Browsing by Author "Li, Fang"

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    A Critical Role of CDKN3 in Bcr-Abl-Mediated Tumorigenesis
    (PLoS, 2014-10) Chen, Qinghuang; Chen, Ke; Guo, Guijie; Li, Fang; Chen, Chao; Wang, Song; Nalepa, Grzegorz; Huang, Shile; Chen, Ji-Long; Department of Medical and Molecular Genetics, IU School of Medicine
    CDKN3 (cyclin-dependent kinase inhibitor 3), a dual specificity protein phosphatase, dephosphorylates cyclin-dependent kinases (CDKs) and thus functions as a key negative regulator of cell cycle progression. Deregulation or mutations of CDNK3 have been implicated in various cancers. However, the role of CDKN3 in Bcr-Abl-mediated chronic myelogenous leukemia (CML) remains unknown. Here we found that CDKN3 acts as a tumor suppressor in Bcr-Abl-mediated leukemogenesis. Overexpression of CDKN3 sensitized the K562 leukemic cells to imanitib-induced apoptosis and dramatically inhibited K562 xenografted tumor growth in nude mouse model. Ectopic expression of CDKN3 significantly reduced the efficiency of Bcr-Abl-mediated transformation of FDCP1 cells to growth factor independence. In contrast, depletion of CDKN3 expression conferred resistance to imatinib-induced apoptosis in the leukemic cells and accelerated the growth of xenograph leukemia in mice. In addition, we found that CDKN3 mutant (CDKN3-C140S) devoid of the phosphatase activity failed to affect the K562 leukemic cell survival and xenografted tumor growth, suggesting that the phosphatase of CDKN3 was required for its tumor suppressor function. Furthermore, we observed that overexpression of CDKN3 reduced the leukemic cell survival by dephosphorylating CDK2, thereby inhibiting CDK2-dependent XIAP expression. Moreover, overexpression of CDKN3 delayed G1/S transition in K562 leukemic cells. Our results highlight the importance of CDKN3 in Bcr-Abl-mediated leukemogenesis, and provide new insights into diagnostics and therapeutics of the leukemia.
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    IUPUI Center for Mathematical Biosciences
    (Office of the Vice Chancellor for Research, 2010-04-09) Boukai, Benzion; Chin, Ray; Dziubek, Andrea; Fokin, Vladimir; Ghosh, Samiran; Kuznetsov, Alexey; Li, Fang; Li, Jiliang; Rader, Andrew; Rubchinsky, Leonid; Sarkar, Jyotirmoy; Guidoboni, Giovanna; Worth, Robert; Zhu, Luoding
    At-Large Mission: “to serve as an umbrella center for spearheading research and programmatic activities in the general bio-mathematics area” • promote and facilitate faculty excellence in mathematical and Computational research in the biosciences; • provide a mechanism and an environment that fosters collaborative research activities across the mathematical sciences and the life and health sciences schools at IUPUI— specifically with the IUSOM; • provide foundations and resources for further strategic development in targeted areas of mathematical and computational biosciences research; and • create greater opportunities and increase competitiveness in seeking and procuring extramural funding.
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    Neurofibromin Deficient Myeloid Cells are Critical Mediators of Aneurysm Formation In Vivo
    (Ovid Technologies Wolters Kluwer -American Heart Association, 2014-03-18) Li, Fang; Downing, Brandon D.; Smiley, Lucy C.; Mund, Julie A.; DiStasi, Matthew R.; Bessler, Waylan K.; Sarchet, Kara N.; Hinds, Daniel M.; Kamendulis, Lisa M.; Hingtgen, Cynthia M.; Case, Jamie; Clapp, D. Wade; Conway, Simon J.; Stansfield, Brian K.; Ingram, David A.; Department of Pediatrics, IU School of Medicine
    Background Neurofibromatosis Type 1 (NF1) is a genetic disorder resulting from mutations in the NF1 tumor suppressor gene. Neurofibromin, the protein product of NF1, functions as a negative regulator of Ras activity in circulating hematopoietic and vascular wall cells, which are critical for maintaining vessel wall homeostasis. NF1 patients have evidence of chronic inflammation resulting in development of premature cardiovascular disease, including arterial aneurysms, which may manifest as sudden death. However, the molecular pathogenesis of NF1 aneurysm formation is unknown. Method and Results Utilizing an angiotensin II-induced aneurysm model, we demonstrate that heterozygous inactivation of Nf1 (Nf1+/−) enhanced aneurysm formation with myeloid cell infiltration and increased oxidative stress in the vessel wall. Using lineage-restricted transgenic mice, we show loss of a single Nf1 allele in myeloid cells is sufficient to recapitulate the Nf1+/− aneurysm phenotype in vivo. Finally, oral administration of simvastatin or the antioxidant apocynin, reduced aneurysm formation in Nf1+/− mice. Conclusion These data provide genetic and pharmacologic evidence that Nf1+/− myeloid cells are the cellular triggers for aneurysm formation in a novel model of NF1 vasculopathy and provide a potential therapeutic target.
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    Optimal Policies in Reliability Modelling of Systems Subject to Sporadic Shocks and Continuous Healing
    (2022-12) Chatterjee, Debolina; Sarkar, Jyotirmoy; Boukai, Benzion; Li, Fang; Wang, Honglang
    Recent years have seen a growth in research on system reliability and maintenance. Various studies in the scientific fields of reliability engineering, quality and productivity analyses, risk assessment, software reliability, and probabilistic machine learning are being undertaken in the present era. The dependency of human life on technology has made it more important to maintain such systems and maximize their potential. In this dissertation, some methodologies are presented that maximize certain measures of system reliability, explain the underlying stochastic behavior of certain systems, and prevent the risk of system failure. An overview of the dissertation is provided in Chapter 1, where we briefly discuss some useful definitions and concepts in probability theory and stochastic processes and present some mathematical results required in later chapters. Thereafter, we present the motivation and outline of each subsequent chapter. In Chapter 2, we compute the limiting average availability of a one-unit repairable system subject to repair facilities and spare units. Formulas for finding the limiting average availability of a repairable system exist only for some special cases: (1) either the lifetime or the repair-time is exponential; or (2) there is one spare unit and one repair facility. In contrast, we consider a more general setting involving several spare units and several repair facilities; and we allow arbitrary life- and repair-time distributions. Under periodic monitoring, which essentially discretizes the time variable, we compute the limiting average availability. The discretization approach closely approximates the existing results in the special cases; and demonstrates as anticipated that the limiting average availability increases with additional spare unit and/or repair facility. In Chapter 3, the system experiences two types of sporadic impact: valid shocks that cause damage instantaneously and positive interventions that induce partial healing. Whereas each shock inflicts a fixed magnitude of damage, the accumulated effect of k positive interventions nullifies the damaging effect of one shock. The system is said to be in Stage 1, when it can possibly heal, until the net count of impacts (valid shocks registered minus valid shocks nullified) reaches a threshold $m_1$. The system then enters Stage 2, where no further healing is possible. The system fails when the net count of valid shocks reaches another threshold $m_2 (> m_1)$. The inter-arrival times between successive valid shocks and those between successive positive interventions are independent and follow arbitrary distributions. Thus, we remove the restrictive assumption of an exponential distribution, often found in the literature. We find the distributions of the sojourn time in Stage 1 and the failure time of the system. Finally, we find the optimal values of the choice variables that minimize the expected maintenance cost per unit time for three different maintenance policies. In Chapter 4, the above defined Stage 1 is further subdivided into two parts: In the early part, called Stage 1A, healing happens faster than in the later stage, called Stage 1B. The system stays in Stage 1A until the net count of impacts reaches a predetermined threshold $m_A$; then the system enters Stage 1B and stays there until the net count reaches another predetermined threshold $m_1 (>m_A)$. Subsequently, the system enters Stage 2 where it can no longer heal. The system fails when the net count of valid shocks reaches another predetermined higher threshold $m_2 (> m_1)$. All other assumptions are the same as those in Chapter 3. We calculate the percentage improvement in the lifetime of the system due to the subdivision of Stage 1. Finally, we make optimal choices to minimize the expected maintenance cost per unit time for two maintenance policies. Next, we eliminate the restrictive assumption that all valid shocks and all positive interventions have equal magnitude, and the boundary threshold is a preset constant value. In Chapter 5, we study a system that experiences damaging external shocks of random magnitude at stochastic intervals, continuous degradation, and self-healing. The system fails if cumulative damage exceeds a time-dependent threshold. We develop a preventive maintenance policy to replace the system such that its lifetime is utilized prudently. Further, we consider three variations on the healing pattern: (1) shocks heal for a fixed finite duration $\tau$; (2) a fixed proportion of shocks are non-healable (that is, $\tau=0$); (3) there are two types of shocks---self healable shocks heal for a finite duration, and non-healable shocks. We implement a proposed preventive maintenance policy and compare the optimal replacement times in these new cases with those in the original case, where all shocks heal indefinitely. Finally, in Chapter 6, we present a summary of the dissertation with conclusions and future research potential.
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    Pathophysiological and behavioral deficits in developing mice following rotational acceleration-deceleration traumatic brain injury
    (Company of Biologists:, 2018-01-30) Wang, Guoxiang; Zhang, Yi Ping; Gao, Zhongwen; Shields, Lisa B. E.; Li, Fang; Chu, Tianci; Lv, Huayi; Moriarty, Thomas; Xu, Xiao-Ming; Yang, Xiaoyu; Shields, Christopher B.; Cai, Jun; Neurological Surgery, School of Medicine
    Abusive head trauma (AHT) is the leading cause of death from trauma in infants and young children. An AHT animal model was developed on 12-day-old mice subjected to 90° head extension-flexion sagittal shaking repeated 30, 60, 80 and 100 times. The mortality and time until return of consciousness were dependent on the number of repeats and severity of the injury. Following 60 episodes of repeated head shakings, the pups demonstrated apnea and/or bradycardia immediately after injury. Acute oxygen desaturation was observed by pulse oximetry during respiratory and cardiac suppression. The cerebral blood perfusion was assessed by laser speckle contrast analysis (LASCA) using a PeriCam PSI system. There was a severe reduction in cerebral blood perfusion immediately after the trauma that did not significantly improve within 24 h. The injured mice began to experience reversible sensorimotor function at 9 days postinjury (dpi), which had completely recovered at 28 dpi. However, cognitive deficits and anxiety-like behavior remained. Subdural/subarachnoid hemorrhage, damage to the brain-blood barrier and parenchymal edema were found in all pups subjected to 60 insults. Proinflammatory response and reactive gliosis were upregulated at 3 dpi. Degenerated neurons were found in the cerebral cortex and olfactory tubercles at 30 dpi. This mouse model of repetitive brain injury by rotational head acceleration-deceleration partially mimics the major pathophysiological and behavioral events that occur in children with AHT. The resultant hypoxia/ischemia suggests a potential mechanism underlying the secondary rotational acceleration-deceleration-induced brain injury in developing mice.
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    Sample Size Determination in Multivariate Parameters With Applications to Nonuniform Subsampling in Big Data High Dimensional Linear Regression
    (2021-12) Wang, Yu; Peng, Hanxiang; Li, Fang; Sarkar, Jyoti; Tan, Fei
    Subsampling is an important method in the analysis of Big Data. Subsample size determination (SSSD) plays a crucial part in extracting information from data and in breaking the challenges resulted from huge data sizes. In this thesis, (1) Sample size determination (SSD) is investigated in multivariate parameters, and sample size formulas are obtained for multivariate normal distribution. (2) Sample size formulas are obtained based on concentration inequalities. (3) Improved bounds for McDiarmid’s inequalities are obtained. (4) The obtained results are applied to nonuniform subsampling in Big Data high dimensional linear regression. (5) Numerical studies are conducted. The sample size formula in univariate normal distribution is a melody in elementary statistics. It appears that its generalization to multivariate normal (or more generally multivariate parameters) hasn’t been caught much attention to the best of our knowledge. In this thesis, we introduce a definition for SSD, and obtain explicit formulas for multivariate normal distribution, in gratifying analogy of the sample size formula in univariate normal. Commonly used concentration inequalities provide exponential rates, and sample sizes based on these inequalities are often loose. Talagrand (1995) provided the missing factor to sharpen these inequalities. We obtained the numeric values of the constants in the missing factor and slightly improved his results. Furthermore, we provided the missing factor in McDiarmid’s inequality. These improved bounds are used to give shrunken sample sizes.