1,545 research outputs found
Contributions of the inhibitor of kappa B kinases (IKKs) in macrophages and neutrophils after Francisella tularensis live vaccine strain (LVS) infection.
No full textThe immune system is a complex network of cells regulated by a number of signaling pathways to drive specific host defenses against invading pathogens. The NF-&kappaB (nuclear factor of the kappa light chain enhancer in B cells) family of inducible transcription factors is a critical regulator of many innate and adaptive immune responses. NF-&kappaB activation by several receptors converges upon two upstream kinases, IKK&alpha and IKK&beta, that regulate gene induction. Many studies report that IKK&beta is the critical kinase involved in NF--&kappaB activation, although at a transcriptional level, both kinases are needed to obtain the full spectrum of gene induction. More recently, in an in vivo bacterial infection model both IKK&alpha and IKK&beta were reported to have anti-inflammatory properties through different mechanisms.The intracellular bacterium Francisella tularensis is able to down modulate inflammatory reactions within macrophages and neutrophils to provide a niche for bacterial growth. To this end, I asked whether disruptions of NF-&kappaB signaling, specifically through IKK&alpha and IKK&beta, could promote inflammation and allow the host more resistance to infection.I used conditional gene targeting of IKK&alpha and IKK&beta to generate mice with specific deletions for either kinase in these cells. These mice were used in a tularemia infection using the live vaccine strain of Francisella tularensis (Ft. LVS) as a model to elucidate the specific contributions of each kinase.Contrary to what has been previously reported for Group B Streptococcus infection models, IKK&beta but not IKK&alpha, was required for host resistance and survival in tularemia infection as 100% of Ft. LVS infected mice succumbed to lethal infection within 10 days.In a sublethal model of infection, both IKK&alpha and IKK&beta contributed in different ways to the maintenance of hepatic granulomas after infection. Depletion of IKK&alpha led to fewer, but sometimes, large necrotic granuloma formation indicating a potential role for IKK&alpha in the clearance of apoptotic cells. IKK&beta depletion resulted disordered granuloma structures and elevated bacterial colonization and growth throughout the infection. This led to increased inflammation as early as 2 days post infection as evidenced by a polarization towards M1 macrophages and IL-12 production. Compensation mechanisms to reduce inflammation such as an increase in myeloid derived suppressor cells or a subsequent M2a macrophage polarization occurred, but were not able to control inflammation or bacterial growth in these mice. In addition, IKK&beta loss resulted in protracted IFN-&gamma production by cytotoxic T lymphocytes.Overall, in an Ft. LVS infection model, IKK&alpha may be more important in neutrophils for the clearance of apoptotic cells, while IKK&beta is required more globally to prevent inflammation and control bacterial colonization that cannot be compensated by anti-inflammatory mechanisms. These functions appear to be correlated with early activation of both macrophages, neutrophils and extrinsic activation of cytotoxic T lymphocytes.Advisor(s): Kenneth B. Marcu. Michael Hadjiargyrou. Committee Member(s): Martha B. Furie; Richard R. Kew; William P. Tansey.Stony Brook University Libraries. SBU Graduate School in Department of Genetics. Lawrence Martin (Dean of Graduate School)
Cell migration to CXCL12 requires simultaneous IKKα and IKKβ-dependent NF-κB signaling
No full textAbstractCXCL12 and its unique receptor CXCR4, is critical for the homing of a variety of cell lineages during both development and tissue repair. CXCL12 is particularly important for the recruitment of hemato/lymphopoietic cells to their target organs. In conjunction with the damage-associated alarmin molecule HMGB1, CXCL12 mediates immune effector and stem/progenitor cell migration towards damaged tissues for subsequent repair. Previously, we showed that cell migration to HMGB1 simultaneously requires both IKKβ and IKKα-dependent NF-κB activation. IKKβ-mediated activation maintains sufficient expression of HMGB1's receptor RAGE, while IKKα-dependent NF-κB activation ensures continuous production of CXCL12, which complexes with HMGB1 to engage CXCR4. Here using fibroblasts and primary mature macrophages, we show that IKKβ and IKKα are simultaneously essential for cell migration in response to CXCL12 alone. Non-canonical NF-κB pathway subunits RelB and p52 are also both essential for cell migration towards CXCL12, suggesting that IKKα is required to drive non-canonical NF-κB signaling. Flow cytometric analyses of CXCR4 expression show that IKKβ, but not IKKα, is required to maintain a critical threshold level of this CXCL12 receptor. Time-lapse video microscopy experiments in primary MEFs reveal that IKKα is required both for polarization of cells towards a CXCL12 gradient and to establish a basal level of velocity towards CXCL12. In addition, CXCL12 modestly up-regulates IKKα-dependent p52 nuclear translocation and IKKα-dependent expression of the CXCL12 gene. On the basis of our collective results we posit that IKKα is needed to maintain the basal expression of a critical protein co-factor required for cell migration to CXCL12
The cytidine deaminases AID and APOBEC-1 exhibit distinct functional properties in a novel yeast selectable system
No full textActivation-induced cytidine deaminase (AID) is indispensable for immunoglobulin maturation by somatic hypermutations and class switch recombination and is supposed to deaminate cytidines in DNA, while its homolog APOBEC-1 edits apolipoprotein (apo) B mRNA by cytidine deamination. We studied the editing activity of APOBEC-1 and AID in yeast using the selectable marker Gal4 linked to its specific inhibitor protein Gal80 via an apo B cassette (Gal4-C) or via the variable region of a mouse immunoglobulin heavy chain gene (Gal4-VH). Expression of APOBEC-1 induced C to U editing in up to 15% of the Gal4-C transcripts, while AID was inactive in this reaction even in the presence of the APOBEC-1 complementation factor. After expression of APOBEC-1 as well as AID approximately 10(-3) of yeast cells survived low stringency selection and expressed beta-galactosidase. Neither AID nor APOBEC-1 mutated the VH sequence of Gal4-VH, and consequently the yeast colonies did not escape high stringent selection. AID, however, induced frequent plasmid recombinations that were only rarely observed with APOBEC-1. In conclusion, AID cannot substitute APOBEC-1 to edit the apo B mRNA, and the expression of AID in yeast is not sufficient for the generation of point mutations in a highly transcribed Gal4-VH sequence. Cofactors for AID induced somatic hypermutations of immunoglobulin variable regions, that are present in B cells and a variety of non-B cells, appear to be missing in yeast. In contrast to APOBEC-1, AID alone does not exhibit an intrinsic specificity for its target sequences
A culture that is hard to defend: extralegal factors in federal death penalty cases
No full textEmpirical research has exposed a troubling pattern of capital punishment in the United States, with extralegal factors such as race, class, and gender strongly correlated with the probability of a death sentence. Capital sentencing also shows significant geographic disparities, although existing research tends to be more descriptive than explanatory. This study offers an alternative conception of local legal culture to explain place-based variation in the outcomes of federal capital trials, accounting for the level of attorney time and expert resources granted by the federal courts to defend against a death sentence. Using frequentist and Bayesian methods—supplemented with expert interviews—we empirically assess the processes determining the total allocation of defense resources in federal death penalty trials at the peak of the federal death penalty—between 1998 and 2004. Our findings strongly connect extralegal factors to the lowest levels of defense resources, which in turn correlate with a higher risk of a death sentence. Far from being idiosyncratic discrepancies, these are systemic and systematic extralegal factors that stand between a defendant and his opportunity to defend against a death sentence. Ultimately, we argue for a reconceptualization of extralegal influences and the relationship between local legal culture and capital case outcomes.Peer reviewe
Kenneth B. Clark (ca. 1989)
No full textThis photograph shows Kenneth B. Clark, an honorary degree recipient at the 1989 Springfield College Commencement Ceremony. He is pictured sitting in a chair with his elbow on the arm of the chair and his chin resting on his hand. The photo is taken by famed photographer, Raimondo Borea. He is wearing a suit. The college gave him the honorary degree because he demonstrated a lifetime commitment to the Humanics philosophy followed by Springfield College.Kenneth B. Clark earned his Ph.D. in social psychology from Columbia University and went on to become a Distinguished Professor of Psychology Emeritus of the City College of the City University of New York. He also is the author of several books and articles, including "Prejudice and Your Child," "Pathos of Power," and "Dark Ghetto." He qualified to present his research on the effects of segregation on children to the United States Supreme Court during the 1954 decision of Brown vs. Board of Education. He and his wife were also co-founders of the Northside Center for Child Development and he also is noted for his work with Harlem Youth Opportunities Unlimited. His previous awards include: 1961 recipient of the Springain Medal, 1985 recipient of the Franklin Delano Roosevelt Four Freedom Award, and 1986 recipient of the Medal of Liberty Award. He served for twenty years as a member of the Board of Regents of the State of New York, and is President of Kenneth B. Clark & Associates, Inc., a firm that provides consultation to educational institutions, corporations and government agencies.Copyright is not owned by Springfield College. Photograph was a print supplied for purposes of promotion for Kenneth B. Clarke's honorary degree. Photograph was taken by Raimondo Borea. On back the photograph is stamped copyright: Raimondo Borea ASMP /245 West 104th Street / New York, N.Y 10025. Please see rights information for use directions.
Generalized measures for physical properties of nonperiodic chains
No full textPT: J; CR: AVISHAI Y, 1990, PHYS REV B, V41, P5492 BORN M, 1965, PRINCIPLES OPTICS BURROWS BL, 1991, J PHYS A-MATH GEN, V24, P3979 DAVISON SG, 1992, BASIC THEORY SURFACE GUMBS G, 1989, J PHYS A-MATH GEN, V22, P951 KIANG D, 1990, AM J PHYS, V58, P1200 KOHMOTO M, 1987, PHYS REV LETT, V58, P2436 KOLAR M, 1991, PHYS REV B, V43, P1034 PATTNAIK RK, 1992, J PHYS A-MATH GEN, V25, P577 THAKUR PK, 1992, J PHYS-CONDENS MAT, V4, P6095; NR: 10; TC: 5; J9: PHYS REV B; PG: 7; GA: QL717Source type: Electronic(1
Transmission through two-dimensional tight-binding lattices
No full textA methodology of transmission through two-dimensional tight-binding lattices is presented. The theory is formulated in terms of matrix algebra and the relationships between the matrices are examined in detail. The features specific to tight-binding systems are contrasted to those for more general transmission problems. Illustrative examples are given to indicate the wide applicability of the methodology.PT: J; CR: BARUT AO, 1992, PHYS REV LETT, V68, P3571 FARCHIONI R, 1996, PHYS REV B, V53, P4294 HUANG DH, 1992, SOLID STATE COMMUN, V84, P1061 IMRY Y, 1986, EUROPHYS LETT, V1, P249 KOLAR M, 1989, J PHYS-CONDENS MAT, V1, P823 PICHARD JL, 1994, THESIS U PARIS ORSAY SCHWABE H, 1997, PHYS REV B, V56, P8026 TSUNETSUGU H, 1988, PHYS REV B, V38, P10109 TSUNETSUGU H, 1990, J PHYS SOC JPN, V59, P3057 TSUNETSUGU H, 1991, PHYS REV B, V43, P8892 UEDA K, 1987, PHYS REV LETT, V58, P1272; NR: 11; TC: 1; J9: PHYS REV B; PG: 6; GA: 372FWSource type: Electronic(1
Many-electron theory of resonant charge transfer: Role of surface states in He and He+ scattering off Si(100)
No full textA many-electron theory of resonant charge transfer, originally formulated for the scattering of an atom with an empty valence orbital from a surface, is extended to treat the case where the valence orbital is initially occupied by one or two electrons. The scattering of He and He+ from the Si(001) surface is investigated. The interaction is assumed to be with the narrow band of surface states, and not the much wider bulk band. As a result, considerable oscillations are found in the ionization and/or neutralization probabilities as a function of the incident energy.PT: J; CR: AMOS AT, 1989, ADV CHEM PHYS, V76, P335 AMOS AT, 1989, SOLID STATE COMMUN, V71, P449 BLOSS W, 1978, SURF SCI, V72, P277 BRAKO R, 1981, SURF SCI, V108, P253 BURROWS BL, 1984, Q APPL MATH, V42, P73 BURROWS BL, 1990, J PHYS A-MATH GEN, V23, P1101 BURROWS BL, 1991, SURF SCI, V253, P365 CHADI DJ, 1975, PHYS STATUS SOLIDI B, V68, P405 HAGSTRUM HD, 1954, PHYS REV, V96, P336 HAGSTRUM HD, 1961, PHYS REV, V122, P83 HERMAN F, 1963, ATOMIC STRUCTURE CAL IHM J, 1980, PHYS REV B, V21, P4592 MUDA Y, 1980, SURF SCI, V97, P283 MUDA Y, 1988, NUCL INSTRUM METH B, V33, P388 MUDA Y, 1988, PHYS REV B, V37, P7048 PAULING L, 1935, INTRO QUANTUM MECHAN ROBERTS N, 1990, SURF SCI, V236, P112 SOUDA R, 1985, SURF SCI, V150, L59 SOUDA R, 1986, NUCL INSTRUM METH B, V15, P114 SOUDA R, 1986, NUCL INSTRUM METH B, V15, P138 SOUDA R, 1986, SURF SCI, V176, P657 SULSTON KW, 1988, PHYS REV B, V37, P9121 SULSTON KW, 1988, SURF SCI, V197, P555 SULSTON KW, 1989, SURF SCI, V244, P543 WEAKLIEM PC, 1990, SURF SCI, V232, L219 WEISENDANGER R, 1990, SURF SCI, V232, P1; NR: 26; TC: 4; J9: PHYS REV B; PG: 11; GA: HZ245Source type: Electronic(1
IKKα/CHUK regulates extracellular matrix remodeling independent of its kinase activity to facilitate articular chondrocyte differentiation.
No full textThe non-canonical NF-κB activating kinase IKKα, encoded by CHUK (conserved-helix-loop-helix-ubiquitous-kinase), has been reported to modulate pro- or anti- inflammatory responses, cellular survival and cellular differentiation. Here, we have investigated the mechanism of action of IKKα as a novel effector of human and murine chondrocyte extracellular matrix (ECM) homeostasis and differentiation towards hypertrophy.IKKα expression was ablated in primary human osteoarthritic (OA) chondrocytes and in immature murine articular chondrocytes (iMACs) derived from IKKα(f/f):CreERT2 mice by retroviral-mediated stable shRNA transduction and Cre recombinase-dependent Lox P site recombination, respectively. MMP-10 was identified as a major target of IKKα in chondrocytes by mRNA profiling, quantitative RT-PCR analysis, immunohistochemistry and immunoblotting. ECM integrity, as assessed by type II collagen (COL2) deposition and the lack of MMP-dependent COL2 degradation products, was enhanced by IKKα ablation in mice. MMP-13 and total collagenase activities were significantly reduced, while TIMP-3 (tissue inhibitor of metalloproteinase-3) protein levels were enhanced in IKKα-deficient chondrocytes. IKKα deficiency suppressed chondrocyte differentiation, as shown by the quantitative inhibition of.Alizarin red staining and the reduced expression of multiple chondrocyte differentiation effectors, including Runx2, Col10a1 and Vegfa,. Importantly, the differentiation of IKKα-deficient chondrocytes was rescued by a kinase-dead IKKα protein mutant.IKKα acts independent of its kinase activity to help drive chondrocyte differentiation towards a hypertrophic-like state. IKKα positively modulates ECM remodeling via multiple downstream targets (including MMP-10 and TIMP-3 at the mRNA and post-transcriptional levels, respectively) to maintain maximal MMP-13 activity, which is required for ECM remodeling leading to chondrocyte differentiation. Chondrocytes are the unique cell component in articular cartilage, which are quiescent and maintain ECM integrity during tissue homeostasis. In OA, chondrocytes reacquire the capacity to proliferate and differentiate and their activation results in pronounced cartilage degeneration. Τηυσ, our findings are also of potential relevance for defining the onset and/or progression of OA disease
Orbital non-orthogonality in surface-state theory
No full textThe introduction of non-orthogonal atomic orbitals, into the tight-binding approximation, gives rise to the existence of overlap terms in electronic band-structure calculations. In contrast to the zero-overlap situation, it is helpful to employ a tensorial Green-function approach to access the surface density of states, and investigate the effects of overlap on its behaviour. (C) 2003 Elsevier B.V. All rights reserved.PT: J; CR: ARTACHO E, 1991, PHYS REV A, V43, P5770 ARTACHO E, 1991, PHYS REV B, V44, P6169 BALLENTINE LE, 1986, J PHYS C SOLID STATE, V19, P981 DAVISON SG, 1992, BASIC THEORY SURFACE EMBERLY E, 1998, PHYS REV LETT, V81, P5205 GRIMLEY TB, 1970, J PHYS C, V3, P1934 HALPERN V, 1972, J PHYS C SOLID STATE, V5, P1953 HOFFMANN R, 1963, J CHEM PHYS, V39, P1397 KALKSTEIN D, 1971, SURF SCI, V26, P85 KRUGER P, 1986, PHYS REV LETT, V57, P1468 LOHEZ D, 1983, PHYS REV B, V27, P5007 LOWDIN PO, 1950, J CHEM PHYS, V18, P365 MCKINNON BA, 1995, PHYS REV B, V52, P14531 MIRABELLA DA, 1994, PHYS REV B, V50, P12152 MOSHINSKY M, 1971, ANN PHYS-NEW YORK, V66, P311 ORDEJON P, 1989, PHYS REV B, V40, P12416 PAPACONSTANTOPOULOS DA, 2003, J PHYS-CONDENS MAT, V15, R413 PETZINGER KG, 1975, SURF SCI, V47, P729 RIEDINGER R, 1985, PHYS LETT A, V107, P333 RIEDINGER R, 1989, PHYS REV B, V39, P13175 SANCHO MPL, 1985, J PHYS C SOLID STATE, V18, P1803 SCHONHAMMER K, 1975, Z PHYSIK B, V22, P143 SLATER JC, 1954, PHYS REV, V94, P1498 SULSTON KW, 2003, PHYS REV B, V67 TAPILIN VM, 1988, SURF SCI, V206, P405 VANDERBILT D, 1980, PHYS REV B, V22, P2927 WILLIAMS AR, 1982, PHYS REV B, V26, P5433; NR: 27; TC: 0; J9: PHYSICA B; PG: 6; GA: 720NXSource type: Electronic(1
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