Browsing by Author "Zhang, Yao"

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    Alleviation of monocyte exhaustion by BCG derivative mycolic acid
    Wu, Yajun; Caldwell, Blake; Wang, Jing; Zhang, Yao; Li, Liwu (Elsevier, 2024-01)
    Monocyte exhaustion with sustained pathogenic inflammation and immune-suppression, a hallmark of sepsis resulting from systemic infections, presents a challenge with limited therapeutic solutions. This study identified Methoxy-Mycolic Acid (M-MA), a branchedmycolic acid derived from Mycobacterium bovis Bacillus Calmette–Gue´ rin (BCG), as a potent agent in alleviating monocyte exhaustion and restoring immune homeostasis. Co-treatment of monocytes with M-MA effectively blocked the expansion of Ly6Chi/CD38hi/PD-L1hi monocytes induced by LPS challenges and restored the expression of immuneenhancing CD86. M-MA treatment restored mitochondrial functions of exhausted monocytes and alleviated their suppressive activities on co-cultured T cells. Independent of TREM2, M-MA blocks Src-STAT1- mediated inflammatory polarization and reduces the production of immune suppressors TAX1BP1 and PLAC8. Whole genome methylation analyses revealed M-MA’s ability to erase the methylation memory of exhausted monocytes, particularly restoring Plac8 methylation. Together, our data suggest M-MA as an effective agent in restoring monocyte homeostasis with a therapeutic potential for treating sepsis.
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    CINET GDS-Calculator: Graph Dynamical Systems Visualization
    Wu, Sichao; Zhang, Yao (2012-12-10)
    This report summarizes the project of Graph Dynamical Systems Visualization, which is a subproject under the umbrella of project CINET. Base on some input information, we extract the character of system dynamics and output corresponding diagrams and charts that reflect the dynamical properties of the system, so that it can provide an intuitive and easy way for the researchers to analyze the GDSs. In the introduction section, some background information about the graph dynamical systems and their applications are given in the introduction. Then, we present the requirement analysis, including the task of the project, as well as the challenge we met. Next, this report records the system developing process, including the workflow, user’s manual, developer’ manual, etc. Finally, we summarize the future work. This report can serve as a combination of user’s manual, developer’s manual, and system manual.
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    Deficiency in Toll-interacting protein (Tollip) skews inflamed yet incompetent innate leukocytes in vivo during DSS-induced septic Colitis
    Diao, Na; Zhang, Yao; Chen, Keqiang; Yuan, Ruoxi; Lee, Christina K.; Geng, Shuo; Kowalski, Elizabeth A.; Li, Liwu (Nature, 2016-10-05)
    Functionally compromised neutrophils contribute to adverse clinical outcomes in patients with severe inflammation and injury such as colitis and sepsis. However, the ontogeny of dysfunctional neutrophil during septic colitis remain poorly understood. We report that the dysfunctional neutrophil may be derived by the suppression of Toll-interacting-protein (Tollip). We observed that Tollip deficient neutrophils had compromised migratory capacity toward bacterial product fMLF due to reduced activity of AKT and reduction of FPR2, reduced potential to generate bacterial-killing neutrophil extra-cellular trap (NET), and compromised bacterial killing activity. On the other hand, Tollip deficient neutrophils had elevated levels of CCR5, responsible for their homing to sterile inflamed tissues. The inflamed and incompetent neutrophil phenotype was also observed in vivo in Tollip deficient mice subjected to DSSinduced colitis. We observed that TUDCA, a compound capable of restoring Tollip cellular function, can potently alleviate the severity of DSS-induced colitis. In humans, we observed significantly reduced Tollip levels in peripheral blood collected from human colitis patients as compared to blood samples from healthy donors. Collectively, our data reveal a novel mechanism in Tollip alteration that underlies the inflamed and incompetent polarization of neutrophils leading to severe outcomes of colitis.
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    Effect of Hybridization on Carcass Traits and Meat Quality of Erlang Mountainous Chickens
    Yin, H. D.; Gilbert, Elizabeth R.; Chen, S. Y.; Wang, Y.; Zhang, Z. C.; Zhao, X. L.; Zhang, Yao; Zhu, Q. (2013-10)
    Native chickens hold a significant share of the market in China. In response to the huge demand from the market, the productivity of Chinese native chickens needs to be improved. Cross breeding is an effective method to increase productivity, although it might affect meat quality. In this study, two pure lines (SD02 and SD03) of Erlang mountainous chickens were hybridized with a yellow feather and faster growing line (SD01). The effect of hybridization on carcass and meat quality (physiochemical and textural traits) was measured in the F-1 population at d 91 of age. The hybrids exhibited higher body weight and dressed weight, and amount of semieviscerated, eviscerated, breast muscle and abdominal fat (p<0.05). Abdominal fat yield also increased (p<0.05) compared to the offspring of the two pure-lines. Meanwhile, there was no significant difference in meat quality traits except for the myofiber diameter and density and the shear force of the breast muscle. Overall, the offspring of cross-lines were similar to pure lines in meat color, pH value, inosinic acid, crude protein, crude fat, dry matter, moisture content and amino acid composition in the breast muscle. These results suggest that productivity can be improved via cross-breeding while maintaining meat quality of the Erlang mountainous chicken.
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    Electronic Transport in Highly Mismatched InAs Films on GaAs
    Zhang, Yao (Virginia Tech, 2013-12-09)
    Electrical properties of Si- and Mg-doped InAs epitaxial layers grown by MOCVD were studied by performing magneto-transport measurements at different temperatures, from 300 K down to 1.2 K. The longitudinal magnetoresistance and Hall effect indicate a three-band system existing in n-type (p-type) InAs, which consists of the surface accumulation (inversion) layer, the bulk electron (hole) layer, and the nucleation layer. Therefore, a classical parabolic background in magnetoresistance due to multi-carrier occurs at low fields. With the magnetic field being further applied, a linear magnetoresistance caused by inhomogeneities is revealed. At liquid helium temperature, the Shubnikov-de Haas magneto-oscillations are also observed. These transport characterizations provide a means of analyzing the band structure at the InAs surface. In a set of n-type InAs epilayers with Si doped at different levels, the bulk electron density increases as the doping level increases. The increased ionized impurities lead to lower electron mobilities due to more Coulomb scatterings. For all the n-type InAs films, except the two active layers (surface and the bulk), the nucleation layer contributes to the film conductivity as well with an electron density of ~ 5 x 10¹⁷ cm⁻³ and a mobility of ~ 2000 cm²}/Vs. In a cooldown process, the electron density of each layer slightly and monotonically decreases whereas the mobility experiences a maximum from the competition between phonon scatterings and Coulomb scatterings. The phonon scattering overwhelms the Coulomb scatting at high temperatures, but declines as temperature decreases, thus the mobility increases. Around 100 K, the temperature-independent ionized impurity scattering becomes comparable with and starts exceeding the phonon scattering, as temperature further lowered, the screening effect of the Coulomb scattering is weakened because of the decreased carrier densities. As a result, the mobility starts dropping. The maximum mobility corresponds to a minimum resistance, which explains the non-trivial temperature dependence of the resistance in the cooldown history. For the p-type InAs film, the doping with Mg in the course of MOCVD growth allows us to obtain a large hole density and a low mobility at 300 K. At low temperatures, holes are frozen out, and a strong negative magnetoresistance with a dip at 0 field are observed, which is the antilocalization signal from accumulation electrons. This is a strong technique to probe the surface quantum states and derive the phase coherence length and the spin flip length of surface electrons.
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    Enhanced Mucosal Defense and Reduced Tumor Burden in Mice with the Compromised Negative Regulator IRAK-M.
    Rothschild, Daniel E.; Zhang, Yao; Diao, Na; Lee, Christina K.; Chen, Keqiang; Caswell, Clayton C.; Slade, Daniel J.; Helm, Richard F.; LeRoith, Tanya; Li, Liwu; Allen, Irving C. (2016-12-03)
    Aberrant inflammation is a hallmark of inflammatory bowel disease (IBD) and colorectal cancer. IRAK-M is a critical negative regulator of TLR signaling and overzealous inflammation. Here we utilize data from human studies and Irak-m(-/-) mice to elucidate the role of IRAK-M in the modulation of gastrointestinal immune system homeostasis. In human patients, IRAK-M expression is up-regulated during IBD and colorectal cancer. Further functional studies in mice revealed that Irak-m(-/-) animals are protected against colitis and colitis associated tumorigenesis. Mechanistically, our data revealed that the gastrointestinal immune system of Irak-m(-/-) mice is highly efficient at eliminating microbial translocation following epithelial barrier damage. This attenuation of pathogenesis is associated with expanded areas of gastrointestinal associated lymphoid tissue (GALT), increased neutrophil migration, and enhanced T-cell recruitment. Further evaluation of Irak-m(-/-) mice revealed a splice variant that robustly activates NF-κB signaling. Together, these data identify IRAK-M as a potential target for future therapeutic intervention.
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    Enhanced Neutrophil Immune Homeostasis Due to Deletion of PHLPP
    Ran, Taojing; Zhang, Yao; Diao, Na; Chen, Keqiang; Lee, Christina K.; Li, Liwu (Frontiers, 2019-09-06)
    Enhanced Neutrophil Immune Homeostasis Due to Deletion of PHLPNeutrophils are known to adopt dynamic and distinct functional phenotypes involved in the modulation of inflammation and immune homeostasis. However, inter-cellular signaling mechanisms that govern neutrophil polarization dynamics are not well understood. Employing a novel model of PHLPP deficient mice, we examined how neutrophils deficient in PHLPP may uniquely modulate immune defense and the host response during acute colitis. We found that PHLPP−/− mice were protected from dextran sodium sulfate (DSS)-induced septic colitis characterized by minimal body weight-loss, alleviated colon tissue destruction and reduced clinical symptoms. PHLPP−/− neutrophils have enhanced immune homeostasis as compared to WT neutrophils, reflected in enhanced migratory capacity toward chemoattractants, and reduced expression of inflammatory mediators due to elevated phosphorylation of AKT, STAT1, and ERK. Further, adoptive transfer of PHLPP deficient neutrophils to WT mice is sufficient to potently alleviate the severity of DSS-induced colitis. Our data reveal that PHLPP deficient neutrophils can be uniquely reprogrammed to a state conducive to host inflammation resolution. As a consequence, PHLPP−/− neutrophils can effectively transfer immune homeostasis in mice subjected to acute colitis. Our findings hold significant and novel insights into the mechanisms by which neutrophils can be effectively reprogrammed into a homeostatic state conducive for treating acute injuries such as septic colitis.
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    Experimental Measurements by Antilocalization of the Interactions between Two-Dimensional Electron Systems and Magnetic Surface Species
    Zhang, Yao (Virginia Tech, 2014-06-18)
    Low-temperature weak-localization (WL) and antilocalization (AL) magnetotransport measurements are sensitive to electron interference, and thus can be used as a probe of quantum states. The spin-dependent interactions between controllable surface magnetism and itinerant electrons in a non-magnetic host provide insight for spin-based technologies, magnetic data storage and quantum information processing. This dissertation studies two different host systems, an In$_{0.53}$Ga$_{0.47}$As quantum well at a distance from the surface of a heterostructure, and an accumulation layer on an InAs surface. Both the systems are two-dimensional electron systems (2DESs), and possess prominent Rashba spin-orbit interaction caused by structural inversion asymmetry, which meets the prerequisites for AL. The surface local moments influence the surrounding electrons in two ways, increasing their spin-orbit scattering, and inducing magnetic spin-flip scattering, which carries information about magnetic interactions. The two effects modify the AL signals in opposing directions: the spin-flip scattering of electrons shrinks the signal, and requires a close proximity to the species, whereas the increase of spin-orbit scattering broadens and increases the signal. Accordingly, we only observe an increase in spin-orbit scattering in the study of the interactions between ferromagnetic Co$_{0.6}$Fe$_{0.4}$ nanopillars and the relatively distant InGaAs quantum well. With these CoFe nanopillars, a decrease in spin decoherence time is observed, attributed to the spatially varying magnetic field from the local moments. A good agreement between the data and a theoretical calculation suggests that the CoFe nanopillars also generate an appreciable average magnetic field normal to the surface, of value $\sim$ 35 G. We also performed a series of comparative AL measurements to experimentally investigate the interactions and spin-exchange between InAs surface accumulation electrons and local magnetic moments of rare earth ions Sm$^{3+}$, Gd$^{3+}$, Ho$^{3+}$, of transition metal ions Ni$^{2+}$, Co$^{2+}$, and Fe$^{3+}$, and of Ni$^{2+}$-, Co$^{2+}$-, and Fe$^{3+}$-phthalocyanines deposited on the surface. The deposited species generate magnetic scattering with magnitude dependent on their electron configurations and effective moments. Particularly for Fe$^{3+}$, the significant spin-flip scattering due to the outermost 3d shell and the fairly high magnetic moments modifies the AL signal into a WL signal. Experiments indicate a temperature-independent magnetic spin-flip scattering for most of the species except for Ho$^{3+}$ and Co$^{2+}$. Ho$^{3+}$ yields electron spin-flip rates proportional to the square root of temperature, resulting from transitions between closely spaced energy levels of spin-orbit multiplets. In the case of Co$^{2+}$, either a spin crossover or a spin-glass system forms, and hence spin-flip rates transit between two saturation regions as temperature varies. Concerning the spin-orbit scattering rate, we observe an increase for all the species, and the increase is correlated with the effective electric fields produced by the species. In both 2DESs, the inelastic time is inversely proportional to temperature, consistent with phase decoherence via the Nyquist mechanism. Our method provides a controlled way to probe the quantum spin interactions of 2DESs, either in a quantum well, or on the surface of InAs.
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    Measurement of the B0 lifetime and flavor-oscillation frequency using hadronic decays reconstructed in 2019-2021 Belle II data
    Ablikim, M.; Achasov, M. N.; Adlarson, P.; Ahmed, S.; Albrecht, M.; Amoroso, A.; An, Q.; Bai, X. H.; Bai, Y.; Bakina, O.; Ferroli, R. Baldini; Balossino, I.; Ban, Y.; Begzsuren, K.; Bennett, J.; Berger, N.; Bertani, M.; Bettoni, D.; Bianchi, F.; Biernat, J.; Bloms, J.; Bortone, A.; Boyko, I.; Briere, R. A.; Cai, H.; Cai, X.; Calcaterra, A.; Cao, G. F.; Cao, N.; Cetin, S. A.; Chang, J. F.; Chang, W. L.; Chelkov, G.; Chen, D. Y.; Chen, G.; Chen, H. S.; Chen, M. L.; Chen, S. J.; Chen, X. R.; Chen, Y. B.; Cheng, W.; Cibinetto, G.; Cossio, F.; Cui, X. F.; Dai, H. L.; Dai, J. P.; Dai, X. C.; Dbeyssi, A.; de Boer, R. B.; Dedovich, D.; Deng, Z. Y.; Denig, A.; Denysenko, I.; Destefanis, M.; De Mori, F.; Ding, Y.; Dong, C.; Dong, J.; Dong, L. Y.; Dong, M. Y.; Du, S. X.; Fang, J.; Fang, S. S.; Fang, Y.; Farinelli, R.; Fava, L.; Feldbauer, F.; Felici, G.; Feng, C. Q.; Fritsch, M.; Fu, C. D.; Fu, Y.; Gao, X. L.; Gao, Y.; Gao, Y.; Gao, Y. G.; Garzia, I.; Gersabeck, E. M.; Gilman, A.; Goetzen, K.; Gong, L.; Gong, W. X.; Gradl, W.; Greco, M.; Gu, L. M.; Gu, M. H.; Gu, S.; Gu, Y. T.; Guan, C. Y.; Guo, A. Q.; Guo, L. B.; Guo, R. P.; Guo, Y. P.; Guskov, A.; Han, S.; Han, T. T.; Han, T. Z.; Hao, X. Q.; Harris, F. A.; He, K. L.; Heinsius, F. H.; Held, T.; Heng, Y. K.; Himmelreich, M.; Holtmann, T.; Hou, Y. R.; Hou, Z. L.; Hu, H. M.; Hu, J. F.; Hu, T.; Hu, Y.; Huang, G. S.; Huang, L. Q.; Huang, X. T.; Huesken, N.; Hussain, T.; Andersson, W. Ikegami; Imoehl, W.; Irshad, M.; Jaeger, S.; Ji, Q.; Ji, Q. P.; Ji, X. B.; Ji, X. L.; Jiang, H. B.; Jiang, X. S.; Jiang, X. Y.; Jiao, J. B.; Jiao, Z.; Jin, S.; Jin, Y.; Johansson, T.; Kalantar-Nayestanaki, N.; Kang, X. S.; Kappert, R.; Kavatsyuk, M.; Ke, B. C.; Keshk, I. K.; Khoukaz, A.; Kiese, P.; Kiuchi, R.; Kliemt, R.; Koch, L.; Kolcu, O. B.; Kopf, B.; Kuemmel, M.; Kuessner, M.; Kupsc, A.; Kurth, M. G.; Kuehn, W.; Lane, J. J.; Lange, J. S.; Larin, P.; Lavezzi, L.; Leithoff, H.; Lellmann, M.; Lenz, T.; Li, C.; Li, C. H.; Li, Cheng; Li, D. M.; Li, F.; Li, G.; Li, H. B.; Li, H. J.; Li, J. L.; Li, J. Q.; Li, Ke; Li, L. K.; Li, Lei; Li, P. L.; Li, P. R.; Li, W. D.; Li, W. G.; Li, X. H.; Li, X. L.; Li, Z. B.; Li, Z. Y.; Liang, H.; Liang, H.; Liang, Y. F.; Liang, Y. T.; Liao, L. Z.; Libby, J.; Lin, C. X.; Liu, B.; Liu, B. J.; Liu, C. X.; Liu, D.; Liu, D. Y.; Liu, F. H.; Liu, Fang; Liu, Feng; Liu, H. B.; Liu, H. M.; Liu, Huanhuan; Liu, Huihui; Liu, J. B.; Liu, J. Y.; Liu, K.; Liu, K. Y.; Liu, Ke; Liu, L.; Liu, L. Y.; Liu, Q.; Liu, S. B.; Liu, T.; Liu, X.; Liu, Y. B.; Liu, Z. A.; Liu, Zhiqing; Long, Y. F.; Lou, X. C.; Lu, H. J.; Lu, J. D.; Lu, J. G.; Lu, X. L.; Lu, Y.; Lu, Y. P.; Luo, C. L.; Luo, M. X.; Luo, P. W.; Luo, T.; Luo, X. L.; Lusso, S.; Lyu, X. R.; Ma, F. C.; Ma, H. L.; Ma, L. L.; Ma, M. M.; Ma, Q. M.; Ma, R. Q.; Ma, R. T.; Ma, X. N.; Ma, X. X.; Ma, X. Y.; Ma, Y. M.; Maas, F. E.; Maggiora, M.; Maldaner, S.; Malde, S.; Malik, Q. A.; Mangoni, A.; Mao, Y. J.; Mao, Z. P.; Marcello, S.; Meng, Z. X.; Messchendorp, J. G.; Mezzadri, G.; Min, T. J.; Mitchell, R. E.; Mo, X. H.; Mo, Y. J.; Muchnoi, N. Yu; Muramatsu, H.; Nakhoul, S.; Nefedov, Y.; Nerling, F.; Nikolaev, I. B.; Ning, Z.; Nisar, S.; Olsen, S. L.; Ouyang, Q.; Pacetti, S.; Pan, Y.; Pan, Y.; Papenbrock, M.; Pathak, A.; Patteri, P.; Pelizaeus, M.; Peng, H. P.; Peters, K.; Pettersson, J.; Ping, J. L.; Ping, R. G.; Pitka, A.; Poling, R.; Prasad, V.; Qi, H.; Qi, M.; Qi, T. Y.; Qian, S.; Qiao, C. F.; Qin, L. Q.; Qin, X. P.; Qin, X. S.; Qin, Z. H.; Qiu, J. F.; Qu, S. Q.; Rashid, K. H.; Ravindran, K.; Redmer, C. F.; Rivetti, A.; Rodin, V.; Rolo, M.; Rong, G.; Rosner, Ch; Rump, M.; Sarantsev, A.; Savrie, M.; Schelhaas, Y.; Schnier, C.; Schoenning, K.; Shan, W.; Shan, X. Y.; Shao, M.; Shen, C. P.; Shen, P. X.; Shen, X. Y.; Shi, H. C.; Shi, R. S.; Shi, X.; Shi, X. D.; Song, J. J.; Song, Q. Q.; Song, Y. X.; Sosio, S.; Spataro, S.; Sui, F. F.; Sun, G. X.; Sun, J. F.; Sun, L.; Sun, S. S.; Sun, T.; Sun, W. Y.; Sun, Y. J.; Sun, Y. K.; Sun, Y. Z.; Sun, Z. T.; Tan, Y. X.; Tang, C. J.; Tang, G. Y.; Thoren, V.; Tsednee, B.; Uman, I.; Wang, B.; Wang, B. L.; Wang, C. W.; Wang, D. Y.; Wang, H. P.; Wang, K.; Wang, L. L.; Wang, M.; Wang, M. Z.; Wang, Meng; Wang, W. P.; Wang, X.; Wang, X. F.; Wang, X. L.; Wang, Y.; Wang, Y.; Wang, Y. D.; Wang, Y. F.; Wang, Y. Q.; Wang, Z.; Wang, Z. Y.; Wang, Ziyi; Wang, Zongyuan; Weber, T.; Wei, D. H.; Weidenkaff, P.; Weidner, F.; Wen, H. W.; Wen, S. P.; White, D. J.; Wiedner, U.; Wilkinson, G.; Wolke, M.; Wollenberg, L.; Wu, J. F.; Wu, L. H.; Wu, L. J.; Wu, Z.; Xia, L.; Xiao, S. Y.; Xiao, Y. J.; Xiao, Z. J.; Xie, Y. G.; Xie, Y. H.; Xing, T. Y.; Xiong, X. A.; Xu, G. F.; Xu, J. J.; Xu, Q. J.; Xu, W.; Xu, X. P.; Yan, L.; Yan, W. B.; Yan, W. C.; Yang, H. J.; Yang, H. X.; Yang, L.; Yang, R. X.; Yang, S. L.; Yang, Y. H.; Yang, Y. X.; Yang, Yifan; Yang, Zhi; Ye, M.; Ye, M. H.; Yin, J. H.; You, Z. Y.; Yu, B. X.; Yu, C. X.; Yu, G.; Yu, J. S.; Yu, T.; Yuan, C. Z.; Yuan, W.; Yuan, X. Q.; Yuan, Y.; Yue, C. X.; Yuncu, A.; Zafar, A. A.; Zeng, Y.; Zhang, B. X.; Zhang, Guangyi; Zhang, H. H.; Zhang, H. Y.; Zhang, J. L.; Zhang, J. Q.; Zhang, J. W.; Zhang, J. Y.; Zhang, J. Z.; Zhang, Jianyu; Zhang, Jiawei; Zhang, L.; Zhang, Lei; Zhang, S.; Zhang, S. F.; Zhang, T. J.; Zhang, X. Y.; Zhang, Y.; Zhang, Y. H.; Zhang, Y. T.; Zhang, Yan; Zhang, Yao; Zhang, Yi; Zhang, Z. H.; Zhang, Z. Y.; Zhao, G.; Zhao, J.; Zhao, J. Y.; Zhao, J. Z.; Zhao, Lei; Zhao, Ling; Zhao, M. G.; Zhao, Q.; Zhao, S. J.; Zhao, Y. B.; Zhao, Z. G.; Zhemchugov, A.; Zheng, B.; Zheng, J. P.; Zheng, Y.; Zheng, Y. H.; Zhong, B.; Zhong, C.; Zhou, L. P.; Zhou, Q.; Zhou, X.; Zhou, X. K.; Zhou, X. R.; Zhu, A. N.; Zhu, J.; Zhu, K.; Zhu, K. J.; Zhu, S. H.; Zhu, W. J.; Zhu, X. L.; Zhu, Y. C.; Zhu, Z. A.; Zou, B. S.; Zou, J. H. (American Physical Society, 2023-05-15)
    We measure the B0 lifetime and flavor-oscillation frequency using B0→D(∗)-π+ decays collected by the Belle II experiment in asymmetric-energy e+e- collisions produced by the SuperKEKB collider operating at the ϒ(4S) resonance. We fit the decay-time distribution of signal decays, where the initial flavor is determined by identifying the flavor of the other B meson in the event. The results, based on 33000 signal decays reconstructed in a data sample corresponding to 190 fb-1, are τB0=(1.499±0.013±0.008) ps, Δmd=(0.516±0.008±0.005) ps-1, where the first uncertainties are statistical and the second are systematic. These results are consistent with the world-average values.
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    Mechanisms of Neutrophil Exhaustion and Resolution
    Lin, Rui-Ci (Virginia Tech, 2023-02-03)
    Sepsis is a systemic inflammatory response to infection, which may ultimately lead to multi-organ failure. Sepsis causes millions of deaths each year and creates tremendous financial burdens on the health care system, yet there is no effective cure for sepsis. Even years after the onset of sepsis, patients who have clinically recovered still die from sepsis-related complications due to chronic immune dysfunction. Neutrophils, the most dominant leukocytes in human circulatory systems, play a critical role in not only promoting inflammation to fight against microbe invasion but also facilitating inflammation resolution to restore immune homeostasis. While dysfunctional/exhausted neutrophils have been implicated in the long-term morbidity and mortality of sepsis, the cause of neutrophil exhaustion and the system to rejuvenate the dysregulated immunity are understudied. To fill in the missing piece here, we conducted our trilogy-like projects. First, we established an in vitro culture system to mimic sepsis-like conditions: murine neutrophils prolonged-stimulated with LPS exhibit exhaustion-related phenotype with the elevated expression of both proinflammatory and immunosuppressive makers on the cell surface as well as dysregulated swarming patterns. We found that by knocking out TRAM (TICAM2), an adaptive molecule regulating TLR4 downstream MyD88-independent signaling pathway, neutrophils exhibit attenuated exhaustion on both phenotypic and functional levels. Of note, TRAM contributes to the development of exhausted neutrophils through activating Src family kinases (SFKs)-STAT1 cascade, and deficiency in TRAM provides protective effects on systemic inflammation, reduces tissue injury, and improves survival in a murine colitis-induced sepsis model. Next, in my second project, we reported that neutrophils can be clustered into three subpopulations even at their naïve state based on the single-cell RNA sequencing (scRNAseq) analyses. Of note, neutrophils in one of the clusters are more mature but less apoptotic with the elevated expression of resolving-associated markers Cd86 and Cd200r, hence we termed these neutrophils as 'resolving neutrophils'. We found that the resolving neutrophil population can be expanded via pharmacologically reprogramming with sodium 4-phenylbutyrate (4-PBA) or genetic deletion of TRAM. Resolving neutrophils not only secrete more pro-resolving mediators, such as ResolvinD1 and SerpinB1, but also exert enhanced phagocytic and bactericidal capacities. Mechanistically, we discovered that the development of resolving phenotype in neutrophils is mediated by the PPARγ/LMO4/STAT3 signaling circuitry, which is constitutively suppressed by TRAM. To explore the translational applications of resolving neutrophils, in my third and final project, we conducted adoptive transfer experiments to examine the effects of TRAM-deficient resolving neutrophils in cecal slurry (CS)-induced septic mice. We found that TRAM-deficient mice are more resilient to severe sepsis with reduced tissue injury and less compromised lung integrity as compared to wild-type (WT) mice, and splenic neutrophils from TRAM deficient septic mice better preserve resolving-related features. Moreover, transfusing TRAM deficient neutrophils in WT septic mice renders therapeutic effects with alleviated lung and kidney damage. We also observed TRAM-deficient neutrophil-mediated resolving memory propagation in vitro to promote resolving features of neutrophils, monocytes, and T cells, as well as to strengthen endothelial cell barrier function. In terms of the mechanism, we reported that TRAM is critical for the secretion of neutrophil elastase, a potent protein to compromise endothelium; hence, endothelial cells cocultured with TRAM deficient neutrophils maintain higher levels of adhesion/tight junction markers than cocultured with WT neutrophils. Taken together, our trilogy projects better define exhausted and resolving neutrophils. And most importantly, our works demonstrate that TRAM, an underappreciated molecule, is responsible for inducing neutrophil exhaustion and suppressing resolving neutrophil generation.
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    Optimizing and Understanding Network Structure for Diffusion
    Zhang, Yao (Virginia Tech, 2017-10-16)
    Given a population contact network and electronic medical records of patients, how to distribute vaccines to individuals to effectively control a flu epidemic? Similarly, given the Twitter following network and tweets, how to choose the best communities/groups to stop rumors from spreading? How to find the best accounts that bridge celebrities and ordinary users? These questions are related to diffusion (aka propagation) phenomena. Diffusion can be treated as a behavior of spreading contagions (like viruses, ideas, memes, etc.) on some underlying network. It is omnipresent in areas such as social media, public health, and cyber security. Examples include diseases like flu spreading on person-to-person contact networks, memes disseminating by online adoption over online friendship networks, and malware propagating among computer networks. When a contagion spreads, network structure (like nodes/edges/groups, etc.) plays a major role in determining the outcome. For instance, a rumor, if propagated by celebrities, can go viral. Similarly, an epidemic can die out quickly, if vulnerable demographic groups are successfully targeted for vaccination. Hence in this thesis, we aim to optimize and understand network structure better in light of diffusion. We optimize graph topologies by removing nodes/edges for controlling rumors/viruses from spreading, and gain a deeper understanding of a network in terms of diffusion by exploring how nodes group together for similar roles of dissemination. We develop several novel graph mining algorithms, with different levels of granularity (node/edge level to group/community level), from model-driven and data-driven perspectives, focusing on topics like immunization on networks, graph summarization, and community detection. In contrast to previous work, we are the first to systematically develops more realistic, implementable and data-based graph algorithms to control contagions. In addition, our thesis is also the first work to use diffusion to effectively summarize graphs and understand communities/groups of networks in a general way. 1. Model-driven. Diffusion processes are usually described using mathematical models, e.g., the Independent Cascade (IC) model in social media, and the Susceptible-Infectious-Recovered (SIR) model in epidemiology. Given such models, we propose to optimize network structure for controlling propagation (the immunization problem) in several practical and implementable settings, taking into account the presence of infections, the uncertain nature of the data and group structure of the population. We develop efficient algorithms for different interventions, such as vaccination (node removal) and quarantining (edge removal). In addition, we study the graph coarsening problem for both static and temporal networks to obtain a better understanding of relations among nodes when a contagion is propagating. We seek to get a much smaller representation of a large network, while preserving its diffusive properties. 2. Data-driven. Model-driven approaches can provide ideal results if underlying diffusion models are given. However, in many situations, diffusion processes are very complicated, and it is challenging or even impossible to pick the most suited model to describe them. In addition, rapid technological development has provided an abundance of data such as tweets and electronic medical records. Hence, in the second part of the thesis, we explore data-driven approaches for diffusion in networks, which can directly work on propagation data by relaxing modeling assumptions of diffusion. To be specific, we first develop data-driven immunization strategies to stop rumors or allocate vaccines by optimizing network topologies, using large-scale national-level diagnostic patient data with billions of flu records. Second, we propose a novel community detection problem to discover "bridge" and "celebrity" communities from social media data, and design case studies to understand roles of nodes/communities using diffusion. Our work has many applications in multiple areas such as epidemiology, sociology and computer science. For example, our work on efficient immunization algorithms, such as data-driven immunization, can help CDC better allocate vaccines to control flu epidemics in major cities. Similarly, in social media, our work on understanding network structure using diffusion can lead to better community discovery, such as finding media accounts that can boost tweet promotions in Twitter.
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    The persistence of low-grade inflammatory monocytes contributes to aggravated Atherosclerosis
    Geng, Shuo; Chen, Keqiang; Yuan, Ruoxi; Maitra, Urmila; Na, Diao; Chen, Chun; Zhang, Yao; Li, Liwu; Xiong, Huabao; Peng, Liang; Hu, Yuan; Qi, Chen-Feng; Pierce, Susan; Ling, Wenhua (Nature, 2016-11-08)
    Sustained low-grade inflammation mediated by non-resolving inflammatory monocytes has long been suspected in the pathogenesis of atherosclerosis; however, the molecular mechanisms responsible for the sustainment of non-resolving inflammatory monocytes during atherosclerosis are poorly understood. Here we observe that subclinical endotoxemia, often seen in humans with chronic inflammation, aggravates murine atherosclerosis through programming monocytes into a non-resolving inflammatory state with elevated Ly6C, CCR5, MCP-1 and reduced SR-B1. The sustainment of inflammatory monocytes is due to the disruption of homeostatic tolerance through the elevation of miR-24 and reduction of the key negative-feedback regulator IRAK-M. miR-24 reduces the levels of Smad4 required for the expression of IRAK-M and also downregulates key lipid-processing molecule SR-B1. IRAK-M deficiency in turn leads to elevated miR-24 levels, sustains disruption of monocyte homeostasis and aggravates atherosclerosis. Our data define an integrated feedback circuit in monocytes and its disruption may lead to non-resolving low-grade inflammation conducive to atherosclerosis.
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    Proposed in vitro model of neutrophil swarming in a chronic, low-level inflammatory state
    Bradford, Elaine Alison (Virginia Tech, 2019-09-24)
    Chronic, low-grade inflammation is an underlying condition across a globally increasing number of debilitating diseases. These diseases include obesity, atherosclerosis, and diabetes and their resultant low-grade inflammation can be effectivity modeled with low dose stimulants such as lipopolysaccharide (LPS). While the innate immunity plays a significant role in fighting infectious disease, an initial exposure to low dose LPS hinders secondary infection clearance and pre-disposes murine models for fatal sepsis. Neutrophils are the most prevalent circulating innate immune cell and their homotypic aggregation, or swarming, is a key mechanism in clearing pathogens greater than 20 μm in size. We hypothesize that neutrophil swarming ability is altered when in a low dose LPS primed state; potentially leading to an overall altered innate immune response in the face of infection. However, an in vitro model does not currently exist to reliably quantify and compare neutrophil swarms across treatment groups. Here we propose a novel model utilizing fungal zymosan coated beads as a uniform target to which neutrophils may swarm.
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    Quantum interference measurement of spin interactions in a bio-organic/semiconductor device structure
    Deo, Vincent; Zhang, Yao; Soghomonian, Victoria G.; Heremans, Jean J. (Springer Nature, 2015-03-30)
    Quantum interference is used to measure the spin interactions between an InAs surface electron system and the iron center in the biomolecule hemin in nanometer proximity in a bio-organic/semiconductor device structure. The interference quantifies the influence of hemin on the spin decoherence properties of the surface electrons. The decoherence times of the electrons serve to characterize the biomolecule, in an electronic complement to the use of spin decoherence times in magnetic resonance. Hemin, prototypical for the heme group in hemoglobin, is used to demonstrate the method, as a representative biomolecule where the spin state of a metal ion affects biological functions. The electronic determination of spin decoherence properties relies on the quantum correction of antilocalization, a result of quantum interference in the electron system. Spin-flip scattering is found to increase with temperature due to hemin, signifying a spin exchange between the iron center and the electrons, thus implying interactions between a biomolecule and a solid-state system in the hemin/InAs hybrid structure. The results also indicate the feasibility of artificial bioinspired materials using tunable carrier systems to mediate interactions between biological entities.
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    Relevance Feedback and Query Expansion
    Wu, Sichao; Zhang, Yao (2012-10-17)
    This module introduces the methods to improve the recall of information retrieval systems, mainly focuses on relevance feedback and query expansion.
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    Resolving monocytes generated through TRAM deletion attenuate atherosclerosis
    Geng, Shuo; Zhang, Yao; Yi, Ziyue; Lu, Ran; Li, Liwu (2021-10-22)
    Polarization of low-grade inflammatory monocytes facilitates the pathogenesis of atherosclerosis. However, underlying mechanisms as well as approaches for resolving monocyte polarization conducive to the regression of atherosclerosis are not well established. In this report, we demonstrate that TRIF-related adaptor molecule (TRAM) mediated monocyte polarization in vivo and in vitro. TRAM controlled monocyte polarization through activating Src family kinase c-SRC, which not only induces STAT1/STAT5-regulated inflammatory mediators CCR2 and SIRP-alpha but also suppresses PPAR gamma-regulated resolving mediator CD200R. Enhanced PPAR gamma and Pex5 due to TRAM deficiency facilitated peroxisome homeostasis and reduction of cellular reactive oxygen species, further contributing to the establishment of a resolving monocyte phenotype. TRAM-deficient monocytes propagated the resolving phenotype to neighboring monocytes through CD200R-mediated intercellular communication. At the translational level, we show that TRAM-deficient mice were resistant to high fat diet-induced pathogenesis of atherosclerosis. We further document that intravenous transfusion of TRAM-deficient resolving monocytes into atherosclerotic mice potently reduced the progression of atherosclerosis. Together, our data reveal that targeting TRAM may facilitate the effective generation of resolving monocytes conducive for the treatment of atherosclerosis.
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    Suppression of Neutrophil Antimicrobial Functions by Total Particulate Matter From Cigarette Smoke
    Zhang, Yao; Geng, Shuo; Prasad, G.L.; Li, Liwu (Frontiers, 2018-10-04)
    Chronic cigarette smoking is widely known to alter immune functions and compromise host defense against microbial infection. Neutrophils play an essential role in the immune defense against microbial pathogens and also participate in the development of the inflammatory responses. However, there is limited information about the effects of cigarette smoking on neutrophil response. In this study, cultured bonemarrow neutrophils were exposed to total particulate matter (TPM) from cigarette smoke. We found that TPM not only reduced LPS-induced TNFa production, but also suppressed neutrophil bactericidal activity. We also observed that TPM priming reduced the expression of NADPH oxidase component gp91 and iNOS, molecules important for bacterial killing. Mechanistically, we documented that TPM-primed neutrophils have reduced STAT1 activation following subsequent LPS challenge. STAT1 is a key transcription factor responsible for the expression of inflammatory genes as well as gp91 and iNOS. Collectively, reduced STAT1 activation and reduced NADPH oxidase/iNOS may potentially explain the compromised anti-microbial function of TPM-programmed neutrophils. Taken together, our findings reveal that the key innate immune neutrophil is subject to reprogramming by smoking to adopt an immune-suppressed state, potentially responsible for chronic smoking-mediated immunosuppression.
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    TICAM2-related pathway mediates neutrophil exhaustion
    Lin, RuiCi; Zhang, Yao; Pradhan, Kisha; Li, Liwu (2020-09-01)
    Pathogenic inflammation and immune suppression are the cardinal features that underlie the pathogenesis of severe systemic inflammatory syndrome and sepsis. Neutrophil exhaustion may play a key role during the establishment of pathogenic inflammation and immune suppression through elevated expression of inflammatory adhesion molecules such as ICAM1 and CD11b as well as immune-suppressors such as PD-L1. However, the mechanism of neutrophil exhaustion is not well understood. We demonstrated that murine primary neutrophils cultured in vitro with the prolonged lipopolysaccharides (LPS) stimulation can effectively develop an exhaustive phenotype resembling human septic neutrophils with elevated expression of ICAM1, CD11b, PD-L1 as well as enhanced swarming and aggregation. Mechanistically, we observed that TICAM2 is involved in the generation of neutrophil exhaustion, as TICAM2 deficient neutrophils have the decreased expression of ICAM1, CD11b, PD-L1, and the reduced aggregation following the prolonged LPS challenge as compared to wild type (WT) neutrophils. LPS drives neutrophil exhaustion through TICAM2 mediated activation of Src family kinases (SFK) and STAT1, as the application of SFK inhibitor Dasatinib blocks neutrophil exhaustion triggered by the prolonged LPS challenge. Functionally, TICAM2 deficient mice were protected from developing severe systemic inflammation and multi-organ injury following the chemical-induced mucosal damage. Together, our data defined a key role of TICAM2 in facilitating neutrophil exhaustion and that targeting TICAM2 may be a potential approach to treating the severe systemic inflammation.
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    Tollip Deficiency Alters Atherosclerosis and Steatosis by Disrupting Lipophagy
    Chen, Keqiang; Yuan, Ruoxi; Zhang, Yao; Geng, Shuo; Li, Liwu (Wolters Kluwer Health, 2017-04-10)
    Background Compromised lipophagy with unknown mechanisms may be critically involved in the intracellular accumulation of lipids, contributing to elevated atherosclerosis and liver steatosis. We hypothesize that toll‐interacting protein (Tollip), a key innate immune molecule involved in the fusion of autolysosome, may play a significant role in lipophagy and modulate lipid accumulation during the pathogenesis of atherosclerosis and liver steatosis. Methods and Results By comparing mice fed with either a Western high‐fat diet or a regular chow diet, we observed that both atherosclerosis and liver steatosis were aggravated in apolipoprotein E–deficient (ApoE−/−)/Tollip−/− mice as compared with ApoE−/− mice. Through electron microscopy analyses, we observed compromised fusion of lipid droplets with lysosomes within aortic macrophages as well as liver hepatocytes from ApoE−/−/Tollip−/− mice as compared with ApoE−/− mice. As a molecular indicator for disrupted lysosome fusion, the levels of p62 were significantly elevated in aortic and liver tissues from ApoE−/−/Tollip−/− mice. Molecules involved in facilitating lipophagy completion such as Ras‐related protein 7 and gamma‐aminobutyric acid receptor‐associated protein were reduced in ApoE−/−/Tollip−/− mice as compared with ApoE−/− mice. Intriguingly, ApoE−/−/Tollip−/− mice had reduced circulating levels of inflammatory cytokines such as tumor necrosis factor‐α and increased levels of transforming growth factor‐β. The reduced inflammation due to Tollip deficiency is consistent with a stable atherosclerotic plaque phenotype with increased levels of plaque collagen and smooth muscle cells in ApoE−/−/Tollip−/− mice. Conclusions Tollip deficiency selectively leads to enlarged yet stable atherosclerotic plaques, increased circulating lipids, liver steatosis, and reduced inflammation. Compromised lipophagy and reduced expression of inflammatory mediators due to Tollip deficiency may be the underlying causes. Our data suggest that lipid accumulation and inflammation may be intertwined yet independent processes during the progression of atherosclerosis and steatosis.
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    TRAM deletion attenuates monocyte exhaustion and alleviates sepsis severity
    Wang, Jing; Wu, Yajun; Lin, Ruici; Zhang, Yao; Li, Liwu (Frontiers, 2023-12-15)
    Monocyte exhaustion characterized by immune-suppressive features can develop during sepsis and contribute to adverse patient outcomes. However, molecular mechanisms responsible for the establishment of immune-suppressive monocytes with reduced expression of immune-enhancing mediators such as CD86 during sepsis are not well understood. In this study, we identified that the TLR4 intracellular adaptor TRAM plays a key role in mediating the sustained reduction of CD86 expression on exhausted monocytes and generating an immune-suppressive monocyte state. TRAM contributes to the prolonged suppression of CD86 through inducing TAX1BP1 as well as SARM1, collectively inhibiting Akt and NFκB. TRAM deficient mice are protected from cecal slurry-induced experimental sepsis and retain immune-competent monocytes with CD86 expression. Our data reveal a key molecular circuitry responsible for monocyte exhaustion and provide a viable target for rejuvenating functional monocytes and treating sepsis.