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Sample records for memory cell characteristics

  1. SONOS Nonvolatile Memory Cell Programming Characteristics

    NASA Technical Reports Server (NTRS)

    MacLeod, Todd C.; Phillips, Thomas A.; Ho, Fat D.

    2010-01-01

    Silicon-oxide-nitride-oxide-silicon (SONOS) nonvolatile memory is gaining favor over conventional EEPROM FLASH memory technology. This paper characterizes the SONOS write operation using a nonquasi-static MOSFET model. This includes floating gate charge and voltage characteristics as well as tunneling current, voltage threshold and drain current characterization. The characterization of the SONOS memory cell predicted by the model closely agrees with experimental data obtained from actual SONOS memory cells. The tunnel current, drain current, threshold voltage and read drain current all closely agreed with empirical data.

  2. Endurance characteristics of phase change memory cells

    NASA Astrophysics Data System (ADS)

    Ruru, Huo; Daolin, Cai; Chen, Bomy; Yifeng, Chen; Yuchan, Wang; Yueqing, Wang; Hongyang, Wei; Qing, Wang; Yangyang, Xia; Dan, Gao; Zhitang, Song

    2016-05-01

    The endurance characteristics of phase change memory are studied. With operational cycles, the resistances of reset and set states gradually change to the opposite direction. What is more, the operational conditions that are needed are also discussed. The failure and the changes are concerned with the compositional change of the phase change material. An abnormal phenomenon that the threshold voltage decreases slightly at first and then increases is observed, which is due to the coaction of interface contact and growing active volume size changing. Project supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (No. XDA09020402), the National Key Basic Research Program of China (Nos. 2013CBA01900, 2010CB934300, 2011CBA00607, 2011CB932804), the National Integrate Circuit Research Program of China (No. 2009ZX02023-003), the National Natural Science Foundation of China (No. 61176122, 61106001, 61261160500, 61376006), and the Science and Technology Council of Shanghai (Nos. 12nm0503701, 13DZ2295700, 12QA1403900, 13ZR1447200, 14ZR1447500).

  3. Single flux-quantum Josephson memory cell using a new threshold characteristic

    SciTech Connect

    Kurosawa, I.; Yagi, A.; Nakagawa, H.; Hayakawa, H.

    1983-12-01

    A new single flux-quantum Josephson memory cell in which nondestructive readout (NDRO) operations can be realized with a simple circuit configuration is proposed. The memory cell utilizes a new type of threshold characteristics in an equivalent asymmetric dc superconducting quantum interference device (SQUID) consisting of a three-junction SQUID gate and a single junction. NDRO operation has been successfully demonstrated in an experimental memory circuit.

  4. Characteristics of a Nonvolatile SRAM Memory Cell Utilizing a Ferroelectric Transistor

    NASA Technical Reports Server (NTRS)

    Mitchell, Cody; Laws, Crystal; MacLeod, Todd C.; Ho, Fat D.

    2011-01-01

    The SRAM cell circuit is a standard for volatile data storage. When utilizing one or more ferroelectric transistors, the hysteresis characteristics give unique properties to the SRAM circuit, providing for investigation into the development of a nonvolatile memory cell. This paper discusses various formations of the SRAM circuit, using ferroelectric transistors, n-channel and p-channel MOSFETs, and resistive loads. With varied source and supply voltages, the effects on the timing and retention characteristics are investigated, including retention times of up to 24 hours.

  5. Disturbance characteristics of half-selected cells in a cross-point resistive switching memory array

    NASA Astrophysics Data System (ADS)

    Chen, Zhe; Li, Haitong; Chen, Hong-Yu; Chen, Bing; Liu, Rui; Huang, Peng; Zhang, Feifei; Jiang, Zizhen; Ye, Hongfei; Gao, Bin; Liu, Lifeng; Liu, Xiaoyan; Kang, Jinfeng; Wong, H.-S. Philip; Yu, Shimeng

    2016-05-01

    Disturbance characteristics of cross-point resistive random access memory (RRAM) arrays are comprehensively studied in this paper. An analytical model is developed to quantify the number of pulses (#Pulse) the cell can bear before disturbance occurs under various sub-switching voltage stresses based on physical understanding. An evaluation methodology is proposed to assess the disturb behavior of half-selected (HS) cells in cross-point RRAM arrays by combining the analytical model and SPICE simulation. The characteristics of cross-point RRAM arrays such as energy consumption, reliable operating cycles and total error bits are evaluated by the methodology. A possible solution to mitigate disturbance is proposed.

  6. Temperature dependence of SET switching characteristics in phase-change memory cells

    NASA Astrophysics Data System (ADS)

    He, Qiang; Li, Zhen; Liu, Chang; Meng, Xiang-ru; Peng, Ju-hong; Lai, Zhi-bo; Miao, Xiang-shui

    2016-09-01

    The temperature dependence of crystallization kinetics of phase-change materials raises a series of reliability issues, while phase-change memory cells work at high temperature or thermal-disturbance condition. These issues hinder the development of ultrahigh-density storage devices. We investigate the evolution of SET switching characteristics of phase-change memory cells at high operating temperature. We show that the high temperature strongly impacts the SET state resistance. As a result, SET failure has been observed with elevated ambient temperature. Our SPICE simulations indicate that transient amorphization behavior during a complete SET pulse period is considered as the potential mechanism of SET failure. By modifying the SET pulse intensity and width linearly, we successfully reduce the SET failure in the experiments. The results illustrate that the demonstrated linear properties may optimize SET pulse performance.

  7. Effect of embedded metal nanocrystals on the resistive switching characteristics in NiN-based resistive random access memory cells

    SciTech Connect

    Yun, Min Ju; Kim, Hee-Dong; Man Hong, Seok; Hyun Park, Ju; Su Jeon, Dong; Geun Kim, Tae

    2014-03-07

    The metal nanocrystals (NCs) embedded-NiN-based resistive random access memory cells are demonstrated using several metal NCs (i.e., Pt, Ni, and Ti) with different physical parameters in order to investigate the metal NC's dependence on resistive switching (RS) characteristics. First, depending on the electronegativity of metal, the size of metal NCs is determined and this affects the operating current of memory cells. If metal NCs with high electronegativity are incorporated, the size of the NCs is reduced; hence, the operating current is reduced owing to the reduced density of the electric field around the metal NCs. Second, the potential wells are formed by the difference of work function between the metal NCs and active layer, and the barrier height of the potential wells affects the level of operating voltage as well as the conduction mechanism of metal NCs embedded memory cells. Therefore, by understanding these correlations between the active layer and embedded metal NCs, we can optimize the RS properties of metal NCs embedded memory cells as well as predict their conduction mechanisms.

  8. Asymmetric dual-gate-structured one-transistor dynamic random access memory cells for retention characteristics improvement

    NASA Astrophysics Data System (ADS)

    Kim, Hyungjin; Lee, Jong-Ho; Park, Byung-Gook

    2016-08-01

    One of the major concerns of one-transistor dynamic random access memory (1T-DRAM) is poor retention time. In this letter, a 1T-DRAM cell with two separated asymmetric gates was fabricated and evaluated to improve sensing margin and retention characteristics. It was observed that significantly enhanced sensing margin and retention time over 1 s were obtained using a negatively biased second gate and trapped electrons in the nitride layer because of increased hole capacity in the floating body. These findings indicate that the proposed device could serve as a promising candidate for overcoming retention issues of 1T-DRAM cells.

  9. Identification of a novel human memory T-cell population with the characteristics of stem-like chemo-resistance.

    PubMed

    Murata, Kenji; Tsukahara, Tomohide; Emori, Makoto; Shibayama, Yuji; Mizushima, Emi; Matsumiya, Hiroshi; Yamashita, Keiji; Kaya, Mitsunori; Hirohashi, Yoshihiko; Kanaseki, Takayuki; Kubo, Terufumi; Himi, Tetsuo; Ichimiya, Shingo; Yamashita, Toshihiko; Sato, Noriyuki; Torigoe, Toshihiko

    2016-06-01

    High-dose chemotherapy may kill not only tumor cells but also immunocytes, and frequently induces severe lymphocytopenia. On the other hand, patients who recover from the nadir maintain immunity against infection, suggesting the existence of an unknown memory T-cell population with stress resistance, long-living capacity, proliferation and differentiation. Recently, the differentiation system of T-cell memory has been clarified using mouse models. However, the human T-cell memory system has great diversity induced by natural antigens derived from many pathogens and tumor cells throughout life, and profoundly differs from the mouse memory system constructed using artificial antigens and transgenic T cells. Here we report a novel human T-cell memory population, "young memory" T (TYM) cells. TYM cells are defined by positive expression of CD73, which represents high aldehyde dehydrogenase 1 (ALDH1) activity and CXCR3 among CD8(+)CD45RA(+)CD62L(+) T cells. TYM proliferate upon TCR stimulation, with differentiation capacity into TCM and TEM and drug resistance. Moreover, TYM are involved in memory function for viral and tumor-associated antigens in healthy donors and cancer patients, respectively. Regulation of TYM might be very attractive for peptide vaccination, adoptive cell-transfer therapy and hematopoietic stem cell transplantation. PMID:27471640

  10. Identification of a novel human memory T-cell population with the characteristics of stem-like chemo-resistance

    PubMed Central

    Murata, Kenji; Tsukahara, Tomohide; Emori, Makoto; Shibayama, Yuji; Mizushima, Emi; Matsumiya, Hiroshi; Yamashita, Keiji; Kaya, Mitsunori; Hirohashi, Yoshihiko; Kanaseki, Takayuki; Kubo, Terufumi; Himi, Tetsuo; Ichimiya, Shingo; Yamashita, Toshihiko; Sato, Noriyuki; Torigoe, Toshihiko

    2016-01-01

    ABSTRACT High-dose chemotherapy may kill not only tumor cells but also immunocytes, and frequently induces severe lymphocytopenia. On the other hand, patients who recover from the nadir maintain immunity against infection, suggesting the existence of an unknown memory T-cell population with stress resistance, long-living capacity, proliferation and differentiation. Recently, the differentiation system of T-cell memory has been clarified using mouse models. However, the human T-cell memory system has great diversity induced by natural antigens derived from many pathogens and tumor cells throughout life, and profoundly differs from the mouse memory system constructed using artificial antigens and transgenic T cells. Here we report a novel human T-cell memory population, “young memory” T (TYM) cells. TYM cells are defined by positive expression of CD73, which represents high aldehyde dehydrogenase 1 (ALDH1) activity and CXCR3 among CD8+CD45RA+CD62L+ T cells. TYM proliferate upon TCR stimulation, with differentiation capacity into TCM and TEM and drug resistance. Moreover, TYM are involved in memory function for viral and tumor-associated antigens in healthy donors and cancer patients, respectively. Regulation of TYM might be very attractive for peptide vaccination, adoptive cell-transfer therapy and hematopoietic stem cell transplantation. PMID:27471640

  11. Natural Killer Cell Memory.

    PubMed

    O'Sullivan, Timothy E; Sun, Joseph C; Lanier, Lewis L

    2015-10-20

    Natural killer (NK) cells have historically been considered short-lived cytolytic cells that can rapidly respond against pathogens and tumors in an antigen-independent manner and then undergo cell death. Recently, however, NK cells have been shown to possess traits of adaptive immunity and can acquire immunological memory in a manner similar to that of T and B cells. In this review, we discuss evidence of NK cell memory and the mechanisms involved in the generation and survival of these innate lymphocytes.

  12. Characteristics of Memory B Cells Elicited by a Highly Efficacious HPV Vaccine in Subjects with No Pre-existing Immunity

    PubMed Central

    Scherer, Erin M.; Smith, Robin A.; Simonich, Cassandra A.; Niyonzima, Nixon; Carter, Joseph J.; Galloway, Denise A.

    2014-01-01

    Licensed human papillomavirus (HPV) vaccines provide near complete protection against the types of HPV that most commonly cause anogenital and oropharyngeal cancers (HPV 16 and 18) when administered to individuals naive to these types. These vaccines, like most other prophylactic vaccines, appear to protect by generating antibodies. However, almost nothing is known about the immunological memory that forms following HPV vaccination, which is required for long-term immunity. Here, we have identified and isolated HPV 16-specific memory B cells from female adolescents and young women who received the quadrivalent HPV vaccine in the absence of pre-existing immunity, using fluorescently conjugated HPV 16 pseudoviruses to label antigen receptors on the surface of memory B cells. Antibodies cloned and expressed from these singly sorted HPV 16-pseudovirus labeled memory B cells were predominantly IgG (>IgA>IgM), utilized diverse variable genes, and potently neutralized HPV 16 pseudoviruses in vitro despite possessing only average levels of somatic mutation. These findings suggest that the quadrivalent HPV vaccine provides an excellent model for studying the development of B cell memory; and, in the context of what is known about memory B cells elicited by influenza vaccination/infection, HIV-1 infection, or tetanus toxoid vaccination, indicates that extensive somatic hypermutation is not required to achieve potent vaccine-specific neutralizing antibody responses. PMID:25330199

  13. I-V Characteristics of a Static Random Access Memory Cell Utilizing Ferroelectric Transistors

    NASA Technical Reports Server (NTRS)

    Laws, Crystal; Mitchell, Cody; Hunt, Mitchell; Ho, Fat D.; MacLeod, Todd C.

    2012-01-01

    I-V characteristics for FeFET different than that of MOSFET Ferroelectric layer features hysteresis trend whereas MOSFET behaves same for both increasing and decreasing VGS FeFET I-V characteristics doesn't show dependence on VDS A Transistor with different channel length and width as well as various resistance and input voltages give different results As resistance values increased, the magnitude of the drain current decreased.

  14. Tier identification (TID) for tiered memory characteristics

    DOEpatents

    Chang, Jichuan; Lim, Kevin T; Ranganathan, Parthasarathy

    2014-03-25

    A tier identification (TID) is to indicate a characteristic of a memory region associated with a virtual address in a tiered memory system. A thread may be serviced according to a first path based on the TID indicating a first characteristic. The thread may be serviced according to a second path based on the TID indicating a second characteristic.

  15. Pathogenic memory type Th2 cells in allergic inflammation.

    PubMed

    Endo, Yusuke; Hirahara, Kiyoshi; Yagi, Ryoji; Tumes, Damon J; Nakayama, Toshinori

    2014-02-01

    Immunological memory is a hallmark of adaptive immunity. Memory CD4 T helper (Th) cells are central to acquired immunity, and vaccines for infectious diseases are developed based on this concept. However, memory Th cells also play a critical role in the pathogenesis of various chronic inflammatory diseases, including asthma. We refer to these populations as 'pathogenic memory Th cells.' Here, we review recent developments highlighting the functions and characteristics of several pathogenic memory type Th2 cell subsets in allergic inflammation. Also discussed are the similarities and differences between pathogenic memory Th2 cells and recently identified type 2 innate lymphoid cells (ILC2), focusing on cytokine production and phenotypic profiles.

  16. Characteristics of Positive Autobiographical Memories in Adulthood

    ERIC Educational Resources Information Center

    Bluck, Susan; Alea, Nicole

    2009-01-01

    The characteristics of positive autobiographical memory narratives were examined in younger and older adults. Narratives were content-coded for the extent to which they contained indicators of affect, sensory imagery, and cognition. Affect was additionally assessed through self-report. Young adults expressed more positive affect and less sensory…

  17. Cell memory-based therapy.

    PubMed

    Anjamrooz, Seyed Hadi

    2015-11-01

    Current cell therapies, despite all of the progress in this field, still faces major ethical, technical and regulatory hurdles. Because these issues possibly stem from the current, restricted, stereotypical view of cell ultrastructure and function, we must think radically about the nature of the cell. In this regard, the author's theory of the cell memory disc offers 'memory-based therapy', which, with the help of immune system rejuvenation, nervous system control and microparticle-based biodrugs, may have substantial therapeutic potential. In addition to its potential value in the study and prevention of premature cell aging, age-related diseases and cell death, memory therapy may improve the treatment of diseases that are currently limited by genetic disorders, risk of tumour formation and the availability and immunocompatibility of tissue transplants. PMID:26256679

  18. Cell memory-based therapy

    PubMed Central

    Anjamrooz, Seyed Hadi

    2015-01-01

    Current cell therapies, despite all of the progress in this field, still faces major ethical, technical and regulatory hurdles. Because these issues possibly stem from the current, restricted, stereotypical view of cell ultrastructure and function, we must think radically about the nature of the cell. In this regard, the author's theory of the cell memory disc offers ‘memory-based therapy’, which, with the help of immune system rejuvenation, nervous system control and microparticle-based biodrugs, may have substantial therapeutic potential. In addition to its potential value in the study and prevention of premature cell aging, age-related diseases and cell death, memory therapy may improve the treatment of diseases that are currently limited by genetic disorders, risk of tumour formation and the availability and immunocompatibility of tissue transplants. PMID:26256679

  19. Novel Field Effect Diode Type Vertical Capacitorless One Transistor Dynamic Random Access Memory Cell with Negative Hold Bit Line Bias Scheme for Improving the Hold Characteristics

    NASA Astrophysics Data System (ADS)

    Imamoto, Takuya; Endoh, Tetsuo

    2013-04-01

    In this paper, the novel field effect diode (FED) type vertical capacitorless one transistor dynamic random access memory (1T-DRAM) cell with negative hold bit line (BL) voltage (VBL) scheme is proposed. In comparison with the conventional planar type, the proposed vertical type with negative hold VBL scheme shows excellent static and disturb retention time. The proposed vertical type memory cell with negative hold VBL scheme achieves 1,000 times longer static retention time and 104 times longer BL disturb retention time at 85 °C than that of the conventional planar type. Furthermore, the proposed vertical type memory cell has a small cell size of 4F2 due to its stacked vertical structure. The proposed FED type vertical capacitorless 1T-DRAM cell with negative hold VBL scheme is shown to be an excellent candidate for stand-alone and embedded memory applications and extends scaling limitations.

  20. Characteristics of near-death experiences memories as compared to real and imagined events memories.

    PubMed

    Thonnard, Marie; Charland-Verville, Vanessa; Brédart, Serge; Dehon, Hedwige; Ledoux, Didier; Laureys, Steven; Vanhaudenhuyse, Audrey

    2013-01-01

    Since the dawn of time, Near-Death Experiences (NDEs) have intrigued and, nowadays, are still not fully explained. Since reports of NDEs are proposed to be imagined events, and since memories of imagined events have, on average, fewer phenomenological characteristics than real events memories, we here compared phenomenological characteristics of NDEs reports with memories of imagined and real events. We included three groups of coma survivors (8 patients with NDE as defined by the Greyson NDE scale, 6 patients without NDE but with memories of their coma, 7 patients without memories of their coma) and a group of 18 age-matched healthy volunteers. Five types of memories were assessed using Memory Characteristics Questionnaire (MCQ--Johnson et al., 1988): target memories (NDE for NDE memory group, coma memory for coma memory group, and first childhood memory for no memory and control groups), old and recent real event memories and old and recent imagined event memories. Since NDEs are known to have high emotional content, participants were requested to choose the most emotionally salient memories for both real and imagined recent and old event memories. Results showed that, in NDE memories group, NDE memories have more characteristics than memories of imagined and real events (p<0.02). NDE memories contain more self-referential and emotional information and have better clarity than memories of coma (all ps<0.02). The present study showed that NDE memories contained more characteristics than real event memories and coma memories. Thus, this suggests that they cannot be considered as imagined event memories. On the contrary, their physiological origins could lead them to be really perceived although not lived in the reality. Further work is needed to better understand this phenomenon.

  1. Role of memory T cell subsets for adoptive immunotherapy.

    PubMed

    Busch, Dirk H; Fräßle, Simon P; Sommermeyer, Daniel; Buchholz, Veit R; Riddell, Stanley R

    2016-02-01

    Adoptive transfer of primary (unmodified) or genetically engineered antigen-specific T cells has demonstrated astonishing clinical results in the treatment of infections and some malignancies. Besides the definition of optimal targets and antigen receptors, the differentiation status of transferred T cells is emerging as a crucial parameter for generating cell products with optimal efficacy and safety profiles. Long-living memory T cells subdivide into phenotypically as well as functionally different subsets (e.g. central memory, effector memory, tissue-resident memory T cells). This diversification process is crucial for effective immune protection, with probably distinct dependencies on the presence of individual subsets dependent on the disease to which the immune response is directed as well as its organ location. Adoptive T cell therapy intends to therapeutically transfer defined T cell immunity into patients. Efficacy of this approach often requires long-term maintenance of transferred cells, which depends on the presence and persistence of memory T cells. However, engraftment and survival of highly differentiated memory T cell subsets upon adoptive transfer is still difficult to achieve. Therefore, the recent observation that a distinct subset of weakly differentiated memory T cells shows all characteristics of adult tissue stem cells and can reconstitute all types of effector and memory T cell subsets, became highly relevant. We here review our current understanding of memory subset formation and T cell subset purification, and its implications for adoptive immunotherapy.

  2. On the bipolar resistive-switching characteristics of Al₂O₃- and HfO₂-based memory cells operated in the soft-breakdown regime

    SciTech Connect

    Goux, L. Fantini, A.; Nigon, R.; Strangio, S.; Degraeve, R.; Kar, G.; Chen, Y. Y.; Jurczak, M.; Raghavan, N.; De Stefano, F.; Afanas'ev, V. V.

    2014-10-07

    In this article, we investigate extensively the bipolar-switching properties of Al₂O₃- and HfO₂-based resistive-switching memory cells operated at low current down to <1 μA. We show that the switching characteristics differ considerably from those typically reported for larger current range (>15 μA), which we relate as intrinsic to soft-breakdown (SBD) regime. We evidence a larger impact of the used switching-oxide in this current range, due to lower density of oxygen-vacancy (V{sub o}) defects in the SBD regime. In this respect, deep resetting and large memory window may be achieved using the stoichiometric Al₂O₃ material due to efficient V{sub o} annihilation, although no complete erasure of the conductive-filament (CF) is obtained. We finally emphasize that the conduction may be described by a quantum point-contact (QPC) model down to very low current level where only a few V{sub o} defects compose the QPC constriction. The large switching variability inherent to this latter aspect is mitigated by CF shape tuning through adequate engineering of an Al₂O₃\\HfO₂ bilayer.

  3. Viral inoculum dose impacts memory T-cell inflation.

    PubMed

    Redeker, Anke; Welten, Suzanne P M; Arens, Ramon

    2014-04-01

    Memory T-cell inflation develops during certain persistent viral infections and is characterized by the accumulation and maintenance of large numbers of effector-memory T cells, albeit with varying degrees in size and phenotype among infected hosts. The underlying mechanisms that control memory T-cell inflation are not yet fully understood. Here, we dissected CMV-specific memory T-cell formation and its connection to the initial infectious dose by varying the inoculum size. After low dose inoculum with mouse CMV, the accumulation of inflationary memory T cells was severely hampered and correlated with reduced reservoirs of latent virus in nonhematopoietic cells and diminished antigen-driven T-cell proliferation. Moreover, lowering of the initial viral dose turned the characteristic effector memory-like inflationary T cells into more central memory-like cells as evidenced by the cell-surface phenotype of CD27(high) , CD62L(+) , CD127(+) , and KLRG1(-) , and by improved secondary expansion potential. These data show the impact of the viral inoculum on the degree of memory T-cell inflation and provide a rationale for the observed variation of human CMV-specific T-cell responses in terms of magnitude and phenotype.

  4. Improving Memory Characteristics of Hydrogenated Nanocrystalline Silicon Germanium Nonvolatile Memory Devices by Controlling Germanium Contents.

    PubMed

    Kim, Jiwoong; Jang, Kyungsoo; Phu, Nguyen Thi Cam; Trinh, Thanh Thuy; Raja, Jayapal; Kim, Taeyong; Cho, Jaehyun; Kim, Sangho; Park, Jinjoo; Jung, Junhee; Lee, Youn-Jung; Yi, Junsin

    2016-05-01

    Nonvolatile memory (NVM) with silicon dioxide/silicon nitride/silicon oxynitride (ONO(n)) charge trap structure is a promising flash memory technology duo that will fulfill process compatibility for system-on-panel displays, down-scaling cell size and low operation voltage. In this research, charge trap flash devices were fabricated with ONO(n) stack gate insulators and an active layer using hydrogenated nanocrystalline silicon germanium (nc-SiGe:H) films at a low temperature. In this study, the effect of the interface trap density on the performance of devices, including memory window and retention, was investigated. The electrical characteristics of NVM devices were studied controlling Ge content from 0% to 28% in the nc-SiGe:H channel layer. The optimal Ge content in the channel layer was found to be around 16%. For nc-SiGe:H NVM with 16% Ge content, the memory window was 3.13 V and the retention data exceeded 77% after 10 years under the programming condition of 15 V for 1 msec. This showed that the memory window increased by 42% and the retention increased by 12% compared to the nc-Si:H NVM that does not contain Ge. However, when the Ge content was more than 16%, the memory window and retention property decreased. Finally, this research showed that the Ge content has an effect on the interface trap density and this enabled us to determine the optimal Ge content. PMID:27483856

  5. Two-Bit/Cell Programming Characteristics of High-Density NOR-Type Flash Memory Device with Recessed Channel Structure and Spacer-Type Nitride Layer

    NASA Astrophysics Data System (ADS)

    Han, Kyoung-Rok; Lee, Jong-Ho

    2006-10-01

    The structure of novel 2-bit/cell silicon-oxide-nitride-oxide-silicon (SONOS) flash memory device was proposed and characterized for sub-50 nm non-volatile memory (NVM) technology. A proposed memory cell has spacer-type storage nodes on both sidewalls in a recessed channel region. It was shown that counter channel doping near the bottom of the recessed channel is very important and can improve the Vth margin for 2-bit/cell operation by ˜2.5 times. By controlling doping profiles of the channel doping and the counter channel doping in the recessed channel region, we could obtain the Vth margin more than ˜1.5 V.

  6. Evidence for Natural Killer Cell Memory

    PubMed Central

    Marcus, Assaf; Raulet, David H.

    2013-01-01

    Natural killer (NK) cells are generally considered part of the innate immune system. However, over the past few years, evidence has accumulated suggesting that NK cells have certain features characteristic of the adaptive immune system. NK cells reportedly respond in an antigen-specific manner to a variety of small molecules and certain viruses, and mediate enhanced responses to these antigens upon re-challenge. In infections with mouse cytomegalovirus (MCMV), MCMV-specific NK cells undergo clonal expansion, and display increased effector function after the resolution of the infection. In addition, inflammatory conditions resulting from exposure to certain cytokines seem to cause prolonged effector function in NK cells in an antigen non-specific fashion. Taken together, these studies reveal new aspects of NK biology, and suggest that NK cells, like T and B cells, may carry out memory responses, and may also exhibit greater capacity to distinguish antigens than was previously recognized. PMID:24028966

  7. Effect of NiO crystallinity on forming characteristics in Pt/NiO/Pt cells as resistive switching memories

    NASA Astrophysics Data System (ADS)

    Nishi, Yusuke; Kimoto, Tsunenobu

    2016-09-01

    Resistive switching (RS) in metal/oxide/metal stack structures plays a key role in resistive RAM. The formation and rupture of conductive filaments have been widely accepted as an origin of RS mechanism especially in binary transition metal oxides. Forming exhibits some analogies with a dielectric breakdown of SiO2 thin films. In this study, Time-Dependent Forming (TDF) characteristics of Pt/NiO/Pt stack structures have been investigated. The results revealed that the formation of conductive filaments at the forming process by applying constant voltage followed a weakest-link theory and that the weakest spots were almost randomly distributed in NiO thin films according to the Poisson statistics. Furthermore, the distribution of TDF characteristics depends on NiO crystallinity. A small variation of initial resistance tends to result in a large variation of time to forming and vice versa.

  8. Memory B cells in mouse models.

    PubMed

    Bergmann, B; Grimsholm, O; Thorarinsdottir, K; Ren, W; Jirholt, P; Gjertsson, I; Mårtensson, I-L

    2013-08-01

    One of the principles behind vaccination, as shown by Edward Jenner in 1796, and host protection is immunological memory, and one of the cells central to this is the antigen-experienced memory B cell that responds rapidly upon re-exposure to the initiating antigen. Classically, memory B cells have been defined as progenies of germinal centre (GC) B cells expressing isotype-switched and substantially mutated B cell receptors (BCRs), that is, membrane-bound antibodies. However, it has become apparent over the last decade that this is not the only pathway to B cell memory. Here, we will discuss memory B cells in mice, as defined by (1) cell surface markers; (2) multiple layers; (3) formation in a T cell-dependent and either GC-dependent or GC-independent manner; (4) formation in a T cell-independent fashion. Lastly, we will touch upon memory B cells in; (5) mouse models of autoimmune diseases. PMID:23679222

  9. Novel therapies for memory cells in autoimmune diseases.

    PubMed

    Bhargava, P; Calabresi, P A

    2015-06-01

    Autoimmune diseases are a major cause of morbidity, and their incidence and prevalence continue to rise. Treatments for these diseases are non-specific and result in significant adverse effects. Targeted therapies may help in improving the risk : benefit ratio associated with treatment. Immunological memory is an important feature of the vertebrate immune system that results in the production of cells that are long-lived and able to respond to antigens in a more robust manner. In the setting of autoimmunity this characteristic becomes detrimental due to the ongoing response to a self-antigen(s). These memory cells have been shown to play key roles in various autoimmune diseases such as type 1 diabetes, multiple sclerosis and psoriasis. Memory T cells and B cells can be identified based on various molecules expressed on their surface. Memory T cells can be divided into three main categories - central memory, effector memory and resident memory cells. These subsets have different proliferative potential and cytokine-producing abilities. Utilizing differentially expressed surface molecules or downstream signalling pathway proteins in these cells it is now possible to target memory cells while sparing naive cells. We will discuss the various available options for such a strategy and several potential strategies that may yield successful therapies in the future.

  10. Memory T cells in organ transplantation: progress and challenges.

    PubMed

    Espinosa, Jaclyn R; Samy, Kannan P; Kirk, Allan D

    2016-06-01

    Antigen-experienced T cells, also known as memory T cells, are functionally and phenotypically distinct from naive T cells. Their enhanced expression of adhesion molecules and reduced requirement for co-stimulation enables them to mount potent and rapid recall responses to subsequent antigen encounters. Memory T cells generated in response to prior antigen exposures can cross-react with other nonidentical, but similar, antigens. This heterologous cross-reactivity not only enhances protective immune responses, but also engenders de novo alloimmunity. This latter characteristic is increasingly recognized as a potential barrier to allograft acceptance that is worthy of immunotherapeutic intervention, and several approaches have been investigated. Calcineurin inhibition effectively controls memory T-cell responses to allografts, but this benefit comes at the expense of increased infectious morbidity. Lymphocyte depletion eliminates allospecific T cells but spares memory T cells to some extent, such that patients do not completely lose protective immunity. Co-stimulation blockade is associated with reduced adverse-effect profiles and improved graft function relative to calcineurin inhibition, but lacks efficacy in controlling memory T-cell responses. Targeting the adhesion molecules that are upregulated on memory T cells might offer additional means to control co-stimulation-blockade-resistant memory T-cell responses. PMID:26923209

  11. TCR Signaling in T Cell Memory.

    PubMed

    Daniels, Mark A; Teixeiro, Emma

    2015-01-01

    T cell memory plays a critical role in our protection against pathogens and tumors. The antigen and its interaction with the T cell receptor (TCR) is one of the initiating elements that shape T cell memory together with inflammation and costimulation. Over the last decade, several transcription factors and signaling pathways that support memory programing have been identified. However, how TCR signals regulate them is still poorly understood. Recent studies have shown that the biochemical rules that govern T cell memory, strikingly, change depending on the TCR signal strength. Furthermore, TCR signal strength regulates the input of cytokine signaling, including pro-inflammatory cytokines. These highlight how tailoring antigenic signals can improve immune therapeutics. In this review, we focus on how TCR signaling regulates T cell memory and how the quantity and quality of TCR-peptide-MHC interactions impact the multiple fates a T cell can adopt in the memory pool. PMID:26697013

  12. The cellular memory disc of reprogrammed cells.

    PubMed

    Anjamrooz, Seyed Hadi

    2013-04-01

    The crucial facts underlying the low efficiency of cellular reprogramming are poorly understood. Cellular reprogramming occurs in nuclear transfer, induced pluripotent stem cell (iPSC) formation, cell fusion, and lineage-switching experiments. Despite these advances, there are three fundamental problems to be addressed: (1) the majority of cells cannot be reprogrammed, (2) the efficiency of reprogramming cells is usually low, and (3) the reprogrammed cells developed from a patient's own cells activate immune responses. These shortcomings present major obstacles for using reprogramming approaches in customised cell therapy. In this Perspective, the author synthesises past and present observations in the field of cellular reprogramming to propose a theoretical picture of the cellular memory disc. The current hypothesis is that all cells undergo an endogenous and exogenous holographic memorisation such that parts of the cellular memory dramatically decrease the efficiency of reprogramming cells, act like a barrier against reprogramming in the majority of cells, and activate immune responses. Accordingly, the focus of this review is mainly to describe the cellular memory disc (CMD). Based on the present theory, cellular memory includes three parts: a reprogramming-resistance memory (RRM), a switch-promoting memory (SPM) and a culture-induced memory (CIM). The cellular memory arises genetically, epigenetically and non-genetically and affects cellular behaviours. [corrected].

  13. Predicting Which Childhood Memories Persist: Contributions of Memory Characteristics

    ERIC Educational Resources Information Center

    Peterson, Carole; Morris, Gwynn; Baker-Ward, Lynne; Flynn, Susan

    2014-01-01

    This investigation identified memory-level predictors of the survivability of 4- to 13-year-old children's earliest recollections over a 2-year period. Data previously reported by Peterson, Warren, and Short (2011) were coded for inclusion of emotion terms and thematic, chronological, and contextual narrative coherence. In addition, the…

  14. Resistive switching characteristics and mechanisms in silicon oxide memory devices

    NASA Astrophysics Data System (ADS)

    Chang, Yao-Feng; Fowler, Burt; Chen, Ying-Chen; Zhou, Fei; Wu, Xiaohan; Chen, Yen-Ting; Wang, Yanzhen; Xue, Fei; Lee, Jack C.

    2016-05-01

    Intrinsic unipolar SiOx-based resistance random access memories (ReRAM) characterization, switching mechanisms, and applications have been investigated. Device structures, material compositions, and electrical characteristics are identified that enable ReRAM cells with high ON/OFF ratio, low static power consumption, low switching power, and high readout-margin using complementary metal-oxide semiconductor transistor (CMOS)-compatible SiOx-based materials. These ideas are combined with the use of horizontal and vertical device structure designs, composition optimization, electrical control, and external factors to help understand resistive switching (RS) mechanisms. Measured temperature effects, pulse response, and carrier transport behaviors lead to compact models of RS mechanisms and energy band diagrams in order to aid the development of computer-aided design for ultralarge-v scale integration. This chapter presents a comprehensive investigation of SiOx-based RS characteristics and mechanisms for the post-CMOS device era.

  15. Targeting memory T cells in type 1 diabetes.

    PubMed

    Ehlers, Mario R; Rigby, Mark R

    2015-11-01

    Type 1 diabetes (T1D) is a chronic autoimmune disease that leads to progressive destruction of pancreatic beta cells. Compared to healthy controls, a characteristic feature of patients with T1D is the presence of self-reactive T cells with a memory phenotype. These autoreactive memory T cells in both the CD4(+) and CD8(+) compartments are likely to be long-lived, strongly responsive to antigenic stimulation with less dependence on costimulation for activation and clonal expansion, and comparatively resistant to suppression by regulatory T cells (Tregs) or downregulation by immune-modulating agents. Persistence of autoreactive memory T cells likely contributes to the difficulty in preventing disease progression in new-onset T1D and maintaining allogeneic islet transplants by regular immunosuppressive regimens. The majority of immune interventions that have demonstrated some success in preserving beta cell function in the new-onset period have been shown to deplete or modulate memory T cells. Based on these and other considerations, preservation of residual beta cells early after diagnosis or restoration of beta cell mass by use of stem cell or transplantation technology will require a successful strategy to control the autoreactive memory T cell compartment, which could include depletion, inhibition of homeostatic cytokines, induction of hyporesponsiveness, or a combination of these approaches.

  16. The evolving roles of memory immune cells in transplantation

    PubMed Central

    Chen, Wenhao; Ghobrial, Rafik M.; Li, Xian C.

    2015-01-01

    Memory cells are the products of immune responses but also exert significant impact on subsequent immunity and immune tolerance, thus placing them in a unique position in transplant research. Memory cells are heterogeneous, including not only memory T cells but also memory B cells and innate memory cells. Memory cells are a critical component of protective immunity against invading pathogens, especially in immunosuppressed patients, but they also mediate graft loss and tolerance resistance. Recent studies suggest that some memory cells unexpectedly act as regulatory cells, promoting rather than hindering transplant survival. This functional diversity makes therapeutic targeting of memory cells a challenging task in transplantation. In this article we highlight recent advances in our understanding of memory cells, focusing on diversity of memory cells and mechanisms involved in their induction and functions. We also provide a broad overview on the challenges and opportunities in targeting memory cells in the induction of transplant tolerance. PMID:26102615

  17. Asymptomatic memory CD8+ T cells

    PubMed Central

    Khan, Arif Azam; Srivastava, Ruchi; Lopes, Patricia Prado; Wang, Christine; Pham, Thanh T; Cochrane, Justin; Thai, Nhi Thi Uyen; Gutierrez, Lucas; BenMohamed, Lbachir

    2014-01-01

    Generation and maintenance of high quantity and quality memory CD8+ T cells determine the level of protection from viral, bacterial, and parasitic re-infections, and hence constitutes a primary goal for T cell epitope-based human vaccines and immunotherapeutics. Phenotypically and functionally characterizing memory CD8+ T cells that provide protection against herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2) infections, which cause blinding ocular herpes, genital herpes, and oro-facial herpes, is critical for better vaccine design. We have recently categorized 2 new major sub-populations of memory symptomatic and asymptomatic CD8+ T cells based on their phenotype, protective vs. pathogenic function, and anatomical locations. In this report we are discussing a new direction in developing T cell-based human herpes vaccines and immunotherapeutics based on the emerging new concept of “symptomatic and asymptomatic memory CD8+ T cells.” PMID:24499824

  18. Modeling of Sonos Memory Cell Erase Cycle

    NASA Technical Reports Server (NTRS)

    Phillips, Thomas A.; MacLeond, Todd C.; Ho, Fat D.

    2010-01-01

    Silicon-oxide-nitride-oxide-silicon (SONOS) nonvolatile semiconductor memories (NVSMS) have many advantages. These memories are electrically erasable programmable read-only memories (EEPROMs). They utilize low programming voltages, endure extended erase/write cycles, are inherently resistant to radiation, and are compatible with high-density scaled CMOS for low power, portable electronics. The SONOS memory cell erase cycle was investigated using a nonquasi-static (NQS) MOSFET model. The SONOS floating gate charge and voltage, tunneling current, threshold voltage, and drain current were characterized during an erase cycle. Comparisons were made between the model predictions and experimental device data.

  19. Modeling of SONOS Memory Cell Erase Cycle

    NASA Technical Reports Server (NTRS)

    Phillips, Thomas A.; MacLeod, Todd C.; Ho, Fat H.

    2011-01-01

    Utilization of Silicon-Oxide-Nitride-Oxide-Silicon (SONOS) nonvolatile semiconductor memories as a flash memory has many advantages. These electrically erasable programmable read-only memories (EEPROMs) utilize low programming voltages, have a high erase/write cycle lifetime, are radiation hardened, and are compatible with high-density scaled CMOS for low power, portable electronics. In this paper, the SONOS memory cell erase cycle was investigated using a nonquasi-static (NQS) MOSFET model. Comparisons were made between the model predictions and experimental data.

  20. Development and psychometric properties of a new measure for memory phenomenology: The Autobiographical Memory Characteristics Questionnaire.

    PubMed

    Boyacioglu, Inci; Akfirat, Serap

    2015-01-01

    The purpose of this study is to develop a valid and reliable measure for the phenomenology of autobiographical memories. The psychometric properties of the Autobiographical Memory Characteristics Questionnaire (AMCQ) were tested in three studies: the factor structure of the AMCQ was examined for childhood memories in Study 1 (N = 305); for autobiographical memories related to romantic relationships in Study 2 (N = 197); and for self-defining memories in Study 3 (N = 262). The explanatory factor analyses performed for each memory type demonstrated the consistency of the AMCQ factor structure across all memory types; while a confirmatory factor analysis on the data garnered from all three studies supported the constructs for the autobiographical memory characteristics defined by the researchers. The AMCQ consists of 63 items and 14 factors, and the internal consistency values of all 14 scales were ranged between .66 and .97. The relationships between the AMCQ scales related to gender and individual emotions, as well as the intercorrelations among the scales, were consistent with both theoretical expectations and previous findings. The results of all the three studies indicated that this new instrument is a reliable and robust measure for memory phenomenology.

  1. A vertically integrated capacitorless memory cell

    NASA Astrophysics Data System (ADS)

    Xiaodong, Tong; Hao, Wu; Lichuan, Zhao; Ming, Wang; Huicai, Zhong

    2013-08-01

    A two-port capacitorless PNPN device with high density, high speed and low power memory fabricated using standard CMOS technology is presented. Experiments and calibrated simulations were conducted which prove that this new memory cell has a high operation speed (ns level), large read current margin (read current ratio of 104×), low process variation, good thermal reliability and available retention time (190 ms). Furthermore, the new memory cell is free of the cyclic endurance/reliability problems induced by hot-carrier injection due to the gateless structure.

  2. Memory Engram Cells Have Come of Age.

    PubMed

    Tonegawa, Susumu; Liu, Xu; Ramirez, Steve; Redondo, Roger

    2015-09-01

    The idea that memory is stored in the brain as physical alterations goes back at least as far as Plato, but further conceptualization of this idea had to wait until the 20(th) century when two guiding theories were presented: the "engram theory" of Richard Semon and Donald Hebb's "synaptic plasticity theory." While a large number of studies have been conducted since, each supporting some aspect of each of these theories, until recently integrative evidence for the existence of engram cells and circuits as defined by the theories was lacking. In the past few years, the combination of transgenics, optogenetics, and other technologies has allowed neuroscientists to begin identifying memory engram cells by detecting specific populations of cells activated during specific learning epochs and by engineering them not only to evoke recall of the original memory, but also to alter the content of the memory. PMID:26335640

  3. Hoxb4 Overexpression in CD4 Memory Phenotype T Cells Increases the Central Memory Population upon Homeostatic Proliferation

    PubMed Central

    Fournier, Marilaine; Labrecque, Nathalie; Bijl, Janet J.

    2013-01-01

    Memory T cell populations allow a rapid immune response to pathogens that have been previously encountered and thus form the basis of success in vaccinations. However, the molecular pathways underlying the development and maintenance of these cells are only starting to be unveiled. Memory T cells have the capacity to self renew as do hematopoietic stem cells, and overlapping gene expression profiles suggested that these cells might use the same self-renewal pathways. The transcription factor Hoxb4 has been shown to promote self-renewal divisions of hematopoietic stem cells resulting in an expansion of these cells. In this study we investigated whether overexpression of Hoxb4 could provide an advantage to CD4 memory phenotype T cells in engrafting the niche of T cell deficient mice following adoptive transfer. Competitive transplantation experiments demonstrated that CD4 memory phenotype T cells derived from mice transgenic for Hoxb4 contributed overall less to the repopulation of the lymphoid organs than wild type CD4 memory phenotype T cells after two months. These proportions were relatively maintained following serial transplantation in secondary and tertiary mice. Interestingly, a significantly higher percentage of the Hoxb4 CD4 memory phenotype T cell population expressed the CD62L and Ly6C surface markers, characteristic for central memory T cells, after homeostatic proliferation. Thus Hoxb4 favours the maintenance and increase of the CD4 central memory phenotype T cell population. These cells are more stem cell like and might eventually lead to an advantage of Hoxb4 T cells after subjecting the cells to additional rounds of proliferation. PMID:24324706

  4. Innate and virtual memory T cells in man.

    PubMed

    Van Kaer, Luc

    2015-07-01

    A hallmark of the antigen-specific B and T lymphocytes of the adaptive immune system is their capacity to "remember" pathogens long after they are first encountered, a property that forms the basis for effective vaccine development. However, studies in mice have provided strong evidence that some naive T cells can develop characteristics of memory T cells in the absence of foreign antigen encounters. Such innate memory T cells may develop in response to lymphopenia or the presence of high levels of the cytokine IL-4, and have also been identified in unmanipulated animals, a phenomenal referred to as "virtual memory." While the presence of innate memory T cells in mice is now widely accepted, their presence in humans has not yet been fully validated. In this issue of the European Journal of Immunology, Jacomet et al. [Eur. J. Immunol. 2015. 45:1926-1933] provide the best evidence to date for innate memory T cells in humans. These findings may contribute significantly to our understanding of human immunity to microbial pathogens and tumors.

  5. Innate and virtual memory T cells in man

    PubMed Central

    Van Kaer, Luc

    2015-01-01

    A hallmark of the antigen-specific B and T lymphocytes of the adaptive immune system is their capacity to “remember” pathogens long after they are first encountered, a property that forms the basis for effective vaccine development. However, studies in mice have provided strong evidence that some naive T cells can develop characteristics of memory T cells in the absence of foreign antigen encounters. Such innate memory T cells may develop in response to lymphopenia or the presence of high levels of the cytokine IL-4, and have also been identified in unmanipulated animals, a phenomenal referred to as “virtual memory.” While the presence of innate memory T cells in mice is now widely accepted, their presence in humans has not yet been fully validated. In this issue of the European Journal of Immunology, Jacomet et al. [Eur. J. Immunol. 2015. 45:XXX-XXX] provide the best evidence to date for innate memory T cells in humans. These findings may contribute significantly to our understanding of human immunity to microbial pathogens and tumors. PMID:26013879

  6. Conditions of steady switching in phase-transition memory cells

    SciTech Connect

    Popov, A. I. Salnikov, S. M.; Anufriev, Yu. V.

    2015-04-15

    Three types of non-volatile memory cells of different designs based on phase transitions are developed and implemented. The effect of the design features of the cells and their active-region sizes on the switching characteristics and normal operation of the cells is considered as a whole. The causes of failure of the cells are analyzed from the obtained series of scanning electron images upon level-by-level etching of the samples. It is shown that the cell design is the most critical factor from the viewpoint of switching to the high-resistance state. The causes of this fact are analyzed and the criterion for providing the steady operation of cells of non-volatile memory based on phase transitions is formulated.

  7. Experimental vortex transitional nondestructive read-out Josephson memory cell

    SciTech Connect

    Tahara, S.; Ishida, I.; Ajisawa, Y.; Wada, Y.

    1989-01-15

    A proposal vortex transitional nondestructive read-out Josephson memory cell is successfully fabricated and tested. The memory cell consists of two superconducting loops in which a single flux quantum is stored and a two-junction interferometer gate as a sense gate. The memory cell employs vortex transitions in the superconducting loops for writing and reading data. The vortex transitional memory operation of the cell contributes to improving its sense discrimination and operating margin. The memory cell is activated by two control signals without timing control signals. Memory cell chips have been fabricated using a niobium planarization process. A +- 21% address signal current margin and a +- 33% sense gate current margin have been obtained experimentally. Successful memory operations of a cell driven by two-junction interferometer gates has been demonstrated. The single flux quantum operations of this memory cell makes it an attractive basic element for a high-speed cache memory.

  8. A Novel Metal-Ferroelectric-Semiconductor Field-Effect Transistor Memory Cell Design

    NASA Technical Reports Server (NTRS)

    Phillips, Thomas A.; Bailey, Mark; Ho, Fat Duen

    2004-01-01

    The use of a Metal-Ferroelectric-Semiconductor Field-Effect Transistor (MFSFET) in a resistive-load SRAM memory cell has been investigated A typical two-transistor resistive-load SRAM memory cell architecture is modified by replacing one of the NMOS transistors with an n-channel MFSFET. The gate of the MFSFET is connected to a polling voltage pulse instead of the other NMOS transistor drain. The polling voltage pulses are of sufficient magnitude to saturate the ferroelectric gate material and force the MFSFET into a particular logic state. The memory cell circuit is further modified by the addition of a PMOS transistor and a load resistor in order to improve the retention characteristics of the memory cell. The retention characteristics of both the "1" and "0" logic states are simulated. The simulations show that the MFSFET memory cell design can maintain both the "1" and "0" logic states for a long period of time.

  9. Place cell activation predicts subsequent memory.

    PubMed

    Robitsek, R Jonathan; White, John A; Eichenbaum, Howard

    2013-10-01

    A major quandary in memory research is how hippocampal place cells, widely recognized as elements of a spatial map, contribute to episodic memory, our capacity to remember unique experiences that depends on hippocampal function. Here we recorded from hippocampal neurons as rats performed a T-maze alternation task in which they were required to remember a preceding experience over a delay in order to make a subsequent spatial choice. As it has been reported previously in other variations of this task, we observed differential firing that predicted correct subsequent choices, even as the animal traversed identical locations prior to the choice. Here we also observed that most place cells also fired differently on correct as compared to error trials. Among these cells, a large majority fired strongly before the delay or during the retrieval phase but were less active or failed to activate when the animal subsequently made an error. These findings join the place cell phenomenon with episodic memory performance dependent on the hippocampus, revealing that memory accuracy can be predicted by the activation of single place cells in the hippocampus.

  10. Production of RANKL by Memory B Cells

    PubMed Central

    Meednu, Nida; Zhang, Hengwei; Owen, Teresa; Sun, Wen; Wang, Victor; Cistrone, Christopher; Rangel-Moreno, Javier; Xing, Lianping; Anolik, Jennifer H.

    2016-01-01

    Objective Rheumatoid arthritis (RA) is a systemic autoimmune disease that often leads to joint damage. The mechanisms of bone damage in RA are complex, involving activation of bone-resorbing osteoclasts (OCs) by synoviocytes and Th17 cells. This study was undertaken to investigate whether B cells play a direct role in osteoclastogenesis through the production of RANKL, the essential cytokine for OC development. Methods RANKL production by total B cells or sorted B cell subpopulations in the peripheral blood and synovial tissue from healthy donors or anti–cyclic citrullinated peptide–positive patients with RA was examined by flow cytometry, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemical analysis. To define direct effects on osteoclastogenesis, B cells were cocultured with CD14+ monocytes, and OCs were enumerated by tartrate-resistant acid phosphatase staining. Results Healthy donor peripheral blood B cells were capable of expressing RANKL upon stimulation, with switched memory B cells (CD27+IgD−) having the highest propensity for RANKL production. Notably, switched memory B cells in the peripheral blood from RA patients expressed significantly more RANKL compared to healthy controls. In RA synovial fluid and tissue, memory B cells were enriched and spontaneously expressed RANKL, with some of these cells visualized adjacent to RANK+ OC precursors. Critically, B cells supported OC differentiation in vitro in a RANKL-dependent manner, and the number of OCs was higher in cultures with RA B cells than in those derived from healthy controls. Conclusion These findings reveal the critical importance of B cells in bone homeostasis and their likely contribution to joint destruction in RA. PMID:26554541

  11. Shape-memory surfaces for cell mechanobiology

    NASA Astrophysics Data System (ADS)

    Ebara, Mitsuhiro

    2015-02-01

    Shape-memory polymers (SMPs) are a new class of smart materials, which have the capability to change from a temporary shape ‘A’ to a memorized permanent shape ‘B’ upon application of an external stimulus. In recent years, SMPs have attracted much attention from basic and fundamental research to industrial and practical applications due to the cheap and efficient alternative to well-known metallic shape-memory alloys. Since the shape-memory effect in SMPs is not related to a specific material property of single polymers, the control of nanoarchitecture of polymer networks is particularly important for the smart functions of SMPs. Such nanoarchitectonic approaches have enabled us to further create shape-memory surfaces (SMSs) with tunable surface topography at nano scale. The present review aims to bring together the exciting design of SMSs and the ever-expanding range of their uses as tools to control cell functions. The goal for these endeavors is to mimic the surrounding mechanical cues of extracellular environments which have been considered as critical parameters in cell fate determination. The untapped potential of SMSs makes them one of the most exciting interfaces of materials science and cell mechanobiology.

  12. Cell-adhesion molecules in memory formation.

    PubMed

    Schmidt, R

    1995-01-23

    After learning events the CNS of higher organisms selects, which acquired informations are permanently stored as a memory trace. This period of memory consolidation is susceptible to interference by biochemical inhibitors of transcription and translation. Ependymin is a specific CNS glycoprotein functionally involved in memory consolidation in goldfish: after active shock-avoidance conditioning ependymin mRNA is rapidly induced in meningeal fibroblasts followed by enhanced synthesis and secretion of several closely related forms of the protein. Intracranial injections of anti-ependymin antisera or antisense oligodeoxynucleotides interfere specifically with memory consolidation, indicating that only de novo synthesized ependymin molecules are involved. Ependymin is capable of directing the growth of central axons in vitro and participates in neuronal regeneration in situ, presumably by its HNK-1 cell-adhesion epitope. Experiments reviewed in this article suggest a model that involves two regulation mechanisms for the function of ependymin in behavioural plasticity: while hormones appear to determine, how much of this cell adhesion molecule is synthesized after learning, local changes of metal cation concentrations in the micro-environment of activated neurons may polymerize ependymin at those synapses, that have to be consolidated to improve their efficacy for future use.

  13. Resident memory T cells in human health and disease

    PubMed Central

    Clark, Rachael A.

    2015-01-01

    Resident memory T cells are non-recirculating memory T cells that persist long term in epithelial barrier tissues, including the gastrointestinal tract, lung, skin and reproductive tract. Resident memory T cells persist in the absence of antigens, have impressive effector functions and provide rapid on-site immune protection against known pathogens in peripheral tissues. A fundamentally distinct gene expression program differentiates resident memory T cells from circulating T cells. Although these cells likely evolved to provide rapid immune protection against pathogens, autoreactive, aberrantly activated and malignant resident memory cells contribute to numerous human inflammatory diseases including mycosis fungoides and psoriasis. This review will discuss both the science and medicine of resident memory T cells, exploring how these cells contribute to healthy immune function and discussing what is known about how these cells contribute to human inflammatory and autoimmune diseases. PMID:25568072

  14. Maintenance of Serological Memory by Polyclonal Activation of Human Memory B Cells

    NASA Astrophysics Data System (ADS)

    Bernasconi, Nadia L.; Traggiai, Elisabetta; Lanzavecchia, Antonio

    2002-12-01

    Production of antibodies can last for a lifetime, through mechanisms that remain poorly understood. Here, we show that human memory B lymphocytes proliferate and differentiate into plasma cells in response to polyclonal stimuli, such as bystander T cell help and CpG DNA. Furthermore, plasma cells secreting antibodies to recall antigens are produced in vivo at levels proportional to the frequency of specific memory B cells, even several years after antigenic stimulation. Although antigen boosting leads to a transient increase in specific antibody levels, ongoing polyclonal activation of memory B cells offers a means to maintain serological memory for a human lifetime.

  15. Trilayer Tunnel Selectors for Memristor Memory Cells.

    PubMed

    Choi, Byung Joon; Zhang, Jiaming; Norris, Kate; Gibson, Gary; Kim, Kyung Min; Jackson, Warren; Zhang, Min-Xian Max; Li, Zhiyong; Yang, J Joshua; Williams, R Stanley

    2016-01-13

    An integrated memory cell with a mem-ristor and a trilayer crested barrier selector, showing repeatable nonlinear current-voltage switching loops is presented. The fully atomic-layer-deposited TaN1+x /Ta2 O5 /TaN1+x crested barrier selector yields a large nonlinearity (>10(4) ), high endurance (>10(8) ), low variability, and low temperature dependence.

  16. Effect with high density nano dot type storage layer structure on 20 nm planar NAND flash memory characteristics

    NASA Astrophysics Data System (ADS)

    Sasaki, Takeshi; Muraguchi, Masakazu; Seo, Moon-Sik; Park, Sung-kye; Endoh, Tetsuo

    2014-01-01

    The merits, concerns and design principle for the future nano dot (ND) type NAND flash memory cell are clarified, by considering the effect of storage layer structure on NAND flash memory characteristics. The characteristics of the ND cell for a NAND flash memory in comparison with the floating gate type (FG) is comprehensively studied through the read, erase, program operation, and the cell to cell interference with device simulation. Although the degradation of the read throughput (0.7% reduction of the cell current) and slower program time (26% smaller programmed threshold voltage shift) with high density (10 × 1012 cm-2) ND NAND are still concerned, the suppress of the cell to cell interference with high density (10 × 1012 cm-2) plays the most important part for scaling and multi-level cell (MLC) operation in comparison with the FG NAND. From these results, the design knowledge is shown to require the control of the number of nano dots rather than the higher nano dot density, from the viewpoint of increasing its memory capacity by MLC operation and suppressing threshold voltage variability caused by the number of dots in the storage layer. Moreover, in order to increase its memory capacity, it is shown the tunnel oxide thickness with ND should be designed thicker (>3 nm) than conventional designed ND cell for programming/erasing with direct tunneling mechanism.

  17. Shape memory polymers for active cell culture.

    PubMed

    Davis, Kevin A; Luo, Xiaofan; Mather, Patrick T; Henderson, James H

    2011-07-04

    Shape memory polymers (SMPs) are a class of "smart" materials that have the ability to change from a fixed, temporary shape to a pre-determined permanent shape upon the application of a stimulus such as heat(1-5). In a typical shape memory cycle, the SMP is first deformed at an elevated temperature that is higher than its transition temperature, T(trans;) [either the melting temperature (T(m;)) or the glass transition temperature (T(g;))]. The deformation is elastic in nature and mainly leads to a reduction in conformational entropy of the constituent network chains (following the rubber elasticity theory). The deformed SMP is then cooled to a temperature below its T(trans;) while maintaining the external strain or stress constant. During cooling, the material transitions to a more rigid state (semi-crystalline or glassy), which kinetically traps or "freezes" the material in this low-entropy state leading to macroscopic shape fixing. Shape recovery is triggered by continuously heating the material through T(trans;) under a stress-free (unconstrained) condition. By allowing the network chains (with regained mobility) to relax to their thermodynamically favored, maximal-entropy state, the material changes from the temporary shape to the permanent shape. Cells are capable of surveying the mechanical properties of their surrounding environment(6). The mechanisms through which mechanical interactions between cells and their physical environment control cell behavior are areas of active research. Substrates of defined topography have emerged as powerful tools in the investigation of these mechanisms. Mesoscale, microscale, and nanoscale patterns of substrate topography have been shown to direct cell alignment, cell adhesion, and cell traction forces(7-14). These findings have underscored the potential for substrate topography to control and assay the mechanical interactions between cells and their physical environment during cell culture, but the substrates used to date

  18. The Effect of Shape Memory on Red Blood Cell Motions

    NASA Astrophysics Data System (ADS)

    Niu, Xiting; Shi, Lingling; Pan, Tsorng-Whay; Glowinski, Roland

    2013-11-01

    An elastic spring model is applied to study the effect of the shape memory on the motion of red blood cell in flows. In shear flow, shape memory also plays an important role to obtain all three motions: tumbling, swinging, and tank-treading. In Poiseuille flow, cell has an equilibrium shape as a slipper or parachute depending on capillary number. To ensure the tank-treading motion while in slippery shape, a modified model is proposed by introducing a shape memory coefficient which describes the degree of shape memory in cells. The effect of the coefficient on the cell motion of red blood cell will be presented.

  19. Transactive memory system links work team characteristics and performance.

    PubMed

    Zhang, Zhi-Xue; Hempel, Paul S; Han, Yu-Lan; Tjosvold, Dean

    2007-11-01

    Teamwork and coordination of expertise among team members with different backgrounds are increasingly recognized as important for team effectiveness. Recently, researchers have examined how team members rely on transactive memory system (TMS; D. M. Wegner, 1987) to share their distributed knowledge and expertise. To establish the ecological validity and generality of TMS research findings, this study sampled 104 work teams from a variety of organizational settings in China and examined the relationships between team characteristics, TMS, and team performance. The results suggest that task interdependence, cooperative goal interdependence, and support for innovation are positively related to work teams' TMS and that TMS is related to team performance; moreover, structural equation analysis indicates that TMS mediates the team characteristics-performance links. Findings have implications both for team leaders to manage their work teams effectively and for team members to improve their team performance.

  20. Spanish Adaptation of the Memory Characteristics Questionnaire (MCQ).

    PubMed

    Pegalajar, Joaquín; Acosta, Alberto; Castillo, Miguel; Higueras, Lorenzo; Padilla, José-Luis

    2015-01-01

    The Memory Characteristics Questionnaire (MCQ) was developed by Johnson, Foley, Suengas, and Raye (1988) to assess the characteristics of memories of external and internal origin, postulated in the source monitoring model (Johnson, Hashtroudi, & Lindsay, 1993). The MCQ was translated into Spanish using a back-translation method. Psychometric properties of the translated MCQ were tested using responses collected from an experimental study simulating a forensic context. Ten police officers and 8 psychologists individually interviewed 240 university students who completed the MCQ after reporting what they had seen in a film. Half of the participants were asked to tell the truth, while the other half were asked to lie. The results have shown adequate psychometric properties of the Spanish MCQ items for the total sample and across experimental conditions. Cronbach's alpha value was .79 for the total sample, .78 for the honest condition, and .76 for the lie condition. Validity evidence of dimensionality supports that the factor structure of Spanish MCQ was equivalent to that proposed by the authors of the original version. Also, a two-factor ANOVA (video clip x condition) was performed to analyze experimental data. Neither interaction effects, F(236) = 1.189; p = .277, nor main effects were found to be significant between those asked to tell the truth and those asked to lie. These results demonstrate that the Spanish MCQ has adequate psychometric properties. PMID:26695474

  1. Spanish Adaptation of the Memory Characteristics Questionnaire (MCQ).

    PubMed

    Pegalajar, Joaquín; Acosta, Alberto; Castillo, Miguel; Higueras, Lorenzo; Padilla, José-Luis

    2015-12-23

    The Memory Characteristics Questionnaire (MCQ) was developed by Johnson, Foley, Suengas, and Raye (1988) to assess the characteristics of memories of external and internal origin, postulated in the source monitoring model (Johnson, Hashtroudi, & Lindsay, 1993). The MCQ was translated into Spanish using a back-translation method. Psychometric properties of the translated MCQ were tested using responses collected from an experimental study simulating a forensic context. Ten police officers and 8 psychologists individually interviewed 240 university students who completed the MCQ after reporting what they had seen in a film. Half of the participants were asked to tell the truth, while the other half were asked to lie. The results have shown adequate psychometric properties of the Spanish MCQ items for the total sample and across experimental conditions. Cronbach's alpha value was .79 for the total sample, .78 for the honest condition, and .76 for the lie condition. Validity evidence of dimensionality supports that the factor structure of Spanish MCQ was equivalent to that proposed by the authors of the original version. Also, a two-factor ANOVA (video clip x condition) was performed to analyze experimental data. Neither interaction effects, F(236) = 1.189; p = .277, nor main effects were found to be significant between those asked to tell the truth and those asked to lie. These results demonstrate that the Spanish MCQ has adequate psychometric properties.

  2. CD4 T-cell memory generation and maintenance.

    PubMed

    Gasper, David J; Tejera, Melba Marie; Suresh, M

    2014-01-01

    Immunologic memory is the adaptive immune system's powerful ability to remember a previous antigen encounter and react with accelerated vigor upon antigen re-exposure. It provides durable protection against reinfection with pathogens and is the foundation for vaccine-induced immunity. Unlike the relatively restricted immunologic purview of memory B cells and CD8 T cells, the field of CD4 T-cell memory must account for multiple distinct lineages with diverse effector functions, the issue of lineage commitment and plasticity, and the variable distribution of memory cells within each lineage. Here, we discuss the evidence for lineage-specific CD4 T-cell memory and summarize the known factors contributing to memory-cell generation, plasticity, and long-term maintenance.

  3. Multi-layer graphene membrane based memory cell

    NASA Astrophysics Data System (ADS)

    Siahlo, Andrei I.; Popov, Andrey M.; Poklonski, Nikolai A.; Lozovik, Yurii E.; Vyrko, Sergey A.; Ratkevich, Sergey V.

    2016-10-01

    The scheme and operational principles of the nanoelectromechanical memory cell based on the bending of a multi-layer graphene membrane by the electrostatic force are proposed. An analysis of the memory cell total energy as a function of the memory cell sizes is used to determine the sizes corresponding to a bistable memory cell with the conducting ON and non-conducting OFF states and to calculate the switching voltage between the OFF and ON states. It is shown that a potential barrier between the OFF and ON states is huge for practically all sizes of a bistable memory cell which excludes spontaneous switching and allows the proposed memory cell to be used for long-term archival storage.

  4. Quiescence of Memory CD8(+) T Cells Is Mediated by Regulatory T Cells through Inhibitory Receptor CTLA-4.

    PubMed

    Kalia, Vandana; Penny, Laura Anne; Yuzefpolskiy, Yevgeniy; Baumann, Florian Martin; Sarkar, Surojit

    2015-06-16

    Immune memory cells are poised to rapidly expand and elaborate effector functions upon reinfection yet exist in a functionally quiescent state. The paradigm is that memorycells remain inactive due to lack of T cell receptor (TCR) stimuli. Here, we report that regulatory T (Treg) cells orchestrate memorycell quiescence by suppressing effector and proliferation programs through inhibitory receptor, cytotoxic-T-lymphocyte-associated protein-4 (CTLA-4). Loss of Treg cells resulted in activation of genome-wide transcriptional programs characteristic of effector T cells and drove transitioning as well as established memory CD8(+) T cells toward terminally differentiated KLRG-1(hi)IL-7Rα(lo)GzmB(hi) phenotype, with compromised metabolic fitness, longevity, polyfunctionality, and protective efficacy. CTLA-4 functionally replaced Treg cells in trans to rescue memorycell defects and restore homeostasis. These studies present the CTLA-4-CD28-CD80/CD86 axis as a potential target to accelerate vaccine-induced immunity and improve T cell memory quality in current cancer immunotherapies proposing transient Treg cell ablation.

  5. Quantifying susceptibility of CD4+ stem memory T-cells to infection by laboratory adapted and clinical HIV-1 strains.

    PubMed

    Flynn, Jacqueline K; Paukovics, Geza; Cashin, Kieran; Borm, Katharina; Ellett, Anne; Roche, Michael; Jakobsen, Martin R; Churchill, Melissa J; Gorry, Paul R

    2014-02-10

    CD4+ T cells are principal targets for human immunodeficiency virus type 1 (HIV-1) infection. CD4+ T cell subsets are heterogeneous cell populations, divided by functional and phenotypic differences into naïve and memory T cells. The memory CD4+ T cells are further segregated into central, effector and transitional memory cell subsets by functional, phenotypic and homeostatic characteristics. Defining the distribution of HIV-1 infection in different T cell subsets is important, as this can play a role in determining the size and composition of the viral reservoir. Both central memory and transitional memory CD4+ T cells have been described as long-lived viral reservoirs for HIV. Recently, the newly described stem memory T cell subset has also been implicated as a long-lived HIV reservoir. Using green fluorescent protein (GFP) reporter strains of HIV-1 and multi parameter flow cytometry, we developed an assay to simultaneously quantify the susceptibility of stem memory (TSCM), central memory, effector memory, transitional memory and naïve CD4+ T cell subsets, to HIV-1 infection in vitro. We show that TSCM are susceptible to infection with laboratory adapted and clinical HIV-1 strains. Our system facilitates the quantitation of HIV-1 infection in alternative T cell subsets by CCR5- and CXCR4-using viruses across different HIV-1 subtypes, and will be useful for studies of HIV-1 pathogenesis and viral reservoirs.

  6. Quantifying Susceptibility of CD4+ Stem Memory T-Cells to Infection by Laboratory Adapted and Clinical HIV-1 Strains

    PubMed Central

    Flynn, Jacqueline K.; Paukovics, Geza; Cashin, Kieran; Borm, Katharina; Ellett, Anne; Roche, Michael; Jakobsen, Martin R.; Churchill, Melissa J.; Gorry, Paul R.

    2014-01-01

    CD4+ T cells are principal targets for human immunodeficiency virus type 1 (HIV-1) infection. CD4+ T cell subsets are heterogeneous cell populations, divided by functional and phenotypic differences into naïve and memory T cells. The memory CD4+ T cells are further segregated into central, effector and transitional memory cell subsets by functional, phenotypic and homeostatic characteristics. Defining the distribution of HIV-1 infection in different T cell subsets is important, as this can play a role in determining the size and composition of the viral reservoir. Both central memory and transitional memory CD4+ T cells have been described as long-lived viral reservoirs for HIV. Recently, the newly described stem memory T cell subset has also been implicated as a long-lived HIV reservoir. Using green fluorescent protein (GFP) reporter strains of HIV-1 and multi parameter flow cytometry, we developed an assay to simultaneously quantify the susceptibility of stem memory (TSCM), central memory, effector memory, transitional memory and naïve CD4+ T cell subsets, to HIV-1 infection in vitro. We show that TSCM are susceptible to infection with laboratory adapted and clinical HIV-1 strains. Our system facilitates the quantitation of HIV-1 infection in alternative T cell subsets by CCR5- and CXCR4-using viruses across different HIV-1 subtypes, and will be useful for studies of HIV-1 pathogenesis and viral reservoirs. PMID:24517971

  7. Switching kinetics of electrochemical metallization memory cells.

    PubMed

    Menzel, Stephan; Tappertzhofen, Stefan; Waser, Rainer; Valov, Ilia

    2013-05-14

    The strongly nonlinear switching kinetics of electrochemical metallization memory (ECM) cells are investigated using an advanced 1D simulation model. It is based on the electrochemical growth and dissolution of a Ag or Cu filament within a solid thin film and accounts for nucleation effects, charge transfer, and cation drift. The model predictions are consistent with experimental switching results of a time range of 12 orders of magnitude obtained from silver iodide (AgI) based ECM cells. By analyzing the simulation results the electrochemical processes limiting the switching kinetics are revealed. This study provides new insights into the understanding of the limiting electrochemical processes determining the switching kinetics of ECM cells. PMID:23549450

  8. Memory CD8+ T Cells: Orchestrators and Key Players of Innate Immunity?

    PubMed

    Lauvau, Grégoire; Goriely, Stanislas

    2016-09-01

    Over the past decades, the dichotomy between innate and adaptive immune responses has largely dominated our understanding of immunology. Upon primary encounter with microbial pathogens, differentiation of adaptive immune cells into functional effectors usually takes several days or even longer, making them contribute to host protection only late during primary infection. However, once generated, antigen-experienced T lymphocytes can persist in the organism and constitute a pool of memory cells that mediate fast and effective protection to a recall infection with the same microbial pathogen. Herein, we challenge this classical paradigm by highlighting the "innate nature" of memory CD8+ T cells. First, within the thymus or in the periphery, naïve CD8+ T cells may acquire phenotypic and functional characteristics of memory CD8+ T cells independently of challenge with foreign antigens. Second, both the "unconventional" and the "conventional" memory cells can rapidly express protective effector functions in response to sets of inflammatory cytokines and chemokines signals, independent of cognate antigen triggering. Third, memory CD8+ T cells can act by orchestrating the recruitment, activation, and licensing of innate cells, leading to broad antimicrobial states. Thus, collectively, memory CD8+ T cells may represent important actors of innate immune defenses.

  9. Memory CD8+ T Cells: Orchestrators and Key Players of Innate Immunity?

    PubMed

    Lauvau, Grégoire; Goriely, Stanislas

    2016-09-01

    Over the past decades, the dichotomy between innate and adaptive immune responses has largely dominated our understanding of immunology. Upon primary encounter with microbial pathogens, differentiation of adaptive immune cells into functional effectors usually takes several days or even longer, making them contribute to host protection only late during primary infection. However, once generated, antigen-experienced T lymphocytes can persist in the organism and constitute a pool of memory cells that mediate fast and effective protection to a recall infection with the same microbial pathogen. Herein, we challenge this classical paradigm by highlighting the "innate nature" of memory CD8+ T cells. First, within the thymus or in the periphery, naïve CD8+ T cells may acquire phenotypic and functional characteristics of memory CD8+ T cells independently of challenge with foreign antigens. Second, both the "unconventional" and the "conventional" memory cells can rapidly express protective effector functions in response to sets of inflammatory cytokines and chemokines signals, independent of cognate antigen triggering. Third, memory CD8+ T cells can act by orchestrating the recruitment, activation, and licensing of innate cells, leading to broad antimicrobial states. Thus, collectively, memory CD8+ T cells may represent important actors of innate immune defenses. PMID:27584152

  10. Memory CD8+ T Cells: Orchestrators and Key Players of Innate Immunity?

    PubMed Central

    Lauvau, Grégoire; Goriely, Stanislas

    2016-01-01

    Over the past decades, the dichotomy between innate and adaptive immune responses has largely dominated our understanding of immunology. Upon primary encounter with microbial pathogens, differentiation of adaptive immune cells into functional effectors usually takes several days or even longer, making them contribute to host protection only late during primary infection. However, once generated, antigen-experienced T lymphocytes can persist in the organism and constitute a pool of memory cells that mediate fast and effective protection to a recall infection with the same microbial pathogen. Herein, we challenge this classical paradigm by highlighting the “innate nature” of memory CD8+ T cells. First, within the thymus or in the periphery, naïve CD8+ T cells may acquire phenotypic and functional characteristics of memory CD8+ T cells independently of challenge with foreign antigens. Second, both the “unconventional” and the “conventional” memory cells can rapidly express protective effector functions in response to sets of inflammatory cytokines and chemokines signals, independent of cognate antigen triggering. Third, memory CD8+ T cells can act by orchestrating the recruitment, activation, and licensing of innate cells, leading to broad antimicrobial states. Thus, collectively, memory CD8+ T cells may represent important actors of innate immune defenses. PMID:27584152

  11. Item recognition memory and the receiver operating characteristic.

    PubMed

    Heathcote, Andrew

    2003-11-01

    Four experiments were conducted to investigate the effects of study time, study repetition, semantic and orthographic similarity, and category length on item recognition memory receiver operating characteristics (ROCs). Analyses of ROC shape rejected A. P. Yonelinas's (1994) dual-process model. The normal unequal variance signal-detection model provided a better account of the data, except for a small but consistent excess of high-confidence errors. It was found that z-transformed ROC slope was increased by similarity, category length, and study item repetition, rejecting R. Ratcliff, G. McKoon, and M. Tindall's (1994) "constancy-of-slopes" generalization for these variables, but slope was relatively unaffected by massed study time.

  12. Primer: making sense of T-cell memory.

    PubMed

    Beverley, Peter C L

    2008-01-01

    Protective memory is a key property of the immune system. Pathogen-associated molecular patterns of invading organisms deliver signals to pattern-recognition receptors that activate the innate immune system. Ligation of the T-cell receptor by peptides bound to MHC antigens and presented by dendritic cells, together with signals produced by the activated innate immune system, initiate T-cell responses. The nature of the T-cell response, consisting of phases of clonal expansion and contraction, and differentiation to effector and memory cells, however, is determined both by the properties of the antigen and the co-stimuli produced by the innate immune system. Short-lived effector and longer-lived memory T cells are generated during primary responses; after the death of most of the effectors, memory cells remain. Memory cells are heterogeneous in phenotype and function; subsets include the relatively quiescent central and more activated effector memory cells, as well as cells able to promote inflammation, help antibody production or regulate other immune responses. Understanding the properties of memory cells will help in the rational design of vaccines for 'difficult' organisms or cancer, as well as immunotherapies for autoimmune diseases. PMID:18172448

  13. Memory NK Cells Take Out the (Mitochondrial) Garbage.

    PubMed

    Wagner, Julia A; Fehniger, Todd A

    2015-08-18

    The molecular mechanisms important to generate innate natural killer cell "memory" are poorly understood. In this issue of Immunity, O'Sullivan et al. (2015) demonstrate that mitophagy plays a critical role in natural killer cell memory formation following viral infection. PMID:26287678

  14. Memory NK Cells Take Out the (Mitochondrial) Garbage.

    PubMed

    Wagner, Julia A; Fehniger, Todd A

    2015-08-18

    The molecular mechanisms important to generate innate natural killer cell "memory" are poorly understood. In this issue of Immunity, O'Sullivan et al. (2015) demonstrate that mitophagy plays a critical role in natural killer cell memory formation following viral infection.

  15. Figuring fact from fiction: unbiased polling of memory T cells.

    PubMed

    Gerlach, Carmen; Loughhead, Scott M; von Andrian, Ulrich H

    2015-05-01

    Immunization generates several memory T cell subsets that differ in their migratory properties, anatomic distribution, and, hence, accessibility to investigation. In this issue, Steinert et al. demonstrate that what was believed to be a minor memory cell subset in peripheral tissues has been dramatically underestimated. Thus, current models of protective immunity require revision.

  16. Group 2 innate lymphoid cells license dendritic cells to potentiate memory TH2 cell responses.

    PubMed

    Halim, Timotheus Y F; Hwang, You Yi; Scanlon, Seth T; Zaghouani, Habib; Garbi, Natalio; Fallon, Padraic G; McKenzie, Andrew N J

    2016-01-01

    Rapid activation of memory CD4(+) T helper 2 (TH2) cells during allergic inflammation requires their recruitment into the affected tissue. Here we demonstrate that group 2 innate lymphoid (ILC2) cells have a crucial role in memory TH2 cell responses, with targeted depletion of ILC2 cells profoundly impairing TH2 cell localization to the lungs and skin of sensitized mice after allergen re-challenge. ILC2-derived interleukin 13 (IL-13) is critical for eliciting production of the TH2 cell-attracting chemokine CCL17 by IRF4(+)CD11b(+)CD103(-) dendritic cells (DCs). Consequently, the sentinel function of DCs is contingent on ILC2 cells for the generation of an efficient memory TH2 cell response. These results elucidate a key innate mechanism in the regulation of the immune memory response to allergens.

  17. Virus-induced polyclonal B cell activation improves protective CTL memory via retained CD27 expression on memory CTL.

    PubMed

    Matter, Matthias; Mumprecht, Sabine; Pinschewer, Daniel D; Pavelic, Viktor; Yagita, Hideo; Krautwald, Stefan; Borst, Jannie; Ochsenbein, Adrian F

    2005-11-01

    Different viruses elicit distinct phenotypes of memory cytotoxic T lymphocytes (CTL). This is reflected in differential expression of homing receptors and costimulatory molecules like CD27. Memory CTL retained CD27 following lymphocytic choriomeningitis virus (LCMV) infection, but not after immunization with recombinant vaccinia virus or tumor cells expressing LCMV glycoprotein. Stable CD27 expression on memory CTL required ligation by CD70 expressed on polyclonally activated B cells during the contraction phase. The functional consequence of CD27 expressed on virus-specific CTL was analyzed in CD27-deficient mice. LCMV infection of CD27(-/-) mice revealed that primary CTL activation and expansion as well as elimination of the virus were independent of CD27 expression. In contrast, ligation of CD27 on memory CTL upon secondary antigen encounter increased clonal expansion and improved protection against re-infection. This points to novel B cell-CTL interactions during viral infection and to a beneficial role of polyclonal B cell activation that represents a characteristic of murine LCMV, human immunodeficiency virus and human hepatitis B and C virus infection. PMID:16231287

  18. Memory T cells maintain protracted protection against malaria.

    PubMed

    Krzych, Urszula; Zarling, Stasya; Pichugin, Alexander

    2014-10-01

    Immunologic memory is one of the cardinal features of antigen-specific immune responses, and the persistence of memory cells contributes to prophylactic immunizations against infectious agents. Adequately maintained memory T and B cell pools assure a fast, effective and specific response against re-infections. However, many aspects of immunologic memory are still poorly understood, particularly immunologic memory inducible by parasites, for example, Plasmodium spp., the causative agents of malaria. For example, memory responses to Plasmodium antigens amongst residents of malaria endemic areas appear to be either inadequately developed or maintained, because persons who survive episodes of childhood malaria remain vulnerable to intermittent malaria infections. By contrast, multiple exposures of humans and laboratory rodents to radiation-attenuated Plasmodium sporozoites (γ-spz) induce sterile and long-lasting protection against experimental sporozoite challenge. Multifactorial immune mechanisms maintain this protracted and sterile protection. While the presence of memory CD4 T cell subsets has been associated with lasting protection in humans exposed to multiple bites from Anopheles mosquitoes infected with attenuated Plasmodium falciparum, memory CD8 T cells maintain protection induced with Plasmodium yoelii and Plasmodium berghei γ-spz in murine models. In this review, we discuss our observations that show memory CD8 T cells specific for antigens expressed by P. berghei liver stage parasites as an indispensable component for the maintenance of protracted protective immunity against experimental malaria infection; moreover, the provision of an Ag-depot assures a quick recall of memory T cells as IFN-γ-producing effector CD8 T cells and IL-4- producing CD4 T cells that collaborate with B cells for an effective antibody response.

  19. Regulated selection of germinal-center cells into the memory B cell compartment.

    PubMed

    Shinnakasu, Ryo; Inoue, Takeshi; Kometani, Kohei; Moriyama, Saya; Adachi, Yu; Nakayama, Manabu; Takahashi, Yoshimasa; Fukuyama, Hidehiro; Okada, Takaharu; Kurosaki, Tomohiro

    2016-07-01

    Despite the importance of memory B cells in protection from reinfection, how such memory cells are selected and generated during germinal-center (GC) reactions remains unclear. We found here that light-zone (LZ) GC B cells with B cell antigen receptors (BCRs) of lower affinity were prone to enter the memory B cell pool. Mechanistically, cells in this memory-prone fraction had higher expression of the transcriptional repressor Bach2 than that of their counterparts with BCRs of higher affinity. Haploinsufficiency of Bach2 resulted in reduced generation of memory B cells, independently of suppression of the gene encoding the transcription factor Blimp-1. Bach2 expression in GC cells was inversely correlated with the strength of help provided by T cells. Thus, we propose an instructive model in which weak help from T cells maintains relatively high expression of Bach2, which predisposes GC cells to enter the memory pool.

  20. Study of multi-level characteristics for 3D vertical resistive switching memory.

    PubMed

    Bai, Yue; Wu, Huaqiang; Wu, Riga; Zhang, Ye; Deng, Ning; Yu, Zhiping; Qian, He

    2014-07-22

    Three-dimensional (3D) integration and multi-level cell (MLC) are two attractive technologies to achieve ultra-high density for mass storage applications. In this work, a three-layer 3D vertical AlOδ/Ta2O5-x/TaOy resistive random access memories were fabricated and characterized. The vertical cells in three layers show good uniformity and high performance (e.g. >1000X HRS/LRS windows, >10(10) endurance cycles, >10(4) s retention times at 125°C). Meanwhile, four level MLC is demonstrated with two operation strategies, current controlled scheme (CCS) and voltage controlled scheme (VCS). The switching mechanism of 3D vertical RRAM cells is studied based on temperature-dependent transport characteristics. Furthermore, the applicability of CCS and VCS in 3D vertical RRAM array is compared using resistor network circuit simulation.

  1. Study of Multi-level Characteristics for 3D Vertical Resistive Switching Memory

    PubMed Central

    Bai, Yue; Wu, Huaqiang; Wu, Riga; Zhang, Ye; Deng, Ning; Yu, Zhiping; Qian, He

    2014-01-01

    Three-dimensional (3D) integration and multi-level cell (MLC) are two attractive technologies to achieve ultra-high density for mass storage applications. In this work, a three-layer 3D vertical AlOδ/Ta2O5-x/TaOy resistive random access memories were fabricated and characterized. The vertical cells in three layers show good uniformity and high performance (e.g. >1000X HRS/LRS windows, >1010 endurance cycles, >104 s retention times at 125°C). Meanwhile, four level MLC is demonstrated with two operation strategies, current controlled scheme (CCS) and voltage controlled scheme (VCS). The switching mechanism of 3D vertical RRAM cells is studied based on temperature-dependent transport characteristics. Furthermore, the applicability of CCS and VCS in 3D vertical RRAM array is compared using resistor network circuit simulation. PMID:25047906

  2. Habit learning and memory in mammals: behavioral and neural characteristics.

    PubMed

    Gasbarri, Antonella; Pompili, Assunta; Packard, Mark G; Tomaz, Carlos

    2014-10-01

    Goal-direct behavior and habit learning represent two forms of instrumental learning; whereas the former is rapidly acquired and regulated by its outcome, the latter is reflexive, elicited by antecedent stimuli rather than their consequences. Habit learning can be generally defined as the acquisition of associations between stimuli and responses. Habits are acquired via experience-dependent plasticity, occurring repeatedly over the course of days or years and becoming remarkably fixed. The distinction between habit learning, as a product of a procedural learning brain system, and a declarative learning system for encoding facts and episodes is based on the hypothesis that memory is composed of multiple systems that have distinct neuroanatomy and operating principles. Here we review recent research analyzing the main behavioral and neural characteristics of habit learning. In particular, we focus on the distinction between goal-directed and habitual behavior, and describe the brain areas and neurotransmitters systems involved in habit learning. The emotional modulation of habit learning in rodents and primates is reviewed, and the implications of habit learning in psychopathology are briefly described. PMID:24981854

  3. Adults’ reports of their earliest memories: Consistency in events, ages, and narrative characteristics over time

    PubMed Central

    Bauer, Patricia J.; Tasdemir-Ozdes, Aylin; Larkina, Marina

    2014-01-01

    Earliest memories have been of interest since the late 1800s, when it was first noted that most adults do not have memories from the first years of life (so-called childhood amnesia). Several characteristics of adults’ earliest memories have been investigated, including emotional content, the perspective from which they are recalled, and vividness. The focus of the present research was a feature of early memories heretofore relatively neglected in the literature, namely, their consistency. Adults reported their earliest memories 2 to 4 times over a 4-year period. Reports of earliest memories were highly consistent in the events identified as the bases for earliest memories, the reported age at the time of the event, and in terms of qualities of the narrative descriptions. These findings imply stability in the boundary that marks the offset of childhood amnesia, as well as in the beginning of a continuous sense of self over time. PMID:24836979

  4. T Cell Factor 1-Expressing Memory-like CD8(+) T Cells Sustain the Immune Response to Chronic Viral Infections.

    PubMed

    Utzschneider, Daniel T; Charmoy, Mélanie; Chennupati, Vijaykumar; Pousse, Laurène; Ferreira, Daniela Pais; Calderon-Copete, Sandra; Danilo, Maxime; Alfei, Francesca; Hofmann, Maike; Wieland, Dominik; Pradervand, Sylvain; Thimme, Robert; Zehn, Dietmar; Held, Werner

    2016-08-16

    Chronic infections promote the terminal differentiation (or "exhaustion") of T cells and are thought to preclude the formation of memorycells. In contrast, we discovered a small subpopulation of virus-specific CD8(+) T cells that sustained the T cell response during chronic infections. These cells were defined by, and depended on, the expression of the transcription factor Tcf1. Transcriptome analysis revealed that this population shared key characteristics of central memory cells but lacked an effector signature. Unlike conventional memory cells, Tcf1-expressing T cells displayed hallmarks of an "exhausted" phenotype, including the expression of inhibitory receptors such as PD-1 and Lag-3. This population was crucial for the T cell expansion that occurred in response to inhibitory receptor blockade during chronic infection. These findings identify a memory-like T cell population that sustains T cell responses and is a prime target for therapeutic interventions to improve the immune response in chronic infections. PMID:27533016

  5. Three Types of Memory for Childhood Sexual Abuse: Relationships to Characteristics of Abuse and Psychological Symptoms

    ERIC Educational Resources Information Center

    Crowley, M. Sue

    2008-01-01

    Data from a clinical sample (N = 88) reporting childhood sexual abuse was compared by types of memory, abuse characteristics, and psychological symptoms. Three types of memory were identified from a questionnaire ("Always" n = 27 [31%], "Recovered" n = 41 [46%], and "Both" n = 20 [23%]). When compared with narrative reports from a subset (n = 30)…

  6. Characteristics of memory dysfunction in body dysmorphic disorder.

    PubMed

    Deckersbach, T; Savage, C R; Phillips, K A; Wilhelm, S; Buhlmann, U; Rauch, S L; Baer, L; Jenike, M A

    2000-09-01

    Although body dysmorphic disorder (BDD) is receiving increasing empirical attention, very little is known about neuropsychological deficits in this disorder. The current study investigated the nature of memory dysfunction in BDD, including the relationship between encoding strategies and verbal and nonverbal memory performance. We evaluated 17 patients with BDD and 17 healthy controls using the Rey-Osterrieth Complex Figure Test (RCFT) and the California Verbal Learning Test (CVLT). BDD patients differed significantly from healthy controls on verbal and nonverbal learning and memory indices. Multiple regression analyses revealed that group differences in free recall were statistically mediated by deficits in organizational strategies in the BDD cohort. These findings are similar to patterns previously observed in obsessive-compulsive disorder (OCD), suggesting a potential relationship between OCD and BDD. Studies in both groups have shown that verbal and nonverbal memory deficits are affected by impaired strategic processing. PMID:11011514

  7. Memory improves precision of cell sensing in fluctuating environments

    PubMed Central

    Aquino, Gerardo; Tweedy, Luke; Heinrich, Doris; Endres, Robert G.

    2014-01-01

    Biological cells are often found to sense their chemical environment near the single-molecule detection limit. Surprisingly, this precision is higher than simple estimates of the fundamental physical limit, hinting towards active sensing strategies. In this work, we analyse the effect of cell memory, e.g. from slow biochemical processes, on the precision of sensing by cell-surface receptors. We derive analytical formulas, which show that memory significantly improves sensing in weakly fluctuating environments. However, surprisingly when memory is adjusted dynamically, the precision is always improved, even in strongly fluctuating environments. In support of this prediction we quantify the directional biases in chemotactic Dictyostelium discoideum cells in a flow chamber with alternating chemical gradients. The strong similarities between cell sensing and control engineering suggest universal problem-solving strategies of living matter. PMID:25023459

  8. Requirement for CD4 T Cell Help in Generating Functional CD8 T Cell Memory

    NASA Astrophysics Data System (ADS)

    Shedlock, Devon J.; Shen, Hao

    2003-04-01

    Although primary CD8 responses to acute infections are independent of CD4 help, it is unknown whether a similar situation applies to secondary responses. We show that depletion of CD4 cells during the recall response has minimal effect, whereas depletion during the priming phase leads to reduced responses by memory CD8 cells to reinfection. Memory CD8 cells generated in CD4+/+ mice responded normally when transferred into CD4-/- hosts, whereas memory CD8 cells generated in CD4-/- mice mounted defective recall responses in CD4+/+ adoptive hosts. These results demonstrate a previously undescribed role for CD4 help in the development of functional CD8 memory.

  9. A SPICE model for a phase-change memory cell based on the analytical conductivity model

    NASA Astrophysics Data System (ADS)

    Yiqun, Wei; Xinnan, Lin; Yuchao, Jia; Xiaole, Cui; Jin, He; Xing, Zhang

    2012-11-01

    By way of periphery circuit design of the phase-change memory, it is necessary to present an accurate compact model of a phase-change memory cell for the circuit simulation. Compared with the present model, the model presented in this work includes an analytical conductivity model, which is deduced by means of the carrier transport theory instead of the fitting model based on the measurement. In addition, this model includes an analytical temperature model based on the 1D heat-transfer equation and the phase-transition dynamic model based on the JMA equation to simulate the phase-change process. The above models for phase-change memory are integrated by using Verilog-A language, and results show that this model is able to simulate the I-V characteristics and the programming characteristics accurately.

  10. Hardware implementation of associative memory characteristics with analogue-type resistive-switching device

    NASA Astrophysics Data System (ADS)

    Moon, Kibong; Park, Sangsu; Jang, Junwoo; Lee, Daeseok; Woo, Jiyong; Cha, Euijun; Lee, Sangheon; Park, Jaesung; Song, Jeonghwan; Koo, Yunmo; Hwang, Hyunsang

    2014-12-01

    We have investigated the analogue memory characteristics of an oxide-based resistive-switching device under an electrical pulse to mimic biological spike-timing-dependent plasticity synapse characteristics. As a synaptic device, a TiN/Pr0.7Ca0.3MnO3-based resistive-switching device exhibiting excellent analogue memory characteristics was used to control the synaptic weight by applying various pulse amplitudes and cycles. Furthermore, potentiation and depression characteristics with the same spikes can be achieved by applying negative and positive pulses, respectively. By adopting complementary metal-oxide-semiconductor devices as neurons and TiN/PCMO devices as synapses, we implemented neuromorphic hardware that mimics associative memory characteristics in real time for the first time. Owing to their excellent scalability, resistive-switching devices, shows promise for future high-density neuromorphic applications.

  11. Dendritic cells drive memory CD8 T-cell homeostasis via IL-15 transpresentation

    PubMed Central

    Stonier, Spencer W.; Ma, Lisa J.; Castillo, Eliseo F.

    2008-01-01

    Interleukin-15 (IL-15) is crucial for the development of naive and memory CD8 T cells and is delivered through a mechanism called transpresentation. Previous studies showed that memory CD8 T cells require IL-15 transpresentation by an as yet unknown cell of hematopoietic origin. We hypothesized that dendritic cells (DCs) transpresent IL-15 to CD8 T cells, and we examined this by developing a transgenic model that limits IL-15 transpresentation to DCs. In this study, IL-15 transpresentation by DCs had little effect on restoring naive CD8 T cells but contributed to the development of memory-phenotype CD8 T cells. The generation of virus-specific, memory CD8 T cells was partially supported by IL-15Rα+ DCs through the preferential enhancement of a subset of KLRG-1+CD27− CD8 T cells. In contrast, these DCs were largely sufficient in driving normal homeostatic proliferation of established memory CD8 T cells, suggesting that memory CD8 T cells grow more dependent on IL-15 transpresentation by DCs. Overall, our study clearly supports a role for DCs in memory CD8 T-cell homeostasis but also provides evidence that other hematopoietic cells are involved in this function. The identification of DCs fulfilling this role will enable future studies to better focus on mechanisms regulating T-cell homeostasis. PMID:18812469

  12. Memory

    MedlinePlus

    ... it has to decide what is worth remembering. Memory is the process of storing and then remembering this information. There are different types of memory. Short-term memory stores information for a few ...

  13. Multilevel Cell Storage and Resistance Variability in Resistive Random Access Memory

    NASA Astrophysics Data System (ADS)

    Pantelis, D. I.; Karakizis, P. N.; Dragatogiannis, D. A.; Charitidis, C. A.

    2016-06-01

    Multilevel per cell (MLC) storage in resistive random access memory (ReRAM) is attractive in achieving high-density and low-cost memory and will be required in future. In this chapter, MLC storage and resistance variability and reliability of multilevel in ReRAM are discussed. Different MLC operation schemes with their physical mechanisms and a comprehensive analysis of resistance variability have been provided. Various factors that can induce variability and their effect on the resistance margin between the multiple resistance levels are assessed. The reliability characteristics and the impact on MLC storage have also been assessed.

  14. Impacts of Co doping on ZnO transparent switching memory device characteristics

    NASA Astrophysics Data System (ADS)

    Simanjuntak, Firman Mangasa; Prasad, Om Kumar; Panda, Debashis; Lin, Chun-An; Tsai, Tsung-Ling; Wei, Kung-Hwa; Tseng, Tseung-Yuen

    2016-05-01

    The resistive switching characteristics of indium tin oxide (ITO)/Zn1-xCoxO/ITO transparent resistive memory devices were investigated. An appropriate amount of cobalt dopant in ZnO resistive layer demonstrated sufficient memory window and switching stability. In contrast, pure ZnO devices demonstrated a poor memory window, and using an excessive dopant concentration led to switching instability. To achieve suitable memory performance, relying only on controlling defect concentrations is insufficient; the grain growth orientation of the resistive layer must also be considered. Stable endurance with an ON/OFF ratio of more than one order of magnitude during 5000 cycles confirmed that the Co-doped ZnO device is a suitable candidate for resistive random access memory application. Additionally, fully transparent devices with a high transmittance of up to 90% at wavelength of 550 nm have been fabricated.

  15. Effects of aging on the characteristics of TiNiPd shape memory alloy thin films

    SciTech Connect

    Zhang Congchun

    2008-07-15

    TiNiPd thin films have been deposited on glass substrate using R.F. magnetron sputtering. Effects of annealing and aging on the microstructure, phase transformation behaviors and shape memory effects of these thin films have been studied by X-ray diffractometry, differential scanning calorimeter, tensile tests and internal friction characteristics. The TiNiPd thin films annealed at 750 deg. C exhibit uniform martensite/austenite transformations and shape memory effect. Aging at 450 deg. C for 1 h improved the uniformity of transformations and shape memory effect. Long time aging decreased transformation temperatures and increased the brittleness of TiNiPd thin films.

  16. Flexible conductive-bridging random-access-memory cell vertically stacked with top Ag electrode, PEO, PVK, and bottom Pt electrode.

    PubMed

    Seung, Hyun-Min; Kwon, Kyoung-Cheol; Lee, Gon-Sub; Park, Jea-Gun

    2014-10-31

    Flexible conductive-bridging random-access-memory (RAM) cells were fabricated with a cross-bar memory cell stacked with a top Ag electrode, conductive polymer (poly(n-vinylcarbazole): PVK), electrolyte (polyethylene oxide: PEO), bottom Pt electrode, and flexible substrate (polyethersulfone: PES), exhibiting the bipolar switching behavior of resistive random access memory (ReRAM). The cell also exhibited bending-fatigue-free nonvolatile memory characteristics: i.e., a set voltage of 1.0 V, a reset voltage of -1.6 V, retention time of >1 × 10(5) s with a memory margin of 9.2 × 10(5), program/erase endurance cycles of >10(2) with a memory margin of 8.4 × 10(5), and bending-fatigue-free cycles of ∼1 × 10(3) with a memory margin (I(on)/I(off)) of 3.3 × 10(5). PMID:25297517

  17. Flexible conductive-bridging random-access-memory cell vertically stacked with top Ag electrode, PEO, PVK, and bottom Pt electrode

    NASA Astrophysics Data System (ADS)

    Seung, Hyun-Min; Kwon, Kyoung-Cheol; Lee, Gon-Sub; Park, Jea-Gun

    2014-10-01

    Flexible conductive-bridging random-access-memory (RAM) cells were fabricated with a cross-bar memory cell stacked with a top Ag electrode, conductive polymer (poly(n-vinylcarbazole): PVK), electrolyte (polyethylene oxide: PEO), bottom Pt electrode, and flexible substrate (polyethersulfone: PES), exhibiting the bipolar switching behavior of resistive random access memory (ReRAM). The cell also exhibited bending-fatigue-free nonvolatile memory characteristics: i.e., a set voltage of 1.0 V, a reset voltage of -1.6 V, retention time of >1 × 105 s with a memory margin of 9.2 × 105, program/erase endurance cycles of >102 with a memory margin of 8.4 × 105, and bending-fatigue-free cycles of ˜1 × 103 with a memory margin (Ion/Ioff) of 3.3 × 105.

  18. Vaccination Expands Antigen-Specific CD4+ Memory T Cells and Mobilizes Bystander Central Memory T Cells.

    PubMed

    Li Causi, Eleonora; Parikh, Suraj C; Chudley, Lindsey; Layfield, David M; Ottensmeier, Christian H; Stevenson, Freda K; Di Genova, Gianfranco

    2015-01-01

    CD4+ T helper memory (Thmem) cells influence both natural and vaccine-boosted immunity, but mechanisms for their maintenance remain unclear. Pro-survival signals from the common gamma-chain cytokines, in particular IL-7, appear important. Previously we showed in healthy volunteers that a booster vaccination with tetanus toxoid (TT) expanded peripheral blood TT-specific Thmem cells as expected, but was accompanied by parallel increase of Thmem cells specific for two unrelated and non cross-reactive common recall antigens. Here, in a new cohort of healthy human subjects, we compare blood vaccine-specific and bystander Thmem cells in terms of differentiation stage, function, activation and proliferative status. Both responses peaked 1 week post-vaccination. Vaccine-specific cytokine-producing Thmem cells were predominantly effector memory, whereas bystander cells were mainly of central memory phenotype. Importantly, TT-specific Thmem cells were activated (CD38High HLA-DR+), cycling or recently divided (Ki-67+), and apparently vulnerable to death (IL-7RαLow and Bcl-2 Low). In contrast, bystander Thmem cells were resting (CD38Low HLA-DR- Ki-67-) with high expression of IL-7Rα and Bcl-2. These findings allow a clear distinction between vaccine-specific and bystander Thmem cells, suggesting the latter do not derive from recent proliferation but from cells mobilized from as yet undefined reservoirs. Furthermore, they reveal the interdependent dynamics of specific and bystander T-cell responses which will inform assessments of responses to vaccines.

  19. Memory.

    ERIC Educational Resources Information Center

    McKean, Kevin

    1983-01-01

    Discusses current research (including that involving amnesiacs and snails) into the nature of the memory process, differentiating between and providing examples of "fact" memory and "skill" memory. Suggests that three brain parts (thalamus, fornix, mammilary body) are involved in the memory process. (JN)

  20. Mechanical memory

    DOEpatents

    Gilkey, Jeffrey C.; Duesterhaus, Michelle A.; Peter, Frank J.; Renn, Rosemarie A.; Baker, Michael S.

    2006-08-15

    A first-in-first-out (FIFO) microelectromechanical memory apparatus (also termed a mechanical memory) is disclosed. The mechanical memory utilizes a plurality of memory cells, with each memory cell having a beam which can be bowed in either of two directions of curvature to indicate two different logic states for that memory cell. The memory cells can be arranged around a wheel which operates as a clocking actuator to serially shift data from one memory cell to the next. The mechanical memory can be formed using conventional surface micromachining, and can be formed as either a nonvolatile memory or as a volatile memory.

  1. Mechanical memory

    DOEpatents

    Gilkey, Jeffrey C.; Duesterhaus, Michelle A.; Peter, Frank J.; Renn, Rosemarie A.; Baker, Michael S.

    2006-05-16

    A first-in-first-out (FIFO) microelectromechanical memory apparatus (also termed a mechanical memory) is disclosed. The mechanical memory utilizes a plurality of memory cells, with each memory cell having a beam which can be bowed in either of two directions of curvature to indicate two different logic states for that memory cell. The memory cells can be arranged around a wheel which operates as a clocking actuator to serially shift data from one memory cell to the next. The mechanical memory can be formed using conventional surface micromachining, and can be formed as either a nonvolatile memory or as a volatile memory.

  2. Every Breath You Take: The Impact of Environment on Resident Memory CD8 T Cells in the Lung

    PubMed Central

    Shane, Hillary L.; Klonowski, Kimberly D.

    2014-01-01

    Resident memory T cells (TRM) are broadly defined as a population of T cells, which persist in non-lymphoid sites long-term, do not re-enter the circulation, and are distinct from central memory T cells (TCM) and circulating effector memory T cells (TEM). Recent studies have described populations of TRM cells in the skin, gut, lungs, and nervous tissue. However, it is becoming increasingly clear that the specific environment in which the TRM reside can further refine their phenotypical and functional properties. Here, we focus on the TRM cells that develop following respiratory infection and reside in the lungs and the lung airways. Specifically, we will review recent studies that have described some of the requirements for establishment of TRM cells in these tissues, and the defining characteristics of TRM in the lungs and lung airways. With continual bombardment of the respiratory tract by both pathogenic and environmental antigens, dynamic fluctuations in the local milieu including homeostatic resources and niche restrictions can impact TRM longevity. Beyond a comprehensive characterization of lung TRM cells, special attention will be placed on studies, which have defined how the microenvironment of the lung influences memory T cell survival at this site. As memory T cell populations in the lung airways are requisite for protection yet wane numerically over time, developing a comprehensive picture of factors which may influence TRM development and persistence at these sites is important for improving T cell-based vaccine design. PMID:25071780

  3. Resistive switching behavior of reduced graphene oxide memory cells for low power nonvolatile device application

    PubMed Central

    Pradhan, Sangram K.; Xiao, Bo; Mishra, Saswat; Killam, Alex; Pradhan, Aswini K.

    2016-01-01

    Graphene Oxide (GO) based low cost flexible electronics and memory cell have recently attracted more attention for the fabrication of emerging electronic devices. As a suitable candidate for resistive random access memory technology, reduced graphene oxide (RGO) can be widely used for non-volatile switching memory applications because of its large surface area, excellent scalability, retention, and endurance properties. We demonstrated that the fabricated metal/RGO/metal memory device exhibited excellent switching characteristics, with on/off ratio of two orders of magnitude and operated threshold switching voltage of less than 1 V. The studies on different cell diameter, thickness, scan voltages and period of time corroborate the reliability of the device as resistive random access memory. The microscopic origin of switching operation is governed by the establishment of conducting filaments due to the interface amorphous layer rupturing and the movement of oxygen in the GO layer. This interesting experimental finding indicates that device made up of thermally reduced GO shows more reliability for its use in next generation electronics devices. PMID:27240537

  4. Resistive switching behavior of reduced graphene oxide memory cells for low power nonvolatile device application

    NASA Astrophysics Data System (ADS)

    Pradhan, Sangram K.; Xiao, Bo; Mishra, Saswat; Killam, Alex; Pradhan, Aswini K.

    2016-05-01

    Graphene Oxide (GO) based low cost flexible electronics and memory cell have recently attracted more attention for the fabrication of emerging electronic devices. As a suitable candidate for resistive random access memory technology, reduced graphene oxide (RGO) can be widely used for non-volatile switching memory applications because of its large surface area, excellent scalability, retention, and endurance properties. We demonstrated that the fabricated metal/RGO/metal memory device exhibited excellent switching characteristics, with on/off ratio of two orders of magnitude and operated threshold switching voltage of less than 1 V. The studies on different cell diameter, thickness, scan voltages and period of time corroborate the reliability of the device as resistive random access memory. The microscopic origin of switching operation is governed by the establishment of conducting filaments due to the interface amorphous layer rupturing and the movement of oxygen in the GO layer. This interesting experimental finding indicates that device made up of thermally reduced GO shows more reliability for its use in next generation electronics devices.

  5. Resistive switching behavior of reduced graphene oxide memory cells for low power nonvolatile device application.

    PubMed

    Pradhan, Sangram K; Xiao, Bo; Mishra, Saswat; Killam, Alex; Pradhan, Aswini K

    2016-01-01

    Graphene Oxide (GO) based low cost flexible electronics and memory cell have recently attracted more attention for the fabrication of emerging electronic devices. As a suitable candidate for resistive random access memory technology, reduced graphene oxide (RGO) can be widely used for non-volatile switching memory applications because of its large surface area, excellent scalability, retention, and endurance properties. We demonstrated that the fabricated metal/RGO/metal memory device exhibited excellent switching characteristics, with on/off ratio of two orders of magnitude and operated threshold switching voltage of less than 1 V. The studies on different cell diameter, thickness, scan voltages and period of time corroborate the reliability of the device as resistive random access memory. The microscopic origin of switching operation is governed by the establishment of conducting filaments due to the interface amorphous layer rupturing and the movement of oxygen in the GO layer. This interesting experimental finding indicates that device made up of thermally reduced GO shows more reliability for its use in next generation electronics devices. PMID:27240537

  6. Recollection is a continuous process: Evidence from plurality memory receiver operating characteristics.

    PubMed

    Slotnick, Scott D; Jeye, Brittany M; Dodson, Chad S

    2016-01-01

    Is recollection a continuous/graded process or a threshold/all-or-none process? Receiver operating characteristic (ROC) analysis can answer this question as the continuous model and the threshold model predict curved and linear recollection ROCs, respectively. As memory for plurality, an item's previous singular or plural form, is assumed to rely on recollection, the nature of recollection can be investigated by evaluating plurality memory ROCs. The present study consisted of four experiments. During encoding, words (singular or plural) or objects (single/singular or duplicate/plural) were presented. During retrieval, old items with the same plurality or different plurality were presented. For each item, participants made a confidence rating ranging from "very sure old", which was correct for same plurality items, to "very sure new", which was correct for different plurality items. Each plurality memory ROC was the proportion of same versus different plurality items classified as "old" (i.e., hits versus false alarms). Chi-squared analysis revealed that all of the plurality memory ROCs were adequately fit by the continuous unequal variance model, whereas none of the ROCs were adequately fit by the two-high threshold model. These plurality memory ROC results indicate recollection is a continuous process, which complements previous source memory and associative memory ROC findings.

  7. Human Memory B Cells in Healthy Gingiva, Gingivitis, and Periodontitis.

    PubMed

    Mahanonda, Rangsini; Champaiboon, Chantrakorn; Subbalekha, Keskanya; Sa-Ard-Iam, Noppadol; Rattanathammatada, Warattaya; Thawanaphong, Saranya; Rerkyen, Pimprapa; Yoshimura, Fuminobu; Nagano, Keiji; Lang, Niklaus P; Pichyangkul, Sathit

    2016-08-01

    The presence of inflammatory infiltrates with B cells, specifically plasma cells, is the hallmark of periodontitis lesions. The composition of these infiltrates in various stages of homeostasis and disease development is not well documented. Human tissue biopsies from sites with gingival health (n = 29), gingivitis (n = 8), and periodontitis (n = 21) as well as gingival tissue after treated periodontitis (n = 6) were obtained and analyzed for their composition of B cell subsets. Ag specificity, Ig secretion, and expression of receptor activator of NF-κB ligand and granzyme B were performed. Although most of the B cell subsets in healthy gingiva and gingivitis tissues were CD19(+)CD27(+)CD38(-) memory B cells, the major B cell component in periodontitis was CD19(+)CD27(+)CD38(+)CD138(+)HLA-DR(low) plasma cells, not plasmablasts. Plasma cell aggregates were observed at the base of the periodontal pocket and scattered throughout the gingiva, especially apically toward the advancing front of the lesion. High expression of CXCL12, a proliferation-inducing ligand, B cell-activating factor, IL-10, IL-6, and IL-21 molecules involved in local B cell responses was detected in both gingivitis and periodontitis tissues. Periodontitis tissue plasma cells mainly secreted IgG specific to periodontal pathogens and also expressed receptor activator of NF-κB ligand, a bone resorption cytokine. Memory B cells resided in the connective tissue subjacent to the junctional epithelium in healthy gingiva. This suggested a role of memory B cells in maintaining periodontal homeostasis. PMID:27335500

  8. Tunneling Electroresistance Effect with Diode Characteristic for Cross-Point Memory.

    PubMed

    Lee, Hong-Sub; Park, Hyung-Ho

    2016-06-22

    Cross-point memory architecture (CPMA) by using memristors has attracted considerable attention because of its high-density integration. However, a common and significant drawback of the CPMA is related to crosstalk issues between cells by sneak currents. This study demonstrated the sneak current free resistive switching characteristic of a ferroelectric tunnel diode (FTD) memristor for a CPMA by utilizing a novel concept of a ferroelectric quadrangle and triangle barrier switch. A FTD of Au/BaTiO3 (5 nm)/Nb-doped SrTiO3 (100) was used to obtain a desirable memristive effect for the CPMA. The FTD could reversibly change the shape of the ferroelectric potential from a quadrangle to a triangle. The effect included high nonlinearity and diode characteristics. It was derived from utilizing different sequences of carrier transport mechanisms such as the direct tunneling current, Fowler-Nordheim tunneling, and thermionic emission. The FTD memristor demonstrated the feasibility of sneak current-free high-density CPMA. PMID:27237433

  9. Tunneling Electroresistance Effect with Diode Characteristic for Cross-Point Memory.

    PubMed

    Lee, Hong-Sub; Park, Hyung-Ho

    2016-06-22

    Cross-point memory architecture (CPMA) by using memristors has attracted considerable attention because of its high-density integration. However, a common and significant drawback of the CPMA is related to crosstalk issues between cells by sneak currents. This study demonstrated the sneak current free resistive switching characteristic of a ferroelectric tunnel diode (FTD) memristor for a CPMA by utilizing a novel concept of a ferroelectric quadrangle and triangle barrier switch. A FTD of Au/BaTiO3 (5 nm)/Nb-doped SrTiO3 (100) was used to obtain a desirable memristive effect for the CPMA. The FTD could reversibly change the shape of the ferroelectric potential from a quadrangle to a triangle. The effect included high nonlinearity and diode characteristics. It was derived from utilizing different sequences of carrier transport mechanisms such as the direct tunneling current, Fowler-Nordheim tunneling, and thermionic emission. The FTD memristor demonstrated the feasibility of sneak current-free high-density CPMA.

  10. Non-Volatile Flash Memory Characteristics of Tetralayer Nickel-Germanide Nanocrystals Embedded Structure.

    PubMed

    Panda, D; Panda, M

    2016-01-01

    Formation of tetralayer memory structure having nickel-germanide nanocrystals using a Ge/Ni multilayers is proposed. X-ray diffraction study shows the NiGe (002) phase formation after proper annealing. Cross sectional HRTEM clearly shows the sharpness and the size (~4-6 nm) of the stacked nanocrystals embedded in the oxide matrix. A large anti-clockwise hysteresis memory win- dow of 13.4 Volt at ± 15 Volt is observed for the optimized samples. This large memory window indicates for the MLC applications. Frequency independent C-V curve confirms about the charge storage in the nanocrystals. A good charge retention and endurance characteristics are exhibited upto 125 °C for the nonvolatile memory application. PMID:27398590

  11. Most microbe-specific naïve CD4⁺ T cells produce memory cells during infection.

    PubMed

    Tubo, Noah J; Fife, Brian T; Pagan, Antonio J; Kotov, Dmitri I; Goldberg, Michael F; Jenkins, Marc K

    2016-01-29

    Infection elicits CD4(+) memory T lymphocytes that participate in protective immunity. Although memory cells are the progeny of naïve T cells, it is unclear that all naïve cells from a polyclonal repertoire have memory cell potential. Using a single-cell adoptive transfer and spleen biopsy method, we found that in mice, essentially all microbe-specific naïve cells produced memory cells during infection. Different clonal memory cell populations had different B cell or macrophage helper compositions that matched effector cell populations generated much earlier in the response. Thus, each microbe-specific naïve CD4(+) T cell produces a distinctive ratio of effector cell types early in the immune response that is maintained as some cells in the clonal population become memory cells.

  12. Functional characteristics of auditory temporal-spatial short-term memory: evidence from serial order errors.

    PubMed

    Parmentier, F B; Jones, D M

    2000-01-01

    The functional characteristics of auditory temporal-spatial short-term memory were explored in 8 experiments in which the to-be-remembered stimuli were sequences of bursts of white noise presented in spatial locations separated in azimuth. Primacy and recency effects were observed in all experiments. A 10-s delay impaired recall for primacy and middle list items but not recency. This effect was shown not to depend on the response modality or on the incidence of omissions or repetitions. Verbal and nonverbal secondary tasks did not affect memory for auditory spatial sounds. Temporal errors rather than spatial errors predominated, suggesting that participants were engaged in a process of maintaining order. This pattern of results may reflect characteristics that serial recall has in common with verbal and spatial recall, but some are unique to the representation of memory for temporal-spatial auditory events.

  13. Transitional Information in Spatial Serial Memory: Path Characteristics Affect Recall Performance

    ERIC Educational Resources Information Center

    Parmentier, Fabrice B. R.; Elford, Greg; Mayberry, Murray

    2005-01-01

    This study examined the role of stimulus characteristics in a visuospatial order reconstruction task in which participants were required to recall the order of sequences of spatial locations. The complexity of the to-be-remembered sequences, as measured by path crossing, path length, and angles, was found to affect serial memory, in terms of both…

  14. Defective CD8 T Cell Memory Following Acute Infection Without CD4 T Cell Help

    NASA Astrophysics Data System (ADS)

    Sun, Joseph C.; Bevan, Michael J.

    2003-04-01

    The CD8+ cytotoxic T cell response to pathogens is thought to be CD4+ helper T cell independent because infectious agents provide their own inflammatory signals. Mice that lack CD4+ T cells mount a primary CD8 response to Listeria monocytogenes equal to that of wild-type mice and rapidly clear the infection. However, protective memory to a challenge is gradually lost in the former animals. Memory CD8+ T cells from normal mice can respond rapidly, but memory CD8+ T cells that are generated without CD4 help are defective in their ability to respond to secondary encounters with antigen. The results highlight a previously undescribed role for CD4 help in promoting protective CD8 memory development.

  15. Humans with chronic granulomatous disease maintain humoral immunologic memory despite low frequencies of circulating memory B cells.

    PubMed

    Moir, Susan; De Ravin, Suk See; Santich, Brian H; Kim, Jin Young; Posada, Jacqueline G; Ho, Jason; Buckner, Clarisa M; Wang, Wei; Kardava, Lela; Garofalo, Mary; Marciano, Beatriz E; Manischewitz, Jody; King, Lisa R; Khurana, Surender; Chun, Tae-Wook; Golding, Hana; Fauci, Anthony S; Malech, Harry L

    2012-12-01

    CD27(+) memory B cells are reduced in the blood of patients with chronic granulomatous disease (CGD) for reasons and consequences that remain unclear. Here we confirm not only decreased CD27(+) but also IgG(+) B cells in the blood of CGD patients compared with healthy donors (HDs). However, among IgG(+) B cells, the ratio of CD27(-) to CD27(+) was significantly higher in CGD patients compared with HDs. Similar to conventional memory B cells, CD27(-)IgG(+) B cells of CGD patients expressed activation markers and had undergone somatic hypermutation, albeit at levels lower than their CD27(+) counterparts. Functional analyses revealed slight reductions in frequencies of total IgG but not influenza-specific memory B-cell responses, as measured by Elispot in CGD patients compared with HDs. Serum IgG levels and influenza-specific antibodies were also normal in these CGD patients. Finally, we provide evidence that influenza-specific memory B cells can be present within the CD27(-)IgG(+) B-cell compartment. Together, these findings show that, despite reduced circulating CD27(+) memory B cells, CGD patients maintain an intact humoral immunologic memory, with potential contribution from CD27(-) B cells.

  16. [Short-term memory characteristics of vibration intensity tactile perception on human wrist].

    PubMed

    Hao, Fei; Chen, Li-Juan; Lu, Wei; Song, Ai-Guo

    2014-12-25

    In this study, a recall experiment and a recognition experiment were designed to assess the human wrist's short-term memory characteristics of tactile perception on vibration intensity, by using a novel homemade vibrotactile display device based on the spatiotemporal combination vibration of multiple micro vibration motors as a test device. Based on the obtained experimental data, the short-term memory span, recognition accuracy and reaction time of vibration intensity were analyzed. From the experimental results, some important conclusions can be made: (1) The average short-term memory span of tactile perception on vibration intensity is 3 ± 1 items; (2) The greater difference between two adjacent discrete intensities of vibrotactile stimulation is defined, the better average short-term memory span human wrist gets; (3) There is an obvious difference of the average short-term memory span on vibration intensity between the male and female; (4) The mechanism of information extraction in short-term memory of vibrotactile display is to traverse the scanning process by comparison; (5) The recognition accuracy and reaction time performance of vibrotactile display compares unfavourably with that of visual and auditory. The results from this study are important for designing vibrotactile display coding scheme. PMID:25516517

  17. Memory CD8+ T Cells Protect Dendritic Cells from CTL Killing1

    PubMed Central

    Watchmaker, Payal B.; Urban, Julie A.; Berk, Erik; Nakamura, Yutaro; Mailliard, Robbie B.; Watkins, Simon C.; van Ham, S. Marieke; Kalinski, Pawel

    2010-01-01

    CD8+ T cells have been shown to be capable of either suppressing or promoting immune responses. To reconcile these contrasting regulatory functions, we compared the ability of human effector and memory CD8+ T cells to regulate survival and functions of dendritic cells (DC). We report that, in sharp contrast to the effector cells (CTLs) that kill DCs in a granzyme B- and perforin-dependent mechanism, memory CD8+ T cells enhance the ability of DCs to produce IL-12 and to induce functional Th1 and CTL responses in naive CD4+ and CD8+ T cell populations. Moreover, memory CD8+ T cells that release the DC-activating factor TNF-α before the release of cytotoxic granules induce DC expression of an endogenous granzyme B inhibitor PI-9 and protect DCs from CTL killing with similar efficacy as CD4+ Th cells. The currently identified DC-protective function of memory CD8+ T cells helps to explain the phenomenon of CD8+ T cell memory, reduced dependence of recall responses on CD4+ T cell help, and the importance of delayed administration of booster doses of vaccines for the optimal outcome of immunization. PMID:18322193

  18. Improved memory characteristics of charge trap memory by employing double layered ZrO2 nanocrystals and inserted Al2O3

    NASA Astrophysics Data System (ADS)

    Tang, Z. J.; Li, R.; Zhang, X. W.; Hu, D.; Zhao, Y. G.

    2016-07-01

    The charge trap memory capacitors incorporating a stacked charge trapping layer consisting of double layered ZrO2 nanocrystals (NCs) and inserted Al2O3 have been fabricated and investigated. It is observed that the memory capacitor with stacked trapping layer exhibits a hysteresis window as large as 14.3 V for ±10 V sweeping gate voltage range, faster program/erase speed, improved endurance performance, and good data retention characteristics with smaller extrapolated ten years charge loss at room temperature and 125 °C compared to single layered NCs. The special energy band alignment and the introduced additional traps of double layered ZrO2 NCs and inserted Al2O3 change the trapping and loss behavior of charges, and jointly contribute to the remarkable memory characteristics. Therefore, the memory capacitor with a stacked charge trapping layer is a promising candidate in future nonvolatile charge trap memory device design and application.

  19. Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells.

    PubMed

    Kawalekar, Omkar U; O'Connor, Roddy S; Fraietta, Joseph A; Guo, Lili; McGettigan, Shannon E; Posey, Avery D; Patel, Prachi R; Guedan, Sonia; Scholler, John; Keith, Brian; Snyder, Nathaniel W; Snyder, Nathaniel; Blair, Ian A; Blair, Ian; Milone, Michael C; June, Carl H

    2016-02-16

    Chimeric antigen receptors (CARs) redirect T cell cytotoxicity against cancer cells, providing a promising approach to cancer immunotherapy. Despite extensive clinical use, the attributes of CAR co-stimulatory domains that impact persistence and resistance to exhaustion of CAR-T cells remain largely undefined. Here, we report the influence of signaling domains of coreceptors CD28 and 4-1BB on the metabolic characteristics of human CAR T cells. Inclusion of 4-1BB in the CAR architecture promoted the outgrowth of CD8(+) central memorycells that had significantly enhanced respiratory capacity, increased fatty acid oxidation and enhanced mitochondrial biogenesis. In contrast, CAR T cells with CD28 domains yielded effector memory cells with a genetic signature consistent with enhanced glycolysis. These results provide, at least in part, a mechanistic insight into the differential persistence of CAR-T cells expressing 4-1BB or CD28 signaling domains in clinical trials and inform the design of future CAR T cell therapies. PMID:26885860

  20. Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells.

    PubMed

    Kawalekar, Omkar U; O'Connor, Roddy S; Fraietta, Joseph A; Guo, Lili; McGettigan, Shannon E; Posey, Avery D; Patel, Prachi R; Guedan, Sonia; Scholler, John; Keith, Brian; Snyder, Nathaniel W; Snyder, Nathaniel; Blair, Ian A; Blair, Ian; Milone, Michael C; June, Carl H

    2016-02-16

    Chimeric antigen receptors (CARs) redirect T cell cytotoxicity against cancer cells, providing a promising approach to cancer immunotherapy. Despite extensive clinical use, the attributes of CAR co-stimulatory domains that impact persistence and resistance to exhaustion of CAR-T cells remain largely undefined. Here, we report the influence of signaling domains of coreceptors CD28 and 4-1BB on the metabolic characteristics of human CAR T cells. Inclusion of 4-1BB in the CAR architecture promoted the outgrowth of CD8(+) central memorycells that had significantly enhanced respiratory capacity, increased fatty acid oxidation and enhanced mitochondrial biogenesis. In contrast, CAR T cells with CD28 domains yielded effector memory cells with a genetic signature consistent with enhanced glycolysis. These results provide, at least in part, a mechanistic insight into the differential persistence of CAR-T cells expressing 4-1BB or CD28 signaling domains in clinical trials and inform the design of future CAR T cell therapies.

  1. Evaluation of Data Retention Characteristics for Ferroelectric Random Access Memories (FRAMs)

    NASA Technical Reports Server (NTRS)

    Sharma, Ashok K.; Teverovsky, Alexander

    2001-01-01

    Data retention and fatigue characteristics of 64 Kb lead zirconate titanate (PZT)-based Ferroelectric Random Access Memories (FRAMs) microcircuits manufactured by Ramtron were examined over temperature range from -85 C to +310 C for ceramic packaged parts and from -85 C to +175 C for plastic parts, during retention periods up to several thousand hours. Intrinsic failures, which were caused by a thermal degradation of the ferroelectric cells, occurred in ceramic parts after tens or hundreds hours of aging at temperatures above 200 C. The activation energy of the retention test failures was 1.05 eV and the extrapolated mean-time-to-failure (MTTF) at room temperature was estimated to be more than 280 years. Multiple write-read cycling (up to 3x10(exp 7)) during the fatigue testing of plastic and ceramic parts did not result in any parametric or functional failures. However, operational currents linearly decreased with the logarithm of number of cycles thus indicating fatigue process in PZT films. Plastic parts, that had more recent date code as compared to ceramic parts, appeared to be using die with improved process technology and showed significantly smaller changes in operational currents and data access times.

  2. Differential role of ICAM ligands in determination of human memory T cell differentiation

    PubMed Central

    Perez, Omar D; Mitchell, Dennis; Nolan, Garry P

    2007-01-01

    Background Leukocyte Function Antigen-1 (LFA-1) is a primary adhesion molecule that plays important roles in T cell activation, leukocyte recirculation, and trans-endothelial migration. By applying a multivariate intracellular phospho-proteomic analysis, we demonstrate that LFA-1 differentially activates signaling molecules. Results Signal intensity was dependent on both ICAM ligand and LFA-1 concentration. In the presence of CD3 and CD28 stimulation, ICAM-2 and ICAM-3 decreased TGFβ1 production more than ICAM-1. In long-term differentiation experiments, stimulation with ICAM-3, CD3, and CD28 generated IFNγ producing CD4+CD45RO+CD62L-CD11aBrightCD27- cells that had increased expression of intracellular BCL2, displayed distinct chemokine receptor profiles, and exhibited distinct migratory characteristics. Only CD3/CD28 with ICAM-3 generated CD4+CD45RO+CD62L-CD11aBrightCD27- cells that were functionally responsive to chemotaxis and exhibited higher frequencies of cells that signaled to JNK and ERK1/2 upon stimulation with MIP3α. Furthermore, these reports identify that the LFA-1 receptor, when presented with multiple ligands, can result in distinct T cell differentiation states and suggest that the combinatorial integration of ICAM ligand interactions with LFA-1 have functional consequences for T cell biology. Conclusion Thus, the ICAM ligands, differentially modulate LFA-1 signaling in T cells and potentiate the development of memory human T cells in vitro. These findings are of importance in a mechanistic understanding of memory cell differentiation and ex vivo generation of memory cell subsets for therapeutic applications. PMID:17233909

  3. CD21(-/low) B cells in human blood are memory cells.

    PubMed

    Thorarinsdottir, K; Camponeschi, A; Cavallini, N; Grimsholm, O; Jacobsson, L; Gjertsson, I; Mårtensson, I-L

    2016-08-01

    The complement receptor 2 (CR2, CD21) is part of a complex (CD21/CD19/CD81) acting as a co-receptor to the B cell receptor (BCR). Simultaneous triggering of the BCR and CD21 lowers the threshold for B cell activation. Although CD21 is important, B cells that express low amounts or lack surface CD21 (CD21(-/low) ) are increased in conditions with chronic inflammation, e.g. autoimmune diseases. However, little is known about the CD21(-/low) B cell subset in peripheral blood from healthy donors. Here, we show that CD21(-/low) cells represent approximately 5% of B cells in peripheral blood from adults but are barely detectable in cord blood, after excluding transitional B cells. The CD21(-/low) subset can be divided into CD38(-) 24(+) and CD38(-) 24(low) cells, where most of the CD38(-) 24(+) are CD27(+) immunoglobulin (Ig)M(+) IgD(+) and the CD38(-) 24(low) are switched CD27(-) . Expression levels of additional markers, e.g. CD95 and CD62L, are similar to those on classical memory B cells. In contrast to naive cells, the majority of CD21(-/low) cells lack expression of the ABCB1 transporter. Stimulation with a combination of BCR, Toll-like receptor (TLR)-7/8 and interleukin (IL)-2 induces proliferation and differentiation of the CD21(-/low) B cells comparable to CD21(+) CD27(+) memory B cells. The response excluding BCR agonist is not on par with that of classical memory B cells, although clearly above that of naive B cells. This is ascribed to a weaker response by the CD38(-) 24(low) subset, implying that some memorycells require not only TLR but also BCR triggering. We conclude that the CD21(-/low) cells in healthy donors are memory B cells. PMID:27010233

  4. Cancer immunotherapy and immunological memory.

    PubMed

    Murata, Kenji; Tsukahara, Tomohide; Torigoe, Toshihiko

    2016-01-01

      Human immunological memory is the key distinguishing hallmark of the adaptive immune system and plays an important role in the prevention of morbidity and the severity of infection. The differentiation system of T cell memory has been clarified using mouse models. However, the human T cell memory system has great diversity induced by natural antigens derived from many pathogens and tumor cells throughout life, and profoundly differs from the mouse memory system constructed using artificial antigens and transgenic T cells. We believe that only human studies can elucidate the human immune system. The importance of immunological memory in cancer immunotherapy has been pointed out, and the trafficking properties and long-lasting anti-tumor capacity of memory T cells play a crucial role in the control of malignant tumors. Adoptive cell transfer of less differentiated T cells has consistently demonstrated superior anti-tumor capacity relative to more differentiated T cells. Therefore, a human T cell population with the characteristics of stem cell memory is thought to be attractive for peptide vaccination and adoptive cell transfer. A novel human memory T cell population that we have identified is closer to the naive state than previous memory T cells in the T cell differentiation lineage, and has the characteristics of stem-like chemoresistance. Here we introduce this novel population and describe the fundamentals of immunological memory in cancer immunotherapy.

  5. Cancer immunotherapy and immunological memory.

    PubMed

    Murata, Kenji; Tsukahara, Tomohide; Torigoe, Toshihiko

    2016-01-01

      Human immunological memory is the key distinguishing hallmark of the adaptive immune system and plays an important role in the prevention of morbidity and the severity of infection. The differentiation system of T cell memory has been clarified using mouse models. However, the human T cell memory system has great diversity induced by natural antigens derived from many pathogens and tumor cells throughout life, and profoundly differs from the mouse memory system constructed using artificial antigens and transgenic T cells. We believe that only human studies can elucidate the human immune system. The importance of immunological memory in cancer immunotherapy has been pointed out, and the trafficking properties and long-lasting anti-tumor capacity of memory T cells play a crucial role in the control of malignant tumors. Adoptive cell transfer of less differentiated T cells has consistently demonstrated superior anti-tumor capacity relative to more differentiated T cells. Therefore, a human T cell population with the characteristics of stem cell memory is thought to be attractive for peptide vaccination and adoptive cell transfer. A novel human memory T cell population that we have identified is closer to the naive state than previous memory T cells in the T cell differentiation lineage, and has the characteristics of stem-like chemoresistance. Here we introduce this novel population and describe the fundamentals of immunological memory in cancer immunotherapy. PMID:27181230

  6. Tissue distribution and dependence of responsiveness of human antigen-specific memory B cells.

    PubMed

    Giesecke, Claudia; Frölich, Daniela; Reiter, Karin; Mei, Henrik E; Wirries, Ina; Kuhly, Rainer; Killig, Monica; Glatzer, Timor; Stölzel, Katharina; Perka, Carsten; Lipsky, Peter E; Dörner, Thomas

    2014-04-01

    Memory B cells (mBCs) are a key to immunologic memory, yet their distribution within lymphoid organs and the individual role of these for mBC functionality remain largely unknown. This study characterized the distribution and phenotype of human (Ag-specific) mBCs in peripheral blood (PB), spleen, tonsil, and bone marrow. We found that the spleen harbors most mBCs, followed by tonsils, BM, and PB, and we detected no major differences in expression of markers associated with higher maturity. Testing the distribution of tetanus toxoid-specific (TT(+)) mBCs revealed their presence in PB during steady state, yet absolute numbers suggested their largest reservoir in the spleen, followed by tonsils. To explore the role of both tissues in the maintenance of reactive B cell memory, we revaccinated controls and splenectomized and tonsillectomized individuals with TT. All donor groups exhibited comparable emergence of anti-TT IgG, TT(+) plasma cells, and TT(+) mBCs in the PB, together with similar molecular characteristics of TT(+) plasma cells. In summary, human mBCs recirculate through PB and reside in different lymphoid organs that do not reflect different mBC maturity stages. The spleen and tonsil, although harboring the largest number of overall and TT(+) mBCs, appear to be dispensable to preserve adequate responsiveness to secondary antigenic challenge.

  7. Characteristics of junctionless charge trap flash memory for 3D stacked NAND flash.

    PubMed

    Oh, Jinho; Na, Heedo; Park, Sunghoon; Sohn, Hyunchul

    2013-09-01

    The electrical characteristics of tunnel barrier engineered-charge trap flash (TBE-CTF) memory devices with junctionless (JL) source and drain (S/D) were investigated. The JL structure is composed of an n(+)-poly-Si based ultra-thin channel and S/D with identical doping concentrations. The band engineered Hf-silicate/Al2O3 tunnel barrier stack was applied to a JL-TBE-CTF memory device in order to enhance the field sensitivity. The Hf-silicate/Al2O3 tunnel barrier, HfO2 trap layer, and Al2O3 blocking layer were deposited by atomic layer deposition. The fabricated device exhibited a large memory window of 9.43 V, as well as high programming and erasing speeds. Moreover, it also showed adequate retention times and endurance properties. Hence, the JL-TBE-CTF memory (which has a low process complexity) is expected to be an appropriate structure for 3D stacked ultra-high density memory applications. PMID:24205672

  8. Evidence for grid cells in a human memory network.

    PubMed

    Doeller, Christian F; Barry, Caswell; Burgess, Neil

    2010-02-01

    Grid cells in the entorhinal cortex of freely moving rats provide a strikingly periodic representation of self-location which is indicative of very specific computational mechanisms. However, the existence of grid cells in humans and their distribution throughout the brain are unknown. Here we show that the preferred firing directions of directionally modulated grid cells in rat entorhinal cortex are aligned with the grids, and that the spatial organization of grid-cell firing is more strongly apparent at faster than slower running speeds. Because the grids are also aligned with each other, we predicted a macroscopic signal visible to functional magnetic resonance imaging (fMRI) in humans. We then looked for this signal as participants explored a virtual reality environment, mimicking the rats' foraging task: fMRI activation and adaptation showing a speed-modulated six-fold rotational symmetry in running direction. The signal was found in a network of entorhinal/subicular, posterior and medial parietal, lateral temporal and medial prefrontal areas. The effect was strongest in right entorhinal cortex, and the coherence of the directional signal across entorhinal cortex correlated with spatial memory performance. Our study illustrates the potential power of combining single-unit electrophysiology with fMRI in systems neuroscience. Our results provide evidence for grid-cell-like representations in humans, and implicate a specific type of neural representation in a network of regions which supports spatial cognition and also autobiographical memory.

  9. Differential mechanisms of memory CD8 T cell maintenance by individual myeloid cell types

    PubMed Central

    Frasca, Loredana; Stonier, Spencer W.; Overwijk, Willem W.; Schluns, Kimberly S.

    2010-01-01

    This study tested the hypothesis that individual myeloid subsets have a differential ability to maintain memory CD8 T cells via IL-15. Although DCs support IL-15-mediated homeostasis of memory CD8 T cells in vivo, whether various DC subsets and other myeloid cells similarly mediate homeostasis is unknown. Therefore, we studied the ability of different myeloid cells to maintain memory CD8 T cells in vitro. Using an in vitro cocoulture system that recapitulated known roles of DCs and IL-15 on memory CD8 T cells, all in vitro-derived or ex vivo-isolated DCs maintained CD8 T cells better than rIL-15 alone, and FLT-3L-DCs are the most efficient compared with GM-DCs, BM-derived macrophages, or freshly isolated DCs. Although FLT-3L-DCs were the least effective at inducing CD8 T cell proliferation, FLT-3L-DCs promoted better CD8 T cell survival and increased Bcl-2 and MCL-2 expression in CD8 T cells. T cell maintenance correlated only partially with DC expression of IL-15Rα and IL-15, suggesting that DCs provided additional support signals. Indeed, in the absence of IL-15 signals, CD70/CD27 further supported CD8 T cell maintenance. IFN-α enhanced CD70 expression by DCs, resulting in increased proliferation of CD8 T cells. Overall, this study supports our hypothesis by demonstrating that specific DC subtypes had a greater capacity to support memory CD8 T cell maintenance and did so through different mechanisms. Furthermore, this study shows that IL-15 trans-presentation can work in conjunction with other signals, such as CD70/CD27 interactions, to mediate CD8 T cell homeostasis efficiently. PMID:20354106

  10. Effector memory and central memory NY-ESO-1-specific re-directed T cells for treatment of multiple myeloma.

    PubMed

    Schuberth, P C; Jakka, G; Jensen, S M; Wadle, A; Gautschi, F; Haley, D; Haile, S; Mischo, A; Held, G; Thiel, M; Tinguely, M; Bifulco, C B; Fox, B A; Renner, C; Petrausch, U

    2013-04-01

    The cancer-testis antigen NY-ESO-1 is a potential target antigen for immune therapy expressed in a subset of patients with multiple myeloma. We generated chimeric antigen receptors (CARs) recognizing the immunodominant NY-ESO-1 peptide 157-165 in the context of HLA-A*02:01 to re-direct autologous CD8(+) T cells towards NY-ESO-1(+) myeloma cells. These re-directed T cells specifically lysed NY-ESO-1(157-165)/HLA-A*02:01-positive cells and secreted IFNγ. A total of 40% of CCR7(-) re-directed T cells had an effector memory phenotype and 5% a central memory phenotype. Based on CCR7 cell sorting, effector and memory CAR-positive T cells were separated and CCR7(+) memory cells demonstrated after antigen-specific re-stimulation downregulation of CCR7 as sign of differentiation towards effector cells accompanied by an increased secretion of memory signature cytokines such as IL-2. To evaluate NY-ESO-1 as potential target antigen, we screened 78 bone marrow biopsies of multiple myeloma patients where NY-ESO-1 protein was found to be expressed by immunohistochemistry in 9.7% of samples. Adoptively transferred NY-ESO-1-specific re-directed T cells protected mice against challenge with endogenously NY-ESO-1-positive myeloma cells in a xenograft model. In conclusion, re-directed effector- and central memory T cells specifically recognized NY-ESO-1(157-165)/ HLA-A*02:01-positive cells resulting in antigen-specific functionality in vitro and in vivo.

  11. Simultaneous assessment of rotavirus-specific memory B cells and serological memory after B cell depletion therapy with rituximab.

    PubMed

    Herrera, Daniel; Rojas, Olga L; Duarte-Rey, Carolina; Mantilla, Rubén D; Angel, Juana; Franco, Manuel A

    2014-01-01

    The mechanisms that contribute to the maintenance of serological memory are still unclear. Rotavirus (RV) memory B cells (mBc) are enriched in IgM(+) and CD27- subpopulations, which are associated with autoimmune diseases pathogenesis. In patients with autoimmune diseases treated with Rituximab (RTX), some autoantibodies (auto-Abs) decrease after treatment, but other auto-Abs and pathogen-specific IgG Abs remain unchanged. Thus, maintenance of autoimmune and pathogen-specific serological memory may depend on the type of antigen and/or Ab isotype evaluated. Antigen-specific mBc and antigen-specific Abs of different isotypes have not been simultaneously assessed in patients after RTX treatment. To study the relationship between mBc subpopulations and serological memory we characterized total, RV- and tetanus toxoid (TT)-specific mBc by flow cytometry in patients with autoimmune diseases before and after treatment with RTX. We also measured total, RV- and TT-Abs, and some auto-Abs by kinetic nephelometry, ELISA, and EliA tests, respectively. Minor differences were observed between the relative frequencies of RV-mBc in healthy controls and patients with autoimmune disease. After RTX treatment, naïve Bc and total, RV- and TT-specific mBc [IgM(+), switched (IgA(+)/IgG(+)), IgM(+) only, IgD(+) only, and CD27- (IgA(+)/IgG(+)/IgM(+))] were significantly diminished. An important decrease in total plasma IgM and minor decreases in total IgG and IgA levels were also observed. IgM rheumatoid factor, IgG anti-CCP, and IgG anti-dsDNA were significantly diminished. In contrast, RV-IgA, RV-IgG and RV-IgG1, and TT-IgG titers remained stable. In conclusion, in patients with autoimmunity, serological memory against RV and TT seem to be maintained by long-lived plasma cells, unaffected by RTX, and an important proportion of total IgM and serological memory against some auto-antigens seem to be maintained by short-lived plasma cells, dependent on mBc precursors depleted by RTX.

  12. Simultaneous Assessment of Rotavirus-Specific Memory B Cells and Serological Memory after B Cell Depletion Therapy with Rituximab

    PubMed Central

    Herrera, Daniel; Rojas, Olga L.; Duarte-Rey, Carolina; Mantilla, Rubén D.; Ángel, Juana; Franco, Manuel A.

    2014-01-01

    The mechanisms that contribute to the maintenance of serological memory are still unclear. Rotavirus (RV) memory B cells (mBc) are enriched in IgM+ and CD27- subpopulations, which are associated with autoimmune diseases pathogenesis. In patients with autoimmune diseases treated with Rituximab (RTX), some autoantibodies (auto-Abs) decrease after treatment, but other auto-Abs and pathogen-specific IgG Abs remain unchanged. Thus, maintenance of autoimmune and pathogen-specific serological memory may depend on the type of antigen and/or Ab isotype evaluated. Antigen-specific mBc and antigen-specific Abs of different isotypes have not been simultaneously assessed in patients after RTX treatment. To study the relationship between mBc subpopulations and serological memory we characterized total, RV- and tetanus toxoid (TT)-specific mBc by flow cytometry in patients with autoimmune diseases before and after treatment with RTX. We also measured total, RV- and TT-Abs, and some auto-Abs by kinetic nephelometry, ELISA, and EliA tests, respectively. Minor differences were observed between the relative frequencies of RV-mBc in healthy controls and patients with autoimmune disease. After RTX treatment, naïve Bc and total, RV- and TT-specific mBc [IgM+, switched (IgA+/IgG+), IgM+ only, IgD+ only, and CD27- (IgA+/IgG+/IgM+)] were significantly diminished. An important decrease in total plasma IgM and minor decreases in total IgG and IgA levels were also observed. IgM rheumatoid factor, IgG anti-CCP, and IgG anti-dsDNA were significantly diminished. In contrast, RV-IgA, RV-IgG and RV-IgG1, and TT-IgG titers remained stable. In conclusion, in patients with autoimmunity, serological memory against RV and TT seem to be maintained by long-lived plasma cells, unaffected by RTX, and an important proportion of total IgM and serological memory against some auto-antigens seem to be maintained by short-lived plasma cells, dependent on mBc precursors depleted by RTX. PMID:24819618

  13. Strategic Priming with Multiple Antigens can Yield Memory Cell Phenotypes Optimized for Infection with Mycobacterium tuberculosis: A Computational Study

    PubMed Central

    Ziraldo, Cordelia; Gong, Chang; Kirschner, Denise E.; Linderman, Jennifer J.

    2016-01-01

    Lack of an effective vaccine results in 9 million new cases of tuberculosis (TB) every year and 1.8 million deaths worldwide. Although many infants are vaccinated at birth with BCG (an attenuated M. bovis), this does not prevent infection or development of TB after childhood. Immune responses necessary for prevention of infection or disease are still unknown, making development of effective vaccines against TB challenging. Several new vaccines are ready for human clinical trials, but these trials are difficult and expensive; especially challenging is determining the appropriate cellular response necessary for protection. The magnitude of an immune response is likely key to generating a successful vaccine. Characteristics such as numbers of central memory (CM) and effector memory (EM) T cells responsive to a diverse set of epitopes are also correlated with protection. Promising vaccines against TB contain mycobacterial subunit antigens (Ag) present during both active and latent infection. We hypothesize that protection against different key immunodominant antigens could require a vaccine that produces different levels of EM and CM for each Ag-specific memory population. We created a computational model to explore EM and CM values, and their ratio, within what we term Memory Design Space. Our model captures events involved in T cell priming within lymph nodes and tracks their circulation through blood to peripheral tissues. We used the model to test whether multiple Ag-specific memory cell populations could be generated with distinct locations within Memory Design Space at a specific time point post vaccination. Boosting can further shift memory populations to memory cell ratios unreachable by initial priming events. By strategically varying antigen load, properties of cellular interactions within the LN, and delivery parameters (e.g., number of boosts) of multi-subunit vaccines, we can generate multiple Ag-specific memory populations that cover a wide range of

  14. Strategic priming with multiple antigens can yield memory cell phenotypes optimized for infection with Mycobacterium tuberculosis: A computational study

    DOE PAGES

    Ziraldo, Cordelia; Gong, Chang; Kirschner, Denise E.; Linderman, Jennifer J.

    2016-01-06

    Lack of an effective vaccine results in 9 million new cases of tuberculosis (TB) every year and 1.8 million deaths worldwide. While many infants are vaccinated at birth with BCG (an attenuated M. bovis), this does not prevent infection or development of TB after childhood. Immune responses necessary for prevention of infection or disease are still unknown, making development of effective vaccines against TB challenging. Several new vaccines are ready for human clinical trials, but these trials are difficult and expensive; especially challenging is determining the appropriate cellular response necessary for protection. The magnitude of an immune response is likelymore » key to generating a successful vaccine. Characteristics such as numbers of central memory (CM) and effector memory (EM) T cells responsive to a diverse set of epitopes are also correlated with protection. Promising vaccines against TB contain mycobacterial subunit antigens (Ag) present during both active and latent infection. We hypothesize that protection against different key immunodominant antigens could require a vaccine that produces different levels of EM and CM for each Ag-specific memory population. We created a computational model to explore EM and CM values, and their ratio, within what we term Memory Design Space. Our model captures events involved in T cell priming within lymph nodes and tracks their circulation through blood to peripheral tissues. We used the model to test whether multiple Ag-specific memory cell populations could be generated with distinct locations within Memory Design Space at a specific time point post vaccination. Boosting can further shift memory populations to memory cell ratios unreachable by initial priming events. By strategically varying antigen load, properties of cellular interactions within the LN, and delivery parameters (e.g., number of boosts) of multi-subunit vaccines, we can generate multiple Ag-specific memory populations that cover a wide range of

  15. Dendritic Cells Enhance HIV Infection of Memory CD4(+) T Cells in Human Lymphoid Tissues.

    PubMed

    Reyes-Rodriguez, Angel L; Reuter, Morgan A; McDonald, David

    2016-02-01

    Dendritic cells (DCs) play a key role in controlling infections by coordinating innate and adaptive immune responses to invading pathogens. Paradoxically, DCs can increase HIV-1 dissemination in vitro by binding and transferring infectious virions to CD4(+) T cells, a process called transinfection. Transinfection has been well characterized in cultured cell lines and circulating primary T cells, but it is unknown whether DCs enhance infection of CD4(+) T cells in vivo. In untreated HIV infection, massive CD4(+) T-cell infection and depletion occur in secondary lymphoid tissues long before decline is evident in the peripheral circulation. To study the role of DCs in HIV infection of lymphoid tissues, we utilized human tonsil tissues, cultured either as tissue blocks or as aggregate suspension cultures, in single-round infection experiments. In these experiments, addition of monocyte-derived DCs (MDDCs) to the cultures increased T-cell infection, particularly in CD4(+) T cells expressing lower levels of HLA-DR. Subset analysis demonstrated that MDDCs increased HIV-1 infection of central and effector memory T-cell populations. Depletion of endogenous myeloid DCs (myDCs) from the cultures decreased memory T-cell infection, and readdition of MDDCs restored infection to predepletion levels. Using an HIV-1 fusion assay, we found that MDDCs equally increased HIV delivery into naïve, central, and effector memory T cells in the cultures, whereas predepletion of myDCs reduced fusion into memory T cells. Together, these data suggest that resident myDCs facilitate memory T-cell infection in lymphoid tissues, implicating DC-mediated transinfection in driving HIV dissemination within these tissues in untreated HIV/AIDS.

  16. The Effects of Instruction on the Frequency and Characteristics of Involuntary Autobiographical Memories.

    PubMed

    Barzykowski, Krystian; Niedźwieńska, Agnieszka

    2016-01-01

    The present study investigated the effects of experimental instruction on the retrieval of involuntary autobiographical memories (IAMs). In previous studies of IAMs, participants were either instructed to record only memories (henceforth, the restricted group) or any thoughts (henceforth, the unrestricted group). However, it is unknown whether these two different types of instructions influence the retrieval of IAMs. The most recent study by Vannucci and her colleagues directly addressed this question and demonstrated that the frequency and phenomenological characteristics of IAMs strongly depended on the type of instruction received. The goal of the present study was to replicate these results while addressing some limitations of the Vannucci et al. study and to test three possible mechanisms proposed to explain the effect of instructions on the retrieval of IAMs. Our results accord well with the data presented by Vannucci et al. When participants were instructed to record only IAMs (the restricted group), they reported more memories and rated them as being retrieved in a more goal-oriented fashion. Their memories also were less clear, vivid, detailed and were less frequently accompanied by physiological reactions, compared to memories reported by the participants in the unrestricted group. In addition, the events to which the memories referred were rated as more unusual and personal by the restricted group. These results are consistent with the assumption that retrieval of IAMs depends on the type of instructions used in a study. In addition, our results suggest that one of the main mechanisms underlying the higher frequency of IAMs in the restricted group may be participants' ability to monitor the stream of consciousness and to extract autobiographical content from this flow. Further implications of the effect of instructions for IAMs research are discussed.

  17. The Effects of Instruction on the Frequency and Characteristics of Involuntary Autobiographical Memories

    PubMed Central

    Niedźwieńska, Agnieszka

    2016-01-01

    The present study investigated the effects of experimental instruction on the retrieval of involuntary autobiographical memories (IAMs). In previous studies of IAMs, participants were either instructed to record only memories (henceforth, the restricted group) or any thoughts (henceforth, the unrestricted group). However, it is unknown whether these two different types of instructions influence the retrieval of IAMs. The most recent study by Vannucci and her colleagues directly addressed this question and demonstrated that the frequency and phenomenological characteristics of IAMs strongly depended on the type of instruction received. The goal of the present study was to replicate these results while addressing some limitations of the Vannucci et al. study and to test three possible mechanisms proposed to explain the effect of instructions on the retrieval of IAMs. Our results accord well with the data presented by Vannucci et al. When participants were instructed to record only IAMs (the restricted group), they reported more memories and rated them as being retrieved in a more goal-oriented fashion. Their memories also were less clear, vivid, detailed and were less frequently accompanied by physiological reactions, compared to memories reported by the participants in the unrestricted group. In addition, the events to which the memories referred were rated as more unusual and personal by the restricted group. These results are consistent with the assumption that retrieval of IAMs depends on the type of instructions used in a study. In addition, our results suggest that one of the main mechanisms underlying the higher frequency of IAMs in the restricted group may be participants’ ability to monitor the stream of consciousness and to extract autobiographical content from this flow. Further implications of the effect of instructions for IAMs research are discussed. PMID:27294408

  18. Naïve and memory B cells exhibit distinct biochemical responses following BCR engagement.

    PubMed

    Moens, Leen; Kane, Alisa; Tangye, Stuart G

    2016-09-01

    Immunological memory is characterized by the rapid reactivation of memory B cells that produce large quantities of high-affinity antigen-specific antibodies. This contrasts the response of naïve B cells, and the primary immune response, which is much slower and of lower affinity. Memory responses are critical for protection against infectious diseases and form the basis of most currently available vaccines. Although we have known about the phenomenon of long-lived memory for centuries, the biochemical differences underlying these diverse responses of naïve and memory B cells is incompletely resolved. Here we investigated the nature of B-cell receptor (BCR) signaling in human splenic naïve, IgM(+) memory and isotype-switched memory B cells following multivalent BCR crosslinking. We observed comparable rapid and transient phosphorylation kinetics for proximal (phosphotyrosine and spleen tyrosine kinase) and propagation (B-cell linker, phospholipase Cγ2) signaling components in these different B-cell subsets. However, the magnitude of activation of downstream components of the BCR signaling pathway were greater in memory compared with naïve cells. Although no differences were observed in the magnitude of Ca(2+) mobilization between subsets, IgM(+) memory B cells exhibited a more rapid Ca(2+) mobilization and a greater depletion of the Ca(2+) endoplasmic reticulum stores, while IgG(+) memory B cells had a prolonged Ca(2+) uptake. Collectively, our findings show that intrinsic signaling features of B-cell subsets contribute to the robust response of human memory B cells over naïve B cells. This has implications for our understanding of memory B-cell responses and provides a framework to modulate these responses in the setting of vaccination and immunopathologies, such as immunodeficiency and autoimmunity. PMID:27101923

  19. Immunological characteristics of mesenchymal stem cells

    PubMed Central

    Machado, Cíntia de Vasconcellos; Telles, Paloma Dias da Silva; Nascimento, Ivana Lucia Oliveira

    2013-01-01

    Although bone marrow is the main source, mesenchymal stem cells have already been isolated from various other tissues, such as the liver, pancreas, adipose tissue, peripheral blood and dental pulp. These plastic adherent cells are morphologically similar to fibroblasts and have a high proliferative potential. This special group of cells possesses two essential characteristics: self-renewal and differentiation, with appropriate stimuli, into various cell types. Mesenchymal stem cells are considered immunologically privileged, since they do not express costimulatory molecules, required for complete T cell activation, on their surface. Several studies have shown that these cells exert an immunosuppressive effect on cells from both innate and acquired immunity systems. Mesenchymal stem cells can regulate the immune response in vitro by inhibiting the maturation of dendritic cells, as well as by suppressing the proliferation and function of T and B lymphocytes and natural killer cells. These special properties of mesenchymal stem cells make them a promising strategy in the treatment of immune mediated disorders, such as graft-versus-host disease and autoimmune diseases, as well as in regenerative medicine. The understanding of immune regulation mechanisms of mesenchymal stem cells, and also those involved in the differentiation of these cells in various lineages is primordial for their successful and safe application in different areas of medicine. PMID:23580887

  20. Quantitative assessment of the functional plasticity of memory CD8(+) T cells.

    PubMed

    Baz, Adriana; Groves, Penny; Buttigieg, Kathy; Apte, Simon H; Kienzle, Norbert; Kelso, Anne

    2016-04-01

    While the functional plasticity of memory CD4(+) T cells has been studied extensively, less is known about this property in memory CD8(+) T cells. Here, we report the direct measurement of plasticity by paired daughter analysis of effector and memory OT-I CD8(+) T cells primed in vivo with ovalbumin. Naïve, effector, and memory OT-I cells were isolated and activated in single-cell culture; then, after the first division, their daughter cells were transferred to new cultures with and without IL-4; expression of IFN-γ and IL-4 mRNAs was measured 5 days later in the resultant subclones. Approximately 40% of clonogenic memory CD8(+) T cells were bipotential in this assay, giving rise to an IL-4(-) subclone in the absence of IL-4 and an IL-4(+) subclone in the presence of IL-4. The frequency of bipotential cells was lower among memory cells than naïve cells but markedly higher than among 8-day effectors. Separation based on high or low expression of CD62L, CD122, CD127, or Ly6C did not identify a phenotypic marker of the bipotential cells. Functional plasticity in memory CD8(+) T-cell populations can therefore reflect modulation at the level of a single memory cell and its progeny.

  1. Quantitative assessment of the functional plasticity of memory CD8(+) T cells.

    PubMed

    Baz, Adriana; Groves, Penny; Buttigieg, Kathy; Apte, Simon H; Kienzle, Norbert; Kelso, Anne

    2016-04-01

    While the functional plasticity of memory CD4(+) T cells has been studied extensively, less is known about this property in memory CD8(+) T cells. Here, we report the direct measurement of plasticity by paired daughter analysis of effector and memory OT-I CD8(+) T cells primed in vivo with ovalbumin. Naïve, effector, and memory OT-I cells were isolated and activated in single-cell culture; then, after the first division, their daughter cells were transferred to new cultures with and without IL-4; expression of IFN-γ and IL-4 mRNAs was measured 5 days later in the resultant subclones. Approximately 40% of clonogenic memory CD8(+) T cells were bipotential in this assay, giving rise to an IL-4(-) subclone in the absence of IL-4 and an IL-4(+) subclone in the presence of IL-4. The frequency of bipotential cells was lower among memory cells than naïve cells but markedly higher than among 8-day effectors. Separation based on high or low expression of CD62L, CD122, CD127, or Ly6C did not identify a phenotypic marker of the bipotential cells. Functional plasticity in memory CD8(+) T-cell populations can therefore reflect modulation at the level of a single memory cell and its progeny. PMID:26799367

  2. Convertible resistive switching characteristics between memory switching and threshold switching in a single ferritin-based memristor.

    PubMed

    Zhang, Chaochao; Shang, Jie; Xue, Wuhong; Tan, Hongwei; Pan, Liang; Yang, Xi; Guo, Shanshan; Hao, Jian; Liu, Gang; Li, Run-Wei

    2016-04-01

    A bio-memristor fabricated with ferritin exhibits novel resistive switching characteristics wherein memory switching and threshold switching are made steadily coexistent and inter-convertible through controlling the magnitude of compliance current presets.

  3. Cutting edge: rapid boosting of cross-reactive memory CD8 T cells broadens the protective capacity of the Flumist vaccine.

    PubMed

    Slütter, Bram; Pewe, Lecia L; Lauer, Peter; Harty, John T

    2013-04-15

    Memory CD8 T cells recognizing conserved proteins from influenza A virus (IAV), such as nucleoprotein, have the potential to provide protection in individuals who lack the proper neutralizing Abs. In this study, we show that the most potent CD8 T cell-inducing influenza vaccine on the market (Flumist) does not induce sufficient numbers of cross-reactive CD8 T cells to provide substantial protection against lethal nonhomologous IAV challenge. However, Flumist-primed CD8 T cells rapidly acquire memory characteristics and can respond to short-interval boosting to greatly enlarge the IAV-specific memory pool, which is sufficient to protect mice from nonhomologous IAV challenge. Thus, a current vaccine strategy, Flumist, may serve as a priming platform for the rapid induction of large numbers of memory CD8 T cells with the capacity for broad protection against influenza.

  4. Rapid boosting of cross-reactive memory CD8 T-cells broadens the protective capacity of the Flumist® vaccine

    PubMed Central

    Slütter, Bram; Pewe, Lecia L.; Lauer, Peter; Harty, John T.

    2013-01-01

    Memory CD8 T-cells recognizing conserved proteins from influenza A virus (IAV) such as nucleoprotein (NP), have the potential to provide protection in individuals who lack the proper neutralizing antibodies. Here we show that the most potent CD8 T-cell inducing influenza vaccine on the market (Flumist®), does not induce sufficient numbers of cross-reactive CD8 T-cells to provide substantial protection against lethal non-homologous IAV challenge. However, Flumist primed CD8 T-cells rapidly acquire memory characteristics and can respond to short interval boosting to greatly enlarge the IAV specific memory pool, sufficient to protect mice from non-homologous IAV challenge. Thus, a current vaccine strategy, Flumist, may serve as a priming platform for rapid induction of large numbers of memory CD8 T-cells with the capacity for broad protection against influenza. PMID:23467935

  5. Determining the state of non-volatile memory cells with floating gate using scanning probe microscopy

    NASA Astrophysics Data System (ADS)

    Hanzii, D.; Kelm, E.; Luapunov, N.; Milovanov, R.; Molodcova, G.; Yanul, M.; Zubov, D.

    2013-01-01

    During a failure analysis of integrated circuits, containing non-volatile memory, it is often necessary to determine its contents while Standard memory reading procedures are not applicable. This article considers how the state of NVM cells with floating gate can be determined using scanning probe microscopy. Samples preparation and measuring procedure are described with the example of Microchip microcontrollers with the EPROM memory (PIC12C508) and flash-EEPROM memory (PIC16F876A).

  6. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia.

    PubMed

    Romee, Rizwan; Rosario, Maximillian; Berrien-Elliott, Melissa M; Wagner, Julia A; Jewell, Brea A; Schappe, Timothy; Leong, Jeffrey W; Abdel-Latif, Sara; Schneider, Stephanie E; Willey, Sarah; Neal, Carly C; Yu, Liyang; Oh, Stephen T; Lee, Yi-Shan; Mulder, Arend; Claas, Frans; Cooper, Megan A; Fehniger, Todd A

    2016-09-21

    Natural killer (NK) cells are an emerging cellular immunotherapy for patients with acute myeloid leukemia (AML); however, the best approach to maximize NK cell antileukemia potential is unclear. Cytokine-induced memory-like NK cells differentiate after a brief preactivation with interleukin-12 (IL-12), IL-15, and IL-18 and exhibit enhanced responses to cytokine or activating receptor restimulation for weeks to months after preactivation. We hypothesized that memory-like NK cells exhibit enhanced antileukemia functionality. We demonstrated that human memory-like NK cells have enhanced interferon-γ production and cytotoxicity against leukemia cell lines or primary human AML blasts in vitro. Using mass cytometry, we found that memory-like NK cell functional responses were triggered against primary AML blasts, regardless of killer cell immunoglobulin-like receptor (KIR) to KIR-ligand interactions. In addition, multidimensional analyses identified distinct phenotypes of control and memory-like NK cells from the same individuals. Human memory-like NK cells xenografted into mice substantially reduced AML burden in vivo and improved overall survival. In the context of a first-in-human phase 1 clinical trial, adoptively transferred memory-like NK cells proliferated and expanded in AML patients and demonstrated robust responses against leukemia targets. Clinical responses were observed in five of nine evaluable patients, including four complete remissions. Thus, harnessing cytokine-induced memory-like NK cell responses represents a promising translational immunotherapy approach for patients with AML.

  7. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia.

    PubMed

    Romee, Rizwan; Rosario, Maximillian; Berrien-Elliott, Melissa M; Wagner, Julia A; Jewell, Brea A; Schappe, Timothy; Leong, Jeffrey W; Abdel-Latif, Sara; Schneider, Stephanie E; Willey, Sarah; Neal, Carly C; Yu, Liyang; Oh, Stephen T; Lee, Yi-Shan; Mulder, Arend; Claas, Frans; Cooper, Megan A; Fehniger, Todd A

    2016-09-21

    Natural killer (NK) cells are an emerging cellular immunotherapy for patients with acute myeloid leukemia (AML); however, the best approach to maximize NK cell antileukemia potential is unclear. Cytokine-induced memory-like NK cells differentiate after a brief preactivation with interleukin-12 (IL-12), IL-15, and IL-18 and exhibit enhanced responses to cytokine or activating receptor restimulation for weeks to months after preactivation. We hypothesized that memory-like NK cells exhibit enhanced antileukemia functionality. We demonstrated that human memory-like NK cells have enhanced interferon-γ production and cytotoxicity against leukemia cell lines or primary human AML blasts in vitro. Using mass cytometry, we found that memory-like NK cell functional responses were triggered against primary AML blasts, regardless of killer cell immunoglobulin-like receptor (KIR) to KIR-ligand interactions. In addition, multidimensional analyses identified distinct phenotypes of control and memory-like NK cells from the same individuals. Human memory-like NK cells xenografted into mice substantially reduced AML burden in vivo and improved overall survival. In the context of a first-in-human phase 1 clinical trial, adoptively transferred memory-like NK cells proliferated and expanded in AML patients and demonstrated robust responses against leukemia targets. Clinical responses were observed in five of nine evaluable patients, including four complete remissions. Thus, harnessing cytokine-induced memory-like NK cell responses represents a promising translational immunotherapy approach for patients with AML. PMID:27655849

  8. Rapid erasure of hippocampal memory following inhibition of dentate gyrus granule cells

    PubMed Central

    Madroñal, Noelia; Delgado-García, José M.; Fernández-Guizán, Azahara; Chatterjee, Jayanta; Köhn, Maja; Mattucci, Camilla; Jain, Apar; Tsetsenis, Theodoros; Illarionova, Anna; Grinevich, Valery; Gross, Cornelius T.; Gruart, Agnès

    2016-01-01

    The hippocampus is critical for the acquisition and retrieval of episodic and contextual memories. Lesions of the dentate gyrus, a principal input of the hippocampus, block memory acquisition, but it remains unclear whether this region also plays a role in memory retrieval. Here we combine cell-type specific neural inhibition with electrophysiological measurements of learning-associated plasticity in behaving mice to demonstrate that dentate gyrus granule cells are not required for memory retrieval, but instead have an unexpected role in memory maintenance. Furthermore, we demonstrate the translational potential of our findings by showing that pharmacological activation of an endogenous inhibitory receptor expressed selectively in dentate gyrus granule cells can induce a rapid loss of hippocampal memory. These findings open a new avenue for the targeted erasure of episodic and contextual memories. PMID:26988806

  9. Rapid erasure of hippocampal memory following inhibition of dentate gyrus granule cells.

    PubMed

    Madroñal, Noelia; Delgado-García, José M; Fernández-Guizán, Azahara; Chatterjee, Jayanta; Köhn, Maja; Mattucci, Camilla; Jain, Apar; Tsetsenis, Theodoros; Illarionova, Anna; Grinevich, Valery; Gross, Cornelius T; Gruart, Agnès

    2016-01-01

    The hippocampus is critical for the acquisition and retrieval of episodic and contextual memories. Lesions of the dentate gyrus, a principal input of the hippocampus, block memory acquisition, but it remains unclear whether this region also plays a role in memory retrieval. Here we combine cell-type specific neural inhibition with electrophysiological measurements of learning-associated plasticity in behaving mice to demonstrate that dentate gyrus granule cells are not required for memory retrieval, but instead have an unexpected role in memory maintenance. Furthermore, we demonstrate the translational potential of our findings by showing that pharmacological activation of an endogenous inhibitory receptor expressed selectively in dentate gyrus granule cells can induce a rapid loss of hippocampal memory. These findings open a new avenue for the targeted erasure of episodic and contextual memories. PMID:26988806

  10. Characterization of memory B cells from thymus and its impact for DLBCL classification.

    PubMed

    Bergkvist, Kim Steve; Nørgaard, Martin Agge; Bøgsted, Martin; Schmitz, Alexander; Nyegaard, Mette; Gaihede, Michael; Bæch, John; Grønholdt, Marie-Louise; Jensen, Frank Svendsen; Johansen, Preben; Urup, Thomas; El-Galaly, Tarec C; Madsen, Jakob; Bødker, Julie Støve; Dybkær, Karen; Johnsen, Hans Erik

    2016-10-01

    The rare memory B cells in thymus (Thy) are considered the cells of origin for primary mediastinal large B-cell lymphoma. The objectives of the present study were to characterize the normal memory B-cell compartment in Thy and to support its association with primary mediastinal B-cell lymphoma. Seven paired human tissue samples from Thy and sternum bone marrow (BM) were harvested during cardiac surgery. B-cell subsets were phenotyped by Euroflow standard and fluorescence-activated cell sorting for microarray analysis on the Human Exon 1.0 ST Arrays platform. Differentially expressed genes between Thy and BM memorycells were identified and correlated with the molecular subclasses of diffuse large B-cell lymphoma. Within Thy, 4% (median; range 2%-14%) of the CD45(+) hematopoietic cells were CD19(+) B cells, with a major fraction being CD27(+)/CD38(-) memorycells (median 80%, range 76%-93%). The BM contained 14% (median; range 3%-27%), of which only a minor fraction (median 5%, range 2%-10%) were memorycells. Global gene expression analysis of the memory B-cell subsets from the two compartments identified 133 genes upregulated in Thy, including AICDA, REL, STAT1, TNF family, SLAMF1, CD80, and CD86. In addition, exons 4 and 5 in the 3' end of AICDA were more highly expressed in Thy than in BM. The Thy memory B-cell gene profile was overexpressed in primary mediastinal B-cell lymphoma compared with other diffuse large B-cell lymphoma subclasses. The present study describes a Thy memory B-cell subset and its gene profile correlated with primary mediastinal B-cell lymphomas, suggesting origin from Thy memorycells.

  11. Characteristics of intrusive memories in a community sample of depressed, recovered depressed and never-depressed individuals.

    PubMed

    Newby, Jill M; Moulds, Michelle L

    2011-04-01

    An accumulating body of evidence has revealed that intrusive autobiographical memories of negative events play a role in depression. Despite increasing understanding of the phenomenological experience of these memories, previous research in this area has been conducted in either nonclinical samples, or in clinical samples without an adequate control group. This study aimed to replicate and extend findings with dysphoric samples by comparing the content and characteristics of intrusive memories in clinically depressed (n=25), recovered (n=30) and never-depressed (n=30) participants. Participants completed mood measures, and a battery of self-report questionnaires that indexed intrusive memory frequency, avoidance and characteristics. Intrusive memories were common and shared strikingly similar characteristics across the three groups. The key finding was that depressed participants reported higher levels of intrusion-related distress, associated emotions (especially sadness and helplessness), interference as a result of the memories and memory vividness compared to the never-depressed group. Despite similar levels of intrusion, there were group differences in avoidance such that depressed participants reported higher levels of avoidance than the never-depressed group. These results provide further support for the proposal that clinical interventions for depression could usefully incorporate components that aim to reduce intrusive autobiographical memories and target avoidance strategies. PMID:21334598

  12. Normally-off type nonvolatile static random access memory with perpendicular spin torque transfer-magnetic random access memory cells and smallest number of transistors

    NASA Astrophysics Data System (ADS)

    Tanaka, Chika; Abe, Keiko; Noguchi, Hiroki; Nomura, Kumiko; Ikegami, Kazutaka; Fujita, Shinobu

    2014-01-01

    In this paper, we present a novel nonvolatile-random access memory (RAM) cell design based on a “normally-off memory architecture” using a perpendicular spin torque transfer-magnetic random access memory (STT-MRAM) based on a four-transistors static random access memory (SRAM) in order to reduce the operating power of mobile processors. After the cell design concept and basic operation are proposed, a stable and reliable operation for read/write is confirmed by circuit simulation.

  13. Bipolar resistive switching characteristics in tantalum nitride-based resistive random access memory devices

    SciTech Connect

    Kim, Myung Ju; Jeon, Dong Su; Park, Ju Hyun; Kim, Tae Geun

    2015-05-18

    This paper reports the bipolar resistive switching characteristics of TaN{sub x}-based resistive random access memory (ReRAM). The conduction mechanism is explained by formation and rupture of conductive filaments caused by migration of nitrogen ions and vacancies; this mechanism is in good agreement with either Ohmic conduction or the Poole-Frenkel emission model. The devices exhibit that the reset voltage varies from −0.82 V to −0.62 V, whereas the set voltage ranges from 1.01 V to 1.30 V for 120 DC sweep cycles. In terms of reliability, the devices exhibit good retention (>10{sup 5 }s) and pulse-switching endurance (>10{sup 6} cycles) properties. These results indicate that TaN{sub x}-based ReRAM devices have a potential for future nonvolatile memory devices.

  14. Enhanced memory characteristics in organic ferroelectric field-effect transistors through thermal annealing

    SciTech Connect

    Sugano, Ryo; Tashiro, Tomoya; Sekine, Tomohito; Fukuda, Kenjiro; Kumaki, Daisuke; Tokito, Shizuo

    2015-11-15

    We report on the memory characteristics of organic ferroelectric field-effect transistors (FeFETs) using spin-coated poly(vinylidene difluoride/trifluoroethylene) (P(VDF/TrFE)) as a gate insulating layer. By thermal annealing the P(VDF/TrFE) layer at temperatures above its melting point, we could significantly improve the on/off current ratio to over 10{sup 4}. Considerable changes in the surface morphology and x-ray diffraction patterns were also observed in the P(VDF/TrFE) layer as a result of the annealing process. The enhanced memory effect is attributed to large polarization effects caused by rearranged ferroelectric polymer chains and improved crystallinity in the organic semiconductor layer of the FeFET devices.

  15. Theoretical study of SET operation in carbon nanotube memory cell

    NASA Astrophysics Data System (ADS)

    Stopa, Michael; Rueckes, Thomas

    2016-04-01

    We present results of self-consistent electronic structure calculations for an electromechanical memory cell consisting of a carbon nanotube (CNT) fabric between titanium leads to elucidate the mechanism whereby the applied bias works to close the current gaps in the CNT fabric. We demonstrate that the asymmetry in the bias conditions required to achieve the “SET” operation of the cell (changing it from a high resistivity to low resistivity) results from the nature of a voltage drop in a compensated semiconducting material and depends sensitively on the background charge as well as on the position of the layer where the conducting gaps occur. The calculations provide insight into the behavior of the material and suggest possible fabrication strategies to modify the functionality.

  16. Regulation of germinal center responses, memory B cells and plasma cell formation-an update.

    PubMed

    Corcoran, Lynn M; Tarlinton, David M

    2016-04-01

    Progress in understanding humoral immunity has been accelerated by the powerful experimental approaches of genetics, genomics and imaging. Excellent reviews of these advances appeared in 2015 in celebration of the 50th anniversary of the discovery of B cell and T cell lineages in the chicken. Here we provide a contemporary model of B cell differentiation, highlighting recent publications illuminating germinal center (GC), memory B cell and antibody-secreting plasma cell biology. The important contributions of CD4T cells to antibody responses have been thoroughly reviewed elsewhere.

  17. Memory characteristics of flexible resistive switching devices with triangular-shaped silicon nanowire bottom electrodes

    NASA Astrophysics Data System (ADS)

    Park, Sukhyung; Cho, Kyoungah; Kim, Sangsig

    2015-05-01

    In this paper, we demonstrate the bipolar resistive switching characteristics of flexible resistive random access memory (ReRAM) devices, whose bottom electrodes are made of silicon nanowires (Si NWs) with a triangular structure, which offer preferential sites for the filaments. The temperature dependence of the low resistance state (LRS) of the resistive Al2O3/ZnO bilayers of ReRAM devices reveals that Ag filaments originating from the top Ag electrodes are responsible for bipolar resistive switching. With respect to the endurance characteristics of the LRS, resistance fluctuation is negligible because of the filaments generated at the specific sites of the vertices of the Si NW bottom electrodes. In addition, the resistive switching characteristics are maintained even after 1000 bending cycles.

  18. Mcl-1 regulates effector and memory CD8 T-cell differentiation during acute viral infection.

    PubMed

    Kim, Eui Ho; Neldner, Brandon; Gui, Jingang; Craig, Ruth W; Suresh, M

    2016-03-01

    Mcl-1, an anti-apoptotic member of Bcl-2 family maintains cell viability during clonal expansion of CD8 T cells, but the cell intrinsic role of Mcl-1 in contraction of effectors or the number of memory CD8 T cells is unknown. Mcl-1 levels decline during the contraction phase but rebound to high levels in memory CD8 T cells. Therefore, by overexpressing Mcl-1 in CD8 T cells we asked whether limiting levels of Mcl-1 promote contraction of effectors and constrain CD8 T-cell memory. Mcl-1 overexpression failed to affect CD8 T-cell expansion, contraction or the magnitude of CD8 T-cell memory. Strikingly, high Mcl-1 levels enhanced mTOR phosphorylation and augmented the differentiation of terminal effector cells and effector memory CD8 T cells to the detriment of poly-cytokine-producing central memory CD8 T cells. Taken together, these findings provided unexpected insights into the role of Mcl-1 in the differentiation of effector and memory CD8 T cells.

  19. Ex vivo characterization and isolation of rare memory B cells with antigen tetramers.

    PubMed

    Franz, Bettina; May, Kenneth F; Dranoff, Glenn; Wucherpfennig, Kai

    2011-07-14

    Studying human antigen-specific memory B cells has been challenging because of low frequencies in peripheral blood, slow proliferation, and lack of antibody secretion. Therefore, most studies have relied on conversion of memory B cells into antibody-secreting cells by in vitro culture. To facilitate direct ex vivo isolation, we generated fluorescent antigen tetramers for characterization of memory B cells by using tetanus toxoid as a model antigen. Brightly labeled memory B cells were identified even 4 years after last immunization, despite low frequencies ranging from 0.01% to 0.11% of class-switched memory B cells. A direct comparison of monomeric to tetrameric antigen labeling demonstrated that a substantial fraction of the B-cell repertoire can be missed when monomeric antigens are used. The specificity of the method was confirmed by antibody reconstruction from single-cell sorted tetramer(+) B cells with single-cell RT-PCR of the B-cell receptor. All antibodies bound to tetanus antigen with high affinity, ranging from 0.23 to 2.2 nM. Furthermore, sequence analysis identified related memory B cell and plasmablast clones isolated more than a year apart. Therefore, antigen tetramers enable specific and sensitive ex vivo characterization of rare memory B cells as well as the production of fully human antibodies.

  20. Differential contributions of central and effector memory T cells to recall responses

    PubMed Central

    Roberts, Alan D.; Ely, Kenneth H.; Woodland, David L.

    2005-01-01

    Although the absolute number of memory CD8+ T cells established in the spleen following antigen encounter remains stable for many years, the relative capacity of these cells to mediate recall responses is not known. Here we used a dual adoptive transfer approach to demonstrate a progressive increase in the quality of memory T cell pools in terms of their ability to proliferate and accumulate at effector sites in response to secondary pathogen challenge. This temporal increase in efficacy occurred in CD62Llo (effector memory) and CD62Lhi (central memory) subpopulations, but was most prominent in the CD62Lhi subpopulation. These data indicate that the contribution of effector memory and central memory T cells to the recall response changes substantially over time. PMID:15983064

  1. Single-Cell Memory Regulates a Neural Circuit for Sensory Behavior.

    PubMed

    Kobayashi, Kyogo; Nakano, Shunji; Amano, Mutsuki; Tsuboi, Daisuke; Nishioka, Tomoki; Ikeda, Shingo; Yokoyama, Genta; Kaibuchi, Kozo; Mori, Ikue

    2016-01-01

    Unveiling the molecular and cellular mechanisms underlying memory has been a challenge for the past few decades. Although synaptic plasticity is proven to be essential for memory formation, the significance of "single-cell memory" still remains elusive. Here, we exploited a primary culture system for the analysis of C. elegans neurons and show that a single thermosensory neuron has an ability to form, retain, and reset a temperature memory. Genetic and proteomic analyses found that the expression of the single-cell memory exhibits inter-individual variability, which is controlled by the evolutionarily conserved CaMKI/IV and Raf pathway. The variable responses of a sensory neuron influenced the neural activity of downstream interneurons, suggesting that modulation of the sensory neurons ultimately determines the behavioral output in C. elegans. Our results provide proof of single-cell memory and suggest that the individual differences in neural responses at the single-cell level can confer individuality.

  2. Memory retrieval by activating engram cells in mouse models of early Alzheimer’s disease

    PubMed Central

    Roy, Dheeraj S.; Arons, Autumn; Mitchell, Teryn I.; Pignatelli, Michele; Ryan, Tomás J.; Tonegawa, Susumu

    2016-01-01

    Summary Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory decline and subsequent loss of broader cognitive functions1. Memory decline in early stages of Alzheimer’s is mostly limited to episodic memory, for which the hippocampus (HPC) plays a crucial role2. However, it has been uncertain whether the observed amnesia in early stages of Alzheimer’s is due to disrupted encoding and consolidation of episodic information, or an impairment in the retrieval of stored memory information. Here we show that in transgenic mouse models of early Alzheimer’s, direct optogenetic activation of hippocampal memory engram cells results in memory retrieval despite the fact that these mice are amnesic in long-term memory tests when natural recall cues are utilized, revealing a retrieval, rather than a storage impairment. Prior to amyloid plaque deposition, the amnesia in these mice is age-dependent3–5, which correlates with a progressive reduction of spine density of hippocampal dentate gyrus (DG) engram cells. We show that optogenetic induction of long-term potentiation (LTP) at perforant path (PP) synapses of DG engram cells restores both spine density and long-term memory. We also demonstrate that an ablation of DG engram cells containing restored spine density prevents the rescue of long-term memory. Thus, selective rescue of spine density in engram cells may lead to an effective strategy for treating memory loss in early stages of Alzheimer’s disease. PMID:26982728

  3. Memory retrieval by activating engram cells in mouse models of early Alzheimer's disease.

    PubMed

    Roy, Dheeraj S; Arons, Autumn; Mitchell, Teryn I; Pignatelli, Michele; Ryan, Tomás J; Tonegawa, Susumu

    2016-03-24

    Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory decline and subsequent loss of broader cognitive functions. Memory decline in the early stages of AD is mostly limited to episodic memory, for which the hippocampus has a crucial role. However, it has been uncertain whether the observed amnesia in the early stages of AD is due to disrupted encoding and consolidation of episodic information, or an impairment in the retrieval of stored memory information. Here we show that in transgenic mouse models of early AD, direct optogenetic activation of hippocampal memory engram cells results in memory retrieval despite the fact that these mice are amnesic in long-term memory tests when natural recall cues are used, revealing a retrieval, rather than a storage impairment. Before amyloid plaque deposition, the amnesia in these mice is age-dependent, which correlates with a progressive reduction in spine density of hippocampal dentate gyrus engram cells. We show that optogenetic induction of long-term potentiation at perforant path synapses of dentate gyrus engram cells restores both spine density and long-term memory. We also demonstrate that an ablation of dentate gyrus engram cells containing restored spine density prevents the rescue of long-term memory. Thus, selective rescue of spine density in engram cells may lead to an effective strategy for treating memory loss in the early stages of AD. PMID:26982728

  4. Memories.

    ERIC Educational Resources Information Center

    Brand, Judith, Ed.

    1998-01-01

    This theme issue of the journal "Exploring" covers the topic of "memories" and describes an exhibition at San Francisco's Exploratorium that ran from May 22, 1998 through January 1999 and that contained over 40 hands-on exhibits, demonstrations, artworks, images, sounds, smells, and tastes that demonstrated and depicted the biological,…

  5. Streptococcus induces circulating CLA(+) memory T-cell-dependent epidermal cell activation in psoriasis.

    PubMed

    Ferran, Marta; Galván, Ana B; Rincón, Catalina; Romeu, Ester R; Sacrista, Marc; Barboza, Erika; Giménez-Arnau, Ana; Celada, Antonio; Pujol, Ramon M; Santamaria-Babí, Luis F

    2013-04-01

    Streptococcal throat infection is associated with a specific variant of psoriasis and with HLA-Cw6 expression. In this study, activation of circulating psoriatic cutaneous lymphocyte-associated antigen (CLA)(+) memory T cells cultured together with epidermal cells occurred only when streptococcal throat extracts were added. This triggered the production of Th1, Th17, and Th22 cytokines, as well as epidermal cell mediators (CXCL8, CXCL9, CXCL10, and CXCL11). Streptococcal extracts (SEs) did not induce any activation with either CLA(-) cells or memory T cells cultured together with epidermal cells from healthy subjects. Intradermal injection of activated culture supernatants into mouse skin induced epidermal hyperplasia. SEs also induced activation when we used epidermal cells from nonlesional skin of psoriatic patients with CLA(+) memory T cells. Significant correlations were found between SE induced upregulation of mRNA expression for ifn-γ, il-17, il-22, ip-10, and serum level of antistreptolysin O in psoriatic patients. This study demonstrates the direct involvement of streptococcal infection in pathological mechanisms of psoriasis, such as IL-17 production and epidermal cell activation.

  6. Transcriptional regulation of effector and memory CD8+ T cell fates

    PubMed Central

    Thaventhiran, James E. D.; Fearon, Douglas T.; Gattinoni, Luca

    2013-01-01

    Immunity to intracellular pathogens and cancer relies on the generation of robust CD8+ T cell effector responses as well as the establishment of immunological memory. During a primary immune response CD8+ T cells experience diverse extracellular environmental cues and cell-cell interactions that trigger downstream transcriptional programs ultimately guiding a CD8+ T cell to undertake either an effector or a memory cell fate. Here, we discuss our current understanding of the signaling pathways and transcriptional networks that regulate effector and memory commitment in CD8+ T lymphocytes. PMID:23747000

  7. Dopaminergic neurons write and update memories with cell-type-specific rules.

    PubMed

    Aso, Yoshinori; Rubin, Gerald M

    2016-01-01

    Associative learning is thought to involve parallel and distributed mechanisms of memory formation and storage. In Drosophila, the mushroom body (MB) is the major site of associative odor memory formation. Previously we described the anatomy of the adult MB and defined 20 types of dopaminergic neurons (DANs) that each innervate distinct MB compartments (Aso et al., 2014a, 2014b). Here we compare the properties of memories formed by optogenetic activation of individual DAN cell types. We found extensive differences in training requirements for memory formation, decay dynamics, storage capacity and flexibility to learn new associations. Even a single DAN cell type can either write or reduce an aversive memory, or write an appetitive memory, depending on when it is activated relative to odor delivery. Our results show that different learning rules are executed in seemingly parallel memory systems, providing multiple distinct circuit-based strategies to predict future events from past experiences. PMID:27441388

  8. IgG-Immune Complexes Promote B Cell Memory by Inducing BAFF.

    PubMed

    Kang, SunAh; Keener, Amanda B; Jones, Shannon Z; Benschop, Robert J; Caro-Maldonado, Alfredo; Rathmell, Jeffrey C; Clarke, Stephen H; Matsushima, Glenn K; Whitmire, Jason K; Vilen, Barbara J

    2016-01-01

    Memory B cell responses are vital for protection against infections but must also be regulated to prevent autoimmunity. Cognate T cell help, somatic hypermutation, and affinity maturation within germinal centers (GCs) are required for high-affinity memory B cell formation; however, the signals that commit GC B cells to the memory pool remain unclear. In this study, we identify a role for IgG-immune complexes (ICs), FcγRs, and BAFF during the formation of memory B cells in mice. We found that early secretion of IgG in response to immunization with a T-dependent Ag leads to IC-FcγR interactions that induce dendritic cells to secrete BAFF, which acts at or upstream of Bcl-6 in activated B cells. Loss of CD16, hematopoietic cell-derived BAFF, or blocking IC:FcγR regions in vivo diminished the expression of Bcl-6, the frequency of GC and memory B cells, and secondary Ab responses. BAFF also contributed to the maintenance and/or expansion of the follicular helper T cell population, although it was dispensable for their formation. Thus, early Ab responses contribute to the optimal formation of B cell memory through IgG-ICs and BAFF. Our work defines a new role for FcγRs in GC and memory B cell responses.

  9. OX40 costimulatory signals potentiate the memory commitment of effector CD8+ T cells.

    PubMed

    Mousavi, Seyed Fazlollah; Soroosh, Pejman; Takahashi, Takeshi; Yoshikai, Yasunobu; Shen, Hao; Lefrançois, Leo; Borst, Jannie; Sugamura, Kazuo; Ishii, Naoto

    2008-11-01

    A T cell costimulatory molecule, OX40, contributes to T cell expansion, survival, and cytokine production. Although several roles for OX40 in CD8(+) T cell responses to tumors and viral infection have been shown, the precise function of these signals in the generation of memory CD8(+) T cells remains to be elucidated. To address this, we examined the generation and maintenance of memory CD8(+) T cells during infection with Listeria monocytogenes in the presence and absence of OX40 signaling. We used the expression of killer cell lectin-like receptor G1 (KLRG1), a recently reported marker, to distinguish between short-lived effector and memory precursor effector T cells (MPECs). Although OX40 was dispensable for the generation of effector T cells in general, the lack of OX40 signals significantly reduced the number and proportion of KLRG1(low) MPECs, and, subsequently, markedly impaired the generation of memory CD8(+) T cells. Moreover, memory T cells that were generated in the absence of OX40 signals in a host animal did not show self-renewal in a second host, suggesting that OX40 is important for the maintenance of memory T cells. Additional experiments making use of an inhibitory mAb against the OX40 ligand demonstrated that OX40 signals are essential during priming, not only for the survival of KLRG1(low) MPECs, but also for their self-renewing ability, both of which contribute to the homeostasis of memory CD8(+) T cells.

  10. Shape memory alloy-based active chiral composite cells

    NASA Astrophysics Data System (ADS)

    Prajapati, Maulik; Roy Mahapatra, D.

    2014-04-01

    Wing morphing is one of the emerging methodology towards improving aerodynamic efficiency of flight vehicle structures. In this paper a morphing structural element is designed and studied which has its origin in the well known chiral structures. The new aspect of design and functionality explored in this paper is that the chiral cell is actuated using thermal Shape Memory Alloy (SMA) actuator wires to provide directional motion. Such structure utilizes the potential of different actuations concepts based on actuator embedded in the chiral structure skin. This paper describes a new class of chiral cell structure with integrated SMA wire for actuation. Chiral topological constructs are obtained by considering passive and active load path decoupling and sub-optimal shape changes. Single cell of chiral honeycomb with actuators are analyzed using finite element simulation results and experiments. To this end, a multi-cell plan-form is characterized showing interesting possibilities in structural morphing applications. The applicability of the developed chiral cell to flexible wing skin, variable stiffness based design and controlling longitudinal-to-transverse stiffness ratio are discussed.

  11. Preferential localization of IgG memory B cells adjacent to contracted germinal centers

    PubMed Central

    Aiba, Yuichi; Kometani, Kohei; Hamadate, Megumi; Moriyama, Saya; Sakaue-Sawano, Asako; Tomura, Michio; Luche, Hervé; Fehling, Hans Jörg; Casellas, Rafael; Kanagawa, Osami; Miyawaki, Atsushi; Kurosaki, Tomohiro

    2010-01-01

    It has long been presumed that after leaving the germinal centers (GCs), memory B cells colonize the marginal zone or join the recirculating pool. Here we demonstrate the preferential localization of nitrophenol-chicken γ-globulin-induced CD38+IgG1+ memory B cells adjacent to contracted GCs in the spleen. The memory B cells in this region proliferated after secondary immunization, a response that was abolished by depletion of CD4+ T cells. We also found that these IgG1+ memory B cells could present antigen on their surface, and that this activity was required for their activation. These results implicate this peri-GC region as an important site for survival and reactivation of memory B cells. PMID:20547847

  12. Bone Marrow T Cells and the Integrated Functions of Recirculating and Tissue-Resident Memory T Cells.

    PubMed

    Di Rosa, Francesca; Gebhardt, Thomas

    2016-01-01

    Changes in T cell trafficking accompany the naive to memory T cell antigen-driven differentiation, which remains an incompletely defined developmental step. Upon priming, each naive T cell encounters essential signals - i.e., antigen, co-stimuli and cytokines - in a secondary lymphoid organ; nevertheless, its daughter effector and memory T cells recirculate and receive further signals during their migration through various lymphoid and non-lymphoid organs. These additional signals from tissue microenvironments have an impact on immune response features, including T cell effector function, expansion and contraction, memory differentiation, long-term maintenance, and recruitment upon antigenic rechallenge into local and/or systemic responses. The critical role of T cell trafficking in providing efficient T cell memory has long been a focus of interest. It is now well recognized that naive and memory T cells have different migratory pathways, and that memory T cells are heterogeneous with respect to their trafficking. We and others have observed that, long time after priming, memory T cells are preferentially found in certain niches such as the bone marrow (BM) or at the skin/mucosal site of pathogen entry, even in the absence of residual antigen. The different underlying mechanisms and peculiarities of resulting immunity are currently under study. In this review, we summarize key findings on BM and tissue-resident memory (TRM) T cells and revisit some issues in memory T cell maintenance within such niches. Moreover, we discuss BM seeding by memory T cells in the context of migration patterns and protective functions of either recirculating or TRM T cells. PMID:26909081

  13. Tissue-Resident Memory T Cells and Fixed Immune Surveillance in Nonlymphoid Organs.

    PubMed

    Carbone, Francis R

    2015-07-01

    T cell immunity is often defined in terms of memory lymphocytes that use the blood to access a range of organs. T cells are involved in two patterns of recirculation. In one, the cells shuttle back and forth between blood and secondary lymphoid organs, whereas in the second, memory cells recirculate between blood and nonlymphoid tissues. The latter is a means by which blood T cells control peripheral infection. It is now clear that there exists a distinct memory T cell subset that is absent from blood but found within nonlymphoid tissues. These nonrecirculating tissue-resident memory T (TRM) cells develop within peripheral compartments and never spread beyond their point of lodgement. This review examines fixed immune surveillance by TRM cells, highlighting features that make them potent controllers of infection in nonlymphoid tissues. These features provide clues about TRM cell specialization, such as their ability to deal with sequestered, persisting infections confined to peripheral compartments.

  14. Different T cell memory in preadolescents after whole-cell or acellular pertussis vaccination.

    PubMed

    Smits, Kaatje; Pottier, Gaelle; Smet, Julie; Dirix, Violette; Vermeulen, Françoise; De Schutter, Iris; Carollo, Maria; Locht, Camille; Ausiello, Clara Maria; Mascart, Françoise

    2013-12-17

    To better understand vaccine-induced protection and its potential failure in light of recent whooping cough resurgence, we evaluated quantity as well as quality of memory T cell responses in B. pertussis-vaccinated preadolescent children. Using a technique based on flow cytometry to detect proliferation, cytokine production and phenotype of antigen-specific cells, we evaluated residual T cell memory in a cohort of preadolescents who received a whole-cell pertussis (wP; n=11) or an acellular pertussis vaccine (aP; n=13) during infancy, and with a median of 4 years elapsed from the last pertussis booster vaccine, which was aP for all children. We demonstrated that B. pertussis-specific memory T cells are detectable in the majority of preadolescent children several years after vaccination. CD4(+) and CD8(+) T cell proliferation in response to pertussis toxin and/or filamentous hemagglutinin was detected in 79% and 60% of the children respectively, and interferon-γ or tumor necrosis factor-α producing CD4(+) T cells were detected in 65% and 53% of the children respectively. Phenotyping of the responding cells showed that the majority of antigen-specific cells, whether defined by proliferation or cytokine production, were CD45RA(-)CCR7(-) effector memory T cells. Although the time since the last booster vaccine was significantly longer for wP-compared to aP-vaccinated children, their proliferation capacity in response to antigenic stimulation was comparable, and more children had a detectable cytokine response after wP- compared to aP-vaccination. This study supports at the immunological level recent epidemiological studies indicating that infant vaccination with wP induces longer lasting immunity than vaccination with aP-vaccines. PMID:24176499

  15. Memory CD4+ T cells do not induce graft-versus-host disease.

    PubMed

    Anderson, Britt E; McNiff, Jennifer; Yan, Jun; Doyle, Hester; Mamula, Mark; Shlomchik, Mark J; Shlomchik, Warren D

    2003-07-01

    Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic stem cell transplantation (alloSCT). Donor T cells that accompany stem cell grafts cause GVHD by attacking recipient tissues; therefore, all patients receive GVHD prophylaxis by depletion of T cells from the allograft or through immunosuppressant drugs. In addition to providing a graft-versus-leukemia effect, donor T cells are critical for reconstituting T cell-mediated immunity. Ideally, immunity to infectious agents would be transferred from donor to host without GVHD. Most donors have been exposed to common pathogens and have an increased precursor frequency of memory T cells against pathogenic antigens. We therefore asked whether memory CD62L-CD44+ CD4+ T cells would induce less GVHD than unfractionated or naive CD4+ T cells. Strikingly, we found that memory CD4 cells induced neither clinical nor histologic GVHD. This effect was not due to the increased number of CD4+CD25+ regulatory T cells found in the CD62L-CD44+ fraction because memory T cells depletion of these cells did not cause GVHD. Memory CD4 cells engrafted and responded to antigen both in vivo and in vitro. If these murine results are applicable to human alloSCT, selective administration of memory T cells could greatly improve post-transplant immune reconstitution.

  16. Oxide degradation mechanism in stacked-gate flash memory using the cell array stress test

    NASA Astrophysics Data System (ADS)

    Tsai, Shih-Hung; Hung, Jui-Sheng; Wang, Na-Fu; Horng, Jui-Hong; Houng, Mau-Phon; Wang, Yeong-Her

    2003-09-01

    The generation of oxide charges and interface states during the program/erase operation in flash memory has been known to degrade the tunnel oxide quality. However, there is still no effective method to analyse the endurance and disturbed performance of the flash memory at the test level. So in this paper, a simple and fast method is applied to characterize the endurance and disturbed performance on a 98K bit flash cell array stress test structure. Based on this structure, the behaviour of the weakest part of the memory array after the program/erase operation can be easily observed. Moreover, the effects of the oxide charges and interface states generated are also discussed. Also, excess hole trapping in the oxide leads to fast charge loss during the disturbance test. The fast charge loss caused by holes is the more serious of these two failure mechanisms because the relatively low high-state VT can be corrected by circuit-level, program/erase-verified sequences. However, poor disturbance characteristics cause logical errors during the reading of an array.

  17. Generation of cellular immune memory and B-cell immunity is impaired by natural killer cells.

    PubMed

    Rydyznski, Carolyn; Daniels, Keith A; Karmele, Erik P; Brooks, Taylor R; Mahl, Sarah E; Moran, Michael T; Li, Caimei; Sutiwisesak, Rujapak; Welsh, Raymond M; Waggoner, Stephen N

    2015-02-27

    The goal of most vaccines is the induction of long-lived memory T and B cells capable of protecting the host from infection by cytotoxic mechanisms, cytokines and high-affinity antibodies. However, efforts to develop vaccines against major human pathogens such as HIV and HCV have not been successful, thereby highlighting the need for novel approaches to circumvent immunoregulatory mechanisms that limit the induction of protective immunity. Here, we show that mouse natural killer (NK) cells inhibit generation of long-lived virus-specific memory T- and B cells as well as virus-specific antibody production after acute infection. Mechanistically, NK cells suppressed CD4 T cells and follicular helper T cells (T(FH)) in a perforin-dependent manner during the first few days of infection, resulting in a weaker germinal centre (GC) response and diminished immune memory. We anticipate that innovative strategies to relieve NK cell-mediated suppression of immunity should facilitate development of efficacious new vaccines targeting difficult-to-prevent infections.

  18. 'Educated' dendritic cells act as messengers from memory to naive T helper cells.

    PubMed

    Alpan, Oral; Bachelder, Eric; Isil, Eda; Arnheiter, Heinz; Matzinger, Polly

    2004-06-01

    Ingested antigens lead to the generation of effector T cells that secrete interleukin 4 (IL-4) rather than interferon-gamma (IFN-gamma) and are capable of influencing naive T cells in their immediate environment to do the same. Using chimeric mice generated by aggregation of two genotypically different embryos, we found that the conversion of a naive T cell occurs only if it can interact with the same antigen-presenting cell, although not necessarily the same antigen, as the effector T cell. Using a two-step culture system in vitro, we found that antigen-presenting dendritic cells can act as 'temporal bridges' to relay information from orally immunized memory CD4 T cells to naive CD4 T cells. The orally immunized T cells use IL-4 and IL-10 (but not CD40 ligand) to 'educate' dendritic cells, which in turn induce naive T cells to produce the same cytokines as those produced by the orally immunized memory T cells.

  19. Mechanistic insights into the impairment of memory B cells and antibody production in the elderly.

    PubMed

    Aberle, Judith H; Stiasny, Karin; Kundi, Michael; Heinz, Franz X

    2013-04-01

    It is well established that immunologic memory generated early in life can be maintained into old age and mediate robust anamnestic antibody responses. Little is known, however, about the initiation of memory B cells in the elderly. We have conducted a prospective analysis of the quantities and functionalities of antigen-specific B cell responses and its association with the functional helper CD4(+)T cell responses. The ability of naïve B cells from old (60-80 years) and young (20-31 years) humans to establish functional memory was examined following primary and booster vaccination with an inactivated-virus vaccine against tick-borne encephalitis. Our data show that the number of antigen-specific memory B cells generated during primary vaccination was ~3-fold lower in old than in young individuals. The maintenance and booster responsiveness of these memory B cells were not compromised, as evidenced by similar increases in specific memory B cell frequencies upon revaccination in old and young adults. In contrast, the Ab response mediated per memory B cell after revaccination was dramatically diminished in the elderly. Also, antigen-specific IL-2-positive CD4(+)T cell responses were strongly reduced in the elderly and displayed an excellent correlation with Ab titres. The data suggest that the dramatically lower antibody response in the elderly could only partially be accounted for by the reduced B cell numbers and was strongly correlated with profound functional defects in CD4 help.

  20. Defining CD4 T cell memory by the epigenetic landscape of CpG DNA methylation.

    PubMed

    Komori, H Kiyomi; Hart, Traver; LaMere, Sarah A; Chew, Pamela V; Salomon, Daniel R

    2015-02-15

    Memory T cells are primed for rapid responses to Ag; however, the molecular mechanisms responsible for priming remain incompletely defined. CpG methylation in promoters is an epigenetic modification, which regulates gene transcription. Using targeted bisulfite sequencing, we examined methylation of 2100 genes (56,000 CpGs) mapped by deep sequencing of T cell activation in human naive and memory CD4 T cells. Four hundred sixty-six CpGs (132 genes) displayed differential methylation between naive and memory cells. Twenty-one genes exhibited both differential methylation and gene expression before activation, linking promoter DNA methylation states to gene regulation; 6 of 21 genes encode proteins closely studied in T cells, whereas 15 genes represent novel targets for further study. Eighty-four genes demonstrated differential methylation between memory and naive cells that correlated to differential gene expression following activation, of which 39 exhibited reduced methylation in memory cells coupled with increased gene expression upon activation compared with naive cells. These reveal a class of primed genes more rapidly expressed in memory compared with naive cells and putatively regulated by DNA methylation. These findings define a DNA methylation signature unique to memory CD4 T cells that correlates with activation-induced gene expression.

  1. Inflammatory IL-15 is required for optimal memory T cell responses

    PubMed Central

    Richer, Martin J.; Pewe, Lecia L.; Hancox, Lisa S.; Hartwig, Stacey M.; Varga, Steven M.; Harty, John T.

    2015-01-01

    Due to their ability to rapidly proliferate and produce effector cytokines, memory CD8+ T cells increase protection following reexposure to a pathogen. However, low inflammatory immunizations do not provide memory CD8+ T cells with a proliferation advantage over naive CD8+ T cells, suggesting that cell-extrinsic factors enhance memory CD8+ T cell proliferation in vivo. Herein, we demonstrate that inflammatory signals are critical for the rapid proliferation of memory CD8+ T cells following infection. Using murine models of viral infection and antigen exposure, we found that type I IFN–driven expression of IL-15 in response to viral infection prepares memory CD8+ T cells for rapid division independently of antigen reexposure by transiently inducing cell-cycle progression via a pathway dependent on mTOR complex-1 (mTORC1). Moreover, exposure to IL-15 allowed more rapid division of memory CD8+ T cells following antigen encounter and enhanced their protective capacity against viral infection. Together, these data reveal that inflammatory IL-15 promotes optimal responses by memory CD8+ T cells. PMID:26241055

  2. Defining CD4 T cell memory by the epigenetic landscape of CpG DNA methylation.

    PubMed

    Komori, H Kiyomi; Hart, Traver; LaMere, Sarah A; Chew, Pamela V; Salomon, Daniel R

    2015-02-15

    Memory T cells are primed for rapid responses to Ag; however, the molecular mechanisms responsible for priming remain incompletely defined. CpG methylation in promoters is an epigenetic modification, which regulates gene transcription. Using targeted bisulfite sequencing, we examined methylation of 2100 genes (56,000 CpGs) mapped by deep sequencing of T cell activation in human naive and memory CD4 T cells. Four hundred sixty-six CpGs (132 genes) displayed differential methylation between naive and memory cells. Twenty-one genes exhibited both differential methylation and gene expression before activation, linking promoter DNA methylation states to gene regulation; 6 of 21 genes encode proteins closely studied in T cells, whereas 15 genes represent novel targets for further study. Eighty-four genes demonstrated differential methylation between memory and naive cells that correlated to differential gene expression following activation, of which 39 exhibited reduced methylation in memory cells coupled with increased gene expression upon activation compared with naive cells. These reveal a class of primed genes more rapidly expressed in memory compared with naive cells and putatively regulated by DNA methylation. These findings define a DNA methylation signature unique to memory CD4 T cells that correlates with activation-induced gene expression. PMID:25576597

  3. Dual operation characteristics of resistance random access memory in indium-gallium-zinc-oxide thin film transistors

    NASA Astrophysics Data System (ADS)

    Yang, Jyun-Bao; Chang, Ting-Chang; Huang, Jheng-Jie; Chen, Yu-Chun; Chen, Yu-Ting; Tseng, Hsueh-Chih; Chu, Ann-Kuo; Sze, Simon M.

    2014-04-01

    In this study, indium-gallium-zinc-oxide thin film transistors can be operated either as transistors or resistance random access memory devices. Before the forming process, current-voltage curve transfer characteristics are observed, and resistance switching characteristics are measured after a forming process. These resistance switching characteristics exhibit two behaviors, and are dominated by different mechanisms. The mode 1 resistance switching behavior is due to oxygen vacancies, while mode 2 is dominated by the formation of an oxygen-rich layer. Furthermore, an easy approach is proposed to reduce power consumption when using these resistance random access memory devices with the amorphous indium-gallium-zinc-oxide thin film transistor.

  4. Dual operation characteristics of resistance random access memory in indium-gallium-zinc-oxide thin film transistors

    SciTech Connect

    Yang, Jyun-Bao; Chen, Yu-Ting; Chu, Ann-Kuo; Chang, Ting-Chang; Huang, Jheng-Jie; Chen, Yu-Chun; Tseng, Hsueh-Chih; Sze, Simon M.

    2014-04-14

    In this study, indium-gallium-zinc-oxide thin film transistors can be operated either as transistors or resistance random access memory devices. Before the forming process, current-voltage curve transfer characteristics are observed, and resistance switching characteristics are measured after a forming process. These resistance switching characteristics exhibit two behaviors, and are dominated by different mechanisms. The mode 1 resistance switching behavior is due to oxygen vacancies, while mode 2 is dominated by the formation of an oxygen-rich layer. Furthermore, an easy approach is proposed to reduce power consumption when using these resistance random access memory devices with the amorphous indium-gallium-zinc-oxide thin film transistor.

  5. Characteristics and mechanism study of cerium oxide based random access memories

    SciTech Connect

    Hsieh, Cheng-Chih; Roy, Anupam; Rai, Amritesh; Chang, Yao-Feng; Banerjee, Sanjay K.

    2015-04-27

    In this work, low operating voltage and high resistance ratio of different resistance states of binary transition metal oxide based resistive random access memories (RRAMs) are demonstrated. Binary transition metal oxides with high dielectric constant have been explored for RRAM application for years. However, CeO{sub x} is considered as a relatively new material to other dielectrics. Since research on CeO{sub x} based RRAM is still at preliminary stage, fundamental characteristics of RRAM such as scalability and mechanism studies need to be done before moving further. Here, we show very high operation window and low switching voltage of CeO{sub x} RRAMs and also compare electrical performance of Al/CeO{sub x}/Au system between different thin film deposition methods and discuss characteristics and resistive switching mechanism.

  6. Additional Electrochemical Treatment Effects on the Switching Characteristics of Anodic Porous Alumina Resistive Switching Memory

    NASA Astrophysics Data System (ADS)

    Otsuka, Shintaro; Takeda, Ryouta; Furuya, Saeko; Shimizu, Tomohiro; Shingubara, Shouso; Iwata, Nobuyuki; Watanabe, Tadataka; Takano, Yoshiki; Takase, Kouichi

    2012-06-01

    We have investigated the current-voltage characteristics of a resistive switching memory (ReRAM), especially the reproducibility of the switching voltage between an insulating state and a metallic state. The poor reproducibility hinders the practical use of this memory. According to a filament model, the variation of the switching voltage may be understood in terms of the random choice of filaments with different conductivities and lengths at each switching. A limitation of the number of conductive paths is expected to lead to the suppression of the variation of switching voltage. In this study, two strategies for the limitation have been proposed using an anodic porous alumina (APA). The first is the reduction of the number of conductive paths by restriction of the contact area between the top electrodes and the insulator. The second is the lowering of the resistivity of the insulator, which makes it possible to grow filaments with the same characteristics by electrochemical treatments using a pulse-electroplating technique.

  7. Genome-wide RNA profiling of long-lasting stem cell-like memory CD8 T cells induced by Yellow Fever vaccination in humans.

    PubMed

    Fuertes Marraco, Silvia A; Soneson, Charlotte; Delorenzi, Mauro; Speiser, Daniel E

    2015-09-01

    The live-attenuated Yellow Fever (YF) vaccine YF-17D induces a broad and polyfunctional CD8 T cell response in humans. Recently, we identified a population of stem cell-like memory CD8 T cells induced by YF-17D that persists at stable frequency for at least 25 years after vaccination. The YF-17D is thus a model system of human CD8 T cell biology that furthermore allows to track and study long-lasting and antigen-specific human memory CD8 T cells. Here, we describe in detail the sample characteristics and preparation of a microarray dataset acquired for genome-wide gene expression profiling of long-lasting YF-specific stem cell-like memory CD8 T cells, compared to the reference CD8 T cell differentiation subsets from total CD8 T cells. We also describe the quality controls, annotations and exploratory analyses of the dataset. The microarray data is available from the Gene Expression Omnibus (GEO) public repository with accession number GSE65804. PMID:26484272

  8. Chronic inflammatory cells with epithelial cell characteristics in teleost fishes.

    PubMed

    Noga, E J; Dykstra, M J; Wright, J F

    1989-09-01

    Certain cells that participate in the chronic inflammatory response of teleost fishes have many features typical of epithelioid cells of mammals. Such features include high metabolic activity, frequent phagolysosomes, and cytoplasmic interdigitations between adjacent cells; however, the epithelioid granulomas formed in response to certain diseases in teleost fishes also have several features associated with epithelial cells. Cases of ulcerative mycosis or acid-fast bacterial infection in Atlantic menhaden (Brevoortia tyrannus), fungal infection in silver perch (Bairdiella chrysoura), and mycobacteriosis in Mozambique tilapia (Oreochromis mossambicus) had epithelioid cells that were joined together by well-formed desmosomes with tonofilaments. "Mature granulomas" of the ulcerative mycosis-infected menhaden stained positively for cytokeratin, a cytoskeletal protein that is considered to be highly specific for epithelial cells. The consistent presence of these heretofore unrecognized epithelial features suggest that they may be characteristic of certain types of cells participating in piscine chronic inflammation. PMID:2686148

  9. Studies on the effect of grain refinement and thermal processing on shape memory characteristics of Cu Al Ni alloys

    NASA Astrophysics Data System (ADS)

    Sampath, V.

    2005-10-01

    Though Ni-Ti shape memory alloys are used extensively in a variety of engineering and medical applications because of their attractive shape memory characteristics, they still suffer from certain drawbacks, such as low transformation temperatures, difficulty in production and processing and high cost of raw materials. Copper-based alloys have, therefore, come as an alternative to Ni-Ti shape memory alloys. They are easier to produce and process and are also less expensive. They are used where Ni-Ti alloys cannot be used. But Cu-Al-Ni shape memory alloys also pose problems since they are brittle and possess lower shape recovery strains and stresses. With a view to increasing the shape memory characteristics and ductility of Cu-Al-Ni shape memory alloys, they were subjected to grain refinement and thermomechanical processing. The present study establishes that grain-refining additions result in considerable reduction in the grain size of the alloys. In addition, grain refinement and alloying cause an increase in the transformation temperatures. The results are analysed in the light of the explanations/theories put forth in recent papers related to Cu-Al-Ni shape memory alloys, and an attempt has been made to compare the results.

  10. Nanovesicle-targeted Kv1.3 knockdown in memory T cells suppresses CD40L expression and memory phenotype.

    PubMed

    Chimote, Ameet A; Hajdu, Peter; Kottyan, Leah C; Harley, John B; Yun, Yeoheung; Conforti, Laura

    2016-05-01

    Ca(2+) signaling controls activation and effector functions of T lymphocytes. Ca(2+) levels also regulate NFAT activation and CD40 ligand (CD40L) expression in T cells. CD40L in activated memory T cells binds to its cognate receptor, CD40, on other cell types resulting in the production of antibodies and pro-inflammatory mediators. The CD40L/CD40 interaction is implicated in the pathogenesis of autoimmune disorders and CD40L is widely recognized as a therapeutic target. Ca(2+) signaling in T cells is regulated by Kv1.3 channels. We have developed lipid nanoparticles that deliver Kv1.3 siRNAs (Kv1.3-NPs) selectively to CD45RO(+) memory T cells and reduce the activation-induced Ca(2+) influx. Herein we report that Kv1.3-NPs reduced NFAT activation and CD40L expression exclusively in CD45RO(+) T cells. Furthermore, Kv1.3-NPs suppressed cytokine release and induced a phenotype switch of T cells from predominantly memory to naïve. These findings indicate that Kv1.3-NPs operate as targeted immune suppressive agents with promising therapeutic potentials.

  11. Antigen availability determines CD8+ T cell-dendritic cell interaction kinetics and memory fate decisions

    PubMed Central

    Henrickson, Sarah E.; Stutte, Susanne; Quigley, Michael; Alexe, Gabriela; Iannacone, Matteo; Flynn, Michael P.; Omid, Shaida; Jesneck, Jonathan L.; Imam, Sabrina; Mempel, Thorsten R.; Mazo, Irina B.; Haining, William N.; von Andrian, Ulrich H.

    2014-01-01

    Summary T cells are activated by antigen (Ag) bearing dendritic cells (DCs) in lymph nodes in 3 phases. The duration of the initial phase of transient, serial DC-T cell interactions is inversely correlated with Ag dose. The second phase, characterized by stable DC-T cell contacts, is believed to be necessary for full-fledged T cell activation. Here we have shown that this is not the case. CD8+ T cells interacting with DCs presenting low-dose, short-lived Ag did not transition to phase 2, while higher Ag dose yielded phase 2 transition. Both antigenic constellations promoted T cell proliferation and effector differentiation, but yielded different transcriptome signatures at 12h and 24h. T cells that experienced phase 2 developed long-lived memory, whereas conditions without stable contacts yielded immunological amnesia. Thus, T cells make fate decisions within hours after Ag exposure resulting in long-term memory or abortive effector responses, correlating with T cell-DCs interaction kinetics. PMID:24054328

  12. Manufacture of Gene-Modified Human T-Cells with a Memory Stem/Central Memory Phenotype

    PubMed Central

    Gomez-Eerland, Raquel; Nuijen, Bastiaan; Heemskerk, Bianca; van Rooij, Nienke; van den Berg, Joost H.; Beijnen, Jos H.; Uckert, Wolfgang; Kvistborg, Pia; Schumacher, Ton N.; Jorritsma, Annelies

    2014-01-01

    Abstract Advances in genetic engineering have made it possible to generate human T-cell products that carry desired functionalities, such as the ability to recognize cancer cells. The currently used strategies for the generation of gene-modified T-cell products lead to highly differentiated cells within the infusion product, and on the basis of data obtained in preclinical models, this is likely to impact the efficacy of these products. We set out to develop a good manufacturing practice (GMP) protocol that yields T-cell receptor (TCR) gene-modified T-cells with more favorable properties for clinical application. Here, we show the robust clinical-scale production of human peripheral blood T-cells with an early memory phenotype that express a MART-1-specific TCR. By combining selection and stimulation using anti-CD3/CD28 beads for retroviral transduction, followed by expansion in the presence of IL-7 and IL-15, production of a well-defined clinical-scale TCR gene-modified T-cell product could be achieved. A major fraction of the T-cells generated in this fashion were shown to coexpress CD62L and CD45RA, and express CD27 and CD28, indicating a central memory or memory stemlike phenotype. Furthermore, these cells produced IFNγ, TNFα, and IL-2 and displayed cytolytic activity against target cells expressing the relevant antigen. The T-cell products manufactured by this robust and validated GMP production process are now undergoing testing in a phase I/IIa clinical trial in HLA-A*02:01 MART-1-positive advanced stage melanoma patients. To our knowledge, this is the first clinical trial protocol in which the combination of IL-7 and IL-15 has been applied for the generation of gene-modified T-cell products. PMID:25143008

  13. The molecular basis of the memory T cell response: differential gene expression and its epigenetic regulation

    PubMed Central

    Weng, Nan-ping; Araki, Yasuto; Subedi, Kalpana

    2015-01-01

    How the immune system remembers a previous encounter with a pathogen and responds more efficiently to a subsequent encounter has been one of the central enigmas for immunologists for over a century. The identification of pathogen-specific memory lymphocytes that arise after an infection provided a cellular basis for immunological memory. But the molecular mechanisms of immunological memory remain only partially understood. The emerging evidence suggests that epigenetic changes have a key role in controlling the distinct transcriptional profiles of memory lymphocytes and thus in shaping their function. In this Review, we summarize the recent progress that has been made in assessing the differential gene expression and chromatin modifications in memory CD4+ and CD8+ T cells, and we present our current understanding of the molecular basis of memory T cell function. PMID:22421787

  14. Increased competition for antigen during priming negatively impacts the generation of memory CD4 T cells

    PubMed Central

    Blair, David A.; Lefrançois, Leo

    2007-01-01

    The factors involved in the differentiation of memory CD4 T cells from naïve precursors are poorly understood. We developed a system to examine the effect of increased competition for antigen by CD4 T cells on the generation of memory in response to infection with a recombinant vesicular stomatitis virus. Competition was initially regulated by increasing the precursor frequency of adoptively transferred naïve T cell antigen receptor transgenic CD4 T cells. Despite robust proliferation at high precursor frequencies, memory CD4 T cells did not develop, whereas decreasing the input number of naïve CD4 T cells promoted memory development after infection. The lack of memory development was linked to reduced blastogenesis and poor effector cell induction, but not to initial recruitment or proliferation of antigen-specific CD4 T cells. To prove that availability of antigen alone could regulate memory CD4 T cell development, we used treatment with an mAb specific for the epitope recognized by the transferred CD4 T cells. At high doses, this mAb effectively inhibited the antigen-specific CD4 T cell response. However, at a very low dose of mAb, primary CD4 T cell expansion was unaffected, although memory development was dramatically reduced. Moreover, the induction of effector function was concomitantly inhibited. Thus, competition for antigen during CD4 T cell priming is a major contributing factor to the development of the memory CD4 T cell pool. PMID:17827281

  15. Activation of bone marrow-resident memory T cells by circulating, antigen-bearing dendritic cells

    PubMed Central

    Cavanagh, Lois L.; Bonasio, Roberto; Mazo, Irina B.; Halin, Cornelia; Cheng, Guiying; van der Velden, Adrianus W. M.; Cariappa, Annaiah; Chase, Catherine; Russell, Paul; Starnbach, Michael N.; Koni, Pandelakis A.; Pillai, Shiv; Weninger, Wolfgang; von Andrian, Ulrich H.

    2006-01-01

    Dendritic cells (DC) carry antigen from peripheral tissues via lymphatics to lymph nodes (LN). We report that differentiated DC can also travel from the periphery into the blood. Circulating DC migrated to the spleen, liver and lung, but not LN. They also homed to the bone marrow (BM) where they were better retained than in most other tissues. DC homing to the BM depended on constitutively expressed VCAM-1 and endothelial selectins in BM microvessels. Two-photon intravital microscopy in BM cavities revealed that DC formed stable antigen-dependent contacts with BM-resident central memory T cells. Moreover, using this novel migratory pathway, antigen-pulsed DC could trigger central memory T cell-mediated recall responses in the BM. PMID:16155571

  16. Generation of human memory stem T cells after haploidentical T-replete hematopoietic stem cell transplantation.

    PubMed

    Cieri, Nicoletta; Oliveira, Giacomo; Greco, Raffaella; Forcato, Mattia; Taccioli, Cristian; Cianciotti, Beatrice; Valtolina, Veronica; Noviello, Maddalena; Vago, Luca; Bondanza, Attilio; Lunghi, Francesca; Marktel, Sarah; Bellio, Laura; Bordignon, Claudio; Bicciato, Silvio; Peccatori, Jacopo; Ciceri, Fabio; Bonini, Chiara

    2015-04-30

    Memory stem T cells (TSCM) have been proposed as key determinants of immunologic memory. However, their exact contribution to a mounting immune response, as well as the mechanisms and timing of their in vivo generation, are poorly understood. We longitudinally tracked TSCM dynamics in patients undergoing haploidentical hematopoietic stem cell transplantation (HSCT), thereby providing novel hints on the contribution of this subset to posttransplant immune reconstitution in humans. We found that donor-derived TSCM are highly enriched early after HSCT. We showed at the antigen-specific and clonal level that TSCM lymphocytes can differentiate directly from naive precursors infused within the graft and that the extent of TSCM generation might correlate with interleukin 7 serum levels. In vivo fate mapping through T-cell receptor sequencing allowed defining the in vivo differentiation landscapes of human naive T cells, supporting the notion that progenies of single naive cells embrace disparate fates in vivo and highlighting TSCM as relevant novel players in the diversification of immunological memory after allogeneic HSCT.

  17. Inability of memory T cells to induce graft-versus-host disease is a result of an abortive alloresponse

    PubMed Central

    Deoliveira, Divino; Cui, Xiuyu; Le, Ngocdiep T.; Son, Jessica; Whitesides, John F.; Chao, Nelson J.

    2007-01-01

    Several groups, including our own, have independently demonstrated that effector memory T cells from non–alloantigen-primed donors do not cause graft-versus-host disease (GVHD). In the current study, we further investigated whether this approach could be extended to all memory T cells, and we studied the underlying mechanisms. Neither total memory T cells nor purified central memory T cells were able to induce GVHD. Memory T cells were at least 3-log less potent than bulk T cells in mediating GVHD. As expected, memory T cells failed to elicit cytotoxicity and proliferated poorly against alloantigens in standard 5-day mixed-lymphocyte cultures. However, the proliferative responses of memory T cells were more comparable with those of bulk and naive T cells when the culture time was shortened. Moreover, the frequencies of IL-2–secreting cells measured by 42-hour enzyme-linked immunosorbent spot (ELISPOT) assay were similar among naive, memory, and bulk T cells. These data indicated that memory T cells are able to respond to alloantigens initially but fail to develop to full potential. The abortive immune response, which was mediated by non–alloantigen-specific memory T cells in response to alloantigens, may explain why memory T cells from unprimed and non–alloantigen-primed donors could not induce GVHD. PMID:17148592

  18. Tissue Distribution of Memory T and B Cells in Rhesus Monkeys following Influenza A Infection.

    PubMed

    Pichyangkul, Sathit; Yongvanitchit, Kosol; Limsalakpetch, Amporn; Kum-Arb, Utaiwan; Im-Erbsin, Rawiwan; Boonnak, Kobporn; Thitithayanont, Arunee; Jongkaewwattana, Anan; Wiboon-ut, Suwimon; Mongkolsirichaikul, Duangrat; Mahanonda, Rangsini; Spring, Michele; Chuang, Ilin; Mason, Carl J; Saunders, David L

    2015-11-01

    Studies of influenza-specific immune responses in humans have largely assessed systemic responses involving serum Ab and peripheral blood T cell responses. However, recent evidence indicates that tissue-resident memory T (TRM) cells play an important role in local murine intrapulmonary immunity. Rhesus monkeys were pulmonary exposed to 2009 pandemic H1N1 virus at days 0 and 28 and immune responses in different tissue compartments were measured. All animals were asymptomatic postinfection. Although only minimal memory immune responses were detected in peripheral blood, a high frequency of influenza nucleoprotein-specific memory T cells was detected in the lung at the "contraction phase," 49-58 d after second virus inoculation. A substantial proportion of lung nucleoprotein-specific memory CD8(+) T cells expressed CD103 and CD69, phenotypic markers of TRM cells. Lung CD103(+) and CD103(-) memory CD8(+) T cells expressed similar levels of IFN-γ and IL-2. Unlike memory T cells, spontaneous Ab secreting cells and memory B cells specific to influenza hemagglutinin were primarily observed in the mediastinal lymph nodes. Little difference in systemic and local immune responses against influenza was observed between young adult (6-8 y) and old animals (18-28 y). Using a nonhuman primate model, we revealed substantial induction of local T and B cell responses following 2009 pandemic H1N1 infection. Our study identified a subset of influenza-specific lung memory T cells characterized as TRM cells in rhesus monkeys. The rhesus monkey model may be useful to explore the role of TRM cells in local tissue protective immunity after rechallenge and vaccination. PMID:26408671

  19. Tissue Distribution of Memory T and B Cells in Rhesus Monkeys following Influenza A Infection

    PubMed Central

    Yongvanitchit, Kosol; Limsalakpetch, Amporn; Kum-Arb, Utaiwan; Im-Erbsin, Rawiwan; Boonnak, Kobporn; Thitithayanont, Arunee; Jongkaewwattana, Anan; Wiboon-ut, Suwimon; Mongkolsirichaikul, Duangrat; Mahanonda, Rangsini; Spring, Michele; Chuang, Ilin; Mason, Carl J.; Saunders, David L.

    2015-01-01

    Studies of influenza-specific immune responses in humans have largely assessed systemic responses involving serum Ab and peripheral blood T cell responses. However, recent evidence indicates that tissue-resident memory T (TRM) cells play an important role in local murine intrapulmonary immunity. Rhesus monkeys were pulmonary exposed to 2009 pandemic H1N1 virus at days 0 and 28 and immune responses in different tissue compartments were measured. All animals were asymptomatic postinfection. Although only minimal memory immune responses were detected in peripheral blood, a high frequency of influenza nucleoprotein–specific memory T cells was detected in the lung at the “contraction phase,” 49–58 d after second virus inoculation. A substantial proportion of lung nucleoprotein-specific memory CD8+ T cells expressed CD103 and CD69, phenotypic markers of TRM cells. Lung CD103+ and CD103- memory CD8+ T cells expressed similar levels of IFN-γ and IL-2. Unlike memory T cells, spontaneous Ab secreting cells and memory B cells specific to influenza hemagglutinin were primarily observed in the mediastinal lymph nodes. Little difference in systemic and local immune responses against influenza was observed between young adult (6–8 y) and old animals (18–28 y). Using a nonhuman primate model, we revealed substantial induction of local T and B cell responses following 2009 pandemic H1N1 infection. Our study identified a subset of influenza-specific lung memory T cells characterized as TRM cells in rhesus monkeys. The rhesus monkey model may be useful to explore the role of TRM cells in local tissue protective immunity after rechallenge and vaccination. PMID:26408671

  20. Protein energy malnutrition impairs homeostatic proliferation of memory CD8 T cells.

    PubMed

    Iyer, Smita S; Chatraw, Janel Hart; Tan, Wendy G; Wherry, E John; Becker, Todd C; Ahmed, Rafi; Kapasi, Zoher F

    2012-01-01

    Nutrition is a critical but poorly understood determinant of immunity. There is abundant epidemiological evidence linking protein malnutrition to impaired vaccine efficacy and increased susceptibility to infections; yet, the role of dietary protein in immune memory homeostasis remains poorly understood. In this study, we show that protein-energy malnutrition induced in mice by low-protein (LP) feeding has a detrimental impact on CD8 memory. Relative to adequate protein (AP)-fed controls, LP feeding in lymphocytic choriomeningitis virus (LCMV)-immune mice resulted in a 2-fold decrease in LCMV-specific CD8 memory T cells. Adoptive transfer of memory cells, labeled with a division tracking dye, from AP mice into naive LP or AP mice demonstrated that protein-energy malnutrition caused profound defects in homeostatic proliferation. Remarkably, this defect occurred despite the lymphopenic environment in LP hosts. Whereas Ag-specific memory cells in LP and AP hosts were phenotypically similar, memory cells in LP hosts were markedly less responsive to polyinosinic-polycytidylic acid-induced acute proliferative signals. Furthermore, upon recall, memory cells in LP hosts displayed reduced proliferation and protection from challenge with LCMV-clone 13, resulting in impaired viral clearance in the liver. The findings show a metabolic requirement of dietary protein in sustaining functional CD8 memory and suggest that interventions to optimize dietary protein intake may improve vaccine efficacy in malnourished individuals.

  1. Nonspecific desensitization, functional memory, and the characteristics of SHIP phosphorylation following IgE-mediated stimulation of human basophils.

    PubMed

    MacGlashan, Donald; Vilariño, Natalia

    2006-07-15

    Previous studies of secretion from basophils have demonstrated the phenomenon called nonspecific desensitization, the ability of one IgE-mediated stimulus to alter the cell's response to other non-cross-reacting IgE-mediated stimuli, and a process that would modify phosphatidylinositol 3,4,5-phosphate levels was speculated to be responsible for nonspecific desensitization. The current studies examined the changes and characteristics of SHIP1 phosphorylation as a measure of SHIP1 participation in the reaction. Based on the earlier studies, two predictions were made that were not observed. First, the kinetics of SHIP1 phosphorylation were similar to reaction kinetics of other early signals and returned to resting levels while nonspecific desensitization remained. Second, in contrast to an expected exaggerated SHIP phosphorylation, cells in a state of nonspecific desensitization showed reduced SHIP phosphorylation (compared with cells not previously exposed to a non-cross-reacting Ag). Discordant with expectations concerning partial recovery from nonspecific desensitization, treatment of cells with DNP-lysine to dissociate bound DNP-HSA, either enhanced or had no effect on SHIP phosphorylation following a second Ag. These experiments also showed a form of desensitization that persisted despite dissociation of the desensitizing Ag. Recent studies and the results of these studies suggest that loss of early signaling components like syk kinase may account for some of the effects of nonspecific desensitization and result in a form of immunological memory of prior stimulation. Taken together, the various characteristics of SHIP phosphorylation were not consistent with expectations for a signaling element involved in nonspecific desensitization, but instead one which itself undergoes nonspecific desensitization. PMID:16818760

  2. Pediatric common variable immunodeficiency: immunologic and phenotypic associations with switched memory B cells.

    PubMed

    Yong, Pierre L; Orange, Jordan S; Sullivan, Kathleen E

    2010-08-01

    Recent studies suggest that patients with common variable immunodeficiency (CVID) and low numbers of switched memory B cells have lower IgG levels and higher rates of autoimmune disease, splenomegaly, and granulomatous disease; however, no prior literature has focused exclusively on pediatric cases. We examined the relationship between switched memory B cells and clinical and immunologic manifestations of CVID in a pediatric population. Forty-five patients were evaluated. Patients were categorized as Group I (<5 switched memory B cells/ml, n = 24) or Group II (> or =5 switched memory B cells/mL, n = 21). CD3(+) T-cell counts and CD19(+) B-cell levels were lower among Group I patients. Only those in Group I had meningitis, sepsis, bronchiectasis, granulomatous lung disease, autoimmune cytopenias, or hematologic malignancies. Segregation of pediatric patients into high risk (Group I) and average risk (Group II) may assist in targeting surveillance appropriately.

  3. Immunologic considerations for generating memory CD8 T cells through vaccination.

    PubMed

    Butler, Noah S; Nolz, Jeffrey C; Harty, John T

    2011-07-01

    Following infection or vaccination, naïve CD8 T cells that receive the appropriate integration of antigenic, co-stimulatory and inflammatory signals undergo a programmed series of biological changes that ultimately results in the generation of memory cells. Memory CD8 T cells, in contrast to naïve cells, more effectively limit or prevent pathogen re-infection because of both qualitative and quantitative changes that occur following their induction. Unlike vaccination strategies aimed at generating antibody production, the ability to generate protective memory CD8 T cells has proven more complicated and problematic. However, recent experimental results have revealed important principles regarding the molecular and genetic basis for memory CD8 T cell formation, as well as identified ways to manipulate their development through vaccination, resulting in potential new avenues to enhance protective immunity.

  4. Temperature dependent retention characteristics of ion-beam modified SONOS memories

    NASA Astrophysics Data System (ADS)

    Simatos, D. P.; Dimitrakis, P.; Normand, P.; Nikolaou, N.; Giannakopoulos, K.; Ladas, S.; Pecassou, B.; BenAssayag, G.; Ioannou-Sougleridis, V.

    2015-12-01

    In this work, we report on the structural and electrical properties of oxide-nitride-oxide (ONO) structures that were formed by low-energy silicon or nitrogen implantation into oxide-nitride stacks. In particular ON stacks (2.5 nm/6 nm) were formed on n-type Si substrates, further implanted with 1 keV Si or N to a fluence of 1016 ions/cm2, and finally wet oxidized at 850 °C for 15 min. TEM imaging showed that the thickness of the blocking oxide layer, formed during wet oxidation, strongly depends on the implanted species. Charging characteristics revealed that Si implanted stacks can trap either electrons or holes resulting to a memory window as large as 8.5 V. In turn N implanted stacks can trap only electrons with a corresponding memory window of 4 V. Room-temperature charge retention measurements showed that the electron loss rate is faster in samples implanted with Si (∼0.32 V/decade) compared to N-samples (∼0.1 V/decade). The 10-year extrapolated memory windows were 1.7 and 2.5 V for Si and N-implanted devices, respectively. Retention measurements within the temperature range of 25-150 °C indicate that the Si implanted stacks exhibit a thermally activated retention, while N-samples showed a temperature independent behavior. These results are mainly attributed to the different nature of traps generated by ion implantation and wet oxidation processing.

  5. Skin vaccination with live virus vectored microneedle arrays induce long lived CD8(+) T cell memory.

    PubMed

    Becker, Pablo D; Hervouet, Catherine; Mason, Gavin M; Kwon, Sung-Yun; Klavinskis, Linda S

    2015-09-01

    A simple dissolvable microneedle array (MA) platform has emerged as a promising technology for vaccine delivery, due to needle-free injection with a formulation that preserves the immunogenicity of live viral vectored vaccines dried in the MA matrix. While recent studies have focused largely on design parameters optimized to induce primary CD8(+) T cell responses, the hallmark of a vaccine is synonymous with engendering long-lasting memory. Here, we address the capacity of dried MA vaccination to programme phenotypic markers indicative of effector/memory CD8(+) T cell subsets and also responsiveness to recall antigen benchmarked against conventional intradermal (ID) injection. We show that despite a slightly lower frequency of dividing T cell receptor transgenic CD8(+) T cells in secondary lymphoid tissue at an early time point, the absolute number of CD8(+) T cells expressing an effector memory (CD62L(-)CD127(+)) and central memory (CD62L(+)CD127(+)) phenotype during peak expansion were comparable after MA and ID vaccination with a recombinant human adenovirus type 5 vector (AdHu5) encoding HIV-1 gag. Similarly, both vaccination routes generated CD8(+) memory T cell subsets detected in draining LNs for at least two years post-vaccination capable of responding to secondary antigen. These data suggest that CD8(+) T cell effector/memory generation and long-term memory is largely unaffected by physical differences in vaccine delivery to the skin via dried MA or ID suspension.

  6. Force-displacement characteristics of simply supported beam laminated with shape memory alloys

    NASA Astrophysics Data System (ADS)

    Wu, Zhi-Qiang; Zhang, Zhen-Hua

    2011-12-01

    As a preliminary step in the nonlinear design of shape memory alloy (SMA) composite structures, the force-displacement characteristics of the SMA layer are studied. The bilinear hysteretic model is adopted to describe the constitutive relationship of SMA material. Under the assumption that there is no point of SMA layer finishing martensitic phase transformation during the loading and unloading process, the generalized restoring force generated by SMA layer is deduced for the case that the simply supported beam vibrates in its first mode. The generalized force is expressed as piecewise-nonlinear hysteretic function of the beam transverse displacement. Furthermore the energy dissipated by SMA layer during one period is obtained by integration, then its dependencies are discussed on the vibration amplitude and the SMA's strain (Ms-Strain) value at the beginning of martensitic phase transformation. It is shown that SMA's energy dissipating capacity is proportional to the stiffness difference of bilinear model and nonlinearly dependent on Ms-Strain. The increasing rate of the dissipating capacity gradually reduces with the amplitude increasing. The condition corresponding to the maximum dissipating capacity is deduced for given value of the vibration amplitude. The obtained results are helpful for designing beams laminated with shape memory alloys.

  7. Dysfunctional memory CD8+ T cells after priming in the absence of the cell cycle regulator E2F4.

    PubMed

    Bancos, Simona; Cao, Qingyu; Bowers, William J; Crispe, Ian Nicholas

    2009-01-01

    The transcriptional repressor E2F4 is important for cell cycle exit and terminal differentiation in epithelial cells, neuronal cells and adipocytes but its role in T lymphocytes proliferation and memory formation is not known. Herein, we investigated the function of E2F4 protein for the formation of functional murine memory T cells. Murine transgenic CD8+ T cells were infected in vitro with lentivirus vector expressing a shRNA targeted against E2F4 followed by in vitro stimulation with SIINFEKL antigenic peptide. For in vivo assays, transduced cells were injected into congenic mice which were then infected with HSV-OVA. The primary response, memory formation and secondary stimulation were determined for CD8+ lentivirus transduced cells. In the absence of E2F4 cell cycle repressor, activated CD8+ T cells underwent intensive proliferation in vitro and in vivo. These cells had the ability to differentiate into memory cells in vivo, but they were defective in recall proliferation. We show that transient suppression of E2F4 during CD8+ T cell priming enhances primary proliferation and has a negative effect on secondary stimulation. These findings demonstrate that the cell cycle repressor E2F4 is essential for the formation of functional memory T cells. A decrease in CD8+ T-lymphocyte compartment would diminish our capacity to control viral infections.

  8. Dysfunctional memory CD8+ T cells after priming in the absence of the cell cycle regulator E2F4

    PubMed Central

    Bancos, Simona; Cao, QingYu; Bowers, William J.; Crispe, Ian Nicholas

    2009-01-01

    The transcriptional repressor E2F4 is important for cell cycle exit and terminal differentiation in epithelial cells, neuronal cells and adipocytes but its role in T lymphocytes proliferation and memory formation is not known. Herein, we investigated the function of E2F4 protein for the formation of functional murine memory T cells. Murine transgenic CD8+ T cells were infected in vitro with lentivirus vector expressing a shRNA targeted against E2F4 followed by in vitro stimulation with SIINFEKL antigenic peptide. For in vivo assays, transduced cells were injected into congenic mice which were then infected with HSV-OVA. The primary response, memory formation and secondary stimulation were determined for CD8+ lentivirus transduced cells. In the absence of E2F4 cell cycle repressor, activated CD8+ T cells underwent intensive proliferation in vitro and in vivo. These cells had the ability to differentiate into memory cells in vivo, but they were defective in recall proliferation. We show that transient suppression of E2F4 during CD8+ T cell priming enhances primary proliferation and has a negative effect on secondary stimulation. These findings demonstrate that the cell cycle repressor E2F4 is essential for the formation of functional memory T cells. A decrease in CD8+ T-lymphocyte compartment would diminish our capacity to control viral infections. PMID:19306992

  9. γδ T cells come to stay: Innate skin memory in the Aldara model.

    PubMed

    Prinz, Immo; Sandrock, Inga

    2015-11-01

    The term immunological memory has long been a trademark restricted to adaptive lymphocytes such as memory B cells and plasma cells as well as memory CD8(+) αβ T cells. In recent years, innate lymphocytes such as NK cells have also been shown to adapt to their environment by antigen-specific expansion and selective survival. However, whether γδ T cells mount comparable memory responses to pathogenic stimuli is less well understood. In this issue of European Journal of Immunology, Hartwig et al. [Eur. J. Immunol. 2015. 45: 3022-3033] identify a subset of IL-17-producing γδ T cells that are capable of establishing long-lived memory in the skin of mice exposed to imiquimod in the Aldara psoriasis model. These γδ T cells uniformly express a Vγ4(+) Vδ4(+) TCR. They produce IL-17A/F and persist in the dermis for long periods of time, also at untreated distal sites. Upon secondary challenge, experienced Vγ4(+) Vδ4(+) cells show enhanced effector functions and mediate exacerbated secondary inflammation. These findings showcase innate γδ T-cell memory that uses a single conserved public TCR combination. Furthermore, they provide mechanistic insight to the observed psoriatic relapses in patients in response to topical treatment with imiquimod.

  10. Type I interferons regulate eomesodermin expression and the development of unconventional memory CD8(+) T cells.

    PubMed

    Martinet, Valérie; Tonon, Sandrine; Torres, David; Azouz, Abdulkader; Nguyen, Muriel; Kohler, Arnaud; Flamand, Véronique; Mao, Chai-An; Klein, William H; Leo, Oberdan; Goriely, Stanislas

    2015-05-08

    CD8(+) T-cell memory phenotype and function are acquired after antigen-driven activation. Memory-like cells may also arise in absence of antigenic exposure in the thymus or in the periphery. Eomesodermin (Eomes) is a key transcription factor for the development of these unconventional memory cells. Herein, we show that type I interferon signalling in CD8(+) T cells directly activates Eomes gene expression. Consistent with this observation, the phenotype, function and age-dependent expansion of 'virtual memory' CD8(+) T cells are strongly affected in absence of type I interferon signalling. In addition, type I interferons induce a sustained expansion of 'virtual memory' CD8(+) T cells in an Eomes-dependent fashion. We further show that the development of 'innate thymic' CD8(+) T cells is dependent on the same pathway. In conclusion, we demonstrate that type I interferon signalling in CD8(+) T cells drives Eomes expression and thereby regulates the function and homeostasis of memory-like CD8(+) T cells.

  11. Directional memory arises from long-lived cytoskeletal asymmetries in polarized chemotactic cells.

    PubMed

    Prentice-Mott, Harrison V; Meroz, Yasmine; Carlson, Andreas; Levine, Michael A; Davidson, Michael W; Irimia, Daniel; Charras, Guillaume T; Mahadevan, L; Shah, Jagesh V

    2016-02-01

    Chemotaxis, the directional migration of cells in a chemical gradient, is robust to fluctuations associated with low chemical concentrations and dynamically changing gradients as well as high saturating chemical concentrations. Although a number of reports have identified cellular behavior consistent with a directional memory that could account for behavior in these complex environments, the quantitative and molecular details of such a memory process remain unknown. Using microfluidics to confine cellular motion to a 1D channel and control chemoattractant exposure, we observed directional memory in chemotactic neutrophil-like cells. We modeled this directional memory as a long-lived intracellular asymmetry that decays slower than observed membrane phospholipid signaling. Measurements of intracellular dynamics revealed that moesin at the cell rear is a long-lived element that when inhibited, results in a reduction of memory. Inhibition of ROCK (Rho-associated protein kinase), downstream of RhoA (Ras homolog gene family, member A), stabilized moesin and directional memory while depolymerization of microtubules (MTs) disoriented moesin deposition and also reduced directional memory. Our study reveals that long-lived polarized cytoskeletal structures, specifically moesin, actomyosin, and MTs, provide a directional memory in neutrophil-like cells even as they respond on short time scales to external chemical cues.

  12. Directional memory arises from long-lived cytoskeletal asymmetries in polarized chemotactic cells

    PubMed Central

    Prentice-Mott, Harrison V.; Meroz, Yasmine; Carlson, Andreas; Levine, Michael A.; Davidson, Michael W.; Irimia, Daniel; Charras, Guillaume T.; Mahadevan, L.; Shah, Jagesh V.

    2016-01-01

    Chemotaxis, the directional migration of cells in a chemical gradient, is robust to fluctuations associated with low chemical concentrations and dynamically changing gradients as well as high saturating chemical concentrations. Although a number of reports have identified cellular behavior consistent with a directional memory that could account for behavior in these complex environments, the quantitative and molecular details of such a memory process remain unknown. Using microfluidics to confine cellular motion to a 1D channel and control chemoattractant exposure, we observed directional memory in chemotactic neutrophil-like cells. We modeled this directional memory as a long-lived intracellular asymmetry that decays slower than observed membrane phospholipid signaling. Measurements of intracellular dynamics revealed that moesin at the cell rear is a long-lived element that when inhibited, results in a reduction of memory. Inhibition of ROCK (Rho-associated protein kinase), downstream of RhoA (Ras homolog gene family, member A), stabilized moesin and directional memory while depolymerization of microtubules (MTs) disoriented moesin deposition and also reduced directional memory. Our study reveals that long-lived polarized cytoskeletal structures, specifically moesin, actomyosin, and MTs, provide a directional memory in neutrophil-like cells even as they respond on short time scales to external chemical cues. PMID:26764383

  13. Characteristics of HfO2/Hf-based bipolar resistive memories

    NASA Astrophysics Data System (ADS)

    Jinshun, Bi; Zhengsheng, Han

    2015-06-01

    Nano-scale Hf/HfO2-based resistive random-access-memory (RRAM) devices were fabricated. The cross-over between top and bottom electrodes of RRAM forms the metal-insulator-metal sandwich structure. The electrical responses of RRAM are studied in detail, including forming process, SET process and RESET process. The correlations between SET voltage and RESET voltage, high resistance state and low resistance state are discussed. The electrical characteristics of RRAM are in a strong relationship with the compliance current in the SET process. The conduction mechanism of nano-scale Hf/HfO2-based RRAM can be explained by the quantum point contact model. Project supported by the National Natural Science Foundation of China (Nos. 11179003, 61176095).

  14. GeTe sequences in superlattice phase change memories and their electrical characteristics

    SciTech Connect

    Ohyanagi, T. Kitamura, M.; Takaura, N.; Araidai, M.; Kato, S.; Shiraishi, K.

    2014-06-23

    We studied GeTe structures in superlattice phase change memories (superlattice PCMs) with a [GeTe/Sb{sub 2}Te{sub 3}] stacked structure by X-ray diffraction (XRD) analysis. We examined the electrical characteristics of superlattice PCMs with films deposited at different temperatures. It was found that XRD spectra differed between the films deposited at 200 °C and 240 °C; the differences corresponded to the differences in the GeTe sequences in the films. We applied first-principles calculations to calculate the total energy of three different GeTe sequences. The results showed the Ge-Te-Ge-Te sequence had the lowest total energy of the three and it was found that with this sequence the superlattice PCMs did not run.

  15. Dependence of memory characteristics of fullerene-containing polymer on the kind of gate metal

    NASA Astrophysics Data System (ADS)

    Nakajima, Anri; Shoji, Atsushi; Nagano, Kohei; Kajihara, Jun

    2015-10-01

    The memory operation of [6,6]-phenyl-C61-butyric-acid-methyl-ester-containing polystyrene nanocomposites was investigated while varying the kind of gate metal used. Moderate magnitudes of flatband voltage shift were observed both after negative and positive programming voltages were applied to the Au gate. Excellent retention characteristics were obtained for electrons, whereas the retention time of holes was much shorter than that of electrons for the gate. An analysis of the band diagram indicated that carriers are injected and stored in the lowest unoccupied molecular orbital or highest occupied molecular orbital levels of fullerene. Au gates are promising from the practical viewpoint because they make the magnitudes of both the writing and erasing voltages small.

  16. Entorhinal Cortical Ocean Cells Encode Specific Contexts and Drive Context-Specific Fear Memory.

    PubMed

    Kitamura, Takashi; Sun, Chen; Martin, Jared; Kitch, Lacey J; Schnitzer, Mark J; Tonegawa, Susumu

    2015-09-23

    Forming distinct representations and memories of multiple contexts and episodes is thought to be a crucial function of the hippocampal-entorhinal cortical network. The hippocampal dentate gyrus (DG) and CA3 are known to contribute to these functions, but the role of the entorhinal cortex (EC) is poorly understood. Here, we show that Ocean cells, excitatory stellate neurons in the medial EC layer II projecting into DG and CA3, rapidly form a distinct representation of a novel context and drive context-specific activation of downstream CA3 cells as well as context-specific fear memory. In contrast, Island cells, excitatory pyramidal neurons in the medial EC layer II projecting into CA1, are indifferent to context-specific encoding or memory. On the other hand, Ocean cells are dispensable for temporal association learning, for which Island cells are crucial. Together, the two excitatory medial EC layer II inputs to the hippocampus have complementary roles in episodic memory. PMID:26402611

  17. The dual targeting of immunosuppressive cells and oxidants promotes effector and memory T-cell functions against lung cancer

    PubMed Central

    Sawant, Anandi; Schafer, Cara C; Ponnazhagan, Selvarangan; Deshane, Jessy S

    2014-01-01

    We have recently demonstrated that the combination of gemcitabine and a superoxide dismutase mimetic protects mice against lung cancer by suppressing the functions of myeloid-derived suppressor cells and by activating memory CD8+ T-cell responses. Persistent memory cells exhibited a glycolytic metabolism, which may have directly enhanced their effector functions. This combinatorial therapeutic regimen may reduce the propensity of some cancer patients to relapse. PMID:24711958

  18. Visualizing Early Splenic Memory CD8+ T Cells Reactivation against Intracellular Bacteria in the Mouse

    PubMed Central

    Bajénoff, Marc; Narni-Mancinelli, Emilie; Brau, Frédéric; Lauvau, Grégoire

    2010-01-01

    Memory CD8+ T cells represent an important effector arm of the immune response in maintaining long-lived protective immunity against viruses and some intracellular bacteria such as Listeria monocytogenes (L.m). Memory CD8+ T cells are endowed with enhanced antimicrobial effector functions that perfectly tail them to rapidly eradicate invading pathogens. It is largely accepted that these functions are sufficient to explain how memory CD8+ T cells can mediate rapid protection. However, it is important to point out that such improved functional features would be useless if memory cells were unable to rapidly find the pathogen loaded/infected cells within the infected organ. Growing evidences suggest that the anatomy of secondary lymphoid organs (SLOs) fosters the cellular interactions required to initiate naive adaptive immune responses. However, very little is known on how the SLOs structures regulate memory immune responses. Using Listeria monocytogenes (L.m) as a murine infection model and imaging techniques, we have investigated if and how the architecture of the spleen plays a role in the reactivation of memory CD8+ T cells and the subsequent control of L.m growth. We observed that in the mouse, memory CD8+ T cells start to control L.m burden 6 hours after the challenge infection. At this very early time point, L.m-specific and non-specific memory CD8+ T cells localize in the splenic red pulp and form clusters around L.m infected cells while naïve CD8+ T cells remain in the white pulp. Within these clusters that only last few hours, memory CD8+ T produce inflammatory cytokines such as IFN-γ and CCL3 nearby infected myeloid cells known to be crucial for L.m killing. Altogether, we describe how memory CD8+ T cells trafficking properties and the splenic micro-anatomy conjugate to create a spatio-temporal window during which memory CD8+ T cells provide a local response by secreting effector molecules around infected cells. PMID:20634957

  19. Efficient Methods To Isolate Human Monoclonal Antibodies from Memory B Cells and Plasma Cells.

    PubMed

    Corti, Davide; Lanzavecchia, Antonio

    2014-10-01

    In this article, we highlight the advantages of isolating human monoclonal antibodies from the human memory B cells and plasma cell repertoires by using high-throughput cellular screens. Memory B cells are immortalized with high efficiency using Epstein-Barr virus (EBV) in the presence of a toll-like receptor (TLR) agonist, while plasma cells are maintained in single-cell cultures by using interleukin 6 (IL-6) or stromal cells. In both cases, multiple parallel assays, including functional assays, can be used to identify rare cells that produce antibodies with unique properties. Using these methods, we have isolated potent and broadly neutralizing antibodies against a variety of viruses, in particular, a pan-influenza-A-neutralizing antibody and an antibody that neutralizes four different paramyxoviruses. Given the high throughput and the possibility of directly screening for function (rather than just binding), these methods are instrumental to implement a target-agnostic approach to identify the most effective antibodies and, consequently, the most promising targets for vaccine design. This approach is exemplified by the identification of unusually potent cytomegalovirus-neutralizing antibodies that led to the identification of the target, a pentameric complex that we are developing as a candidate vaccine. PMID:26104354

  20. Storage Characteristics of Lithium Ion Cells

    NASA Technical Reports Server (NTRS)

    Ratnakumar, B. V.; Smart, M. C.; Blosiu, J. O.; Surampudi, S.

    2000-01-01

    Lithium ion cells are being developed under the NASA/Air Force Consortium for the upcoming aerospace missions. First among these missions are the Mars 2001 Lander and Mars 2003 Lander and Rover missions. Apart from the usual needs of high specific energy, energy density and long cycle life, a critical performance characteristic for the Mars missions is low temperature performance. The batteries need to perform well at -20 C, with at least 70% of the rated capacity realizable at moderate discharge rates (C/5). Several modifications have been made to the lithium ion chemistry, mainly with respect to the electrolyte, both at JPL' and elsewhere to achieve this. Another key requirement for the battery is its storageability during pre-cruise and cruise periods. For the Mars programs, the cruise period is relatively short, about 12 months, compared to the Outer Planets missions (3-8 years). Yet, the initial results of our storage studies reveal that the cells do sustain noticeable permanent degradation under certain storage conditions, typically of 10% over two months duration at ambient temperatures, attributed to impedance buildup. The build up of the cell impedance or the decay in the cell capacity is affected by various storage parameters, i.e., storage temperature, storage duration, storage mode (open circuit, on buss or cycling at low rates) and state of charge. Our preliminary studies indicate that low storage temperatures and states of charge are preferable. In some cases, we have observed permanent capacity losses of approx. 10% over eight-week storage at 40 C, compared to approx. 0-2% at O C. Also, we are attempting to determine the impact of cell chemistry and design upon the storageability of Li ion cells.

  1. The taming of the cell: shape-memory nanopatterns direct cell orientation

    PubMed Central

    Ebara, Mitsuhiro; Uto, Koichiro; Idota, Naokazu; Hoffman, John M; Aoyagi, Takao

    2014-01-01

    We report here that the direction of aligned cells on nanopatterns can be tuned to a perpendicular direction without use of any biochemical reagents. This was enabled by shape-memory activation of nanopatterns that transition from a memorized temporal pattern to the original permanent pattern by heating. The thermally induced shape-memory nanopatterns were prepared by chemically crosslinking semi-crystalline poly(ε-caprolactone) (PCL) in a mold to show shape-memory effects over its melting temperature (Tm = 33°C). Permanent surface patterns were first generated by crosslinking the PCL macromonomers in a mold, and temporary surface patterns were then embossed onto the permanent patterns. The temporary surface patterns could be easily triggered to transition quickly to the permanent surface patterns by a 37°C heat treatment, while surface wettability was independent of temperature. To investigate the role of dynamic and reversible surface nanopatterns on cell alignment on the PCL films before and after a topographic transition, NIH 3T3 fibroblasts were seeded on fibronectin-coated PCL films with a temporary grooved topography (grooves with a height of 300 nm and width of 2 μm were spaced 9 μm apart). Interestingly, cells did not change their direction immediately after the surface transition. However, cell alignment was gradually lost with time, and finally cells realigned parallel to the permanent grooves that emerged. The addition of a cytoskeletal inhibitor prevented realignment. These results clearly indicate that cells can sense dynamic changes in the surrounding environments and spontaneously adapt to a new environment by remodeling their cytoskeleton. These findings will serve as the basis for new development of spatiotemporal tunable materials to direct cell fate. PMID:24872707

  2. Hippocampus-based contextual memory alters the morphological characteristics of astrocytes in the dentate gyrus.

    PubMed

    Choi, Moonseok; Ahn, Sangzin; Yang, Eun-Jeong; Kim, Hyunju; Chong, Young Hae; Kim, Hye-Sun

    2016-07-26

    Astrocytes have been reported to exist in two states, the resting and the reactive states. Morphological changes in the reactive state of astrocytes include an increase in thickness and number of processes, and an increase in the size of the cell body. Molecular changes also occur, such as an increase in the expression of glial fibrillary acidic protein (GFAP). However, the morphological and molecular changes during the process of learning and memory have not been elucidated. In the current study, we subjected Fvb/n mice to contextual fear conditioning, and checked for morphological and molecular changes in astrocytes. 1 h after fear conditioning, type II and type III astrocytes exhibited a unique status with an increased number of processes and decreased GFAP expression which differed from the typical resting or reactive state. In addition, the protein level of excitatory excitatory amino acid transporter 2 (EAAT2) was increased 1 h to 24 h after contextual fear conditioning while EAAT1 did not show any alterations. Connexin 43 (Cx43) protein was found to be increased at 24 h after fear conditioning. These data suggest that hippocampus-based contextual memory process induces changes in the status of astrocytes towards a novel status different from typical resting or reactive states. These morphological and molecular changes may be in line with functional changes.

  3. Memristive behavior in a junctionless flash memory cell

    SciTech Connect

    Orak, Ikram; Ürel, Mustafa; Dana, Aykutlu; Bakan, Gokhan

    2015-06-08

    We report charge storage based memristive operation of a junctionless thin film flash memory cell when it is operated as a two terminal device by grounding the gate. Unlike memristors based on nanoionics, the presented device mode, which we refer to as the flashristor mode, potentially allows greater control over the memristive properties, allowing rational design. The mode is demonstrated using a depletion type n-channel ZnO transistor grown by atomic layer deposition (ALD), with HfO{sub 2} as the tunnel dielectric, Al{sub 2}O{sub 3} as the control dielectric, and non-stoichiometric silicon nitride as the charge storage layer. The device exhibits the pinched hysteresis of a memristor and in the unoptimized device, R{sub off}/R{sub on} ratios of about 3 are presented with low operating voltages below 5 V. A simplified model predicts R{sub off}/R{sub on} ratios can be improved significantly by adjusting the native threshold voltage of the devices. The repeatability of the resistive switching is excellent and devices exhibit 10{sup 6 }s retention time, which can, in principle, be improved by engineering the gate stack and storage layer properties. The flashristor mode can find use in analog information processing applications, such as neuromorphic computing, where well-behaving and highly repeatable memristive properties are desirable.

  4. Chemokine receptor CXCR3 facilitates CD8+ T cell differentiation into short-lived effector cells leading to memory degeneration

    PubMed Central

    Kurachi, Makoto; Kurachi, Junko; Suenaga, Fumiko; Tsukui, Tatsuya; Abe, Jun; Ueha, Satoshi; Tomura, Michio; Sugihara, Kei; Takamura, Shiki; Kakimi, Kazuhiro

    2011-01-01

    Strength of inflammatory stimuli during the early expansion phase plays a crucial role in the effector versus memory cell fate decision of CD8+ T cells. But it is not known how early lymphocyte distribution after infection has an impact on this process. We demonstrate that the chemokine receptor CXCR3 is involved in promoting CD8+ T cell commitment to an effector fate rather than a memory fate by regulating T cell recruitment to an antigen/inflammation site. After systemic viral or bacterial infection, the contraction of CXCR3−/− antigen-specific CD8+ T cells is significantly attenuated, resulting in massive accumulation of fully functional memory CD8+ T cells. Early after infection, CXCR3−/− antigen-specific CD8+ T cells fail to cluster at the marginal zone in the spleen where inflammatory cytokines such as IL-12 and IFN-α are abundant, thus receiving relatively weak inflammatory stimuli. Consequently, CXCR3−/− CD8+ T cells exhibit transient expression of CD25 and preferentially differentiate into memory precursor effector cells as compared with wild-type CD8+ T cells. This series of events has important implications for development of vaccination strategies to generate increased numbers of antigen-specific memory CD8+ T cells via inhibition of CXCR3-mediated T cell migration to inflamed microenvironments. PMID:21788406

  5. Analog memory and spike-timing-dependent plasticity characteristics of a nanoscale titanium oxide bilayer resistive switching device.

    PubMed

    Seo, Kyungah; Kim, Insung; Jung, Seungjae; Jo, Minseok; Park, Sangsu; Park, Jubong; Shin, Jungho; Biju, Kuyyadi P; Kong, Jaemin; Lee, Kwanghee; Lee, Byounghun; Hwang, Hyunsang

    2011-06-24

    We demonstrated analog memory, synaptic plasticity, and a spike-timing-dependent plasticity (STDP) function with a nanoscale titanium oxide bilayer resistive switching device with a simple fabrication process and good yield uniformity. We confirmed the multilevel conductance and analog memory characteristics as well as the uniformity and separated states for the accuracy of conductance change. Finally, STDP and a biological triple model were analyzed to demonstrate the potential of titanium oxide bilayer resistive switching device as synapses in neuromorphic devices. By developing a simple resistive switching device that can emulate a synaptic function, the unique characteristics of synapses in the brain, e.g. combined memory and computing in one synapse and adaptation to the outside environment, were successfully demonstrated in a solid state device. PMID:21572200

  6. Tracking genetically engineered lymphocytes long-term reveals the dynamics of T cell immunological memory.

    PubMed

    Oliveira, Giacomo; Ruggiero, Eliana; Stanghellini, Maria Teresa Lupo; Cieri, Nicoletta; D'Agostino, Mattia; D'Agostino, Mattio; Fronza, Raffaele; Lulay, Christina; Dionisio, Francesca; Mastaglio, Sara; Greco, Raffaella; Peccatori, Jacopo; Aiuti, Alessandro; Ambrosi, Alessandro; Biasco, Luca; Bondanza, Attilio; Lambiase, Antonio; Traversari, Catia; Vago, Luca; von Kalle, Christof; Schmidt, Manfred; Bordignon, Claudio; Ciceri, Fabio; Bonini, Chiara

    2015-12-01

    Long-lasting immune protection from pathogens and cancer requires the generation of memory T cells able to survive long-term. To unravel the immunological requirements for long-term persistence of human memory T cells, we characterized and traced, over several years, T lymphocytes genetically modified to express the thymidine kinase (TK) suicide gene that were infused in 10 patients after haploidentical hematopoietic stem cell transplantation (HSCT). At 2 to 14 years after infusion and in the presence of a broad and resting immune system, we could still detect effectors/effector memory (TEM/EFF), central memory (TCM), and stem memory (TSCM) TK(+) cells, circulating at low but stable levels in all patients. Longitudinal analysis of cytomegalovirus (CMV)- and Flu-specific TK(+) cells indicated that antigen recognition was dominant in driving in vivo expansion and persistence at detectable levels. The amount of infused TSCM cells positively correlated with early expansion and with the absolute counts of long-term persisting gene-marked cells. By combining T cell sorting with sequencing of integration (IS), TCRα and TCRβ clonal markers, we showed that T cells retrieved long-term were enriched in clones originally shared in different memory T cell subsets, whereas dominant long-term clonotypes appeared to preferentially originate from infused TSCM and TCM clones. Together, these results indicate that long-term persistence of gene-modified memory T cells after haploidentical HSCT is influenced by antigen exposure and by the original phenotype of infused cells. Cancer adoptive immunotherapy might thus benefit from cellular products enriched in lymphocytes with an early-differentiated phenotype.

  7. Tracking genetically engineered lymphocytes long-term reveals the dynamics of T cell immunological memory.

    PubMed

    Oliveira, Giacomo; Ruggiero, Eliana; Stanghellini, Maria Teresa Lupo; Cieri, Nicoletta; D'Agostino, Mattia; D'Agostino, Mattio; Fronza, Raffaele; Lulay, Christina; Dionisio, Francesca; Mastaglio, Sara; Greco, Raffaella; Peccatori, Jacopo; Aiuti, Alessandro; Ambrosi, Alessandro; Biasco, Luca; Bondanza, Attilio; Lambiase, Antonio; Traversari, Catia; Vago, Luca; von Kalle, Christof; Schmidt, Manfred; Bordignon, Claudio; Ciceri, Fabio; Bonini, Chiara

    2015-12-01

    Long-lasting immune protection from pathogens and cancer requires the generation of memory T cells able to survive long-term. To unravel the immunological requirements for long-term persistence of human memory T cells, we characterized and traced, over several years, T lymphocytes genetically modified to express the thymidine kinase (TK) suicide gene that were infused in 10 patients after haploidentical hematopoietic stem cell transplantation (HSCT). At 2 to 14 years after infusion and in the presence of a broad and resting immune system, we could still detect effectors/effector memory (TEM/EFF), central memory (TCM), and stem memory (TSCM) TK(+) cells, circulating at low but stable levels in all patients. Longitudinal analysis of cytomegalovirus (CMV)- and Flu-specific TK(+) cells indicated that antigen recognition was dominant in driving in vivo expansion and persistence at detectable levels. The amount of infused TSCM cells positively correlated with early expansion and with the absolute counts of long-term persisting gene-marked cells. By combining T cell sorting with sequencing of integration (IS), TCRα and TCRβ clonal markers, we showed that T cells retrieved long-term were enriched in clones originally shared in different memory T cell subsets, whereas dominant long-term clonotypes appeared to preferentially originate from infused TSCM and TCM clones. Together, these results indicate that long-term persistence of gene-modified memory T cells after haploidentical HSCT is influenced by antigen exposure and by the original phenotype of infused cells. Cancer adoptive immunotherapy might thus benefit from cellular products enriched in lymphocytes with an early-differentiated phenotype. PMID:26659572

  8. Interleukin-2-Dependent Allergen-Specific Tissue-Resident Memory Cells Drive Asthma.

    PubMed

    Hondowicz, Brian D; An, Dowon; Schenkel, Jason M; Kim, Karen S; Steach, Holly R; Krishnamurty, Akshay T; Keitany, Gladys J; Garza, Esteban N; Fraser, Kathryn A; Moon, James J; Altemeier, William A; Masopust, David; Pepper, Marion

    2016-01-19

    Exposure to inhaled allergens generates T helper 2 (Th2) CD4(+) T cells that contribute to episodes of inflammation associated with asthma. Little is known about allergen-specific Th2 memory cells and their contribution to airway inflammation. We generated reagents to understand how endogenous CD4(+) T cells specific for a house dust mite (HDM) allergen form and function. After allergen exposure, HDM-specific memory cells persisted as central memory cells in the lymphoid organs and tissue-resident memory cells in the lung. Experimental blockade of lymphocyte migration demonstrated that lung-resident cells were sufficient to induce airway hyper-responsiveness, which depended upon CD4(+) T cells. Investigation into the differentiation of pathogenic Trm cells revealed that interleukin-2 (IL-2) signaling was required for residency and directed a program of tissue homing migrational cues. These studies thus identify IL-2-dependent resident Th2 memory cells as drivers of lung allergic responses.

  9. Clinical Characteristics of Adults Reporting Repressed, Recovered, or Continuous Memories of Childhood Sexual Abuse

    ERIC Educational Resources Information Center

    McNally, Richard J.; Perlman, Carol A.; Ristuccia, Carel S.; Clancy, Susan A.

    2006-01-01

    The authors assessed women and men who either reported continuous memories of their childhood sexual abuse (CSA, n = 92), reported recovering memories of CSA (n = 38), reported believing they harbored repressed memories of CSA (n = 42), or reported never having been sexually abused (n = 36). Men and women were indistinguishable on all clinical and…

  10. Characteristics and specificity of acquired immunologic memory to Mycobacterium tuberculosis infection

    SciTech Connect

    Orme, I.M.

    1988-05-15

    The results herein show that mice infected with Mycobacterium tuberculosis and then exposed to a protracted course of isoniazid chemotherapy possess a heightened state of acquired resistance to subsequent challenge with the homologous organism. Our results provide the first evidence, moreover, that this resistance is mediated by a long-lived, cyclophosphamide- and irradiation-resistant L3T4+ Lyt-2- lymphocyte capable of giving rise to an accelerated re-emergence of resistance in the animal upon rechallenge. Evidence is also provided to show that triggering of this memory-immune T cell population in the re-challenged host was associated with the rapid emergence of non-specific resistance to secondary bacterial infection; however, the accelerated emergence of this population was only observed if the challenge inoculum consisted of the living organism. The relevance of this latter finding to strategies for vaccine development is discussed.

  11. TLR7 and TLR9 responsive human B cells share phenotypic and genetic characteristics

    PubMed Central

    Simchoni, Noa; Cunningham-Rundles, Charlotte

    2015-01-01

    B cells activated by nucleic-acid sensing Toll-like receptor 7 and TLR9 proliferate and secrete immune globulins. Memory B cells are presumably more responsive due to higher TLR expression levels, but selectivity and differential outcomes remain largely unknown. In this study, peripheral blood human B cells were stimulated by TLR7 or TLR9 ligands, with or without IFNα, and compared to activators CD40L plus IL-21, to identify differentially responsive cell populations, defined phenotypically and by BCR characteristics. While all activators induced differentiation and antibody secretion, TLR stimulation expanded IgM+ memory and plasma cell lineage committed populations and favored secretion of IgM, unlike CD40L/IL-21 which drove IgM and IgG more evenly. Patterns of proliferation similarly differed, with CD40L/IL-21 inducing proliferation of most memory and naïve B cells, in contrast to TLRs which induced robust proliferation in a subset of these cells. On deep sequencing of the IgH locus, TLR responsive B cells shared patterns of IgHV and IgHJ usage, clustering apart from CD40L/IL-21 and control conditions. TLR activators, but not CD40L/IL-21, similarly promoted increased sharing of CDR3 sequences. TLR responsive B cells were characterized by more somatic hypermutation, shorter CDR3 segments, and less negative charges. TLR activation also induced long positively charged CDR3 segments, suggestive of autoreactive antibodies. Testing this, culture supernatants from TLR stimulated B cells were found to bind HEp-2 cells, while those from CD40L/IL-21 stimulated cells did not. Human B cells possess selective sensitivity to TLR stimulation, with distinctive phenotypic and genetic signatures. PMID:25740945

  12. Fast, memory-efficient cell location in unstructured grids for visualization.

    PubMed

    Garth, Christoph; Joy, Kenneth I

    2010-01-01

    Applying certain visualization techniques to datasets described on unstructured grids requires the interpolation of variables of interest at arbitrary locations within the dataset's domain of definition. Typical solutions to the problem of finding the grid element enclosing a given interpolation point make use of a variety of spatial subdivision schemes. However, existing solutions are memory- intensive, do not scale well to large grids, or do not work reliably on grids describing complex geometries. In this paper, we propose a data structure and associated construction algorithm for fast cell location in unstructured grids, and apply it to the interpolation problem. Based on the concept of bounding interval hierarchies, the proposed approach is memory-efficient, fast and numerically robust. We examine the performance characteristics of the proposed approach and compare it to existing approaches using a number of benchmark problems related to vector field visualization. Furthermore, we demonstrate that our approach can successfully accommodate large datasets, and discuss application to visualization on both CPUs and GPUs. PMID:20975196

  13. Fast, memory-efficient cell location in unstructured grids for visualization.

    PubMed

    Garth, Christoph; Joy, Kenneth I

    2010-01-01

    Applying certain visualization techniques to datasets described on unstructured grids requires the interpolation of variables of interest at arbitrary locations within the dataset's domain of definition. Typical solutions to the problem of finding the grid element enclosing a given interpolation point make use of a variety of spatial subdivision schemes. However, existing solutions are memory- intensive, do not scale well to large grids, or do not work reliably on grids describing complex geometries. In this paper, we propose a data structure and associated construction algorithm for fast cell location in unstructured grids, and apply it to the interpolation problem. Based on the concept of bounding interval hierarchies, the proposed approach is memory-efficient, fast and numerically robust. We examine the performance characteristics of the proposed approach and compare it to existing approaches using a number of benchmark problems related to vector field visualization. Furthermore, we demonstrate that our approach can successfully accommodate large datasets, and discuss application to visualization on both CPUs and GPUs.

  14. PLZF+ Innate T Cells Support the TGF-β-Dependent Generation of Activated/Memory-Like Regulatory T Cells

    PubMed Central

    Kang, Byung Hyun; Park, Hyo Jin; Park, Hi Jung; Lee, Jae-II; Park, Seong Hoe; Jung, Kyeong Cheon

    2016-01-01

    PLZF-expressing invariant natural killer T cells and CD4 T cells are unique subsets of innate T cells. Both are selected via thymocyte-thymocyte interaction, and they contribute to the generation of activated/memory-like CD4 and CD8 T cells in the thymus via the production of IL-4. Here, we investigated whether PLZF+ innate T cells also affect the development and function of Foxp3+ regulatory CD4 T cells. Flow cytometry analysis of the thymus and spleen from both CIITA transgenic C57BL/6 and wild-type BALB/c mice, which have abundant PLZF+ CD4 T cells and invariant natural killer T cells, respectively, revealed that Foxp3+ T cells in these mice exhibited a CD103+ activated/memory-like phenotype. The frequency of CD103+ regulatory T cells was considerably decreased in PLZF+ cell-deficient CIITATgPlzflu/lu and BALB/c.CD1d−/− mice as well as in an IL-4-deficient background, such as in CIITATgIL-4−/− and BALB/c.lL-4−/− mice, indicating that the acquisition of an activated/memory-like phenotype was dependent on PLZF+ innate T cells and IL-4. Using fetal thymic organ culture, we further demonstrated that IL-4 in concert with TGF-β enhanced the acquisition of the activated/memory-like phenotype of regulatory T cells. In functional aspects, the activated/memory-like phenotype of Treg cells was directly related to their suppressive function; regulatory T cells of CIITATgPIV−/− mice more efficiently suppressed ovalbumin-induced allergic airway inflammation compared with their counterparts from wild-type mice. All of these findings suggest that PLZF+ innate T cells also augmented the generation of activated/memory-like regulation via IL-4 production. PMID:27101876

  15. Time cells in the hippocampus: a new dimension for mapping memories.

    PubMed

    Eichenbaum, Howard

    2014-11-01

    Recent studies have revealed the existence of hippocampal neurons that fire at successive moments in temporally structured experiences. Several studies have shown that such temporal coding is not attributable to external events, specific behaviours or spatial dimensions of an experience. Instead, these cells represent the flow of time in specific memories and have therefore been dubbed 'time cells'. The firing properties of time cells parallel those of hippocampal place cells; time cells thus provide an additional dimension that is integrated with spatial mapping. The robust representation of both time and space in the hippocampus suggests a fundamental mechanism for organizing the elements of experience into coherent memories.

  16. Limited clonal relatedness between gut IgA plasma cells and memory B cells after oral immunization

    PubMed Central

    Bemark, Mats; Hazanov, Helena; Strömberg, Anneli; Komban, Rathan; Holmqvist, Joel; Köster, Sofia; Mattsson, Johan; Sikora, Per; Mehr, Ramit; Lycke, Nils Y.

    2016-01-01

    Understanding how memory B cells are induced and relate to long-lived plasma cells is important for vaccine development. Immunity to oral vaccines has been considered short-lived because of a poor ability to develop IgA B-cell memory. Here we demonstrate that long-lived mucosal IgA memory is readily achieved by oral but not systemic immunization in mouse models with NP hapten conjugated with cholera toxin and transfer of B1-8high/GFP+ NP-specific B cells. Unexpectedly, memory B cells are poorly related to long-lived plasma cells and less affinity-matured. They are α4β7-integrin+CD73+PD-L2+CD80+ and at systemic sites mostly IgM+, while 80% are IgA+ in Peyer's patches. On reactivation, most memory B cells in Peyer's patches are GL7−, but expand in germinal centres and acquire higher affinity and more mutations, demonstrating strong clonal selection. CCR9 expression is found only in Peyer's patches and appears critical for gut homing. Thus, gut mucosal memory possesses unique features not seen after systemic immunization. PMID:27596266

  17. Limited clonal relatedness between gut IgA plasma cells and memory B cells after oral immunization.

    PubMed

    Bemark, Mats; Hazanov, Helena; Strömberg, Anneli; Komban, Rathan; Holmqvist, Joel; Köster, Sofia; Mattsson, Johan; Sikora, Per; Mehr, Ramit; Lycke, Nils Y

    2016-01-01

    Understanding how memory B cells are induced and relate to long-lived plasma cells is important for vaccine development. Immunity to oral vaccines has been considered short-lived because of a poor ability to develop IgA B-cell memory. Here we demonstrate that long-lived mucosal IgA memory is readily achieved by oral but not systemic immunization in mouse models with NP hapten conjugated with cholera toxin and transfer of B1-8(high)/GFP(+) NP-specific B cells. Unexpectedly, memory B cells are poorly related to long-lived plasma cells and less affinity-matured. They are α4β7-integrin(+)CD73(+)PD-L2(+)CD80(+) and at systemic sites mostly IgM(+), while 80% are IgA(+) in Peyer's patches. On reactivation, most memory B cells in Peyer's patches are GL7(-), but expand in germinal centres and acquire higher affinity and more mutations, demonstrating strong clonal selection. CCR9 expression is found only in Peyer's patches and appears critical for gut homing. Thus, gut mucosal memory possesses unique features not seen after systemic immunization. PMID:27596266

  18. Functional classification of memory CD8(+) T cells by CX3CR1 expression.

    PubMed

    Böttcher, Jan P; Beyer, Marc; Meissner, Felix; Abdullah, Zeinab; Sander, Jil; Höchst, Bastian; Eickhoff, Sarah; Rieckmann, Jan C; Russo, Caroline; Bauer, Tanja; Flecken, Tobias; Giesen, Dominik; Engel, Daniel; Jung, Steffen; Busch, Dirk H; Protzer, Ulrike; Thimme, Robert; Mann, Matthias; Kurts, Christian; Schultze, Joachim L; Kastenmüller, Wolfgang; Knolle, Percy A

    2015-09-25

    Localization of memory CD8(+) T cells to lymphoid or peripheral tissues is believed to correlate with proliferative capacity or effector function. Here we demonstrate that the fractalkine-receptor/CX3CR1 distinguishes memory CD8(+) T cells with cytotoxic effector function from those with proliferative capacity, independent of tissue-homing properties. CX3CR1-based transcriptome and proteome-profiling defines a core signature of memory CD8(+) T cells with effector function. We find CD62L(hi)CX3CR1(+) memory T cells that reside within lymph nodes. This population shows distinct migration patterns and positioning in proximity to pathogen entry sites. Virus-specific CX3CR1(+) memory CD8(+) T cells are scarce during chronic infection in humans and mice but increase when infection is controlled spontaneously or by therapeutic intervention. This CX3CR1-based functional classification will help to resolve the principles of protective CD8(+) T-cell memory.

  19. Shortened Intervals during Heterologous Boosting Preserve Memory CD8 T Cell Function but Compromise Longevity.

    PubMed

    Thompson, Emily A; Beura, Lalit K; Nelson, Christine E; Anderson, Kristin G; Vezys, Vaiva

    2016-04-01

    Developing vaccine strategies to generate high numbers of Ag-specific CD8 T cells may be necessary for protection against recalcitrant pathogens. Heterologous prime-boost-boost immunization has been shown to result in large quantities of functional memory CD8 T cells with protective capacities and long-term stability. Completing the serial immunization steps for heterologous prime-boost-boost can be lengthy, leaving the host vulnerable for an extensive period of time during the vaccination process. We show in this study that shortening the intervals between boosting events to 2 wk results in high numbers of functional and protective Ag-specific CD8 T cells. This protection is comparable to that achieved with long-term boosting intervals. Short-boosted Ag-specific CD8 T cells display a canonical memory T cell signature associated with long-lived memory and have identical proliferative potential to long-boosted T cells Both populations robustly respond to antigenic re-exposure. Despite this, short-boosted Ag-specific CD8 T cells continue to contract gradually over time, which correlates to metabolic differences between short- and long-boosted CD8 T cells at early memory time points. Our studies indicate that shortening the interval between boosts can yield abundant, functional Ag-specific CD8 T cells that are poised for immediate protection; however, this is at the expense of forming stable long-term memory. PMID:26903479

  20. Target morphology and cell memory: a model of regenerative pattern formation.

    PubMed

    Bessonov, Nikolai; Levin, Michael; Morozova, Nadya; Reinberg, Natalia; Tosenberger, Alen; Volpert, Vitaly

    2015-12-01

    Despite the growing body of work on molecular components required for regenerative repair, we still lack a deep understanding of the ability of some animal species to regenerate their appropriate complex anatomical structure following damage. A key question is how regenerating systems know when to stop growth and remodeling - what mechanisms implement recognition of correct morphology that signals a stop condition? In this work, we review two conceptual models of pattern regeneration that implement a kind of pattern memory. In the first one, all cells communicate with each other and keep the value of the total signal received from the other cells. If a part of the pattern is amputated, the signal distribution changes. The difference fromthe original signal distribution stimulates cell proliferation and leads to pattern regeneration, in effect implementing an error minimization process that uses signaling memory to achieve pattern correction. In the second model, we consider a more complex pattern organization with different cell types. Each tissue contains a central (coordinator) cell that controls the tissue and communicates with the other central cells. Each of them keeps memory about the signals received from other central cells. The values of these signals depend on the mutual cell location, and the memory allows regeneration of the structure when it is modified. The purpose of these models is to suggest possible mechanisms of pattern regeneration operating on the basis of cell memory which are compatible with diverse molecular implementation mechanisms within specific organisms. PMID:26889161

  1. Target morphology and cell memory: a model of regenerative pattern formation

    PubMed Central

    Bessonov, Nikolai; Levin, Michael; Morozova, Nadya; Reinberg, Natalia; Tosenberger, Alen; Volpert, Vitaly

    2015-01-01

    Despite the growing body of work on molecular components required for regenerative repair, we still lack a deep understanding of the ability of some animal species to regenerate their appropriate complex anatomical structure following damage. A key question is how regenerating systems know when to stop growth and remodeling – what mechanisms implement recognition of correct morphology that signals a stop condition? In this work, we review two conceptual models of pattern regeneration that implement a kind of pattern memory. In the first one, all cells communicate with each other and keep the value of the total signal received from the other cells. If a part of the pattern is amputated, the signal distribution changes. The difference fromthe original signal distribution stimulates cell proliferation and leads to pattern regeneration, in effect implementing an error minimization process that uses signaling memory to achieve pattern correction. In the second model, we consider a more complex pattern organization with different cell types. Each tissue contains a central (coordinator) cell that controls the tissue and communicates with the other central cells. Each of them keeps memory about the signals received from other central cells. The values of these signals depend on the mutual cell location, and the memory allows regeneration of the structure when it is modified. The purpose of these models is to suggest possible mechanisms of pattern regeneration operating on the basis of cell memory which are compatible with diverse molecular implementation mechanisms within specific organisms. PMID:26889161

  2. Effects of drying temperature and ethanol concentration on bipolar switching characteristics of natural Aloe vera-based memory devices.

    PubMed

    Lim, Zhe Xi; Cheong, Kuan Yew

    2015-10-28

    Extracted, formulated, and processed natural Aloe vera has been used as an active layer for memory applications. The functional memory device is realized by a bottom-up structure of ITO/Aloe vera/Al in which the Aloe vera is spin-coated after mixing with different concentrations of ethanol (0-80 wt%) and subsequently dried at different temperatures (50-120 °C). From the current density-voltage measurements, the device can exhibit a reproducible bipolar switching characteristic with pure Aloe vera dried at 50 °C. It is proposed that charges are transported across the Aloe vera layer via space-charge-limited conduction (SCLC), and clusters of interstitial space formed by the functional groups of acemannans and de-esterified pectins in the dried Aloe vera contribute to the memory effect. The formation of charge traps in the Aloe vera layer is dependent on the drying temperature. The drying temperature of a memory-switching Aloe vera layer can be extended to 120 °C with the addition of appropriate amounts of ethanol. The concept of using natural Aloe vera as an active material for memory applications has been demonstrated, and the read memory window, ON/OFF ratio, and retention time are approximately 5.0 V, 10(3), and >10(4) s, respectively. PMID:26400096

  3. Effects of drying temperature and ethanol concentration on bipolar switching characteristics of natural Aloe vera-based memory devices.

    PubMed

    Lim, Zhe Xi; Cheong, Kuan Yew

    2015-10-28

    Extracted, formulated, and processed natural Aloe vera has been used as an active layer for memory applications. The functional memory device is realized by a bottom-up structure of ITO/Aloe vera/Al in which the Aloe vera is spin-coated after mixing with different concentrations of ethanol (0-80 wt%) and subsequently dried at different temperatures (50-120 °C). From the current density-voltage measurements, the device can exhibit a reproducible bipolar switching characteristic with pure Aloe vera dried at 50 °C. It is proposed that charges are transported across the Aloe vera layer via space-charge-limited conduction (SCLC), and clusters of interstitial space formed by the functional groups of acemannans and de-esterified pectins in the dried Aloe vera contribute to the memory effect. The formation of charge traps in the Aloe vera layer is dependent on the drying temperature. The drying temperature of a memory-switching Aloe vera layer can be extended to 120 °C with the addition of appropriate amounts of ethanol. The concept of using natural Aloe vera as an active material for memory applications has been demonstrated, and the read memory window, ON/OFF ratio, and retention time are approximately 5.0 V, 10(3), and >10(4) s, respectively.

  4. Distinct effects of saracatinib on memory CD8+ T cell differentiation.

    PubMed

    Takai, Shinji; Sabzevari, Helen; Farsaci, Benedetto; Schlom, Jeffrey; Greiner, John W

    2012-05-01

    Immunologic memory involving CD8(+) T cells is a hallmark of an adaptive Ag-specific immune response and constitutes a critical component of protective immunity. Designing approaches that enhance long-term T cell memory would, for the most part, fortify vaccines and enhance host protection against infectious diseases and, perhaps, cancer immunotherapy. A better understanding of the cellular programs involved in the Ag-specific T cell response has led to new approaches that target the magnitude and quality of the memory T cell response. In this article, we show that T cells from TCR transgenic mice for the nucleoprotein of influenza virus NP68 exhibit the distinct phases--priming, expansion, contraction, and memory--of an Ag-specific T cell response when exposed in vitro to the cognate peptide. Saracatinib, a specific inhibitor of Src family kinases, administered at low doses during the expansion or contraction phases, increased CD62L(high)/CD44(high) central memory CD8(+) T cells and IFN-γ production but suppressed immunity when added during the priming phase. These effects by saracatinib were not accompanied by the expected decline of Src family kinases but were accompanied by Akt-mammalian target of rapamycin suppression and/or mediated via another pathway. Increased central memory cells by saracatinib were recapitulated in mice using a poxvirus-based influenza vaccine, thus underscoring the importance of dose and timing of the inhibitor in the context of memory T cell differentiation. Finally, vaccine plus saracatinib treatment showed better protection against tumor challenge. The immune-potentiating effects on CD8(+) T cells by a low dose of saracatinib might afford better protection from pathogens or cancer when combined with vaccine.

  5. Exercise training increases the näive to memory T cell ratio in old mice.

    PubMed

    Woods, J A; Ceddia, M A; Zack, M D; Lowder, T W; Lu, Q

    2003-10-01

    Aging is associated with changes in T cells including involution of the thymus gland and an imbalance in the proportion of näive (CD44lo) and memory (CD44hi) T cells in the periphery. Reversal of these changes may improve immunity in the aged. We sought to determine whether 4 months of moderately intense treadmill running (EXC; 5 days/week, 45 min/day, 13-22 m/min) in 2 month (Y) and 18 month (O) old male Balb/c mice would alter T lymphocyte profiles in the thymus and spleen when compared to sedentary controls (CON). Splenocytes and thymocytes were harvested 24-48 h after the last exercise session and analyzed using immunofluorescence and flow cytometry. While there were significant age-related changes (lower cell number, altered subsets) in the thymuses of O when compared to Y mice, exercise training failed to affect any of these measures in mice of either age. Aged mice exhibited a significantly (p < .05) higher percentage of splenic memory cells and a lower percentage of näive cells in both the CD4 and CD8 T cell subsets. Interestingly, exercise training significantly (p < .05) increased the percentage of näive and decreased the percentage of memory cells in both the CD4+ (69.6+/-1.7% näive and 30.4+/-1.7% memory for OCON vs. 75.0+/-1.5% näive and 25.0+/-1.5% memory in OEXC) and CD8+ (60.0+/-2.6% näive and 40.0+/-2.6% memory in OCON vs. 76.7+/-2.7% näive and 23.3+/-2.7% memory in OEXC) T cells subsets in O, but not Y, mice. This effect was due to a decrease in the absolute number of memory cells and not an increase in the absolute number of näive cells. We conclude that 4 months of EXC has little restorative effect on the thymus in aged mice, but can restore the percentages of näive and memory cells in the spleen towards that of young mice, perhaps due to removal of memory cells.

  6. Remembering one's ID/E-ntity: E/ID protein regulation of T cell memory.

    PubMed

    Omilusik, Kyla D; Shaw, Laura A; Goldrath, Ananda W

    2013-10-01

    Upon infection, CD8(+) T cells proliferate and differentiate into armed effector cells capable of eliminating the assaulting pathogen. Although the majority of the antigen-specific T cells will die as the immune response wanes, a few will survive indefinitely to establish the memory population and provide long-lived protection against reinfection. E protein transcription factors and their inhibitors, ID proteins, operate to balance expression of genes that control CD8(+) T cell differentiation through this process. Here, we discuss the role of ID2 and ID3 in promoting the generation and survival of effector and memory populations, particularly highlighting their reciprocal roles in shaping the CD8(+) T cell response unique to the inflammatory milieu. We further examine this coordinated control of gene expression in the context of additional transcription factors within the transcriptional network that programs CD8(+) effector and memory T cell differentiation.

  7. Nature of "memory" in T-cell-mediated antibacterial immunity: anamnestic production of mediator T cells.

    PubMed Central

    North, R J

    1975-01-01

    Mice that survived an immunizing infection with Listeria monocytogenes remained specifically resistant to lethal secondary infection for several months. This acquired, long-lived state of resistance was not dependent on activated macrophages that remained after the primary response. It depended, instead, on an acquired long-lived capacity on the part of immunized mice for generating mediator T cells faster and in larger numbers than normal mice. The number of mediator T cells generated in response to secondary infection was proportional to the level of infection. The results suggest that the accelerated production of mediator T cells that occurs in response to secondary infection represents the expression of a state of immunological T-cell memory. PMID:811558

  8. Two CMOS memory cells suitable for the design of SEU-tolerant VLSI circuits

    SciTech Connect

    Velazco, R.; Bessot, D. ); Duzellier, S. ); Ecoffet, R. ); Koga, R. )

    1994-12-01

    Two new CMOS memory cells, called HIT cells, designed to be SEU-immune are presented. Compared to previously reported design hardened solutions, the HIT cells feature better electrical performances and consume less silicon area. SEU tests performed on a prototype chip prove the efficiency of the approach.

  9. Distinct dendritic cell subsets dictate the fate decision between effector and memory CD8(+) T cell differentiation by a CD24-dependent mechanism.

    PubMed

    Kim, Taeg S; Gorski, Stacey A; Hahn, Steven; Murphy, Kenneth M; Braciale, Thomas J

    2014-03-20

    The contribution of different DC subsets to effector and memory CD8(+) T cell generation during infection and the mechanism by which DCs controls these fate decisions is unclear. Here we demonstrated that the CD103(+) and CD11b(hi) migratory respiratory DC (RDC) subsets after influenza virus infection activated naive virus-specific CD8(+) T cells differentially. CD103(+) RDCs supported the generation of CD8(+) T effector (Teff) cells, which migrate from lymph nodes to the infected lungs. In contrast, migrant CD11b(hi) RDCs activated CD8(+) T cells characteristic of central memory CD8(+) T (CD8(+) Tcm) cells including retention within the draining lymph nodes. CD103(+) RDCs expressed CD24 at an elevated level, contributing to the propensity of this DC subpopulation to support CD8(+) Teff cell differentiation. Mechanistically, CD24 was shown to regulate CD8(+) T cell activation through HMGB1-mediated engagement of T cell RAGE. Thus, there is distribution of labor among DC subsets in regulating CD8(+) T cell differentiation.

  10. Effect of electrode material on characteristics of non-volatile resistive memory consisting of Ag2S nanoparticles

    NASA Astrophysics Data System (ADS)

    Jang, Jaewon

    2016-07-01

    In this study, Ag2S nanoparticles are synthesized and used as the active material for two-terminal resistance switching memory devices. Sintered Ag2S films are successfully crystallized on plastic substrates with synthesized Ag2S nanoparticles, after a relatively low-temperature sintering process (200 °C). After the sintering process, the crystallite size is increased from 6.8 nm to 80.3 nm. The high ratio of surface atoms to inner atoms of nanoparticles reduces the melting point temperature, deciding the sintering process temperature. In order to investigate the resistance switching characteristics, metal/Ag2S/metal structures are fabricated and tested. The effect of the electrode material on the non-volatile resistive memory characteristics is studied. The bottom electrochemically inert materials, such as Au and Pt, were critical for maintaining stable memory characteristics. By using Au and Pt inert bottom electrodes, we are able to significantly improve the memory endurance and retention to more than 103 cycles and 104 sec, respectively.

  11. The transcriptional regulators Id2 and Id3 control the formation of distinct memory CD8+ T cell subsets.

    PubMed

    Yang, Cliff Y; Best, J Adam; Knell, Jamie; Yang, Edward; Sheridan, Alison D; Jesionek, Adam K; Li, Haiyan S; Rivera, Richard R; Lind, Kristin Camfield; D'Cruz, Louise M; Watowich, Stephanie S; Murre, Cornelis; Goldrath, Ananda W

    2011-11-06

    During infection, naive CD8(+) T cells differentiate into effector cells, which are armed to eliminate pathogens, and memory cells, which are poised to protect against reinfection. The transcriptional program that regulates terminal differentiation into short-lived effector-memory versus long-lived memory cells is not clearly defined. Through the use of mice expressing reporters for the DNA-binding inhibitors Id2 and Id3, we identified Id3(hi) precursors of long-lived memory cells before the peak of T cell population expansion or upregulation of cell-surface receptors that indicate memory potential. Deficiency in Id2 or Id3 resulted in loss of distinct CD8(+) effector and memory populations, which demonstrated unique roles for these inhibitors of E-protein transcription factors. Furthermore, cytokines altered the expression of Id2 and Id3 differently, which provides insight into how external cues influence gene expression.

  12. Time cells in the hippocampus: a new dimension for mapping memories

    PubMed Central

    Eichenbaum, Howard

    2015-01-01

    Recent studies have revealed the existence of hippocampal neurons that fire at successive moments in temporally structured experiences. Several studies have shown that such temporal coding is not attributable to external events, specific behaviours or spatial dimensions of an experience. Instead, these cells represent the flow of time in specific memories and have therefore been dubbed ‘time cells’. The firing properties of time cells parallel those of hippocampal place cells; time cells thus provide an additional dimension that is integrated with spatial mapping. The robust representation of both time and space in the hippocampus suggests a fundamental mechanism for organizing the elements of experience into coherent memories. PMID:25269553

  13. Memory T cell–driven differentiation of naive cells impairs adoptive immunotherapy

    PubMed Central

    Klebanoff, Christopher A.; Scott, Christopher D.; Leonardi, Anthony J.; Yamamoto, Tori N.; Cruz, Anthony C.; Ouyang, Claudia; Ramaswamy, Madhu; Roychoudhuri, Rahul; Ji, Yun; Eil, Robert L.; Sukumar, Madhusudhanan; Crompton, Joseph G.; Palmer, Douglas C.; Borman, Zachary A.; Clever, David; Thomas, Stacy K.; Patel, Shashankkumar; Yu, Zhiya; Muranski, Pawel; Liu, Hui; Wang, Ena; Marincola, Francesco M.; Gros, Alena; Gattinoni, Luca; Rosenberg, Steven A.; Siegel, Richard M.; Restifo, Nicholas P.

    2015-01-01

    Adoptive cell transfer (ACT) of purified naive, stem cell memory, and central memory T cell subsets results in superior persistence and antitumor immunity compared with ACT of populations containing more-differentiated effector memory and effector T cells. Despite a clear advantage of the less-differentiated populations, the majority of ACT trials utilize unfractionated T cell subsets. Here, we have challenged the notion that the mere presence of less-differentiated T cells in starting populations used to generate therapeutic T cells is sufficient to convey their desirable attributes. Using both mouse and human cells, we identified a T cell–T cell interaction whereby antigen-experienced subsets directly promote the phenotypic, functional, and metabolic differentiation of naive T cells. This process led to the loss of less-differentiated T cell subsets and resulted in impaired cellular persistence and tumor regression in mouse models following ACT. The T memory–induced conversion of naive T cells was mediated by a nonapoptotic Fas signal, resulting in Akt-driven cellular differentiation. Thus, induction of Fas signaling enhanced T cell differentiation and impaired antitumor immunity, while Fas signaling blockade preserved the antitumor efficacy of naive cells within mixed populations. These findings reveal that T cell subsets can synchronize their differentiation state in a process similar to quorum sensing in unicellular organisms and suggest that disruption of this quorum-like behavior among T cells has potential to enhance T cell–based immunotherapies. PMID:26657860

  14. Altered Memory Circulating T Follicular Helper-B Cell Interaction in Early Acute HIV Infection

    PubMed Central

    Muir, Roshell; Metcalf, Talibah; Tardif, Virginie; Takata, Hiroshi; Phanuphak, Nittaya; Kroon, Eugene; Colby, Donn J.; Trichavaroj, Rapee; Valcour, Victor; Robb, Merlin L.; Michael, Nelson L.; Ananworanich, Jintanat; Trautmann, Lydie; Haddad, Elias K.

    2016-01-01

    The RV254 cohort of HIV-infected very early acute (4thG stage 1 and 2) (stage 1/2) and late acute (4thG stage 3) (stage 3) individuals was used to study T helper- B cell responses in acute HIV infection and the impact of early antiretroviral treatment (ART) on T and B cell function. To investigate this, the function of circulating T follicular helper cells (cTfh) from this cohort was examined, and cTfh and memory B cell populations were phenotyped. Impaired cTfh cell function was observed in individuals treated in stage 3 when compared to stage 1/2. The cTfh/B cell cocultures showed lower B cell survival and IgG secretion at stage 3 compared to stage 1/2. This coincided with lower IL-10 and increased RANTES and TNF-α suggesting a role for inflammation in altering cTfh and B cell responses. Elevated plasma viral load in stage 3 was found to correlate with decreased cTfh-mediated B cell IgG production indicating a role for increased viremia in cTfh impairment and dysfunctional humoral response. Phenotypic perturbations were also evident in the mature B cell compartment, most notably a decrease in resting memory B cells in stage 3 compared to stage 1/2, coinciding with higher viremia. Our coculture assay also suggested that intrinsic memory B cell defects could contribute to the impaired response despite at a lower level. Overall, cTfh-mediated B cell responses are significantly altered in stage 3 compared to stage 1/2, coinciding with increased inflammation and a reduction in memory B cells. These data suggest that early ART for acutely HIV infected individuals could prevent immune dysregulation while preserving cTfh function and B cell memory. PMID:27463374

  15. Sustained CD8+ T cell memory inflation after infection with a single-cycle cytomegalovirus.

    PubMed

    Snyder, Christopher M; Cho, Kathy S; Bonnett, Elizabeth L; Allan, Jane E; Hill, Ann B

    2011-10-01

    Cytomegalovirus (CMV) is a β-herpesvirus that establishes a lifelong latent or persistent infection. A hallmark of chronic CMV infection is the lifelong persistence of large numbers of virus-specific CD8+ effector/effector memory T cells, a phenomenon called "memory inflation". How the virus continuously stimulates these T cells without being eradicated remains an enigma. The prevailing view is that CMV establishes a low grade "smoldering" infection characterized by tiny bursts of productive infection which are rapidly extinguished, leaving no detectable virus but replenishing the latent pool and leaving the immune system in a highly charged state. However, since abortive reactivation with limited viral gene expression is known to occur commonly, we investigated the necessity for virus reproduction in maintaining the inflationary T cell pool. We inhibited viral replication or spread in vivo using two different mutants of murine CMV (MCMV). First, famcyclovir blocked the replication of MCMV encoding the HSV Thymidine Kinase gene, but had no impact on the CD8+ T cell memory inflation once the infection was established. Second, MCMV that lacks the essential glycoprotein L, and thus is completely unable to spread from cell to cell, also drove memory inflation if the virus was administered systemically. Our data suggest that CMV which cannot spread from the cells it initially infects can repeatedly generate viral antigens to drive memory inflation without suffering eradication of the latent genome pool. PMID:21998590

  16. Memory T cell subsets in tuberculosis: what should we be targeting?

    PubMed

    Henao-Tamayo, Marcela; Ordway, Diane J; Orme, Ian M

    2014-09-01

    The purpose of vaccination is to establish a stable population of long lived memory T cells. In the context of tuberculosis, the BCG vaccine has been widely used for well over 60 years, but during that time its weaknesses, particularly its ineffectiveness in adults, has been increasingly recognized. In this commentary we review what is known about memory T cells, both in general and in the context of their role in expressing specific acquired resistance to tuberculosis. Current knowledge indicates that both effector memory and central memory can be generated, depending on the experimental conditions, but both in animal models and in clinical studies it is clear that effector memory T cells are the predominant subset. These issues are of importance, given the concerted effort to make new TB vaccines, not all of which may work in precisely the same manner. At the present time whether a TB vaccine would work better if it targeted one specific T cell subset rather than another is as yet completely unknown, and this is now further complicated by new evidence that suggests other subsets such as IL-17 secreting CD4 T cells and cells with stem cell-like qualities may also play important roles.

  17. CD27 stimulation promotes the frequency of IL-7R expressing memory precursors and prevents IL-12 mediated loss of CD8+ T cell memory in the absence of CD4+ T cell help

    PubMed Central

    Dong, Han; Franklin, Nathan. A.; Roberts, Drew J.; Yagita, Hideo; Glennie, Martin J.; Bullock, Timothy N.J.

    2012-01-01

    Fully functional CD8+ T cell memory is highly dependent upon CD4+ T cell support. CD4+ T cells play a critical role in inducing the expression of CD70, the ligand for CD27, on dendritic cells. Here we demonstrate that CD27 stimulation during primary CD8+ T cell responses regulates the ability to mount secondary CD8+ T cell responses. CD27 stimulation during vaccinia and dendritic cell immunization controls the expression of the IL-7 receptor (CD127), which has been shown to be necessary for memory CD8+ T cell survival. Further, CD27 stimulation during primary CD8+ T cell responses to vaccinia virus restrained the late expression on memory precursor cells of cytokine receptors that support terminal differentiation. The formation of CD8+ T cell memory precursors and secondary CD8+ T cell responses were restored in the absence of CD27 costimulation when endogenous IL-12 was not available. Similarly, the lesion in CD8+ T cell memory that occurs in the absence ofCD4+ T cells did not occur in mice lacking IL-12. These data indicate that CD4+ T cell help and, by extension, CD27 stimulation supports CD8+ T cell memory by modulating the expression of cytokine receptors that influence the differentiation and survival of memory CD8+ T cells. PMID:22422886

  18. Brain-resident memory T cells represent an autonomous cytotoxic barrier to viral infection.

    PubMed

    Steinbach, Karin; Vincenti, Ilena; Kreutzfeldt, Mario; Page, Nicolas; Muschaweckh, Andreas; Wagner, Ingrid; Drexler, Ingo; Pinschewer, Daniel; Korn, Thomas; Merkler, Doron

    2016-07-25

    Tissue-resident memory T cells (TRM) persist at sites of prior infection and have been shown to enhance pathogen clearance by recruiting circulating immune cells and providing bystander activation. Here, we characterize the functioning of brain-resident memory T cells (bTRM) in an animal model of viral infection. bTRM were subject to spontaneous homeostatic proliferation and were largely refractory to systemic immune cell depletion. After viral reinfection in mice, bTRM rapidly acquired cytotoxic effector function and prevented fatal brain infection, even in the absence of circulating CD8(+) memory T cells. Presentation of cognate antigen on MHC-I was essential for bTRM-mediated protective immunity, which involved perforin- and IFN-γ-dependent effector mechanisms. These findings identify bTRM as an organ-autonomous defense system serving as a paradigm for TRM functioning as a self-sufficient first line of adaptive immunity. PMID:27377586

  19. Epidermal Fatty Acid Binding Protein (E-FABP) Is Not Required for the Generation or Maintenance of Effector and Memory T Cells following Infection with Listeria monocytogenes.

    PubMed

    Li, Bing; Schmidt, Nathan W

    2016-01-01

    Following activation of naïve T cells there are dynamic changes in the metabolic pathways used by T cells to support both the energetic needs of the cell and the macromolecules required for growth and proliferation. Among other changes, lipid metabolism undergoes dynamic transitions between fatty acid oxidation and fatty acid synthesis as cells progress from naïve to effector and effector to memory T cells. The hydrophobic nature of lipids requires that they be bound to protein chaperones within a cell. Fatty acid binding proteins (FABPs) represent a large class of lipid chaperones, with epidermal FABP (E-FABP) expressed in T cells. The objective of this study was to determine the contribution of E-FABP in antigen-specific T cell responses. Following infection with Listeria monocytogenes, we observed similar clonal expansion, contraction and formation of memory CD8 T cells in WT and E-FABP-/- mice, which also exhibited similar phenotypic and functional characteristics. Analysis of Listeria-specific CD4 T cells also revealed no defect in the expansion, contraction, and formation of memory CD4 T cells in E-FABP-/- mice. These data demonstrate that E-FABP is dispensable for antigen-specific T cell responses following a bacterial infection. PMID:27588422

  20. Epidermal Fatty Acid Binding Protein (E-FABP) Is Not Required for the Generation or Maintenance of Effector and Memory T Cells following Infection with Listeria monocytogenes

    PubMed Central

    Li, Bing; Schmidt, Nathan W.

    2016-01-01

    Following activation of naïve T cells there are dynamic changes in the metabolic pathways used by T cells to support both the energetic needs of the cell and the macromolecules required for growth and proliferation. Among other changes, lipid metabolism undergoes dynamic transitions between fatty acid oxidation and fatty acid synthesis as cells progress from naïve to effector and effector to memory T cells. The hydrophobic nature of lipids requires that they be bound to protein chaperones within a cell. Fatty acid binding proteins (FABPs) represent a large class of lipid chaperones, with epidermal FABP (E-FABP) expressed in T cells. The objective of this study was to determine the contribution of E-FABP in antigen-specific T cell responses. Following infection with Listeria monocytogenes, we observed similar clonal expansion, contraction and formation of memory CD8 T cells in WT and E-FABP-/- mice, which also exhibited similar phenotypic and functional characteristics. Analysis of Listeria-specific CD4 T cells also revealed no defect in the expansion, contraction, and formation of memory CD4 T cells in E-FABP-/- mice. These data demonstrate that E-FABP is dispensable for antigen-specific T cell responses following a bacterial infection. PMID:27588422

  1. Oct1 and OCA-B are selectively required for CD4 memory T cell function.

    PubMed

    Shakya, Arvind; Goren, Alon; Shalek, Alex; German, Cody N; Snook, Jeremy; Kuchroo, Vijay K; Yosef, Nir; Chan, Raymond C; Regev, Aviv; Williams, Matthew A; Tantin, Dean

    2015-11-16

    Epigenetic changes are crucial for the generation of immunological memory. Failure to generate or maintain these changes will result in poor memory responses. Similarly, augmenting or stabilizing the correct epigenetic states offers a potential method of enhancing memory. Yet the transcription factors that regulate these processes are poorly defined. We find that the transcription factor Oct1 and its cofactor OCA-B are selectively required for the in vivo generation of CD4(+) memory T cells. More importantly, the memory cells that are formed do not respond properly to antigen reencounter. In vitro, both proteins are required to maintain a poised state at the Il2 target locus in resting but previously stimulated CD4(+) T cells. OCA-B is also required for the robust reexpression of multiple other genes including Ifng. ChIPseq identifies ∼50 differentially expressed direct Oct1 and OCA-B targets. We identify an underlying mechanism involving OCA-B recruitment of the histone lysine demethylase Jmjd1a to targets such as Il2, Ifng, and Zbtb32. The findings pinpoint Oct1 and OCA-B as central mediators of CD4(+) T cell memory.

  2. Oct1 and OCA-B are selectively required for CD4 memory T cell function

    PubMed Central

    Shakya, Arvind; Goren, Alon; Shalek, Alex; German, Cody N.; Snook, Jeremy; Kuchroo, Vijay K.; Yosef, Nir; Chan, Raymond C.; Regev, Aviv

    2015-01-01

    Epigenetic changes are crucial for the generation of immunological memory. Failure to generate or maintain these changes will result in poor memory responses. Similarly, augmenting or stabilizing the correct epigenetic states offers a potential method of enhancing memory. Yet the transcription factors that regulate these processes are poorly defined. We find that the transcription factor Oct1 and its cofactor OCA-B are selectively required for the in vivo generation of CD4+ memory T cells. More importantly, the memory cells that are formed do not respond properly to antigen reencounter. In vitro, both proteins are required to maintain a poised state at the Il2 target locus in resting but previously stimulated CD4+ T cells. OCA-B is also required for the robust reexpression of multiple other genes including Ifng. ChIPseq identifies ∼50 differentially expressed direct Oct1 and OCA-B targets. We identify an underlying mechanism involving OCA-B recruitment of the histone lysine demethylase Jmjd1a to targets such as Il2, Ifng, and Zbtb32. The findings pinpoint Oct1 and OCA-B as central mediators of CD4+ T cell memory. PMID:26481684

  3. Do negative affect characteristics and subjective memory concerns increase risk for late life anxiety?

    PubMed

    Wilkes, Chelsey M; Wilson, Helen W; Woodard, John L; Calamari, John E

    2013-08-01

    To better understand the development and exacerbation of late-life anxiety, we tested a risk model positing that trait negative affect (NA) characteristics would interact with cognitive functioning, thereby increasing some older adults' risk for increased anxiety symptoms. The moderator-mediator model consisted of measures of NA, cognitive functioning, and their interaction, as predictors of later Hamilton Anxiety Rating Scale scores (HARS) via a mediational process, subjective memory concerns (SMCs). Older adults (aged 65-years and over; M(age)=76.7 years, SD=6.90 years) completed evaluations four times over approximately 18 months. A latent growth curve model including Anxiety Sensitivity Index total score (ASI), Mattis Dementia Rating Scale-2 (DRS) total raw score, the ASI×DRS interaction, a SMC measure as mediator, HARS intercept (scores at times 3 and 4), and HARS slope provided good fit. The ASI×DRS-2 interaction at Time 1 predicted HARS slope score (β=-.34, p<.05). When ASI score was high, stronger cognitive functioning was associated with fewer anxiety symptoms. The indirect effect of ASI score predicting HARS score 18-months later through the SMC mediator was statistically significant (β=.08, p<.05). Results suggest that the cognitive functioning changes associated with aging might contribute to the development of anxiety symptoms in older adults with specific NA traits. Implications for predicting and preventing late life anxiety disorders are discussed.

  4. A zero density change phase change memory material: GeTe-O structural characteristics upon crystallisation

    PubMed Central

    Zhou, Xilin; Dong, Weiling; Zhang, Hao; Simpson, Robert E.

    2015-01-01

    Oxygen-doped germanium telluride phase change materials are proposed for high temperature applications. Up to 8 at.% oxygen is readily incorporated into GeTe, causing an increased crystallisation temperature and activation energy. The rhombohedral structure of the GeTe crystal is preserved in the oxygen doped films. For higher oxygen concentrations the material is found to phase separate into GeO2 and TeO2, which inhibits the technologically useful abrupt change in properties. Increasing the oxygen content in GeTe-O reduces the difference in film thickness and mass density between the amorphous and crystalline states. For oxygen concentrations between 5 and 6 at.%, the amorphous material and the crystalline material have the same density. Above 6 at.% O doping, crystallisation exhibits an anomalous density change, where the volume of the crystalline state is larger than that of the amorphous. The high thermal stability and zero-density change characteristic of Oxygen-incorporated GeTe, is recommended for efficient and low stress phase change memory devices that may operate at elevated temperatures. PMID:26068587

  5. Rheumatoid arthritis-associated RBPJ polymorphism alters memory CD4+ T cells.

    PubMed

    Orent, William; Mchenry, Allison R; Rao, Deepak A; White, Charles; Klein, Hans-Ulrich; Bassil, Ribal; Srivastava, Gyan; Replogle, Joseph M; Raj, Towfique; Frangieh, Michael; Cimpean, Maria; Cuerdon, Nicole; Chibnik, Lori; Khoury, Samia J; Karlson, Elizabeth W; Brenner, Michael B; De Jager, Philip; Bradshaw, Elizabeth M; Elyaman, Wassim

    2016-01-15

    Notch signaling has recently emerged as an important regulator of immune responses in autoimmune diseases. The recombination signal-binding protein for immunoglobulin kappa J region (RBPJ) is a transcriptional repressor, but converts into a transcriptional activator upon activation of the canonical Notch pathway. Genome-wide association studies of rheumatoid arthritis (RA) identified a susceptibility locus, rs874040(CC), which implicated the RBPJ gene. Here, chromatin state mapping generated using the chromHMM algorithm reveals strong enhancer regions containing DNase I hypersensitive sites overlapping the rs874040 linkage disequilibrium block in human memory, but not in naïve CD4(+) T cells. The rs874040 overlapping this chromatin state was associated with increased RBPJ expression in stimulated memory CD4(+) T cells from healthy subjects homozygous for the risk allele (CC) compared with memory CD4(+) T cells bearing the protective allele (GG). Transcriptomic analysis of rs874040(CC) memory T cells showed a repression of canonical Notch target genes IL (interleukin)-9, IL-17 and interferon (IFN)γ in the basal state. Interestingly, activation of the Notch pathway using soluble Notch ligand, Jagged2-Fc, induced IL-9 and IL-17A while delta-like 4Fc, another Notch ligand, induced higher IFNγ expression in the rs874040(CC) memory CD4(+) T cells compared with their rs874040(GG) counterparts. In RA, RBPJ expression is elevated in memory T cells from RA patients compared with control subjects, and this was associated with induced inflammatory cytokines IL-9, IL-17A and IFNγ in response to Notch ligation in vitro. These findings demonstrate that the rs874040(CC) allele skews memory T cells toward a pro-inflammatory phenotype involving Notch signaling, thus increasing the susceptibility to develop RA. PMID:26604133

  6. Dopaminergic neurons write and update memories with cell-type-specific rules

    PubMed Central

    Aso, Yoshinori; Rubin, Gerald M

    2016-01-01

    Associative learning is thought to involve parallel and distributed mechanisms of memory formation and storage. In Drosophila, the mushroom body (MB) is the major site of associative odor memory formation. Previously we described the anatomy of the adult MB and defined 20 types of dopaminergic neurons (DANs) that each innervate distinct MB compartments (Aso et al., 2014a, 2014b). Here we compare the properties of memories formed by optogenetic activation of individual DAN cell types. We found extensive differences in training requirements for memory formation, decay dynamics, storage capacity and flexibility to learn new associations. Even a single DAN cell type can either write or reduce an aversive memory, or write an appetitive memory, depending on when it is activated relative to odor delivery. Our results show that different learning rules are executed in seemingly parallel memory systems, providing multiple distinct circuit-based strategies to predict future events from past experiences. DOI: http://dx.doi.org/10.7554/eLife.16135.001 PMID:27441388

  7. How do spatial learning and memory occur in the brain? Coordinated learning of entorhinal grid cells and hippocampal place cells.

    PubMed

    Pilly, Praveen K; Grossberg, Stephen

    2012-05-01

    Spatial learning and memory are important for navigation and formation of episodic memories. The hippocampus and medial entorhinal cortex (MEC) are key brain areas for spatial learning and memory. Place cells in hippocampus fire whenever an animal is located in a specific region in the environment. Grid cells in the superficial layers of MEC provide inputs to place cells and exhibit remarkable regular hexagonal spatial firing patterns. They also exhibit a gradient of spatial scales along the dorsoventral axis of the MEC, with neighboring cells at a given dorsoventral location having different spatial phases. A neural model shows how a hierarchy of self-organizing maps, each obeying the same laws, responds to realistic rat trajectories by learning grid cells with hexagonal grid firing fields of multiple spatial scales and place cells with unimodal firing fields that fit neurophysiological data about their development in juvenile rats. The hippocampal place fields represent much larger spaces than the grid cells to support navigational behaviors. Both the entorhinal and hippocampal self-organizing maps amplify and learn to categorize the most energetic and frequent co-occurrences of their inputs. Top-down attentional mechanisms from hippocampus to MEC help to dynamically stabilize these spatial memories in both the model and neurophysiological data. Spatial learning through MEC to hippocampus occurs in parallel with temporal learning through lateral entorhinal cortex to hippocampus. These homologous spatial and temporal representations illustrate a kind of "neural relativity" that may provide a substrate for episodic learning and memory.

  8. Lung airway-surveilling CXCR3hi memory CD8+ T cells are critical for protection against Influenza A virus

    PubMed Central

    Slütter, Bram; Pewe, Lecia L.; Kaech, Susan M.; Harty, John T.

    2013-01-01

    Summary Inducing memory CD8+ T-cells specific for conserved antigens from Influenza A virus (IAV) is a potential strategy for broadly protective vaccines. Here we show that memory CD8 T-cells in the airways played an important role in early control of IAV. Expression of chemokine receptor CXCR3 was critical for memory CD8 T-cells to populate the airways during the steady state and vaccination approaches were designed to favor the establishment of memory CD8 T-cells in the airways. Specifically, we found that interleukin-12 (IL-12) signaling shortly after immunization limited CXCR3 expression on memory CD8 T-cells. Neutralization of IL-12 or adjuvants that did not induce high amounts of IL-12, enhanced CXCR3 expression, sustained airway localization of memory CD8 T-cells and resulted in superior protection against IAV. PMID:24238342

  9. Lung airway-surveilling CXCR3(hi) memory CD8(+) T cells are critical for protection against influenza A virus.

    PubMed

    Slütter, Bram; Pewe, Lecia L; Kaech, Susan M; Harty, John T

    2013-11-14

    Inducing memory CD8(+) T cells specific for conserved antigens from influenza A virus (IAV) is a potential strategy for broadly protective vaccines. Here we show that memory CD8(+) T cells in the airways played an important role in early control of IAV. Expression of the chemokine receptor CXCR3 was critical for memory CD8(+) T cells to populate the airways during the steady state and vaccination approaches were designed to favor the establishment of memory CD8(+) T cells in the airways. Specifically, we found that interleukin-12 (IL-12) signaling shortly after immunization limited CXCR3 expression on memory CD8(+) T cells. Neutralization of IL-12 or adjuvants that did not induce high amounts of IL-12 enhanced CXCR3 expression, sustained airway localization of memory CD8(+) T cells, and resulted in superior protection against IAV.

  10. CD4⁺ effector and memory cell populations protect against Cryptosporidium parvum infection.

    PubMed

    McNair, Nina N; Mead, Jan R

    2013-01-01

    Cryptosporidium parvum is a protozoan parasite that infects the epithelial cells of the small intestine causing diarrheal illness in humans. While T cells are known to be important in resistance and recovery from infection, little has been characterized as to the phenotypic expression of surface effector and memory markers after infection. We used an acute model of infection (C57BL/6 interleukin-12p40), which develops long-standing resistance to re-infection, to characterize expression of different effector and memory cells. Using flow cytometry, we found that heterogeneous populations were generated after infection, consisting of both CD62L(high) central memory T cells (T(CM)) and CD62L(low) effector memory T cells (T(EM)) that were competent to produce the Th type 1 effector cytokine, IFN-γ. Both CD4⁺ and CD8⁺ T(CM) and T(EM) populations persisted in the absence of infection (up to 60 days post-infection). Additionally, transfer of either CD62L(low)CD4⁺ T(EM) or CD62L(high)CD4⁺ T(CM) into naive recipients resulted in a protective response. Taken together, these studies show that distinct subsets of effector and memory CD4⁺ T cells develop after infection with C. parvum, and mediate protective immunity to re-challenge.

  11. Effect of Quarterly Element Addition of Cobalt on Phase Transformation Characteristics of Cu-Al-Ni Shape Memory Alloys

    NASA Astrophysics Data System (ADS)

    Saud, Safaa Najah; Abu Bakar, Tuty Asma; Hamzah, Esah; Ibrahim, Mustafa Khaleel; Bahador, Abollah

    2015-08-01

    In the current study, a new type of Cu-based shape memory alloys with the function of shape memory effect was successfully produced with the introduction of high-purity Co precipitates between the phases of Cu-Al-Ni shape memory alloy. The microstructure, transformation characteristics, and mechanical properties were systematically investigated by means of differential scanning calorimetry, field emission scanning electron microscopy, energy dispersive spectroscopy (EDS), transmission electron microscopy, X-ray diffraction (XRD), a tensile test, a hardness test, and a shape memory effect test. The typical microstructures show that a new phase was formed, known as the γ 2 phase, and the volume friction and the size of this phase were gradually increased with the increasing Co content. According to the results of the XRD and EDS, it was confirmed that the γ 2 phase represents a compound of Al75Co22Ni3. However, the presence of γ 2 phase in the modified alloys was found to result in an increase of the transformation temperatures in comparison with the unmodified alloy. Nevertheless, it was found that with 1 wt pct of Co addition, a maximum ductility of 7 pct was achieved, corresponding to an increase in the strain recovery by the shape memory effect to 95 pct with respect to the unmodified alloy of 50 pct.

  12. VACCINES. A mucosal vaccine against Chlamydia trachomatis generates two waves of protective memory T cells.

    PubMed

    Stary, Georg; Olive, Andrew; Radovic-Moreno, Aleksandar F; Gondek, David; Alvarez, David; Basto, Pamela A; Perro, Mario; Vrbanac, Vladimir D; Tager, Andrew M; Shi, Jinjun; Yethon, Jeremy A; Farokhzad, Omid C; Langer, Robert; Starnbach, Michael N; von Andrian, Ulrich H

    2015-06-19

    Genital Chlamydia trachomatis (Ct) infection induces protective immunity that depends on interferon-γ-producing CD4 T cells. By contrast, we report that mucosal exposure to ultraviolet light (UV)-inactivated Ct (UV-Ct) generated regulatory T cells that exacerbated subsequent Ct infection. We show that mucosal immunization with UV-Ct complexed with charge-switching synthetic adjuvant particles (cSAPs) elicited long-lived protection in conventional and humanized mice. UV-Ct-cSAP targeted immunogenic uterine CD11b(+)CD103(-) dendritic cells (DCs), whereas UV-Ct accumulated in tolerogenic CD11b(-)CD103(+) DCs. Regardless of vaccination route, UV-Ct-cSAP induced systemic memory T cells, but only mucosal vaccination induced effector T cells that rapidly seeded uterine mucosa with resident memory T cells (T(RM) cells). Optimal Ct clearance required both T(RM) seeding and subsequent infection-induced recruitment of circulating memory T cells. Thus, UV-Ct-cSAP vaccination generated two synergistic memory T cell subsets with distinct migratory properties.

  13. Bim/Bcl-2 balance is critical for maintaining naive and memory T cell homeostasis.

    PubMed

    Wojciechowski, Sara; Tripathi, Pulak; Bourdeau, Tristan; Acero, Luis; Grimes, H Leighton; Katz, Jonathan D; Finkelman, Fred D; Hildeman, David A

    2007-07-01

    We examined the role of the antiapoptotic molecule Bcl-2 in combating the proapoptotic molecule Bim in control of naive and memory T cell homeostasis using Bcl-2(-/-) mice that were additionally deficient in one or both alleles of Bim. Naive T cells were significantly decreased in Bim(+/-)Bcl-2(-/-) mice, but were largely restored in Bim(-/-)Bcl-2(-/-) mice. Similarly, a synthetic Bcl-2 inhibitor killed wild-type, but not Bim(-/-), T cells. Further, T cells from Bim(+/-)Bcl-2(-/-) mice died rapidly ex vivo and were refractory to cytokine-driven survival in vitro. In vivo, naive CD8(+) T cells required Bcl-2 to combat Bim to maintain peripheral survival, whereas naive CD4(+) T cells did not. In contrast, Bim(+/-)Bcl-2(-/-) mice generated relatively normal numbers of memory T cells after lymphocytic choriomeningitis virus infection. Accumulation of memory T cells in Bim(+/-)Bcl-2(-/-) mice was likely caused by their increased proliferative renewal because of the lymphopenic environment of the mice. Collectively, these data demonstrate a critical role for a balance between Bim and Bcl-2 in controlling homeostasis of naive and memory T cells.

  14. Bim/Bcl-2 balance is critical for maintaining naive and memory T cell homeostasis

    PubMed Central

    Wojciechowski, Sara; Tripathi, Pulak; Bourdeau, Tristan; Acero, Luis; Grimes, H. Leighton; Katz, Jonathan D.; Finkelman, Fred D.; Hildeman, David A.

    2007-01-01

    We examined the role of the antiapoptotic molecule Bcl-2 in combating the proapoptotic molecule Bim in control of naive and memory T cell homeostasis using Bcl-2−/− mice that were additionally deficient in one or both alleles of Bim. Naive T cells were significantly decreased in Bim+/−Bcl-2−/− mice, but were largely restored in Bim−/−Bcl-2−/− mice. Similarly, a synthetic Bcl-2 inhibitor killed wild-type, but not Bim−/−, T cells. Further, T cells from Bim+/−Bcl-2−/− mice died rapidly ex vivo and were refractory to cytokine-driven survival in vitro. In vivo, naive CD8+ T cells required Bcl-2 to combat Bim to maintain peripheral survival, whereas naive CD4+ T cells did not. In contrast, Bim+/−Bcl-2−/− mice generated relatively normal numbers of memory T cells after lymphocytic choriomeningitis virus infection. Accumulation of memory T cells in Bim+/−Bcl-2−/− mice was likely caused by their increased proliferative renewal because of the lymphopenic environment of the mice. Collectively, these data demonstrate a critical role for a balance between Bim and Bcl-2 in controlling homeostasis of naive and memory T cells. PMID:17591857

  15. VACCINES. A mucosal vaccine against Chlamydia trachomatis generates two waves of protective memory T cells.

    PubMed

    Stary, Georg; Olive, Andrew; Radovic-Moreno, Aleksandar F; Gondek, David; Alvarez, David; Basto, Pamela A; Perro, Mario; Vrbanac, Vladimir D; Tager, Andrew M; Shi, Jinjun; Yethon, Jeremy A; Farokhzad, Omid C; Langer, Robert; Starnbach, Michael N; von Andrian, Ulrich H

    2015-06-19

    Genital Chlamydia trachomatis (Ct) infection induces protective immunity that depends on interferon-γ-producing CD4 T cells. By contrast, we report that mucosal exposure to ultraviolet light (UV)-inactivated Ct (UV-Ct) generated regulatory T cells that exacerbated subsequent Ct infection. We show that mucosal immunization with UV-Ct complexed with charge-switching synthetic adjuvant particles (cSAPs) elicited long-lived protection in conventional and humanized mice. UV-Ct-cSAP targeted immunogenic uterine CD11b(+)CD103(-) dendritic cells (DCs), whereas UV-Ct accumulated in tolerogenic CD11b(-)CD103(+) DCs. Regardless of vaccination route, UV-Ct-cSAP induced systemic memory T cells, but only mucosal vaccination induced effector T cells that rapidly seeded uterine mucosa with resident memory T cells (T(RM) cells). Optimal Ct clearance required both T(RM) seeding and subsequent infection-induced recruitment of circulating memory T cells. Thus, UV-Ct-cSAP vaccination generated two synergistic memory T cell subsets with distinct migratory properties. PMID:26089520

  16. Low-Affinity Memory CD8+ T Cells Mediate Robust Heterologous Immunity.

    PubMed

    Krummey, Scott M; Martinez, Ryan J; Andargachew, Rakieb; Liu, Danya; Wagener, Maylene; Kohlmeier, Jacob E; Evavold, Brian D; Larsen, Christian P; Ford, Mandy L

    2016-03-15

    Heterologous immunity is recognized as a significant barrier to transplant tolerance. Whereas it has been established that pathogen-elicited memory T cells can have high or low affinity for cross-reactive allogeneic peptide-MHC, the role of TCR affinity during heterologous immunity has not been explored. We established a model with which to investigate the impact of TCR-priming affinity on memory T cell populations following a graft rechallenge. In contrast to high-affinity priming, low-affinity priming elicited fully differentiated memory T cells with a CD45RB(hi) status. High CD45RB status enabled robust secondary responses in vivo, as demonstrated by faster graft rejection kinetics and greater proliferative responses. CD45RB blockade prolonged graft survival in low affinity-primed mice, but not in high affinity-primed mice. Mechanistically, low affinity-primed memory CD8(+) T cells produced more IL-2 and significantly upregulated IL-2Rα expression during rechallenge. We found that CD45RB(hi) status was also a stable marker of priming affinity within polyclonal CD8(+) T cell populations. Following high-affinity rechallenge, low affinity-primed CD45RB(hi) cells became CD45RB(lo), demonstrating that CD45RB status acts as an affinity-based differentiation switch on CD8(+) T cells. Thus, these data establish a novel mechanism by which CD45 isoforms tune low affinity-primed memory CD8(+) T cells to become potent secondary effectors following heterologous rechallenge. These findings have direct implications for allogeneic heterologous immunity by demonstrating that despite a lower precursor frequency, low-affinity priming is sufficient to generate memory cells that mediate potent secondary responses against a cross-reactive graft challenge. PMID:26864034

  17. Real-time tracking of cell cycle progression during CD8+ effector and memory T-cell differentiation

    PubMed Central

    Kinjyo, Ichiko; Qin, Jim; Tan, Sioh-Yang; Wellard, Cameron J.; Mrass, Paulus; Ritchie, William; Doi, Atsushi; Cavanagh, Lois L.; Tomura, Michio; Sakaue-Sawano, Asako; Kanagawa, Osami; Miyawaki, Atsushi; Hodgkin, Philip D.; Weninger, Wolfgang

    2015-01-01

    The precise pathways of memory T-cell differentiation are incompletely understood. Here we exploit transgenic mice expressing fluorescent cell cycle indicators to longitudinally track the division dynamics of individual CD8+ T cells. During influenza virus infection in vivo, naive T cells enter a CD62Lintermediate state of fast proliferation, which continues for at least nine generations. At the peak of the anti-viral immune response, a subpopulation of these cells markedly reduces their cycling speed and acquires a CD62Lhi central memory cell phenotype. Construction of T-cell family division trees in vitro reveals two patterns of proliferation dynamics. While cells initially divide rapidly with moderate stochastic variations of cycling times after each generation, a slow-cycling subpopulation displaying a CD62Lhi memory phenotype appears after eight divisions. Phenotype and cell cycle duration are inherited by the progeny of slow cyclers. We propose that memory precursors cell-intrinsically modulate their proliferative activity to diversify differentiation pathways. PMID:25709008

  18. B cells expressing IL-10 mRNA modulate memory T cells after DNA-Hsp65 immunization.

    PubMed

    Fontoura, I C; Trombone, A P F; Almeida, L P; Lorenzi, J C C; Rossetti, R A M; Malardo, T; Padilha, E; Schluchting, W; Silva, R L L; Gembre, A F; Fiuza, J E C; Silva, C L; Panunto-Castelo, A; Coelho-Castelo, A A M

    2015-12-01

    In DNA vaccines, the gene of interest is cloned into a bacterial plasmid that is engineered to induce protein production for long periods in eukaryotic cells. Previous research has shown that the intramuscular immunization of BALB/c mice with a naked plasmid DNA fragment encoding the Mycobacterium leprae 65-kDa heat-shock protein (pcDNA3-Hsp65) induces protection against M. tuberculosis challenge. A key stage in the protective immune response after immunization is the generation of memory T cells. Previously, we have shown that B cells capture plasmid DNA-Hsp65 and thereby modulate the formation of CD8+ memory T cells after M. tuberculosis challenge in mice. Therefore, clarifying how B cells act as part of the protective immune response after DNA immunization is important for the development of more-effective vaccines. The aim of this study was to investigate the mechanisms by which B cells modulate memory T cells after DNA-Hsp65 immunization. C57BL/6 and BKO mice were injected three times, at 15-day intervals, with 100 µg naked pcDNA-Hsp65 per mouse. Thirty days after immunization, the percentages of effector memory T (TEM) cells (CD4+ and CD8+/CD44high/CD62Llow) and memory CD8+ T cells (CD8+/CD44high/CD62Llow/CD127+) were measured with flow cytometry. Interferon γ, interleukin 12 (IL-12), and IL-10 mRNAs were also quantified in whole spleen cells and purified B cells (CD43-) with real-time qPCR. Our data suggest that a B-cell subpopulation expressing IL-10 downregulated proinflammatory cytokine expression in the spleen, increasing the survival of CD4+ TEM cells and CD8+ TEM/CD127+ cells. PMID:26397973

  19. B cells expressing IL-10 mRNA modulate memory T cells after DNA-Hsp65 immunization

    PubMed Central

    Fontoura, I. C.; Trombone, A.P.F.; Almeida, L. P.; Lorenzi, J. C. C.; Rossetti, R. A. M.; Malardo, T.; Padilha, E.; Schluchting, W.; Silva, R. L. L.; Gembre, A. F.; Fiuza, J. E. C.; Silva, C. L.; Panunto-Castelo, A.; Coelho-Castelo, A. A. M.

    2015-01-01

    In DNA vaccines, the gene of interest is cloned into a bacterial plasmid that is engineered to induce protein production for long periods in eukaryotic cells. Previous research has shown that the intramuscular immunization of BALB/c mice with a naked plasmid DNA fragment encoding the Mycobacterium leprae 65-kDa heat-shock protein (pcDNA3-Hsp65) induces protection against M. tuberculosis challenge. A key stage in the protective immune response after immunization is the generation of memory T cells. Previously, we have shown that B cells capture plasmid DNA-Hsp65 and thereby modulate the formation of CD8+ memory T cells after M. tuberculosis challenge in mice. Therefore, clarifying how B cells act as part of the protective immune response after DNA immunization is important for the development of more-effective vaccines. The aim of this study was to investigate the mechanisms by which B cells modulate memory T cells after DNA-Hsp65 immunization. C57BL/6 and BKO mice were injected three times, at 15-day intervals, with 100 µg naked pcDNA-Hsp65 per mouse. Thirty days after immunization, the percentages of effector memory T (TEM) cells (CD4+ and CD8+/CD44high/CD62Llow) and memory CD8+ T cells (CD8+/CD44high/CD62Llow/CD127+) were measured with flow cytometry. Interferon γ, interleukin 12 (IL-12), and IL-10 mRNAs were also quantified in whole spleen cells and purified B cells (CD43−) with real-time qPCR. Our data suggest that a B-cell subpopulation expressing IL-10 downregulated proinflammatory cytokine expression in the spleen, increasing the survival of CD4+ TEM cells and CD8+ TEM/CD127+ cells. PMID:26397973

  20. Qualitative Characteristics of Memories for Real, Imagined, and Media-Based Events

    ERIC Educational Resources Information Center

    Gordon, Ruthanna; Gerrig, Richard J.; Franklin, Nancy

    2009-01-01

    People's memories must be able to represent experiences with multiple types of origins--including the real world and our own imaginations, but also printed texts (prose-based media), movies, and television (screen-based media). This study was intended to identify cues that distinguish prose- and screen-based media memories from each other, as well…

  1. The Cognitive and Behavioral Characteristics of Children with Low Working Memory

    ERIC Educational Resources Information Center

    Alloway, Tracy Packiam; Gathercole, Susan Elizabeth; Kirkwood, Hannah; Elliott, Julian

    2009-01-01

    This study explored the cognitive and behavioral profiles of children with working memory impairments. In an initial screening of 3,189 five- to eleven-year-olds, 308 were identified as having very low working memory scores. Cognitive skills (IQ, vocabulary, reading, and math), classroom behavior, and self-esteem were assessed. The majority of the…

  2. Human memory T cells with a naive phenotype accumulate with aging and respond to persistent viruses.

    PubMed

    Pulko, Vesna; Davies, John S; Martinez, Carmine; Lanteri, Marion C; Busch, Michael P; Diamond, Michael S; Knox, Kenneth; Bush, Erin C; Sims, Peter A; Sinari, Shripad; Billheimer, Dean; Haddad, Elias K; Murray, Kristy O; Wertheimer, Anne M; Nikolich-Žugich, Janko

    2016-08-01

    The number of naive T cells decreases and susceptibility to new microbial infections increases with age. Here we describe a previously unknown subset of phenotypically naive human CD8(+) T cells that rapidly secreted multiple cytokines in response to persistent viral antigens but differed transcriptionally from memory and effector T cells. The frequency of these CD8(+) T cells, called 'memory T cells with a naive phenotype' (TMNP cells), increased with age and after severe acute infection and inversely correlated with the residual capacity of the immune system to respond to new infections with age. CD8(+) TMNP cells represent a potential new target for the immunotherapy of persistent infections and should be accounted for and subtracted from the naive pool if truly naive T cells are needed to respond to antigens. PMID:27270402

  3. Rescue of CD8+ T cell vaccine memory following sublethal γ irradiation

    PubMed Central

    McFarland, Hugh I.; Berkson, Julia D.; Lee, Jay P.; Elkahloun, Abdel G.; Mason, Karen P.; Rosenberg, Amy S.

    2015-01-01

    Sublethal γ irradiation eliminates CD8+ T cell mediated memory responses. In this work, we explored how these memory responses could be rescued in the aftermath of such exposure. We utilized two models of CD8+ T cell mediated immunity: a mouse model of Listeria monocytogenes (LM) infection in which CD8+ T cells specific for LM expressed antigens (Listeriolysin O, LLO) can be tracked, and a murine skin graft model in which CD8+ T cells mediate rejection across a MHC class I (Dd) disparity. In the LM immunized mice, LL0 specific CD8+ T memory cells were lost on irradiation, preserved with rapid revaccination with an attenuated strain 1-3 days post-irradiation (PI), and these mice survived a subsequent wild type LM challenge. A genetic “signature of rescue” identified a group of immune-associated mRNA maintained or upregulated following irradiation and rescue. A number of these factors, including IL-36γ, dectin-2 (Clec4n), and mir101c are upregulated rapidly after exposure of mice to sublethal γ radiation alone and are sustained by early, but not later rescue. Such factors will be evaluated as potential therapeutics to replace individual vaccines for global rescue of CD8+ T memory cell responses following sublethal γ irradiation. The skin allograft model mirrored that of the LM model in that the accelerated Dd skin allograft rejection response was lost in mice exposed to sublethal γ radiation, but infusion of allogeneic Dd expressing bone marrow cells 1-4 days PI preserved the CD8+ T memory mediated accelerated rejection response, further suggesting that innate immune responses may not always be essential to rescue of CD8+ memory T cells following γ irradiation. PMID:26122582

  4. Persistence of skin-resident memory T cells within an epidermal niche

    PubMed Central

    Zaid, Ali; Mackay, Laura K.; Rahimpour, Azad; Braun, Asolina; Veldhoen, Marc; Carbone, Francis R.; Manton, Jonathan H.; Heath, William R.; Mueller, Scott N.

    2014-01-01

    Barrier tissues such as the skin contain various populations of immune cells that contribute to protection from infections. These include recently identified tissue-resident memory T cells (TRM). In the skin, these memory CD8+ T cells reside in the epidermis after being recruited to this site by infection or inflammation. In this study, we demonstrate prolonged persistence of epidermal TRM preferentially at the site of prior infection despite sustained migration. Computational simulation of TRM migration within the skin over long periods revealed that the slow rate of random migration effectively constrains these memory cells within the region of skin in which they form. Notably, formation of TRM involved a concomitant local reduction in dendritic epidermal γδ T-cell numbers in the epidermis, indicating that these populations persist in mutual exclusion and may compete for local survival signals. Accordingly, we show that expression of the aryl hydrocarbon receptor, a transcription factor important for dendritic epidermal γδ T-cell maintenance in skin, also contributes to the persistence of skin TRM. Together, these data suggest that skin tissue-resident memory T cells persist within a tightly regulated epidermal T-cell niche. PMID:24706879

  5. Location, Location, Location: Localized Memory Cells Take Residence in the Allergic Lung.

    PubMed

    Lloyd, Clare M; Harker, James A

    2016-01-19

    Understanding the localization of cells is important as local environmental cues influence both phenotype and effector function. In this issue of Immunity, Pepper and colleagues find that allergen-specific tissue-resident memorycells are maintained by IL-2 and are key drivers of allergic pathology.

  6. Persistence of skin-resident memory T cells within an epidermal niche.

    PubMed

    Zaid, Ali; Mackay, Laura K; Rahimpour, Azad; Braun, Asolina; Veldhoen, Marc; Carbone, Francis R; Manton, Jonathan H; Heath, William R; Mueller, Scott N

    2014-04-01

    Barrier tissues such as the skin contain various populations of immune cells that contribute to protection from infections. These include recently identified tissue-resident memory T cells (TRM). In the skin, these memory CD8(+) T cells reside in the epidermis after being recruited to this site by infection or inflammation. In this study, we demonstrate prolonged persistence of epidermal TRM preferentially at the site of prior infection despite sustained migration. Computational simulation of TRM migration within the skin over long periods revealed that the slow rate of random migration effectively constrains these memory cells within the region of skin in which they form. Notably, formation of TRM involved a concomitant local reduction in dendritic epidermal γδ T-cell numbers in the epidermis, indicating that these populations persist in mutual exclusion and may compete for local survival signals. Accordingly, we show that expression of the aryl hydrocarbon receptor, a transcription factor important for dendritic epidermal γδ T-cell maintenance in skin, also contributes to the persistence of skin TRM. Together, these data suggest that skin tissue-resident memory T cells persist within a tightly regulated epidermal T-cell niche.

  7. Bovine central memory T cells are highly proliferative in response to bovine tuberculosis infection

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Long-term (i.e., 14 days) cultured IFN-gamma responses of peripheral blood mononuclear cells are used as a correlate of T cell central memory (Tcm) responses in both humans and cattle. With bovine tuberculosis, vaccine-elicited long-term IFN-gamma ELISPOT assays are a correlate of protection. Recent...

  8. Effector and memory T cell subsets in the response to bovine tuberculosis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Long-term (i.e., 14 days) cultured IFN-gamma ELISPOT assays of peripheral blood mononuclear cells (PBMC) are used to access T cell central memory (Tcm) responses in both cattle and humans. With bovine tuberculosis, vaccine-elicited long-term IFN-gamma ELISPOT response correlates with protection; how...

  9. Location, Location, Location: Localized Memory Cells Take Residence in the Allergic Lung.

    PubMed

    Lloyd, Clare M; Harker, James A

    2016-01-19

    Understanding the localization of cells is important as local environmental cues influence both phenotype and effector function. In this issue of Immunity, Pepper and colleagues find that allergen-specific tissue-resident memorycells are maintained by IL-2 and are key drivers of allergic pathology. PMID:26789918

  10. Manipulating Memory CD8 T Cell Numbers by Timed Enhancement of IL-2 Signals.

    PubMed

    Kim, Marie T; Kurup, Samarchith P; Starbeck-Miller, Gabriel R; Harty, John T

    2016-09-01

    As a result of the growing burden of tumors and chronic infections, manipulating CD8 T cell responses for clinical use has become an important goal for immunologists. In this article, we show that dendritic cell (DC) immunization coupled with relatively early (days 1-3) or late (days 4-6) administration of enhanced IL-2 signals increase peak effector CD8 T cell numbers, but only early IL-2 signals enhance memory numbers. IL-2 signals delivered at relatively late time points drive terminal differentiation and marked Bim-mediated contraction and do not increase memory T cell numbers. In contrast, early IL-2 signals induce effector cell metabolic profiles that are more conducive to memory formation. Of note, downregulation of CD80 and CD86 was observed on DCs in vivo following early IL-2 treatment. Mechanistically, early IL-2 treatment enhanced CTLA-4 expression on regulatory T cells, and CTLA-4 blockade alongside IL-2 treatment in vivo prevented the decrease in CD80 and CD86, supporting a cell-extrinsic role for CTLA-4 in downregulating B7 ligand expression on DCs. Finally, DC immunization followed by early IL-2 treatment and anti-CTLA-4 blockade resulted in lower memory CD8 T cell numbers compared with the DC+early IL-2 treatment group. These data suggest that curtailed signaling through the B7-CD28 costimulatory axis during CD8 T cell activation limits terminal differentiation and preserves memory CD8 T cell formation; thus, it should be considered in future T cell-vaccination strategies. PMID:27439516

  11. Investigating the bistability characteristics of GaN/AlN resonant tunneling diodes for ultrafast nonvolatile memory

    NASA Astrophysics Data System (ADS)

    Nagase, Masanori; Takahashi, Tokio; Shimizu, Mitsuaki

    2015-03-01

    The bistability characteristics of GaN/AlN resonant tunneling diodes (RTDs) grown on a sapphire substrate by metalorganic vapor phase epitaxy (MOVPE) were investigated to better understand their physical origin and explore their use in nonvolatile memories. The bistability current-voltage (I-V) characteristics of GaN/AlN RTDs, which were due to intersubband transitions and electron accumulation in the quantum well, were clearly observed over a wide temperature range between 50 and 300 K. However, the I-V characteristics sometimes degraded at temperatures above 250 K. Complex staircase structures were observed in the voltage region showing a negative differential resistance in the I-V curve, and the forward current increased or decreased rapidly as the forward-bias voltage increased. Repeated measurements of the I-V characteristics over the wide temperature range between 50 and 300 K revealed that the bistability characteristics of GaN/AlN RTDs degraded owing to the leakage of electrons accumulating in the quantum well through a deep level in the AlN barrier associated with crystal defects such as dislocations and impurities. Therefore, reduction in crystal defect and impurity densities in the AlN barrier, and a careful design that considers deep levels are important for realizing realize ultrafast nonvolatile memories based on the bistability characteristics of GaN/AlN RTDs.

  12. Defective T Memory Cell Differentiation after Varicella Zoster Vaccination in Older Individuals

    PubMed Central

    Wagar, Lisa E.; Mackey, Sally; Hu, Jinyu; Maecker, Holden; Davis, Mark M.; Dekker, Cornelia L.; Tian, Lu; Weyand, Cornelia M.; Goronzy, Jörg J.

    2016-01-01

    Vaccination with attenuated live varicella zoster virus (VZV) can prevent zoster reactivation, but protection is incomplete especially in an older population. To decipher the molecular mechanisms underlying variable vaccine responses, T- and B-cell responses to VZV vaccination were examined in individuals of different ages including identical twin pairs. Contrary to the induction of VZV-specific antibodies, antigen-specific T cell responses were significantly influenced by inherited factors. Diminished generation of long-lived memory T cells in older individuals was mainly caused by increased T cell loss after the peak response while the expansion of antigen-specific T cells was not affected by age. Gene expression in activated CD4 T cells at the time of the peak response identified gene modules related to cell cycle regulation and DNA repair that correlated with the contraction phase of the T cell response and consequently the generation of long-lived memory cells. These data identify cell cycle regulatory mechanisms as targets to reduce T cell attrition in a vaccine response and to improve the generation of antigen-specific T cell memory, in particular in an older population. PMID:27764254

  13. The Distribution of Human Stem Cell–like Memory T Cell in Lung Cancer

    PubMed Central

    Hong, Hai; Gu, Yong; Sheng, Si Yuan; Lu, Chuan Gang; Zou, Jian Yong

    2016-01-01

    Human stem cell–like memory T (Tscm) cells are long-lived, self-renewing memory lymphocytes that can differentiate into effector cells and mediate strong antitumour response in murine model. The distribution and function of Tscm cells in human lung cancer remain unknown. In this study, we investigated the properties of human Tscm cells in the blood and lymph node of non–small cell lung cancer (NSCLC) patients. There were more CD4+ Tscm cells in blood from NSCLC patients than from healthy donors, fewer CD4+ and CD8+ TSCM cells in blood than in lymph node from NSCLC patients. To further analyze their properties, we stimulated peripheral blood mononuclear cells from NSCLC patients by mitogens to examine cytokine production. Our data suggest that both CD4 and CD8 Tscm cells in blood produced interferon-γ significantly increased in NSCLC patients compare with healthy subjects. In addition, fewer Tscm cells produced interferon-γ in lymph node than in blood from NSCLC patients. Our results strongly suggest that the distribution and function of CD4 Tscm cells in NSCLC patients is upregulated. Understanding of the properties of stem-like memory T cells will supply a good rationale for designing the new adoptive immunotherapy in cancer. PMID:27244531

  14. Opposite effects of interleukin-4 on memory T helper cell development depend on interleukin-2.

    PubMed

    Bemer, V; Motta, I; Perret, R; Truffa-Bachi, P

    1996-01-01

    We previously reported that cyclosporin A (CSA) promotes the generation of T helper memory cells during antigenic priming of murine spleen cells in vitro. More recently, we have demonstrated that interleukin-2 (IL2) has a downmodulating effect on T helper memory cell generation. The present data address the role of the other T cell growth factor, IL4, upon induction of these cells. The data presented here show that IL4 can interfere with this process: addition of rIL4 to immunosuppressed priming cultures leads to a considerable decrease in the helper activity of the recovered cells. However, in standard cultures, in which IL2 is normally produced, no effect of IL4 on T helper memory cell generation was found. Addition of IL4 has important consequences for cytokines produced upon antigenic restimulation. In standard cultures, IL4 primes for cells expressing high levels of IL2 and IL4 mRNA. Strikingly, in immunosuppressed priming cultures, IL4 counterbalances the CSA-induced blockade of the IFN gamma gene. Taken together, our results suggest that the unique role of IL4 is to drive T helper memory precursors into an IL4 production differentiation pathway. However, IL4 has a downmodulating effect on memory T helper cell induction when IL2 is not produced. These results confirm that synergy between IL2 and IL4 is mandatory for the directive role of IL4 upon IL4-producing cells. Furthermore, the finding that IL4 promotes the induction of IFN gamma in a CSA-resistant pathway represents a new tool for analysis of regulation of the IFN gamma gene.

  15. Transcriptional profiles reveal a stepwise developmental program of memory CD8(+) T cell differentiation.

    PubMed

    Roychoudhuri, Rahul; Lefebvre, Francois; Honda, Mitsuo; Pan, Li; Ji, Yun; Klebanoff, Christopher A; Nichols, Carmen N; Fourati, Slim; Hegazy, Ahmed N; Goulet, Jean-Philippe; Gattinoni, Luca; Nabel, Gary J; Gilliet, Michel; Cameron, Mark; Restifo, Nicholas P; Sékaly, Rafick P; Flatz, Lukas

    2015-02-11

    The generation of CD8(+) T-cell memory is a major aim of vaccination. While distinct subsets of CD8(+) T-cells are generated following immunization that differ in their ability to confer long-term immunity against infection, the transcriptional profiles of these subsets within endogenous vaccine-induced CD8(+) T cell responses have not been resolved. Here, we measure global transcriptional profiles of endogenous effector (TEFF), effector memory (TEM) and central memory (TCM) CD8(+) T-cells arising from immunization with three distinct prime-boost vaccine regimens. While a proportion of transcripts were uniquely regulated within distinct CD8(+) T cell populations, we observed progressive up- or down-regulation in the expression of a majority of differentially expressed transcripts when subsets were compared in the order TN>TCM>TEM>TEFF. Strikingly, when we compared global differences in gene expression between TN, TCM, TEM and TEFF cells with known transcriptional changes that result when CD8(+) T cells repetitively encounter antigen, our analysis overwhelmingly favored a model whereby cumulative antigen stimulation drives differentiation specifically from TN>TCM>TEM>TEFF and this was common to all vaccines tested. These findings provide insight into the molecular basis of immunological memory and identify potential biomarkers for characterization of vaccine-induced responses and prediction of vaccine efficacy.

  16. Memory CD8(+) T Cells Require Increased Concentrations of Acetate Induced by Stress for Optimal Function.

    PubMed

    Balmer, Maria L; Ma, Eric H; Bantug, Glenn R; Grählert, Jasmin; Pfister, Simona; Glatter, Timo; Jauch, Annaïse; Dimeloe, Sarah; Slack, Emma; Dehio, Philippe; Krzyzaniak, Magdalena A; King, Carolyn G; Burgener, Anne-Valérie; Fischer, Marco; Develioglu, Leyla; Belle, Réka; Recher, Mike; Bonilla, Weldy V; Macpherson, Andrew J; Hapfelmeier, Siegfried; Jones, Russell G; Hess, Christoph

    2016-06-21

    How systemic metabolic alterations during acute infections impact immune cell function remains poorly understood. We found that acetate accumulates in the serum within hours of systemic bacterial infections and that these increased acetate concentrations are required for optimal memory CD8(+) T cell function in vitro and in vivo. Mechanistically, upon uptake by memory CD8(+) T cells, stress levels of acetate expanded the cellular acetyl-coenzyme A pool via ATP citrate lyase and promoted acetylation of the enzyme GAPDH. This context-dependent post-translational modification enhanced GAPDH activity, catalyzing glycolysis and thus boosting rapid memory CD8(+) T cell responses. Accordingly, in a murine Listeria monocytogenes model, transfer of acetate-augmented memory CD8(+) T cells exerted superior immune control compared to control cells. Our results demonstrate that increased systemic acetate concentrations are functionally integrated by CD8(+) T cells and translate into increased glycolytic and functional capacity. The immune system thus directly relates systemic metabolism with immune alertness. PMID:27212436

  17. Ultraviolet B suppresses immunity by inhibiting effector and memory T cells.

    PubMed

    Rana, Sabita; Byrne, Scott Napier; MacDonald, Linda Joanne; Chan, Carling Yan-Yan; Halliday, Gary Mark

    2008-04-01

    Contact hypersensitivity is a T-cell-mediated response to a hapten. Exposing C57BL/6 mice to UV B radiation systemically suppresses both primary and secondary contact hypersensitivity responses. The effects of UVB on in vivo T-cell responses during UVB-induced immunosuppression are unknown. We show here that UVB exposure, before contact sensitization, inhibits the expansion of effector CD4+ and CD8+ T cells in skin-draining lymph nodes and reduces the number of CD4+ and IFN-gamma+ CD8+ T cells infiltrating challenged ear skin. In the absence of UVB, at 10 weeks after initial hapten exposure, the ear skin of sensitized mice was infiltrated by dermal effector memory CD8+ T cells at the site of challenge. However, if mice were previously exposed to UVB, this cell population was absent, suggesting an impaired development of peripheral memory T cells. This finding occurred in the absence of UVB-induced regulatory CD4+ T cells and did not involve prostaglandin E2, suggesting that the importance of these two factors in mediating or initiating UVB-induced immunosuppression is dependent on UVB dose. Together these data indicate that in vivo T-cell responses are prone to immunoregulation by UVB, including a novel effect on both the activated T-cell pool size and the development of memory T cells in peripheral compartments. PMID:18292235

  18. Different Subsets of T Cells, Memory, Effector Functions, and CAR-T Immunotherapy.

    PubMed

    Golubovskaya, Vita; Wu, Lijun

    2016-01-01

    This review is focused on different subsets of T cells: CD4 and CD8, memory and effector functions, and their role in CAR-T therapy--a cellular adoptive immunotherapy with T cells expressing chimeric antigen receptor. The CAR-T cells recognize tumor antigens and induce cytotoxic activities against tumor cells. Recently, differences in T cell functions and the role of memory and effector T cells were shown to be important in CAR-T cell immunotherapy. The CD4⁺ subsets (Th1, Th2, Th9, Th17, Th22, Treg, and Tfh) and CD8⁺ memory and effector subsets differ in extra-cellular (CD25, CD45RO, CD45RA, CCR-7, L-Selectin [CD62L], etc.); intracellular markers (FOXP3); epigenetic and genetic programs; and metabolic pathways (catabolic or anabolic); and these differences can be modulated to improve CAR-T therapy. In addition, CD4⁺ Treg cells suppress the efficacy of CAR-T cell therapy, and different approaches to overcome this suppression are discussed in this review. Thus, next-generation CAR-T immunotherapy can be improved, based on our knowledge of T cell subsets functions, differentiation, proliferation, and signaling pathways to generate more active CAR-T cells against tumors.

  19. Different Subsets of T Cells, Memory, Effector Functions, and CAR-T Immunotherapy

    PubMed Central

    Golubovskaya, Vita; Wu, Lijun

    2016-01-01

    This review is focused on different subsets of T cells: CD4 and CD8, memory and effector functions, and their role in CAR-T therapy––a cellular adoptive immunotherapy with T cells expressing chimeric antigen receptor. The CAR-T cells recognize tumor antigens and induce cytotoxic activities against tumor cells. Recently, differences in T cell functions and the role of memory and effector T cells were shown to be important in CAR-T cell immunotherapy. The CD4+ subsets (Th1, Th2, Th9, Th17, Th22, Treg, and Tfh) and CD8+ memory and effector subsets differ in extra-cellular (CD25, CD45RO, CD45RA, CCR-7, L-Selectin [CD62L], etc.); intracellular markers (FOXP3); epigenetic and genetic programs; and metabolic pathways (catabolic or anabolic); and these differences can be modulated to improve CAR-T therapy. In addition, CD4+ Treg cells suppress the efficacy of CAR-T cell therapy, and different approaches to overcome this suppression are discussed in this review. Thus, next-generation CAR-T immunotherapy can be improved, based on our knowledge of T cell subsets functions, differentiation, proliferation, and signaling pathways to generate more active CAR-T cells against tumors. PMID:26999211

  20. Foxp3+ T cells inhibit antitumor immune memory modulated by mTOR inhibition.

    PubMed

    Wang, Yanping; Sparwasser, Tim; Figlin, Robert; Kim, Hyung L

    2014-04-15

    Inhibition of mTOR signaling enhances antitumor memory lymphocytes. However, pharmacologic mTOR inhibition also enhances regulatory T-cell (Treg) activity. To counter this effect, Treg control was added to mTOR inhibition in preclinical models. Tregs were controlled with CD4-depleting antibodies because CD4 depletion has high translational potential and already has a well-established safety profile in patients. The antitumor activity of the combination therapy was CD8 dependent and controlled growth of syngeneic tumors even when an adoptive immunotherapy was not used. Lymphocytes resulting from the combination therapy could be transferred into naïve mice to inhibit aggressive growth of lung metastases. The combination therapy enhanced CD8 memory formation as determined by memory markers and functional studies of immune recall. Removal of FoxP3-expressing T lymphocytes was the mechanism underlying immunologic memory formation following CD4 depletion. This was confirmed using transgenic DEREG (depletion of regulatory T cells) mice to specifically remove Foxp3(+) T cells. It was further confirmed with reciprocal studies where stimulation of immunologic memory because of CD4 depletion was completely neutralized by adoptively transferring tumor-specific Foxp3(+) T cells. Also contributing to tumor control, Tregs that eventually recovered following CD4 depletion were less immunosuppressive. These results provide a rationale for further study of mTOR inhibition and CD4 depletion in patients.

  1. Cosmic ray-induced soft errors in static MOS memory cells

    NASA Technical Reports Server (NTRS)

    Sivo, L. L.; Peden, J. C.; Brettschneider, M.; Price, W.; Pentecost, P.

    1979-01-01

    Previous analytical models were extended to predict cosmic ray-induced soft error rates in static MOS memory devices. The effect is due to ionization and can be introduced by high energy, heavy ion components of the galactic environment. The results indicate that the sensitivity of memory cells is directly related to the density of the particular MOS technology which determines the node capacitance values. Hence, CMOS is less sensitive than e.g., PMOS. In addition, static MOS memory cells are less sensitive than dynamic ones due to differences in the mechanisms of storing bits. The flip-flop of a static cell is inherently stable against cosmic ray-induced bit flips. Predicted error rates on a CMOS RAM and a PMOS shift register are in general agreement with previous spacecraft flight data.

  2. Self-compliance Pt/HfO2/Ti/Si one-diode-one-resistor resistive random access memory device and its low temperature characteristics

    NASA Astrophysics Data System (ADS)

    Lu, Chao; Yu, Jue; Chi, Xiao-Wei; Lin, Guang-Yang; Lan, Xiao-Ling; Huang, Wei; Wang, Jian-Yuan; Xu, Jian-Fang; Wang, Chen; Li, Cheng; Chen, Song-Yan; Liu, Chunli; Lai, Hong-Kai

    2016-04-01

    A bipolar one-diode-one-resistor (1D1R) device with a Pt/HfO2/Ti/n-Si(001) structure was demonstrated. The 1D1R resistive random access memory (RRAM) device consists of a Ti/n-Si(001) diode and a Pt/HfO2/Ti resistive switching cell. By using the Ti layer as the shared electrode for both the diode and the resistive switching cell, the 1D1R device exhibits the property of stable self-compliance and the characteristic of robust resistive switching with high uniformity. The high/low resistance ratio reaches 103. The electrical RESET/SET curve does not deteriorate after 68 loops. Low-temperature studies show that the 1D1R RRAM device has a critical working temperature of 250 K, and at temperatures below 250 K, the device fails to switch its resistances.

  3. CD27 costimulation contributes substantially to the expansion of functional memory CD8(+) T cells after peptide immunization.

    PubMed

    Taraban, Vadim Y; Rowley, Tania F; Kerr, Jonathan P; Willoughby, Jane E; Johnson, Peter M W; Al-Shamkhani, Aymen; Buchan, Sarah L

    2013-12-01

    Naive T cells require signals from multiple costimulatory receptors to acquire full effector function and differentiate to long-lived memory cells. The costimulatory receptor, CD27, is essential for optimal T-cell priming and memory differentiation in a variety of settings, although whether CD27 is similarly required during memory CD8(+) T-cell reactivation remains controversial. We have used OVA and anti-CD40 to establish a memory CD8(+) T-cell population and report here that their secondary expansion, driven by peptide and anti-CD40, polyI:C, or LPS, requires CD27. Furthermore, antigenic peptide and a soluble form of the CD27 ligand, CD70 (soluble recombinant CD70 (sCD70)), is sufficient for secondary memory CD8(+) T-cell accumulation at multiple anatomical sites, dependent on CD80/86. Prior to boost, resting effector- and central-memory CD8(+) T cells both expressed CD27 with greater expression on central memory cells. Nonetheless, both populations upregulated CD27 after TCR engagement and accumulated in proportion after boosting with Ag and sCD70. Mechanistically, sCD70 increased the frequency of divided and cytolytic memory T cells, conferred resistance to apoptosis and enabled retardation of tumor growth in vivo. These data demonstrate the central role played by CD27/70 during secondary CD8(+) T-cell activation to a peptide Ag, and identify sCD70 as an immunotherapeutic adjuvant for antitumor immunity.

  4. Alterations in Memory and Impact on Academic Outcomes in Children Following Allogeneic Hematopoietic Cell Transplantation.

    PubMed

    Lajiness-O'Neill, R; Hoodin, F; Kentor, R; Heinrich, K; Colbert, A; Connelly, J A

    2015-11-01

    The prevalence of late effects following allogeneic hematopoietic cell transplantation (HCT), a curative treatment for pediatric leukemia, is high: 79% of HCT recipients experience chronic medical conditions. The few extant studies of cognitive late effects have focused on intelligence and are equivocal about HCT neurotoxicity. In an archival study of 30 children (mean transplant age = 6 years), we characterize neuropsychological predictors of academic outcomes. Mean intellectual and academic abilities were average, but evidenced extreme variability, particularly on measures of attention and memory: ∼25% of the sample exhibited borderline performance or lower. Medical predictors of outcome revealed paradoxically better memory associated with more severe acute graft-versus-host disease (GVHD) and associated with steroid treatment. Processing speed and memory accounted for 69% and 61% of variance in mathematics and reading outcomes, respectively. Thus, our findings revealed neurocognitive areas of vulnerability in processing speed and memory following HCT that contribute to subsequent academic difficulties. PMID:26319492

  5. Memory B cell compartment constitution and susceptibility to recurrent lower respiratory tract infections in young children.

    PubMed

    Siebert, Johan N; L'huillier, Arnaud G; Grillet, Stéphane; Delhumeau, Cécile; Siegrist, Claire-Anne; Posfay-Barbe, Klara M

    2013-06-01

    A proportion of children have recurrent LRTIs, mostly as a result of Spn, which persist after 2 years of age. Here, we investigate, by flow cytofluorometry, the constitution of the memory B cell compartment in 90 healthy children and 49 children with recurrent LRTIs to determine if an increased susceptibility to recurrent LRTIs results from a delayed or abnormal ontogeny with poor antibody-mediated protection. Total IgA, IgM, IgG, and IgG subclasses were measured by nephelometry, as well as antipneumococcal antibodies by ELISA. Pneumococcal vaccination status was obtained. We show that the memory B cells increase between birth and 2 years of age (1.6% vs. 21.1%, P<0.001) without further significant increase noted per additional years (3-4 years old: 23.3%; 4-5 years old: 22.2%, P>0.40) to reach adult-like values (31.8±11.8%, P=0.08). Proportions of switched and IgM memory B cells were similar in children and adults. Comparatively, LRTI children had no delay in the constitution of their memory B cell compartment (2-3 years old: 26.9%; 3-4 years old: 18.2%; 4-5 years old: 26.8%, P>0.05). Their switched and IgM memory B cells were similar among age categories, and the distribution was overall similar to that of healthy controls. LRTI children had normal total and pneumococcal serotype-specific antibody values but showed a rapid waning of antipneumococcal antibody levels after vaccination. In summary, our results show that the memory B cell compartment is already similarly constituted at 2 years of age in healthy and LRTI children and thus, cannot explain the increased susceptibility to bacterial pneumonia. However, the waning of antibodies might predispose children to recurrent infections in the absence of revaccination.

  6. [Characteristics of the interaction of image and conditioned reflex memory during the ontogeny of chimpanzees].

    PubMed

    Firsov, L A; Bogacheva, I N; Kuz'min, S K

    1984-01-01

    Interaction of a stable conditioned reflex and trace visual image of a natural alimentary stimulus was studied in two groups of chimpanzee youngs. A. higher stability of visual imaginative memory was observed in animals of the elder group.

  7. Reprogramming of cell fate: epigenetic memory and the erasure of memories past

    PubMed Central

    Nashun, Buhe; Hill, Peter WS; Hajkova, Petra

    2015-01-01

    Cell identity is a reflection of a cell type-specific gene expression profile, and consequently, cell type-specific transcription factor networks are considered to be at the heart of a given cellular phenotype. Although generally stable, cell identity can be reprogrammed in vitro by forced changes to the transcriptional network, the most dramatic example of which was shown by the induction of pluripotency in somatic cells by the ectopic expression of defined transcription factors alone. Although changes to cell fate can be achieved in this way, the efficiency of such conversion remains very low, in large part due to specific chromatin signatures constituting an epigenetic barrier to the transcription factor-mediated reprogramming processes. Here we discuss the two-way relationship between transcription factor binding and chromatin structure during cell fate reprogramming. We additionally explore the potential roles and mechanisms by which histone variants, chromatin remodelling enzymes, and histone and DNA modifications contribute to the stability of cell identity and/or provide a permissive environment for cell fate change during cellular reprogramming. PMID:25820261

  8. HIV-dependent depletion of influenza-specific memory B cells impacts B cell responsiveness to seasonal influenza immunisation

    PubMed Central

    Wheatley, Adam K.; Kristensen, Anne B.; Lay, William N.; Kent, Stephen J.

    2016-01-01

    Infection with HIV drives significant alterations in B cell phenotype and function that can markedly influence antibody responses to immunisation. Anti-retroviral therapy (ART) can partially reverse many aspects of B cell dysregulation, however complete normalisation of vaccine responsiveness is not always observed. Here we examine the effects of underlying HIV infection upon humoral immunity to seasonal influenza vaccines. Serological and memory B cell responses were assessed in 26 HIV+ subjects receiving ART and 30 healthy controls immunised with the 2015 Southern Hemisphere trivalent inactivated influenza vaccine (IIV3). Frequencies and phenotypes of influenza hemagglutinin (HA)-specific B cells were assessed by flow cytometry using recombinant HA probes. Serum antibody was measured using hemagglutination inhibition assays. Serological responses to IIV3 were comparable between HIV+ and HIV− subjects. Likewise, the activation and expansion of memory B cell populations specific for vaccine-component influenza strains was observed in both cohorts, however peak frequencies were diminished in HIV+ subjects compared to uninfected controls. Lower circulating frequencies of memory B cells recognising vaccine-component and historical influenza strains were observed in HIV+ subjects at baseline, that were generally restored to levels comparable with HIV− controls post-vaccination. HIV infection is therefore associated with depletion of selected HA-specific memory B cell pools. PMID:27220898

  9. C/EBP homologous protein (CHOP) deficiency aggravates hippocampal cell apoptosis and impairs memory performance.

    PubMed

    Chen, Chang-Mu; Wu, Cheng-Tien; Chiang, Chih-Kang; Liao, Bor-Wu; Liu, Shing-Hwa

    2012-01-01

    Neurodegenerative disorders are growing burdens in modern societies because of increased life expectancy. Most neurodegenerative disorders commonly possess a similar neuropathological feature--the accumulation of abnormal protein aggregates or inclusions (misfolded proteins) in the brain. One of the main functions of endoplasmic reticulum (ER) is to initiate proper protein folding to facilitate protein secretion through the induction of unfolded protein response (UPR). C/EBP homologous protein (CHOP) induction has been demonstrated to be a signaling event underlying ER stress-induced cell apoptosis. In this study, we explored the role of CHOP in the hippocampal cell apoptosis and memory performance injury under an induced ER stress condition. Adult male wild type (C57BL/6J) and CHOP knockout (CHOP-/-) mice were intracerebroventricularly injected with tunicamycin. Tunicamycin can induce ER stress and cell apoptosis in mouse hippocampus. Compared with wild type mice, CHOP-/- mice showed an enhanced hippocampal cell apoptosis, worse performance in memory-related behavioral tests, and attenuated IRE-1 expression under tunicamycin treatment. The aggravated cell apoptosis and worse memory performance in CHOP-/- mice might be due to the deficiency of CHOP protein resulted in the impaired adaptive/pathological transcriptional response, the decreased IRE-1 and XBP-1 expressions, and the increased JNK phosphorylation to cope with ER stress. Taken together, these results suggest that CHOP may play a protective role in the hippocampal cell apoptosis and impairment of memory performance.

  10. Virus-specific CD4+ memory phenotype T cells are abundant in unexposed adults

    PubMed Central

    Su, Laura F.; Kidd, Brian A.; Han, Arnold; Kotzin, Jonathan J.; Davis, Mark M.

    2013-01-01

    While T cell memory is generally thought to require direct antigen exposure, we find an abundance of memory phenotype cells (20–90%, averaging over 50%) of CD4+ T cells specific for viral antigens in adults that have never been infected. These cells express the appropriate memory markers and genes, rapidly produce cytokines, and have clonally expanded. This contrasts with newborns where the same T cell receptor (TCR) specificities are almost entirely naïve, which may explain the vulnerability of young children to infections. One mechanism for this phenomenon is TCR cross-reactivity to environmental antigens and in support of this we find extensive cross-recognition by HIV-1 and influenza-reactive T lymphocytes to other microbial peptides and the expansion of one of these following influenza vaccination. Thus the presence of these memory phenotype T cells has significant implications for immunity to novel pathogens, child and adult health, and the influence of pathogen-rich versus hygienic environments. PMID:23395677

  11. Differential characteristics of the aging process and the vascular cognitive impairment in the organization of memory retrieval.

    PubMed

    Di Cesare, Franco; D'Ilario, Daniele; Fioravanti, Mario

    2012-11-15

    Early identification of cognitive impairment in patients with chronic cerebral vascular disorders can allow for evaluating the time course of the disease up to the phase of conversion to dementia. The specific indicators of pathological cognitive decline should be identifiable vs. the concurrent age-associated changes in memory which accompany the aging process. We propose a method which evaluates memory dysfunctions in vascular cognitive impairment (VCI) as distinct from age-associated memory changes. This method is based on a serial learning task of concrete frequent words and it consists in controlling the effects of age and cerebral pathology on various characteristics of immediate recall, including serial effect and productivity. Ninety participants underwent a between group examination: younger adults vs. older adults vs. VCI patients who were outpatients with a positive history for chronic cerebral vascular disorder, positive neuroimaging examination, a Hachinski ischemic score ≥ 5 and a mild to moderate cognitive impairment. VCI patients show a reduced efficiency of retrieval and recall organization while, age-associated cognitive changes consist of a modification of the serial position effects. In particular, VCI patients, as distinct from same-age normal cases, can perform an only partial utilization of the inherent structure of the memory task with a very limited efficiency of relearning which is not sufficiently supported by the facilitating factors due to task repetition.

  12. Cutting edge: CCR7+ and CCR7- memory T cells do not differ in immediate effector cell function.

    PubMed

    Unsoeld, Heike; Krautwald, Stefan; Voehringer, David; Kunzendorf, Ulrich; Pircher, Hanspeter

    2002-07-15

    It has been proposed that expression of the chemokine receptor CCR7 represents a defining factor for nonpolarized central (CCR7(+)) and polarized effector memory (CCR7(-)) T cells. In this study, we have tested this hypothesis using in vivo-activated T cells from P14 and SMARTA TCR-transgenic (tg) mice specific for MHC class I- and II-restricted epitopes of the lymphocytic choriomeningitis virus (LCMV) glycoprotein. CCR7 cell surface expression on TCR-tg cells was monitored with a CC chemokine ligand 19-Ig fusion protein. CC chemokine ligand 19-Ig staining separated TCR-tg cells activated by LCMV infection into CCR7(-) and CCR7(+) effector/memory T cell populations. Nonetheless, both T cell populations isolated from spleen and liver produced identical amounts of IFN-gamma after short-term Ag stimulation. Furthermore, CCR7(+) and CCR7(-) CD8 TCR-tg cells from LCMV-infected mice exhibited similar lytic activity against LCMV peptide-coated target cells. These results question the proposed concept of differential effector cell function of CCR7(+) and CCR7(-) memory T cells. PMID:12097363

  13. Ventromedial Prefrontal Cortex Pyramidal Cells Have a Temporal Dynamic Role in Recall and Extinction of Cocaine-Associated Memory

    PubMed Central

    Rotaru, Diana C.; Heinsbroek, Jasper A.; Gouwenberg, Yvonne; Deisseroth, Karl; Stuber, Garret D.; Mansvelder, Huibert D.; Smit, August B.

    2013-01-01

    In addicts, associative memories related to the rewarding effects of drugs of abuse can evoke powerful craving and drug seeking urges, but effective treatment to suppress these memories is not available. Detailed insight into the neural circuitry that mediates expression of drug-associated memory is therefore of crucial importance. Substantial evidence from rodent models of addictive behavior points to the involvement of the ventromedial prefrontal cortex (vmPFC) in conditioned drug seeking, but specific knowledge of the temporal role of vmPFC pyramidal cells is lacking. To this end, we used an optogenetics approach to probe the involvement of vmPFC pyramidal cells in expression of a recent and remote conditioned cocaine memory. In mice, we expressed Channelrhodopsin-2 (ChR2) or Halorhodopsin (eNpHR3.0) in pyramidal cells of the vmPFC and studied the effect of activation or inhibition of these cells during expression of a cocaine-contextual memory on days 1–2 (recent) and ∼3 weeks (remote) after conditioning. Whereas optical activation of pyramidal cells facilitated extinction of remote memory, without affecting recent memory, inhibition of pyramidal cells acutely impaired recall of recent cocaine memory, without affecting recall of remote memory. In addition, we found that silencing pyramidal cells blocked extinction learning at the remote memory time-point. We provide causal evidence of a critical time-dependent switch in the contribution of vmPFC pyramidal cells to recall and extinction of cocaine-associated memory, indicating that the circuitry that controls expression of cocaine memories reorganizes over time. PMID:24227731

  14. Genetic Regulation of Fate Decisions in Therapeutic T Cells to Enhance Tumor Protection and Memory Formation.

    PubMed

    Veliça, Pedro; Zech, Mathias; Henson, Sian; Holler, Angelika; Manzo, Teresa; Pike, Rebecca; Santos E Sousa, Pedro; Zhang, Lei; Heinz, Niels; Schiedlmeier, Bernhard; Pule, Martin; Stauss, Hans; Chakraverty, Ronjon

    2015-07-01

    A key challenge in the field of T-cell immunotherapy for cancer is creating a suitable platform for promoting differentiation of effector cells while at the same time enabling self-renewal needed for long-term memory. Although transfer of less differentiated memory T cells increases efficacy through greater expansion and persistence in vivo, the capacity of such cells to sustain effector functions within immunosuppressive tumor microenvironments may still be limiting. We have therefore directly compared the impact of effector versus memory differentiation of therapeutic T cells in tumor-bearing mice by introducing molecular switches that regulate cell fate decisions via mTOR. Ectopic expression of RAS homolog enriched in brain (RHEB) increased mTORC1 signaling, promoted a switch to aerobic glycolysis, and increased expansion of effector T cells. By rapidly infiltrating tumors, RHEB-transduced T cells significantly reduced the emergence of immunoedited escape variants. In contrast, expression of proline-rich Akt substrate of 40 kDa (PRAS40) inhibited mTORC1, promoted quiescence, and blocked tumor infiltration. Fate mapping studies following transient expression of PRAS40 demonstrated that mTORC1(low) T cells made no contribution to initial tumor control but instead survived to become memory cells proficient in generating recall immunity. Our data support the design of translational strategies for generating heterogeneous T-cell immunity against cancer, with the appropriate balance between promoting effector differentiation and self-renewal. Unlike pharmacologic inhibitors, the genetic approach described here allows for upregulation as well as inhibition of the mTORC1 pathway and is highly selective for the therapeutic T cells without affecting systemic mTORC1 functions.

  15. Therapeutic effect of mesenchymal multipotent stromal cells on memory in animals with Alzheimer-type neurodegeneration.

    PubMed

    Bobkova, N V; Poltavtseva, R A; Samokhin, A N; Sukhikh, G T

    2013-11-01

    Transplantation of human mesenchymal multipotent stromal cells improved spatial memory in bulbectomized mice with Alzheimer-type neurodegeneration. The positive effect was observed in 1 month after intracerebral transplantation and in 3 months after systemic injection of mesenchymal multipotent stromal cells. No cases of malignant transformation were noted. These findings indicate prospects of using mesenchymal multipotent stromal cells for the therapy of Alzheimer disease and the possibility of their systemic administration for attaining the therapeutic effect.

  16. Effects of Asiatic Acid on Spatial Working Memory and Cell Proliferation in the Adult Rat Hippocampus.

    PubMed

    Sirichoat, Apiwat; Chaijaroonkhanarak, Wunnee; Prachaney, Parichat; Pannangrong, Wanassanan; Leksomboon, Ratana; Chaichun, Amnart; Wigmore, Peter; Welbat, Jariya Umka

    2015-10-05

    Asiatic acid is a pentacyclic triterpene from Centella asiatica. Previous studies have reported that asiatic acid exhibits antioxidant and neuroprotective activities in cell culture. It also prevents memory deficits in animal models. The objective of this study was to investigate the relationship between spatial working memory and changes in cell proliferation within the hippocampus after administration of asiatic acid to male Spraque-Dawley rats. Control rats received vehicle (propylene glycol) while treated rats received asiatic acid (30 mg/kg) orally for 14 or 28 days. Spatial memory was determined using the novel object location (NOL) test. In animals administered asiatic acid for both 14 and 28 days, the number of Ki-67 positive cells in the subgranular zone of the dentate gyrus was significantly higher than in control animals. This was associated with a significant increase in their ability to discriminate between novel and familiar object locations in a novel object discrimination task, a hippocampus-dependent spatial memory test. Administration of asiatic acid also significantly increased doublecortin (DCX) and Notch1 protein levels in the hippocampus. These findings demonstrate that asiatic acid treatment may be a potent cognitive enhancer which improves hippocampal-dependent spatial memory, likely by increasing hippocampal neurogenesis.

  17. SPATIAL MEMORY IMPAIRMENT AND HIPPOCAMPAL CELL LOSS INDUCED BY OKADAIC ACID (EXPERIMENTAL STUDY).

    PubMed

    Chighladze, M; Dashniani, M; Beselia, G; Kruashvili, L; Naneishvili, T

    2016-01-01

    In the present study, we evaluated and compared effect of intracerebroventricular (ICV) and intrahippocampal bilateral microinjection of okadaic acid (OA) on spatial memory function assessed in one day water maze paradigm and hippocampal structure in rats. Rats were divided in following groups: Control(icv) - rats injected with ICV and aCSF; Control(hipp) - rats injected intrahippocampally with aCSF; OAicv - rats injected with ICV and OA; OAhipp - rats injected intrahippocampally with OA. Nissl staining of hippocampal sections showed that the pyramidal cell loss in OAhipp group is significantly higher than that in the OAicv. The results of behavioral experiments showed that ICV or intrahippocampal bilateral microinjection of OA did not affect learning process and short-term spatial memory but induced impairment in spatial long-term memory assessed in probe test performance 24 h after training. OA-induced spatial memory impairment may be attributed to the hippocampal cell death. Based on these results OA induced memory deficit and hippocampal cell loss in rat may be considered as a potential animal model for preclinical evaluation of antidementic drug activity.

  18. Performance and Safety Characteristics of Lithium-molybdenum Disulfide Cells

    NASA Technical Reports Server (NTRS)

    Stiles, J. A.

    1984-01-01

    The lithium-molybdenum disulfide system offers attractive characteristics including high rate capability, successful operation up to 75 C, a very low self-discharge rate, a good cycle life and safety characteristics which compare favorably to those of other lithium cells. Moreover, the materials and manufacturing costs for the system is effectively controlled, so the cells should ultimately be competitive with currently marketed rechargeable cells.

  19. Study of self-compliance behaviors and internal filament characteristics in intrinsic SiOx-based resistive switching memory

    NASA Astrophysics Data System (ADS)

    Chang, Yao-Feng; Fowler, Burt; Zhou, Fei; Chen, Ying-Chen; Lee, Jack C.

    2016-01-01

    Self-compliance characteristics and reliability optimization are investigated in intrinsic unipolar silicon oxide (SiOx)-based resistive switching (RS) memory using TiW/SiOx/TiW device structures. The program window (difference between SET voltage and RESET voltage) is dependent on external series resistance, demonstrating that the SET process is due to a voltage-triggered mechanism. The program window has been optimized for program/erase disturbance immunity and reliability for circuit-level applications. The SET and RESET transitions have also been characterized using a dynamic conductivity method, which distinguishes the self-compliance behavior due to an internal series resistance effect (filament) in SiOx-based RS memory. By using a conceptual "filament/resistive gap (GAP)" model of the conductive filament and a proton exchange model with appropriate assumptions, the internal filament resistance and GAP resistance can be estimated for high- and low-resistance states (HRS and LRS), and are found to be independent of external series resistance. Our experimental results not only provide insights into potential reliability issues but also help to clarify the switching mechanisms and device operating characteristics of SiOx-based RS memory.

  20. Epidermal Th22 and Tc17 cells form a localized disease memory in clinically healed psoriasis.

    PubMed

    Cheuk, Stanley; Wikén, Maria; Blomqvist, Lennart; Nylén, Susanne; Talme, Toomas; Ståhle, Mona; Eidsmo, Liv

    2014-04-01

    Psoriasis is a common and chronic inflammatory skin disease in which T cells play a key role. Effective treatment heals the skin without scarring, but typically psoriasis recurs in previously affected areas. A pathogenic memory within the skin has been proposed, but the nature of such site-specific disease memory is unknown. Tissue-resident memory T (TRM) cells have been ascribed a role in immunity after resolved viral skin infections. Because of their localization in the epidermal compartment of the skin, TRM may contribute to tissue pathology during psoriasis. In this study, we investigated whether resolved psoriasis lesions contain TRM cells with the ability to maintain and potentially drive recurrent disease. Three common and effective therapies, narrowband-UVB treatment and long-term biologic treatment systemically inhibiting TNF-α or IL-12/23 signaling were studied. Epidermal T cells were highly activated in psoriasis and a high proportion of CD8 T cells expressed TRM markers. In resolved psoriasis, a population of cutaneous lymphocyte-associated Ag, CCR6, CD103, and IL-23R expressing epidermal CD8 T cells was highly enriched. Epidermal CD8 T cells expressing the TRM marker CD103 responded to ex vivo stimulation with IL-17A production and epidermal CD4 T cells responded with IL-22 production after as long as 6 y of TNF-α inhibition. Our data suggest that epidermal TRM cells are retained in resolved psoriasis and that these cells are capable of producing cytokines with a critical role in psoriasis pathogenesis. We provide a potential mechanism for a site-specific T cell-driven disease memory in psoriasis.

  1. Entorhinal Cortical Ocean Cells Encode Specific Contexts and Drive Context-Specific Fear Memory

    PubMed Central

    Kitamura, Takashi; Sun, Chen; Martin, Jared; Kitch, Lacey J; Schnitzer, Mark J; Tonegawa, Susumu

    2016-01-01

    Summary Forming distinct representations and memories of multiple contexts and episodes is thought to be a crucial function of the hippocampal-entorhinal cortical network. The hippocampal dentate gyrus (DG) and CA3 are known to contribute to these functions but the role of the entorhinal cortex (EC) is poorly understood. Here, we show that Ocean cells, excitatory stellate neurons in the medial EC layer II projecting into DG and CA3, rapidly form a distinct representation of a novel context and drive context-specific activation of downstream CA3 cells as well as context-specific fear memory. In contrast, Island cells, excitatory pyramidal neurons in the medial EC layer II projecting into CA1, are indifferent to context-specific encoding or memory. On the other hand, Ocean cells are dispensable for temporal association learning, for which Island cells are crucial. Together, the two excitatory medial EC layer II inputs to the hippocampus have complementary roles in episodic memory. PMID:26402611

  2. Growth and self-assembly of BaTiO{sub 3} nanocubes for resistive switching memory cells

    SciTech Connect

    Chu, Dewei; Lin, Xi; Younis, Adnan; Li, Chang Ming; Dang, Feng; Li, Sean

    2014-06-01

    In this work, the self-assembled BaTiO{sub 3} nanocubes based resistive switching memory capacitors are fabricated with hydrothermal and drop-coating approaches. The device exhibits excellent bipolar resistance switching characteristics with ON/OFF ratio of 58–70, better reliability and stability over various polycrystalline BaTiO{sub 3} nanostructures. It is believed that the inter cube junctions is responsible for such a switching behaviour and it can be described by the filament model. The effect of film thickness on switching ratio (ON/OFF) was also investigated in details. - Graphical abstract: This work describes a novel resistive switching memory cell based on self-assembled BaTiO{sub 3} nanocubes. - Highlights: • BaTiO{sub 3} nanocubes were prepared by one step facile hydrothermal method. • Self-assembled BaTiO{sub 3} nanocubes thin films were obtained by drop-coating approach. • The BaTiO{sub 3} nanocubes show excellent resistive switching properties for memory applications.

  3. Diet-induced obesity does not impact the generation and maintenance of primary memory CD8 T cells1

    PubMed Central

    Khan, Shaniya H.; Hemann, Emily A.; Legge, Kevin L.; Norian, Lyse A.; Badovinac, Vladimir P.

    2014-01-01

    The extent to which obesity compromises the differentiation and maintenance of protective memory CD8 T cell responses and renders obese individuals susceptible to infection remains unknown. Here, we show that diet-induced obesity did not impact the maintenance of pre-existing memory CD8 T cells including acquisition of a long-term memory phenotype (i.e. CD27hi, CD62Lhi, KLRG1low) and function (i.e. cytokine production, secondary expansion, and memory CD8 T cell-mediated protection). In addition, obesity did not influence the differentiation and maintenance of newly evoked memory CD8 T cell responses in inbred and outbred hosts generated in response to different types of systemic (LCMV, L. monocytogenes) and/or localized (influenza virus) infections. Interestingly, the rate of naïve-to-memory CD8 T cell differentiation after a peptide-coated dendritic cell (DC) immunization was similar in lean and obese hosts suggesting that obesity associated inflammation, unlike pathogen- or adjuvant-induced inflammation, did not influence the development of endogenous memory CD8 T cell responses. Therefore, our studies reveal that the obese environment does not influence the development or maintenance of memory CD8 T cell responses that are either primed before or after obesity is established, a surprising notion with important implications for future studies aiming to elucidate the role obesity plays in host susceptibility to infections. PMID:25378592

  4. Evaluation of EBV transformation of human memory B-cells isolated by FACS and MACS techniques.

    PubMed

    Sadreddini, Sanam; Jadidi-Niaragh, Farhad; Younesi, Vahid; Pourlak, Tala; Afkham, Amir; Shokri, Fazel; Yousefi, Mehdi

    2016-07-01

    Several studies have been performed to develop effective neutralizing monoclonal antibodies. The Epstein-Barr virus (EBV) can efficiently immortalize B-cells to establish lymphoblastoid cell lines (LCL) and so it has been used extensively for transformation of B-cells to produce and secrete immunoglobulin. The present study addressed the effect of TLR7/8 agonist (R848), feeder cells layer and fluorescence-activated cell sorting (FACS) and magnetic-activated cell sorting (MACS) cell separation methods on the transformation efficiency of antibody-producing memory B-cells. For these studies, the antigen used for analyses of antibody formation was the tetanus neurotoxin (TeNT) derived from Clostridium tetani. The results here showed that employing an HFFF.PI6 feeder cell layer, R848 agonist and FACS-mediated purification of memory B-cells led to increased transformation efficiency. Altogether, the effects of the R848 and the feeder cells provided an efficient method for EBV transformation of human B-cells. Moreover, there was an advantage in using FACS sorting of B-cells over the MACS method in the context of EBV transformation and immortalization of precursors of antigen-specific B-cells.

  5. Evaluation of EBV transformation of human memory B-cells isolated by FACS and MACS techniques.

    PubMed

    Sadreddini, Sanam; Jadidi-Niaragh, Farhad; Younesi, Vahid; Pourlak, Tala; Afkham, Amir; Shokri, Fazel; Yousefi, Mehdi

    2016-07-01

    Several studies have been performed to develop effective neutralizing monoclonal antibodies. The Epstein-Barr virus (EBV) can efficiently immortalize B-cells to establish lymphoblastoid cell lines (LCL) and so it has been used extensively for transformation of B-cells to produce and secrete immunoglobulin. The present study addressed the effect of TLR7/8 agonist (R848), feeder cells layer and fluorescence-activated cell sorting (FACS) and magnetic-activated cell sorting (MACS) cell separation methods on the transformation efficiency of antibody-producing memory B-cells. For these studies, the antigen used for analyses of antibody formation was the tetanus neurotoxin (TeNT) derived from Clostridium tetani. The results here showed that employing an HFFF.PI6 feeder cell layer, R848 agonist and FACS-mediated purification of memory B-cells led to increased transformation efficiency. Altogether, the effects of the R848 and the feeder cells provided an efficient method for EBV transformation of human B-cells. Moreover, there was an advantage in using FACS sorting of B-cells over the MACS method in the context of EBV transformation and immortalization of precursors of antigen-specific B-cells. PMID:27043044

  6. Multi-Bit Nano-Electromechanical Nonvolatile Memory Cells (Zigzag T Cells) for the Suppression of Bit-to-Bit Interference.

    PubMed

    Choi, Woo Young; Han, Jae Hwan; Cha, Tae Min

    2016-05-01

    Multi-bit nano-electromechanical (NEM) nonvolatile memory cells such as T cells were proposed for higher memory density. However, they suffered from bit-to-bit interference (BI). In order to suppress BI without sacrificing cell size, this paper proposes zigzag T cell structures. The BI suppression of the proposed zigzag T cell is verified by finite-element modeling (FEM). Based on the FEM results, the design of zigzag T cells is optimized.

  7. The cells that mediate innate immune memory and their functional significance in inflammatory and infectious diseases.

    PubMed

    Gardiner, Clair M; Mills, Kingston H G

    2016-08-01

    Immunological memory mediated by antigen-specific T and B cells is the foundation of adaptive immunity and is fundamental to the heightened and rapid protective immune response induced by vaccination or following re-infection with the same pathogen. While the innate immune system has classically been considered to be non-specific and devoid of memory, it now appears that it can be trained following exposure to microbes or their products and that this may confer a form of memory on innate immune cells. The evidence for immunological memory outside of T and B cells has been best established for natural killer (NK) cells, where it has been known for decades that NK cells have heighten responses following immunological re-challenge. Furthermore, recent studies have demonstrated that monocyte/macrophages, and probably dendritic cells, can be re-programmed through epigenetic modification, following exposure to pathogens or their products, resulting in heighted responses following a second stimulation. Unlike antigen-specific memory of the adaptive immune system, the second stimulation does not have to be with the same pathogen or antigen. Indirect evidence for this comes from reports on the non-specific beneficial effect of certain live vaccines, such as Bacillus Calmette Guerin (BCG) against unrelated childhood infectious diseases. It also appears that certain pathogen or pathogen-derived molecules can prime immune cells, especially macrophages, to secrete more anti-inflammatory and less pro-inflammatory cyokines, thus opening up the possibility of exploiting innate immune training as a new therapeutic approach for inflammatory diseases.

  8. The cells that mediate innate immune memory and their functional significance in inflammatory and infectious diseases.

    PubMed

    Gardiner, Clair M; Mills, Kingston H G

    2016-08-01

    Immunological memory mediated by antigen-specific T and B cells is the foundation of adaptive immunity and is fundamental to the heightened and rapid protective immune response induced by vaccination or following re-infection with the same pathogen. While the innate immune system has classically been considered to be non-specific and devoid of memory, it now appears that it can be trained following exposure to microbes or their products and that this may confer a form of memory on innate immune cells. The evidence for immunological memory outside of T and B cells has been best established for natural killer (NK) cells, where it has been known for decades that NK cells have heighten responses following immunological re-challenge. Furthermore, recent studies have demonstrated that monocyte/macrophages, and probably dendritic cells, can be re-programmed through epigenetic modification, following exposure to pathogens or their products, resulting in heighted responses following a second stimulation. Unlike antigen-specific memory of the adaptive immune system, the second stimulation does not have to be with the same pathogen or antigen. Indirect evidence for this comes from reports on the non-specific beneficial effect of certain live vaccines, such as Bacillus Calmette Guerin (BCG) against unrelated childhood infectious diseases. It also appears that certain pathogen or pathogen-derived molecules can prime immune cells, especially macrophages, to secrete more anti-inflammatory and less pro-inflammatory cyokines, thus opening up the possibility of exploiting innate immune training as a new therapeutic approach for inflammatory diseases. PMID:26979658

  9. Nonvolatile memory cells based on MoS2/graphene heterostructures.

    PubMed

    Bertolazzi, Simone; Krasnozhon, Daria; Kis, Andras

    2013-04-23

    Memory cells are an important building block of digital electronics. We combine here the unique electronic properties of semiconducting monolayer MoS2 with the high conductivity of graphene to build a 2D heterostructure capable of information storage. MoS2 acts as a channel in an intimate contact with graphene electrodes in a field-effect transistor geometry. Our prototypical all-2D transistor is further integrated with a multilayer graphene charge trapping layer into a device that can be operated as a nonvolatile memory cell. Because of its band gap and 2D nature, monolayer MoS2 is highly sensitive to the presence of charges in the charge trapping layer, resulting in a factor of 10(4) difference between memory program and erase states. The two-dimensional nature of both the contact and the channel can be harnessed for the fabrication of flexible nanoelectronic devices with large-scale integration.

  10. TLR4 ligands lipopolysaccharide and monophosphoryl lipid a differentially regulate effector and memory CD8+ T Cell differentiation.

    PubMed

    Cui, Weiguo; Joshi, Nikhil S; Liu, Ying; Meng, Hailong; Kleinstein, Steven H; Kaech, Susan M

    2014-05-01

    Vaccines formulated with nonreplicating pathogens require adjuvants to help bolster immunogenicity. The role of adjuvants in Ab production has been well studied, but how they influence memory CD8(+) T cell differentiation remains poorly defined. In this study we implemented dendritic cell-mediated immunization to study the effects of commonly used adjuvants, TLR ligands, on effector and memory CD8(+) T cell differentiation in mice. Intriguingly, we found that the TLR4 ligand LPS was far more superior to other TLR ligands in generating memory CD8(+) T cells upon immunization. LPS boosted clonal expansion similar to the other adjuvants, but fewer of the activated CD8(+) T cells died during contraction, generating a larger pool of memory cells. Surprisingly, monophosphoryl lipid A (MPLA), another TLR4 ligand, enhanced clonal expansion of effector CD8(+) T cells, but it also promoted their terminal differentiation and contraction; thus, fewer memory CD8(+) T cells formed, and MPLA-primed animals were less protected against secondary infection compared with those primed with LPS. Furthermore, gene expression profiling revealed that LPS-primed effector cells displayed a stronger pro-memory gene expression signature, whereas the gene expression profile of MPLA-primed effector cells aligned closer with terminal effector CD8(+) T cells. Lastly, we demonstrated that the LPS-TLR4-derived "pro-memory" signals were MyD88, but not Toll/IL-1R domain-containing adapter inducing IFN-β, dependent. This study reveals the influential power of adjuvants on the quantity and quality of CD8(+) T cell memory, and that attention to adjuvant selection is crucial because boosting effector cell expansion may not always equate with more memory T cells or greater protection.

  11. Cutting Edge: Resident Memory CD8 T Cells Express High-Affinity TCRs.

    PubMed

    Frost, Elizabeth L; Kersh, Anna E; Evavold, Brian D; Lukacher, Aron E

    2015-10-15

    Tissue-resident memory T (TRM) cells serve as vanguards of antimicrobial host defense in nonlymphoid tissues, particularly at barrier epithelia and in organs with nonrenewable cell types (e.g., brain). In this study, we asked whether an augmented ability to sense Ag complemented their role as early alarms of pathogen invasion. Using mouse polyomavirus, we show that brain-resident mouse polyomavirus-specific CD8 T cells, unlike memory cells in the spleen, progressively increase binding to MHC class I tetramers and CD8 coreceptor expression. Using the two-dimensional micropipette adhesion-frequency assay, we show that TRM cells in brain, as well as in kidney, express TCRs with up to 20-fold higher affinity than do splenic memory T cells, whereas effector cells express TCRs of similar high affinity in all organs. Together, these data demonstrate that TRM cells retain high TCR affinity, which endows them with the high Ag sensitivity needed for front-line defense against infectious agents. PMID:26371252

  12. Cyclic AMP pathway modifies memory through neural cell adhesion molecule alterations in the rat hippocampus.

    PubMed

    Razmi, Ali; Sahebgharani, Mousa; Khani, Mohammad Hossein; Paylakhi, Seyed Hassan; Faizi, Mehrdad; Zarrindast, Mohammad-Reza

    2014-01-01

    Neural Cell Adhesion Molecules (NCAMs) are known to influence memory by affecting neural cell-cell and cell-extracellular matrix junctions. This study investigated the possible role of cAMP pathway in the expression of hippocampal NCAM and its polysialylated derivative (PSA-NCAM). The following pharmacological tools were employed for manipulation of cAMP pathway: a) forskolin; the activator of adenylyl cyclase (AC), b) 8-Br-cAMP; a protein kinase A (PKA) agonist, c) 8-pCPT-2'-O-Me-cAMP; a selective enhancer of exchange protein activated by cAMP (Epac) and d) Rp-cAMP; a PKA inhibitor. Memory acquisition was tested by passive avoidance paradigm after injecting the above compounds for three consecutive days into the CA1 region of dorsal hippocampus of rats. Forskolin and 8-Br-cAMP enhanced memory retrieval while Rp-cAMP significantly reduced memory and NCAM levels. 8-pCPT-2'-O-Me-cAMP failed to alter memory performance or NCAM levels as compared to vehicle. We observed no significant changes in PSA-NCAM, however the expression of St8sia4 and St8sia2 (the polysialyltransferase isoforms) were altered. The mRNA levels of St8sia4 was down-regulated by 8-Br-cAMP, Rp-cAMP and 8-pCPT while forskolin led to almost 3 and 5 fold increase in mRNAs of St8sia2 and St8sia4, respectively. The current insight might endorse the predominant role of PKA as compared to Epac in cAMP pathway in expression of NCAM and memory function. PMID:24901853

  13. Reversible Reprogramming of Circulating Memory T Follicular Helper Cell Function during Chronic HIV Infection.

    PubMed

    Cubas, Rafael; van Grevenynghe, Julien; Wills, Saintedym; Kardava, Lela; Santich, Brian H; Buckner, Clarisa M; Muir, Roshell; Tardif, Virginie; Nichols, Carmen; Procopio, Francesco; He, Zhong; Metcalf, Talibah; Ghneim, Khader; Locci, Michela; Ancuta, Petronella; Routy, Jean-Pierre; Trautmann, Lydie; Li, Yuxing; McDermott, Adrian B; Koup, Rick A; Petrovas, Constantinos; Migueles, Steven A; Connors, Mark; Tomaras, Georgia D; Moir, Susan; Crotty, Shane; Haddad, Elias K

    2015-12-15

    Despite the overwhelming benefits of antiretroviral therapy (ART) in curtailing viral load in HIV-infected individuals, ART does not fully restore cellular and humoral immunity. HIV-infected individuals under ART show reduced responses to vaccination and infections and are unable to mount an effective antiviral immune response upon ART cessation. Many factors contribute to these defects, including persistent inflammation, especially in lymphoid tissues, where T follicular helper (Tfh) cells instruct and help B cells launch an effective humoral immune response. In this study we investigated the phenotype and function of circulating memory Tfh cells as a surrogate of Tfh cells in lymph nodes and found significant impairment of this cell population in chronically HIV-infected individuals, leading to reduced B cell responses. We further show that these aberrant memory Tfh cells exhibit an IL-2-responsive gene signature and are more polarized toward a Th1 phenotype. Treatment of functional memory Tfh cells with IL-2 was able to recapitulate the detrimental reprogramming. Importantly, this defect was reversible, as interfering with the IL-2 signaling pathway helped reverse the abnormal differentiation and improved Ab responses. Thus, reversible reprogramming of memory Tfh cells in HIV-infected individuals could be used to enhance Ab responses. Altered microenvironmental conditions in lymphoid tissues leading to altered Tfh cell differentiation could provide one explanation for the poor responsiveness of HIV-infected individuals to new Ags. This explanation has important implications for the development of therapeutic interventions to enhance HIV- and vaccine-mediated Ab responses in patients under ART.

  14. Reversible Reprogramming of Circulating Memory T Follicular Helper Cell Function during Chronic HIV Infection

    PubMed Central

    Cubas, Rafael; van Grevenynghe, Julien; Wills, Saintedym; Kardava, Lela; Santich, Brian H.; Buckner, Clarisa M.; Muir, Roshell; Tardif, Virginie; Nichols, Carmen; Procopio, Francesco; He, Zhong; Metcalf, Talibah; Ghneim, Khader; Locci, Michela; Ancuta, Petronella; Routy, Jean-Pierre; Trautmann, Lydie; Li, Yuxing; McDermott, Adrian B.; Koup, Rick A.; Petrovas, Constantinos; Migueles, Steven A.; Connors, Mark; Tomaras, Georgia D.; Moir, Susan; Crotty, Shane

    2015-01-01

    Despite the overwhelming benefits of antiretroviral therapy (ART) in curtailing viral load in HIV-infected individuals, ART does not fully restore cellular and humoral immunity. HIV-infected individuals under ART show reduced responses to vaccination and infections and are unable to mount an effective antiviral immune response upon ART cessation. Many factors contribute to these defects, including persistent inflammation, especially in lymphoid tissues, where T follicular helper (Tfh) cells instruct and help B cells launch an effective humoral immune response. In this study we investigated the phenotype and function of circulating memory Tfh cells as a surrogate of Tfh cells in lymph nodes and found significant impairment of this cell population in chronically HIV-infected individuals, leading to reduced B cell responses. We further show that these aberrant memory Tfh cells exhibit an IL-2–responsive gene signature and are more polarized toward a Th1 phenotype. Treatment of functional memory Tfh cells with IL-2 was able to recapitulate the detrimental reprogramming. Importantly, this defect was reversible, as interfering with the IL-2 signaling pathway helped reverse the abnormal differentiation and improved Ab responses. Thus, reversible reprogramming of memory Tfh cells in HIV-infected individuals could be used to enhance Ab responses. Altered microenvironmental conditions in lymphoid tissues leading to altered Tfh cell differentiation could provide one explanation for the poor responsiveness of HIV-infected individuals to new Ags. This explanation has important implications for the development of therapeutic interventions to enhance HIV- and vaccine-mediated Ab responses in patients under ART. PMID:26546609

  15. Unique transcriptional profile of liver-resident memory CD8+ T cells induced by immunization with malaria sporozoites

    PubMed Central

    Tse, Sze-Wah; Cockburn, Ian A.; Zhang, Hao; Scott, Alan L.; Zavala, Fidel

    2013-01-01

    Sterile immunity against live Plasmodium infection can be achieved by immunization with radiation attenuated sporozoites. This protection is known to be mediated in part by antigen-specific memory CD8+ T cells, presumably those residing in the liver. We characterized and compared the transcriptional profile of parasite-specific memory CD8+ T cells residing in the liver and spleen after immunization of mice with irradiated sporozoites. Microarray-based expression analysis of these memory CD8+ T cells indicated that liver resident memory cells display a distinct gene expression profile. We found major differences in the expression of immune function genes as well as genes involved in the cell cycle, cell trafficking, transcription and intracellular signaling. Importantly, the malaria parasite-induced liver resident CD8+ T cells display a transcriptional profile different to that described for CD8+ T cells following other microbial challenges. PMID:23594961

  16. A new model for CD8+ T cell memory inflation based upon a recombinant adenoviral vector1

    PubMed Central

    Bolinger, Beatrice; Sims, Stuart; O’Hara, Geraldine; de Lara, Catherine; Tchilian, Elma; Firner, Sonja; Engeler, Daniel; Ludewig, Burkhard; Klenerman, Paul

    2013-01-01

    CD8+ T cell memory inflation, first described in murine cytomegalovirus (MCMV) infection, is characterized by the accumulation of high-frequency, functional antigen-specific CD8+ T cell pools with an effector-memory phenotype and enrichment in peripheral organs. Although persistence of antigen is considered essential, the rules underpinning memory inflation are still unclear. The MCMV model is, however, complicated by the virus’s low-level persistence, and stochastic reactivation. We developed a new model of memory inflation based upon a βgal-recombinant adenovirus vector (Ad-LacZ). After i.v. administration in C57BL/6 mice we observe marked memory inflation in the βgal96 epitope, while a second epitope, βgal497, undergoes classical memory formation. The inflationary T cell responses show kinetics, distribution, phenotype and functions similar to those seen in MCMV and are reproduced using alternative routes of administration. Memory inflation in this model is dependent on MHC Class II. As in MCMV, only the inflating epitope showed immunoproteasome-independence. These data define a new model for memory inflation, which is fully replication-independent, internally controlled and reproduces the key immunologic features of the CD8+ T cell response. This model provides insight into the mechanisms responsible for memory inflation, and since it is based on a vaccine vector, also is relevant to novel T cell-inducing vaccines in humans. PMID:23509359

  17. The cognitive and behavioral characteristics of children with low working memory.

    PubMed

    Alloway, Tracy Packiam; Gathercole, Susan Elizabeth; Kirkwood, Hannah; Elliott, Julian

    2009-01-01

    This study explored the cognitive and behavioral profiles of children with working memory impairments. In an initial screening of 3,189 five- to eleven-year-olds, 308 were identified as having very low working memory scores. Cognitive skills (IQ, vocabulary, reading, and math), classroom behavior, and self-esteem were assessed. The majority of the children struggled in the learning measures and verbal ability. They also obtained atypically high ratings of cognitive problems/inattentive symptoms and were judged to have short attention spans, high levels of distractibility, problems in monitoring the quality of their work, and difficulties in generating new solutions to problems. These data provide rich new information on the cognitive and behavioral profiles that characterize children with low working memory.

  18. Front-Line Memory T Cells Think Outside the T-box… Mostly.

    PubMed

    Snyder, Christopher M

    2015-12-15

    Tissue-resident memory T (Trm) cells patrol barrier tissues. In this issue of Immunity, Carbone and colleagues show that downregulation of T-box proteins Eomesodermin and T-bet is critical for their differentiation, but residual levels of T-bet are important for long-term Trm survival and function.

  19. Effector and memory T cell subsets in the response to bovine tuberculosis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Long-term (i.e., 14d) cultured IFN-gamma ELISPOT assays of PBMC are used as a correlate of T cell central memory (Tcm) responses in cattle and humans. With bovine tuberculosis, vaccine-elicited Tcm responses correlate with protection against experimental Mycobacterium bovis infection. The objective ...

  20. Bovine central memory T cells are highly proliferative in response to bovine tuberculosis infection

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Long-term (i.e., 14 days) cultured IFN-gamma ELISPOT assays measure central memory T cell (Tcm) responses in both humans and cattle. With bovine tuberculosis, vaccine-elicited long-term IFN-gamma ELISPOT responses correlate with protection. In other species, Tcm’s pose low activation threshold and a...

  1. Excellent resistive memory characteristics and switching mechanism using a Ti nanolayer at the Cu/TaOx interface

    PubMed Central

    2012-01-01

    Excellent resistive switching memory characteristics were demonstrated for an Al/Cu/Ti/TaOx/W structure with a Ti nanolayer at the Cu/TaOx interface under low voltage operation of ± 1.5 V and a range of current compliances (CCs) from 0.1 to 500 μA. Oxygen accumulation at the Ti nanolayer and formation of a defective high-κ TaOx film were confirmed by high-resolution transmission electron microscopy, energy dispersive X-ray spectroscopy, and X-ray photo-electron spectroscopy. The resistive switching memory characteristics of the Al/Cu/Ti/TaOx/W structure, such as HRS/LRS (approximately 104), stable switching cycle stability (>106) and multi-level operation, were improved compared with those of Al/Cu/TaOx/W devices. These results were attributed to the control of Cu migration/dissolution by the insertion of a Ti nanolayer at the Cu/TaOx interface. In contrast, CuOx formation at the Cu/TaOx interface was observed in an Al/Cu/TaOx/W structure, which hindered dissolution of the Cu filament and resulted in a small resistance ratio of approximately 10 at a CC of 500 μA. A high charge-trapping density of 6.9 × 1016 /cm2 was observed in the Al/Cu/Ti/TaOx/W structure from capacitance-voltage hysteresis characteristics, indicating the migration of Cu ions through defect sites. The switching mechanism was successfully explained for structures with and without the Ti nanolayer. By using a new approach, the nanoscale diameter of Cu filament decreased from 10.4 to 0.17 nm as the CC decreased from 500 to 0.1 μA, resulting in a large memory size of 7.6 T to 28 Pbit/sq in. Extrapolated 10-year data retention of the Ti nanolayer device was also obtained. The findings of this study will not only improve resistive switching memory performance but also aid future design of nanoscale nonvolatile memory. PMID:22734564

  2. NK Cell-Mediated Regulation of Protective Memory Responses against Intracellular Ehrlichial Pathogens

    PubMed Central

    Habib, Samar; El Andaloussi, Abdeljabar; Hisham, Ahmed; Ismail, Nahed

    2016-01-01

    Ehrlichiae are gram-negative obligate intracellular bacteria that cause potentially fatal human monocytic ehrlichiosis. We previously showed that natural killer (NK) cells play a critical role in host defense against Ehrlichia during primary infection. However, the contribution of NK cells to the memory response against Ehrlichia remains elusive. Primary infection of C57BL/6 mice with Ehrlichia muris provides long-term protection against a second challenge with the highly virulent Ixodes ovatus Ehrlichia (IOE), which ordinarily causes fatal disease in naïve mice. Here, we show that the depletion of NK cells in E. muris-primed mice abrogates the protective memory response against IOE. Approximately, 80% of NK cell-depleted E. muris-primed mice succumbed to lethal IOE infection on days 8–10 after IOE infection, similar to naïve mice infected with the same dose of IOE. The lack of a recall response in NK cell-depleted mice correlated with an increased bacterial burden, extensive liver injury, decreased frequency of Ehrlichia-specific IFN-γ-producing memory CD4+ and CD8+ T-cells, and a low titer of Ehrlichia-specific antibodies. Intraperitoneal infection of mice with E. muris resulted in the production of IL-15, IL-12, and IFN-γ as well as an expansion of activated NKG2D+ NK cells. The adoptive transfer of purified E. muris-primed hepatic and splenic NK cells into Rag2-/-Il2rg-/- recipient mice provided protective immunity against challenge with E. muris. Together, these data suggest that E. muris-induced memory-like NK cells, which contribute to the protective, recall response against Ehrlichia. PMID:27092553

  3. Characteristics of Mitochondrial Transformation into Human Cells.

    PubMed

    Kesner, E E; Saada-Reich, A; Lorberboum-Galski, H

    2016-01-01

    Mitochondria can be incorporated into mammalian cells by simple co-incubation of isolated mitochondria with cells, without the need of transfection reagents or any other type of intervention. This phenomenon was termed mitochondrial transformation, and although it was discovered in 1982, currently little is known regarding its mechanism(s). Here we demonstrate that mitochondria can be transformed into recipient cells very quickly, and co-localize with endogenous mitochondria. The isolated mitochondria interact directly with cells, which engulf the mitochondria with cellular extensions in a way, which may suggest the involvement of macropinocytosis or macropinocytosis-like mechanisms in mitochondrial transformation. Indeed, macropinocytosis inhibitors but not clathrin-mediated endocytosis inhibition-treatments, blocks mitochondria transformation. The integrity of the mitochondrial outer membrane and its proteins is essential for the transformation of the mitochondria into cells; cells can distinguish mitochondria from similar particles and transform only intact mitochondria. Mitochondrial transformation is blocked in the presence of the heparan sulfate molecules pentosan polysulfate and heparin, which indicate crucial involvement of cellular heparan sulfate proteoglycans in the mitochondrial transformation process.

  4. Characteristics of Mitochondrial Transformation into Human Cells

    PubMed Central

    Kesner, E. E.; Saada-Reich, A.; Lorberboum-Galski, H.

    2016-01-01

    Mitochondria can be incorporated into mammalian cells by simple co-incubation of isolated mitochondria with cells, without the need of transfection reagents or any other type of intervention. This phenomenon was termed mitochondrial transformation, and although it was discovered in 1982, currently little is known regarding its mechanism(s). Here we demonstrate that mitochondria can be transformed into recipient cells very quickly, and co-localize with endogenous mitochondria. The isolated mitochondria interact directly with cells, which engulf the mitochondria with cellular extensions in a way, which may suggest the involvement of macropinocytosis or macropinocytosis-like mechanisms in mitochondrial transformation. Indeed, macropinocytosis inhibitors but not clathrin-mediated endocytosis inhibition-treatments, blocks mitochondria transformation. The integrity of the mitochondrial outer membrane and its proteins is essential for the transformation of the mitochondria into cells; cells can distinguish mitochondria from similar particles and transform only intact mitochondria. Mitochondrial transformation is blocked in the presence of the heparan sulfate molecules pentosan polysulfate and heparin, which indicate crucial involvement of cellular heparan sulfate proteoglycans in the mitochondrial transformation process. PMID:27184109

  5. Effector-memory T cells develop in islets and report islet pathology in type 1 diabetes.

    PubMed

    Chee, Jonathan; Ko, Hyun-Ja; Skowera, Ania; Jhala, Gaurang; Catterall, Tara; Graham, Kate L; Sutherland, Robyn M; Thomas, Helen E; Lew, Andrew M; Peakman, Mark; Kay, Thomas W H; Krishnamurthy, Balasubramanian

    2014-01-15

    CD8(+) T cells are critical in human type 1 diabetes and in the NOD mouse. In this study, we elucidated the natural history of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-specific CD8(+) T cells in NOD diabetes using MHC-tetramer technology. IGRP206-214-specific T cells in the peripheral lymphoid tissue increased with age, and their numbers correlated with insulitis progression. IGRP206-214-specific T cells in the peripheral lymphoid tissue expressed markers of chronic Ag stimulation, and their numbers were stable after diagnosis of diabetes, consistent with their memory phenotype. IGRP206-214-specific T cells in NOD mice expand, acquire the phenotype of effector-memory T cells in the islets, and emigrate to the peripheral lymphoid tissue. Our observations suggest that enumeration of effector-memory T cells of multiple autoantigen specificities in the periphery of type 1 diabetic subjects could be a reliable reporter for progression of islet pathology.

  6. Skin-resident memory CD4+ T cells enhance protection against Leishmania major infection

    PubMed Central

    Glennie, Nelson D.; Yeramilli, Venkata A.; Beiting, Daniel P.; Volk, Susan W.; Weaver, Casey T.

    2015-01-01

    Leishmaniasis causes a significant disease burden worldwide. Although Leishmania-infected patients become refractory to reinfection after disease resolution, effective immune protection has not yet been achieved by human vaccines. Although circulating Leishmania-specific T cells are known to play a critical role in immunity, the role of memory T cells present in peripheral tissues has not been explored. Here, we identify a population of skin-resident Leishmania-specific memory CD4+ T cells. These cells produce IFN-γ and remain resident in the skin when transplanted by skin graft onto naive mice. They function to recruit circulating T cells to the skin in a CXCR3-dependent manner, resulting in better control of the parasites. Our findings are the first to demonstrate that CD4+ TRM cells form in response to a parasitic infection, and indicate that optimal protective immunity to Leishmania, and thus the success of a vaccine, may depend on generating both circulating and skin-resident memory T cells. PMID:26216123

  7. Depletion of primary cilia from mature dentate granule cells impairs hippocampus-dependent contextual memory

    PubMed Central

    Rhee, Soyoung; Kirschen, Gregory W.; Gu, Yan; Ge, Shaoyu

    2016-01-01

    The primary cilium, a sensory organelle, regulates cell proliferation and neuronal development of dentate granule cells in the hippocampus. However, its role in the function of mature dentate granule cells remains unknown. Here we specifically depleted and disrupted ciliary proteins IFT20 and Kif3A (respectively) in mature dentate granule cells and investigated hippocampus-dependent contextual memory and long-term plasticity at mossy fiber synapses. We found that depletion of IFT20 in these cells significantly impaired context-dependent fear-related memory. Furthermore, we tested synaptic plasticity of mossy fiber synapses in area CA3 and found increased long-term potentiation upon depletion of IFT20 or disruption of Kif3A. Our findings suggest a role of primary cilia in the memory function of mature dentate granule cells, which may result from abnormal mossy fiber synaptic plasticity. A direct link between the primary cilia of mature dentate granule cells and behavior will require further investigation using independent approaches to manipulate primary cilia. PMID:27678193

  8. ZBTB32 Restricts the Duration of Memory B Cell Recall Responses.

    PubMed

    Jash, Arijita; Wang, Yinan; Weisel, Florian J; Scharer, Christopher D; Boss, Jeremy M; Shlomchik, Mark J; Bhattacharya, Deepta

    2016-08-15

    Memory B cell responses are more rapid and of greater magnitude than are primary Ab responses. The mechanisms by which these secondary responses are eventually attenuated remain unknown. We demonstrate that the transcription factor ZBTB32 limits the rapidity and duration of Ab recall responses. ZBTB32 is highly expressed by mouse and human memory B cells but not by their naive counterparts. Zbtb32(-/-) mice mount normal primary Ab responses to T-dependent Ags. However, Zbtb32(-/-) memory B cell-mediated recall responses occur more rapidly and persist longer than do control responses. Microarray analyses demonstrate that Zbtb32(-/-) secondary bone marrow plasma cells display elevated expression of genes that promote cell cycle progression and mitochondrial function relative to wild-type controls. BrdU labeling and adoptive transfer experiments confirm more rapid production and a cell-intrinsic survival advantage of Zbtb32(-/-) secondary plasma cells relative to wild-type counterparts. ZBTB32 is therefore a novel negative regulator of Ab recall responses. PMID:27357154

  9. C-Myc regulation by costimulatory signals modulates the generation of CD8+ memory T cells during viral infection.

    PubMed

    Haque, Mohammad; Song, Jianyong; Fino, Kristin; Wang, Youfei; Sandhu, Praneet; Song, Xinmeng; Norbury, Christopher; Ni, Bing; Fang, Deyu; Salek-Ardakani, Shahram; Song, Jianxun

    2016-01-01

    The signalling mechanisms of costimulation in the development of memory T cells remain to be clarified. Here, we show that the transcription factor c-Myc in CD8(+) T cells is controlled by costimulatory molecules, which modulates the development of memory CD8(+) T cells. C-Myc expression was dramatically reduced in Cd28(-/-) or Ox40(-/-) memory CD8(+) T cells, and c-Myc over-expression substantially reversed the defects in the development of T-cell memory following viral infection. C-Myc regulated the expression of survivin, an inhibitor of apoptosis, which promoted the generation of virus-specific memory CD8(+) T cells. Moreover, over-expression of survivin with bcl-xL, a downstream molecule of NF-κB and intracellular target of costimulation that controls survival, in Cd28(-/-) or Ox40(-/-) CD8(+) T cells, reversed the defects in the generation of memory T cells in response to viral infection. These results identify c-Myc as a key controller of memory CD8(+) T cells from costimulatory signals.

  10. C-Myc regulation by costimulatory signals modulates the generation of CD8+ memory T cells during viral infection.

    PubMed

    Haque, Mohammad; Song, Jianyong; Fino, Kristin; Wang, Youfei; Sandhu, Praneet; Song, Xinmeng; Norbury, Christopher; Ni, Bing; Fang, Deyu; Salek-Ardakani, Shahram; Song, Jianxun

    2016-01-01

    The signalling mechanisms of costimulation in the development of memory T cells remain to be clarified. Here, we show that the transcription factor c-Myc in CD8(+) T cells is controlled by costimulatory molecules, which modulates the development of memory CD8(+) T cells. C-Myc expression was dramatically reduced in Cd28(-/-) or Ox40(-/-) memory CD8(+) T cells, and c-Myc over-expression substantially reversed the defects in the development of T-cell memory following viral infection. C-Myc regulated the expression of survivin, an inhibitor of apoptosis, which promoted the generation of virus-specific memory CD8(+) T cells. Moreover, over-expression of survivin with bcl-xL, a downstream molecule of NF-κB and intracellular target of costimulation that controls survival, in Cd28(-/-) or Ox40(-/-) CD8(+) T cells, reversed the defects in the generation of memory T cells in response to viral infection. These results identify c-Myc as a key controller of memory CD8(+) T cells from costimulatory signals. PMID:26791245

  11. C-Myc regulation by costimulatory signals modulates the generation of CD8+ memory T cells during viral infection

    PubMed Central

    Haque, Mohammad; Song, Jianyong; Fino, Kristin; Wang, Youfei; Sandhu, Praneet; Song, Xinmeng; Norbury, Christopher; Ni, Bing; Fang, Deyu; Salek-Ardakani, Shahram; Song, Jianxun

    2016-01-01

    The signalling mechanisms of costimulation in the development of memory T cells remain to be clarified. Here, we show that the transcription factor c-Myc in CD8+ T cells is controlled by costimulatory molecules, which modulates the development of memory CD8+ T cells. C-Myc expression was dramatically reduced in Cd28−/− or Ox40−/− memory CD8+ T cells, and c-Myc over-expression substantially reversed the defects in the development of T-cell memory following viral infection. C-Myc regulated the expression of survivin, an inhibitor of apoptosis, which promoted the generation of virus-specific memory CD8+ T cells. Moreover, over-expression of survivin with bcl-xL, a downstream molecule of NF-κB and intracellular target of costimulation that controls survival, in Cd28−/− or Ox40−/− CD8+ T cells, reversed the defects in the generation of memory T cells in response to viral infection. These results identify c-Myc as a key controller of memory CD8+ T cells from costimulatory signals. PMID:26791245

  12. Characteristics and EGFP expression of goat mammary gland epithelial cells.

    PubMed

    Zheng, Y-M; He, X-Y; Zhang, Y

    2010-12-01

    The aims of this study were (i) to establish a goat mammary gland epithelial (GMGE) cell line, and (ii) to determine if these GMGE cells could be maintained long-term in culture by continuous subculturing following transfection with a reporter gene, enhanced green fluorescence protein (EGFP). Primary culture of GMGE cells was achieved by outgrowth of migrating cells from the fragments of the mammary gland tissue of a lactating goat. The passage 16 GMGE cells were transfected with EGFP gene using lipofection. The expression of Cell keratins of epithelial cells in GMGE cells was test by immunofluorescence. Βeta-Casein gene mRNA was test for GMGE cells by RT-PCR. The results showed that when grown at low density on a plastic substratum, the GMGE cells formed islands, and when grown to confluency, the cells formed a monolayer and aggregated with the characteristic cobble-stone morphology of epithelial cells. GMGE cells could form dome-like structure which looked like nipple, and the lumen-like structures formed among the cells. Several blister-like structures appeared in the appearance of the cells. The GMGE cells contained different cell types, majority of the cells were short shuttle-like or polygon which were beehive-like. A part of cells were round and flat, a small number of cells were elongated. Some of the GMGE cells contained milk drops. The cell nuclei were round which had 2-4 obvious cores. The expression of Cell keratins demonstrated the property of epithelial cells in GMGE cells by immunofluorescence. The GMGE cells could express transcript encoding a Βeta-Casein protein. EGFP gene was successfully transferred into the GMGE cells, and the transfected cells could be maintained long-term in culture by continuous subculturing. In conclusion, we have established a EGFP gene transfected GMGE (ET-GMGE) cell line and maintained it long-term in culture by continuous subculturing. PMID:20113446

  13. Characteristics and EGFP expression of goat mammary gland epithelial cells.

    PubMed

    Zheng, Y-M; He, X-Y; Zhang, Y

    2010-12-01

    The aims of this study were (i) to establish a goat mammary gland epithelial (GMGE) cell line, and (ii) to determine if these GMGE cells could be maintained long-term in culture by continuous subculturing following transfection with a reporter gene, enhanced green fluorescence protein (EGFP). Primary culture of GMGE cells was achieved by outgrowth of migrating cells from the fragments of the mammary gland tissue of a lactating goat. The passage 16 GMGE cells were transfected with EGFP gene using lipofection. The expression of Cell keratins of epithelial cells in GMGE cells was test by immunofluorescence. Βeta-Casein gene mRNA was test for GMGE cells by RT-PCR. The results showed that when grown at low density on a plastic substratum, the GMGE cells formed islands, and when grown to confluency, the cells formed a monolayer and aggregated with the characteristic cobble-stone morphology of epithelial cells. GMGE cells could form dome-like structure which looked like nipple, and the lumen-like structures formed among the cells. Several blister-like structures appeared in the appearance of the cells. The GMGE cells contained different cell types, majority of the cells were short shuttle-like or polygon which were beehive-like. A part of cells were round and flat, a small number of cells were elongated. Some of the GMGE cells contained milk drops. The cell nuclei were round which had 2-4 obvious cores. The expression of Cell keratins demonstrated the property of epithelial cells in GMGE cells by immunofluorescence. The GMGE cells could express transcript encoding a Βeta-Casein protein. EGFP gene was successfully transferred into the GMGE cells, and the transfected cells could be maintained long-term in culture by continuous subculturing. In conclusion, we have established a EGFP gene transfected GMGE (ET-GMGE) cell line and maintained it long-term in culture by continuous subculturing.

  14. Complexity of the human memory B-cell compartment is determined by the versatility of clonal diversification in germinal centers.

    PubMed

    Budeus, Bettina; Schweigle de Reynoso, Stefanie; Przekopowitz, Martina; Hoffmann, Daniel; Seifert, Marc; Küppers, Ralf

    2015-09-22

    Our knowledge about the clonal composition and intraclonal diversity of the human memory B-cell compartment and the relationship between memory B-cell subsets is still limited, although these are central issues for our understanding of adaptive immunity. We performed a deep sequencing analysis of rearranged immunoglobulin (Ig) heavy chain genes from biological replicates, covering more than 100,000 memory B lymphocytes from two healthy adults. We reveal a highly similar B-cell receptor repertoire among the four main human IgM(+) and IgG(+) memory B-cell subsets. Strikingly, in both donors, 45% of sequences could be assigned to expanded clones, demonstrating that the human memory B-cell compartment is characterized by many, often very large, B-cell clones. Twenty percent of the clones consisted of class switched and IgM(+)(IgD(+)) members, a feature that correlated significantly with clone size. Hence, we provide strong evidence that the vast majority of Ig mutated B cells--including IgM(+)IgD(+)CD27(+) B cells--are post-germinal center (GC) memory B cells. Clone members showed high intraclonal sequence diversity and high intraclonal versatility in Ig class and IgG subclass composition, with particular patterns of memory B-cell clone generation in GC reactions. In conclusion, GC produce amazingly large, complex, and diverse memory B-cell clones, equipping the human immune system with a versatile and highly diverse compartment of IgM(+)(IgD(+)) and class-switched memory B cells.

  15. Complexity of the human memory B-cell compartment is determined by the versatility of clonal diversification in germinal centers.

    PubMed

    Budeus, Bettina; Schweigle de Reynoso, Stefanie; Przekopowitz, Martina; Hoffmann, Daniel; Seifert, Marc; Küppers, Ralf

    2015-09-22

    Our knowledge about the clonal composition and intraclonal diversity of the human memory B-cell compartment and the relationship between memory B-cell subsets is still limited, although these are central issues for our understanding of adaptive immunity. We performed a deep sequencing analysis of rearranged immunoglobulin (Ig) heavy chain genes from biological replicates, covering more than 100,000 memory B lymphocytes from two healthy adults. We reveal a highly similar B-cell receptor repertoire among the four main human IgM(+) and IgG(+) memory B-cell subsets. Strikingly, in both donors, 45% of sequences could be assigned to expanded clones, demonstrating that the human memory B-cell compartment is characterized by many, often very large, B-cell clones. Twenty percent of the clones consisted of class switched and IgM(+)(IgD(+)) members, a feature that correlated significantly with clone size. Hence, we provide strong evidence that the vast majority of Ig mutated B cells--including IgM(+)IgD(+)CD27(+) B cells--are post-germinal center (GC) memory B cells. Clone members showed high intraclonal sequence diversity and high intraclonal versatility in Ig class and IgG subclass composition, with particular patterns of memory B-cell clone generation in GC reactions. In conclusion, GC produce amazingly large, complex, and diverse memory B-cell clones, equipping the human immune system with a versatile and highly diverse compartment of IgM(+)(IgD(+)) and class-switched memory B cells. PMID:26324941

  16. Progressive CD4+ central–memory T cell decline results in CD4+ effector–memory insufficiency and overt disease in chronic SIV infection

    PubMed Central

    Okoye, Afam; Meier-Schellersheim, Martin; Brenchley, Jason M.; Hagen, Shoko I.; Walker, Joshua M.; Rohankhedkar, Mukta; Lum, Richard; Edgar, John B.; Planer, Shannon L.; Legasse, Alfred; Sylwester, Andrew W.; Piatak, Michael; Lifson, Jeffrey D.; Maino, Vernon C.; Sodora, Donald L.; Douek, Daniel C.; Axthelm, Michael K.; Grossman, Zvi; Picker, Louis J.

    2007-01-01

    Primary simian immunodeficiency virus (SIV) infections of rhesus macaques result in the dramatic depletion of CD4+ CCR5+ effector–memory T (TEM) cells from extra-lymphoid effector sites, but in most infections, an increased rate of CD4+ memory T cell proliferation appears to prevent collapse of effector site CD4+ TEM cell populations and acute-phase AIDS. Eventually, persistent SIV replication results in chronic-phase AIDS, but the responsible mechanisms remain controversial. Here, we demonstrate that in the chronic phase of progressive SIV infection, effector site CD4+ TEM cell populations manifest a slow, continuous decline, and that the degree of this depletion remains a highly significant correlate of late-onset AIDS. We further show that due to persistent immune activation, effector site CD4+ TEM cells are predominantly short-lived, and that their homeostasis is strikingly dependent on the production of new CD4+ TEM cells from central–memory T (TCM) cell precursors. The instability of effector site CD4+ TEM cell populations over time was not explained by increasing destruction of these cells, but rather was attributable to progressive reduction in their production, secondary to decreasing numbers of CCR5− CD4+ TCM cells. These data suggest that although CD4+ TEM cell depletion is a proximate mechanism of immunodeficiency, the tempo of this depletion and the timing of disease onset are largely determined by destruction, failing production, and gradual decline of CD4+ TCM cells. PMID:17724130

  17. Modulation of mTOR Signalling Triggers the Formation of Stem Cell-like Memory T Cells

    PubMed Central

    Scholz, Godehard; Jandus, Camilla; Zhang, Lianjun; Grandclément, Camille; Lopez-Mejia, Isabel C.; Soneson, Charlotte; Delorenzi, Mauro; Fajas, Lluis; Held, Werner; Dormond, Olivier; Romero, Pedro

    2016-01-01

    Robust, long-lasting immune responses are elicited by memory T cells that possess properties of stem cells, enabling them to persist long-term and to permanently replenish the effector pools. Thus, stem cell-like memory T (TSCM) cells are of key therapeutic value and efforts are underway to characterize TSCM cells and to identify means for their targeted induction. Here, we show that inhibition of mechanistic/mammalian Target of Rapamycin (mTOR) complex 1 (mTORC1) by rapamycin or the Wnt-β-catenin signalling activator TWS119 in activated human naive T cells leads to the induction of TSCM cells. We show that these compounds switch T cell metabolism to fatty acid oxidation as favoured metabolic programme for TSCM cell generation. Of note, pharmacologically induced TSCM cells possess superior functional features as a long-term repopulation capacity after adoptive transfer. Furthermore, we provide insights into the transcriptome of TSCM cells. Our data identify a mechanism of pharmacological mTORC1 inhibitors, allowing us to confer stemness to human naive T cells which may be significantly relevant for the design of innovative T cell-based cancer immunotherapies. PMID:26981571

  18. Mitigation of Memory Effects in Beta Scintillation Cells for Radioactive Gas Detection

    SciTech Connect

    Seifert, Carolyn E; McIntyre, Justin I; Antolick, Kathryn C; Carman, April J; Cooper, Matthew W; Hayes, James C; Heimbigner, Tom R; Hubbard, C W; Litke, Kevin E; Ripplinger, Mike D; Suarez, Reynold

    2005-08-31

    The Automated Radioxenon Sampler/Analyzer (ARSA) developed at PNNL measures the relative concentrations of xenon isotopes using a coincidence system. Previous tests of the ARSA system have shown that latent radioactivity remains in the plastic cells after evacuation of the gases, leading to a “memory effect” in which the background count rate is dependent on the sample history. The increased background results in lower detection sensitivity. Two possible solutions to the memory effect are explored in this work: depositing a thin layer of metal on the plastic cell (“metallization”), and using an inorganic scintillating cell composed of yttrium aluminum perovskite (YAP). In both cases, the presence of inorganic material at the surface is intended to inhibit the diffusion of gases into the cell walls.

  19. From sensorimotor learning to memory cells in prefrontal and temporal association cortex: a neurocomputational study of disembodiment.

    PubMed

    Pulvermüller, Friedemann; Garagnani, Max

    2014-08-01

    Memory cells, the ultimate neurobiological substrates of working memory, remain active for several seconds and are most commonly found in prefrontal cortex and higher multisensory areas. However, if correlated activity in "embodied" sensorimotor systems underlies the formation of memory traces, why should memory cells emerge in areas distant from their antecedent activations in sensorimotor areas, thus leading to "disembodiment" (movement away from sensorimotor systems) of memory mechanisms? We modelled the formation of memory circuits in six-area neurocomputational architectures, implementing motor and sensory primary, secondary and higher association areas in frontotemporal cortices along with known between-area neuroanatomical connections. Sensorimotor learning driven by Hebbian neuroplasticity led to formation of cell assemblies distributed across the different areas of the network. These action-perception circuits (APCs) ignited fully when stimulated, thus providing a neural basis for long-term memory (LTM) of sensorimotor information linked by learning. Subsequent to ignition, activity vanished rapidly from APC neurons in sensorimotor areas but persisted in those in multimodal prefrontal and temporal areas. Such persistent activity provides a mechanism for working memory for actions, perceptions and symbols, including short-term phonological and semantic storage. Cell assembly ignition and "disembodied" working memory retreat of activity to multimodal areas are documented in the neurocomputational models' activity dynamics, at the level of single cells, circuits, and cortical areas. Memory disembodiment is explained neuromechanistically by APC formation and structural neuroanatomical features of the model networks, especially the central role of multimodal prefrontal and temporal cortices in bridging between sensory and motor areas. These simulations answer the "where" question of cortical working memory in terms of distributed APCs and their inner structure

  20. Effect of antigen-induced suppressor B cells on development of memory B cells, carrier-specific helper T cells, and antibody-forming cells

    SciTech Connect

    Kalinkovich, A.G.; Luganskaya, E.L.; Pinegin, B.V.

    1986-12-01

    This paper studies the presence of an Fc receptor on the surface of antigen-induced suppressor B cells (AISB), their sensitivity to antiproliferative agents, their interaction with other immunoregulator cells and with the precursors of antibody-forming cells (AFC). Mice were used in the experiments and were irradiated in a dose of 8.5 Gy (/sup 137/Cs). The effect of AISB on memory B cells is shown as is the effect of AISB on development of carrier-specific helper T cells. Also presented is the effect of AISB on development of AFC.

  1. Color Memory of University Students: Influence of Color Experience and Color Characteristic

    ERIC Educational Resources Information Center

    Bynum, Carlisle; Epps, Helen H.; Kaya, Naz

    2006-01-01

    The ability to select a previously viewed color specimen from an array of specimens that differ in hue, value, or chroma varies among individuals, and may be related to one's basic color discrimination ability or to prior experience with color. This study investigated short-term color memory of 40 college students, 20 of whom were interior design…

  2. Do Irrelevant Sounds Impair the Maintenance of All Characteristics of Speech in Memory?

    ERIC Educational Resources Information Center

    Gabriel, D.; Gaudrain, E.; Lebrun-Guillaud, G.; Sheppard, F.; Tomescu, I. M.; Schnider, A.

    2012-01-01

    Several studies have shown that maintaining in memory some attributes of speech, such as the content or pitch of an interlocutor's message, is markedly reduced in the presence of background sounds made of spectrotemporal variations. However, experimental paradigms showing this interference have only focused on one attribute of speech at a time,…

  3. Receiver Operating Characteristic Analysis of Eyewitness Memory: Comparing the Diagnostic Accuracy of Simultaneous versus Sequential Lineups

    ERIC Educational Resources Information Center

    Mickes, Laura; Flowe, Heather D.; Wixted, John T.

    2012-01-01

    A police lineup presents a real-world signal-detection problem because there are two possible states of the world (the suspect is either innocent or guilty), some degree of information about the true state of the world is available (the eyewitness has some degree of memory for the perpetrator), and a decision is made (identifying the suspect or…

  4. [Characteristics of the lymphoid cells of rabbits].

    PubMed

    Bondarev, I M; Selitskaia, R P; Mikhaĭlov, A B

    1978-01-01

    By means of scanning electron microscopy it has been stated that the thymus gland, spleen, paratracheal lymph node, Peyer's patches and appendix in an intact rabbit of "Shinshilla" strain have T- and B-lymphocytes in different proportion. T-lymphocytes are seen as spherical cells with rough surface, with a few microprocesses, have 3.0 +/- 0.1 mcm--4.7 +/- 0.2 mcm in diameter depending on their location. B-lymphocytes are seen as spherical cells with a considerable amount of microvilli on their surface, have 2.9 +/- 0.1 mcm--4.4 +/- 0.1 mcm in diameter depending also on their location. In the thymus gland, cells with rough surface, a few microprocesses and crater-like hollows prevail. In the spleen and lymph node, most of the cells are of similar diameter and have microvilli on the surface. Lymphoid population in the Peyer's patch and appendix is represented by large cells with microprocesses. PMID:305239

  5. Thin silicon solar cell performance characteristics

    NASA Technical Reports Server (NTRS)

    Gay, C. F.

    1978-01-01

    Refined techniques for surface texturizing, back surface field and back surface reflector formation were evaluated for use with shallow junction, single-crystal silicon solar cells. Each process was characterized individually and collectively as a function of device thickness and bulk resistivity. Among the variables measured and reported are open circuit voltage, short circuit current and spectral response. Substantial improvements were obtained by the utilization of a low cost aluminum paste process to simultaneously remove the unwanted n(+) diffused region, form the back surface field and produce an ohmic contact metallization. The highly effective BSF which results from applying this process has allowed fabrication of cells 0.05 mm thick with initial outputs as high as 79.5 mW/4 sq cm (28 C, AM0) and superior electron radiation tolerance. Cells of 0.02 mm to 0.04 mm thickness have been fabricated with power to mass ratios well in excess of 2 watts per gram.

  6. Generation of Recombinant Monoclonal Antibodies from Immunised Mice and Rabbits via Flow Cytometry and Sorting of Antigen-Specific IgG+ Memory B Cells

    PubMed Central

    Starkie, Dale. O; Compson, Joanne E.; Rapecki, Stephen; Lightwood, Daniel J.

    2016-01-01

    Single B cell screening strategies, which avoid both hybridoma fusion and combinatorial display, have emerged as important technologies for efficiently sampling the natural antibody repertoire of immunized animals and humans. Having access to a range of methods to interrogate different B cell subsets provides an attractive option to ensure large and diverse panels of high quality antibody are produced. The generation of multiple antibodies and having the ability to find rare B cell clones producing IgG with unique and desirable characteristics facilitates the identification of fit-for-purpose molecules that can be developed into therapeutic agents or research reagents. Here, we describe a multi-parameter flow cytometry single-cell sorting technique for the generation of antigen-specific recombinant monoclonal antibodies from single IgG+ memory B cells. Both mouse splenocytes and rabbit PBMC from immunised animals were used as a source of B cells. Reagents staining both B cells and other unwanted cell types enabled efficient identification of class-switched IgG+ memory B cells. Concurrent staining with antigen labelled separately with two spectrally-distinct fluorophores enabled antigen-specific B cells to be identified, i.e. those which bind to both antigen conjugates (double-positive). These cells were then typically sorted at one cell per well using FACS directly into a 96-well plate containing reverse transcriptase reaction mix. Following production of cDNA, PCR was performed to amplify cognate heavy and light chain variable region genes and generate transcriptionally-active PCR (TAP) fragments. These linear expression cassettes were then used directly in a mammalian cell transfection to generate recombinant antibody for further testing. We were able to successfully generate antigen-specific recombinant antibodies from both the rabbit and mouse IgG+ memory B cell subset within one week. This included the generation of an anti-TNFR2 blocking antibody from mice

  7. B-cell memory and the persistence of antibody responses.

    PubMed Central

    MacLennan, I C; García de Vinuesa, C; Casamayor-Palleja, M

    2000-01-01

    Antigens such as viral envelope proteins and bacterial exotoxins induce responses which result in the production of neutralizing antibody. These responses persist for years and provide highly efficient defence against reinfection. During these antibody responses a proportion of participating B cells mutate the genes that encode their immunoglobulin variable regions. This can increase the affinity of the antibody, but can also induce autoreactive B cells. Selection mechanisms operate which allow the cells with high affinity for the provoking antigen to persist, while other B cells recruited into the response die. PMID:10794052

  8. Excellent scalability including self-heating phenomena of vertical-channel field-effect-diode type capacitor-less one transistor dynamic random access memory cell

    NASA Astrophysics Data System (ADS)

    Imamoto, Takuya; Endoh, Tetsuo

    2014-01-01

    The scalability study and the impact of the self-heating effect (SHE) on memory operation of the bulk vertical-channel field effect diode (FED) type capacitorless one transistor (1T) dynamic random access memory (DRAM) cell are investigated via device simulator for the first time. The vertical-channel FED type 1T-DRAM cell shows the excellent hold characteristics (100 ms at 358 K of ambient temperature) with large enough read current margin (1 µA/cell) even when silicon pillar diameter (D) is scaled down from 20 to 12 nm. It is also shown that by employing the vertical-channel FED type, maximum lattice temperature in the memory cell due to SHE (T_{\\text{L}}^{\\text{Max}}) can be suppressed to a negligible small value and only reach 300.6 from 300 K ambient temperature due to the low lateral electric field, while the vertical-channel bipolar junction transistor (BJT) type 1T-DRAM shows significant SHE (T_{\\text{L}}^{\\text{Max}} = 330.6 K). Moreover, this excellent thermal characteristic can be maintained even when D is scaled down from 20 to 12 nm.

  9. Cell light scattering characteristic research based on FDTD algorithm

    NASA Astrophysics Data System (ADS)

    Lin, Xiaogang; Zhu, Hao; Li, Wenchao; Ye, Changbin

    2015-10-01

    As with the number of cancer increases year by year, so it is important to be found and treated earlier. With biological cells and tissues are sensitive to infrared and visible light, cell morphology and physical structure of the optical properties can easily obtain, we can provide theoretical basis for the early diagnosis of cancer by observing the difference of optical properties between normal and cancerous cells. Compared with Mie scattering theory, finite difference time domain (FDTD) algorithm can analyze any complex structure model. In this paper we use mathematical modeling method to establish the single cell mathematical model and with finite difference time domain algorithm to simulate the propagation and scattering of light in the biological cells, you can calculate the scattering of electromagnetic field distribution at anytime and anywhere. With radar cross section (RCS) to measure the results of the scattering characteristics. Due to the difference between normal cells and cancerous cells are embodied in cell shape, size and the refractive index, through the simulation we can get different cell parameters of light scattering information, Find out the cell parameters change the changing rule of the influence on the scattering characteristics and find out change regularity of scattering characteristics. These data can judge very accurate of the cells is normal or cancerous cells.

  10. Incomplete DNA methylation underlies a transcriptional memory of the somatic cell in human iPS cells

    PubMed Central

    Ohi, Yuki; Qin, Han; Hong, Chibo; Blouin, Laure; Polo, Jose M.; Guo, Tingxia; Qi, Zhongxia; Downey, Sara L.; Manos, Philip D.; Rossi, Derrick J.; Yu, Jingwei; Hebrok, Matthias; Hochedlinger, Konrad; Costello, Joseph F.; Song, Jun S.; Ramalho-Santos, Miguel

    2013-01-01

    Human induced pluripotent stem (iPS) cells are remarkably similar to embryonic stem (ES) cells, but recent reports suggest that there may be important differences between them. We performed a systematic comparison of human iPS cells generated from hepatocytes (representative of endoderm), skin fibroblasts (mesoderm) and melanocytes (ectoderm). All low passage iPS cells analyzed retain a transcriptional memory of the original cells. The persistent expression of somatic genes can be partially explained by incomplete promoter DNA methylation. This epigenetic mechanism underlies a robust form of memory that can be found in iPS cells generated by multiple laboratories using different methods, including RNA transfection. Incompletely silenced genes tend to be isolated from other genes that are repressed during reprogramming, indicating that recruitment of the silencing machinery may be inefficient at isolated genes. Knockdown of the incompletely reprogrammed gene C9orf64 reduces the efficiency of human iPS cell generation, suggesting that somatic memory genes may be functionally relevant during reprogramming. PMID:21499256

  11. Antigen-dependent and -independent contributions to primary memory CD8 T cell activation and protection following infection.

    PubMed

    Martin, Matthew D; Badovinac, Vladimir P

    2015-12-10

    Memory CD8 T-cell activation, including expression of IFN-γ and granzymeB, can be induced by antigen (Ag)-dependent signals through the T-cell-receptor, or by pathogen-derived inflammatory cytokines in an Ag-independent manner. Recent studies have come to conflicting results regarding the contributions of Ag and/or inflammation to memory CD8 T-cell activation. Additionally, research has indicated that inflammation-driven CD8 T-cell responses during un-related infections (bystander activation) have the potential to provide protection, but whether protection occurs in immuno-competent hosts is unclear. To investigate these questions, we examined activation of virus-specific memory CD8 T-cells following infection with L. monocytogenes either expressing or not cognate Ag. We show that Ag and inflammation act synergistically in vitro to induce memory activation. In vivo, we found that when memory CD8 T-cells significantly contribute to clearance of infection, early activation and continued responses by these cells are enhanced by cognate Ag recognition. Mechanistically, we show that bystander responses by memory are dependent upon the dose of infection and the amount of inflammation elicited following infection and are able to provide protection in IFN-γ deficient mice, but not in immuno-competent hosts. The data elucidate the requirements for memory CD8 T-cell activation and the protective role of bystander responses.

  12. Antigen-dependent and –independent contributions to primary memory CD8 T cell activation and protection following infection

    PubMed Central

    Martin, Matthew D.; Badovinac, Vladimir P.

    2015-01-01

    Memory CD8 T-cell activation, including expression of IFN-γ and granzymeB, can be induced by antigen (Ag)-dependent signals through the T-cell-receptor, or by pathogen-derived inflammatory cytokines in an Ag-independent manner. Recent studies have come to conflicting results regarding the contributions of Ag and/or inflammation to memory CD8 T-cell activation. Additionally, research has indicated that inflammation-driven CD8 T-cell responses during un-related infections (bystander activation) have the potential to provide protection, but whether protection occurs in immuno-competent hosts is unclear. To investigate these questions, we examined activation of virus-specific memory CD8 T-cells following infection with L. monocytogenes either expressing or not cognate Ag. We show that Ag and inflammation act synergistically in vitro to induce memory activation. In vivo, we found that when memory CD8 T-cells significantly contribute to clearance of infection, early activation and continued responses by these cells are enhanced by cognate Ag recognition. Mechanistically, we show that bystander responses by memory are dependent upon the dose of infection and the amount of inflammation elicited following infection and are able to provide protection in IFN-γ deficient mice, but not in immuno-competent hosts. The data elucidate the requirements for memory CD8 T-cell activation and the protective role of bystander responses. PMID:26658291

  13. Partial reconstitution of virus-specific memory CD8{sup +} T cells following whole body {gamma}-irradiation

    SciTech Connect

    Grayson, Jason M. . E-mail: jgrayson@wfubmc.edu; Laniewski, Nathan G.; Holbrook, Beth C.

    2006-04-25

    CD8{sup +} memory T cells are critical in providing immunity to viral infection. Previous studies documented that antigen-specific CD8{sup +} memory T cells are more resistant to radiation-induced apoptosis than naive T cells. Here, we determined the number and in vivo function of memory CD8{sup +} T cells as immune reconstitution progressed following irradiation. Immediately following irradiation, the number of memory CD8{sup +} T cells declined 80%. As reconstitution progressed, the number of memory cells reached a zenith at 33% of pre-irradiation levels, and was maintained for 120 days post-irradiation. In vitro, memory CD8{sup +} T cells were able to produce cytokines at all times post-irradiation, but when adoptively transferred, they were not able to expand upon rechallenge immediately following irradiation, but regained this ability as reconstitution progressed. When proliferation was examined in vitro, irradiated memory CD8{sup +} T cells were able to respond to mitogenic growth but were unable to divide.

  14. Production of IL-10 by CD4+ regulatory T cells during the resolution of infection promotes the maturation of memory CD8+ T cells

    PubMed Central

    Laidlaw, Brian J; Cui, Weiguo; Amezquita, Robert A; Gray, Simon M; Guan, Tianxia; Lu, Yisi; Kobayashi, Yasushi; Flavell, Richard A; Kleinstein, Steven H; Craft, Joe; Kaech, Susan M

    2016-01-01

    Memory CD8+ T cells are critical for host defense upon reexposure to intracellular pathogens. We found that interleukin 10 (IL-10) derived from CD4+ regulatory T cells (Treg cells) was necessary for the maturation of memory CD8+ T cells following acute infection with lymphocytic choriomeningitis virus (LCMV). Treg cell–derived IL-10 was most important during the resolution phase, calming inflammation and the activation state of dendritic cells. Adoptive transfer of IL-10-sufficient Treg cells during the resolution phase ‘restored’ the maturation of memory CD8+ T cells in IL-10-deficient mice. Our data indicate that Treg cell–derived IL-10 is needed to insulate CD8+ T cells from inflammatory signals, and reveal that the resolution phase of infection is a critical period that influences the quality and function of developing memory CD8+ T cells. PMID:26147684

  15. Defect states and charge trapping characteristics of HfO{sub 2} films for high performance nonvolatile memory applications

    SciTech Connect

    Zhang, Y.; Shao, Y. Y.; Lu, X. B. Zeng, M.; Zhang, Z.; Gao, X. S.; Zhang, X. J.; Liu, J.-M.; Dai, J. Y.

    2014-10-27

    In this work, we present significant charge trapping memory effects of the metal-hafnium oxide-SiO{sub 2}-Si (MHOS) structure. The devices based on 800 °C annealed HfO{sub 2} film exhibit a large memory window of ∼5.1 V under ±10 V sweeping voltages and excellent charge retention properties with only small charge loss of ∼2.6% after more than 10{sup 4 }s retention. The outstanding memory characteristics are attributed to the high density of deep defect states in HfO{sub 2} films. We investigated the defect states in the HfO{sub 2} films by photoluminescence and photoluminescence excitation measurements and found that the defect states distributed in deep energy levels ranging from 1.1 eV to 2.9 eV below the conduction band. Our work provides further insights for the charge trapping mechanisms of the HfO{sub 2} based MHOS devices.

  16. Improved characteristics for MOHOS memory with oxygen-rich GdO as charge storage layer annealed by NH3

    NASA Astrophysics Data System (ADS)

    Liu, Lu; Xu, J. P.; Chen, J. X.; Lai, P. T.

    2014-06-01

    Characteristics of metal-oxide-high- k-oxide-silicon (MOHOS) memories with oxygen-rich or oxygen-deficient GdO as charge storage layer annealed by NH3 or N2 are investigated. Transmission electron microscopy, X-ray photoelectron spectroscopy and X-ray diffraction are used to analyze the cross-sectional quality, composition and crystallinity, respectively, of the stacked gate dielectric with a structure of Al/Al2O3/GdO/SiO2/Si. The MOHOS capacitor with oxygen-rich GdO annealed in NH3 exhibits a good trade-off among its memory properties: large memory window (4.8 V at ±12 V, 1 s), high programming speed (2.6 V at ±12 V/100 μs), good endurance and retention properties (window degradation of 5 % after 105 program/erase cycles and charge loss of 18.6 % at 85 °C after 10 years, respectively) due to passivation of oxygen vacancies, generation of deep-level traps in the grain boundaries of the GdO layer and suppression of the interlayer between GdO and SiO2 by the NH3 annealing.

  17. Effect of CO2 laser welding on the shape-memory and corrosion characteristics of TiNi alloys

    NASA Astrophysics Data System (ADS)

    Hsu, Y. T.; Wang, Y. R.; Wu, S. K.; Chen, C.

    2001-03-01

    A CO2 laser has been employed to join binary Ti50Ni50 and Ti49.5Ni50.5 shape-memory alloys (SMAs), with an emphasis on the shape-memory and corrosion characteristics. Experimental results showed that a slightly lowered martensite start ( M S) temperature and no deterioration in shape-memory character of both alloys were found after laser welding. The welded Ti50Ni50, with an increased amount of B2 phase in the weld metal (WM), had higher strength and considerably lower elongation than the base metal (BM). Potentiodynamic tests revealed the satisfactory performance of laser-welded Ti50Ni50 in 1.5 M H2SO4 and 1.5 M HNO3 solutions. However, the WM exhibited a significantly higher corrosion rate and a less stable passivity than the BM in artificial saliva. On the other hand, the pseudoelastic behavior of the laser weld was investigated only for the Ti49.5Ni50.5 alloy, to facilitate tension cycling at room temperature. The cyclic deformation of Ti49.5Ni50.5 indicated that the stress required to form stress-induced martensite ( σ m) and the permanent residual strain ( ɛ p) were higher after welding at a given number of cycles ( N), which were certainly related to the more inhomogeneous nature of the WM.

  18. Spontaneous imagery in women with bulimia nervosa: an investigation into content, characteristics and links to childhood memories.

    PubMed

    Somerville, Kate; Cooper, Myra; Hackmann, Ann

    2007-12-01

    The study investigated the presence and characteristics of spontaneous imagery in women with bulimia nervosa (BN) and their links to childhood memories. Using a semi-structured interview, data was collected from three groups of female participants: BN participants (N=13), dieting (N=18) and non-dieting controls (N=20). BN participants reported more spontaneous images than non-dieting control participants. Their images were recurrent and significantly more negative and anxiety provoking than those of controls. They involved more sensory modalities than in dieting controls and were more vivid than in non-dieting controls. BN images typically involved the visual, organic and cutaneous modalities. They were linked to a specific childhood memory, similar in emotional tone and sensory modalities. Once depression was controlled, many of the between-group differences became non-significant. The results suggest that imagery may be a significant feature of BN, potentially distinguishing those with BN from controls, although further research into the link between mood, imagery and memory is needed. The findings have clinical implications, particularly for assessment and for the application of imagery rescripting in BN.

  19. Distinct hippocampal time cell sequences represent odor memories in immobilized rats.

    PubMed

    MacDonald, Christopher J; Carrow, Stephen; Place, Ryan; Eichenbaum, Howard

    2013-09-01

    Previous studies have revealed the existence of hippocampal "time cells," principal neurons in CA1 that fire at specific moments in temporally organized experiences. However, in all these studies, animals were in motion; and so, temporal modulation might be due, at least in part, to concurrent or planned movement through space or self-generated movement (path integration). Here the activity of hippocampal CA1 neurons was recorded in head-fixed and immobile rats while they remembered odor stimuli across a delay period. Many neurons selectively and reliably activated at brief moments during the delay, as confirmed by several analyses of temporal modulation, during a strong ongoing θ rhythm. Furthermore, each odor memory was represented by a temporally organized ensemble of time cells composed mostly of neurons that were unique to each memory and some that fired at the same or different moments among multiple memories. These results indicate that ongoing or intended movement through space is not necessary for temporal representations in the hippocampus, and highlight the potential role of time cells as a mechanism for representing the flow of time in distinct memories.

  20. A Single Human Papillomavirus Vaccine Dose Improves B Cell Memory in Previously Infected Subjects.

    PubMed

    Scherer, Erin M; Smith, Robin A; Gallego, Daniel F; Carter, Joseph J; Wipf, Gregory C; Hoyos, Manuela; Stern, Michael; Thurston, Tate; Trinklein, Nathan D; Wald, Anna; Galloway, Denise A

    2016-08-01

    Although licensed human papillomavirus (HPV) vaccines are most efficacious in persons never infected with HPV, they also reduce infection and disease in previously infected subjects, indicating natural immunity is not entirely protective against HPV re-infection. The aim of this exploratory study was to examine the B cell memory elicited by HPV infection and evaluate whether vaccination merely boosts antibody (Ab) levels in previously infected subjects or also improves the quality of B cell memory. Toward this end, the memory B cells (Bmem) of five unvaccinated, HPV-seropositive subjects were isolated and characterized, and subject recall responses to a single HPV vaccine dose were analyzed. Vaccination boosted Ab levels 24- to 930-fold (median 77-fold) and Bmem numbers 3- to 27-fold (median 6-fold). In addition, Abs cloned from naturally elicited Bmem were generally non-neutralizing, whereas all those isolated following vaccination were neutralizing. Moreover, Ab and plasmablast responses indicative of memory recall responses were only observed in two subjects. These results suggest HPV vaccination augments both the magnitude and quality of natural immunity and demonstrate that sexually active persons could also benefit from HPV vaccination. This study may have important public policy implications, especially for the older 'catch-up' group within the vaccine's target population. PMID:27423190

  1. T Cell Responses: Naive to Memory and Everything in Between

    ERIC Educational Resources Information Center

    Pennock, Nathan D.; White, Jason T.; Cross, Eric W.; Cheney, Elizabeth E.; Tamburini, Beth A.; Kedl, Ross M.

    2013-01-01

    The authors describe the actions that take place in T cells because of their amazing capacity to proliferate and adopt functional roles aimed at clearing a host of an infectious agent. There is a drastic decline in the T cell population once the primary response is over and the infection is terminated. What remains afterward is a population of T…

  2. Memory and modularity in cell-fate decision making

    NASA Astrophysics Data System (ADS)

    Norman, Thomas M.; Lord, Nathan D.; Paulsson, Johan; Losick, Richard

    2013-11-01

    Genetically identical cells sharing an environment can display markedly different phenotypes. It is often unclear how much of this variation derives from chance, external signals, or attempts by individual cells to exert autonomous phenotypic programs. By observing thousands of cells for hundreds of consecutive generations under constant conditions, we dissect the stochastic decision between a solitary, motile state and a chained, sessile state in Bacillus subtilis. We show that the motile state is `memoryless', exhibiting no autonomous control over the time spent in the state. In contrast, the time spent as connected chains of cells is tightly controlled, enforcing coordination among related cells in the multicellular state. We show that the three-protein regulatory circuit governing the decision is modular, as initiation and maintenance of chaining are genetically separable functions. As stimulation of the same initiating pathway triggers biofilm formation, we argue that autonomous timing allows a trial commitment to multicellularity that external signals could extend.

  3. Tissue-Specific B-Cell Dysfunction and Generalized Memory B-Cell Loss during Acute SIV Infection

    PubMed Central

    Peruchon, Sandrine; Chaoul, Nada; Burelout, Chantal; Delache, Benoit; Brochard, Patricia; Laurent, Pascale; Cognasse, Fabrice; Prévot, Sophie; Garraud, Olivier; Le Grand, Roger; Richard, Yolande

    2009-01-01

    Background Primary HIV-infected patients display severe and irreversible damage to different blood B-cell subsets which is not restored by highly efficient anti-retroviral therapy (HAART). Because longitudinal investigations of primary HIV-infection is limited by the availability of lymphoid organs, we studied the tissue-specific B-cell dysfunctions in acutely simian immunodeficiency virus (SIV) mac251-infected Cynomolgus macaques. Methods and Findings Experiments were performed on three groups of macaques infected for 14, 21 or 28 days and on three groups of animals treated with HAART for two-weeks either initiated at 4 h, 7 or 14 days post-infection (p.i.). We have simultaneously compared changes in B-cell phenotypes and functions and tissue organization of B-cell areas in various lymphoid organs. We showed that SIV induced a steady decline in SIgG-expressing memory (SIgD−CD27+) B-cells in spleen and lymph nodes during the first 4 weeks of infection, concomitant to selective homing/sequestration of B-cells to the small intestine and spleen. SIV non-specific Ig production was transiently increased before D14p.i., whereas SIV-specific Ig production was only detectable after D14p.i., coinciding with the presence of CD8+ T-cells and IgG-expressing plasma cells within germinal centres. Transient B-cell apoptosis on D14p.i. and commitment to terminal differentiation contributed to memory B-cell loss. HAART abrogated B-cell apoptosis, homing to the small intestine and SIV-specific Ig production but had minimal effect on early Ig production, increased B-cell proportions in spleen and loss of memory B-cells. Therefore, virus–B-cell interactions and SIV-induced inflammatory cytokines may differently contribute to early B-cell dysfunction and impaired SIV/HIV-specific antibody response. Conclusions These data establish tissue-specific impairments in B-cell trafficking and functions and a generalized and steady memory B-cell loss in secondary lymphoid organs

  4. Fast Response, Open-Celled Porous, Shape Memory Effect Actuators with Integrated Attachments

    NASA Technical Reports Server (NTRS)

    Jardine, Andrew Peter (Inventor)

    2015-01-01

    This invention relates to the exploitation of porous foam articles exhibiting the Shape Memory Effect as actuators. Each foam article is composed of a plurality of geometric shapes, such that some geometric shapes can fit snugly into or around rigid mating connectors that attach the Shape Memory foam article intimately into the load path between a static structure and a moveable structure. The foam is open-celled, composed of a plurality of interconnected struts whose mean diameter can vary from approximately 50 to 500 microns. Gases and fluids flowing through the foam transfer heat rapidly with the struts, providing rapid Shape Memory Effect transformations. Embodiments of porous foam articles as torsional actuators and approximately planar structures are disposed. Simple, integral connection systems exploiting the ability to supply large loads to a structure, and that can also supply hot and cold gases and fluids to effect rapid actuation are also disposed.

  5. Episodic-like memory trace in awake replay of hippocampal place cell activity sequences.

    PubMed

    Takahashi, Susumu

    2015-01-01

    Episodic memory retrieval of events at a specific place and time is effective for future planning. Sequential reactivation of the hippocampal place cells along familiar paths while the animal pauses is well suited to such a memory retrieval process. It is, however, unknown whether this awake replay represents events occurring along the path. Using a subtask switching protocol in which the animal experienced three subtasks as 'what' information in a maze, I here show that the replay represents a trial type, consisting of path and subtask, in terms of neuronal firing timings and rates. The actual trial type to be rewarded could only be reliably predicted from replays that occurred at the decision point. This trial-type representation implies that not only 'where and when' but also 'what' information is contained in the replay. This result supports the view that awake replay is an episodic-like memory retrieval process. PMID:26481131

  6. Episodic-like memory trace in awake replay of hippocampal place cell activity sequences.

    PubMed

    Takahashi, Susumu

    2015-01-01

    Episodic memory retrieval of events at a specific place and time is effective for future planning. Sequential reactivation of the hippocampal place cells along familiar paths while the animal pauses is well suited to such a memory retrieval process. It is, however, unknown whether this awake replay represents events occurring along the path. Using a subtask switching protocol in which the animal experienced three subtasks as 'what' information in a maze, I here show that the replay represents a trial type, consisting of path and subtask, in terms of neuronal firing timings and rates. The actual trial type to be rewarded could only be reliably predicted from replays that occurred at the decision point. This trial-type representation implies that not only 'where and when' but also 'what' information is contained in the replay. This result supports the view that awake replay is an episodic-like memory retrieval process.

  7. Culture-differentiated CD8(+) T cells acquire innate memory-like traits and respond to a pathogen-associated molecule.

    PubMed

    Biswas, Ratna; Mukherjee, Subhadeep; Sinha, Debolina; Ghosh, Amlan Kanti; Biswas, Tapas

    2014-04-01

    Selection of conventional CD4(+) or CD8(+) T cells is usually driven by the interaction of double-positive CD4(+)CD8(+) thymocytes with epithelial cells. Here, we demonstrate preferential selection of CD8(+) thymocytes from in vitro differentiation of CD4(+)CD8(+) double-positive thymocytes exhibiting the characteristics of nonconventional innate memory CD8(+) cells. In contrast to conventional CD8(+) thymocytes, these culture-differentiated CD8(+) cells are eomesodermin positive and robustly express CXCR3, CD44, CD122 and TLR2. Interestingly, the pathogen-associated molecule porin promotes preferential differentiation of the CD8(+) single-positive subset in association with promyelocytic leukemia zinc-finger upregulation and interleukin (IL)-4 production. On priming with anti-CD3 antibody, porin augmented TLR2 and IFN-γ indicating a role of the TLR ligand in acquisition of innate memory response of CD8(+) thymocytes. In addition, porin has a cooperative role with IL-15 on the expansion of memory-phenotype CD8(+) T cells along with its effector function. Thus, the study opens an avenue to unfold the cues for development of these cells and the strategies adopted for bolstering immunity during primary infection.

  8. Identification of Pertussis-Specific Effector Memory T Cells in Preschool Children

    PubMed Central

    Schure, Rose-Minke; Öztürk, Kemal; Berbers, Guy; Sanders, Elisabeth; van Twillert, Inonge; Carollo, Maria; Mascart, Françoise; Ausiello, Clara M.; van Els, Cecile A. C. M.; Smits, Kaat; Buisman, Anne-Marie

    2015-01-01

    Whooping cough remains a problem despite vaccination, and worldwide resurgence of pertussis is evident. Since cellular immunity plays a role in long-term protection against pertussis, we studied pertussis-specific T-cell responses. Around the time of the preschool acellular pertussis (aP) booster dose at 4 years of age, T-cell memory responses were compared in children who were primed during infancy with either a whole-cell pertussis (wP) or an aP vaccine. Peripheral blood mononuclear cells (PBMCs) were isolated and stimulated with pertussis vaccine antigens for 5 days. T cells were characterized by flow-based analysis of carboxyfluorescein succinimidyl ester (CFSE) dilution and CD4, CD3, CD45RA, CCR7, gamma interferon (IFN-γ), and tumor necrosis factor alpha (TNF-α) expression. Before the aP preschool booster vaccination, both the proliferated pertussis toxin (PT)-specific CD4+ and CD8+ T-cell fractions (CFSEdim) were higher in aP- than in wP-primed children. Post-booster vaccination, more pertussis-specific CD4+ effector memory cells (CD45RA− CCR7−) were induced in aP-primed children than in those primed with wP. The booster vaccination did not appear to significantly affect the T-cell memory subsets and functionality in aP-primed or wP-primed children. Although the percentages of Th1 cytokine-producing cells were alike in aP- and wP-primed children pre-booster vaccination, aP-primed children produced more Th1 cytokines due to higher numbers of proliferated pertussis-specific effector memory cells. At present, infant vaccinations with four aP vaccines in the first year of life result in pertussis-specific CD4+ and CD8+ effector memory T-cell responses that persist in children until 4 years of age and are higher than those in wP-primed children. The booster at 4 years of age is therefore questionable; this may be postponed to 6 years of age. PMID:25787136

  9. IL-15 induces CD4+ effector memory T cell production and tissue emigration in nonhuman primates

    PubMed Central

    Picker, Louis J.; Reed-Inderbitzin, Edward F.; Hagen, Shoko I.; Edgar, John B.; Hansen, Scott G.; Legasse, Alfred; Planer, Shannon; Piatak, Michael; Lifson, Jeffrey D.; Maino, Vernon C.; Axthelm, Michael K.; Villinger, Francois

    2006-01-01

    HIV infection selectively targets CD4+ effector memory T (TEM) cells, resulting in dramatic depletion of CD4+ T cells in mucosal effector sites in early infection. Regeneration of the TEM cell compartment is slow and incomplete, even when viral replication is controlled by antiretroviral therapy (ART). Here, we demonstrate that IL-15 dramatically increases in vivo proliferation of rhesus macaque (RM) CD4+ and CD8+ TEM cells with little effect on the naive or central memory T (TCM) cell subsets, a response pattern that is quite distinct from that of either IL-2 or IL-7. TEM cells produced in response to IL-15 did not accumulate in blood. Rather, 5-bromo-2′-deoxyuridine (BrdU) labeling studies suggest that many of these cells rapidly disperse to extralymphoid effector sites, where they manifest (slow) decay kinetics indistinguishable from that of untreated controls. In RMs with uncontrolled SIV infection and highly activated immune systems, IL-15 did not significantly increase CD4+ TEM cell proliferation, but with virologic control and concomitant reduction in immune activation by ART, IL-15 responsiveness was again observed. These data suggest that therapeutic use of IL-15 in the setting of ART might facilitate specific restoration of the CD4+ T cell compartment that is the primary target of HIV with less risk of exhausting precursor T cell compartments or generating potentially deleterious regulatory subsets. PMID:16691294

  10. Osteogenic Capacity of Human Adipose-Derived Stem Cells is Preserved Following Triggering of Shape Memory Scaffolds.

    PubMed

    Tseng, Ling-Fang; Wang, Jing; Baker, Richard M; Wang, Guirong; Mather, Patrick T; Henderson, James H

    2016-08-01

    Recent advances in shape memory polymers have enabled the study of programmable, shape-changing, cytocompatible tissue engineering scaffolds. For treatment of bone defects, scaffolds with shape memory functionality have been studied for their potential for minimally invasive delivery, conformal fitting to defect margins, and defect stabilization. However, the extent to which the osteogenic differentiation capacity of stem cells resident in shape memory scaffolds is preserved following programmed shape change has not yet been determined. As a result, the feasibility of shape memory polymer scaffolds being employed in stem cell-based treatment strategies remains unclear. To test the hypothesis that stem cell osteogenic differentiation can be preserved during and following triggering of programmed architectural changes in shape memory polymer scaffolds, human adipose-derived stem cells were seeded in shape memory polymer foam scaffolds or in shape memory polymer fibrous scaffolds programmed to expand or contract, respectively, when warmed to body temperature. Osteogenic differentiation in shape-changing and control scaffolds was compared using mineral deposition, protein production, and gene expression assays. For both shape-changing and control scaffolds, qualitatively and quantitatively comparable amounts of mineral deposition were observed; comparable levels of alkaline phosphatase activity were measured; and no significant differences in the expression of genetic markers of osteogenesis were detected. These findings support the feasibility of employing shape memory in scaffolds for stem cell-based therapies for bone repair. PMID:27401991

  11. BAFF enhances chemotaxis of primary human B cells: a particular synergy between BAFF and CXCL13 on memory B cells.

    PubMed

    Badr, Gamal; Borhis, Gwenoline; Lefevre, Eric A; Chaoul, Nada; Deshayes, Frederique; Dessirier, Valérie; Lapree, Genevieve; Tsapis, Andreas; Richard, Yolande

    2008-03-01

    B-cell-activating factor of the TNF family, (BAFF), and a proliferation-inducing ligand (APRIL) regulate B-lymphocyte survival and activation. We report that BAFF, but not APRIL, increased the chemotactic response of primary human B cells to CCL21, CXCL12, and CXCL13. The BAFF-induced increase in B-cell chemotaxis was totally abolished by blockade of BAFF-R and was strongly dependent on the activation of PI3K/AKT, NF-kappaB, and p38MAPK pathways. BAFF had similar effects on the chemotaxis of naive and memory B cells in response to CCL21 but increased more strongly that of memory B cells to CXCL13 than that of naive B cells. Our findings indicate a previously unreported role for the BAFF/BAFF-R pair in mature B-cell chemotaxis. The synergy between CXCL13 and BAFF produced by stromal cells and follicular dendritic cells may have important implications for B-cell homeostasis, the development of normal B-cell areas, and for the formation of germinal center-like follicles that may be observed in various autoimmune diseases.

  12. Physiological and transcriptional memory in guard cells during repetitive dehydration stress.

    PubMed

    Virlouvet, Laetitia; Fromm, Michael

    2015-01-01

    Arabidopsis plants subjected to a daily dehydration stress and watered recovery cycle display physiological and transcriptional stress memory. Previously stressed plants have stomatal apertures that remain partially closed during a watered recovery period, facilitating reduced transpiration during a subsequent dehydration stress. Guard cells (GCs) display transcriptional memory that is similar to that in leaf tissues for some genes, but display GC-specific transcriptional memory for other genes. The rate-limiting abscisic acid (ABA) biosynthetic genes NINE-CIS-EPOXYCAROTENOID DIOXYGENASE 3 (NCED3) and ALDEHYDE OXIDASE 3 (AAO3) are expressed at much higher levels in GCs, particularly during the watered recovery interval, relative to their low levels in leaves. A genetic analysis using mutants in the ABA signaling pathway indicated that GC stomatal memory is ABA-dependent, and that ABA-dependent SNF1-RELATED PROTEIN KINASE 2.2 (SnRK2.2), SnRK2.3 and SnRK2.6 have distinguishable roles in the process. SnRK2.6 is more important for overall stomatal control, while SnRK2.2 and SnRK2.3 are more important for implementing GC stress memory in the subsequent dehydration response. Collectively, our results support a model of altered ABA production in GCs that maintains a partially closed stomatal aperture during an overnight watered recovery period.

  13. B Cells Negatively Regulate the Establishment of CD49b+T-bet+ Resting Memory T Helper Cells in the Bone Marrow

    PubMed Central

    Hojyo, Shintaro; Sarkander, Jana; Männe, Christian; Mursell, Mathias; Hanazawa, Asami; Zimmel, David; Zhu, Jinfang; Paul, William E.; Fillatreau, Simon; Löhning, Max; Radbruch, Andreas; Tokoyoda, Koji

    2016-01-01

    During an immune reaction, some antigen-experienced CD4 T cells relocate from secondary lymphoid organs (SLOs) to the bone marrow (BM) in a CD49b-dependent manner and reside and rest there as professional memory CD4 T cells. However, it remains unclear how the precursors of BM memory CD4 T cells are generated in the SLOs. While several studies have so far shown that B cell depletion reduces the persistence of memory CD4 T cells in the spleen, we here show that B cell depletion enhances the establishment of memory CD4 T cells in the BM and that B cell transfer conversely suppresses it. Interestingly, the number of antigen-experienced CD4 T cells in the BM synchronizes the number of CD49b+T-bet+ antigen-experienced CD4 T cells in the spleen. CD49b+T-bet+ antigen-experienced CD4 T cells preferentially localize in the red pulp area of the spleen and the BM in a T-bet-independent manner. We suggest that B cells negatively control the generation of CD49b+T-bet+ precursors of resting memory CD4 T cells in the spleen and may play a role in bifurcation of activated effector and resting memory CD4 T cell lineages. PMID:26870041

  14. Effect of annealing treatment on the electrical characteristics of Pt/Cr-embedded ZnO/Pt resistance random access memory devices

    SciTech Connect

    Chang, Li-Chun; Kao, Hsuan-Ling; Liu, Keng-Hao

    2014-03-15

    ZnO/Cr/ZnO trilayer films sandwiched with Pt electrodes were prepared for nonvolatile resistive memory applications. The threshold voltage of a ZnO device embedded with a 3-nm Cr interlayer was approximately 50% lower than that of a ZnO monolayer device. This study investigated threshold voltage as a function of Cr thickness. Both the ZnO monolayer device and the Cr-embedded ZnO device structures exhibited resistance switching under electrical bias both before and after rapid thermal annealing (RTA) treatment, but resistive switching effects in the two cases exhibited distinct characteristics. Compared with the as-fabricated device, the memory cell after RTA demonstrated remarkable device parameter improvements, including a lower threshold voltage, a lower write current, and a higher R{sub off}/R{sub on} ratio. Both transmission electron microscope observations and Auger electron spectroscopy revealed that the Cr charge trapping layer in Cr-embedded ZnO dispersed uniformly into the storage medium after RTA, and x-ray diffraction and x-ray photoelectron spectroscopy analyses demonstrated that the Cr atoms lost electrons to become Cr{sup 3+} ions after dispersion. These results indicated that the altered status of Cr in ZnO/Cr/ZnO trilayer films during RTA treatment was responsible for the switching mechanism transition.

  15. Comparative analysis of influence of gamma radiation on programmable memory characteristics

    NASA Astrophysics Data System (ADS)

    Lončar, Boris; Kočinac, Saša

    2012-12-01

    The aim of this paper is to examine the reliability of erasable programmable read only memory (EPROM) and electrically erasable programmable read only memory (EEPROM) components subjected to the influence of gamma radiation. This problem is of considerable significance for both military industry and space technology. We present total dose results for the NM27C512 8F85 EPROM and M24128 - B W BN 5 T P EEPROM components. There is evidence that EPROM components radioactive reliability is better than that of EEPROM components. Furthermore, the changes EPROM's undergoes are reversible, so that after erasing process and reprogramming all EPROM components are fully functional. On the other hand, EEPROM's changes are irreversible and when subjected to the influence of gamma radiation, all EEPROM components become permanently nonfunctional. The obtained results are analyzed and explained via the interaction of gamma radiation with oxide layers.

  16. Hippocampal "time cells" bridge the gap in memory for discontiguous events.

    PubMed

    MacDonald, Christopher J; Lepage, Kyle Q; Eden, Uri T; Eichenbaum, Howard

    2011-08-25

    The hippocampus is critical to remembering the flow of events in distinct experiences and, in doing so, bridges temporal gaps between discontiguous events. Here, we report a robust hippocampal representation of sequence memories, highlighted by "time cells" that encode successive moments during an empty temporal gap between the key events, while also encoding location and ongoing behavior. Furthermore, just as most place cells "remap" when a salient spatial cue is altered, most time cells form qualitatively different representations ("retime") when the main temporal parameter is altered. Hippocampal neurons also differentially encode the key events and disambiguate different event sequences to compose unique, temporally organized representations of specific experiences. These findings suggest that hippocampal neural ensembles segment temporally organized memories much the same as they represent locations of important events in spatially defined environments.

  17. Airway inflammation and IgE production induced by dust mite allergen-specific memory/effector Th2 cell line can be effectively attenuated by IL-35.

    PubMed

    Huang, Chiung-Hui; Loo, Evelyn Xiu-Ling; Kuo, I-Chun; Soh, Gim Hooi; Goh, Denise Li-Meng; Lee, Bee Wah; Chua, Kaw Yan

    2011-07-01

    CD4(+) memory/effector T cells play a central role in orchestrating the rapid and robust immune responses upon re-encounter with specific Ags. However, the immunologic mechanism(s) underlying these responses are still not fully understood. To investigate this, we generated an allergen (major house dust mite allergen, Blo t 5)-specific murine Th2 cell line that secreted IL-4, IL-5, IL-10, and IL-13, but not IL-9 or TNF-α, upon activation by the cognate Ag. These cells also exhibited CD44(high)CD62L(-) and CD127(+) (IL-7Rα(+)) phenotypes, which are characteristics of memory/effector T cells. Experiments involving adoptive transfer of this Th2 cell line in mice, followed by three intranasal challenges with Blo t 5, induced a dexamethasone-sensitive eosinophilic airway inflammation. This was accompanied by elevation of Th2 cytokines and CC- and CXC-motif chemokines, as well as recruitment of lymphocytes and polymorphic mononuclear cells into the lungs. Moreover, Blo t 5-specific IgE was detected 4 d after the last intranasal challenge, whereas elevation of Blo t 5-specific IgG1 was found at week two. Finally, pulmonary delivery of the pVAX-IL-35 DNA construct effectively downregulated Blo t 5-specific allergic airway inflammation, and i.m. injection of pVAX-IL-35 led to long-lasting suppression of circulating Blo t 5-specific and total IgE. This model provides a robust research tool to elucidate the immunopathogenic role of memory/effector Th2 cells in allergic airway inflammation. Our results suggested that IL-35 could be a potential therapeutic target for allergic asthma through its attenuating effects on allergen-specific CD4(+) memory/effector Th2 cell-mediated airway inflammation.

  18. Compartmentalization of Total and Virus-Specific Tissue-Resident Memory CD8+ T Cells in Human Lymphoid Organs

    PubMed Central

    Li, Jane; Smith, Corey; Edwards, Jarem; Sierro, Frederic; Feng, Carl G.; Khanna, Rajiv; Bell, Andrew; Hislop, Andrew D.; Tangye, Stuart G.; Rickinson, Alan B.; Gebhardt, Thomas; Britton, Warwick J.

    2016-01-01

    Disruption of T cell memory during severe immune suppression results in reactivation of chronic viral infections, such as Epstein Barr virus (EBV) and Cytomegalovirus (CMV). How different subsets of memory T cells contribute to the protective immunity against these viruses remains poorly defined. In this study we examined the compartmentalization of virus-specific, tissue resident memory CD8+ T cells in human lymphoid organs. This revealed two distinct populations of memory CD8+ T cells, that were CD69+CD103+ and CD69+CD103—, and were retained within the spleen and tonsils in the absence of recent T cell stimulation. These two types of memory cells were distinct not only in their phenotype and transcriptional profile, but also in their anatomical localization within tonsils and spleen. The EBV-specific, but not CMV-specific, CD8+ memory T cells preferentially accumulated in the tonsils and acquired a phenotype that ensured their retention at the epithelial sites where EBV replicates. In vitro studies revealed that the cytokine IL-15 can potentiate the retention of circulating effector memory CD8+ T cells by down-regulating the expression of sphingosine-1-phosphate receptor, required for T cell exit from tissues, and its transcriptional activator, Kruppel-like factor 2 (KLF2). Within the tonsils the expression of IL-15 was detected in regions where CD8+ T cells localized, further supporting a role for this cytokine in T cell retention. Together this study provides evidence for the compartmentalization of distinct types of resident memory T cells that could contribute to the long-term protection against persisting viral infections. PMID:27540722

  19. Antigen availability determines CD8⁺ T cell-dendritic cell interaction kinetics and memory fate decisions.

    PubMed

    Henrickson, Sarah E; Perro, Mario; Loughhead, Scott M; Senman, Balimkiz; Stutte, Susanne; Quigley, Michael; Alexe, Gabriela; Iannacone, Matteo; Flynn, Michael P; Omid, Shaida; Jesneck, Jonathan L; Imam, Sabrina; Mempel, Thorsten R; Mazo, Irina B; Haining, W Nicholas; von Andrian, Ulrich H

    2013-09-19

    T cells are activated by antigen (Ag)-bearing dendritic cells (DCs) in lymph nodes in three phases. The duration of the initial phase of transient, serial DC-T cell interactions is inversely correlated with Ag dose. The second phase, characterized by stable DC-T cell contacts, is believed to be necessary for full-fledged T cell activation. Here we have shown that this is not the case. CD8⁺ T cells interacting with DCs presenting low-dose, short-lived Ag did not transition to phase 2, whereas higher Ag dose yielded phase 2 transition. Both antigenic constellations promoted T cell proliferation and effector differentiation but yielded different transcriptome signatures at 12 hr and 24 hr. T cells that experienced phase 2 developed long-lived memory, whereas conditions without stable contacts yielded immunological amnesia. Thus, T cells make fate decisions within hours after Ag exposure, resulting in long-term memory or abortive effector responses, correlating with T cell-DCs interaction kinetics.

  20. Antigen availability determines CD8⁺ T cell-dendritic cell interaction kinetics and memory fate decisions.

    PubMed

    Henrickson, Sarah E; Perro, Mario; Loughhead, Scott M; Senman, Balimkiz; Stutte, Susanne; Quigley, Michael; Alexe, Gabriela; Iannacone, Matteo; Flynn, Michael P; Omid, Shaida; Jesneck, Jonathan L; Imam, Sabrina; Mempel, Thorsten R; Mazo, Irina B; Haining, W Nicholas; von Andrian, Ulrich H

    2013-09-19

    T cells are activated by antigen (Ag)-bearing dendritic cells (DCs) in lymph nodes in three phases. The duration of the initial phase of transient, serial DC-T cell interactions is inversely correlated with Ag dose. The second phase, characterized by stable DC-T cell contacts, is believed to be necessary for full-fledged T cell activation. Here we have shown that this is not the case. CD8⁺ T cells interacting with DCs presenting low-dose, short-lived Ag did not transition to phase 2, whereas higher Ag dose yielded phase 2 transition. Both antigenic constellations promoted T cell proliferation and effector differentiation but yielded different transcriptome signatures at 12 hr and 24 hr. T cells that experienced phase 2 developed long-lived memory, whereas conditions without stable contacts yielded immunological amnesia. Thus, T cells make fate decisions within hours after Ag exposure, resulting in long-term memory or abortive effector responses, correlating with T cell-DCs interaction kinetics. PMID:24054328

  1. Epigenetic Control of Smooth Muscle Cell Identity and Lineage Memory.

    PubMed

    Gomez, Delphine; Swiatlowska, Pamela; Owens, Gary K

    2015-12-01

    Vascular smooth muscle cells (SMCs), like all cells, acquire a cell-specific epigenetic signature during development that includes acquisition of a unique repertoire of histone and DNA modifications. These changes are postulated to induce an open chromatin state (referred to as euchromatin) on the repertoire of genes that are expressed in differentiated SMC, including SMC-selective marker genes like Acta2 and Myh11, as well as housekeeping genes expressed by most cell types. In contrast, genes that are silenced in differentiated SMC acquire modifications associated with a closed chromatin state (ie, heterochromatin) and transcriptional silencing. Herein, we review mechanisms that regulate epigenetic control of the differentiated state of SMC. In addition, we identify some of the major limitations in the field and future challenges, including development of innovative new tools and approaches, for performing single-cell epigenetic assays and locus-selective editing of the epigenome that will allow direct studies of the functional role of specific epigenetic controls during development, injury repair, and disease, including major cardiovascular diseases, such as atherosclerosis, hypertension, and microvascular disease, associated with diabetes mellitus.

  2. Staphylococcal Enterotoxin B (SEB) Induces Memory CD4 T Cell Anergy in vivo and Impairs Recall Immunity to Unrelated Antigens

    PubMed Central

    Janik, David K; Lee, William T

    2015-01-01

    Introduction Naïve and memory T cells can utilize unique regulatory pathways to promote protection but prevent self-reactivity. A bacterial superantigen SEB exploits unique TCR proximal signaling processes in memory CD4 T cells to induce clonal anergy. The aim of this study was to determine if SEB could antagonize memory CD4 T cells in vivo and whether there would be consequences on recall immune responses. We evaluated Ab responses to a T-dependent antigen as a measurement of memory T cell helper function. Method BALB/c mice were primed with TNP-RGG to elicit memory B cells and also immunized with an ovalbumin peptide to elicit memory helper T cells. Another group of TNP-RGG immunized mice were used as adoptive transfer recipients of exogenous DO11.10 memory T cells. Mice were challenged with TNP-OVA with or without prior administration of SEB. B cells secreting IgM or IgG TNP-specific Ab were enumerated by ELISPOT as indicators of primary versus secondary humoral immunity. Results Comparing the SEB and non-SEB-treated groups, the SEB-treated group failed to produce TNP-specific IgG in response to challenge with TNP-OVA, even if they were previously immunized with OVA. All groups produced IgM, indicating that the primary Ab responses and naïve helper T cells were not impacted by SEB. SEB had no negative impact when DO11.10 × Fyn−/− memory T cells were used as donor cells. Conclusion The present study indicated that SEB selectively targeted memory CD4 T cells in vivo and prevented helper function. Consequently, recall humoral immunity was lost. The data are most consistent with in vivo T cell anergy as opposed to indirect suppression as elimination of Fyn kinase restored helper function. These data suggest that bacterial superantigens can impair post-vaccination memory cell responses to unrelated antigens via their ability to target Vb families and antagonize memory cell activation. PMID:26807307

  3. Resistance switching memory operation using the bistability in current-voltage characteristics of GaN/AlN resonant tunneling diodes

    NASA Astrophysics Data System (ADS)

    Nagase, Masanori; Takahashi, Tokio; Shimizu, Mitsuaki

    2016-10-01

    Resistance switching memory operations using the bistability in the current-voltage (I-V) characteristics of GaN/AlN resonant tunneling diodes (RTDs) were investigated to realize an ultrafast nonvolatile memory operating at a picosecond time scale. Resistance switching memory operations based on electron accumulation due to intersubband transitions and electron release due to tunneling current were demonstrated with high reproducibility at room temperature when the leakage of electrons accumulating in the quantum well from the deep level in the AlN barrier was suppressed. A nonvolatile memory for the processor core in a normally off computing system is expected to be realized using the bistability in the I-V characteristics of GaN/AlN RTDs.

  4. Oseltamivir Prophylaxis Reduces Inflammation and Facilitates Establishment of Cross-Strain Protective T Cell Memory to Influenza Viruses

    PubMed Central

    Hurt, Aeron C.; Oshansky, Christine M.; Oh, Ding Yuan; Reading, Patrick C.; Chua, Brendon Y.; Sun, Yilun; Tang, Li; Handel, Andreas; Jackson, David C.; Turner, Stephen J.; Thomas, Paul G.; Kedzierska, Katherine

    2015-01-01

    CD8+ T cells directed against conserved viral regions elicit broad immunity against distinct influenza viruses, promote rapid virus elimination and enhanced host recovery. The influenza neuraminidase inhibitor, oseltamivir, is prescribed for therapy and prophylaxis, although it remains unclear how the drug impacts disease severity and establishment of effector and memory CD8+ T cell immunity. We dissected the effects of oseltamivir on viral replication, inflammation, acute CD8+ T cell responses and the establishment of immunological CD8+ T cell memory. In mice, ferrets and humans, the effect of osteltamivir on viral titre was relatively modest. However, prophylactic oseltamivir treatment in mice markedly reduced morbidity, innate responses, inflammation and, ultimately, the magnitude of effector CD8+ T cell responses. Importantly, functional memory CD8+ T cells established during the drug-reduced effector phase were capable of mounting robust recall responses. Moreover, influenza-specific memory CD4+ T cells could be also recalled after the secondary challenge, while the antibody levels were unaffected. This provides evidence that long-term memory T cells can be generated during an oseltamivir-interrupted infection. The anti-inflammatory effect of oseltamivir was verified in H1N1-infected patients. Thus, in the case of an unpredicted influenza pandemic, while prophylactic oseltamivir treatment can reduce disease severity, the capacity to generate memory CD8+ T cells specific for the newly emerged virus is uncompromised. This could prove especially important for any new influenza pandemic which often occurs in separate waves. PMID:26086392

  5. Therapeutic target of memory B cells depletion helps to tailor administration frequency of rituximab in myasthenia gravis.

    PubMed

    Lebrun, Christine; Bourg, Véronique; Bresch, Saskia; Cohen, Mikael; Rosenthal-Allieri, Maria Alessandra; Desnuelle, Claude; Ticchioni, Michel

    2016-09-15

    Rituximab (RTX) has demonstrated efficacy in limiting relapses in myasthenia gravis (MG). We investigated the interest of CD27+ memory B cell monitoring in patients as a biological marker of clinical relapse. Twenty-four patients have been treated with RTX (375mg/m(2)/week-month as an induction treatment). Maintenance treatment consisted with either systematic treatment every 3months or only when CD27+ memory B cells were detectable. After the induction treatment, the mean infusions were 1.3/year compared with 4/year. We suggest that RTX administration frequency can be decreased safely by monitoring the re-emerging CD27+ memory B cells. PMID:27609279

  6. The Effect of Cellular Stress on T and B Cell Memory Pathways in Immunized and Unimmunized BALB/c Mice.

    PubMed

    Wang, Yufei; Rahman, Durdana; Mistry, Mukesh; Lehner, Thomas

    2016-09-23

    Immunological memory is a fundamental function of vaccination. The antigenic breakdown products of the vaccine may not persist, and undefined tonic stimulation has been proposed to maintain the specific memory. We have suggested that cellular stress agents to which the immune cells are constantly exposed may be responsible for tonic stimulation. Here we have studied four stress agents: sodium arsenite, an oxidative agent; Gramicidin, eliciting K(+) efflux and calcium influx; dithiocarbamate, a metal ionophore; and aluminum hydroxide (alum), an immunological adjuvant. The aims of this study are to extend these investigations to T and B cell responses of unimmunized and ovalbumin (OVA)-immunized BALB/c mice, and furthermore, to ascertain whether stress is involved in optimal expression of memory B cells, as demonstrated in CD4(+) T cells. Examination of the homeostatic pathway defined by IL-15/IL-15R (IL-15 receptor) interaction and the inflammasome pathway defined by the IL-1-IL-1R interaction between dendritic cells (DC) and CD4(+) T cells suggests that both pathways are involved in the development of optimal expression of CD4(+)CD45RO(+) memory T cells in unimmunized and OVA-immunized BALB/c mice. Furthermore, significant direct correlation was found between CD4(+)CD44(+) memory T cells and both IL-15 of the homeostatic and IL-1β of the inflammasome pathways. However, CD19(+)CD27(+) memory B cells in vivo seem to utilize only the IL-15/IL-15R homeostatic pathway, although the proliferative responses are enhanced by the stress agents. Altogether, stress agents may up-regulate unimmunized and OVA-immunized CD4(+)CD44(+) memory T cells by the homeostatic and inflammasome pathways. However, the CD19(+)CD27(+) memory B cells utilize only the homeostatic pathway. PMID:27502276

  7. The Effect of Cellular Stress on T and B Cell Memory Pathways in Immunized and Unimmunized BALB/c Mice*

    PubMed Central

    Wang, Yufei; Rahman, Durdana; Mistry, Mukesh; Lehner, Thomas

    2016-01-01

    Immunological memory is a fundamental function of vaccination. The antigenic breakdown products of the vaccine may not persist, and undefined tonic stimulation has been proposed to maintain the specific memory. We have suggested that cellular stress agents to which the immune cells are constantly exposed may be responsible for tonic stimulation. Here we have studied four stress agents: sodium arsenite, an oxidative agent; Gramicidin, eliciting K+ efflux and calcium influx; dithiocarbamate, a metal ionophore; and aluminum hydroxide (alum), an immunological adjuvant. The aims of this study are to extend these investigations to T and B cell responses of unimmunized and ovalbumin (OVA)-immunized BALB/c mice, and furthermore, to ascertain whether stress is involved in optimal expression of memory B cells, as demonstrated in CD4+ T cells. Examination of the homeostatic pathway defined by IL-15/IL-15R (IL-15 receptor) interaction and the inflammasome pathway defined by the IL-1-IL-1R interaction between dendritic cells (DC) and CD4+ T cells suggests that both pathways are involved in the development of optimal expression of CD4+CD45RO+ memory T cells in unimmunized and OVA-immunized BALB/c mice. Furthermore, significant direct correlation was found between CD4+CD44+ memory T cells and both IL-15 of the homeostatic and IL-1β of the inflammasome pathways. However, CD19+CD27+ memory B cells in vivo seem to utilize only the IL-15/IL-15R homeostatic pathway, although the proliferative responses are enhanced by the stress agents. Altogether, stress agents may up-regulate unimmunized and OVA-immunized CD4+CD44+ memory T cells by the homeostatic and inflammasome pathways. However, the CD19+CD27+ memory B cells utilize only the homeostatic pathway. PMID:27502276

  8. Diet-Induced Obesity in Mice Reduces the Maintenance of Influenza-Specific CD8+ Memory T Cells12

    PubMed Central

    Karlsson, Erik A.; Sheridan, Patricia A.; Beck, Melinda A.

    2010-01-01

    Obesity has been associated with increasing the risk for type 2 diabetes and heart disease, but its influence on the immune response to viral infection is understudied. Memory T cells generated during a primary influenza infection are important for protection against subsequent influenza exposures. Previously, we have demonstrated that diet-induced obese (DIO) mice have increased morbidity and mortality following secondary influenza infection compared with lean mice. To determine whether the problem resided in a failure to maintain functional, influenza-specific CD8+ memory T cells, male DIO and lean mice were infected with influenza X-31. At 84 d postinfection, DIO mice had a 10% reduction in memory T cell numbers. This reduction may have resulted from significantly reduced memory T cell expression of interleukin 2 receptor β (IL-2R β, CD122), but not IL-7 receptor α (CD127), which are both required for memory cell maintenance. Peripheral leptin resistance in the DIO mice may be a contributing factor to the impairment. Indeed, leptin receptor mRNA expression was significantly reduced in the lungs of obese mice, whereas suppressor of cytokine signaling (Socs)1 and Socs3 mRNA expression were increased. It is imperative to understand how the obese state alters memory T cells, because impairment in maintenance of functional memory responses has important implications for vaccine efficacy in an obese population. PMID:20592105

  9. Modulation of Autoimmune T-Cell Memory by Stem Cell Educator Therapy: Phase 1/2 Clinical Trial

    PubMed Central

    Delgado, Elias; Perez-Basterrechea, Marcos; Suarez-Alvarez, Beatriz; Zhou, Huimin; Revuelta, Eva Martinez; Garcia-Gala, Jose Maria; Perez, Silvia; Alvarez-Viejo, Maria; Menendez, Edelmiro; Lopez-Larrea, Carlos; Tang, Ruifeng; Zhu, Zhenlong; Hu, Wei; Moss, Thomas; Guindi, Edward; Otero, Jesus; Zhao, Yong

    2015-01-01

    Background Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease that causes a deficit of pancreatic islet β cells. The complexities of overcoming autoimmunity in T1D have contributed to the challenges the research community faces when devising successful treatments with conventional immune therapies. Overcoming autoimmune T cell memory represents one of the key hurdles. Methods In this open-label, phase 1/phase 2 study, Caucasian T1D patients (N = 15) received two treatments with the Stem Cell Educator (SCE) therapy, an approach that uses human multipotent cord blood-derived multipotent stem cells (CB-SCs). SCE therapy involves a closed-loop system that briefly treats the patient's lymphocytes with CB-SCs in vitro and returns the “educated” lymphocytes (but not the CB-SCs) into the patient's blood circulation. This study is registered with ClinicalTrials.gov, NCT01350219. Findings Clinical data demonstrated that SCE therapy was well tolerated in all subjects. The percentage of naïve CD4+ T cells was significantly increased at 26 weeks and maintained through the final follow-up at 56 weeks. The percentage of CD4+ central memory T cells (TCM) was markedly and constantly increased at 18 weeks. Both CD4+ effector memory T cells (TEM) and CD8+ TEM cells were considerably decreased at 18 weeks and 26 weeks respectively. Additional clinical data demonstrated the modulation of C–C chemokine receptor 7 (CCR7) expressions on naïve T, TCM, and TEM cells. Following two treatments with SCE therapy, islet β-cell function was improved and maintained in individuals with residual β-cell function, but not in those without residual β-cell function. Interpretation Current clinical data demonstrated the safety and efficacy of SCE therapy in immune modulation. SCE therapy provides lasting reversal of autoimmune memory that could improve islet β-cell function in Caucasian subjects. Funding Obra Social “La Caixa”, Instituto de Salud Carlos III, Red de

  10. A regulatory role for the memory B cell as suppressor-inducer of feedback control

    SciTech Connect

    Kennedy, M.W.; Thomas, D.B.

    1983-02-01

    A regulatory role is proposed for the antigen-responsive B cell, as suppressor-inducer of feedback control during the secondary response in vivo. In a double adoptive transfer of memory cells primed to a thymus-dependent antigen from one irradiated host to another, antigen-specific suppressors are generated after a critical time in the primary recipient, able to entirely ablate a secondary anti-hapten response. Positive cell selection in the fluorescence-activated cell sorter confirmed that suppression was mediated by an Lyt-2+ T cell; however, positively selected B cells were also inhibitory and able to induce suppressors in a carrier-specific manner: Bhapten induced suppressors in a carrier-primed population, and Bcarrier induced suppressors in a hapten-carrier population. At the peak of the antibody response in the primary host, memory B cells and their progeny were unable to differentiate further to plasma cells due to their intrinsic suppressor-inducer activity, but this autoregulatory circuit could be severed by adoptive transfer to carrier-primed, X-irradiated recipients.

  11. Distinct activation thresholds of human conventional and innate-like memory T cells

    PubMed Central

    Slichter, Chloe K.; Miller, Hannah W.; Seymour, Brenda J.; McNevin, John P.; Diaz, Gabriela; Czartoski, Julie L.; McElrath, M. Juliana; Gottardo, Raphael

    2016-01-01

    Conventional memory CD8+ T cells and mucosal-associated invariant T cells (MAIT cells) are found in blood, liver, and mucosal tissues and have similar effector potential following activation, specifically expression of IFN-γ and granzyme B. To better understand each subset’s unique contributions to immunity and pathology, we interrogated inflammation- and TCR-driven activation requirements using human memory CD8+ T and MAIT cells isolated from blood and mucosal tissue biopsies in ex vivo functional assays and single cell gene expression experiments. We found that MAIT cells had a robust IFN-γ and granzyme B response to inflammatory signals but limited responsiveness when stimulated directly via their TCR. Importantly, this is not due to an overall hyporesponsiveness to TCR signals. When delivered together, TCR and inflammatory signals synergize to elicit potent effector function in MAIT cells. This unique control of effector function allows MAIT cells to respond to the same TCR signal in a dichotomous and situation-specific manner. We propose that this could serve to prevent responses to antigen in noninflamed healthy mucosal tissue, while maintaining responsiveness and great sensitivity to inflammation-eliciting infections. We discuss the implications of these findings in context of inflammation-inducing damage to tissues such as BM transplant conditioning or HIV infection. PMID:27331143

  12. Virtual memory T cells develop and mediate bystander protective immunity in an IL-15-dependent manner

    PubMed Central

    White, Jason T.; Cross, Eric W.; Burchill, Matthew A.; Danhorn, Thomas; McCarter, Martin D.; Rosen, Hugo R.; O'Connor, Brian; Kedl, Ross M.

    2016-01-01

    Virtual memory cells (VM) are an antigen-specific, memory phenotype CD8 T-cell subset found in lymphoreplete, unchallenged mice. Previous studies indicated that VM cells were the result of homeostatic proliferation (HP) resembling the proliferation observed in a lymphopenic environment. Here we demonstrate that HP is ongoing in lymphoreplete mice, the degree of which is dictated by the number of naive CD8 T cells with a sufficiently high affinity for self-antigen interacting with peripheral IL-15. VM cell transcriptional profiles suggest a capacity to mediate protective immunity via antigen non-specific bystander killing, a function we show is dependent on IL-15. Finally, we show a VM-like population of human cells that accumulate with age and traffic to the liver, displaying phenotypic and functional attributes consistent with the bystander protective functions of VM cells identified in the mouse. These data identify developmental and functional attributes of VM cells, including their likely role in protective immunity. PMID:27097762

  13. Virtual memory T cells develop and mediate bystander protective immunity in an IL-15-dependent manner.

    PubMed

    White, Jason T; Cross, Eric W; Burchill, Matthew A; Danhorn, Thomas; McCarter, Martin D; Rosen, Hugo R; O'Connor, Brian; Kedl, Ross M

    2016-01-01

    Virtual memory cells (VM) are an antigen-specific, memory phenotype CD8 T-cell subset found in lymphoreplete, unchallenged mice. Previous studies indicated that VM cells were the result of homeostatic proliferation (HP) resembling the proliferation observed in a lymphopenic environment. Here we demonstrate that HP is ongoing in lymphoreplete mice, the degree of which is dictated by the number of naive CD8 T cells with a sufficiently high affinity for self-antigen interacting with peripheral IL-15. VM cell transcriptional profiles suggest a capacity to mediate protective immunity via antigen non-specific bystander killing, a function we show is dependent on IL-15. Finally, we show a VM-like population of human cells that accumulate with age and traffic to the liver, displaying phenotypic and functional attributes consistent with the bystander protective functions of VM cells identified in the mouse. These data identify developmental and functional attributes of VM cells, including their likely role in protective immunity. PMID:27097762

  14. Constitutive Lck Activity Drives Sensitivity Differences between CD8+ Memory T Cell Subsets.

    PubMed

    Moogk, Duane; Zhong, Shi; Yu, Zhiya; Liadi, Ivan; Rittase, William; Fang, Victoria; Dougherty, Janna; Perez-Garcia, Arianne; Osman, Iman; Zhu, Cheng; Varadarajan, Navin; Restifo, Nicholas P; Frey, Alan B; Krogsgaard, Michelle

    2016-07-15

    CD8(+) T cells develop increased sensitivity following Ag experience, and differences in sensitivity exist between T cell memory subsets. How differential TCR signaling between memory subsets contributes to sensitivity differences is unclear. We show in mouse effector memory T cells (TEM) that >50% of lymphocyte-specific protein tyrosine kinase (Lck) exists in a constitutively active conformation, compared with <20% in central memory T cells (TCM). Immediately proximal to Lck signaling, we observed enhanced Zap-70 phosphorylation in TEM following TCR ligation compared with TCM Furthermore, we observed superior cytotoxic effector function in TEM compared with TCM, and we provide evidence that this results from a lower probability of TCM reaching threshold signaling owing to the decreased magnitude of TCR-proximal signaling. We provide evidence that the differences in Lck constitutive activity between CD8(+) TCM and TEM are due to differential regulation by SH2 domain-containing phosphatase-1 (Shp-1) and C-terminal Src kinase, and we use modeling of early TCR signaling to reveal the significance of these differences. We show that inhibition of Shp-1 results in increased constitutive Lck activity in TCM to levels similar to TEM, as well as increased cytotoxic effector function in TCM Collectively, this work demonstrates a role for constitutive Lck activity in controlling Ag sensitivity, and it suggests that differential activities of TCR-proximal signaling components may contribute to establishing the divergent effector properties of TCM and TEM. This work also identifies Shp-1 as a potential target to improve the cytotoxic effector functions of TCM for adoptive cell therapy applications. PMID:27271569

  15. Mechanical memory and dosing influence stem cell fate

    NASA Astrophysics Data System (ADS)

    Yang, Chun; Tibbitt, Mark W.; Basta, Lena; Anseth, Kristi S.

    2014-06-01

    We investigated whether stem cells remember past physical signals and whether these can be exploited to dose cells mechanically. We found that the activation of the Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding domain (TAZ) as well as the pre-osteogenic transcription factor RUNX2 in human mesenchymal stem cells (hMSCs) cultured on soft poly(ethylene glycol) (PEG) hydrogels (Young’s modulus E ~ 2 kPa) depended on previous culture time on stiff tissue culture polystyrene (TCPS; E ~ 3 GPa). In addition, mechanical dosing of hMSCs cultured on initially stiff (E ~ 10 kPa) and then soft (E ~ 2 kPa) phototunable PEG hydrogels resulted in either reversible or—above a threshold mechanical dose—irreversible activation of YAP/TAZ and RUNX2. We also found that increased mechanical dosing on supraphysiologically stiff TCPS biases hMSCs towards osteogenic differentiation. We conclude that stem cells possess mechanical memory—with YAP/TAZ acting as an intracellular mechanical rheostat—that stores information from past physical environments and influences the cells’ fate.

  16. Antigen-specific culture of memory-like CD8 T cells for adoptive immunotherapy.

    PubMed

    Litterman, Adam J; Zellmer, David M; LaRue, Rebecca S; Jameson, Stephen C; Largaespada, David A

    2014-09-01

    Cytotoxic T cells typically are expanded ex vivo in culture with IL2 for adoptive immunotherapy. This culture period leads to a differentiated phenotype and acquisition of effector function, as well as a loss of in vivo proliferative capability and antitumor efficacy. Here, we report antigen-specific and polyclonal expansion of cytotoxic T cells in a cocktail of cytokines and small molecules that leads to a memory-like phenotype in mouse and human cells even during extended culture, leading to enhanced in vivo expansion and tumor control in mice.

  17. Radiosensitivity of CD45RO+ memory and CD45RO- naive T cells in culture.

    PubMed

    Uzawa, A; Suzuki, G; Nakata, Y; Akashi, M; Ohyama, H; Akanuma, A

    1994-01-01

    Radiosensitivities of various human T-cell subsets were investigated by a proliferation assay and by a single-cell gel electrophoresis assay. Each T-cell subset was purified using a cell sorter and was induced to proliferate by ionomycin and interleukin 2. Unsorted T cells showed biphasic dose-survival curves, indicating the heterogeneity of T cells in terms of radiosensitivity. Purified CD4+ helper and CD8+ killer T cells showed similar biphasic dose-survival curves. Hence both T-cell subsets were composed of cells of different radiosensitivity. The T-cell subsets belonging to different activation stages such as CD45RO+ memory and CD45RO- naive T cells had different dose-survival curves. The former was more radiosensitive than the latter. The high radiosensitivity of CD45RO+ cells was also demonstrated by single-cell gel electrophoresis after irradiation. This is the first demonstration that a particular cell surface marker on T cells is correlated with greater radiosensitivity.

  18. Functional Characteristics of Multipotent Mesenchymal Stromal Cells from Pituitary Adenomas.

    PubMed

    Megnis, Kaspars; Mandrika, Ilona; Petrovska, Ramona; Stukens, Janis; Rovite, Vita; Balcere, Inga; Jansone, Laima Sabine; Peculis, Raitis; Pirags, Valdis; Klovins, Janis

    2016-01-01

    Pituitary adenomas are one of the most common endocrine and intracranial neoplasms. Although they are theoretically monoclonal in origin, several studies have shown that they contain different multipotent cell types that are thought to play an important role in tumor initiation, maintenance, and recurrence after therapy. In the present study, we isolated and characterized cell populations from seven pituitary somatotroph, nonhormonal, and lactotroph adenomas. The obtained cells showed characteristics of multipotent mesenchymal stromal cells as observed by cell morphology, cell surface marker CD90, CD105, CD44, and vimentin expression, as well as differentiation to osteogenic and adipogenic lineages. They are capable of growth and passaging under standard laboratory cell culture conditions and do not manifest any hormonal cell characteristics. Multipotent mesenchymal stromal cells are present in pituitary adenomas regardless of their clinical manifestation and show no considerable expression of somatostatin 1-5 and dopamine 2 receptors. Most likely obtained cells are a part of tissue-supportive cells in pituitary adenoma microenvironment. PMID:27340409

  19. Functional Characteristics of Multipotent Mesenchymal Stromal Cells from Pituitary Adenomas

    PubMed Central

    Megnis, Kaspars; Mandrika, Ilona; Petrovska, Ramona; Stukens, Janis; Rovite, Vita; Balcere, Inga; Jansone, Laima Sabine; Peculis, Raitis; Pirags, Valdis

    2016-01-01

    Pituitary adenomas are one of the most common endocrine and intracranial neoplasms. Although they are theoretically monoclonal in origin, several studies have shown that they contain different multipotent cell types that are thought to play an important role in tumor initiation, maintenance, and recurrence after therapy. In the present study, we isolated and characterized cell populations from seven pituitary somatotroph, nonhormonal, and lactotroph adenomas. The obtained cells showed characteristics of multipotent mesenchymal stromal cells as observed by cell morphology, cell surface marker CD90, CD105, CD44, and vimentin expression, as well as differentiation to osteogenic and adipogenic lineages. They are capable of growth and passaging under standard laboratory cell culture conditions and do not manifest any hormonal cell characteristics. Multipotent mesenchymal stromal cells are present in pituitary adenomas regardless of their clinical manifestation and show no considerable expression of somatostatin 1–5 and dopamine 2 receptors. Most likely obtained cells are a part of tissue-supportive cells in pituitary adenoma microenvironment. PMID:27340409

  20. Memory CD4+ T cells are required for optimal NK cell effector functions against the opportunistic fungal pathogen Pneumocystis murina.

    PubMed

    Kelly, Michelle N; Zheng, Mingquan; Ruan, Sanbao; Kolls, Jay; D'Souza, Alain; Shellito, Judd E

    2013-01-01

    Little is known about the role of NK cells or their interplay with other immune cells during opportunistic infections. Using our murine model of Pneumocystis pneumonia, we found that loss of NK cells during immunosuppression results in substantial Pneumocystis lung burden. During early infection of C57B/6 CD4(+) T cell-depleted mice, there were significantly fewer NK cells in the lung tissue compared with CD4(+) T cell-intact animals, and the NK cells present demonstrated decreased upregulation of the activation marker NKp46 and production of the effector cytokine, IFN-γ. Furthermore, coincubation studies revealed a significant increase in fungal killing when NK cells were combined with CD4(+) T cells compared with either cell alone, which was coincident with a significant increase in perforin production by NK cells. Finally, however, we found through adoptive transfer that memory CD4(+) T cells are required for significant NK cell upregulation of the activation marker NK group 2D and production of IFN-γ, granzyme B, and perforin during Pneumocystis infection. To the best of our knowledge, this study is the first to demonstrate a role for NK cells in immunity to Pneumocystis pneumonia, as well as to establish a functional relationship between CD4(+) T cells and NK cells in the host response to an opportunistic fungal pathogen.

  1. The estimation of long-term memory characteristics in MEA neuronal culture recordings.

    PubMed

    Esposti, Federico; Signorini, Maria Gabriella

    2008-01-01

    The nonlinear analysis of multichannel MEA recordings from neuronal networks is becoming a central topic in Neuroengineering. Up-to-date these kind of analyses required complex ad hoc methods. In this paper we introduce a new approach that allows the analysis of the whole-neuronal-network-activity with well-established nonlinear signal processing methods. In particular, we show here the estimation of long-term-memory behaviors through the Periodogram method in the bursting activity of cortical neuron cultures during development. Moreover, we show how this method is able to highlight structural activity changes of the network.

  2. Characterization of Effector and Memory T Cell Subsets in the Immune Response to Bovine Tuberculosis in Cattle

    PubMed Central

    Maggioli, Mayara F.; Palmer, Mitchell V.; Thacker, Tyler C.; Vordermeier, H. Martin; Waters, W. Ray

    2015-01-01

    Cultured IFN-γ ELISPOT assays are primarily a measure of central memory T cell (Tcm) responses with humans; however, this important subset of lymphocytes is poorly characterized in cattle. Vaccine-elicited cultured IFN-γ ELISPOT responses correlate with protection against bovine tuberculosis in cattle. However, whether this assay measures cattle Tcm responses or not is uncertain. The objective of the present study was to characterize the relative contribution of Tcm (CCR7+, CD62Lhi, CD45RO+), T effector memory (Tem, defined as: CCR7-, CD62Llow/int, CD45RO+), and T effector cells (CCR7-, CD62L-/low, CD45RO-), in the immune response to Mycobacterium bovis. Peripheral blood mononuclear cells (PBMC) from infected cattle were stimulated with a cocktail of M. bovis purified protein derivative, rTb10.4 and rAg85A for 13 days with periodic addition of fresh media and rIL-2. On day 13, cultured PBMC were re-stimulated with medium alone, rESAT-6:CFP10 or PPDb with fresh autologous adherent cells for antigen presentation. Cultured cells (13 days) or fresh PBMCs (ex vivo response) from the same calves were analyzed for IFN-γ production, proliferation, and CD4, CD45RO, CD62L, CD44, and CCR7 expression via flow cytometry after overnight stimulation. In response to mycobacterial antigens, ~75% of CD4+ IFN-γ+ cells in long-term cultures expressed a Tcm phenotype while less than 10% of the ex vivo response consisted of Tcm cells. Upon re-exposure to antigen, long-term cultured cells were highly proliferative, a distinctive characteristic of Tcm, and the predominant phenotype within the long-term cultures switched from Tcm to Tem. These findings suggest that proliferative responses of Tcm cells to some extent occurs simultaneously with reversion to effector phenotypes (mostly Tem). The present study characterizes Tcm cells of cattle and their participation in the response to M. bovis infection. PMID:25879774

  3. VDNROM: A novel four-physical-bits/cell vertical channel dual-nitride-trapping-layers ROM for high density flash memory applications

    NASA Astrophysics Data System (ADS)

    Zhou, Falong; Cai, Yimao; Huang, Ru; Li, Yan; Shan, Xiaonan; Liu, Jia; Guo, Ao; Zhang, Xing; Wang, Yangyuan

    2007-11-01

    A novel vertical channel dual-nitride-trapping-layer ROM (VDNROM) flash memory with oxide-nitride-oxide-nitride-oxide (ONONO) dielectrics stack is proposed and experimentally demonstrated. Compared with the conventional planar NROM cell, since the cell area of the proposed vertical structure is independent of the gate length, the VDNROM structure can relax the limitation of the gate length scaling, and can have high capability of cell area shrinking. The fabrication process of this VDNROM device is basically compatible with planar CMOS technology. The VDNROM cell can be programmed and erased by the hot carrier injection to the localized trapping dual-nitride layers, so it can achieve a four-physical-bits storage capability each cell. The reliability behaviors including the cycling endurance and the bake retention at 150 °C have also been investigated and show the acceptable characteristics. The experiment results verify the VDNROM cell as a good candidate for high density applications.

  4. Early effector cells survive the contraction phase in malaria infection and generate both central and effector memory T cells.

    PubMed

    Opata, Michael M; Carpio, Victor H; Ibitokou, Samad A; Dillon, Brian E; Obiero, Joshua M; Stephens, Robin

    2015-06-01

    CD4 T cells orchestrate immunity against blood-stage malaria. However, a major challenge in designing vaccines to the disease is poor understanding of the requirements for the generation of protective memory T cells (Tmem) from responding effector T cells (Teff) in chronic parasite infection. In this study, we use a transgenic mouse model with T cells specific for the merozoite surface protein (MSP)-1 of Plasmodium chabaudi to show that activated T cells generate three distinct Teff subsets with progressive activation phenotypes. The earliest observed Teff subsets (CD127(-)CD62L(hi)CD27(+)) are less divided than CD62L(lo) Teff and express memory genes. Intermediate (CD62L(lo)CD27(+)) effector subsets include the most multicytokine-producing T cells, whereas fully activated (CD62L(lo)CD27(-)) late effector cells have a terminal Teff phenotype (PD-1(+), Fas(hi), AnnexinV(+)). We show that although IL-2 promotes expansion, it actually slows terminal effector differentiation. Using adoptive transfer, we show that only early Teff survive the contraction phase and generate the terminal late Teff subsets, whereas in uninfected recipients, they become both central and effector Tmem. Furthermore, we show that progression toward full Teff activation is promoted by increased duration of infection, which in the long-term promotes Tem differentiation. Therefore, we have defined markers of progressive activation of CD4 Teff at the peak of malaria infection, including a subset that survives the contraction phase to make Tmem, and show that Ag and cytokine levels during CD4 T cell expansion influence the proportion of activated cells that can survive contraction and generate memory in malaria infection.

  5. Early effector cells survive the contraction phase in malaria infection and generate both central and effector memory T cells.

    PubMed

    Opata, Michael M; Carpio, Victor H; Ibitokou, Samad A; Dillon, Brian E; Obiero, Joshua M; Stephens, Robin

    2015-06-01

    CD4 T cells orchestrate immunity against blood-stage malaria. However, a major challenge in designing vaccines to the disease is poor understanding of the requirements for the generation of protective memory T cells (Tmem) from responding effector T cells (Teff) in chronic parasite infection. In this study, we use a transgenic mouse model with T cells specific for the merozoite surface protein (MSP)-1 of Plasmodium chabaudi to show that activated T cells generate three distinct Teff subsets with progressive activation phenotypes. The earliest observed Teff subsets (CD127(-)CD62L(hi)CD27(+)) are less divided than CD62L(lo) Teff and express memory genes. Intermediate (CD62L(lo)CD27(+)) effector subsets include the most multicytokine-producing T cells, whereas fully activated (CD62L(lo)CD27(-)) late effector cells have a terminal Teff phenotype (PD-1(+), Fas(hi), AnnexinV(+)). We show that although IL-2 promotes expansion, it actually slows terminal effector differentiation. Using adoptive transfer, we show that only early Teff survive the contraction phase and generate the terminal late Teff subsets, whereas in uninfected recipients, they become both central and effector Tmem. Furthermore, we show that progression toward full Teff activation is promoted by increased duration of infection, which in the long-term promotes Tem differentiation. Therefore, we have defined markers of progressive activation of CD4 Teff at the peak of malaria infection, including a subset that survives the contraction phase to make Tmem, and show that Ag and cytokine levels during CD4 T cell expansion influence the proportion of activated cells that can survive contraction and generate memory in malaria infection. PMID:25911759

  6. Extremely small test cell structure for resistive random access memory element with removable bottom electrode

    SciTech Connect

    Koh, Sang-Gyu; Kishida, Satoru; Kinoshita, Kentaro

    2014-02-24

    We established a method of preparing an extremely small memory cell by fabricating a resistive random access memory (ReRAM) structure on the tip of a cantilever of an atomic force microscope. This structure has the high robustness against the drift of the cantilever, and the effective cell size was estimated to be less than 10 nm in diameter due to the electric field concentration at the tip of the cantilever, which was confirmed using electric field simulation. The proposed structure, which has a removable bottom electrode, enables not only the preparation of a tiny ReRAM structure but also the performance of unique experiments, by making the most of its high robustness against the drift of the cantilever.

  7. THE EMERGING ROLE OF RESIDENT MEMORY T CELLS IN PROTECTIVE IMMUNITY AND INFLAMMATORY DISEASE

    PubMed Central

    Park, Changook; Kupper, Thomas S

    2015-01-01

    Over the past decade, it has become clear that there is an important subset of memory T cells that resides in tissues — tissue resident memory T cells (TRM). There is an emerging understanding that TRM have a role in human tissue specific immune and inflammatory diseases. Furthermore, the nature of the molecular signals that maintain TRM in tissues is the subject of much investigation. In addition while it is logical for TRM to be located in barrier tissues at interfaces with the environment in human and mouse, TRM have also been found in brain, kidney, joint, and other non-barrier tissues in both species. Their biology and behavior make it likely that they play a role in chronic relapsing and remitting diseases of both barrier and non-barrier tissues. This review will discuss recent understandings of the biology of TRM with a particular focus on their role in disease. PMID:26121195

  8. Ethnicity and difference in dengue virus-specific memory T cell responses in Cuban individuals.

    PubMed

    de la C Sierra, Beatriz; García, Gissell; Pérez, Ana B; Morier, Luis; Alvarez, Mayling; Kourí, Gustavo; Guzmán, María G

    2006-01-01

    The different risk factors associated with dengue hemorrhagic fever pathogenesis needs yet additional clarification. The exceptional epidemiological circumstances in Cuba allow their evaluation in a well-defined situation. In the present study the memory T cell response of 80 Cuban donors previously infected with dengue-1 and dengue-2 during the 1977 and 1981 epidemics, and belonging to different ethnic groups, was examined. White people showed, in contrast to black people, stronger and remarkably cross-reactive dengue virus-specific memory CD4(+) T lymphocyte proliferation and interferon-gamma release. The observed variation in T cell response according to ethnicity could be related to the immunopathogenesis of dengue hemorrhagic fever, and may partially explain the epidemiological evidence that black individuals are at lower risk for the most severe dengue clinical course compared with white individuals.

  9. Memory Th1 Cells Are Protective in Invasive Staphylococcus aureus Infection.

    PubMed

    Brown, Aisling F; Murphy, Alison G; Lalor, Stephen J; Leech, John M; O'Keeffe, Kate M; Mac Aogáin, Micheál; O'Halloran, Dara P; Lacey, Keenan A; Tavakol, Mehri; Hearnden, Claire H; Fitzgerald-Hughes, Deirdre; Humphreys, Hilary; Fennell, Jérôme P; van Wamel, Willem J; Foster, Timothy J; Geoghegan, Joan A; Lavelle, Ed C; Rogers, Thomas R; McLoughlin, Rachel M

    2015-01-01

    Mechanisms of protective immunity to Staphylococcus aureus infection in humans remain elusive. While the importance of cellular immunity has been shown in mice, T cell responses in humans have not been characterised. Using a murine model of recurrent S. aureus peritonitis, we demonstrated that prior exposure to S. aureus enhanced IFNγ responses upon subsequent infection, while adoptive transfer of S. aureus antigen-specific Th1 cells was protective in naïve mice. Translating these findings, we found that S. aureus antigen-specific Th1 cells were also significantly expanded during human S. aureus bloodstream infection (BSI). These Th1 cells were CD45RO+, indicative of a memory phenotype. Thus, exposure to S. aureus induces memory Th1 cells in mice and humans, identifying Th1 cells as potential S. aureus vaccine targets. Consequently, we developed a model vaccine comprising staphylococcal clumping factor A, which we demonstrate to be an effective human T cell antigen, combined with the Th1-driving adjuvant CpG. This novel Th1-inducing vaccine conferred significant protection during S. aureus infection in mice. This study notably advances our understanding of S. aureus cellular immunity, and demonstrates for the first time that a correlate of S. aureus protective immunity identified in mice may be relevant in humans. PMID:26539822

  10. Memory Th1 Cells Are Protective in Invasive Staphylococcus aureus Infection

    PubMed Central

    Lalor, Stephen J.; Leech, John M.; O’Keeffe, Kate M.; Mac Aogáin, Micheál; O’Halloran, Dara P.; Lacey, Keenan A.; Tavakol, Mehri; Hearnden, Claire H.; Fitzgerald-Hughes, Deirdre; Humphreys, Hilary; Fennell, Jérôme P.; van Wamel, Willem J.; Foster, Timothy J.; Geoghegan, Joan A.; Lavelle, Ed C.; Rogers, Thomas R.; McLoughlin, Rachel M.

    2015-01-01

    Mechanisms of protective immunity to Staphylococcus aureus infection in humans remain elusive. While the importance of cellular immunity has been shown in mice, T cell responses in humans have not been characterised. Using a murine model of recurrent S. aureus peritonitis, we demonstrated that prior exposure to S. aureus enhanced IFNγ responses upon subsequent infection, while adoptive transfer of S. aureus antigen-specific Th1 cells was protective in naïve mice. Translating these findings, we found that S. aureus antigen-specific Th1 cells were also significantly expanded during human S. aureus bloodstream infection (BSI). These Th1 cells were CD45RO+, indicative of a memory phenotype. Thus, exposure to S. aureus induces memory Th1 cells in mice and humans, identifying Th1 cells as potential S. aureus vaccine targets. Consequently, we developed a model vaccine comprising staphylococcal clumping factor A, which we demonstrate to be an effective human T cell antigen, combined with the Th1-driving adjuvant CpG. This novel Th1-inducing vaccine conferred significant protection during S. aureus infection in mice. This study notably advances our understanding of S. aureus cellular immunity, and demonstrates for the first time that a correlate of S. aureus protective immunity identified in mice may be relevant in humans. PMID:26539822

  11. gp49B-mediated negative regulation of antibody production by memory and marginal zone B cells.

    PubMed

    Fukao, Saori; Haniuda, Kei; Nojima, Takuya; Takai, Toshiyuki; Kitamura, Daisuke

    2014-07-15

    The rapid Ab responses observed after primary and secondary immunizations are mainly derived from marginal zone (MZ) and memory B cells, respectively, but it is largely unknown how these responses are negatively regulated. Several inhibitory receptors have been identified and their roles have been studied, but mainly on follicular B cells and much less so on MZ B, and never on memory B cells. gp49B is an Ig superfamily member that contains two ITIMs in its cytoplasmic tail, and it has been shown to negatively regulate mast cell, macrophage, and NK cell responses. In this study, we demonstrate that gp49B is preferentially expressed on memory and MZ B cells. We show that gp49B(-/-) mice produce more IgM after a primary immunization and more IgM and IgG1 after a secondary immunization than gp49B(+/+) mice in T cell-dependent immune responses. Memory and MZ B cells from gp49B(-/-) mice also produce more Abs upon in vitro stimulation with CD40 than those from gp49B(+/+) mice. The in vitro IgM production by MZ B cells from gp49B(+/+), but not gp49B(-/-), mice is suppressed by interaction with a putative gp49B ligand, the integrin αvβ3 heterodimer. In addition, gp49B(-/-) mice exhibited exaggerated IgE production in the memory recall response. These results suggest that plasma cell development from memory and MZ B cells, as well as subsequent Ab production, are suppressed via gp49B. In memory B cells, this suppression also prevents excessive IgE production, thus curtailing allergic diseases.

  12. Serine protease inhibitor-6 differentially affects the survival of effector and memory alloreactive CD8-T cells.

    PubMed

    Azzi, J; Ohori, S; Ting, C; Uehara, M; Abdoli, R; Smith, B D; Safa, K; Solhjou, Z; Lukyanchykov, P; Patel, J; McGrath, M; Abdi, R

    2015-01-01

    The clonal expansion of effector T cells and subsequent generation of memory T cells are critical in determining the outcome of transplantation. While cytotoxic T lymphocytes induce direct cytolysis of target cells through secretion of Granzyme-B (GrB), they also express cytoplasmic serine protease inhibitor-6 (Spi6) to protect themselves from GrB that has leaked from granules. Here, we studied the role of GrB/Spi6 axis in determining clonal expansion of alloreactive CD8-T cells and subsequent generation of memory CD8-T cells in transplantation. CD8-T cells from Spi6(-/-) mice underwent more GrB mediated apoptosis upon alloantigen stimulation in vitro and in vivo following adoptive transfer into an allogeneic host. Interestingly, while OT1.Spi6(-/-) CD8 T cells showed significantly lower clonal expansion following skin transplants from OVA mice, there was no difference in the size of the effector memory CD8-T cells long after transplantation. Furthermore, lack of Spi6 resulted in a decrease of short-lived-effector-CD8-cells but did not impact the pool of memory-precursor-effector-CD8-cells. Similar results were found in heart transplant models. Our findings suggest that the final alloreactive CD8-memory-pool-size is independent from the initial clonal-proliferation as memory precursors express low levels of GrB and therefore are independent of Spi6 for survival. These data advance our understanding of memory T cells generation in transplantation and provide basis for Spi6 based strategies to target effector T cells.

  13. Serine Protease Inhibitor-6 Differentially Affects the Survival of Effector and Memory Alloreactive CD8-T Cells

    PubMed Central

    Azzi, J.; Ohori, S.; Ting, C.; Uehara, M.; Abdoli, R.; Smith, B. D.; Safa, K.; Solhjou, Z.; Lukyanchykov, P.; Patel, J.; McGrath, M.; Abdi, R.

    2016-01-01

    The clonal expansion of effector T cells and subsequent generation of memory T cells are critical in determining the outcome of transplantation. While cytotoxic T lymphocytes induce direct cytolysis of target cells through secretion of Granzyme-B (GrB), they also express cytoplasmic serine protease inhibitor-6 (Spi6) to protect themselves from GrB that has leaked from granules. Here, we studied the role of GrB/Spi6 axis in determining clonal expansion of alloreactive CD8-T cells and subsequent generation of memory CD8-T cells in transplantation. CD8-T cells from Spi6−/− mice underwent more GrB mediated apoptosis upon alloantigen stimulation in vitro and in vivo following adoptive transfer into an allogeneic host. Interestingly, while OT1.Spi6−/− CD8 T cells showed significantly lower clonal expansion following skin transplants from OVA mice, there was no difference in the size of the effector memory CD8-T cells long after transplantation. Furthermore, lack of Spi6 resulted in a decrease of short-lived-effector-CD8-cells but did not impact the pool of memory-precursor-effector-CD8-cells. Similar results were found in heart transplant models. Our findings suggest that the final alloreactive CD8-memory-pool-size is independent from the initial clonal-proliferation as memory precursors express low levels of GrB and therefore are independent of Spi6 for survival. These data advance our understanding of memory T cells generation in transplantation and provide basis for Spi6 based strategies to target effector T cells. PMID:25534448

  14. SEU hardened memory cells for a CCSDS Reed-Solomon encoder

    NASA Technical Reports Server (NTRS)

    Whitaker, Sterling; Canaris, John; Liu, Kathy

    1991-01-01

    A design technique to harden CMOS memory circuits against single event upset (SEU) in the space environment is reported. The design technique provides a recovery mechanism which is independent of the shape of the upsetting event. A RAM cell and flip-flop design are presented to demonstrate the method. The flip-flop was used in the control circuitry for a Reed-Solomon encoder designed for the Space Station and Explorer platforms.

  15. TCR stimulation without co-stimulatory signals induces expression of "tolerogenic" genes in memory CD4 T cells but does not compromise cell proliferation.

    PubMed

    Xie, Aini; Zheng, Xiong; Khattar, Mithun; Schroder, Paul; Stepkowski, Stanislaw; Xia, Jiahong; Chen, Wenhao

    2015-02-01

    Memory T cells resist co-stimulatory blockade and present a unique therapeutic challenge in transplantation and autoimmune diseases. Herein, we determined whether memory T cells express less "tolerogenic" genes than naïve T cells to reinforce a proliferative response under the deprivation of co-stimulatory signals. The expression of ∼40 tolerogenic genes in memory and naïve CD4(+) T cells was thus assessed during an in vitro TCR stimulation without co-stimulation. Briefly, upon TCR stimulation with an anti-CD3 mAb alone, memory CD4(+) T cells exhibited more proliferation than naïve CD4(+) T cells. To our surprise, at 24h upon anti-CD3 mAb stimulation, memory CD4(+) T cells expressed more than a 5-fold higher level of the transcription factor Egr2 and a 20-fold higher level of the transmembrane E3 ubiquitin ligase GRAIL than those in naïve T cells. Hence, the high-level expression of tolerogenic genes, Egr2 and GRAIL, in memory CD4(+) T cells does not prevent cell proliferation. Importantly, anti-CD3 mAb-stimulated memory CD4(+) T cells expressed high protein/gene levels of phosphorylated STAT5, Nedd4, Bcl-2, and Bcl-XL. Therefore, co-stimulation-independent proliferation of memory CD4(+) T cells may be due to elevated expression of molecules that support cell proliferation and survival, but not lack of tolerogenic molecules.

  16. Centrocytes rapidly adopt a memory B cell phenotype on co-culture with autologous germinal centre T cell-enriched preparations.

    PubMed

    Casamayor-Palleja, M; Feuillard, J; Ball, J; Drew, M; MacLennan, I C

    1996-05-01

    B cells, after mutating their Ig B-region genes in germinal centres (GC), undergo apoptosis, unless they receive antigen-dependent selection signals. The signals appear to be delivered by GC T cells, require CD40 ligand expression and may induce differentiation to memory cells. Cultured GC B cells are prevented from entering apoptosis by ligating their surface CD40, but the resulting phenotype is not associated with B cells found in vivo. Conversely, GC B cells rapidly adopt a memory B cell phenotype on culture with autologous memory CD4(+) T cells that have been induced to express CD40 ligand transiently. This effect is prevented by blocking CD40 ligand. Naive CD4(+) T cells, induced to express CD40 ligand, do not prevent GC B cells undergoing apoptosis.

  17. Realisation of all 16 Boolean logic functions in a single magnetoresistance memory cell

    NASA Astrophysics Data System (ADS)

    Gao, Shuang; Yang, Guang; Cui, Bin; Wang, Shouguo; Zeng, Fei; Song, Cheng; Pan, Feng

    2016-06-01

    Stateful logic circuits based on next-generation nonvolatile memories, such as magnetoresistance random access memory (MRAM), promise to break the long-standing von Neumann bottleneck in state-of-the-art data processing devices. For the successful commercialisation of stateful logic circuits, a critical step is realizing the best use of a single memory cell to perform logic functions. In this work, we propose a method for implementing all 16 Boolean logic functions in a single MRAM cell, namely a magnetoresistance (MR) unit. Based on our experimental results, we conclude that this method is applicable to any MR unit with a double-hump-like hysteresis loop, especially pseudo-spin-valve magnetic tunnel junctions with a high MR ratio. Moreover, after simply reversing the correspondence between voltage signals and output logic values, this method could also be applicable to any MR unit with a double-pit-like hysteresis loop. These results may provide a helpful solution for the final commercialisation of MRAM-based stateful logic circuits in the near future.Stateful logic circuits based on next-generation nonvolatile memories, such as magnetoresistance random access memory (MRAM), promise to break the long-standing von Neumann bottleneck in state-of-the-art data processing devices. For the successful commercialisation of stateful logic circuits, a critical step is realizing the best use of a single memory cell to perform logic functions. In this work, we propose a method for implementing all 16 Boolean logic functions in a single MRAM cell, namely a magnetoresistance (MR) unit. Based on our experimental results, we conclude that this method is applicable to any MR unit with a double-hump-like hysteresis loop, especially pseudo-spin-valve magnetic tunnel junctions with a high MR ratio. Moreover, after simply reversing the correspondence between voltage signals and output logic values, this method could also be applicable to any MR unit with a double-pit-like hysteresis

  18. Neuronal characteristics of small-cell lung cancer

    PubMed Central

    Onganer, P U; Seckl, M J; Djamgoz, M B A

    2005-01-01

    Wide ranging experimental evidence suggests that human small-cell lung cancer (SCLC) has a number of molecular and subcellular characteristics normally associated with neurones. This review outlines and discusses these characteristics in the light of recent developments in the field. Emphasis is placed upon neuronal cell adhesion molecules, neurone-restrictive silencer factor, neurotransmitters/peptides and voltage-gated ion, especially Na+ channels. The hypothesis is put forward that acquisition of such characteristics and the membrane ‘excitability' that would follow can accelerate metastatic progression. The clinical potential of the neuronal characteristics of SCLC, in particular ion channel expression/activity, is discussed in relation to possible novel diagnostic and therapeutic modalities. PMID:16265346

  19. Murine Splenic Natural Killer Cells Do Not Develop Immunological Memory after Re-Encounter with Mycobacterium bovis BCG.

    PubMed

    Kawahara, Mamoru; Hasegawa, Nozomi; Takaku, Hiroshi

    2016-01-01

    Several lines of evidence have recently suggested that natural killer (NK) cells develop immunological memory against viral infections. However, there is no apparent evidence that NK cells acquire specific memory against Mycobacterium bovis bacillus Calmette-Guérin (BCG), the only currently licensed vaccine for preventing tuberculosis. In the present study, we investigated whether murine splenic NK cells can be activated by BCG in a dendritic cell (DC)-independent or -dependent manner, and furthermore examined whether these NK cells acquire specific memory following BCG vaccination. NK cells isolated from spleens of BCG-immunized mice produced interferon (IFN)γ through direct BCG stimulation in the absence of antigen-presenting cells; however, NK cells from control animals similarly directly responded to BCG, and the response level was not statistically significant between the immunized and the naïve NK cells. When purified NK cells that had been exposed to BCG were cocultured with RAW murine macrophages infected with BCG, the antibacterial activity of the macrophages was strongly enhanced; however, its level was similar to that by naïve NK cells, which had not been exposed to BCG. When splenocytes harvested from BCG-immunized mice were stimulated with purified protein derivative (PPD) derived from Mycobacterium tuberculosis, a specific IFNγ response was clearly observed, mainly attributed to NK cells and memory CD4+ T cells. To investigate whether these NK cells as well as the T cells are activated by cell-cell interaction with DCs presenting mycobacterial antigens, NK cells isolated from BCG-immunized mice were cocultured with splenocytes harvested from naïve mice in the presence of PPD stimulation. However, no IFNγ response was found in the NK cells. These results suggest that murine splenic NK cells do not develop BCG-specific immunological memory in either a DC-independent or -dependent manner.

  20. A model of episodic memory: mental time travel along encoded trajectories using grid cells.

    PubMed

    Hasselmo, Michael E

    2009-11-01

    The definition of episodic memory includes the concept of mental time travel: the ability to re-experience a previously experienced trajectory through continuous dimensions of space and time, and to recall specific events or stimuli along this trajectory. Lesions of the hippocampus and entorhinal cortex impair human episodic memory function and impair rat performance in tasks that could be solved by retrieval of trajectories. Recent physiological data suggests a novel model for encoding and retrieval of trajectories, and for associating specific stimuli with specific positions along the trajectory. During encoding in the model, external input drives the activity of head direction cells. Entorhinal grid cells integrate the head direction input to update an internal representation of location, and drive hippocampal place cells. Trajectories are encoded by Hebbian modification of excitatory synaptic connections between hippocampal place cells and head direction cells driven by external action. Associations are also formed between hippocampal cells and sensory stimuli. During retrieval, a sensory input cue activates hippocampal cells that drive head direction activity via previously modified synapses. Persistent spiking of head direction cells maintains the direction and speed of the action, updating the activity of entorhinal grid cells that thereby further update place cell activity. Additional cells, termed arc length cells, provide coding of trajectory segments based on the one-dimensional arc length from the context of prior actions or states, overcoming ambiguity where the overlap of trajectory segments causes multiple head directions to be associated with one place. These mechanisms allow retrieval of complex, self-crossing trajectories as continuous curves through space and time. PMID:19615456

  1. Features of Memory-Like and PD-1(+) Human NK Cell Subsets.

    PubMed

    Della Chiesa, Mariella; Pesce, Silvia; Muccio, Letizia; Carlomagno, Simona; Sivori, Simona; Moretta, Alessandro; Marcenaro, Emanuela

    2016-01-01

    Human NK cells are distinguished into CD56(bright)CD16(-) cells and CD56(dim)CD16(+) cells. These two subsets are conventionally associated with differential functional outcomes and are heterogeneous with respect to the expression of KIR and CD94/NKG2 heterodimers that represent the two major types of HLA-class I-specific receptors. Recent studies indicated that immature CD56(bright) NK cells, homogeneously expressing the inhibitory CD94/NKG2A receptor, are precursors of CD56(dim) NK cells that, in turn, during their process of differentiation, lose expression of CD94/NKG2A and subsequentially acquire inhibitory KIRs and LIR-1. The terminally differentiated phenotype of CD56(dim) cells is marked by the expression of the CD57 molecule that is associated with poor responsiveness to cytokine stimulation, but retained cytolytic capacity. Remarkably, this NKG2A(-)KIR(+)LIR-1(+)CD57(+)CD56(dim) NK cell subset when derived from individuals previously exposed to pathogens, such as human cytomegalovirus (HCMV), may contain "memory-like" NK cells. These cells are generally characterized by an upregulation of the activating receptor CD94/NKG2C and a downregulation of the inhibitory receptor Siglec-7. The "memory-like" NK cells are persistent over time and display some hallmarks of adaptive immunity, i.e., clonal expansion, more effective antitumor and antiviral immune responses, longevity, as well as given epigenetic modifications. Interestingly, unknown cofactors associated with HCMV infection may induce the onset of a recently identified fully mature NK cell subset, characterized by marked downregulation of the activating receptors NKp30 and NKp46 and by the unexpected expression of the inhibitory PD-1 receptor. This phenotype correlates with an impaired antitumor NK cell activity that can be partially restored by antibody-mediated disruption of PD-1/PD-L interaction.

  2. A model of episodic memory: mental time travel along encoded trajectories using grid cells.

    PubMed

    Hasselmo, Michael E

    2009-11-01

    The definition of episodic memory includes the concept of mental time travel: the ability to re-experience a previously experienced trajectory through continuous dimensions of space and time, and to recall specific events or stimuli along this trajectory. Lesions of the hippocampus and entorhinal cortex impair human episodic memory function and impair rat performance in tasks that could be solved by retrieval of trajectories. Recent physiological data suggests a novel model for encoding and retrieval of trajectories, and for associating specific stimuli with specific positions along the trajectory. During encoding in the model, external input drives the activity of head direction cells. Entorhinal grid cells integrate the head direction input to update an internal representation of location, and drive hippocampal place cells. Trajectories are encoded by Hebbian modification of excitatory synaptic connections between hippocampal place cells and head direction cells driven by external action. Associations are also formed between hippocampal cells and sensory stimuli. During retrieval, a sensory input cue activates hippocampal cells that drive head direction activity via previously modified synapses. Persistent spiking of head direction cells maintains the direction and speed of the action, updating the activity of entorhinal grid cells that thereby further update place cell activity. Additional cells, termed arc length cells, provide coding of trajectory segments based on the one-dimensional arc length from the context of prior actions or states, overcoming ambiguity where the overlap of trajectory segments causes multiple head directions to be associated with one place. These mechanisms allow retrieval of complex, self-crossing trajectories as continuous curves through space and time.

  3. Features of Memory-Like and PD-1(+) Human NK Cell Subsets.

    PubMed

    Della Chiesa, Mariella; Pesce, Silvia; Muccio, Letizia; Carlomagno, Simona; Sivori, Simona; Moretta, Alessandro; Marcenaro, Emanuela

    2016-01-01

    Human NK cells are distinguished into CD56(bright)CD16(-) cells and CD56(dim)CD16(+) cells. These two subsets are conventionally associated with differential functional outcomes and are heterogeneous with respect to the expression of KIR and CD94/NKG2 heterodimers that represent the two major types of HLA-class I-specific receptors. Recent studies indicated that immature CD56(bright) NK cells, homogeneously expressing the inhibitory CD94/NKG2A receptor, are precursors of CD56(dim) NK cells that, in turn, during their process of differentiation, lose expression of CD94/NKG2A and subsequentially acquire inhibitory KIRs and LIR-1. The terminally differentiated phenotype of CD56(dim) cells is marked by the expression of the CD57 molecule that is associated with poor responsiveness to cytokine stimulation, but retained cytolytic capacity. Remarkably, this NKG2A(-)KIR(+)LIR-1(+)CD57(+)CD56(dim) NK cell subset when derived from individuals previously exposed to pathogens, such as human cytomegalovirus (HCMV), may contain "memory-like" NK cells. These cells are generally characterized by an upregulation of the activating receptor CD94/NKG2C and a downregulation of the inhibitory receptor Siglec-7. The "memory-like" NK cells are persistent over time and display some hallmarks of adaptive immunity, i.e., clonal expansion, more effective antitumor and antiviral immune responses, longevity, as well as given epigenetic modifications. Interestingly, unknown cofactors associated with HCMV infection may induce the onset of a recently identified fully mature NK cell subset, characterized by marked downregulation of the activating receptors NKp30 and NKp46 and by the unexpected expression of the inhibitory PD-1 receptor. This phenotype correlates with an impaired antitumor NK cell activity that can be partially restored by antibody-mediated disruption of PD-1/PD-L interaction. PMID:27683578

  4. Features of Memory-Like and PD-1+ Human NK Cell Subsets

    PubMed Central

    Della Chiesa, Mariella; Pesce, Silvia; Muccio, Letizia; Carlomagno, Simona; Sivori, Simona; Moretta, Alessandro; Marcenaro, Emanuela

    2016-01-01

    Human NK cells are distinguished into CD56brightCD16− cells and CD56dimCD16+ cells. These two subsets are conventionally associated with differential functional outcomes and are heterogeneous with respect to the expression of KIR and CD94/NKG2 heterodimers that represent the two major types of HLA-class I-specific receptors. Recent studies indicated that immature CD56bright NK cells, homogeneously expressing the inhibitory CD94/NKG2A receptor, are precursors of CD56dim NK cells that, in turn, during their process of differentiation, lose expression of CD94/NKG2A and subsequentially acquire inhibitory KIRs and LIR-1. The terminally differentiated phenotype of CD56dim cells is marked by the expression of the CD57 molecule that is associated with poor responsiveness to cytokine stimulation, but retained cytolytic capacity. Remarkably, this NKG2A−KIR+LIR-1+CD57+CD56dim NK cell subset when derived from individuals previously exposed to pathogens, such as human cytomegalovirus (HCMV), may contain “memory-like” NK cells. These cells are generally characterized by an upregulation of the activating receptor CD94/NKG2C and a downregulation of the inhibitory receptor Siglec-7. The “memory-like” NK cells are persistent over time and display some hallmarks of adaptive immunity, i.e., clonal expansion, more effective antitumor and antiviral immune responses, longevity, as well as given epigenetic modifications. Interestingly, unknown cofactors associated with HCMV infection may induce the onset of a recently identified fully mature NK cell subset, characterized by marked downregulation of the activating receptors NKp30 and NKp46 and by the unexpected expression of the inhibitory PD-1 receptor. This phenotype correlates with an impaired antitumor NK cell activity that can be partially restored by antibody-mediated disruption of PD-1/PD-L interaction. PMID:27683578

  5. IL-15 promotes the survival of naive and memory phenotype CD8+ T cells.

    PubMed

    Berard, Marion; Brandt, Katja; Bulfone-Paus, Silvia; Tough, David F

    2003-05-15

    IL-15 stimulates the proliferation of memory phenotype CD44(high)CD8(+) T cells and is thought to play a key role in regulating the turnover of these cells in vivo. We have investigated whether IL-15 also has the capacity to affect the life span of naive phenotype (CD44(low)) CD8(+) T cells. We report that IL-15 promotes the survival of both CD44(low) and CD44(high) CD8(+) T cells, doing so at much lower concentrations than required to induce proliferation of CD44(high) cells. Rescue from apoptosis was associated with the up-regulation of Bcl-2 in both cell types, whereas elevated expression of Bcl-x(L) was observed among CD44(high) but not CD44(low) CD8(+) cells. An investigation into the role of IL-15R subunits in mediating the effects of IL-15 revealed distinct contributions of the alpha- and beta- and gamma-chains. Most strikingly, IL-15R alpha was not essential for either induction of proliferation or promotion of survival by IL-15, but did greatly enhance the sensitivity of cells to low concentrations of IL-15. By contrast, the beta- and gamma-chains of the IL-15R were absolutely required for the proliferative and pro-survival effects of IL-15, although it was not necessary for CD44(high)CD8(+) cells to express higher levels of IL-15R beta than CD44(low) cells to proliferate in response to IL-15. These results show that IL-15 has multiple effects on CD8 T cells and possesses the potential to regulate the life span of naive as well as memory CD8(+) T cells. PMID:12734346

  6. Features of Memory-Like and PD-1+ Human NK Cell Subsets

    PubMed Central

    Della Chiesa, Mariella; Pesce, Silvia; Muccio, Letizia; Carlomagno, Simona; Sivori, Simona; Moretta, Alessandro; Marcenaro, Emanuela

    2016-01-01

    Human NK cells are distinguished into CD56brightCD16− cells and CD56dimCD16+ cells. These two subsets are conventionally associated with differential functional outcomes and are heterogeneous with respect to the expression of KIR and CD94/NKG2 heterodimers that represent the two major types of HLA-class I-specific receptors. Recent studies indicated that immature CD56bright NK cells, homogeneously expressing the inhibitory CD94/NKG2A receptor, are precursors of CD56dim NK cells that, in turn, during their process of differentiation, lose expression of CD94/NKG2A and subsequentially acquire inhibitory KIRs and LIR-1. The terminally differentiated phenotype of CD56dim cells is marked by the expression of the CD57 molecule that is associated with poor responsiveness to cytokine stimulation, but retained cytolytic capacity. Remarkably, this NKG2A−KIR+LIR-1+CD57+CD56dim NK cell subset when derived from individuals previously exposed to pathogens, such as human cytomegalovirus (HCMV), may contain “memory-like” NK cells. These cells are generally characterized by an upregulation of the activating receptor CD94/NKG2C and a downregulation of the inhibitory receptor Siglec-7. The “memory-like” NK cells are persistent over time and display some hallmarks of adaptive immunity, i.e., clonal expansion, more effective antitumor and antiviral immune responses, longevity, as well as given epigenetic modifications. Interestingly, unknown cofactors associated with HCMV infection may induce the onset of a recently identified fully mature NK cell subset, characterized by marked downregulation of the activating receptors NKp30 and NKp46 and by the unexpected expression of the inhibitory PD-1 receptor. This phenotype correlates with an impaired antitumor NK cell activity that can be partially restored by antibody-mediated disruption of PD-1/PD-L interaction.

  7. Rapid isolation of dengue-neutralizing antibodies from single cell-sorted human antigen-specific memory B-cell cultures.

    PubMed

    Cox, Kara S; Tang, Aimin; Chen, Zhifeng; Horton, Melanie S; Yan, Hao; Wang, Xin-Min; Dubey, Sheri A; DiStefano, Daniel J; Ettenger, Andrew; Fong, Rachel H; Doranz, Benjamin J; Casimiro, Danilo R; Vora, Kalpit A

    2016-01-01

    Monitoring antigen-specific memory B cells and the antibodies they encode is important for understanding the specificity, breadth and duration of immune response to an infection or vaccination. The antibodies isolated could further help design vaccine antigens for raising relevant protective immune responses. However, developing assays to measure and isolate antigen-specific memory B cells is technically challenging due to the low frequencies of these cells that exist in the circulating blood. Here, we describe a flow cytometry method to identify and isolate dengue envelope-specific memory B cells using a labeled dengue envelope protein. We enumerated dengue-envelope specific memory B cells from a cohort of dengue seropositive donors using this direct flow cytometry assay. A more established and conventional assay, the cultured B ELISPOT, was used as a benchmark comparator. Furthermore, we were able to confirm the single-sorted memory B-cell specificity by culturing B cells and differentiating them into plasma cells using cell lines expressing CD40L. The culture supernatants were assayed for antigen binding and the ability of the antibodies to neutralize the cognate dengue virus. Moreover, we successfully isolated the heavy and light Ig sequences and expressed them as full-length recombinant antibodies to reproduce the activity seen in culture supernatants. Mapping of these antibodies revealed a novel epitope for dengue 2 virus serotype. In conclusion, we established a reproducible methodology to enumerate antigen-specific memory B cells and assay their encoded antibodies for functional characterization.

  8. Rapid isolation of dengue-neutralizing antibodies from single cell-sorted human antigen-specific memory B-cell cultures

    PubMed Central

    Cox, Kara S.; Tang, Aimin; Chen, Zhifeng; Horton, Melanie S.; Yan, Hao; Wang, Xin-Min; Dubey, Sheri A.; DiStefano, Daniel J.; Ettenger, Andrew; Fong, Rachel H.; Doranz, Benjamin J.; Casimiro, Danilo R.; Vora, Kalpit A.

    2016-01-01

    Monitoring antigen-specific memory B cells and the antibodies they encode is important for understanding the specificity, breadth and duration of immune response to an infection or vaccination. The antibodies isolated could further help design vaccine antigens for raising relevant protective immune responses. However, developing assays to measure and isolate antigen-specific memory B cells is technically challenging due to the low frequencies of these cells that exist in the circulating blood. Here, we describe a flow cytometry method to identify and isolate dengue envelope-specific memory B cells using a labeled dengue envelope protein. We enumerated dengue-envelope specific memory B cells from a cohort of dengue seropositive donors using this direct flow cytometry assay. A more established and conventional assay, the cultured B ELISPOT, was used as a benchmark comparator. Furthermore, we were able to confirm the single-sorted memory B-cell specificity by culturing B cells and differentiating them into plasma cells using cell lines expressing CD40L. The culture supernatants were assayed for antigen binding and the ability of the antibodies to neutralize the cognate dengue virus. Moreover, we successfully isolated the heavy and light Ig sequences and expressed them as full-length recombinant antibodies to reproduce the activity seen in culture supernatants. Mapping of these antibodies revealed a novel epitope for dengue 2 virus serotype. In conclusion, we established a reproducible methodology to enumerate antigen-specific memory B cells and assay their encoded antibodies for functional characterization. PMID:26491897

  9. Rapid isolation of dengue-neutralizing antibodies from single cell-sorted human antigen-specific memory B-cell cultures.

    PubMed

    Cox, Kara S; Tang, Aimin; Chen, Zhifeng; Horton, Melanie S; Yan, Hao; Wang, Xin-Min; Dubey, Sheri A; DiStefano, Daniel J; Ettenger, Andrew; Fong, Rachel H; Doranz, Benjamin J; Casimiro, Danilo R; Vora, Kalpit A

    2016-01-01

    Monitoring antigen-specific memory B cells and the antibodies they encode is important for understanding the specificity, breadth and duration of immune response to an infection or vaccination. The antibodies isolated could further help design vaccine antigens for raising relevant protective immune responses. However, developing assays to measure and isolate antigen-specific memory B cells is technically challenging due to the low frequencies of these cells that exist in the circulating blood. Here, we describe a flow cytometry method to identify and isolate dengue envelope-specific memory B cells using a labeled dengue envelope protein. We enumerated dengue-envelope specific memory B cells from a cohort of dengue seropositive donors using this direct flow cytometry assay. A more established and conventional assay, the cultured B ELISPOT, was used as a benchmark comparator. Furthermore, we were able to confirm the single-sorted memory B-cell specificity by culturing B cells and differentiating them into plasma cells using cell lines expressing CD40L. The culture supernatants were assayed for antigen binding and the ability of the antibodies to neutralize the cognate dengue virus. Moreover, we successfully isolated the heavy and light Ig sequences and expressed them as full-length recombinant antibodies to reproduce the activity seen in culture supernatants. Mapping of these antibodies revealed a novel epitope for dengue 2 virus serotype. In conclusion, we established a reproducible methodology to enumerate antigen-specific memory B cells and assay their encoded antibodies for functional characterization. PMID:26491897

  10. Tissue-resident memory CD8+ T cells continuously patrol skin epithelia to quickly recognize local antigen

    PubMed Central

    Ariotti, Silvia; Beltman, Joost B.; Chodaczek, Grzegorz; Hoekstra, Mirjam E.; van Beek, Anna E.; Gomez-Eerland, Raquel; Ritsma, Laila; van Rheenen, Jacco; Marée, Athanasius F. M.; Zal, Tomasz; de Boer, Rob J.; Haanen, John B. A. G.; Schumacher, Ton N.

    2012-01-01

    Recent work has demonstrated that following the clearance of infection a stable population of memory T cells remains present in peripheral organs and contributes to the control of secondary infections. However, little is known about how tissue-resident memory T cells behave in situ and how they encounter newly infected target cells. Here we demonstrate that antigen-specific CD8+ T cells that remain in skin following herpes simplex virus infection show a steady-state crawling behavior in between keratinocytes. Spatially explicit simulations of the migration of these tissue-resident memory T cells indicate that the migratory dendritic behavior of these cells allows the detection of antigen-expressing target cells in physiologically relevant time frames of minutes to hours. Furthermore, we provide direct evidence for the identification of rare antigen-expressing epithelial cells by skin-patrolling memory T cells in vivo. These data demonstrate the existence of skin patrol by memory T cells and reveal the value of this patrol in the rapid detection of renewed infections at a previously infected site. PMID:23150545

  11. Expansion of Activated Peripheral Blood Memory B Cells in Rheumatoid Arthritis, Impact of B Cell Depletion Therapy, and Biomarkers of Response

    PubMed Central

    Adlowitz, Diana G.; Barnard, Jennifer; Biear, Jamie N.; Cistrone, Christopher; Owen, Teresa; Wang, Wensheng; Palanichamy, Arumugam; Ezealah, Ezinma; Campbell, Debbie; Wei, Chungwen; Looney, R. John; Sanz, Inaki; Anolik, Jennifer H.

    2015-01-01

    Although B cell depletion therapy (BCDT) is effective in a subset of rheumatoid arthritis (RA) patients, both mechanisms and biomarkers of response are poorly defined. Here we characterized abnormalities in B cell populations in RA and the impact of BCDT in order to elucidate B cell roles in the disease and response biomarkers. In active RA patients both CD27+IgD- switched memory (SM) and CD27-IgD- double negative memory (DN) peripheral blood B cells contained significantly higher fractions of CD95+ and CD21- activated cells compared to healthy controls. After BCD the predominant B cell populations were memory, and residual memory B cells displayed a high fraction of CD21- and CD95+ compared to pre-depletion indicating some resistance of these activated populations to anti-CD20. The residual memory populations also expressed more Ki-67 compared to pre-treatment, suggesting homeostatic proliferation in the B cell depleted state. Biomarkers of clinical response included lower CD95+ activated memory B cells at depletion time points and a higher ratio of transitional B cells to memory at reconstitution. B cell function in terms of cytokine secretion was dependent on B cell subset and changed with BCD. Thus, SM B cells produced pro-inflammatory (TNF) over regulatory (IL10) cytokines as compared to naïve/transitional. Notably, B cell TNF production decreased after BCDT and reconstitution compared to untreated RA. Our results support the hypothesis that the clinical and immunological outcome of BCDT depends on the relative balance of protective and pathogenic B cell subsets established after B cell depletion and repopulation. PMID:26047509

  12. Optical system for determining physical characteristics of a solar cell

    DOEpatents

    Sopori, Bhushan L.

    2001-01-01

    The invention provides an improved optical system for determining the physical characteristics of a solar cell. The system comprises a lamp means for projecting light in a wide solid-angle onto the surface of the cell; a chamber for receiving the light through an entrance port, the chamber having an interior light absorbing spherical surface, an exit port for receiving a beam of light reflected substantially normal to the cell, a cell support, and an lower aperture for releasing light into a light absorbing baffle; a means for dispersing the reflection into monochromatic components; a means for detecting an intensity of the components; and a means for reporting the determination.

  13. Inference of cell-cell interactions from population density characteristics and cell trajectories on static and growing domains.

    PubMed

    Ross, Robert J H; Yates, C A; Baker, R E

    2015-06-01

    A key feature of cell migration is how cell movement is affected by cell-cell interactions. Furthermore, many cell migratory processes such as neural crest stem cell migration [Thomas and Erickson, 2008; McLennan et al., 2012] occur on growing domains or in the presence of a chemoattractant. Therefore, it is important to study interactions between migrating cells in the context of domain growth and directed motility. Here we compare discrete and continuum models describing the spatial and temporal evolution of a cell population for different types of cell-cell interactions on static and growing domains. We suggest that cell-cell interactions can be inferred from population density characteristics in the presence of motility bias, and these population density characteristics for different cell-cell interactions are conserved on both static and growing domains. We also study the expected displacement of a tagged cell, and show that different types of cell-cell interactions can give rise to cell trajectories with different characteristics. These characteristics are conserved in the presence of domain growth, however, they are diminished in the presence of motility bias. Our results are relevant for researchers who study the existence and role of cell-cell interactions in biological systems, so far as we suggest that different types of cell-cell interactions could be identified from cell density and trajectory data.

  14. Macrophage characteristics of stem cells revealed by transcriptome profiling

    SciTech Connect

    Charriere, Guillaume M.; Cousin, Beatrice; Arnaud, Emmanuelle; Saillan-Barreau, Corinne; Andre, Mireille; Massoudi, Ali; Dani, Christian; Penicaud, Luc; Casteilla, Louis . E-mail: casteil@toulouse.inserm.fr

    2006-10-15

    We previously showed that the phenotypes of adipocyte progenitors and macrophages were close. Using functional analyses and microarray technology, we first tested whether this intriguing relationship was specific to adipocyte progenitors or could be shared with other progenitors. Measurements of phagocytic activity and gene profiling analysis of different progenitor cells revealed that the latter hypothesis should be retained. These results encouraged us to pursue and to confirm our analysis with a gold-standard stem cell population, embryonic stem cells or ESC. The transcriptomic profiles of ESC and macrophages were clustered together, unlike differentiated ESC. In addition, undifferentiated ESC displayed higher phagocytic activity than other progenitors, and they could phagocytoze apoptotic bodies. These data suggest that progenitors and stem cells share some characteristics of macrophages. This opens new perspectives on understanding stem cell phenotype and functionalities such as a putative role of stem cells in tissue remodeling by discarding dead cells but also their immunomodulation or fusion properties.

  15. Dynamic Memory Cells Using MoS2 Field-Effect Transistors Demonstrating Femtoampere Leakage Currents.

    PubMed

    Kshirsagar, Chaitanya U; Xu, Weichao; Su, Yang; Robbins, Matthew C; Kim, Chris H; Koester, Steven J

    2016-09-27

    Two-dimensional semiconductors such as transition-metal dichalcogenides (TMDs) are of tremendous interest for scaled logic and memory applications. One of the most promising TMDs for scaled transistors is molybdenum disulfide (MoS2), and several recent reports have shown excellent performance and scalability for MoS2 MOSFETs. An often overlooked feature of MoS2 is that its wide band gap (1.8 eV in monolayer) and high effective masses should lead to extremely low off-state leakage currents. These features could be extremely important for dynamic memory applications where the refresh rate is the primary factor affecting the power consumption. Theoretical predictions suggest that leakage currents in the 10(-18) to 10(-15) A/μm range could be possible, even in scaled transistor geometries. Here, we demonstrate the operation of one- and two-transistor dynamic memory circuits using MoS2 MOSFETs. We characterize the retention times in these circuits and show that the two-transistor memory cell reveals MoS2 MOSFETs leakage currents as low as 1.7 × 10(-15) A/μm, a value that is below the noise floor of conventional DC measurements. These results have important implications for the future use of MoS2 MOSFETs in low-power circuit applications.

  16. Dynamic Memory Cells Using MoS2 Field-Effect Transistors Demonstrating Femtoampere Leakage Currents.

    PubMed

    Kshirsagar, Chaitanya U; Xu, Weichao; Su, Yang; Robbins, Matthew C; Kim, Chris H; Koester, Steven J

    2016-09-27

    Two-dimensional semiconductors such as transition-metal dichalcogenides (TMDs) are of tremendous interest for scaled logic and memory applications. One of the most promising TMDs for scaled transistors is molybdenum disulfide (MoS2), and several recent reports have shown excellent performance and scalability for MoS2 MOSFETs. An often overlooked feature of MoS2 is that its wide band gap (1.8 eV in monolayer) and high effective masses should lead to extremely low off-state leakage currents. These features could be extremely important for dynamic memory applications where the refresh rate is the primary factor affecting the power consumption. Theoretical predictions suggest that leakage currents in the 10(-18) to 10(-15) A/μm range could be possible, even in scaled transistor geometries. Here, we demonstrate the operation of one- and two-transistor dynamic memory circuits using MoS2 MOSFETs. We characterize the retention times in these circuits and show that the two-transistor memory cell reveals MoS2 MOSFETs leakage currents as low as 1.7 × 10(-15) A/μm, a value that is below the noise floor of conventional DC measurements. These results have important implications for the future use of MoS2 MOSFETs in low-power circuit applications. PMID:27559610

  17. Annealing characteristics of irradiated hydrogenated amorphous silicon solar cells

    NASA Technical Reports Server (NTRS)

    Payson, J. S.; Abdulaziz, S.; Li, Y.; Woodyard, J. R.

    1991-01-01

    It was shown that 1 MeV proton irradiation with fluences of 1.25E14 and 1.25E15/sq cm reduces the normalized I(sub SC) of a-Si:H solar cell. Solar cells recently fabricated showed superior radiation tolerance compared with cells fabricated four years ago; the improvement is probably due to the fact that the new cells are thinner and fabricated from improved materials. Room temperature annealing was observed for the first time in both new and old cells. New cells anneal at a faster rate than old cells for the same fluence. From the annealing work it is apparent that there are at least two types of defects and/or annealing mechanisms. One cell had improved I-V characteristics following irradiation as compared to the virgin cell. The work shows that the photothermal deflection spectroscopy (PDS) and annealing measurements may be used to predict the qualitative behavior of a-Si:H solar cells. It was anticipated that the modeling work will quantitatively link thin film measurements with solar cell properties. Quantitative predictions of the operation of a-Si:H solar cells in a space environment will require a knowledge of the defect creation mechanisms, defect structures, role of defects on degradation, and defect passivation and annealing mechanisms. The engineering data and knowledge base for justifying space flight testing of a-Si:H alloy based solar cells is being developed.

  18. Mechanisms of regulating cell topology in proliferating epithelia: impact of division plane, mechanical forces, and cell memory.

    PubMed

    Li, Yingzi; Naveed, Hammad; Kachalo, Sema; Xu, Lisa X; Liang, Jie

    2012-01-01

    Regulation of cell growth and cell division has a fundamental role in tissue formation, organ development, and cancer progression. Remarkable similarities in the topological distributions were found in a variety of proliferating epithelia in both animals and plants. At the same time, there are species with significantly varied frequency of hexagonal cells. Moreover, local topology has been shown to be disturbed on the boundary between proliferating and quiescent cells, where cells have fewer sides than natural proliferating epithelia. The mechanisms of regulating these topological changes remain poorly understood. In this study, we use a mechanical model to examine the effects of orientation of division plane, differential proliferation, and mechanical forces on animal epithelial cells. We find that regardless of orientation of division plane, our model can reproduce the commonly observed topological distributions of cells in natural proliferating animal epithelia with the consideration of cell rearrangements. In addition, with different schemes of division plane, we are able to generate different frequency of hexagonal cells, which is consistent with experimental observations. In proliferating cells interfacing quiescent cells, our results show that differential proliferation alone is insufficient to reproduce the local changes in cell topology. Rather, increased tension on the boundary, in conjunction with differential proliferation, can reproduce the observed topological changes. We conclude that both division plane orientation and mechanical forces play important roles in cell topology in animal proliferating epithelia. Moreover, cell memory is also essential for generating specific topological distributions.

  19. Murine Splenic Natural Killer Cells Do Not Develop Immunological Memory after Re-Encounter with Mycobacterium bovis BCG

    PubMed Central

    Kawahara, Mamoru; Hasegawa, Nozomi; Takaku, Hiroshi

    2016-01-01

    Several lines of evidence have recently suggested that natural killer (NK) cells develop immunological memory against viral infections. However, there is no apparent evidence that NK cells acquire specific memory against Mycobacterium bovis bacillus Calmette—Guérin (BCG), the only currently licensed vaccine for preventing tuberculosis. In the present study, we investigated whether murine splenic NK cells can be activated by BCG in a dendritic cell (DC)-independent or -dependent manner, and furthermore examined whether these NK cells acquire specific memory following BCG vaccination. NK cells isolated from spleens of BCG-immunized mice produced interferon (IFN)γ through direct BCG stimulation in the absence of antigen-presenting cells; however, NK cells from control animals similarly directly responded to BCG, and the response level was not statistically significant between the immunized and the naïve NK cells. When purified NK cells that had been exposed to BCG were cocultured with RAW murine macrophages infected with BCG, the antibacterial activity of the macrophages was strongly enhanced; however, its level was similar to that by naïve NK cells, which had not been exposed to BCG. When splenocytes harvested from BCG-immunized mice were stimulated with purified protein derivative (PPD) derived from Mycobacterium tuberculosis, a specific IFNγ response was clearly observed, mainly attributed to NK cells and memory CD4+ T cells. To investigate whether these NK cells as well as the T cells are activated by cell−cell interaction with DCs presenting mycobacterial antigens, NK cells isolated from BCG-immunized mice were cocultured with splenocytes harvested from naïve mice in the presence of PPD stimulation. However, no IFNγ response was found in the NK cells. These results suggest that murine splenic NK cells do not develop BCG-specific immunological memory in either a DC-independent or -dependent manner. PMID:26999357

  20. Inhibitory receptor expression on memory CD8 T cells following Ad vector immunization.

    PubMed

    Penaloza-MacMaster, Pablo; Alayo, Quazim A; Ra, Joshua; Provine, Nicholas M; Larocca, Rafael; Lee, Benjamin; Barouch, Dan H

    2016-09-22

    T cells are an important component of immune responses, and their function is influenced by their expression of inhibitory receptors. Immunization with alternative serotype adenovirus (Ad) vectors induces highly functional T cell responses with lower programmed cell death 1 (PD-1) expression and increased boostability relative to Ad5 vectors. However, a detailed phenotypic characterization of other inhibitory receptors is lacking, and it is unknown whether Ad5-induced CD8 T cells eventually recover function with time. In this report, we measure the expression of various inhibitory receptors and memory markers during early and late time points following vaccination with Ad5 and alternative serotype Ad vectors. CD8 T cells induced by Ad5 exhibited increased expression of the inhibitory receptor Tim-3 and showed decreased central memory differentiation as compared with alternative serotype Ad vectors, even a year following immunization. Moreover, relative to Ad5-primed mice, Ad26-primed mice exhibited substantially improved recall of SIV Gag-specific CD8 T cell responses following heterologous boosting with MVA or Ad35 vectors. We also demonstrate that low doses of Ad5 priming resulted in more boostable immune responses with lower PD-1 expression as compared to high Ad5 doses, suggesting a role for vector dose in influencing immune dysfunction following Ad5 vaccination. These data suggest that Ad5 vectors induce a long-term pattern of immune exhaustion that can be partly overcome by lowering vector dose and modulating inhibitory signals. PMID:27566899

  1. Low Frequency of Circulating CD8+ T Stem Cell Memory Cells in Chronic Chagasic Patients with Severe Forms of the Disease

    PubMed Central

    Mateus, Jose; Lasso, Paola; Pavia, Paula; Rosas, Fernando; Roa, Nubia; Valencia-Hernández, Carlos Andrés; González, John Mario; Puerta, Concepción J.; Cuéllar, Adriana

    2015-01-01

    Background CD8+ T cells have been shown to play a crucial role in Trypanosoma cruzi infection. Memory CD8+ T cells can be categorised based on their distinct differentiation stages and functional activities as follows: stem cell memory (TSCM), central memory (TCM), transitional memory (TTM), effector memory (TEM) and terminal effector (TTE) cells. Currently, the immune mechanisms that control T. cruzi in the chronic phase of the infection are unknown. Methodology/Principal Findings To characterise the CD8+ T cell subsets that could be participating in the control of T. cruzi infection, in this study, we compared total and T. cruzi-specific circulating CD8+ T cells with distinctive phenotypic and functional features in chronic chagasic patients (CCPs) with different degrees of cardiac dysfunction. We observed a decreased frequency of total TSCM along with an increased frequency of TTE in CCPs with severe disease. Antigen-specific TSCM cells were not detectable in CCPs with severe forms of the disease. A functional profile of CD8+ T cell subsets among CCPs revealed a high frequency of monofunctional CD8+ T cells in the most severe patients with IFN-γ+- or TNF-α+-producing cells. Conclusions/Significance These findings suggest that CD8+ TSCM cells may be associated with the immune response to T. cruzi and outcome of Chagas disease, given that these cells may be involved in repopulating the T cell pool that controls infection. PMID:25569149

  2. Memory characteristics of hysteresis and creep in multi-layer piezoelectric actuators: An experimental analysis

    NASA Astrophysics Data System (ADS)

    Biggio, Matteo; Butcher, Mark; Giustiniani, Alessandro; Masi, Alessandro; Storace, Marco

    2014-02-01

    In this paper we provide an experimental characterization of creep and hysteresis in a multi-layer piezoelectric actuator (PEA), taking into account their relationships in terms of memory structure. We fit the well-known log-t model to the response of the PEA when driven by piecewise-constant signals, and find that both the instantaneous and the delayed response of the PEA display hysteretic dependence on the voltage level. We investigate experimentally the dependence of the creep coefficient on the input history, by driving the PEA along first-order reversal curves and congruent minor loops, and find that it displays peculiar features like strict congruence of the minor loops and discontinuities. We finally explain the observed experimental behaviors in terms of a slow relaxation of the staircase interface line in the Preisach plane.

  3. The Effects of Cell Phone Conversations on the Attention and Memory of Bystanders

    PubMed Central

    Galván, Veronica V.; Vessal, Rosa S.; Golley, Matthew T.

    2013-01-01

    The pervasive use of cell phones impacts many people–both cell phone users and bystanders exposed to conversations. This study examined the effects of overhearing a one-sided (cell phone) conversation versus a two-sided conversation on attention and memory. In our realistic design, participants were led to believe they were participating in a study examining the relationship between anagrams and reading comprehension. While the participant was completing an anagram task, the researcher left the room and participants overheard a scripted conversation, either two confederates talking with each other or one confederate talking on a cell phone. Upon the researcher’s return, the participant took a recognition memory task with words from the conversation, and completed a questionnaire measuring the distracting nature of the conversation. Participants who overheard the one-sided conversation rated the conversation as significantly higher in distractibility than those who overheard the two-sided conversation. Also, participants in the one-sided condition scored higher on the recognition task. In particular they were more confident and accurate in their responses to words from the conversation than participants in the two-sided condition. However, participants’ scores on the anagram task were not significantly different between conditions. As in real world situations, individual participants could pay varying amounts of attention to the conversation since they were not explicitly instructed to ignore it. Even though the conversation was irrelevant to the anagram task and contained less words and noise, one-sided conversations still impacted participants’ self-reported distractibility and memory, thus showing people are more attentive to cell phone conversations than two-sided conversations. Cell phone conversations may be a common source of distraction causing negative consequences in workplace environments and other public places. PMID:23516514

  4. IL-2 and IL-15 regulate CD8+ memory T-cell differentiation but are dispensable for protective recall responses.

    PubMed

    Mathieu, Cédric; Beltra, Jean-Christophe; Charpentier, Tania; Bourbonnais, Sara; Di Santo, James P; Lamarre, Alain; Decaluwe, Hélène

    2015-12-01

    The ability to mount effective secondary responses is a cardinal feature of memory CD8(+) T cells. An understanding of the factors that regulate the generation and recall capacities of memory T cells remains to be ascertained. Several cues indicate that two highly related cytokines, IL-2 and IL-15, share redundant functions in this process. To establish their combined roles in memory CD8(+) T-cell development, maintenance, and secondary responses, we compared the outcome of adoptively transferred IL2Rβ(+/-) or IL2Rβ(-/-) CD8(+) T cells after an acute viral infection in mice. Our results demonstrate that both IL-2 and IL-15 signals condition the differentiation of primary and secondary short-lived effector cells by altering the transcriptional network governing lineage choices. These two cytokines also regulate the homeostasis of the memory T-cell pool, with effector memory CD8(+) T cells being the most sensitive to these two interleukins. Noticeably, the inability to respond to both cytokines limits the proliferation and survival of primary and secondary effectors cells, whereas it does not preclude potent cytotoxic functions and viral control either initially or upon rechallenge. Globally, these results indicate that lack of IL-2 and IL-15 signaling modulates the CD8(+) T-cell differentiation program but does not impede adequate effector functions.

  5. Amino-Terminal Extended Peptide Single-Chain Trimers are Potent Synthetic Agonists for Memory Human CD8+ T cells

    PubMed Central

    Carreno, Beatriz M.; Becker-Hapak, Michelle; Chan, Megan; Lie, Wen-Rong; Wang, Xiaoli; Hansen, Ted H.; Linette, Gerald P.

    2012-01-01

    Upon antigen exposure, most memory T cells undergo re-stimulation induced cell death. Here we describe a novel synthetic agonist, an amino-terminal extended decamer peptide expressed as a single chain trimer, the AT-SCT, that preferentially promotes the growth of memory human CD8+ T cells with minimal re-stimulation-induced cell death. Using the CMV pp65 and melanoma gp100 antigens, we observe the in vitro numerical expansion of a clonally diverse poly-functional population of antigen-specific CD8+ T cells from normal individuals and vaccinated melanoma patients, respectively. Memory CD8+ T cells stimulated with AT-SCT presented on MHC class I/II null cells show reduced cytokine production, slower kinetics of TCR down-regulation and decreased cell death when compared to native nonamer SCT-activated T cells. However, both ERK phosphorylation and cell cycle kinetics are identical in AT-SCT- and SCT-activated T cells. Probing of SCT and AT-SCT peptide-MHC (p-MHC) complexes using fluorochrome-conjugated TCR multimers suggest that nonamer and decamer-linked peptides may be anchored differently to HLA-A2 peptide binding groove. Our findings demonstrate that modified p-MHC structures such as AT-SCT can be engineered as T cell agonists to promote the growth and expansion of memory human CD8+ T cells. PMID:22573808

  6. Exposure of FVIII in the Presence of Phosphatidyl Serine Reduces Generation of Memory B-Cells and Induces Regulatory T-Cell-Mediated Hyporesponsiveness in Hemophilia A Mice.

    PubMed

    Ramakrishnan, Radha; Davidowitz, Andrew; Balu-Iyer, Sathy V

    2015-08-01

    A major complication of replacement therapy with Factor VIII (FVIII) for hemophilia A (HA) is the development of unwanted immune responses. Previous studies showed that administration of FVIII in the presence of phosphatidyl serine (PS) reduced the development of anti-FVIII antibodies in HA mice. However, the impact of PS-mediated effects on immunological memory, such as generation of memory B-cells, is not clear. The effect of PS on memory B-cells was therefore investigated using adoptive transfer approach in FVIII(-/-) HA mice. Adoptive transfer of memory B-cells from a PS-FVIII-treated group to naïve mice followed by challenge of the recipient mice with FVIII showed a significantly reduced anti-FVIII antibody response in the recipient mice, compared with animals that received memory B-cells from free FVIII and FVIII-charge matched phosphatidyl glycerol (PG) group. The decrease in memory B-cell response is accompanied by an increase in FoxP3 expressing regulatory T-cells (Tregs). Flow cytometry studies showed that the generation of Tregs is higher in PS-treated animals as compared with FVIII and FVIII-PG treated animals. The PS-mediated hyporesponsiveness was found to be antigen-specific. The PS-FVIII immunization showed hyporesponsiveness toward FVIII rechallenge but not against ovalbumin (OVA) rechallenge, an unrelated antigen. This demonstrates that PS reduces immunologic memory of FVIII and induces antigen-specific peripheral tolerance in HA mice.

  7. Charge-trapping characteristics of fluorinated thin ZrO{sub 2} film for nonvolatile memory applications

    SciTech Connect

    Huang, X. D. E-mail: laip@eee.hku.hk; Shi, R. P.; Lai, P. T. E-mail: laip@eee.hku.hk

    2014-04-21

    The effects of fluorine treatment on the charge-trapping characteristics of thin ZrO{sub 2} film are investigated by physical and electrical characterization techniques. The formation of silicate interlayer at the ZrO{sub 2}/SiO{sub 2} interface is effectively suppressed by fluorine passivation. However, excessive fluorine diffusion into the Si substrate deteriorates the quality of the SiO{sub 2}/Si interface. Compared with the ZrO{sub 2}-based memory devices with no or excessive fluorine treatment, the one with suitable fluorine-treatment time shows higher operating speed and better retention due to less resistance of built-in electric field (formed by trapped electrons) against electron injection from the substrate and smaller trap-assisted tunneling leakage, resulting from improved ZrO{sub 2}/SiO{sub 2} and SiO{sub 2}/Si interfaces.

  8. Improved characteristics of amorphous indium-gallium-zinc-oxide-based resistive random access memory using hydrogen post-annealing

    NASA Astrophysics Data System (ADS)

    Kang, Dae Yun; Lee, Tae-Ho; Kim, Tae Geun

    2016-08-01

    The authors report an improvement in resistive switching (RS) characteristics of amorphous indium-gallium-zinc-oxide (a-IGZO)-based resistive random access memory devices using hydrogen post-annealing. Because this a-IGZO thin film has oxygen off-stoichiometry in the form of deficient and excessive oxygen sites, the film properties can be improved by introducing hydrogen atoms through the annealing process. After hydrogen post-annealing, the device exhibited a stable bipolar RS, low-voltage set and reset operation, long retention (>105 s), good endurance (>106 cycles), and a narrow distribution in each current state. The effect of hydrogen post-annealing is also investigated by analyzing the sample surface using X-ray photon spectroscopy and atomic force microscopy.

  9. Coexpression of TIGIT and FCRL3 identifies Helios+ human memory regulatory T cells.

    PubMed

    Bin Dhuban, Khalid; d'Hennezel, Eva; Nashi, Emil; Bar-Or, Amit