compared to a reference standard. METHODS:The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) methodology was used to perform a review of studies that have measured the diagnostic accuracy of VCE. Studies were included if they measured ED use of VCE for upper GI hemorrhage as compared to a reference standard of an esophagogastroduodenoscopy (EGD). A meta-analysis was performed on select patients using a fixed effects and random-effects model to determine the primary outcome of diagnostic test accuracy. RESULTS:40 studies were screened for eligibility and five studies representing 193 patients met the inclusion and exclusion criteria. All patients received both a VCE and an EGD. The sensitivity and specificity of VCE were 0.724 and 0.748, respectively. The diagnostic odds ratio was 6.29 (95% CI: 3.23-12.25) and the summary receiver operating characteristic curve was 0.782. CONCLUSIONS:VCE demonstrated high accuracy for detecting upper GI hemorrhage in this meta-analysis of existing studies. In light of the potential advantages of VCE in the ED, further research is warranted to further establish its role.