Sample records for generated response functions

  1. Amplitude Frequency Response Measurement: A Simple Technique

    ERIC Educational Resources Information Center

    Satish, L.; Vora, S. C.

    2010-01-01

    A simple method is described to combine a modern function generator and a digital oscilloscope to configure a setup that can directly measure the amplitude frequency response of a system. This is achieved by synchronously triggering both instruments, with the function generator operated in the "Linear-Sweep" frequency mode, while the oscilloscope…

  2. 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.

  3. A Response Function Approach for Rapid Far-Field Tsunami Forecasting

    NASA Astrophysics Data System (ADS)

    Tolkova, Elena; Nicolsky, Dmitry; Wang, Dailin

    2017-08-01

    Predicting tsunami impacts at remote coasts largely relies on tsunami en-route measurements in an open ocean. In this work, these measurements are used to generate instant tsunami predictions in deep water and near the coast. The predictions are generated as a response or a combination of responses to one or more tsunameters, with each response obtained as a convolution of real-time tsunameter measurements and a pre-computed pulse response function (PRF). Practical implementation of this method requires tables of PRFs in a 3D parameter space: earthquake location-tsunameter-forecasted site. Examples of hindcasting the 2010 Chilean and the 2011 Tohoku-Oki tsunamis along the US West Coast and beyond demonstrated high accuracy of the suggested technology in application to trans-Pacific seismically generated tsunamis.

  4. Neutron light output response and resolution functions in EJ-309 liquid scintillation detectors

    DOE PAGES

    Enqvist, Andreas; Lawrence, Christopher C.; Wieger, Brian M.; ...

    2013-03-26

    Here, the neutron light output response functions and detector resolution functions were measured at Ohio University's tandem Van de Graaff generator for three cylindrical EJ-309 liquid scintillator cells, having dimensions 12.7(circle divide)-by-12.7, 7.6-by-7.6, and 7.6-by-5.1 cm. A 7.44 MeV deuteron beam was used on an Al-27 target generating a continuous spectrum over the energy range from a few hundred keV to over 10 MeV. The light output response functions are determined using an exponential fit. Detector resolution functions are obtained for the 12.7-by-12.7 and 7.6-by-7.6 cm detectors. It is demonstrated that the dependence on detector size is important for themore » light output response functions, but not to the same extent for the resolution function, even when photomultiplier tubes, detector material, and other detector characteristics are carefully matched.« less

  5. Manipulating neural activity in physiologically classified neurons: triumphs and challenges

    PubMed Central

    Gore, Felicity; Schwartz, Edmund C.; Salzman, C. Daniel

    2015-01-01

    Understanding brain function requires knowing both how neural activity encodes information and how this activity generates appropriate responses. Electrophysiological, imaging and immediate early gene immunostaining studies have been instrumental in identifying and characterizing neurons that respond to different sensory stimuli, events and motor actions. Here we highlight approaches that have manipulated the activity of physiologically classified neurons to determine their role in the generation of behavioural responses. Previous experiments have often exploited the functional architecture observed in many cortical areas, where clusters of neurons share response properties. However, many brain structures do not exhibit such functional architecture. Instead, neurons with different response properties are anatomically intermingled. Emerging genetic approaches have enabled the identification and manipulation of neurons that respond to specific stimuli despite the lack of discernable anatomical organization. These approaches have advanced understanding of the circuits mediating sensory perception, learning and memory, and the generation of behavioural responses by providing causal evidence linking neural response properties to appropriate behavioural output. However, significant challenges remain for understanding cognitive processes that are probably mediated by neurons with more complex physiological response properties. Currently available strategies may prove inadequate for determining how activity in these neurons is causally related to cognitive behaviour. PMID:26240431

  6. Regulation of the sphingosine-recycling pathway for ceramide generation by oxidative stress, and its role in controlling c-Myc/Max function

    PubMed Central

    Sultan, Iyad; Senkal, Can E.; Ponnusamy, Suriyan; Bielawski, Jacek; Szulc, Zdzislaw; Bielawska, Alicja; Hannun, Yusuf A.; Ogretmen, Besim

    2005-01-01

    In the present study, the regulation of the sphingosine-recycling pathway in A549 human lung adenocarcinoma cells by oxidative stress was investigated. The generation of endogenous long-chain ceramide in response to exogenous C6-cer (C6-ceramide), which is FB1 (fumonisin B1)-sensitive, was employed to probe the sphingosine-recycling pathway. The data showed that ceramide formation via this pathway was significantly blocked by GSH and NAC (N-acetylcysteine) whereas it was enhanced by H2O2, as detected by both palmitate labelling and HPLC/MS. Similar data were also obtained using a novel approach that measures the incorporation of 17Sph (sphingosine containing 17 carbons) of 17C6-cer (C6-cer containing a 17Sph backbone) into long-chain 17C16-cer in cells by HPLC/MS, which was significantly decreased and increased in response to GSH and H2O2 respectively. TNF (tumour necrosis factor)-α, which decreases the levels of endogenous GSH, increased the generation of C16-cer in response to C6-cer, and this was blocked by exogenous GSH or NAC, or by the overexpression of TPx I (thioredoxin peroxidase I), an enzyme that reduces the generation of intracellular ROS (reactive oxygen species). Additional data showed that ROS regulated both the deacylation and reacylation steps of C6-cer. At a functional level, C6-cer inhibited the DNA-binding function of the c-Myc/Max oncogene. Inhibition of the generation of longchain ceramide in response to C6-cer by FB1 or NAC significantly blocked the modulation of the c-Myc/Max function. These data demonstrate that the sphingosine-recycling pathway for the generation of endogenous long-chain ceramide in response to exogenous C6-cer is regulated by ROS, and plays an important biological role in controlling c-Myc function. PMID:16201965

  7. Multi-channel spatialization systems for audio signals

    NASA Technical Reports Server (NTRS)

    Begault, Durand R. (Inventor)

    1993-01-01

    Synthetic head related transfer functions (HRTF's) for imposing reprogrammable spatial cues to a plurality of audio input signals included, for example, in multiple narrow-band audio communications signals received simultaneously are generated and stored in interchangeable programmable read only memories (PROM's) which store both head related transfer function impulse response data and source positional information for a plurality of desired virtual source locations. The analog inputs of the audio signals are filtered and converted to digital signals from which synthetic head related transfer functions are generated in the form of linear phase finite impulse response filters. The outputs of the impulse response filters are subsequently reconverted to analog signals, filtered, mixed, and fed to a pair of headphones.

  8. Multi-channel spatialization system for audio signals

    NASA Technical Reports Server (NTRS)

    Begault, Durand R. (Inventor)

    1995-01-01

    Synthetic head related transfer functions (HRTF's) for imposing reprogramable spatial cues to a plurality of audio input signals included, for example, in multiple narrow-band audio communications signals received simultaneously are generated and stored in interchangeable programmable read only memories (PROM's) which store both head related transfer function impulse response data and source positional information for a plurality of desired virtual source locations. The analog inputs of the audio signals are filtered and converted to digital signals from which synthetic head related transfer functions are generated in the form of linear phase finite impulse response filters. The outputs of the impulse response filters are subsequently reconverted to analog signals, filtered, mixed and fed to a pair of headphones.

  9. The Small GTPase Rif Is Dispensable for Platelet Filopodia Generation in Mice

    PubMed Central

    Goggs, Robert; Savage, Joshua S.; Mellor, Harry; Poole, Alastair W.

    2013-01-01

    Background Formation of filopodia and other shape change events are vital for platelet hemostatic function. The mechanisms regulating filopodia formation by platelets are incompletely understood however. In particular the small GTPase responsible for initiating filopodia formation by platelets remains elusive. The canonical pathway involving Cdc42 is not essential for filopodia formation in mouse platelets. The small GTPase Rif (RhoF) provides an alternative route to filopodia generation in other cell types and is expressed in both human and mouse platelets. Hypothesis/Objective We hypothesized that Rif might be responsible for generating filopodia by platelets and generated a novel knockout mouse model to investigate the functional role of Rif in platelets. Methodology/Principal Findings Constitutive RhoF−/− mice are viable and have normal platelet, leukocyte and erythrocyte counts and indices. RhoF−/− platelets form filopodia and spread normally on various agonist surfaces in static conditions and under arterial shear. In addition, RhoF−/− platelets have normal actin dynamics, are able to activate and aggregate normally and secrete from alpha and dense granules in response to collagen related peptide and thrombin stimulation. Conclusions The small GTPase Rif does not appear to be critical for platelet function in mice. Functional overlap between Rif and other small GTPases may be responsible for the non-essential role of Rif in platelets. PMID:23359340

  10. Structural frequency functions for an impulsive, distributed forcing function

    NASA Technical Reports Server (NTRS)

    Bateman, Vesta I.

    1987-01-01

    The response of a penetrator structure to a spatially distributed mechanical impulse with a magnitude approaching field test force levels (1-2 Mlb) were measured. The frequency response function calculated from the response to this unique forcing function is compared to frequency response functions calculated from response to point forces of about 2000 pounds. The results show that the strain gages installed on the penetrator case respond similiarly to a point, axial force and to a spatially distributed, axial force. This result suggests that the distributed axial force generated in a penetration event may be reconstructed as a point axial force when the penetrator behaves in linear manner.

  11. Generation of functional human pancreatic β cells in vitro

    PubMed Central

    Pagliuca, Felicia W.; Millman, Jeffrey R.; Gürtler, Mads; Segel, Michael; Van Dervort, Alana; Ryu, Jennifer Hyoje; Peterson, Quinn P.; Greiner, Dale; Melton, Douglas A.

    2015-01-01

    Summary The generation of insulin-producing pancreatic β cells from stem cells in vitro would provide an unprecedented cell source for drug discovery and cell transplantation therapy in diabetes. However, insulin-producing cells previously generated from human pluripotent stem cells (hPSC) lack many functional characteristics of bona fide β cells. Here we report a scalable differentiation protocol that can generate hundreds of millions of glucose-responsive β cells from hPSC in vitro. These stem cell derived β cells (SC-β) express markers found in mature β cells, flux Ca2+ in response to glucose, package insulin into secretory granules and secrete quantities of insulin comparable to adult β cells in response to multiple sequential glucose challenges in vitro. Furthermore, these cells secrete human insulin into the serum of mice shortly after transplantation in a glucose-regulated manner, and transplantation of these cells ameliorates hyperglycemia in diabetic mice. PMID:25303535

  12. Analyzing the Stability of Price Response Functions: Measuring the Influence of Different Parameters in a Monte Carlo Comparison

    NASA Astrophysics Data System (ADS)

    Brusch, Michael; Baier, Daniel

    The usage and the estimation of price response function is very important for strategic marketing decisions. Typically price response functions with an empirical basis are used. However, such price response functions are subject to a lot of disturbing influence factors, e.g., the assumed profit maximum price and the assumed corresponding quantity of sales. In such cases, the question how stable the found price response function is was not answered sufficiently up to now. In this paper, the question will be pursued how much (and what kind of) errors in market research are pardonable for a stable price response function. For the comparisons, a factorial design with synthetically generated and disturbed data is used.

  13. Rod Electroretinograms Elicited by Silent Substitution Stimuli from the Light-Adapted Human Eye

    PubMed Central

    Maguire, John; Parry, Neil R. A.; Kremers, Jan; Kommanapalli, Deepika; Murray, Ian J.; McKeefry, Declan J.

    2016-01-01

    Purpose To demonstrate that silent substitution stimuli can be used to generate electroretinograms (ERGs) that effectively isolate rod photoreceptor function in humans without the need for dark adaptation, and that this approach constitutes a viable alternative to current clinical standard testing protocols. Methods Rod-isolating and non-isolating sinusoidal flicker stimuli were generated on a 4 primary light-emitting diode (LED) Ganzfeld stimulator to elicit ERGs from participants with normal and compromised rod function who had not undergone dark-adaptation. Responses were subjected to Fourier analysis, and the amplitude and phase of the fundamental were used to examine temporal frequency and retinal illuminance response characteristics. Results Electroretinograms elicited by rod-isolating silent substitution stimuli exhibit low-pass temporal frequency response characteristics with an upper response limit of 30 Hz. Responses are optimal between 5 and 8 Hz and between 10 and 100 photopic trolands (Td). There is a significant correlation between the response amplitudes obtained with the silent substitution method and current standard clinical protocols. Analysis of signal-to-noise ratios reveals significant differences between subjects with normal and compromised rod function. Conclusions Silent substitution provides an effective method for the isolation of human rod photoreceptor function in subjects with normal as well as compromised rod function when stimuli are used within appropriate parameter ranges. Translational Relevance This method of generating rod-mediated ERGs can be achieved without time-consuming periods of dark adaptation, provides improved isolation of rod- from cone-based activity, and will lead to the development of faster clinical electrophysiologic testing protocols with improved selectivity. PMID:27617180

  14. From Whole-Brain Data to Functional Circuit Models: The Zebrafish Optomotor Response.

    PubMed

    Naumann, Eva A; Fitzgerald, James E; Dunn, Timothy W; Rihel, Jason; Sompolinsky, Haim; Engert, Florian

    2016-11-03

    Detailed descriptions of brain-scale sensorimotor circuits underlying vertebrate behavior remain elusive. Recent advances in zebrafish neuroscience offer new opportunities to dissect such circuits via whole-brain imaging, behavioral analysis, functional perturbations, and network modeling. Here, we harness these tools to generate a brain-scale circuit model of the optomotor response, an orienting behavior evoked by visual motion. We show that such motion is processed by diverse neural response types distributed across multiple brain regions. To transform sensory input into action, these regions sequentially integrate eye- and direction-specific sensory streams, refine representations via interhemispheric inhibition, and demix locomotor instructions to independently drive turning and forward swimming. While experiments revealed many neural response types throughout the brain, modeling identified the dimensions of functional connectivity most critical for the behavior. We thus reveal how distributed neurons collaborate to generate behavior and illustrate a paradigm for distilling functional circuit models from whole-brain data. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Prostaglandins and Inflammation

    PubMed Central

    Ricciotti, Emanuela; FitzGerald, Garret A.

    2011-01-01

    Prostaglandins are lipid autacoids derived from arachidonic acid. They both sustain homeostatic functions and mediate pathogenic mechanisms, including the inflammatory response. They are generated from arachidonate by the action of cyclooxygenase (COX) isoenzymes and their biosynthesis is blocked by nonsteroidal anti-inflammatory drugs (NSAIDs), including those selective for inhibition of COX-2. Despite the clinical efficacy of NSAIDs, prostaglandins may function in both the promotion and resolution of inflammation. This review summarizes insights into the mechanisms of prostaglandin generation and the roles of individual mediators and their receptors in modulating the inflammatory response. Prostaglandin biology has potential clinical relevance for atherosclerosis, the response to vascular injury and aortic aneurysm. PMID:21508345

  16. Vestibulo-ocular and vestibulospinal function before and after cochlear implant surgery

    NASA Technical Reports Server (NTRS)

    Black, F. O.; Lilly, D. J.; Peterka, R. J.; Fowler, L. P.; Simmons, F. B.

    1987-01-01

    Vestibular function in cochlear implant candidates varies from normal to total absence of function. In patients with intact vestibular function preoperatively, invasion of the otic capsule places residual vestibular function at risk. Speech-processing strategies that result in large amplitude electrical transients or strategies that employ high amplitude broad frequency carrier signals have the potential for disrupting vestibular function. Five patients were tested with and without electrical stimulation via cochlear electrodes. Two patients experienced subjective vestibular effects that were quickly resolved. No long-term vestibular effects were noted for the two types of second generation cochlear implants evaluated. Histopathological findings from another patient, who had electrically generated vestibular reflex responses to intramodiolar electrodes, indicated that responses elicited were a function of several variables including electrode location, stimulus intensity, stimulus amplitude, and stimulus frequency. Differential auditory, vestibulocolic, and vestibulospinal reflexes were demonstrated from the same electrode as a function of stimulus amplitude, frequency, and duration.

  17. Production of ABA responses requires both the nuclear and cytoplasmic functional involvement of PYR1

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Park, EunJoo; Kim, Tae-Houn

    Abscisic acid (ABA) enhances stress tolerant responses in plants against unfavorable environmental conditions. In Arabidopsis, ABA promotes interactions between PYR/PYL/RCARs and PP2C, thereby allowing SnRK2s to phosphorylate downstream components required for the regulation of gene expression or for gating ion channels. Because PYR1 is known to localize to nucleus and cytoplasm it is a question whether nuclear or cytoplasmic PYR1 confer different functions to the ABA signaling pathway, as has been previously shown for regulatory proteins. In order to answer this question, transgenic lines expressing nuclear PYR1 were generated in an ABA insensitive mutant background. Enforced nuclear expression of PYR1more » was examined by confocal microscopy and western blot analysis. Physiological analyses of the transgenic lines demonstrated that nuclear PYR1 is sufficient to generate ABA responses, such as, the inhibition of seed germination, root growth inhibition, the induction of gene expression, and stomatal closing movement. However, for the full recovery of ABA responses in the mutant background cytoplasmic PYR1 was required. The study suggests both nuclear and cytoplasmic PYR1 participate in the control of ABA signal transduction. - Highlights: • Nuclear and cytoplasmic functions of PYR1 were studied in the mutant which lacked majority of ABA responses. • Nuclear PYR1 reconstituted partially the ABA responses during seed germination, root growth, and guard cell movement. • Both the nuclear and cytoplasmic functions of PYR1 were required for the full generation of ABA responses.« less

  18. Characteristics of human dendritic cells generated in a microgravity analog culture system

    NASA Technical Reports Server (NTRS)

    Savary, C. A.; Grazziuti, M. L.; Przepiorka, D.; Tomasovic, S. P.; McIntyre, B. W.; Woodside, D. G.; Pellis, N. R.; Pierson, D. L.; Rex, J. H.; McIntire, L. V. (Principal Investigator)

    2001-01-01

    Generation of an effective immune response requires that antigens be processed and presented to T lymphocytes by antigen-presenting cells, the most efficient of which are dendritic cells (DC). Because of their influence on both the innate and the acquired arms of immunity, a defect in DC would be expected to result in a broad impairment of immune function, not unlike that observed in astronauts during or after space flight. In the study reported here, we investigated whether DC generation and function are altered in a culture environment that models microgravity, i.e., the rotary-cell culture system (RCCS). We observed that RCCS supported the generation of DC identified by morphology, phenotype (HLA-DR+ and lacking lineage-associated markers), and function (high allostimulatory activity). However, the yield of DC from RCCS was significantly lower than that from static cultures. RCCS-generated DC were less able to phagocytose Aspergillus fumigatus conidia and expressed a lower density of surface HLA-DR. The proportion of DC expressing CD80 was also significantly reduced in RCCS compared to static cultures. When exposed to fungal antigens, RCCS-generated DC produced lower levels of interleukin-12 and failed to upregulate some costimulatory/adhesion molecules involved in antigen presentation. These data suggest that DC generation, and some functions needed to mount an effective immune response to pathogens, may be disturbed in the microgravity environment of space.

  19. 77 FR 23161 - Onsite Emergency Response Capabilities

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-18

    ... entire facility. The emergency diesel generators started at all six units, providing alternating current... known as station blackout (SBO). One diesel generator remained functional on Unit 6. Despite the actions...

  20. Determination of a response function of a thermocouple using a short acoustic pulse.

    PubMed

    Tashiro, Yusuke; Biwa, Tetsushi; Yazaki, Taichi

    2007-04-01

    This paper reports on an experimental technique to determine a response function of a thermocouple using a short acoustic pulse wave. A pulse of 10 ms is generated in a tube filled with 1 bar helium gas. The temperature is measured using the thermocouple. The reference temperature is deduced from the measured pressure on the basis of a laminar oscillating flow theory. The response function of the thermocouple is obtained as a function of frequency below 50 Hz through a comparison between the measured and reference temperatures.

  1. Alterations in dendritic cell function in aged mice: potential implications for immunotherapy design.

    PubMed

    Paula, Carine; Motta, Adriana; Schmitz, Carla; Nunes, Claudia P; Souza, Ana Paula; Bonorino, Cristina

    2009-02-01

    It is known that immune system functions decrease with age, and that adaptive immune responses, especially CD4+ T cell function, seem to be the main affected point in immunity with aging. Dendritic cells (DC) are the major antigen presenting cell (APC), and at least part of the defects observed in adaptive immunity of aged individuals could be due to diminished potential of bone marrow to generate new DC, or defects in DC function. In this study, we investigated if the ability of aged bone marrow (BM) to generate new DC in vitro, as well as aged BM-derived DC responses to lypopolysaccharide (LPS). Because DC are important tools in newly developing anti-tumor therapies, we also studied the ability of aged DC to phagocytose and present antigen from necrotic tumor cells. We found that aged BM generated fewer DC in vitro compared to young BM. While LPS-induced DC maturation is reduced in DC of aged mice, a high TNF-alpha production is observed in aged DC even without LPS stimulation. While phagocytosis of tumor cells is not affected by age, and DC derived from aged BM show a higher TNF-alpha production in response to phagocytosis, presentation of tumor antigens was decreased in aged DC. Because class II upregulation in response to phagocytosis was similar between aged and young DC, this could indicate an age associated processing defect in the exogenous pathway. These findings suggest that age of BM used to generate DC does not impair their phagocytic ability or TNF-alpha production, however leads to a decreased yield in mature DC, reduced response to LPS, and diminished antigen processing/presentation potential. Our results are relevant to optimization DC-based vaccine design for aged populations.

  2. An Active Metamaterial Platform for Chiral Responsive Optoelectronics.

    PubMed

    Kang, Lei; Lan, Shoufeng; Cui, Yonghao; Rodrigues, Sean P; Liu, Yongmin; Werner, Douglas H; Cai, Wenshan

    2015-08-05

    Chiral-selective non-linear optics and optoelectronic signal generation are demonstrated in an electrically active photonic metamaterial. The metamaterial reveals significant chiroptical responses in both harmonic generation and the photon drag effect, correlated to the resonance behavior in the linear regime. The multifunctional chiral metamaterial with dual electrical and optical functionality enables transduction of chiroptical responses to electrical signals for integrated photonics. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Thermal Density Functional Theory: Time-Dependent Linear Response and Approximate Functionals from the Fluctuation-Dissipation Theorem

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Pribram-Jones, Aurora; Grabowski, Paul E.; Burke, Kieron

    We present that the van Leeuwen proof of linear-response time-dependent density functional theory (TDDFT) is generalized to thermal ensembles. This allows generalization to finite temperatures of the Gross-Kohn relation, the exchange-correlation kernel of TDDFT, and fluctuation dissipation theorem for DFT. Finally, this produces a natural method for generating new thermal exchange-correlation approximations.

  4. Thermal Density Functional Theory: Time-Dependent Linear Response and Approximate Functionals from the Fluctuation-Dissipation Theorem

    DOE PAGES

    Pribram-Jones, Aurora; Grabowski, Paul E.; Burke, Kieron

    2016-06-08

    We present that the van Leeuwen proof of linear-response time-dependent density functional theory (TDDFT) is generalized to thermal ensembles. This allows generalization to finite temperatures of the Gross-Kohn relation, the exchange-correlation kernel of TDDFT, and fluctuation dissipation theorem for DFT. Finally, this produces a natural method for generating new thermal exchange-correlation approximations.

  5. An Abbreviated Protocol for In Vitro Generation of Functional Human Embryonic Stem Cell-Derived Beta-Like Cells

    PubMed Central

    Massumi, Mohammad; Pourasgari, Farzaneh; Nalla, Amarnadh; Batchuluun, Battsetseg; Nagy, Kristina; Neely, Eric; Gull, Rida; Nagy, Andras; Wheeler, Michael B.

    2016-01-01

    The ability to yield glucose-responsive pancreatic beta-cells from human pluripotent stem cells in vitro will facilitate the development of the cell replacement therapies for the treatment of Type 1 Diabetes. Here, through the sequential in vitro targeting of selected signaling pathways, we have developed an abbreviated five-stage protocol (25–30 days) to generate human Embryonic Stem Cell-Derived Beta-like Cells (ES-DBCs). We showed that Geltrex, as an extracellular matrix, could support the generation of ES-DBCs more efficiently than that of the previously described culture systems. The activation of FGF and Retinoic Acid along with the inhibition of BMP, SHH and TGF-beta led to the generation of 75% NKX6.1+/NGN3+ Endocrine Progenitors. The inhibition of Notch and tyrosine kinase receptor AXL, and the treatment with Exendin-4 and T3 in the final stage resulted in 35% mono-hormonal insulin positive cells, 1% insulin and glucagon positive cells and 30% insulin and NKX6.1 co-expressing cells. Functionally, ES-DBCs were responsive to high glucose in static incubation and perifusion studies, and could secrete insulin in response to successive glucose stimulations. Mitochondrial metabolic flux analyses using Seahorse demonstrated that the ES-DBCs could efficiently metabolize glucose and generate intracellular signals to trigger insulin secretion. In conclusion, targeting selected signaling pathways for 25–30 days was sufficient to generate ES-DBCs in vitro. The ability of ES-DBCs to secrete insulin in response to glucose renders them a promising model for the in vitro screening of drugs, small molecules or genes that may have potential to influence beta-cell function. PMID:27755557

  6. Local and linear chemical reactivity response functions at finite temperature in density functional theory

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Franco-Pérez, Marco, E-mail: francopj@mcmaster.ca, E-mail: ayers@mcmaster.ca, E-mail: jlgm@xanum.uam.mx, E-mail: avela@cinvestav.mx; Departamento de Química, Universidad Autónoma Metropolitana-Iztapalapa, Av. San Rafael Atlixco 186, México, D.F. 09340; Ayers, Paul W., E-mail: francopj@mcmaster.ca, E-mail: ayers@mcmaster.ca, E-mail: jlgm@xanum.uam.mx, E-mail: avela@cinvestav.mx

    2015-12-28

    We explore the local and nonlocal response functions of the grand canonical potential density functional at nonzero temperature. In analogy to the zero-temperature treatment, local (e.g., the average electron density and the local softness) and nonlocal (e.g., the softness kernel) intrinsic response functions are defined as partial derivatives of the grand canonical potential with respect to its thermodynamic variables (i.e., the chemical potential of the electron reservoir and the external potential generated by the atomic nuclei). To define the local and nonlocal response functions of the electron density (e.g., the Fukui function, the linear density response function, and the dualmore » descriptor), we differentiate with respect to the average electron number and the external potential. The well-known mathematical relationships between the intrinsic response functions and the electron-density responses are generalized to nonzero temperature, and we prove that in the zero-temperature limit, our results recover well-known identities from the density functional theory of chemical reactivity. Specific working equations and numerical results are provided for the 3-state ensemble model.« less

  7. Local and linear chemical reactivity response functions at finite temperature in density functional theory.

    PubMed

    Franco-Pérez, Marco; Ayers, Paul W; Gázquez, José L; Vela, Alberto

    2015-12-28

    We explore the local and nonlocal response functions of the grand canonical potential density functional at nonzero temperature. In analogy to the zero-temperature treatment, local (e.g., the average electron density and the local softness) and nonlocal (e.g., the softness kernel) intrinsic response functions are defined as partial derivatives of the grand canonical potential with respect to its thermodynamic variables (i.e., the chemical potential of the electron reservoir and the external potential generated by the atomic nuclei). To define the local and nonlocal response functions of the electron density (e.g., the Fukui function, the linear density response function, and the dual descriptor), we differentiate with respect to the average electron number and the external potential. The well-known mathematical relationships between the intrinsic response functions and the electron-density responses are generalized to nonzero temperature, and we prove that in the zero-temperature limit, our results recover well-known identities from the density functional theory of chemical reactivity. Specific working equations and numerical results are provided for the 3-state ensemble model.

  8. KAOS/LIB-V: A library of nuclear response functions generated by KAOS-V code from ENDF/B-V and other data files

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Farawila, Y.; Gohar, Y.; Maynard, C.

    1989-04-01

    KAOS/LIB-V: A library of processed nuclear responses for neutronics analyses of nuclear systems has been generated. The library was prepared using the KAOS-V code and nuclear data from ENDF/B-V. The library includes kerma (kinetic energy released in materials) factors and other nuclear response functions for all materials presently of interest in fusion and fission applications for 43 nonfissionable and 15 fissionable isotopes and elements. The nuclear response functions include gas production and tritium-breeding functions, and all important reaction cross sections. KAOS/LIB-V employs the VITAMIN-E weighting function and energy group structure of 174 neutron groups. Auxiliary nuclear data bases, e.g., themore » Japanese evaluated nuclear data library JENDL-2 were used as a source of isotopic cross sections when these data are not provided in ENDF/B-V files for a natural element. These are needed mainly to estimate average quantities such as effective Q-values for the natural element. This analysis of local energy deposition was instrumental in detecting and understanding energy balance deficiencies and other problems in the ENDF/B-V data. Pertinent information about the library and a graphical display of the main nuclear response functions for all materials in the library are given. 35 refs.« less

  9. Functional desensitization to isoproterenol without reducing cAMP production in canine failing cardiocytes.

    PubMed

    Laurent, C E; Cardinal, R; Rousseau, G; Vermeulen, M; Bouchard, C; Wilkinson, M; Armour, J A; Bouvier, M

    2001-02-01

    To corroborate alterations in the functional responses to beta-adrenergic receptor (beta-AR) stimulation with changes in beta-AR signaling in failing cardiomyocytes, contractile and L-type Ca(2+) current responses to isoproterenol along with stimulated cAMP generation were compared among cardiomyocytes isolated from canines with tachycardia-induced heart failure or healthy hearts. The magnitude of shortening of failing cardiomyocytes was significantly depressed (by 22 +/- 4.4%) under basal conditions, and the maximal response to isoproterenol was significantly reduced (by 45 +/- 18%). Similar results were obtained when the responses in the rate of contraction and rate of relaxation to isoproterenol were considered. The L-type Ca(2+) current amplitude measured in failing cardiomyocytes under basal conditions was unchanged, but the responses to isoproterenol were significantly reduced compared with healthy cells. Isoproterenol-stimulated cAMP generation was similar in sarcolemmal membranes derived from the homogenates of failing (45 +/- 6.8) and healthy cardiomyocytes (52 +/- 8.5 pmol cAMP. mg protein(-1). min(-1)). However, stimulated cAMP generation was found to be significantly reduced when the membranes were derived from the homogenates of whole tissue (failing: 67 +/- 8.1 vs. healthy: 140 +/- 27.8 pmol cAMP. mg protein(-1). min(-1)). Total beta-AR density was not reduced in membranes derived from either whole tissue or isolated cardiomyocyte homogenates, but the beta(1)/beta(2) ratio was significantly reduced in the former (failing: 45/55 vs. healthy: 72/28) without being altered in the latter (failing: 72/28, healthy: 77/23). We thus conclude that, in tachycardia-induced heart failure, reduction in the functional responses of isolated cardiomyocytes to beta-AR stimulation may be attributed to alterations in the excitation-contraction machinery rather than to limitation of cAMP generation.

  10. Centralized and Decentralized Control for Demand Response

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lu, Shuai; Samaan, Nader A.; Diao, Ruisheng

    2011-04-29

    Demand response has been recognized as an essential element of the smart grid. Frequency response, regulation and contingency reserve functions performed traditionally by generation resources are now starting to involve demand side resources. Additional benefits from demand response include peak reduction and load shifting, which will defer new infrastructure investment and improve generator operation efficiency. Technical approaches designed to realize these functionalities can be categorized into centralized control and decentralized control, depending on where the response decision is made. This paper discusses these two control philosophies and compares their relative advantages and disadvantages in terms of delay time, predictability, complexity,more » and reliability. A distribution system model with detailed household loads and controls is built to demonstrate the characteristics of the two approaches. The conclusion is that the promptness and reliability of decentralized control should be combined with the predictability and simplicity of centralized control to achieve the best performance of the smart grid.« less

  11. Non-equivalent antigen presenting capabilities of dendritic cells and macrophages in generating brain-infiltrating CD8 + T cell responses.

    PubMed

    Malo, Courtney S; Huggins, Matthew A; Goddery, Emma N; Tolcher, Heather M A; Renner, Danielle N; Jin, Fang; Hansen, Michael J; Pease, Larry R; Pavelko, Kevin D; Johnson, Aaron J

    2018-02-12

    The contribution of antigen-presenting cell (APC) types in generating CD8 + T cell responses in the central nervous system (CNS) is not fully defined, limiting the development of vaccines and understanding of immune-mediated neuropathology. Here, we generate a transgenic mouse that enables cell-specific deletion of the H-2Kb MHC class I molecule. By deleting H-2K b on dendritic cells and macrophages, we compare the effect of each APC in three distinct models of neuroinflammation: picornavirus infection, experimental cerebral malaria, and a syngeneic glioma. Dendritic cells and macrophages both activate CD8 + T cell responses in response to these CNS immunological challenges. However, the extent to which each of these APCs contributes to CD8 + T cell priming varies. These findings reveal distinct functions for dendritic cells and macrophages in generating CD8 + T cell responses to neurological disease.

  12. Stem cell derived phenotypic human neuromuscular junction model for dose response evaluation of therapeutics.

    PubMed

    Santhanam, Navaneetha; Kumanchik, Lee; Guo, Xiufang; Sommerhage, Frank; Cai, Yunqing; Jackson, Max; Martin, Candace; Saad, George; McAleer, Christopher W; Wang, Ying; Lavado, Andrea; Long, Christopher J; Hickman, James J

    2018-06-01

    There are currently no functional neuromuscular junction (hNMJ) systems composed of human cells that could be used for drug evaluations or toxicity testing in vitro. These systems are needed to evaluate NMJs for diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy or other neurodegenerative diseases or injury states. There are certainly no model systems, animal or human, that allows for isolated treatment of motoneurons or muscle capable of generating dose response curves to evaluate pharmacological activity of these highly specialized functional units. A system was developed in which human myotubes and motoneurons derived from stem cells were cultured in a serum-free medium in a BioMEMS construct. The system is composed of two chambers linked by microtunnels to enable axonal outgrowth to the muscle chamber that allows separate stimulation of each component and physiological NMJ function and MN stimulated tetanus. The muscle's contractions, induced by motoneuron activation or direct electrical stimulation, were monitored by image subtraction video recording for both frequency and amplitude. Bungarotoxin, BOTOX ® and curare dose response curves were generated to demonstrate pharmacological relevance of the phenotypic screening device. This quantifiable functional hNMJ system establishes a platform for generating patient-specific NMJ models by including patient-derived iPSCs. Copyright © 2018 Elsevier Ltd. All rights reserved.

  13. Test Generation Algorithm for Fault Detection of Analog Circuits Based on Extreme Learning Machine

    PubMed Central

    Zhou, Jingyu; Tian, Shulin; Yang, Chenglin; Ren, Xuelong

    2014-01-01

    This paper proposes a novel test generation algorithm based on extreme learning machine (ELM), and such algorithm is cost-effective and low-risk for analog device under test (DUT). This method uses test patterns derived from the test generation algorithm to stimulate DUT, and then samples output responses of the DUT for fault classification and detection. The novel ELM-based test generation algorithm proposed in this paper contains mainly three aspects of innovation. Firstly, this algorithm saves time efficiently by classifying response space with ELM. Secondly, this algorithm can avoid reduced test precision efficiently in case of reduction of the number of impulse-response samples. Thirdly, a new process of test signal generator and a test structure in test generation algorithm are presented, and both of them are very simple. Finally, the abovementioned improvement and functioning are confirmed in experiments. PMID:25610458

  14. Method and system for providing precise multi-function modulation

    NASA Technical Reports Server (NTRS)

    Davarian, Faramaz (Inventor); Sumida, Joe T. (Inventor)

    1989-01-01

    A method and system is disclosed which provides precise multi-function digitally implementable modulation for a communication system. The invention provides a modulation signal for a communication system in response to an input signal from a data source. A digitized time response is generated from samples of a time domain representation of a spectrum profile of a selected modulation scheme. The invention generates and stores coefficients for each input symbol in accordance with the selected modulation scheme. The output signal is provided by a plurality of samples, each sample being generated by summing the products of a predetermined number of the coefficients and a predetermined number of the samples of the digitized time response. In a specific illustrative implementation, the samples of the output signals are converted to analog signals, filtered and used to modulate a carrier in a conventional manner. The invention is versatile in that it allows for the storage of the digitized time responses and corresponding coefficient lookup table of a number of modulation schemes, any of which may then be selected for use in accordance with the teachings of the invention.

  15. Executive Functions in Children with Communications Impairments, in Relation to Autistic Symptomatology. I: Generativity

    ERIC Educational Resources Information Center

    Bishop, Dorothy V. M.; Norbury, Courtenay Frazier

    2005-01-01

    Previous research has found that people with autism generate few novel responses in ideational fluency tasks, and it has been suggested this deficit is a specific correlate of stereotyped/repetitive behavior. We assessed generativity in children with pragmatic language impairment (PLI) who showed communicative abnormalities resembling those seen…

  16. Precision medicine for cancer with next-generation functional diagnostics.

    PubMed

    Friedman, Adam A; Letai, Anthony; Fisher, David E; Flaherty, Keith T

    2015-12-01

    Precision medicine is about matching the right drugs to the right patients. Although this approach is technology agnostic, in cancer there is a tendency to make precision medicine synonymous with genomics. However, genome-based cancer therapeutic matching is limited by incomplete biological understanding of the relationship between phenotype and cancer genotype. This limitation can be addressed by functional testing of live patient tumour cells exposed to potential therapies. Recently, several 'next-generation' functional diagnostic technologies have been reported, including novel methods for tumour manipulation, molecularly precise assays of tumour responses and device-based in situ approaches; these address the limitations of the older generation of chemosensitivity tests. The promise of these new technologies suggests a future diagnostic strategy that integrates functional testing with next-generation sequencing and immunoprofiling to precisely match combination therapies to individual cancer patients.

  17. System and method of active vibration control for an electro-mechanically cooled device

    DOEpatents

    Lavietes, Anthony D.; Mauger, Joseph; Anderson, Eric H.

    2000-01-01

    A system and method of active vibration control of an electro-mechanically cooled device is disclosed. A cryogenic cooling system is located within an environment. The cooling system is characterized by a vibration transfer function, which requires vibration transfer function coefficients. A vibration controller generates the vibration transfer function coefficients in response to various triggering events. The environments may differ by mounting apparatus, by proximity to vibration generating devices, or by temperature. The triggering event may be powering on the cooling system, reaching an operating temperature, or a reset action. A counterbalance responds to a drive signal generated by the vibration controller, based on the vibration signal and the vibration transfer function, which adjusts vibrations. The method first places a cryogenic cooling system within a first environment and then generates a first set of vibration transfer function coefficients, for a vibration transfer function of the cooling system. Next, the cryogenic cooling system is placed within a second environment and a second set of vibration transfer function coefficients are generated. Then, a counterbalance is driven, based on the vibration transfer function, to reduce vibrations received by a vibration sensitive element.

  18. Doing better by getting worse: posthypnotic amnesia improves random number generation.

    PubMed

    Terhune, Devin Blair; Brugger, Peter

    2011-01-01

    Although forgetting is often regarded as a deficit that we need to control to optimize cognitive functioning, it can have beneficial effects in a number of contexts. We examined whether disrupting memory for previous numerical responses would attenuate repetition avoidance (the tendency to avoid repeating the same number) during random number generation and thereby improve the randomness of responses. Low suggestible and low dissociative and high dissociative highly suggestible individuals completed a random number generation task in a control condition, following a posthypnotic amnesia suggestion to forget previous numerical responses, and in a second control condition following the cancellation of the suggestion. High dissociative highly suggestible participants displayed a selective increase in repetitions during posthypnotic amnesia, with equivalent repetition frequency to a random system, whereas the other two groups exhibited repetition avoidance across conditions. Our results demonstrate that temporarily disrupting memory for previous numerical responses improves random number generation.

  19. Doing Better by Getting Worse: Posthypnotic Amnesia Improves Random Number Generation

    PubMed Central

    Terhune, Devin Blair; Brugger, Peter

    2011-01-01

    Although forgetting is often regarded as a deficit that we need to control to optimize cognitive functioning, it can have beneficial effects in a number of contexts. We examined whether disrupting memory for previous numerical responses would attenuate repetition avoidance (the tendency to avoid repeating the same number) during random number generation and thereby improve the randomness of responses. Low suggestible and low dissociative and high dissociative highly suggestible individuals completed a random number generation task in a control condition, following a posthypnotic amnesia suggestion to forget previous numerical responses, and in a second control condition following the cancellation of the suggestion. High dissociative highly suggestible participants displayed a selective increase in repetitions during posthypnotic amnesia, with equivalent repetition frequency to a random system, whereas the other two groups exhibited repetition avoidance across conditions. Our results demonstrate that temporarily disrupting memory for previous numerical responses improves random number generation. PMID:22195022

  20. Semantic based man-machine interface for real-time communication

    NASA Technical Reports Server (NTRS)

    Ali, M.; Ai, C.-S.

    1988-01-01

    A flight expert system (FLES) was developed to assist pilots in monitoring, diagnosing and recovering from in-flight faults. To provide a communications interface between the flight crew and FLES, a natural language interface (NALI) was implemented. Input to NALI is processed by three processors: (1) the semantics parser; (2) the knowledge retriever; and (3) the response generator. First the semantic parser extracts meaningful words and phrases to generate an internal representation of the query. At this point, the semantic parser has the ability to map different input forms related to the same concept into the same internal representation. Then the knowledge retriever analyzes and stores the context of the query to aid in resolving ellipses and pronoun references. At the end of this process, a sequence of retrievel functions is created as a first step in generating the proper response. Finally, the response generator generates the natural language response to the query. The architecture of NALI was designed to process both temporal and nontemporal queries. The architecture and implementation of NALI are described.

  1. Comparison of Response Surface Construction Methods for Derivative Estimation Using Moving Least Squares, Kriging and Radial Basis Functions

    NASA Technical Reports Server (NTRS)

    Krishnamurthy, Thiagarajan

    2005-01-01

    Response construction methods using Moving Least Squares (MLS), Kriging and Radial Basis Functions (RBF) are compared with the Global Least Squares (GLS) method in three numerical examples for derivative generation capability. Also, a new Interpolating Moving Least Squares (IMLS) method adopted from the meshless method is presented. It is found that the response surface construction methods using the Kriging and RBF interpolation yields more accurate results compared with MLS and GLS methods. Several computational aspects of the response surface construction methods also discussed.

  2. Diversity in T cell memory: An embarrassment of riches

    PubMed Central

    Jameson, Stephen C.; Masopust, David

    2010-01-01

    The adaptive immune response meets the needs of the organism to generate effector cells capable of controlling pathogens, but also leads to production of memory cells, which mediate more effective protection during rechallenge. In this review we focus on the generation, maintenance and function of memory T cells, with a special emphasis on the increasing evidence for great diversity among functional memory T cell subsets. PMID:20064446

  3. Method and apparatus for measuring response time

    DOEpatents

    Johanson, Edward W.; August, Charles

    1985-01-01

    A method of measuring the response time of an electrical instrument which generates an output signal in response to the application of a specified input, wherein the output signal varies as a function of time and when subjected to a step input approaches a steady-state value, comprises the steps of: (a) applying a step input of predetermined value to the electrical instrument to generate an output signal; (b) simultaneously starting a timer; (c) comparing the output signal to a reference signal to generate a stop signal when the output signal is substantially equal to the reference signal, the reference signal being a specified percentage of the steady-state value of the output signal corresponding to the predetermined value of the step input; and (d) applying the stop signal when generated to stop the timer.

  4. Method and apparatus for measuring response time

    DOEpatents

    Johanson, E.W.; August, C.

    1983-08-11

    A method of measuring the response time of an electrical instrument which generates an output signal in response to the application of a specified input, wherein the output signal varies as a function of time and when subjected to a step input approaches a steady-state value, comprises the steps of: (a) applying a step input of predetermined value to the electrical instrument to generate an output signal; (b) simultaneously starting a timer; (c) comparing the output signal to a reference signal to generate a stop signal when the output signal is substantially equal to the reference signal, the reference signal being a specified percentage of the steady-state value of the output signal corresponding to the predetermined value of the step input; and (d) applying the stop signal when generated to stop the timer.

  5. Piezoelectric Actuator Modeling Using MSC/NASTRAN and MATLAB

    NASA Technical Reports Server (NTRS)

    Reaves, Mercedes C.; Horta, Lucas G.

    2003-01-01

    This paper presents a procedure for modeling structures containing piezoelectric actuators using MSCMASTRAN and MATLAB. The paper describes the utility and functionality of one set of validated modeling tools. The tools described herein use MSCMASTRAN to model the structure with piezoelectric actuators and a thermally induced strain to model straining of the actuators due to an applied voltage field. MATLAB scripts are used to assemble the dynamic equations and to generate frequency response functions. The application of these tools is discussed using a cantilever aluminum beam with a surface mounted piezoelectric actuator as a sample problem. Software in the form of MSCINASTRAN DMAP input commands, MATLAB scripts, and a step-by-step procedure to solve the example problem are provided. Analysis results are generated in terms of frequency response functions from deflection and strain data as a function of input voltage to the actuator.

  6. In vitro selection of shape-changing DNA nanostructures capable of binding-induced cargo release.

    PubMed

    Oh, Seung Soo; Plakos, Kory; Xiao, Yi; Eisenstein, Michael; Soh, H Tom

    2013-11-26

    Many biological systems employ allosteric regulatory mechanisms, which offer a powerful means of directly linking a specific binding event to a wide spectrum of molecular functionalities. There is considerable interest in generating synthetic allosteric regulators that can perform useful molecular functions for applications in diagnostics, imaging and targeted therapies, but generating such molecules through either rational design or directed evolution has proven exceptionally challenging. To address this need, we present an in vitro selection strategy for generating conformation-switching DNA nanostructures that selectively release a small-molecule payload in response to binding of a specific trigger molecule. As an exemplar, we have generated a DNA nanostructure that hybridizes with a separate 'cargo strand' containing an abasic site. This abasic site stably sequesters a fluorescent cargo molecule in an inactive state until the DNA nanostructure encounters an ATP trigger molecule. This ATP trigger causes the nanostructure to release the cargo strand, thereby liberating the fluorescent payload and generating a detectable fluorescent readout. Our DNA nanostructure is highly sensitive, with an EC50 of 30 μM, and highly specific, releasing its payload in response to ATP but not to other chemically similar nucleotide triphosphates. We believe that this selection approach could be generalized to generate synthetic nanostructures capable of selective and controlled release of other small-molecule cargos in response to a variety of triggers, for both research and clinical applications.

  7. Unfolded protein response (UPR) signaling regulates arsenic trioxide-mediated macrophage innate immune function disruption

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Srivastava, Ritesh K.; Li, Changzhao; Chaudhary, Sandeep C.

    Arsenic exposure is known to disrupt innate immune functions in humans and in experimental animals. In this study, we provide a mechanism by which arsenic trioxide (ATO) disrupts macrophage functions. ATO treatment of murine macrophage cells diminished internalization of FITC-labeled latex beads, impaired clearance of phagocytosed fluorescent bacteria and reduced secretion of pro-inflammatory cytokines. These impairments in macrophage functions are associated with ATO-induced unfolded protein response (UPR) signaling pathway characterized by the enhancement in proteins such as GRP78, p-PERK, p-eIF2α, ATF4 and CHOP. The expression of these proteins is altered both at transcriptional and translational levels. Pretreatment with chemical chaperon,more » 4-phenylbutyric acid (PBA) attenuated the ATO-induced activation in UPR signaling and afforded protection against ATO-induced disruption of macrophage functions. This treatment also reduced ATO-mediated reactive oxygen species (ROS) generation. Interestingly, treatment with antioxidant N-acetylcysteine (NAC) prior to ATO exposure, not only reduced ROS production and UPR signaling but also improved macrophage functions. These data demonstrate that UPR signaling and ROS generation are interdependent and are involved in the arsenic-induced pathobiology of macrophage. These data also provide a novel strategy to block the ATO-dependent impairment in innate immune responses. - Highlights: • Inorganic arsenic to humans and experimental animals disrupt innate immune responses. • The mechanism underlying arsenic impaired macrophage functions involves UPR signaling. • Chemical chaperon attenuates arsenic-mediated macrophage function impairment. • Antioxidant, NAC blocks impairment in arsenic-treated macrophage functions.« less

  8. Computer method for identification of boiler transfer functions

    NASA Technical Reports Server (NTRS)

    Miles, J. H.

    1971-01-01

    An iterative computer method is described for identifying boiler transfer functions using frequency response data. An objective penalized performance measure and a nonlinear minimization technique are used to cause the locus of points generated by a transfer function to resemble the locus of points obtained from frequency response measurements. Different transfer functions can be tried until a satisfactory empirical transfer function to the system is found. To illustrate the method, some examples and some results from a study of a set of data consisting of measurements of the inlet impedance of a single tube forced flow boiler with inserts are given.

  9. ACIRF user's guide: Theory and examples

    NASA Astrophysics Data System (ADS)

    Dana, Roger A.

    1989-12-01

    Design and evaluation of radio frequency systems that must operate through ionospheric disturbances resulting from high altitude nuclear detonations requires an accurate channel model. This model must include the effects of high gain antennas that may be used to receive the signals. Such a model can then be used to construct realizations of the received signal for use in digital simulations of trans-ionospheric links or for use in hardware channel simulators. The FORTRAN channel model ACIRF (Antenna Channel Impulse Response Function) generates random realizations of the impulse response function at the outputs of multiple antennas. This user's guide describes the FORTRAN program ACIRF (version 2.0) that generates realizations of channel impulse response functions at the outputs of multiple antennas with arbitrary beamwidths, pointing angles, and relatives positions. This channel model is valid under strong scattering conditions when Rayleigh fading statistics apply. Both frozen-in and turbulent models for the temporal fluctuations are included in this version of ACIRF. The theory of the channel model is described and several examples are given.

  10. Mammalian TRPV4 (VR-OAC) directs behavioral responses to osmotic and mechanical stimuli in Caenorhabditis elegans

    PubMed Central

    Liedtke, Wolfgang; Tobin, David M.; Bargmann, Cornelia I.; Friedman, Jeffrey M.

    2003-01-01

    All animals detect osmotic and mechanical stimuli, but the molecular basis for these responses is incompletely understood. The vertebrate transient receptor potential channel vanilloid subfamily 4 (TRPV4) (VR-OAC) cation channel has been suggested to be an osmo/mechanosensory channel. To assess its function in vivo, we expressed TRPV4 in Caenorhabditis elegans sensory neurons and examined its ability to generate behavioral responses to sensory stimuli. C. elegans ASH neurons function as polymodal sensory neurons that generate a characteristic escape behavior in response to mechanical, osmotic, or olfactory stimuli. These behaviors require the TRPV channel OSM-9 because osm-9 mutants do not avoid nose touch, high osmolarity, or noxious odors. Expression of mammalian TRPV4 in ASH neurons of osm-9 worms restored avoidance responses to hypertonicity and nose touch, but not the response to odorant repellents. Mutations known to reduce TRPV4 channel activity also reduced its ability to direct nematode avoidance behavior. TRPV4 function in ASH required the endogenous C. elegans osmotic and nose touch avoidance genes ocr-2, odr-3, osm-10, and glr-1, indicating that TRPV4 is integrated into the normal ASH sensory apparatus. The osmotic and mechanical avoidance responses of TRPV4-expressing animals were different in their sensitivity and temperature dependence from the responses of wild-type animals, suggesting that the TRPV4 channel confers its characteristic properties on the transgenic animals' behavior. These results provide evidence that TRPV4 can function as a component of an osmotic/mechanical sensor in vivo. PMID:14581619

  11. Enterocyte protein tyrosine nitration in response to Eimeria infection in broilers

    USDA-ARS?s Scientific Manuscript database

    Activation of pathogen-sensing mechanisms in intestinal cells initiate the generation of pathway effectors that perturb normal nutritional enterocyte (ETC) functions. Among the conserved pathway mediator molecules generated are nitric oxide (NO) and superoxide anion (SOA) which are known to interac...

  12. Reduced order modeling of head related transfer functions for virtual acoustic displays

    NASA Astrophysics Data System (ADS)

    Willhite, Joel A.; Frampton, Kenneth D.; Grantham, D. Wesley

    2003-04-01

    The purpose of this work is to improve the computational efficiency in acoustic virtual applications by creating and testing reduced order models of the head related transfer functions used in localizing sound sources. State space models of varying order were generated from zero-elevation Head Related Impulse Responses (HRIRs) using Kungs Single Value Decomposition (SVD) technique. The inputs to the models are the desired azimuths of the virtual sound sources (from minus 90 deg to plus 90 deg, in 10 deg increments) and the outputs are the left and right ear impulse responses. Trials were conducted in an anechoic chamber in which subjects were exposed to real sounds that were emitted by individual speakers across a numbered speaker array, phantom sources generated from the original HRIRs, and phantom sound sources generated with the different reduced order state space models. The error in the perceived direction of the phantom sources generated from the reduced order models was compared to errors in localization using the original HRIRs.

  13. Mouse neutrophils lacking lamin B receptor expression exhibit aberrant development and lack critical functional responses

    PubMed Central

    Gaines, Peter; Tien, Chiung W.; Olins, Ada L.; Olins, Donald E.; Shultz, Leonard D.; Carney, Lisa; Berliner, Nancy

    2008-01-01

    Objective The capacity of neutrophils to eradicate bacterial infections is dependent on normal development and the activation of functional responses, which include chemotaxis and the generation of oxygen radicals during the respiratory burst. A unique feature of the neutrophil is its highly lobulated nucleus, which is thought to facilitate chemotaxis but may also play a role in other critical neutrophil functions. Nuclear lobulation is dependent on the expression of the inner nuclear envelope protein, the lamin B receptor (LBR), mutations of which cause hypolobulated neutrophil nuclei in human Pelger-Huët anomaly (PHA) and the "ichthyosis" (ic) phenotype in mice. In this study we have investigated roles for LBR in mediating neutrophil development and the activation of multiple neutrophil functions, including chemotaxis and the respiratory burst. Materials and Methods A progenitor EML cell line was generated from an ic/ic mouse, and derived cells that lacked LBR expression were induced to mature neutrophils and then examined for abnormal morphology and functional responses. Results Neutrophils derived from EML-ic/ic cells exhibited nuclear hypolobulation identical to that observed in ichthyosis mice. The ic/ic neutrophils also displayed abnormal chemotaxis, supporting the notion that nuclear segmentation augments neutrophil extravasation. Furthermore, promyelocytic forms of ic/ic cells displayed decreased proliferative responses and produced a deficient respiratory burst upon terminal maturation. Conclusions Our studies of promyelocytes that lack LBR expression have identified roles for LBR in regulating not only the morphologic maturation of the neutrophil nucleus but also proliferative and functional responses that are critical to innate immunity. PMID:18550262

  14. Antiorthostatic suspension for 14 days does not diminish the oxidative response of neutrophils in mice

    NASA Technical Reports Server (NTRS)

    Smolen, J. E.; Fossett, M. C.; Joe, Y.; Prince, J. E.; Priest, E.; Kanwar, S.; Smith, C. W.

    2000-01-01

    The effects of long-term spaceflight on inflammatory responses have not been well-studied in either humans or animals. It is thus important to determine if the functions of immune and inflammatory cells are altered in models of spaceflight. One such animal model is antiorthostatic suspension (AOS), in which the experimental animal is subjected to a head-down tilt that mimics both the stress and the cephalad fluid shift experienced in spaceflight. A previous study reported that the peritoneal neutrophils from mice experiencing AOS generated less superoxide than unsuspended controls. We expanded on this study using several different stimuli and measuring the oxidative response of murine neutrophils in a variety of ways. These responses included the rate, lag period, and dose/response characteristics for superoxide generation, FACS analysis with dihydrodichlorofluorescein as a substrate, and a chemiluminescence response with luminol as a substrate. We also examined phagocytosis of three different microorganisms. While some effects of orthostatic suspension (attributable to the stress of the apparatus) were observed, no clear effects of AOS on oxidative function of the peritoneal neutrophils were seen.

  15. Stars and Stripes in the Cerebellar Cortex: A Voltage Sensitive Dye Study

    PubMed Central

    Rokni, Dan; Llinas, Rodolfo; Yarom, Yosef

    2007-01-01

    The lattice-like structure of the cerebellar cortex and its anatomical organization in two perpendicular axes provided the foundations for many theories of cerebellar function. However, the functional organization does not always match the anatomical organization. Thus direct measurement of the functional organization is central to our understanding of cerebellar processing. Here we use voltage sensitive dye imaging in the isolated cerebellar preparation to characterize the spatio-temporal organization of the climbing and mossy fiber (MF) inputs to the cerebellar cortex. Spatial and temporal parameters were used to develop reliable criteria to distinguish climbing fiber (CF) responses from MF responses. CF activation excited postsynaptic neurons along a parasagittal cortical band. These responses were composed of slow (∼25 ms), monophasic depolarizing signals. Neither the duration nor the spatial distribution of CF responses were affected by inhibition. Activation of MF generated responses that were organized in radial patches, and were composed of a fast (∼5 ms) depolarizing phase followed by a prolonged (∼100 ms) negative wave. Application of a GABAA blocker eliminated the hyperpolarizing phase and prolonged the depolarizing phase, but did not affect the spatial distribution of the response, thus suggesting that it is not the inhibitory system that is responsible for the inability of the MF input to generate beams of activity that propagate along the parallel fiber system. PMID:18958242

  16. Hydrogen Peroxide Signaling in Plant Development and Abiotic Responses: Crosstalk with Nitric Oxide and Calcium

    PubMed Central

    Niu, Lijuan; Liao, Weibiao

    2016-01-01

    Hydrogen peroxide (H2O2), as a reactive oxygen species, is widely generated in many biological systems. It has been considered as an important signaling molecule that mediates various physiological and biochemical processes in plants. Normal metabolism in plant cells results in H2O2 generation, from a variety of sources. Also, it is now clear that nitric oxide (NO) and calcium (Ca2+) function as signaling molecules in plants. Both H2O2 and NO are involved in plant development and abiotic responses. A wide range of evidences suggest that NO could be generated under similar stress conditions and with similar kinetics as H2O2. The interplay between H2O2 and NO has important functional implications to modulate transduction processes in plants. Moreover, close interaction also exists between H2O2 and Ca2+ in response to development and abiotic stresses in plants. Cellular responses to H2O2 and Ca2+ signaling systems are complex. There is quite a bit of interaction between H2O2 and Ca2+ signaling in responses to several stimuli. This review aims to introduce these evidences in our understanding of the crosstalk among H2O2, NO, and Ca2+ signaling which regulates plant growth and development, and other cellular and physiological responses to abiotic stresses. PMID:26973673

  17. Prospects of second generation artificial intelligence tools in calibration of chemical sensors.

    PubMed

    Braibanti, Antonio; Rao, Rupenaguntla Sambasiva; Ramam, Veluri Anantha; Rao, Gollapalli Nageswara; Rao, Vaddadi Venkata Panakala

    2005-05-01

    Multivariate data driven calibration models with neural networks (NNs) are developed for binary (Cu++ and Ca++) and quaternary (K+, Ca++, NO3- and Cl-) ion-selective electrode (ISE) data. The response profiles of ISEs with concentrations are non-linear and sub-Nernstian. This task represents function approximation of multi-variate, multi-response, correlated, non-linear data with unknown noise structure i.e. multi-component calibration/prediction in chemometric parlance. Radial distribution function (RBF) and Fuzzy-ARTMAP-NN models implemented in the software packages, TRAJAN and Professional II, are employed for the calibration. The optimum NN models reported are based on residuals in concentration space. Being a data driven information technology, NN does not require a model, prior- or posterior- distribution of data or noise structure. Missing information, spikes or newer trends in different concentration ranges can be modeled through novelty detection. Two simulated data sets generated from mathematical functions are modeled as a function of number of data points and network parameters like number of neurons and nearest neighbors. The success of RBF and Fuzzy-ARTMAP-NNs to develop adequate calibration models for experimental data and function approximation models for more complex simulated data sets ensures AI2 (artificial intelligence, 2nd generation) as a promising technology in quantitation.

  18. Strong second harmonic generation in two-dimensional ferroelectric IV-monochalcogenides

    NASA Astrophysics Data System (ADS)

    Panday, Suman Raj; Fregoso, Benjamin M.

    2017-11-01

    The two-dimensional ferroelectrics GeS, GeSe, SnS and SnSe are expected to have large spontaneous in-plane electric polarization and enhanced shift-current response. Using density functional methods, we show that these materials also exhibit the largest effective second harmonic generation reported so far. It can reach magnitudes up to 10~nm~V-1 which is about an order of magnitude larger than that of prototypical GaAs. To rationalize this result we model the optical response with a simple one-dimensional two-band model along the spontaneous polarization direction. Within this model the second-harmonic generation tensor is proportional to the shift-current response tensor. The large shift current and second harmonic responses of GeS, GeSe, SnS and SnSe make them promising non-linear materials for optoelectronic applications.

  19. Differentiation of Inflammation-Responsive Astrocytes from Glial Progenitors Generated from Human Induced Pluripotent Stem Cells.

    PubMed

    Santos, Renata; Vadodaria, Krishna C; Jaeger, Baptiste N; Mei, Arianna; Lefcochilos-Fogelquist, Sabrina; Mendes, Ana P D; Erikson, Galina; Shokhirev, Maxim; Randolph-Moore, Lynne; Fredlender, Callie; Dave, Sonia; Oefner, Ruth; Fitzpatrick, Conor; Pena, Monique; Barron, Jerika J; Ku, Manching; Denli, Ahmet M; Kerman, Bilal E; Charnay, Patrick; Kelsoe, John R; Marchetto, Maria C; Gage, Fred H

    2017-06-06

    Astrocyte dysfunction and neuroinflammation are detrimental features in multiple pathologies of the CNS. Therefore, the development of methods that produce functional human astrocytes represents an advance in the study of neurological diseases. Here we report an efficient method for inflammation-responsive astrocyte generation from induced pluripotent stem cells (iPSCs) and embryonic stem cells. This protocol uses an intermediate glial progenitor stage and generates functional astrocytes that show levels of glutamate uptake and calcium activation comparable with those observed in human primary astrocytes. Stimulation of stem cell-derived astrocytes with interleukin-1β or tumor necrosis factor α elicits a strong and rapid pro-inflammatory response. RNA-sequencing transcriptome profiling confirmed that similar gene expression changes occurred in iPSC-derived and primary astrocytes upon stimulation with interleukin-1β. This protocol represents an important tool for modeling in-a-dish neurological diseases with an inflammatory component, allowing for the investigation of the role of diseased astrocytes in neuronal degeneration. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  20. Identification of boiler inlet transfer functions and estimation of system parameters

    NASA Technical Reports Server (NTRS)

    Miles, J. H.

    1972-01-01

    An iterative computer method is described for identifying boiler transfer functions using frequency response data. An objective penalized performance measure and a nonlinear minimization technique are used to cause the locus of points generated by a transfer function to resemble the locus of points obtained from frequency response measurements. Different transfer functions can be tried until a satisfactory empirical transfer function of the system is found. To illustrate the method, some examples and some results from a study of a set of data consisting of measurements of the inlet impedance of a single tube forced flow boiler with inserts are given.

  1. Cyclophosphamide induces bone marrow to yield higher numbers of precursor dendritic cells in vitro capable of functional antigen presentation to T cells in vivo

    PubMed Central

    Salem, Mohamed L.; El-Naggar, Sabry A.; Cole, David J.

    2009-01-01

    We have shown recently that cyclophosphamide (CTX) treatment induced a marked increase in the numbers of immature dendritic cells (DCs) in blood, coinciding with enhanced antigen-specific responses of the adoptively transferred CD8+ T cells. Because this DC expansion was preceded by DC proliferation in bone marrow (BM), we tested whether BM post CTX treatment can generate higher numbers of functional DCs. BM was harvested three days after treatment of C57BL/6 mice with PBS or CTX and cultured with GM-CSF/IL-4 in vitro. Compared with control, BM from CTX-treated mice showed faster generation and yielded higher numbers of DCs with superior activation in response to toll-like receptor (TLR) agonists. Vaccination with peptide-pulsed DCs generated from BM from CTX-treated mice induced comparable adjuvant effects to those induced by control DCs. Taken together, post CTX BM harbors higher numbers of DC precursors capable of differentiating into functional DCs, which be targeted to create host microenvironment riches in activated DCs upon treatment with TLR agonists. PMID:20036354

  2. 7 CFR 276.1 - Responsibilities and rights.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... responsible for preventing losses or shortages of Federal funds in the issuance of benefits to households... unaccounted shortages that occur during issuance, unless otherwise specified. Issuance functions begin with the State agency's creation of a record-for-issuance to generate each month's issuances from the...

  3. Spectral response analysis of PVDF capacitive sensors

    NASA Astrophysics Data System (ADS)

    Reyes-Ramírez, B.; García-Segundo, C.; García-Valenzuela, A.

    2013-06-01

    We investigate the spectral response to ultrasound waves in water of low-noise capacitive sensors based on PVDF polymer piezoelectric films. First, we analyze theoretically the mechanical-to-electrical transduction as a function of the frequency of ultrasonic signals and derive an analytic expression of the sensor's transfer function. Then we present experimental results of the frequency response of a home-made PDVF in water to test signals from 1 to 20 MHz induced by a commercial hydrophone powered by a signal generator and compare with our theoretical model.

  4. B cells as multi-functional players during Mycobacterium tuberculosis infection and disease.

    PubMed

    du Plessis, Willem J; Walzl, Gerhard; Loxton, André G

    2016-03-01

    Immunity to tuberculosis is still understood to be driven and maintained by T-cell derived immune responses. With a steady influx of data, it is becoming clear that B cells, the mediators of humoral immunity, have the capacity to function in roles not previously appreciated within the traditional B cell dogma. In this review we aim to discuss B cells, from its generation through to its functioning as effectors in both the innate and adaptive immune response, within the tuberculosis domain. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Analysis of the transfer function for layered piezoelectric ultrasonic sensors

    NASA Astrophysics Data System (ADS)

    Gutiérrrez-Reyes, E.; García-Segundo, C.; García-Valenzuela, A.; Reyes-Ramírez, B.; Gutiérrez-Juárez, G.; Guadarrama-Santana, A.

    2017-06-01

    We model theoretically the voltage response to an acoustic pulse of a multilayer system forming a low noise capacitive sensor including a Polyvinylidene Fluoride piezoelectric film. First we model a generic piezoelectric detector consisting of a piezoelectric film between two metallic electrodes that are the responsible to convert the acoustic signal into a voltage signal. Then we calculate the pressure-to-voltage transfer function for a N-layer piezo-electric capacitor detector, allowing to study the effects of the electrode and protective layers thickness in typical layered piezoelectric sensors. The derived transfer function, when multiplied by the Fourier transform of the incident acoustic pulse, gives the voltage electric response in the frequency domain. An important concern regarding the transfer function is that it may have zeros at specific frequencies, and thus inverting the voltage Fourier transform of the pulse to recover the pressure signal in the time domain is not always, in principle, possible. Our formulas can be used to predict the existence and locations of such zeroes. We illustrate the use of the transfer function by predicting the electric signal generated at a multilayer piezoelectric sensor to an ultrasonic pulse generated photoacoustically by a laser pulse at a three media system with impedance mismatch. This theoretical calculations are compared with our own experimental measurements.

  6. Causal impulse response for circular sources in viscous media

    PubMed Central

    Kelly, James F.; McGough, Robert J.

    2008-01-01

    The causal impulse response of the velocity potential for the Stokes wave equation is derived for calculations of transient velocity potential fields generated by circular pistons in viscous media. The causal Green’s function is numerically verified using the material impulse response function approach. The causal, lossy impulse response for a baffled circular piston is then calculated within the near field and the far field regions using expressions previously derived for the fast near field method. Transient velocity potential fields in viscous media are computed with the causal, lossy impulse response and compared to results obtained with the lossless impulse response. The numerical error in the computed velocity potential field is quantitatively analyzed for a range of viscous relaxation times and piston radii. Results show that the largest errors are generated in locations near the piston face and for large relaxation times, and errors are relatively small otherwise. Unlike previous frequency-domain methods that require numerical inverse Fourier transforms for the evaluation of the lossy impulse response, the present approach calculates the lossy impulse response directly in the time domain. The results indicate that this causal impulse response is ideal for time-domain calculations that simultaneously account for diffraction and quadratic frequency-dependent attenuation in viscous media. PMID:18397018

  7. Control system for fluid heated steam generator

    DOEpatents

    Boland, J.F.; Koenig, J.F.

    1984-05-29

    A control system for controlling the location of the nucleate-boiling region in a fluid heated steam generator comprises means for measuring the temperature gradient (change in temperature per unit length) of the heating fluid along the steam generator; means for determining a control variable in accordance with a predetermined function of temperature gradients and for generating a control signal in response thereto; and means for adjusting the feedwater flow rate in accordance with the control signal.

  8. Control system for fluid heated steam generator

    DOEpatents

    Boland, James F.; Koenig, John F.

    1985-01-01

    A control system for controlling the location of the nucleate-boiling region in a fluid heated steam generator comprises means for measuring the temperature gradient (change in temperature per unit length) of the heating fluid along the steam generator; means for determining a control variable in accordance with a predetermined function of temperature gradients and for generating a control signal in response thereto; and means for adjusting the feedwater flow rate in accordance with the control signal.

  9. Functional Convergence of Neurons Generated in the Developing and Adult Hippocampus

    PubMed Central

    Piatti, Verónica C; Morgenstern, Nicolás A; Zhao, Chunmei; van Praag, Henriette; Gage, Fred H; Schinder, Alejandro F

    2006-01-01

    The dentate gyrus of the hippocampus contains neural progenitor cells (NPCs) that generate neurons throughout life. Developing neurons of the adult hippocampus have been described in depth. However, little is known about their functional properties as they become fully mature dentate granule cells (DGCs). To compare mature DGCs generated during development and adulthood, NPCs were labeled at both time points using retroviruses expressing different fluorescent proteins. Sequential electrophysiological recordings from neighboring neurons of different ages were carried out to quantitatively study their major synaptic inputs: excitatory projections from the entorhinal cortex and inhibitory afferents from local interneurons. Our results show that DGCs generated in the developing and adult hippocampus display a remarkably similar afferent connectivity with regard to both glutamate and GABA, the major neurotransmitters. We also demonstrate that adult-born neurons can fire action potentials in response to an excitatory drive, exhibiting a firing behavior comparable to that of neurons generated during development. We propose that neurons born in the developing and adult hippocampus constitute a functionally homogeneous neuronal population. These observations are critical to understanding the role of adult neurogenesis in hippocampal function. PMID:17121455

  10. B cell function in the immune response to helminths

    PubMed Central

    Harris, Nicola

    2010-01-01

    Similar T helper (Th)2-type immune responses are generated against different helminths parasites, but the mechanisms that initiate Th2 immunity, and the specific immune components that mediate protection against these parasites, can vary greatly. B cells are increasingly recognized as important during the Th2-type immune response to helminths, and B cell activation might be a target for effective vaccine development. Antibody production is a function of B cells during helminth infection and understanding how polyclonal and antigen-specific antibodies contribute should provide important insights into how protective immunity develops. In addition, B cells might also contribute to the host response against helminths through antibody-independent functions including, antigen-presentation, as well as regulatory and effector activity. In this review, we examine the role of B cells during Th2-type immune response to these multicellular parasites. PMID:21159556

  11. Generation of protective T cell-independent antiviral antibody responses in SCID mice reconstituted with follicular or marginal zone B cells.

    PubMed

    Guay, Heath M; Mishra, Rabinarayan; Garcea, Robert L; Welsh, Raymond M; Szomolanyi-Tsuda, Eva

    2009-07-01

    B cells generated in the bone marrow of adult mice enter the periphery as transitional B cells and subsequently differentiate into one of two phenotypically and functionally distinct subsets, marginal zone (MZ) or follicular (Fo) B cells. Recent reports indicate, however, that in response to environmental cues, such as lymphopenia, mature Fo B cells can change to display phenotypic markers characteristic of MZ B cells. Previously, we found that splenic B cells transferred to SCID mice responded to polyoma virus (PyV) infection with T cell-independent (TI) IgM and IgG secretion, reducing the viral load and protecting mice from the lethal effect of the infection. The contribution of MZ and Fo B cell subsets to this antiviral TI-2 response, however, has not been addressed. In this study, we show that both sort-purified MZ and Fo B cells generate protective TI Ab responses to PyV infection when transferred into SCID mice. Moreover, the transferred Fo B cells in the spleens of the PyV-infected SCID mice change phenotype, with many of them displaying MZ B cell characteristics. These findings demonstrate the plasticity of the B cell subsets in virus-infected hosts and show for the first time that B cells derived exclusively from Fo B cells can effectively function in antiviral TI-2 responses.

  12. Passenger comfort response times as a function of aircraft motion

    NASA Technical Reports Server (NTRS)

    Rinalducci, E. J.

    1975-01-01

    The relationship between a passenger's response time of changes in level of comfort experienced as a function of aircraft motion was examined. The aircraft used in this investigation was capable of providing a wide range of vertical and transverse accelerations by means of direct lift flap control surfaces and side force generator surfaces in addition to normal control surfaces. Response times to changes in comfort were recorded along with the passenger's rating of comfort on a five point scale. In addition, a number of aircraft motion variables including vertical and transverse accelerations were also recorded. Results indicate some relationship between human comfort response times to reaction time data.

  13. 77 FR 135 - Exelon Generation Company, LLC, Oyster Creek Nuclear Generating Station; Exemption

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-03

    ...) exercise from September 27, 2011, to June 2012. The licensee's request states that Hurricane Irene passed... that OCNGS reschedule specific functions of the offsite portion of the biennial EP exercise scheduled... postpone the exercise until 2012, citing the ongoing response to the Hurricane Irene aftermath. By letter...

  14. Optimal culture conditions for the generation of natural killer cell-induced dendritic cells for cancer immunotherapy.

    PubMed

    Nguyen-Pham, Thanh-Nhan; Yang, Deok-Hwan; Nguyen, Truc-Anh Thi; Lim, Mi-Seon; Hong, Cheol Yi; Kim, Mi-Hyun; Lee, Hyun Ju; Lee, Youn-Kyung; Cho, Duck; Bae, Soo-Young; Ahn, Jae-Sook; Kim, Yeo-Kyeoung; Chung, Ik-Joo; Kim, Hyeoung-Joon; Lee, Je-Jung

    2012-01-01

    Dendritic cell (DC)-based vaccines continue to be considered an attractive tool for cancer immunotherapy. DCs require an additional signal from the environment or other immune cells to polarize the development of immune responses toward T helper 1 (Th1) or Th2 responses. DCs play a role in natural killer (NK) cell activation, and NK cells are also able to activate and induce the maturation of DCs. We investigated the types of NK cells that can induce the maturation and enhanced function of DCs and the conditions under which these interactions occur. DCs that were activated by resting NK cells in the presence of inflammatory cytokines exhibited increased expression of several costimulatory molecules and an enhanced ability to produce IL-12p70. NK cell-stimulated DCs potently induced Th1 polarization and exhibited the ability to generate tumor antigen-specific cytotoxic T lymphocyte responses. Our data demonstrate that functional DCs can be generated by coculturing immature DCs with freshly isolated resting NK cells in the presence of Toll-like receptor agonists and proinflammatory cytokines and that the resulting DCs effectively present antigens to induce tumor-specific T-cell responses, which suggests that these cells may be useful for cancer immunotherapy.

  15. Tissue Engineering of the Corneal Endothelium: A Review of Carrier Materials

    PubMed Central

    Teichmann, Juliane; Valtink, Monika; Nitschke, Mirko; Gramm, Stefan; Funk, Richard H.W.; Engelmann, Katrin; Werner, Carsten

    2013-01-01

    Functional impairment of the human corneal endothelium can lead to corneal blindness. In order to meet the high demand for transplants with an appropriate human corneal endothelial cell density as a prerequisite for corneal function, several tissue engineering techniques have been developed to generate transplantable endothelial cell sheets. These approaches range from the use of natural membranes, biological polymers and biosynthetic material compositions, to completely synthetic materials as matrices for corneal endothelial cell sheet generation. This review gives an overview about currently used materials for the generation of transplantable corneal endothelial cell sheets with a special focus on thermo-responsive polymer coatings. PMID:24956190

  16. Consequences of Ignoring Guessing when Estimating the Latent Density in Item Response Theory

    ERIC Educational Resources Information Center

    Woods, Carol M.

    2008-01-01

    In Ramsay-curve item response theory (RC-IRT), the latent variable distribution is estimated simultaneously with the item parameters. In extant Monte Carlo evaluations of RC-IRT, the item response function (IRF) used to fit the data is the same one used to generate the data. The present simulation study examines RC-IRT when the IRF is imperfectly…

  17. Hydrogen peroxide generation by the pepper extracellular peroxidase CaPO2 activates local and systemic cell death and defense response to bacterial pathogens.

    PubMed

    Choi, Hyong Woo; Kim, Young Jin; Lee, Sung Chul; Hong, Jeum Kyu; Hwang, Byung Kook

    2007-11-01

    Reactive oxygen species (ROS) are responsible for mediating cellular defense responses in plants. Controversy has existed over the origin of ROS in plant defense. We have isolated a novel extracellular peroxidase gene, CaPO2, from pepper (Capsicum annuum). Local or systemic expression of CaPO2 is induced in pepper by avirulent Xanthomonas campestris pv vesicatoria (Xcv) infection. We examined the function of the CaPO2 gene in plant defense using the virus-induced gene silencing technique and gain-of-function transgenic plants. CaPO2-silenced pepper plants were highly susceptible to Xcv infection. Virus-induced gene silencing of the CaPO2 gene also compromised hydrogen peroxide (H(2)O(2)) accumulation and hypersensitive cell death in leaves, both locally and systemically, during avirulent Xcv infection. In contrast, overexpression of CaPO2 in Arabidopsis (Arabidopsis thaliana) conferred enhanced disease resistance accompanied by cell death, H(2)O(2) accumulation, and PR gene induction. In CaPO2-overexpression Arabidopsis leaves infected by Pseudomonas syringae pv tomato, H(2)O(2) generation was sensitive to potassium cyanide (a peroxidase inhibitor) but insensitive to diphenylene iodonium (an NADPH oxidase inhibitor), suggesting that H(2)O(2) generation depends on peroxidase in Arabidopsis. Together, these results indicate that the CaPO2 peroxidase is involved in ROS generation, both locally and systemically, to activate cell death and PR gene induction during the defense response to pathogen invasion.

  18. Response variance in functional maps: neural darwinism revisited.

    PubMed

    Takahashi, Hirokazu; Yokota, Ryo; Kanzaki, Ryohei

    2013-01-01

    The mechanisms by which functional maps and map plasticity contribute to cortical computation remain controversial. Recent studies have revisited the theory of neural Darwinism to interpret the learning-induced map plasticity and neuronal heterogeneity observed in the cortex. Here, we hypothesize that the Darwinian principle provides a substrate to explain the relationship between neuron heterogeneity and cortical functional maps. We demonstrate in the rat auditory cortex that the degree of response variance is closely correlated with the size of its representational area. Further, we show that the response variance within a given population is altered through training. These results suggest that larger representational areas may help to accommodate heterogeneous populations of neurons. Thus, functional maps and map plasticity are likely to play essential roles in Darwinian computation, serving as effective, but not absolutely necessary, structures to generate diverse response properties within a neural population.

  19. Response Variance in Functional Maps: Neural Darwinism Revisited

    PubMed Central

    Takahashi, Hirokazu; Yokota, Ryo; Kanzaki, Ryohei

    2013-01-01

    The mechanisms by which functional maps and map plasticity contribute to cortical computation remain controversial. Recent studies have revisited the theory of neural Darwinism to interpret the learning-induced map plasticity and neuronal heterogeneity observed in the cortex. Here, we hypothesize that the Darwinian principle provides a substrate to explain the relationship between neuron heterogeneity and cortical functional maps. We demonstrate in the rat auditory cortex that the degree of response variance is closely correlated with the size of its representational area. Further, we show that the response variance within a given population is altered through training. These results suggest that larger representational areas may help to accommodate heterogeneous populations of neurons. Thus, functional maps and map plasticity are likely to play essential roles in Darwinian computation, serving as effective, but not absolutely necessary, structures to generate diverse response properties within a neural population. PMID:23874733

  20. Contributions of early cortical processing and reading ability to functional status in individuals at clinical high risk for psychosis.

    PubMed

    Carrión, Ricardo E; Cornblatt, Barbara A; McLaughlin, Danielle; Chang, Jeremy; Auther, Andrea M; Olsen, Ruth H; Javitt, Daniel C

    2015-05-01

    There is a growing recognition that individuals at clinical high risk need intervention for functional impairments, along with emerging psychosis, as the majority of clinical high risk (CHR) individuals show persistent deficits in social and role functioning regardless of transition to psychosis. Recent studies have demonstrated reduced reading ability as a potential cause of functional disability in schizophrenia, related to underlying deficits in generation of mismatch negativity (MMN). The present study extends these findings to subjects at CHR. The sample consisted of 34 CHR individuals and 33 healthy comparison subjects (CNTLs) from the Recognition and Prevention (RAP) Program at the Zucker Hillside Hospital in New York. At baseline, reading measures were collected, along with MMN to pitch, duration, and intensity deviants, and measures of neurocognition, and social and role (academic/work) functioning. CHR subjects showed impairments in reading ability, neurocognition, and MMN generation, relative to CNTLs. Lower-amplitude MMN responses were correlated with worse reading ability, slower processing speed, and poorer social and role functioning. However, when entered into a simultaneous regression, only reduced responses to deviance in sound duration and volume predicted poor social and role functioning, respectively. Deficits in reading ability exist even prior to illness onset in schizophrenia and may represent a decline in performance from prior abilities. As in schizophrenia, deficits are related to impaired MMN generation, suggesting specific contributions of sensory-level impairment to neurocognitive processes related to social and role function. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Information-generated Influence as a Function of Locus-of-Control Patterns in Children

    ERIC Educational Resources Information Center

    Wolk, Stephen; Eliot, John

    1974-01-01

    Investigated the degree to which an individual disregards information about himself and his environment, as a function of his locus of control patterns, and hence is less responsive to or influenced by a given segment of information. Subjects were 341 fourth- and fifth-grade children. (SDH)

  2. Hierarchy of temporal responses of multivariate self-excited epidemic processes

    NASA Astrophysics Data System (ADS)

    Saichev, Alexander; Maillart, Thomas; Sornette, Didier

    2013-04-01

    Many natural and social systems are characterized by bursty dynamics, for which past events trigger future activity. These systems can be modelled by so-called self-excited Hawkes conditional Poisson processes. It is generally assumed that all events have similar triggering abilities. However, some systems exhibit heterogeneity and clusters with possibly different intra- and inter-triggering, which can be accounted for by generalization into the "multivariate" self-excited Hawkes conditional Poisson processes. We develop the general formalism of the multivariate moment generating function for the cumulative number of first-generation and of all generation events triggered by a given mother event (the "shock") as a function of the current time t. This corresponds to studying the response function of the process. A variety of different systems have been analyzed. In particular, for systems in which triggering between events of different types proceeds through a one-dimension directed or symmetric chain of influence in type space, we report a novel hierarchy of intermediate asymptotic power law decays ˜ 1/ t 1-( m+1) θ of the rate of triggered events as a function of the distance m of the events to the initial shock in the type space, where 0 < θ < 1 for the relevant long-memory processes characterizing many natural and social systems. The richness of the generated time dynamics comes from the cascades of intermediate events of possibly different kinds, unfolding via random changes of types genealogy.

  3. Double-heterojunction nanorod light-responsive LEDs for display applications.

    PubMed

    Oh, Nuri; Kim, Bong Hoon; Cho, Seong-Yong; Nam, Sooji; Rogers, Steven P; Jiang, Yiran; Flanagan, Joseph C; Zhai, You; Kim, Jae-Hwan; Lee, Jungyup; Yu, Yongjoon; Cho, Youn Kyoung; Hur, Gyum; Zhang, Jieqian; Trefonas, Peter; Rogers, John A; Shim, Moonsub

    2017-02-10

    Dual-functioning displays, which can simultaneously transmit and receive information and energy through visible light, would enable enhanced user interfaces and device-to-device interactivity. We demonstrate that double heterojunctions designed into colloidal semiconductor nanorods allow both efficient photocurrent generation through a photovoltaic response and electroluminescence within a single device. These dual-functioning, all-solution-processed double-heterojunction nanorod light-responsive light-emitting diodes open feasible routes to a variety of advanced applications, from touchless interactive screens to energy harvesting and scavenging displays and massively parallel display-to-display data communication. Copyright © 2017, American Association for the Advancement of Science.

  4. Relationship between the mechanisms of gamma rhythm generation and the magnitude of the macroscopic phase response function in a population of excitatory and inhibitory modified quadratic integrate-and-fire neurons

    NASA Astrophysics Data System (ADS)

    Akao, Akihiko; Ogawa, Yutaro; Jimbo, Yasuhiko; Ermentrout, G. Bard; Kotani, Kiyoshi

    2018-01-01

    Gamma oscillations are thought to play an important role in brain function. Interneuron gamma (ING) and pyramidal interneuron gamma (PING) mechanisms have been proposed as generation mechanisms for these oscillations. However, the relation between the generation mechanisms and the dynamical properties of the gamma oscillation are still unclear. Among the dynamical properties of the gamma oscillation, the phase response function (PRF) is important because it encodes the response of the oscillation to inputs. Recently, the PRF for an inhibitory population of modified theta neurons that generate an ING rhythm was computed by the adjoint method applied to the associated Fokker-Planck equation (FPE) for the model. The modified theta model incorporates conductance-based synapses as well as the voltage and current dynamics. Here, we extended this previous work by creating an excitatory-inhibitory (E-I) network using the modified theta model and described the population dynamics with the corresponding FPE. We conducted a bifurcation analysis of the FPE to find parameter regions which generate gamma oscillations. In order to label the oscillatory parameter regions by their generation mechanisms, we defined ING- and PING-type gamma oscillation in a mathematically plausible way based on the driver of the inhibitory population. We labeled the oscillatory parameter regions by these generation mechanisms and derived PRFs via the adjoint method on the FPE in order to investigate the differences in the responses of each type of oscillation to inputs. PRFs for PING and ING mechanisms are derived and compared. We found the amplitude of the PRF for the excitatory population is larger in the PING case than in the ING case. Finally, the E-I population of the modified theta neuron enabled us to analyze the PRFs of PING-type gamma oscillation and the entrainment ability of E and I populations. We found a parameter region in which PRFs of E and I are both purely positive in the case of PING oscillations. The different entrainment abilities of E and I stimulation as governed by the respective PRFs was compared to direct simulations of finite populations of model neurons. We find that it is easier to entrain the gamma rhythm by stimulating the inhibitory population than by stimulating the excitatory population as has been found experimentally.

  5. Characterization of nonGaussian atmospheric turbulence for prediction of aircraft response statistics

    NASA Technical Reports Server (NTRS)

    Mark, W. D.

    1977-01-01

    Mathematical expressions were derived for the exceedance rates and probability density functions of aircraft response variables using a turbulence model that consists of a low frequency component plus a variance modulated Gaussian turbulence component. The functional form of experimentally observed concave exceedance curves was predicted theoretically, the strength of the concave contribution being governed by the coefficient of variation of the time fluctuating variance of the turbulence. Differences in the functional forms of response exceedance curves and probability densities also were shown to depend primarily on this same coefficient of variation. Criteria were established for the validity of the local stationary assumption that is required in the derivations of the exceedance curves and probability density functions. These criteria are shown to depend on the relative time scale of the fluctuations in the variance, the fluctuations in the turbulence itself, and on the nominal duration of the relevant aircraft impulse response function. Metrics that can be generated from turbulence recordings for testing the validity of the local stationary assumption were developed.

  6. Detector response function of an energy-resolved CdTe single photon counting detector.

    PubMed

    Liu, Xin; Lee, Hyoung Koo

    2014-01-01

    While spectral CT using single photon counting detector has shown a number of advantages in diagnostic imaging, knowledge of the detector response function of an energy-resolved detector is needed to correct the signal bias and reconstruct the image more accurately. The objective of this paper is to study the photo counting detector response function using laboratory sources, and investigate the signal bias correction method. Our approach is to model the detector response function over the entire diagnostic energy range (20 keV

  7. Reactive oxygen species generation and signaling in plants

    PubMed Central

    Tripathy, Baishnab Charan; Oelmüller, Ralf

    2012-01-01

    The introduction of molecular oxygen into the atmosphere was accompanied by the generation of reactive oxygen species (ROS) as side products of many biochemical reactions. ROS are permanently generated in plastids, peroxisomes, mitochiondria, the cytosol and the apoplast. Imbalance between ROS generation and safe detoxification generates oxidative stress and the accumulating ROS are harmful for the plants. On the other hand, specific ROS function as signaling molecules and activate signal transduction processes in response to various stresses. Here, we summarize the generation of ROS in the different cellular compartments and the signaling processes which are induced by ROS. PMID:23072988

  8. Functional approach to exploring climatic and landscape controls of runoff generation: 1. Behavioral constraints on runoff volume

    NASA Astrophysics Data System (ADS)

    Li, Hong-Yi; Sivapalan, Murugesu; Tian, Fuqiang; Harman, Ciaran

    2014-12-01

    Inspired by the Dunne diagram, the climatic and landscape controls on the partitioning of annual runoff into its various components (Hortonian and Dunne overland flow and subsurface stormflow) are assessed quantitatively, from a purely theoretical perspective. A simple distributed hydrologic model has been built sufficient to simulate the effects of different combinations of climate, soil, and topography on the runoff generation processes. The model is driven by a sequence of simple hypothetical precipitation events, for a large combination of climate and landscape properties, and hydrologic responses at the catchment scale are obtained through aggregation of grid-scale responses. It is found, first, that the water balance responses, including relative contributions of different runoff generation mechanisms, could be related to a small set of dimensionless similarity parameters. These capture the competition between the wetting, drying, storage, and drainage functions underlying the catchment responses, and in this way, provide a quantitative approximation of the conceptual Dunne diagram. Second, only a subset of all hypothetical catchment/climate combinations is found to be "behavioral," in terms of falling sufficiently close to the Budyko curve, describing mean annual runoff as a function of climate aridity. Furthermore, these behavioral combinations are mostly consistent with the qualitative picture presented in the Dunne diagram, indicating clearly the commonality between the Budyko curve and the Dunne diagram. These analyses also suggest clear interrelationships amongst the "behavioral" climate, soil, and topography parameter combinations, implying these catchment properties may be constrained to be codependent in order to satisfy the Budyko curve.

  9. A Model of Best Vitelliform Macular Dystrophy in Rats

    PubMed Central

    Marmorstein, Alan D.; Stanton, J. Brett; Yocom, John; Bakall, Benjamin; Schiavone, Marc T.; Wadelius, Claes; Marmorstein, Lihua Y.; Peachey, Neal S.

    2010-01-01

    PURPOSE The VMD2 gene, mutated in Best macular dystrophy (BMD) encodes bestrophin, a 68-kDa basolateral plasma membrane protein expressed in retinal pigment epithelial (RPE) cells. BMD is characterized by a depressed light peak (LP) in the electro-oculogram. Bestrophin is thought to be the Cl channel that generates the LP. The goal was to generate an animal model of BMD and to determine the effects of bestrophin overexpression on the RPE-generated components of the ERG. METHODS Bestrophin or bestrophin mutants (W93C or R218C) were overexpressed in the RPE of rats by injection of replication-defective adenovirus. Immunofluorescence microscopy and ERG recordings were used to study subsequent effects. RESULTS Bestrophin was confined to the basolateral plasma membrane of the RPE. Neither wild-type (wt) nor mutant bestrophin affected the a- or b-waves of the ERG. Wt bestrophin, however, increased the c-wave and fast oscillation (FO), but not the LP. In contrast, both mutants had little or no effect on the c-wave and FO, but did reduce LP amplitude. LP amplitudes across a range of stimuli were not altered by wt bestrophin, though the luminance response function was desensitized. LP response functions were unaffected by bestrophin R218C but were significantly altered by bestrophin W93C. CONCLUSIONS A model of BMD was developed in the present study. Because overexpression of wt bestrophin shifted luminance response but did not alter the range of LP response amplitudes, the authors conclude that the rate-limiting step for generating LP amplitude occurs before activation of bestrophin or that bestrophin does not directly generate the LP conductance. PMID:15452084

  10. Analytical ultrasonics for evaluation of composite materials response. Part 2: Generation and detection

    NASA Technical Reports Server (NTRS)

    Duke, J. C., Jr.; Henneke, E. G., II

    1986-01-01

    To evaluate the response of composite materials, it is imperative that the input excitation as well as the observed output be well characterized. This characterization ideally should be in terms of displacements as a function of time with high spatial resolution. Additionally, the ability to prescribe these features for the excitation is highly desirable. Various methods for generating and detecting ultrasound in advanced composite materials are examined. Characterization and tailoring of input excitation is considered for contact and noncontact, mechanical, and electromechanical devices. Type of response as well as temporal and spatial resolution of detection methods are discussed as well. Results of investigations at Virginia Tech in application of these techniques to characterizing the response of advanced composites are presented.

  11. Effect of color on pilot performance and transfer functions using a full-spectrum, calligraphic, color display system

    NASA Technical Reports Server (NTRS)

    Chase, W. D.

    1976-01-01

    The use of blue and red color in out-of-window cockpit displays, in full-spectrum calligraphic computer-generated display systems, is studied with attention given to pilot stereographic depth perception and response to visual cues. Displays for vertical approach, with dynamic and frozen-range landing approach and perspective arrays, are analyzed. Pilot transfer function and the transfer function associated with the contrasted approach and perspective arrays are discussed. Out-of-window blue lights are perceived by pilots as indicating greater distance depth, red lights as indicating proximity. The computer-generated chromatic display was adapted to flight simulators for the tests.

  12. Calibrating Item Families and Summarizing the Results Using Family Expected Response Functions

    ERIC Educational Resources Information Center

    Sinharay, Sandip; Johnson, Matthew S.; Williamson, David M.

    2003-01-01

    Item families, which are groups of related items, are becoming increasingly popular in complex educational assessments. For example, in automatic item generation (AIG) systems, a test may consist of multiple items generated from each of a number of item models. Item calibration or scoring for such an assessment requires fitting models that can…

  13. Regulation and physiological functions of mammalian phospholipase C.

    PubMed

    Nakamura, Yoshikazu; Fukami, Kiyoko

    2017-04-01

    Phospholipase C (PLC) is a key enzyme in phosphoinositide metabolism. PLC hydrolyses phosphatidylinositol 4,5-bis-phosphate to generate two second messengers, inositol 1,4,5-trisphosphate and diacylglycerol, that generate diverse cellular responses. PLC is activated by various signalling molecules, including Ca2+, heterometric G proteins, small G proteins, and receptor/non-receptor tyrosine kinases. In addition to their enzymatic activity, some PLC subtypes also function as a guanine nucleotide exchange factor, GTPase-activating protein, and adaptor protein, independent of their lipase activity. There are 13 PLC isozymes in mammals, and they are categorized into six classes based on structure. Generation and analysis of genetically modified mice has revealed the unexpectedly diverse physiological functions of PLC isozymes. Although all PLC isozymes catalyze the same reaction, each PLC isozyme has unique physiological functions. This review focuses on the regulation and physiological functions of PLCs. © The Authors 2017. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

  14. Langerhans cells from women with cervical precancerous lesions become functionally responsive against human papillomavirus after activation with stabilized Poly-I:C.

    PubMed

    Da Silva, Diane M; Woodham, Andrew W; Skeate, Joseph G; Rijkee, Laurie K; Taylor, Julia R; Brand, Heike E; Muderspach, Laila I; Roman, Lynda D; Yessaian, Annie A; Pham, Huyen Q; Matsuo, Koji; Lin, Yvonne G; McKee, Greg M; Salazar, Andres M; Kast, W Martin

    2015-12-01

    Human papillomavirus (HPV)-mediated suppression of Langerhans cell (LC) function can lead to persistent infection and development of cervical intraepithelial neoplasia (CIN). Women with HPV-induced high-grade CIN2/3 have not mounted an effective immune response against HPV, yet it is unknown if LC-mediated T cell activation from such women is functionally impaired against HPV. We investigated the functional activation of in vitro generated LC and their ability to induce HPV16-specific T cells from CIN2/3 patients after exposure to HPV16 followed by treatment with stabilized Poly-I:C (s-Poly-I:C). LC from patients exposed to HPV16 demonstrated a lack of costimulatory molecule expression, inflammatory cytokine secretion, and chemokine-directed migration. Conversely, s-Poly-I:C caused significant phenotypic and functional activation of HPV16-exposed LC, which resulted in de novo generation of HPV16-specific CD8(+) T cells. Our results highlight that LC of women with a history of persistent HPV infection can present HPV antigens and are capable of inducing an adaptive T cell immune response when given the proper stimulus, suggesting that s-Poly-I:C compounds may be attractive immunomodulators for LC-mediated clearance of persistent HPV infection. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Accommodation measurements of horizontally scanning holographic display.

    PubMed

    Takaki, Yasuhiro; Yokouchi, Masahito

    2012-02-13

    Eye accommodation is considered to function properly for three-dimensional (3D) images generated by holography. We developed a horizontally scanning holographic display technique that enlarges both the screen size and viewing zone angle. A 3D image generated by this technique can be easily seen by both eyes. In this study, we measured the accommodation responses to a 3D image generated by the horizontally scanning holographic display technique that has a horizontal viewing zone angle of 14.6° and screen size of 4.3 in. We found that the accommodation responses to a 3D image displayed within 400 mm from the display screen were similar to those of a real object.

  16. Alcohol exposure differentially effects anti-tumor immunity in females by altering dendritic cell function.

    PubMed

    Thompson, Matthew G; Navarro, Flor; Chitsike, Lennox; Ramirez, Luis; Kovacs, Elizabeth J; Watkins, Stephanie K

    2016-12-01

    Dendritic cells (DCs) are a critical component of anti-tumor immunity due to their ability to induce a robust immune response to antigen (Ag). Alcohol was previously shown to reduce DC ability to present foreign Ag and promote pro-inflammatory responses in situations of infection and trauma. However the impact of alcohol exposure on generation of an anti-tumor response, especially in the context of generation of an immune vaccine has not been examined. In the clinic, DC vaccines are typically generated from autologous blood, therefore prior exposure to substances such as alcohol may be a critical factor to consider regarding the effectiveness in generating an immune response. In this study, we demonstrate for the first time that ethanol differentially affects DC and tumor Ag-specific T cell responses depending on sex. Signaling pathways were found to be differentially regulated in DC in females compared to males and these differences were exacerbated by ethanol treatment. DC from female mice treated with ethanol were unable to activate Ag-specific cytotoxic T cells (CTL) as shown by reduced expression of CD44, CD69, and decreased production of granzyme B and IFNγ. Furthermore, although FOXO3, an immune suppressive mediator of DC function, was found to be upregulated in DC from female mice, ethanol related suppression was independent of FOXO3. These findings demonstrate for the first time differential impacts of alcohol on the immune system of females compared to males and may be a critical consideration for determining the effectiveness of an immune based therapy for cancer in patients that consume alcohol. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  17. The Fifth Generation. An annotated bibliography

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Bramer, M.; Bramer, D.

    The Japanese Fifth Generation Computer System project constitutes a radical reappraisal of the functions which an advanced computer system should be able to perform, the programming languages needed to implement such functions, and the machine architectures suitable for supporting the chosen languages. The book guides the reader through the ever-growing literature on the project, and the international responses, including the United Kingdom Government's Alvey Program and the MCC Program in the United States. Evaluative abstracts are given, including books, journal articles, unpublished reports and material at both overview and technical levels.

  18. Modeling and performance assessment in QinetiQ of EO and IR airborne reconnaissance systems

    NASA Astrophysics Data System (ADS)

    Williams, John W.; Potter, Gary E.

    2002-11-01

    QinetiQ are the technical authority responsible for specifying the performance requirements for the procurement of airborne reconnaissance systems, on behalf of the UK MoD. They are also responsible for acceptance of delivered systems, overseeing and verifying the installed system performance as predicted and then assessed by the contractor. Measures of functional capability are central to these activities. The conduct of these activities utilises the broad technical insight and wide range of analysis tools and models available within QinetiQ. This paper focuses on the tools, methods and models that are applicable to systems based on EO and IR sensors. The tools, methods and models are described, and representative output for systems that QinetiQ has been responsible for is presented. The principle capability applicable to EO and IR airborne reconnaissance systems is the STAR (Simulation Tools for Airborne Reconnaissance) suite of models. STAR generates predictions of performance measures such as GRD (Ground Resolved Distance) and GIQE (General Image Quality) NIIRS (National Imagery Interpretation Rating Scales). It also generates images representing sensor output, using the scene generation software CAMEO-SIM and the imaging sensor model EMERALD. The simulated image 'quality' is fully correlated with the predicted non-imaging performance measures. STAR also generates image and table data that is compliant with STANAG 7023, which may be used to test ground station functionality.

  19. Dynamic response and transfer function of social systems: A neuro-inspired model of collective human activity patterns.

    PubMed

    Lymperopoulos, Ilias N

    2017-10-01

    The interaction of social networks with the external environment gives rise to non-stationary activity patterns reflecting the temporal structure and strength of exogenous influences that drive social dynamical processes far from an equilibrium state. Following a neuro-inspired approach, based on the dynamics of a passive neuronal membrane, and the firing rate dynamics of single neurons and neuronal populations, we build a state-of-the-art model of the collective social response to exogenous interventions. In this regard, we analyze online activity patterns with a view to determining the transfer function of social systems, that is, the dynamic relationship between external influences and the resulting activity. To this end, first we estimate the impulse response (Green's function) of collective activity, and then we show that the convolution of the impulse response with a time-varying external influence field accurately reproduces empirical activity patterns. To capture the dynamics of collective activity when the generating process is in a state of statistical equilibrium, we incorporate into the model a noisy input convolved with the impulse response function, thus precisely reproducing the fluctuations of stationary collective activity around a resting value. The outstanding goodness-of-fit of the model results to empirical observations, indicates that the model explains human activity patterns generated by time-dependent external influences in various socio-economic contexts. The proposed model can be used for inferring the temporal structure and strength of external influences, as well as the inertia of collective social activity. Furthermore, it can potentially predict social activity patterns. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Comparison of dose response functions for EBT3 model GafChromic™ film dosimetry system.

    PubMed

    Aldelaijan, Saad; Devic, Slobodan

    2018-05-01

    Different dose response functions of EBT3 model GafChromic™ film dosimetry system have been compared in terms of sensitivity as well as uncertainty vs. error analysis. We also made an assessment of the necessity of scanning film pieces before and after irradiation. Pieces of EBT3 film model were irradiated to different dose values in Solid Water (SW) phantom. Based on images scanned in both reflection and transmission mode before and after irradiation, twelve different response functions were calculated. For every response function, a reference radiochromic film dosimetry system was established by generating calibration curve and by performing the error vs. uncertainty analysis. Response functions using pixel values from the green channel demonstrated the highest sensitivity in both transmission and reflection mode. All functions were successfully fitted with rational functional form, and provided an overall one-sigma uncertainty of better than 2% for doses above 2 Gy. Use of pre-scanned images to calculate response functions resulted in negligible improvement in dose measurement accuracy. Although reflection scanning mode provides higher sensitivity and could lead to a more widespread use of radiochromic film dosimetry, it has fairly limited dose range and slightly increased uncertainty when compared to transmission scan based response functions. Double-scanning technique, either in transmission or reflection mode, shows negligible improvement in dose accuracy as well as a negligible increase in dose uncertainty. Normalized pixel value of the images scanned in transmission mode shows linear response in a dose range of up to 11 Gy. Copyright © 2018 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

  1. Generation of the neutron response function of an NE213 scintillator for fusion applications

    NASA Astrophysics Data System (ADS)

    Binda, F.; Eriksson, J.; Ericsson, G.; Hellesen, C.; Conroy, S.; Nocente, M.; Sundén, E. Andersson; JET Contributors

    2017-09-01

    In this work we present a method to evaluate the neutron response function of an NE213 liquid scintillator. This method is particularly useful when the proton light yield function of the detector has not been measured, since it is based on a proton light yield function taken from literature, MCNPX simulations, measurements of gamma-rays from a calibration source and measurements of neutrons from fusion experiments with ohmic plasmas. The inclusion of the latter improves the description of the proton light yield function in the energy range of interest (around 2.46 MeV). We apply this method to an NE213 detector installed at JET, inside the radiation shielding of the magnetic proton recoil (MPRu) spectrometer, and present the results from the calibration along with some examples of application of the response function to perform neutron emission spectroscopy (NES) of fusion plasmas. We also investigate how the choice of the proton light yield function affects the NES analysis, finding that the result does not change significantly. This points to the fact that the method for the evaluation of the neutron response function is robust and gives reliable results.

  2. A Double-Blind Atropine Trial for Active Learning of Autonomic Function

    ERIC Educational Resources Information Center

    Fry, Jeffrey R.; Burr, Steven A.

    2011-01-01

    Here, we describe a human physiology laboratory class measuring changes in autonomic function over time in response to atropine. Students use themselves as subjects, generating ownership and self-interest in the learning as well as directly experiencing the active link between physiology and pharmacology in people. The class is designed to…

  3. Effect of Urea and Thiourea on Generation of Xenogeneic Extracellular Matrix Scaffolds for Tissue Engineering

    PubMed Central

    Wong, Maelene L.; Wong, Janelle L.; Horn, Rebecca M.; Sannajust, Kimberley C.; Rice, Dawn A.

    2016-01-01

    Effective solubilization of proteins by chaotropes in proteomic applications motivates their use in solubilization-based antigen removal/decellularization strategies. A high urea concentration has previously been reported to significantly reduce lipophilic antigen content of bovine pericardium (BP); however, structure and function of the resultant extracellular matrix (ECM) scaffold were compromised. It has been recently demonstrated that in vivo ECM scaffold fate is determined by two primary outcome measures as follows: (1) sufficient reduction in antigen content to avoid graft-specific adaptive immune responses and (2) maintenance of native ECM structural proteins to avoid graft-specific innate responses. In this work, we assessed residual antigenicity, ECM architecture, ECM content, thermal stability, and tensile properties of BP subjected to a gradient of urea concentrations to determine whether an intermediate concentration exists at which both antigenicity and structure–function primary outcome measures for successful in vivo scaffold outcome can simultaneously be achieved. Alteration in tissue structure–function properties at various urea concentrations with decreased effectiveness for antigen removal makes use of urea-mediated antigen removal unlikely to be suitable for functional scaffold generation. PMID:27230226

  4. Herpes simplex virus-2 in the genital mucosa: insights into the mucosal host response and vaccine development.

    PubMed

    Lee, Amanda J; Ashkar, Ali A

    2012-02-01

    Herpes simplex virus (HSV)-2 is the predominant cause of genital herpes and has been implicated in HIV infection and transmission. Thus far, vaccines developed against HSV-2 have been clinically ineffective in preventing infection. This review aims to summarize the innate and adaptive immune responses against HSV-2 and examines the current status of vaccine development. Both innate and adaptive immune responses are essential for an effective primary immune response and the generation of immunity. The innate response involves Toll-like receptors, natural killer cells, plasmacytoid dendritic cells, and type I, II, and III interferons. The adaptive response requires a balance between CD4+ and CD8+ T-cells for optimal viral clearance. T-regulatory cells may be involved, although their exact function has yet to be determined. Current vaccine development involves the use of HSV-2 peptides or attenuated/replication-defective HSV-2 to generate adaptive anti-HSV-2 immune responses, however the generation of innate responses may also be an important consideration. Although vaccine development has primarily focused on the adaptive response, arguments for innate involvement are emerging. A greater understanding of the innate and adaptive processes underlying the response to HSV-2 infection will provide the foundation for the development of an effective vaccine.

  5. Response functions for neutron skyshine analysis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Gui, A.A.; Shultis, J.K.; Faw, R.E.

    1997-02-01

    Neutron and associated secondary photon line-beam response functions (LBRFs) for point monodirectional neutron sources are generated using the MCNP Monte Carlo code for use in neutron skyshine analysis employing the integral line-beam method. The LBRFs are evaluated at 14 neutron source energies ranging from 0.01 to 14 MeV and at 18 emission angles from 1 to 170 deg, as measured from the source-to-detector axis. The neutron and associated secondary photon conical-beam response functions (CBRFs) for azimuthally symmetric neutron sources are also evaluated at 13 neutron source energies in the same energy range and at 13 polar angles of source collimationmore » from 1 to 89 deg. The response functions are approximated by an empirical three-parameter function of the source-to-detector distance. These response function approximations are available for a source-to-detector distance up to 2,500 m and, for the first time, give dose equivalent responses that are required for modern radiological assessments. For the CBRFs, ground correction factors for neutrons and secondary photons are calculated and also approximated by empirical formulas for use in air-over-ground neutron skyshine problems with azimuthal symmetry. In addition, simple procedures are proposed for humidity and atmospheric density corrections.« less

  6. Reference values for developing responsive functional outcome measures across the lifespan.

    PubMed

    McKay, Marnee J; Baldwin, Jennifer N; Ferreira, Paulo; Simic, Milena; Vanicek, Natalie; Burns, Joshua

    2017-04-18

    To generate a reference dataset of commonly performed functional outcome measures in 1,000 children and adults and investigate the influence of demographic, anthropometric, strength, and flexibility characteristics. Twelve functional outcome measures were collected from 1,000 healthy individuals aged 3-101 years: 6-minute walk test, 30-second chair stand test, timed stairs test, long jump, vertical jump, choice stepping reaction time, balance (Star Excursion Balance Test, tandem stance eyes open and closed, single-leg stance eyes closed), and dexterity (9-hole peg test, Functional Dexterity Test). Correlation and multiple regression analyses were performed to identify factors independently associated with each measure. Age- and sex-stratified reference values for functional outcome measures were generated. Functional performance increased through childhood and adolescence, plateaued during adulthood, and declined in older adulthood. While balance did not differ between the sexes, male participants generally performed better at gross motor tasks while female participants performed better at dexterous tasks. Height was the most consistent correlate of functional performance in children, while lower limb muscle strength was a major determinant in adolescents and adults. In older adults, age, lower limb strength, and joint flexibility explained up to 63% of the variance in functional measures. These normative reference values provide a framework to accurately track functional decline associated with neuromuscular disorders and assist development and validation of responsive outcome measures for therapeutic trials. © 2017 American Academy of Neurology.

  7. Concurrent variation of response bias and sensitivity in an operant-psychophysical test.

    NASA Technical Reports Server (NTRS)

    Terman, M.; Terman, J. S.

    1972-01-01

    The yes-no signal detection procedure was applied to a single-response operant paradigm in which rats discriminated between a standard auditory intensity and attenuated comparison values. The payoff matrix was symmetrical (with reinforcing brain stimulation for correct detections and brief time-out for errors), but signal probability and intensity differences were varied to generate a family of isobias and isosensitivity functions. The d' parameter remained fairly constant across a wide range of bias levels. Isobias functions deviated from a strict matching strategy as discrimination difficulty increased, although an orderly relation was maintained between signal probability value and the degree and direction of response bias.

  8. Optical generation of millimeter-wave pulses using a fiber Bragg grating in a fiber-optics system.

    PubMed

    Ye, Qing; Qu, Ronghui; Fang, Zujie

    2007-04-10

    A scheme is proposed to transform an optical pulse into a millimeter-wave frequency modulation pulse by using a weak fiber Bragg grating (FBG) in a fiber-optics system. The Fourier transformation method is used to obtain the required spectrum response function of the FBG for the Gaussian pulse, soliton pulse, and Lorenz shape pulse. On the condition of the first-order Born approximation of the weak fiber grating, the relation of the refractive index distribution and the spectrum response function of the FBG satisfies the Fourier transformation, and the corresponding refractive index distribution forms are obtained for single-frequency modulation and linear-frequency modulation millimeter-wave pulse generation. The performances of the designed fiber gratings are also studied by a numerical simulation method for a supershort pulse transmission.

  9. Proinflammatory tachykinins that signal through the neurokinin 1 receptor promote survival of dendritic cells and potent cellular immunity.

    PubMed

    Janelsins, Brian M; Mathers, Alicia R; Tkacheva, Olga A; Erdos, Geza; Shufesky, William J; Morelli, Adrian E; Larregina, Adriana T

    2009-03-26

    Dendritic cells (DCs) are the preferred targets for immunotherapy protocols focused on stimulation of cellular immune responses. However, regardless of initial promising results, ex vivo generated DCs do not always promote immune-stimulatory responses. The outcome of DC-dependent immunity is regulated by proinflammatory cytokines and neuropeptides. Proinflammatory neuropeptides of the tachykinin family, including substance P (SP) and hemokinin-1 (HK-1), bind the neurokinin 1 receptor (NK1R) and promote stimulatory immune responses. Nevertheless, the ability of pro-inflammatory tachykinins to affect the immune functions of DCs remains elusive. In the present work, we demonstrate that mouse bone marrow-derived DCs (BMDCs) generated in the presence of granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin-4 (IL-4), express functional NK1R. Signaling via NK1R with SP, HK-1, or the synthetic agonist [Sar(9)Met(O(2))(11)]-SP rescues DCs from apoptosis induced by deprivation of GM-CSF and IL-4. Mechanistic analysis demonstrates that NK1R agonistic binding promotes DC survival via PI3K-Akt signaling cascade. In adoptive transfer experiments, NK1R-signaled BMDCs loaded with Ag exhibit increased longevity in draining lymph nodes, resulting in enhanced and prolonged effector cellular immunity. Our results contribute to the understanding of the interactions between the immune and nervous systems that control DC function and present a novel approach for ex vivo-generation of potent immune-stimulatory DCs.

  10. Interhemispheric Plasticity following Intermittent Theta Burst Stimulation in Chronic Poststroke Aphasia

    PubMed Central

    Griffis, Joseph C.; Nenert, Rodolphe; Allendorfer, Jane B.; Szaflarski, Jerzy P.

    2016-01-01

    The effects of noninvasive neurostimulation on brain structure and function in chronic poststroke aphasia are poorly understood. We investigated the effects of intermittent theta burst stimulation (iTBS) applied to residual language-responsive cortex in chronic patients using functional and anatomical MRI data acquired before and after iTBS. Lateralization index (LI) analyses, along with comparisons of inferior frontal gyrus (IFG) activation and connectivity during covert verb generation, were used to assess changes in cortical language function. Voxel-based morphometry (VBM) was used to assess effects on regional grey matter (GM). LI analyses revealed a leftward shift in IFG activity after treatment. While left IFG activation increased, right IFG activation decreased. Changes in right to left IFG connectivity during covert verb generation also decreased after iTBS. Behavioral correlations revealed a negative relationship between changes in right IFG activation and improvements in fluency. While anatomical analyses did not reveal statistically significant changes in grey matter volume, the fMRI results provide evidence for changes in right and left IFG function after iTBS. The negative relationship between post-iTBS changes in right IFG activity during covert verb generation and improvements in fluency suggests that iTBS applied to residual left-hemispheric language areas may reduce contralateral responses related to language production and facilitate recruitment of residual language areas after stroke. PMID:26881111

  11. Interhemispheric Plasticity following Intermittent Theta Burst Stimulation in Chronic Poststroke Aphasia.

    PubMed

    Griffis, Joseph C; Nenert, Rodolphe; Allendorfer, Jane B; Szaflarski, Jerzy P

    2016-01-01

    The effects of noninvasive neurostimulation on brain structure and function in chronic poststroke aphasia are poorly understood. We investigated the effects of intermittent theta burst stimulation (iTBS) applied to residual language-responsive cortex in chronic patients using functional and anatomical MRI data acquired before and after iTBS. Lateralization index (LI) analyses, along with comparisons of inferior frontal gyrus (IFG) activation and connectivity during covert verb generation, were used to assess changes in cortical language function. Voxel-based morphometry (VBM) was used to assess effects on regional grey matter (GM). LI analyses revealed a leftward shift in IFG activity after treatment. While left IFG activation increased, right IFG activation decreased. Changes in right to left IFG connectivity during covert verb generation also decreased after iTBS. Behavioral correlations revealed a negative relationship between changes in right IFG activation and improvements in fluency. While anatomical analyses did not reveal statistically significant changes in grey matter volume, the fMRI results provide evidence for changes in right and left IFG function after iTBS. The negative relationship between post-iTBS changes in right IFG activity during covert verb generation and improvements in fluency suggests that iTBS applied to residual left-hemispheric language areas may reduce contralateral responses related to language production and facilitate recruitment of residual language areas after stroke.

  12. LH pulses and the corpus luteum: the luteal phase deficiency LPD).

    PubMed

    Wuttke, W; Pitzel, L; Seidlová-Wuttke, D; Hinney, B

    2001-01-01

    The proper function of the GnRH pulse generator in the hypothalamus is essential for normal ovarian function, hence also for proper function of the corpus luteum. During the luteal phase LH pulses stimulate progesterone release, which is essential for normal endometrial transformation. Approximately one-half of all luteal phase deficiencies (LPD) are due to improper function of the GnRH pulse generator. Obviously, following ovulation the increased serum progesterone levels oversuppress the GnRH pulse generator, resulting in too few LH pulses and therefore improper luteal function. Also, latent hyperprolactinemia may lead to an LPD which can be effectively treated with plant extracts containing dopaminergic (prolactin-suppressing) compounds. Our increasing knowledge of auto- and paracrine mechanisms between nonsteroidogenic and steroidogenic cells now allow subclassification of LPDs of ovarian origin. The so-called small luteal cells are LH-responsive. If they develop improperly the regularly occurring LH pulses are unable to stimulate progesterone secretion from the small luteal cells, which results in what we call the small luteal cell defect. In addition, there is also evidence that the large luteal cells may function improperly. Hence, basal progesterone release is too low while LH-stimulated progesterone release from the small luteal cells appears to be intact. This subclassification of luteal phase deficiency results in the suggestion of different treatments. In cases where the corpus luteum is LH-responsive, such as the hypothalamic corpus luteum insufficiency and the large luteal cell defect, HCG treatment or pulsatile treatment with GnRH is advisable. In the case of LH/hCG-unresponsive small luteal cell defect a progesterone substitution is suggested.

  13. Dynamic test input generation for multiple-fault isolation

    NASA Technical Reports Server (NTRS)

    Schaefer, Phil

    1990-01-01

    Recent work is Causal Reasoning has provided practical techniques for multiple fault diagnosis. These techniques provide a hypothesis/measurement diagnosis cycle. Using probabilistic methods, they choose the best measurements to make, then update fault hypotheses in response. For many applications such as computers and spacecraft, few measurement points may be accessible, or values may change quickly as the system under diagnosis operates. In these cases, a hypothesis/measurement cycle is insufficient. A technique is presented for a hypothesis/test-input/measurement diagnosis cycle. In contrast to generating tests a priori for determining device functionality, it dynamically generates tests in response to current knowledge about fault probabilities. It is shown how the mathematics previously used for measurement specification can be applied to the test input generation process. An example from an efficient implementation called Multi-Purpose Causal (MPC) is presented.

  14. Adapting Educational Measurement to the Demands of Test-Based Accountability

    ERIC Educational Resources Information Center

    Koretz, Daniel

    2015-01-01

    Accountability has become a primary function of large-scale testing in the United States. The pressure on educators to raise scores is vastly greater than it was several decades ago. Research has shown that high-stakes testing can generate behavioral responses that inflate scores, often severely. I argue that because of these responses, using…

  15. Mechanics of the fast-start: muscle function and the role of intramuscular pressure in the escape behavior of amia calva and polypterus palmas

    PubMed

    Westneat; Hale; Mchenry; Long

    1998-11-01

    The fast-start escape response is a rapid, powerful body motion used to generate high accelerations of the body in virtually all fishes. Although the neurobiology and behavior of the fast-start are often studied, the patterns of muscle activity and muscle force production during escape are less well understood. We studied the fast-starts of two basal actinopterygian fishes (Amia calva and Polypterus palmas) to investigate the functional morphology of the fast-start and the role of intramuscular pressure (IMP) in escape behavior. Our goals were to determine whether IMP increases during fast starts, to look for associations between muscle activity and elevated IMP, and to determine the functional role of IMP in the mechanics of the escape response. We simultaneously recorded the kinematics, muscle activity patterns and IMP of four A. calva and three P. palmas during the escape response. Both species generated high IMPs of up to 90 kPa (nearly 1 atmosphere) above ambient during the fast-start. The two species showed similar pressure magnitudes but had significantly different motor patterns and escape performance. Stage 1 of the fast-start was generated by simultaneous contraction of locomotor muscle on both sides of the body, although electromyogram amplitudes on the contralateral (convex) side of the fish were significantly lower than on the ipsilateral (concave) side. Simultaneous recordings of IMP, escape motion and muscle activity suggest that pressure change is caused by the contraction and radial swelling of cone-shaped myomeres. We develop a model of IMP production that incorporates myomere geometry, the concept of constant-volume muscular hydrostats, the relationship between fiber angle and muscle force, and the forces that muscle fibers produce. The timing profile of pressure change, behavior and muscle action indicates that elevated muscle pressure is a mechanism of stiffening the body and functions in force transmission during the escape response.

  16. Neutron response function characterization of 4He scintillation detectors

    DOE PAGES

    Kelley, Ryan P.; Rolison, Lucas M.; Lewis, Jason M.; ...

    2015-04-15

    Time-of-flight measurements were conducted to characterize the neutron energy response of pressurized 4He fast neutron scintillation detectors for the first time, using the Van de Graaff generator at Ohio University. The time-of-flight spectra and pulse height distributions were measured. This data was used to determine the light output response function, which was found to be linear at energies below 3.5 MeV. The intrinsic efficiency of the detector as a function of incident energy was also calculated: the average efficiency up to 10 MeV was 3.1%, with a maximum efficiency of 6.6% at 1.05 MeV. Furthermore, these results will enable developmentmore » of neutron spectrum unfolding algorithms for neutron spectroscopy applications with these detectors.« less

  17. Production of functional proteins: balance of shear stress and gravity

    NASA Technical Reports Server (NTRS)

    Kaysen, James Howard (Inventor); Hammond, Timothy Grant (Inventor); Goodwin, Thomas John (Inventor)

    2011-01-01

    A method for the production of functional proteins including hormones by renal cells in a three dimensional culturing process responsive to shear stress uses a rotating wall vessel. Natural mixture of renal cells expresses the enzyme 1-.alpha.-hydroxylase which can be used to generate the active form of vitamin D: 1,25-diOH vitamin D.sub.3. The fibroblast cultures and co-culture of renal cortical cells express the gene for erythropoietin and secrete erythropoietin into the culture supernatant. Other shear stress response genes are also modulated by shear stress, such as toxin receptors megalin and cubulin (gp280). Also provided is a method of treating an in-need individual with the functional proteins produced in a three dimensional co-culture process responsive to shear stress using a rotating wall vessel.

  18. Mitochondrial respiration controls lysosomal function during inflammatory T cell responses

    PubMed Central

    Baixauli, Francesc; Acín-Pérez, Rebeca; Villarroya-Beltrí, Carolina; Mazzeo, Carla; Nuñez-Andrade, Norman; Gabandé-Rodriguez, Enrique; Dolores Ledesma, Maria; Blázquez, Alberto; Martin, Miguel Angel; Falcón-Pérez, Juan Manuel; Redondo, Juan Miguel; Enríquez, Jose Antonio; Mittelbrunn, Maria

    2016-01-01

    Summary The endolysosomal system is critical for the maintenance of cellular homeostasis. However, how endolysosomal compartment is regulated by mitochondrial function is largely unknown. We have generated a mouse model with defective mitochondrial function in CD4+ T lymphocytes by genetic deletion of the mitochondrial transcription factor A (Tfam). Mitochondrial respiration-deficiency impairs lysosome function, promotes p62 and sphingomyelin accumulation and disrupts endolysosomal trafficking pathways and autophagy, thus linking a primary mitochondrial dysfunction to a lysosomal storage disorder. The impaired lysosome function in Tfam-deficient cells subverts T cell differentiation toward pro-inflammatory subsets and exacerbates the in vivo inflammatory response. Restoration of NAD+ levels improves lysosome function and corrects the inflammatory defects in Tfam-deficient T cells. Our results uncover a mechanism by which mitochondria regulate lysosome function to preserve T cell differentiation and effector functions, and identify novel strategies for intervention in mitochondrial-related diseases. PMID:26299452

  19. Thermo-responsive cell culture carriers based on poly(vinyl methyl ether)—the effect of biomolecular ligands to balance cell adhesion and stimulated detachment

    NASA Astrophysics Data System (ADS)

    Teichmann, Juliane; Nitschke, Mirko; Pette, Dagmar; Valtink, Monika; Gramm, Stefan; Härtel, Frauke V.; Noll, Thomas; Funk, Richard H. W.; Engelmann, Katrin; Werner, Carsten

    2015-08-01

    Two established material systems for thermally stimulated detachment of adherent cells were combined in a cross-linked polymer blend to merge favorable properties. Through this approach poly(N-isopropylacrylamide) (PNiPAAm) with its superior switching characteristic was paired with a poly(vinyl methyl ether)-based composition that allows adjusting physico-chemical and biomolecular properties in a wide range. Beyond pure PNiPAAm, the proposed thermo-responsive coating provides thickness, stiffness and swelling behavior, as well as an apposite density of reactive sites for biomolecular functionalization, as effective tuning parameters to meet specific requirements of a particular cell type regarding initial adhesion and ease of detachment. To illustrate the strength of this approach, the novel cell culture carrier was applied to generate transplantable sheets of human corneal endothelial cells (HCEC). Sheets were grown, detached, and transferred onto planar targets. Cell morphology, viability and functionality were analyzed by immunocytochemistry and determination of transepithelial electrical resistance (TEER) before and after sheet detachment and transfer. HCEC layers showed regular morphology with appropriate TEER. Cells were positive for function-associated marker proteins ZO-1, Na+/K+-ATPase, and paxillin, and extracellular matrix proteins fibronectin, laminin and collagen type IV before and after transfer. Sheet detachment and transfer did not impair cell viability. Subsequently, a potential application in ophthalmology was demonstrated by transplantation onto de-endothelialized porcine corneas in vitro. The novel thermo-responsive cell culture carrier facilitates the generation and transfer of functional HCEC sheets. This paves the way to generate tissue engineered human corneal endothelium as an alternative transplant source for endothelial keratoplasty.

  20. Thermo-responsive cell culture carriers based on poly(vinyl methyl ether)-the effect of biomolecular ligands to balance cell adhesion and stimulated detachment.

    PubMed

    Teichmann, Juliane; Nitschke, Mirko; Pette, Dagmar; Valtink, Monika; Gramm, Stefan; Härtel, Frauke V; Noll, Thomas; Funk, Richard H W; Engelmann, Katrin; Werner, Carsten

    2015-08-01

    Two established material systems for thermally stimulated detachment of adherent cells were combined in a cross-linked polymer blend to merge favorable properties. Through this approach poly( N -isopropylacrylamide) (PNiPAAm) with its superior switching characteristic was paired with a poly(vinyl methyl ether)-based composition that allows adjusting physico-chemical and biomolecular properties in a wide range. Beyond pure PNiPAAm, the proposed thermo-responsive coating provides thickness, stiffness and swelling behavior, as well as an apposite density of reactive sites for biomolecular functionalization, as effective tuning parameters to meet specific requirements of a particular cell type regarding initial adhesion and ease of detachment. To illustrate the strength of this approach, the novel cell culture carrier was applied to generate transplantable sheets of human corneal endothelial cells (HCEC). Sheets were grown, detached, and transferred onto planar targets. Cell morphology, viability and functionality were analyzed by immunocytochemistry and determination of transepithelial electrical resistance (TEER) before and after sheet detachment and transfer. HCEC layers showed regular morphology with appropriate TEER. Cells were positive for function-associated marker proteins ZO-1, Na + /K + -ATPase, and paxillin, and extracellular matrix proteins fibronectin, laminin and collagen type IV before and after transfer. Sheet detachment and transfer did not impair cell viability. Subsequently, a potential application in ophthalmology was demonstrated by transplantation onto de-endothelialized porcine corneas in vitro . The novel thermo-responsive cell culture carrier facilitates the generation and transfer of functional HCEC sheets. This paves the way to generate tissue engineered human corneal endothelium as an alternative transplant source for endothelial keratoplasty.

  1. Thermo-responsive cell culture carriers based on poly(vinyl methyl ether)—the effect of biomolecular ligands to balance cell adhesion and stimulated detachment

    PubMed Central

    Teichmann, Juliane; Nitschke, Mirko; Pette, Dagmar; Valtink, Monika; Gramm, Stefan; Härtel, Frauke V; Noll, Thomas; Funk, Richard H W; Engelmann, Katrin; Werner, Carsten

    2015-01-01

    Two established material systems for thermally stimulated detachment of adherent cells were combined in a cross-linked polymer blend to merge favorable properties. Through this approach poly(N-isopropylacrylamide) (PNiPAAm) with its superior switching characteristic was paired with a poly(vinyl methyl ether)-based composition that allows adjusting physico-chemical and biomolecular properties in a wide range. Beyond pure PNiPAAm, the proposed thermo-responsive coating provides thickness, stiffness and swelling behavior, as well as an apposite density of reactive sites for biomolecular functionalization, as effective tuning parameters to meet specific requirements of a particular cell type regarding initial adhesion and ease of detachment. To illustrate the strength of this approach, the novel cell culture carrier was applied to generate transplantable sheets of human corneal endothelial cells (HCEC). Sheets were grown, detached, and transferred onto planar targets. Cell morphology, viability and functionality were analyzed by immunocytochemistry and determination of transepithelial electrical resistance (TEER) before and after sheet detachment and transfer. HCEC layers showed regular morphology with appropriate TEER. Cells were positive for function-associated marker proteins ZO-1, Na+/K+-ATPase, and paxillin, and extracellular matrix proteins fibronectin, laminin and collagen type IV before and after transfer. Sheet detachment and transfer did not impair cell viability. Subsequently, a potential application in ophthalmology was demonstrated by transplantation onto de-endothelialized porcine corneas in vitro. The novel thermo-responsive cell culture carrier facilitates the generation and transfer of functional HCEC sheets. This paves the way to generate tissue engineered human corneal endothelium as an alternative transplant source for endothelial keratoplasty. PMID:27877823

  2. Calculation of response matrix of CaSO 4:Dy based neutron dosimeter using Monte Carlo code FLUKA and measurement of 241Am-Be spectra

    NASA Astrophysics Data System (ADS)

    Chatterjee, S.; Bakshi, A. K.; Tripathy, S. P.

    2010-09-01

    Response matrix for CaSO 4:Dy based neutron dosimeter was generated using Monte Carlo code FLUKA in the energy range thermal to 20 MeV for a set of eight Bonner spheres of diameter 3-12″ including the bare one. Response of the neutron dosimeter was measured for the above set of spheres for 241Am-Be neutron source covered with 2 mm lead. An analytical expression for the response function was devised as a function of sphere mass. Using Frascati Unfolding Iteration Tool (FRUIT) unfolding code, the neutron spectrum of 241Am-Be was unfolded and compared with standard IAEA spectrum for the same.

  3. Nonparametric Hierarchical Bayesian Model for Functional Brain Parcellation

    PubMed Central

    Lashkari, Danial; Sridharan, Ramesh; Vul, Edward; Hsieh, Po-Jang; Kanwisher, Nancy; Golland, Polina

    2011-01-01

    We develop a method for unsupervised analysis of functional brain images that learns group-level patterns of functional response. Our algorithm is based on a generative model that comprises two main layers. At the lower level, we express the functional brain response to each stimulus as a binary activation variable. At the next level, we define a prior over the sets of activation variables in all subjects. We use a Hierarchical Dirichlet Process as the prior in order to simultaneously learn the patterns of response that are shared across the group, and to estimate the number of these patterns supported by data. Inference based on this model enables automatic discovery and characterization of salient and consistent patterns in functional signals. We apply our method to data from a study that explores the response of the visual cortex to a collection of images. The discovered profiles of activation correspond to selectivity to a number of image categories such as faces, bodies, and scenes. More generally, our results appear superior to the results of alternative data-driven methods in capturing the category structure in the space of stimuli. PMID:21841977

  4. Free Radicals Generated by Ionizing Radiation Signal Nuclear Translocation of p53

    NASA Technical Reports Server (NTRS)

    Martinez, J. D.; Pennington, M. E.; Craven, M. T.; Warters, R. L.

    1997-01-01

    The p53 tumor suppressor is a transcription factor that regulates several pathways, which function collectively to maintain the integrity of the genome. Nuclear localization is critical for wild-type function. However, the signals that regulate subcellular localization of p53 have not been identified. Here, we examine the effect of ionizing radiation on the subcellular localization of p53 in two cell lines in which p63 is normally sequestered in the cytoplasm and found that ionizing radiation caused a biphasic translocation response. p53 entered the nucleus 1-2 hours postirradiation (early response), subsequently emerged from the nucleus, and then again entered the nucleus 12-24 hours after the cells had been irradiated (delayed response). These changes in subcellular localization could be completely blocked by the free radical scavenger, WR1065. By comparison, two DNA-damaging agents that do not generate free radicals, mitomycin C and doxorubicin, caused translocation only after 12-24 h of exposure to the drugs, and this effect could not be inhibited by WR1065. Hence, although all three DNA-damaging agents induced relocalization of p53 to the nucleus, only the translocation caused by radiation was sensitive to free radical scavenging. We suggest that the free radicals generated by ionizing radiation can signal p53 translocation to the nucleus.

  5. Photon entanglement signatures in difference-frequency-generation

    PubMed Central

    Roslyak, Oleksiy; Mukamel, Shaul

    2010-01-01

    In response to quantum optical fields, pairs of molecules generate coherent nonlinear spectroscopy signals. Homodyne signals are given by sums over terms each being a product of Liouville space pathways of the pair of molecules times the corresponding optical field correlation function. For classical fields all field correlation functions may be factorized and become identical products of field amplitudes. The signal is then given by the absolute square of a susceptibility which in turn is a sum over pathways of a single molecule. The molecular pathways of different molecules in the pair are uncorrelated in this case (each path of a given molecule can be accompanied by any path of the other). However, entangled photons create an entanglement between the molecular pathways. We use the superoperator nonequlibrium Green’s functions formalism to demonstrate the signatures of this pathway-entanglement in the difference frequency generation signal. Comparison is made with an analogous incoherent two-photon fluorescence signal. PMID:19158927

  6. CD22 is required for formation of memory B cell precursors within germinal centers.

    PubMed

    Chappell, Craig P; Draves, Kevin E; Clark, Edward A

    2017-01-01

    CD22 is a BCR co-receptor that regulates B cell signaling, proliferation and survival and is required for T cell-independent Ab responses. To investigate the role of CD22 during T cell-dependent (TD) Ab responses and memory B cell formation, we analyzed Ag-specific B cell responses generated by wild-type (WT) or CD22-/- B cells following immunization with a TD Ag. CD22-/- B cells mounted normal early Ab responses yet failed to generate either memory B cells or long-lived plasma cells, whereas WT B cells formed both populations. Surprisingly, B cell expansion and germinal center (GC) differentiation were comparable between WT and CD22-/- B cells. CD22-/- B cells, however, were significantly less capable of generating a population of CXCR4hiCD38hi GC B cells, which we propose represent memory B cell precursors within GCs. These results demonstrate a novel role for CD22 during TD humoral responses evident during primary GC formation and underscore that CD22 functions not only during B cell maturation but also during responses to both TD and T cell-independent antigens.

  7. CD22 is required for formation of memory B cell precursors within germinal centers

    PubMed Central

    Chappell, Craig P.; Draves, Kevin E.

    2017-01-01

    CD22 is a BCR co-receptor that regulates B cell signaling, proliferation and survival and is required for T cell-independent Ab responses. To investigate the role of CD22 during T cell-dependent (TD) Ab responses and memory B cell formation, we analyzed Ag-specific B cell responses generated by wild-type (WT) or CD22-/- B cells following immunization with a TD Ag. CD22-/- B cells mounted normal early Ab responses yet failed to generate either memory B cells or long-lived plasma cells, whereas WT B cells formed both populations. Surprisingly, B cell expansion and germinal center (GC) differentiation were comparable between WT and CD22-/- B cells. CD22-/- B cells, however, were significantly less capable of generating a population of CXCR4hiCD38hi GC B cells, which we propose represent memory B cell precursors within GCs. These results demonstrate a novel role for CD22 during TD humoral responses evident during primary GC formation and underscore that CD22 functions not only during B cell maturation but also during responses to both TD and T cell-independent antigens. PMID:28346517

  8. How actin crosslinking and bundling proteins cooperate to generate an enhanced cell mechanical response

    NASA Technical Reports Server (NTRS)

    Tseng, Yiider; Kole, Thomas P.; Lee, Jerry S H.; Fedorov, Elena; Almo, Steven C.; Schafer, Benjamin W.; Wirtz, Denis

    2005-01-01

    Actin-crosslinking proteins organize actin filaments into dynamic and complex subcellular scaffolds that orchestrate important mechanical functions, including cell motility and adhesion. Recent mutation studies have shown that individual crosslinking proteins often play seemingly non-essential roles, leading to the hypothesis that they have considerable redundancy in function. We report live-cell, in vitro, and theoretical studies testing the mechanical role of the two ubiquitous actin-crosslinking proteins, alpha-actinin and fascin, which co-localize to stress fibers and the basis of filopodia. Using live-cell particle tracking microrheology, we show that the addition of alpha-actinin and fascin elicits a cell mechanical response that is significantly greater than that originated by alpha-actinin or fascin alone. These live-cell measurements are supported by quantitative rheological measurements with reconstituted actin filament networks containing pure proteins that show that alpha-actinin and fascin can work in concert to generate enhanced cell stiffness. Computational simulations using finite element modeling qualitatively reproduce and explain the functional synergy of alpha-actinin and fascin. These findings highlight the cooperative activity of fascin and alpha-actinin and provide a strong rationale that an evolutionary advantage might be conferred by the cooperative action of multiple actin-crosslinking proteins with overlapping but non-identical biochemical properties. Thus the combination of structural proteins with similar function can provide the cell with unique properties that are required for biologically optimal responses.

  9. Quantitative characterization of collagen in the fibrotic capsule surrounding implanted polymeric microparticles through second harmonic generation imaging

    DOE PAGES

    Akilbekova, Dana; Bratlie, Kaitlin M.; Abraham, Thomas

    2015-06-30

    The collagenous capsule formed around an implant will ultimately determine the nature of its in vivo fate. To provide a better understanding of how surface modifications can alter the collagen orientation and composition in the fibrotic capsule, we used second harmonic generation (SHG) microscopy to evaluate collagen organization and structure generated in mice subcutaneously injected with chemically functionalized polystyrene particles. SHG is sensitive to the orientation of a molecule, making it a powerful tool for measuring the alignment of collagen fibers. Additionally, SHG arises from the second order susceptibility of the interrogated molecule in response to the electric field. Variationmore » in these tensor components distinguishes different molecular sources of SHG, providing collagen type specificity. Here, we demonstrated the ability of SHG to differentiate collagen type I and type III quantitatively and used this method to examine fibrous capsules of implanted polystyrene particles. Data presented in this work shows a wide range of collagen fiber orientations and collagen compositions in response to surface functionalized polystyrene particles. Dimethylamino functionalized particles were able to form a thin collagenous matrix resembling healthy skin. These findings have the potential to improve the fundamental understanding of how material properties influence collagen organization and composition quantitatively.« less

  10. Quantitative Characterization of Collagen in the Fibrotic Capsule Surrounding Implanted Polymeric Microparticles through Second Harmonic Generation Imaging.

    PubMed

    Akilbekova, Dana; Bratlie, Kaitlin M

    2015-01-01

    The collagenous capsule formed around an implant will ultimately determine the nature of its in vivo fate. To provide a better understanding of how surface modifications can alter the collagen orientation and composition in the fibrotic capsule, we used second harmonic generation (SHG) microscopy to evaluate collagen organization and structure generated in mice subcutaneously injected with chemically functionalized polystyrene particles. SHG is sensitive to the orientation of a molecule, making it a powerful tool for measuring the alignment of collagen fibers. Additionally, SHG arises from the second order susceptibility of the interrogated molecule in response to the electric field. Variation in these tensor components distinguishes different molecular sources of SHG, providing collagen type specificity. Here, we demonstrated the ability of SHG to differentiate collagen type I and type III quantitatively and used this method to examine fibrous capsules of implanted polystyrene particles. Data presented in this work shows a wide range of collagen fiber orientations and collagen compositions in response to surface functionalized polystyrene particles. Dimethylamino functionalized particles were able to form a thin collagenous matrix resembling healthy skin. These findings have the potential to improve the fundamental understanding of how material properties influence collagen organization and composition quantitatively.

  11. Quantitative Characterization of Collagen in the Fibrotic Capsule Surrounding Implanted Polymeric Microparticles through Second Harmonic Generation Imaging

    PubMed Central

    Akilbekova, Dana; Bratlie, Kaitlin M.

    2015-01-01

    The collagenous capsule formed around an implant will ultimately determine the nature of its in vivo fate. To provide a better understanding of how surface modifications can alter the collagen orientation and composition in the fibrotic capsule, we used second harmonic generation (SHG) microscopy to evaluate collagen organization and structure generated in mice subcutaneously injected with chemically functionalized polystyrene particles. SHG is sensitive to the orientation of a molecule, making it a powerful tool for measuring the alignment of collagen fibers. Additionally, SHG arises from the second order susceptibility of the interrogated molecule in response to the electric field. Variation in these tensor components distinguishes different molecular sources of SHG, providing collagen type specificity. Here, we demonstrated the ability of SHG to differentiate collagen type I and type III quantitatively and used this method to examine fibrous capsules of implanted polystyrene particles. Data presented in this work shows a wide range of collagen fiber orientations and collagen compositions in response to surface functionalized polystyrene particles. Dimethylamino functionalized particles were able to form a thin collagenous matrix resembling healthy skin. These findings have the potential to improve the fundamental understanding of how material properties influence collagen organization and composition quantitatively. PMID:26125551

  12. Quantitative characterization of collagen in the fibrotic capsule surrounding implanted polymeric microparticles through second harmonic generation imaging

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Akilbekova, Dana; Bratlie, Kaitlin M.; Abraham, Thomas

    The collagenous capsule formed around an implant will ultimately determine the nature of its in vivo fate. To provide a better understanding of how surface modifications can alter the collagen orientation and composition in the fibrotic capsule, we used second harmonic generation (SHG) microscopy to evaluate collagen organization and structure generated in mice subcutaneously injected with chemically functionalized polystyrene particles. SHG is sensitive to the orientation of a molecule, making it a powerful tool for measuring the alignment of collagen fibers. Additionally, SHG arises from the second order susceptibility of the interrogated molecule in response to the electric field. Variationmore » in these tensor components distinguishes different molecular sources of SHG, providing collagen type specificity. Here, we demonstrated the ability of SHG to differentiate collagen type I and type III quantitatively and used this method to examine fibrous capsules of implanted polystyrene particles. Data presented in this work shows a wide range of collagen fiber orientations and collagen compositions in response to surface functionalized polystyrene particles. Dimethylamino functionalized particles were able to form a thin collagenous matrix resembling healthy skin. These findings have the potential to improve the fundamental understanding of how material properties influence collagen organization and composition quantitatively.« less

  13. Response Surface Modeling Using Multivariate Orthogonal Functions

    NASA Technical Reports Server (NTRS)

    Morelli, Eugene A.; DeLoach, Richard

    2001-01-01

    A nonlinear modeling technique was used to characterize response surfaces for non-dimensional longitudinal aerodynamic force and moment coefficients, based on wind tunnel data from a commercial jet transport model. Data were collected using two experimental procedures - one based on modem design of experiments (MDOE), and one using a classical one factor at a time (OFAT) approach. The nonlinear modeling technique used multivariate orthogonal functions generated from the independent variable data as modeling functions in a least squares context to characterize the response surfaces. Model terms were selected automatically using a prediction error metric. Prediction error bounds computed from the modeling data alone were found to be- a good measure of actual prediction error for prediction points within the inference space. Root-mean-square model fit error and prediction error were less than 4 percent of the mean response value in all cases. Efficacy and prediction performance of the response surface models identified from both MDOE and OFAT experiments were investigated.

  14. Timescales of Land Surface Evapotranspiration Response

    NASA Technical Reports Server (NTRS)

    Scott, Russell; Entekhabi, Dara; Koster, Randal; Suarez, Max

    1997-01-01

    Soil and vegetation exert strong control over the evapotranspiration rate, which couples the land surface water and energy balances. A method is presented to quantify the timescale of this surface control using daily general circulation model (GCM) simulation values of evapotranspiration and precipitation. By equating the time history of evaporation efficiency (ratio of actual to potential evapotranspiration) to the convolution of precipitation and a unit kernel (temporal weighting function), response functions are generated that can be used to characterize the timescales of evapotranspiration response for the land surface model (LSM) component of GCMS. The technique is applied to the output of two multiyear simulations of a GCM, one using a Surface-Vegetation-Atmosphere-Transfer (SVAT) scheme and the other a Bucket LSM. The derived response functions show that the Bucket LSM's response is significantly slower than that of the SVAT across the globe. The analysis also shows how the timescales of interception reservoir evaporation, bare soil evaporation, and vegetation transpiration differ within the SVAT LSM.

  15. Interactive algebraic grid-generation technique

    NASA Technical Reports Server (NTRS)

    Smith, R. E.; Wiese, M. R.

    1986-01-01

    An algebraic grid generation technique and use of an associated interactive computer program are described. The technique, called the two boundary technique, is based on Hermite cubic interpolation between two fixed, nonintersecting boundaries. The boundaries are referred to as the bottom and top, and they are defined by two ordered sets of points. Left and right side boundaries which intersect the bottom and top boundaries may also be specified by two ordered sets of points. when side boundaries are specified, linear blending functions are used to conform interior interpolation to the side boundaries. Spacing between physical grid coordinates is determined as a function of boundary data and uniformly space computational coordinates. Control functions relating computational coordinates to parametric intermediate variables that affect the distance between grid points are embedded in the interpolation formulas. A versatile control function technique with smooth-cubic-spline functions is presented. The technique works best in an interactive graphics environment where computational displays and user responses are quickly exchanged. An interactive computer program based on the technique and called TBGG (two boundary grid generation) is also described.

  16. Pulmonary stromal cells induce the generation of regulatory DC attenuating T-cell-mediated lung inflammation.

    PubMed

    Li, Qian; Guo, Zhenhong; Xu, Xiongfei; Xia, Sheng; Cao, Xuetao

    2008-10-01

    The tissue microenvironment may affect the development and function of immune cells such as DC. Whether and how the pulmonary stromal microenvironment can affect the development and function of lung DC need to be investigated. Regulatory DC (DCreg) can regulate T-cell response. We wondered whether such regulatory DC exist in the lung and what is the effect of the pulmonary stromal microenvironment on the generation of DCreg. Here we demonstrate that murine pulmonary stromal cells can drive immature DC, which are regarded as being widely distributed in the lung, to proliferate and differentiate into a distinct subset of DCreg, which express high levels of CD11b but low levels of MHC class II (I-A), CD11c, secrete high amounts of IL-10, NO and prostaglandin E2 (PGE2) and suppress T-cell proliferation. The natural counterpart of DCreg in the lung with similar phenotype and regulatory function has been identified. Pulmonary stroma-derived TGF-beta is responsible for the differentiation of immature DC to DCreg, and DCreg-derived PGE2 contributes to their suppression of T-cell proliferation. Moreover, DCreg can induce the generation of CD4+CD25+Foxp3+ Treg. Importantly, infusion with DCreg attenuates T-cell-mediated eosinophilic airway inflammation in vivo. Therefore, the pulmonary microenvironment may drive the generation of DCreg, thus contributing to the maintenance of immune homoeostasis and the control of inflammation in the lung.

  17. The auditory neural network in man

    NASA Technical Reports Server (NTRS)

    Galambos, R.

    1975-01-01

    The principles of anatomy and physiology necessary for understanding brain wave recordings made from the scalp of normal people are briefly discussed. Brain waves evoked by sounds are described and certain of their features are related to the physical aspects of the stimulus and to the psychological state of the listener. The position is taken that data obtained through scalp probes can reveal a large amount of detail about brain functioning and that analysis of such records enable detection of the response of the nervous system to an acoustic message at the moment of its inception and to the progress of the message through the brain. Brain events responsible for distinguishing between similar signals and making decisions about them appear to generate characteristic and identifiable electrical waves. Some theoretical speculation about these data are introduced with the aim of generating a more heuristic model of the functioning brain.

  18. Galectin-9-CD44 interaction enhances stability and function of adaptive regulatory T cells | Center for Cancer Research

    Cancer.gov

    The β-galactoside-binding protein galectin-9 is critical in regulating the immune response, but the mechanism by which it functions remains unclear. We have demonstrated that galectin-9 is highly expressed by induced regulatory T cells (iTreg) and was crucial for the generation and function of iTreg cells, but not natural regulatory T (nTreg) cells. Galectin-9 expression

  19. Graft function assessment in mouse models of single- and dual- kidney transplantation.

    PubMed

    Wang, Lei; Wang, Ximing; Jiang, Shan; Wei, Jin; Buggs, Jacentha; Fu, Liying; Zhang, Jie; Liu, Ruisheng

    2018-05-23

    Animal models of kidney transplantation (KTX) are widely used in studying immune response of hosts to implanted grafts. Additionally, KTX can be used in generating kidney-specific knockout animal models by transplantation of kidneys from donors with global knockout of a gene to wild type recipients or vise verse. Dual kidney transplantation (DKT) provides a more physiological environment for recipients than single kidney transplantation (SKT). However, DKT in mice is rare due to technical challenges. In this study, we successfully performed DKT in mice and compared the hemodynamic response and graft function with SKT. The surgical time, complications and survival rate of DKT were not significantly different from SKT, where survival rates were above 85%. Mice with DKT showed less injury and quicker recovery with lower plasma creatinine (Pcr) and higher GFR than SKT mice (Pcr = 0.34 and 0.17 mg/dl in DKT vs. 0.50 and 0.36 mg/dl in SKT at 1 and 3 days, respectively; GFR = 215 and 131 µl/min for DKT and SKT, respectively). In addition, the DKT exhibited better renal functional reserve and long-term outcome of renal graft function than SKT based on the response to acute volume expansion. In conclusion, we have successfully generated a mouse DKT model. The hemodynamic responses of DKT better mimic physiological situations with less kidney injury and better recovery than SKT because of reduced confounding factors such as single nephron hyperfiltration. We anticipate DKT in mice will provide an additional tool for evaluation of renal significance in physiology and disease.

  20. Calculation of Coupled Vibroacoustics Response Estimates from a Library of Available Uncoupled Transfer Function Sets

    NASA Technical Reports Server (NTRS)

    Smith, Andrew; LaVerde, Bruce; Hunt, Ron; Fulcher, Clay; Towner, Robert; McDonald, Emmett

    2012-01-01

    The design and theoretical basis of a new database tool that quickly generates vibroacoustic response estimates using a library of transfer functions (TFs) is discussed. During the early stages of a launch vehicle development program, these response estimates can be used to provide vibration environment specification to hardware vendors. The tool accesses TFs from a database, combines the TFs, and multiplies these by input excitations to estimate vibration responses. The database is populated with two sets of uncoupled TFs; the first set representing vibration response of a bare panel, designated as H(sup s), and the second set representing the response of the free-free component equipment by itself, designated as H(sup c). For a particular configuration undergoing analysis, the appropriate H(sup s) and H(sup c) are selected and coupled to generate an integrated TF, designated as H(sup s +c). This integrated TF is then used with the appropriate input excitations to estimate vibration responses. This simple yet powerful tool enables a user to estimate vibration responses without directly using finite element models, so long as suitable H(sup s) and H(sup c) sets are defined in the database libraries. The paper discusses the preparation of the database tool and provides the assumptions and methodologies necessary to combine H(sup s) and H(sup c) sets into an integrated H(sup s + c). An experimental validation of the approach is also presented.

  1. Framing anomaly in the effective theory of the fractional quantum Hall effect.

    PubMed

    Gromov, Andrey; Cho, Gil Young; You, Yizhi; Abanov, Alexander G; Fradkin, Eduardo

    2015-01-09

    We consider the geometric part of the effective action for the fractional quantum Hall effect (FQHE). It is shown that accounting for the framing anomaly of the quantum Chern-Simons theory is essential to obtain the correct gravitational linear response functions. In the lowest order in gradients, the linear response generating functional includes Chern-Simons, Wen-Zee, and gravitational Chern-Simons terms. The latter term has a contribution from the framing anomaly which fixes the value of thermal Hall conductivity and contributes to the Hall viscosity of the FQH states on a sphere. We also discuss the effects of the framing anomaly on linear responses for non-Abelian FQH states.

  2. Cytokines and the Inception of CD8 T Cell Responses

    PubMed Central

    Cox, Maureen A.; Harrington, Laurie E.; Zajac, Allan J.

    2011-01-01

    The activation and differentiation of CD8 T cells is a necessary first step that endows these cells with the phenotypic and functional properties required for the control of intracellular pathogens. The induction of the CD8 T cell responses typically results in the development of a massive overall population of effector cells, comprised of both highly functional but short-lived terminally differentiated cells, as well as a smaller subset of precursors that are predisposed to survive and transition into the memory T cell pool. In this article we discuss how inflammatory cytokines and IL-2 bias the initial response towards short-lived effector generation and also highlight the potential counterbalancing role of IL-21. PMID:21371940

  3. Genetic separation of phototropism from blue light inhibition of hypocotyl elongation on Arabidopsis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Liscum, E.; Young, J.C.; Hangarter, R.P.

    1991-05-01

    Phototropism and inhibition of stem elongation occur in response to blue light-induced inhibition of cell elongation. However, phototropism is a low fluence response and inhibition of hypocotyl elongation is a high irradiance response. The authors have isolated several mutant lines of Arabidopsis which lack blue light-induced inhibition of hypocotyl elongation but retain normal phototropic functions. In addition, a mutant line which completely lacks the phototropic response retains normal blue light-induced inhibition of hypocotyl elongation. F1 progeny of crosses between these two mutant classes exhibited wild-type phototropism and inhibition of hypocotyl elongation in response to blue light stimuli. In the F2more » generation, one in sixteen seedlings were double mutants lacking both phototropism and blue light-induced hypocotyl growth inhibition. These studies conclusively show that blue light-induced phototropism and hypocotyl growth inhibition function through genetically distinct signal transduction or response systems.« less

  4. Prediction of spectral acceleration response ordinates based on PGA attenuation

    USGS Publications Warehouse

    Graizer, V.; Kalkan, E.

    2009-01-01

    Developed herein is a new peak ground acceleration (PGA)-based predictive model for 5% damped pseudospectral acceleration (SA) ordinates of free-field horizontal component of ground motion from shallow-crustal earthquakes. The predictive model of ground motion spectral shape (i.e., normalized spectrum) is generated as a continuous function of few parameters. The proposed model eliminates the classical exhausted matrix of estimator coefficients, and provides significant ease in its implementation. It is structured on the Next Generation Attenuation (NGA) database with a number of additions from recent Californian events including 2003 San Simeon and 2004 Parkfield earthquakes. A unique feature of the model is its new functional form explicitly integrating PGA as a scaling factor. The spectral shape model is parameterized within an approximation function using moment magnitude, closest distance to the fault (fault distance) and VS30 (average shear-wave velocity in the upper 30 m) as independent variables. Mean values of its estimator coefficients were computed by fitting an approximation function to spectral shape of each record using robust nonlinear optimization. Proposed spectral shape model is independent of the PGA attenuation, allowing utilization of various PGA attenuation relations to estimate the response spectrum of earthquake recordings.

  5. Programming function into mechanical forms by directed assembly of silk bulk materials

    PubMed Central

    Patel, Nereus; Duggan, Thomas; Perotto, Giovanni; Shirman, Elijah; Li, Chunmei; Kaplan, David L.; Omenetto, Fiorenzo G.

    2017-01-01

    We report simple, water-based fabrication methods based on protein self-assembly to generate 3D silk fibroin bulk materials that can be easily hybridized with water-soluble molecules to obtain multiple solid formats with predesigned functions. Controlling self-assembly leads to robust, machinable formats that exhibit thermoplastic behavior consenting material reshaping at the nanoscale, microscale, and macroscale. We illustrate the versatility of the approach by realizing demonstrator devices where large silk monoliths can be generated, polished, and reshaped into functional mechanical components that can be nanopatterned, embed optical function, heated on demand in response to infrared light, or can visualize mechanical failure through colorimetric chemistries embedded in the assembled (bulk) protein matrix. Finally, we show an enzyme-loaded solid mechanical part, illustrating the ability to incorporate biological function within the bulk material with possible utility for sustained release in robust, programmably shapeable mechanical formats. PMID:28028213

  6. Production of functional proteins: balance of shear stress and gravity

    NASA Technical Reports Server (NTRS)

    Kaysen, James Howard (Inventor); Hammond, Timothy Grant (Inventor); Goodwin, Thomas John (Inventor)

    2004-01-01

    The present invention provides a method for production of functional proteins including hormones by renal cells in a three dimensional co-culture process responsive to shear stress using a rotating wall vessel. Natural mixture of renal cells expresses the enzyme 1-a-hydroxylase which can be used to generate the active form of vitamin D: 1,25-diOH vitamin D3. The fibroblast cultures and co-culture of renal cortical cells express the gene for erythropoietin and secrete erythropoietin into the culture supernatant. Other shear stress response genes are also modulated by shear stress, such as toxin receptors megalin and cubulin (gp280). Also provided is a method of treating in-need individual with the functional proteins produced in a three dimensional co-culture process responsive to shear stress using a rotating wall vessel.

  7. Pseudomonas aeruginosa Airway Infection Recruits and Modulates Neutrophilic Myeloid-Derived Suppressor Cells

    PubMed Central

    Öz, Hasan H.; Zhou, Benyuan; Voss, Pina; Carevic, Melanie; Schroth, Carolin; Frey, Nina; Rieber, Nikolaus; Hector, Andreas; Hartl, Dominik

    2016-01-01

    Pseudomonas aeruginosa is an opportunistic pathogen that causes infections mainly in patients with cystic fibrosis (CF) lung disease. Despite innate and adaptive immune responses upon infection, P. aeruginosa is capable of efficiently escaping host defenses, but the underlying immune mechanisms remain poorly understood. Myeloid-derived suppressor cells (MDSCs) are innate immune cells that are functionally characterized by their potential to suppress T- and natural killer (NK)-cell responses. Here we demonstrate, using an airway in vivo infection model, that P. aeruginosa recruits and activates neutrophilic MDSCs, which functionally suppress T-cell responses. We further show that the CF gene defect (CF transmembrane conductance regulator, CFTR) modulates the functionality, but not the recruitment or generation of neutrophilic MDSCs. Collectively, we define a mechanism by which P. aeruginosa airway infection undermines host immunity by modulating neutrophilic MDSCs in vivo. PMID:27965936

  8. Production of functional proteins: balance of shear stress and gravity

    NASA Technical Reports Server (NTRS)

    Hammond, Timothy Grant (Inventor); Kaysen, James Howard (Inventor); Goodwin, Thomas John (Inventor)

    2007-01-01

    The present invention provides a method for production of functional proteins including hormones by renal cells in a three dimensional co-culture process responsive to shear stress using a rotating wall vessel. Natural mixture of renal cells expresses the enzyme 1-a-hydroxylase which can be used to generate the active form of vitamin D: 1,25-diOH vitamin D3. The fibroblast cultures and co-culture of renal cortical cells express the gene for erythropoietin and secrete erythropoietin into the culture supernatant. Other shear stress response genes are also modulated by shear stress, such as toxin receptors megalin and cubulin (gp280). Also provided is a method of treating in-need individual with the functional proteins produced in a three dimensional co-culture process responsive to shear stress using a rotating wall vessel.

  9. Shaping the CD4+ memory immune response against tuberculosis: the role of antigen persistence, location and multi-functionality.

    PubMed

    Ancelet, Lindsay; Kirman, Joanna

    2012-02-01

    Abstract Effective vaccination against intracellular pathogens, such as tuberculosis (TB), relies on the generation and maintenance of CD4 memory T cells. An incomplete understanding of the memory immune response has hindered the rational design of a new, more effective TB vaccine. This review discusses how the persistence of antigen, the location of memory cells, and their multifunctional ability shape the CD4 memory T cell response against TB.

  10. Induction of myeloma-specific cytotoxic T lymphocytes responses by natural killer cells stimulated-dendritic cells in patients with multiple myeloma.

    PubMed

    Nguyen-Pham, Thanh-Nhan; Im, Chang-Min; Nguyen, Truc-Anh Thi; Lim, Mi-Seon; Hong, Cheol Yi; Kim, Mi-Hyun; Lee, Hyun Ju; Lee, Youn-Kyung; Cho, Duck; Ahn, Jae-Sook; Yang, Deok-Hwan; Kim, Yeo-Kyeoung; Chung, Ik-Joo; Kim, Hyeoung-Joon; Lee, Je-Jung

    2011-09-01

    The interaction between dendritic cells (DCs) and natural killer (NK) cells plays a key role in inducing DC maturation for subsequent T-cell priming. We investigated to generate potent DCs by stimulated with NK cells to induce myeloma-specific cytotoxic T lymphocytes (CTLs). NK cells-stimulated-DCs exhibited high expression of costimulatory molecules and high production of IL-12p70. These DCs induce high potency of Th1 polarization and exhibit a high ability to generate myeloma-specific CTLs responses. These results suggest that functionally potent DCs can be generated by stimulation with NK cells and may provide an effective source of DC-based immunotherapy in multiple myeloma. Copyright © 2011 Elsevier Ltd. All rights reserved.

  11. Identification of visual evoked response parameters sensitive to pilot mental state

    NASA Technical Reports Server (NTRS)

    Zacharias, G. L.

    1988-01-01

    Systems analysis techniques were developed and demonstrated for modeling the electroencephalographic (EEG) steady state visual evoked response (ssVER), for use in EEG data compression and as an indicator of mental workload. The study focused on steady state frequency domain stimulation and response analysis, implemented with a sum-of-sines (SOS) stimulus generator and an off-line describing function response analyzer. Three major tasks were conducted: (1) VER related systems identification material was reviewed; (2) Software for experiment control and data analysis was developed and implemented; and (3) ssVER identification and modeling was demonstrated, via a mental loading experiment. It was found that a systems approach to ssVER functional modeling can serve as the basis for eventual development of a mental workload indicator. The review showed how transient visual evoked response (tVER) and ssVER research are related at the functional level, the software development showed how systems techniques can be used for ssVER characterization, and the pilot experiment showed how a simple model can be used to capture the basic dynamic response of the ssVER, under varying loads.

  12. Transcriptional and functional defects of dendritic cells derived from the MUTZ-3 leukaemia line

    PubMed Central

    Rasaiyaah, Jane; Noursadeghi, Mahdad; Kellam, Paul; Chain, Benjamin

    2009-01-01

    Dendritic cells (DC) generated from MUTZ-3, an immortalized acute myeloid leukaemia-derived cell line, have potential application as a model for the study of human DC, and as a tool with which to stimulate immunotherapeutic responses to cancer. However, the relationship of MUTZ-3 DC to their non-transformed counterparts remains incompletely understood. Immunoselected CD14+ MUTZ-3 cells were used to generate a homogeneous population of DC (M3DC). These cells had a cell surface phentoype and morphology characteristic of conventional monocyte-derived DC (MDDC). Whole genome transcriptome comparison of M3DC and MDDC however, revealed extensive differences between these two cell types. Functional ontology-based data analysis revealed three enriched clusters of genes downregulated in M3DC, with functions in pathogen recognition, DC maturation and cytokine/chemokine signalling. Downregulation of protein expression was confirmed for several of these genes. The molecular differences were accompanied by a profoundly impaired phenotypic and functional response of M3DC to microbial stimulation. The immortalized phenotype of MUTZ-3 therefore reflects not only deregulated proliferative capacity, but substantial perturbation of normal antigen-presenting cell function. These results have important implications for studies using MUTZ-3 as a model of MDDC or for cancer immunotherapy. PMID:19538250

  13. The function of small RNAs in plant biotic stress response.

    PubMed

    Huang, Juan; Yang, Meiling; Zhang, Xiaoming

    2016-04-01

    Small RNAs (sRNAs) play essential roles in plants upon biotic stress. Plants utilize RNA silencing machinery to facilitate pathogen-associated molecular pattern-triggered immunity and effector-triggered immunity to defend against pathogen attack or to facilitate defense against insect herbivores. Pathogens, on the other hand, are also able to generate effectors and sRNAs to counter the host immune response. The arms race between plants and pathogens/insect herbivores has triggered the evolution of sRNAs, RNA silencing machinery and pathogen effectors. A great number of studies have been performed to investigate the roles of sRNAs in plant defense, bringing in the opportunity to utilize sRNAs in plant protection. Transgenic plants with pathogen-derived resistance ability or transgenerational defense have been generated, which show promising potential as solutions for pathogen/insect herbivore problems in the field. Here we summarize the recent progress on the function of sRNAs in response to biotic stress, mainly in plant-pathogen/insect herbivore interaction, and the application of sRNAs in disease and insect herbivore control. © 2016 Institute of Botany, Chinese Academy of Sciences.

  14. Inhibition of polymorphonuclear leukocyte function by Legionella pneumophila exoproducts.

    PubMed

    Sahney, N N; Lambe, B C; Summersgill, J T; Miller, R D

    1990-08-01

    Total exoproducts (relative molecular mass greater than 10,000) from wild-type strains of Legionella pneumophila markedly inhibited human polymorphonuclear leukocyte (PMN) superoxide anion generation, at sub-lethal concentrations, in response to four stimuli [1.7, 0, 0.6 and 3.4% of control for zymosan activated particles (ZAP), phorbol myristate acetate (PMA), calcium ionophore (A 23187), and formyl-methionyl-leucyl-phenylalanine (fMLP), respectively]. PMN chemotaxis towards fMLP and spontaneous migration, were also dramatically inhibited (2.8 and 2.9% of buffer-treated controls, respectively). In contrast, total exoproducts from the cas-1 strain of L. pneumophila, a protease-deficient mutant generated by ethyl methane sulfonate mutagenesis, failed to inhibit PMN superoxide production in response to ZAP and PMA and only partially inhibited PMN response to A 23187 and fMLP. PMN spontaneous migration was unaffected by treatment with total exoproducts from the mutant, while directed chemotaxis was partially inhibited (51.4%). These data demonstrated that L. pneumophila total exoproducts, primarily protease had significant inhibitory effects on normal PMN function and may play an important contributory role in the pathogenesis of legionnaire's disease.

  15. A machine learning methodology for the selection and classification of spontaneous spinal cord dorsum potentials allows disclosure of structured (non-random) changes in neuronal connectivity induced by nociceptive stimulation

    PubMed Central

    Martin, Mario; Contreras-Hernández, Enrique; Béjar, Javier; Esposito, Gennaro; Chávez, Diógenes; Glusman, Silvio; Cortés, Ulises; Rudomin, Pablo

    2015-01-01

    Previous studies aimed to disclose the functional organization of the neuronal networks involved in the generation of the spontaneous cord dorsum potentials (CDPs) generated in the lumbosacral spinal segments used predetermined templates to select specific classes of spontaneous CDPs. Since this procedure was time consuming and required continuous supervision, it was limited to the analysis of two specific types of CDPs (negative CDPs and negative positive CDPs), thus excluding potentials that may reflect activation of other neuronal networks of presumed functional relevance. We now present a novel procedure based in machine learning that allows the efficient and unbiased selection of a variety of spontaneous CDPs with different shapes and amplitudes. The reliability and performance of the present method is evaluated by analyzing the effects on the probabilities of generation of different classes of spontaneous CDPs induced by the intradermic injection of small amounts of capsaicin in the anesthetized cat, a procedure known to induce a state of central sensitization leading to allodynia and hyperalgesia. The results obtained with the selection method presently described allowed detection of spontaneous CDPs with specific shapes and amplitudes that are assumed to represent the activation of functionally coupled sets of dorsal horn neurones that acquire different, structured configurations in response to nociceptive stimuli. These changes are considered as responses tending to adequate transmission of sensory information to specific functional requirements as part of homeostatic adjustments. PMID:26379540

  16. Stochastic Matching and the Voluntary Nature of Choice

    PubMed Central

    Neuringer, Allen; Jensen, Greg; Piff, Paul

    2007-01-01

    Attempts to characterize voluntary behavior have been ongoing for thousands of years. We provide experimental evidence that judgments of volition are based upon distributions of responses in relation to obtained rewards. Participants watched as responses, said to be made by “actors,” appeared on a computer screen. The participant's task was to estimate how well each actor represented the voluntary choices emitted by a real person. In actuality, all actors' responses were generated by algorithms based on Baum's (1979) generalized matching function. We systematically varied the exponent values (sensitivity parameter) of these algorithms: some actors matched response proportions to received reinforcer proportions, others overmatched (predominantly chose the highest-valued alternative), and yet others undermatched (chose relatively equally among the alternatives). In each of five experiments, we found that the matching actor's responses were judged most closely to approximate voluntary choice. We found also that judgments of high volition depended upon stochastic (or probabilistic) generation. Thus, stochastic responses that match reinforcer proportions best represent voluntary human choice. PMID:17725049

  17. Initial Results from the Variable Intensity Sonic Boom Database

    NASA Technical Reports Server (NTRS)

    Haering, Edward A., Jr.; Cliatt, Larry J., II; Gabrielson, Thomas; Sparrow, Victor W.; Locey, Lance L.; Bunce, Thomas J.

    2008-01-01

    43 sonic booms generated (a few were evanescent waves) a) Overpressures of 0.08 to 2.20 lbf/sq ft; b) Rise-times of about 0.7 to 50 ms. Objectives: a) Structural response of a house of modern construction; b) Sonic boom propagation code validation. Approach: a) Measure shockwave directionality; b) Determine effect of height above ground on acoustic level; c) Generate atmospheric turbulence filter functions.

  18. "The Future Is Ours Too": A Training Process to Enable the Learning Perception and Increase Self-Efficacy in the Use of Tablets in the Elderly

    ERIC Educational Resources Information Center

    Gatti, Fabiana M.; Brivio, Eleonora; Galimberti, Carlo

    2017-01-01

    The generational digital divide can be understood as a response to the physical and psychosocial decline of older people. Recently, there has been interest in reducing the generational digital divide because of societal costs, and several studies state that tablets seem to help the elderly due to usability and functions that easily fulfill the…

  19. Differential cardiac effects in rats exposed to atmospheric ...

    EPA Pesticide Factsheets

    The results of this study demonstrate that atmospheric smog generated from both isoprene and toluene cause cardiac effects in rats. In addition, it appears that smog from toluene is more toxic in terms of cardiac arrhythmogenicity. Smog, which is a complex mixture of particulate matter and gaseous irritants (ozone, sulfur dioxide, reactive aldehydes), as well as components which react with sunlight to form secondary pollutants, has recently been linked to increased risk of adverse cardiac responses. The components, and therefore health effects, of atmospheric smog are determined by the fuel used to generate them. In this study we examined the difference between isoprene- and toluene-generated smog in causing cardiac effects in rats and hypothesized that both atmospheres would cause cardiac electrical and functional changes in rats. Male Wistar-Kyoto rats were exposed to either atmospheric smog generated by the USEPA’s mobile reaction chamber using either isoprene or toluene, or filtered air for four hours. One day later, rats were anesthetized and left ventricular functional responses to dobutamine were measured using a Millar probe and arrhythmia sensitivity to aconitine. Baseline left ventricular pressure (LVP) was lower in toluene-exposed animals but not isoprene when compared to air. Increases in LVP with increasing doses of dobutamine were impaired only in toluene-exposed rats. Both isoprene and toluene impaired the rate of ventri

  20. Creating Fidelitious Climate Data Records from Meteosat First Generation Observations

    NASA Astrophysics Data System (ADS)

    Quast, Ralf; Govaerts, Yves; Ruthrich, Frank; Giering, Ralf; Roebeling, Rob

    2016-08-01

    A novel method for reconstructing the spectral response function of the Meteosat visible (VIS) channels is presented and applied to the Meteosat-10 Spinning Enhanced Visible and Infrared Imager (SEVIRI) high-resolution visible (HRV) channel as the first real-world benchmark. The method incorporates advanced radiative transfer modelling and inverse modelling techniques. Once established, EUMETSAT will use the reconstructed spectral response and uncertainty information to increase the calibration accuracy of Meteosat First Generation VIS observations, which will provide the basis for the Fidelity and Uncertainty in Climate data records from Earth Observations (FIDUCEO) Horizon 2020 project to produce new fundamental (reflectance) and thematic (albedo and aerosol) climate data records.

  1. Nanoscale stiffness of individual dendritic molecules and their aggregates

    NASA Astrophysics Data System (ADS)

    Tsukruk, Vladimir V.; Shulha, Hennady; Zhai, Xiaowen

    2003-02-01

    We demonstrate that carefully designed micromapping of the surface stiffness with nanoscale resolution could reveal quantitative data on the elastic properties of compliant, dendritic organic molecules with nanoparticulate dimensions below 3 nm. Much higher elastic modulus was observed for individual, fourth generation dendritic molecules due to their more shape persistent conformation. Large, reversible, elastic deformation is a distinct characteristic of the nanomechanical response observed for individual dendritic molecules. Such a "rubbery" response could be an indication of spatial constraints imposed on vitrification of dendritic molecules tethered to the functionalized interface. Surprisingly, an increased stiffness was also found for the third generation dendritic molecules within long aggregates.

  2. Generation of Human Nasal Epithelial Cell Spheroids for Individualized Cystic Fibrosis Transmembrane Conductance Regulator Study.

    PubMed

    Brewington, John J; Filbrandt, Erin T; LaRosa, Francis J; Moncivaiz, Jessica D; Ostmann, Alicia J; Strecker, Lauren M; Clancy, John P

    2018-04-11

    While the introduction of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator drugs has revolutionized care in Cystic Fibrosis (CF), the genotype-directed therapy model currently in use has several limitations. First, rare or understudied mutation groups are excluded from definitive clinical trials. Moreover, as additional modulator drugs enter the market, it will become difficult to optimize the modulator choices for an individual subject. Both of these issues are addressed with the use of patient-derived, individualized preclinical model systems of CFTR function and modulation. Human nasal epithelial cells (HNEs) are an easily accessible source of respiratory tissue for such a model. Herein, we describe the generation of a three-dimensional spheroid model of CFTR function and modulation using primary HNEs. HNEs are isolated from subjects in a minimally invasive fashion, expanded in conditional reprogramming conditions, and seeded into the spheroid culture. Within 2 weeks of seeding, spheroid cultures generate HNE spheroids that can be stimulated with 3',5'-cyclic adenosine monophosphate (cAMP)-generating agonists to activate CFTR function. Spheroid swelling is then quantified as a proxy of CFTR activity. HNE spheroids capitalize on the minimally invasive, yet respiratory origin of nasal cells to generate an accessible, personalized model relevant to an epithelium reflecting disease morbidity and mortality. Compared to the air-liquid interface HNE cultures, spheroids are relatively quick to mature, which reduces the overall contamination rate. In its current form, the model is limited by low throughput, though this is offset by the relative ease of tissue acquisition. HNE spheroids can be used to reliably quantify and characterize CFTR activity at the individual level. An ongoing study to tie this quantification to in vivo drug response will determine if HNE spheroids are a true preclinical predictor of patient response to CFTR modulation.

  3. Role of inhibition in the specification of orientation selectivity of cells in the cat striate cortex.

    PubMed

    Bonds, A B

    1989-01-01

    Mechanisms supporting orientation selectivity of cat striate cortical cells were studied by stimulation with two superimposed sine-wave gratings of different orientations. One grating (base) generated a discharge of known amplitude which could be modified by the second grating (mask). Masks presented at nonoptimal orientations usually reduced the base-generated response, but the degree of reduction varied widely between cells. Cells with narrow orientation tuning tended to be more susceptible to mask presence than broadly tuned cells; similarly, simple cells generally showed more response reduction than did complex cells. The base and mask stimuli were drifted at different temporal frequencies which, in simple cells, permitted the identification of individual response components from each stimulus. This revealed that the reduction of the base response by the mask usually did not vary regularly with mask orientation, although response facilitation from the mask was orientation selective. In some sharply tuned simple cells, response reduction had clear local maxima near the limits of the cell's orientation-tuning function. Response reduction resulted from a nearly pure rightward shift of the response versus log contrast function. The lowest mask contrast yielding reduction was within 0.1-0.3 log unit of the lowest contrast effective for excitation. The temporal-frequency bandpass of the response-reduction mechanism resembled that of most cortical cells. The spatial-frequency bandpass was much broader than is typical for single cortical cells, spanning essentially the entire visual range of the cat. These findings are compatible with a model in which weak intrinsic orientation-selective excitation is enhanced in two stages: (1) control of threshold by nonorientation-selective inhibition that is continuously dependent on stimulus contrast; and (2) in the more narrowly tuned cells, orientation-selective inhibition that has local maxima serving to increase the slope of the orientation-tuning function.

  4. GET electronics samples data analysis

    NASA Astrophysics Data System (ADS)

    Giovinazzo, J.; Goigoux, T.; Anvar, S.; Baron, P.; Blank, B.; Delagnes, E.; Grinyer, G. F.; Pancin, J.; Pedroza, J. L.; Pibernat, J.; Pollacco, E.; Rebii, A.; Roger, T.; Sizun, P.

    2016-12-01

    The General Electronics for TPCs (GET) has been developed to equip a generation of time projection chamber detectors for nuclear physics, and may also be used for a wider range of detector types. The goal of this paper is to propose first analysis procedures to be applied on raw data samples from the GET system, in order to correct for systematic effects observed on test measurements. We also present a method to estimate the response function of the GET system channels. The response function is required in analysis where the input signal needs to be reconstructed, in terms of time distribution, from the registered output samples.

  5. Inference Engine in an Intelligent Ship Course-Keeping System

    PubMed Central

    2017-01-01

    The article presents an original design of an expert system, whose function is to automatically stabilize ship's course. The focus is put on the inference engine, a mechanism that consists of two functional components. One is responsible for the construction of state space regions, implemented on the basis of properly processed signals recorded by sensors from the input and output of an object. The other component is responsible for generating a control decision based on the knowledge obtained in the first module. The computing experiments described herein prove the effective and correct operation of the proposed system. PMID:29317859

  6. Rule-Guided Executive Control of Response Inhibition: Functional Topography of the Inferior Frontal Cortex

    PubMed Central

    Cai, Weidong; Leung, Hoi-Chung

    2011-01-01

    Background The human inferior frontal cortex (IFC) is a large heterogeneous structure with distinct cytoarchitectonic subdivisions and fiber connections. It has been found involved in a wide range of executive control processes from target detection, rule retrieval to response control. Since these processes are often being studied separately, the functional organization of executive control processes within the IFC remains unclear. Methodology/Principal Findings We conducted an fMRI study to examine the activities of the subdivisions of IFC during the presentation of a task cue (rule retrieval) and during the performance of a stop-signal task (requiring response generation and inhibition) in comparison to a not-stop task (requiring response generation but not inhibition). We utilized a mixed event-related and block design to separate brain activity in correspondence to transient control processes from rule-related and sustained control processes. We found differentiation in control processes within the IFC. Our findings reveal that the bilateral ventral-posterior IFC/anterior insula are more active on both successful and unsuccessful stop trials relative to not-stop trials, suggesting their potential role in the early stage of stopping such as triggering the stop process. Direct countermanding seems to be outside of the IFC. In contrast, the dorsal-posterior IFC/inferior frontal junction (IFJ) showed transient activity in correspondence to the infrequent presentation of the stop signal in both tasks and the left anterior IFC showed differential activity in response to the task cues. The IFC subdivisions also exhibited similar but distinct patterns of functional connectivity during response control. Conclusions/Significance Our findings suggest that executive control processes are distributed across the IFC and that the different subdivisions of IFC may support different control operations through parallel cortico-cortical and cortico-striatal circuits. PMID:21673969

  7. Optical pulse response of a fibre ring resonator

    NASA Astrophysics Data System (ADS)

    Pandian, G. S.; Seraji, Faramarz E.

    1991-06-01

    This article presents the optical pulse response analysis of a fiber ring resonator. It is shown that several interesting functions, namely optical pulse generation, and equalization of fiber dispersion can be realized by using the resonator. The theory is presented in an easy to understand manner, by first considering the steady-state response. The results of the transient pulse response are explained in relation to the steady state results. The results related to optical pulse shaping will be of interest to the future when coherent optical pulse and switching circuits will become available.

  8. A model-free method for mass spectrometer response correction. [for oxygen consumption and cardiac output calculation

    NASA Technical Reports Server (NTRS)

    Shykoff, Barbara E.; Swanson, Harvey T.

    1987-01-01

    A new method for correction of mass spectrometer output signals is described. Response-time distortion is reduced independently of any model of mass spectrometer behavior. The delay of the system is found first from the cross-correlation function of a step change and its response. A two-sided time-domain digital correction filter (deconvolution filter) is generated next from the same step response data using a regression procedure. Other data are corrected using the filter and delay. The mean squared error between a step response and a step is reduced considerably more after the use of a deconvolution filter than after the application of a second-order model correction. O2 consumption and CO2 production values calculated from data corrupted by a simulated dynamic process return to near the uncorrupted values after correction. Although a clean step response or the ensemble average of several responses contaminated with noise is needed for the generation of the filter, random noise of magnitude not above 0.5 percent added to the response to be corrected does not impair the correction severely.

  9. Optical polarization based logic functions (XOR or XNOR) with nonlinear Gallium nitride nanoslab.

    PubMed

    Bovino, F A; Larciprete, M C; Giardina, M; Belardini, A; Centini, M; Sibilia, C; Bertolotti, M; Passaseo, A; Tasco, V

    2009-10-26

    We present a scheme of XOR/XNOR logic gate, based on non phase-matched noncollinear second harmonic generation from a medium of suitable crystalline symmetry, Gallium nitride. The polarization of the noncollinear generated beam is a function of the polarization of both pump beams, thus we experimentally investigated all possible polarization combinations, evidencing that only some of them are allowed and that the nonlinear interaction of optical signals behaves as a polarization based XOR. The experimental results show the peculiarity of the nonlinear optical response associated with noncollinear excitation, and are explained using the expression for the effective second order optical nonlinearity in noncollinear scheme.

  10. Calculation of zero-offset vertical seismic profiles generated by a horizontal point force acting on the surface of an elastic half-space

    USGS Publications Warehouse

    Hsi-Ping, Liu

    1990-01-01

    Impulse responses including near-field terms have been obtained in closed form for the zero-offset vertical seismic profiles generated by a horizontal point force acting on the surface of an elastic half-space. The method is based on the correspondence principle. Through transformation of variables, the Fourier transform of the elastic impulse response is put in a form such that the Fourier transform of the corresponding anelastic impulse response can be expressed as elementary functions and their definite integrals involving distance angular frequency, phase velocities, and attenuation factors. These results are used for accurate calculation of shear-wave arrival rise times of synthetic seismograms needed for data interpretation of anelastic-attenuation measurements in near-surface sediment. -Author

  11. Antigen-specific Treg cells in immunological tolerance: implications for allergic diseases

    PubMed Central

    Abdel-Gadir, Azza; Massoud, Amir H.; Chatila, Talal A.

    2018-01-01

    Allergic diseases are chronic inflammatory disorders in which there is failure to mount effective tolerogenic immune responses to inciting allergens. The alarming rise in the prevalence of allergic diseases in recent decades has spurred investigations to elucidate the mechanisms of breakdown in tolerance in these disorders and means of restoring it. Tolerance to allergens is critically dependent on the generation of allergen-specific regulatory T (Treg) cells, which mediate a state of sustained non-responsiveness to the offending allergen. In this review, we summarize recent advances in our understanding of mechanisms governing the generation and function of allergen-specific Treg cells and their subversion in allergic diseases. We will also outline approaches to harness allergen-specific Treg cell responses to restore tolerance in these disorders. PMID:29375821

  12. Toward ab initio molecular dynamics modeling for sum-frequency generation spectra; an efficient algorithm based on surface-specific velocity-velocity correlation function.

    PubMed

    Ohto, Tatsuhiko; Usui, Kota; Hasegawa, Taisuke; Bonn, Mischa; Nagata, Yuki

    2015-09-28

    Interfacial water structures have been studied intensively by probing the O-H stretch mode of water molecules using sum-frequency generation (SFG) spectroscopy. This surface-specific technique is finding increasingly widespread use, and accordingly, computational approaches to calculate SFG spectra using molecular dynamics (MD) trajectories of interfacial water molecules have been developed and employed to correlate specific spectral signatures with distinct interfacial water structures. Such simulations typically require relatively long (several nanoseconds) MD trajectories to allow reliable calculation of the SFG response functions through the dipole moment-polarizability time correlation function. These long trajectories limit the use of computationally expensive MD techniques such as ab initio MD and centroid MD simulations. Here, we present an efficient algorithm determining the SFG response from the surface-specific velocity-velocity correlation function (ssVVCF). This ssVVCF formalism allows us to calculate SFG spectra using a MD trajectory of only ∼100 ps, resulting in the substantial reduction of the computational costs, by almost an order of magnitude. We demonstrate that the O-H stretch SFG spectra at the water-air interface calculated by using the ssVVCF formalism well reproduce those calculated by using the dipole moment-polarizability time correlation function. Furthermore, we applied this ssVVCF technique for computing the SFG spectra from the ab initio MD trajectories with various density functionals. We report that the SFG responses computed from both ab initio MD simulations and MD simulations with an ab initio based force field model do not show a positive feature in its imaginary component at 3100 cm(-1).

  13. Intramuscular Administration of a Synthetic CpG-Oligodeoxynucleotide Modulates Functional Responses of Neutrophils of Neonatal Foals

    PubMed Central

    Cohen, Noah D.; Bourquin, Jessica R.; Bordin, Angela I.; Kuskie, Kyle R.; Brake, Courtney N.; Weaver, Kaytee B.; Liu, Mei; Felippe, M. Julia B.; Kogut, Michael H.

    2014-01-01

    Neutrophils play an important role in protecting against infection. Foals have age-dependent deficiencies in neutrophil function that may contribute to their predisposition to infection. Thus, we investigated the ability of a CpG-ODN formulated with Emulsigen to modulate functional responses of neutrophils in neonatal foals. Eighteen foals were randomly assigned to receive either a CpG-ODN with Emulsigen (N = 9) or saline intramuscularly at ages 1 and 7 days. At ages 1, 3, 9, 14, and 28, blood was collected and neutrophils were isolated from each foal. Neutrophils were assessed for basal and Rhodococcus equi-stimulated mRNA expression of the cytokines interferon-γ (IFN-γ), interleukin (IL)-4, IL-6, and IL-8 using real-time PCR, degranulation by quantifying the amount of β-D glucuronidase activity, and reactive oxygen species (ROS) generation using flow cytometry. In vivo administration of the CpG-ODN formulation on days 1 and 7 resulted in significantly (P<0.05) increased IFN-γ mRNA expression by foal neutrophils on days 3, 9, and 14. Degranulation was significantly (P<0.05) lower for foals in the CpG-ODN-treated group than the control group at days 3 and 14, but not at other days. No effect of treatment on ROS generation was detected. These results indicate that CpG-ODN administration to foals might improve innate and adaptive immune responses that could protect foals against infectious diseases and possibly improve responses to vaccination. PMID:25333660

  14. Novel Optical Methods for Identification, Imaging, and Preservation of the Cavernous Nerves Responsible for Penile Erections during Prostate Cancer Surgery

    DTIC Science & Technology

    2009-03-01

    wavelength, pulse energy, and pulse rate) to produce strongest and most rapid erectile response as measured by intracavernosal pressure in the penis ...PC Fiber Rod Housing Optics 5-mm-ID Port Probe Handle Probe Stem Enlarged View of Probe Tip Oscilloscope FunctionGenerator Thulium Fiber Laser Shutter...rapid erectile response as measured by intracavernosal pressure (ICP) in the penis . ICP values were increased from an initial range of 30-40 mmHg

  15. Ethylene Response Factor TERF1, Regulated by ETHYLENE-INSENSITIVE3-like Factors, Functions in Reactive Oxygen Species (ROS) Scavenging in Tobacco (Nicotiana tabacum L.).

    PubMed

    Zhang, Hongbo; Li, Ang; Zhang, Zhijin; Huang, Zejun; Lu, Pingli; Zhang, Dingyu; Liu, Xinmin; Zhang, Zhong-Feng; Huang, Rongfeng

    2016-07-20

    The phytohormone ethylene plays a crucial role in the production and accumulation of reactive oxygen species (ROS) in plants under stress conditions. Ethylene response factors (ERFs) are important ethylene-signaling regulators functioning in plant defense responses against biotic and abiotic stresses. However, the roles of ERFs during plant adapting to ROS stress have not yet been well documented. Our studies previously reported that a tomato ERF transcription factor TERF1 functions in the regulation of plant ethylene responses and stress tolerance. Here, we report our findings regarding the roles of TERF1 in ROS scavenging. In this study, we revealed that the transcription of TERF1 is regulated by upstream EIN3-like (EIN3, ethylene-insensitive 3) regulators LeEIL3 and LeEIL4 in tomato (Solanum lycopersicum), and is also inducible by exogenous applied ROS-generating reagents. Ectopic expression of TERF1 in tobacco promoted the expression of genes involved in oxidative stress responses, including carbonic anhydrase functioning in hypersensitive defense, catalase and glutathione peroxidase catalyzing oxidative reactions, and GDP-D-mannose pyrophosphorylase functioning in ascorbic acid biosynthesis, reduced the ROS content induced by ethylene treatment, and enhanced stress tolerance of tobacco seedlings to hydrogen peroxide (H2O2). Cumulatively, these findings suggest that TERF1 is an ethylene inducible factor regulating ROS scavenging during stress responses.

  16. An electrophysiological study of task demands on concreteness effects: evidence for dual coding theory.

    PubMed

    Welcome, Suzanne E; Paivio, Allan; McRae, Ken; Joanisse, Marc F

    2011-07-01

    We examined ERP responses during the generation of word associates or mental images in response to concrete and abstract concepts. Of interest were the predictions of dual coding theory (DCT), which proposes that processing lexical concepts depends on functionally independent but interconnected verbal and nonverbal systems. ERP responses were time-locked to either stimulus onset or response to compensate for potential latency differences across conditions. During word associate generation, but not mental imagery, concrete items elicited a greater N400 than abstract items. A concreteness effect emerged at a later time point during the mental imagery task. Data were also analyzed using time-frequency analysis that investigated synchronization of neuronal populations over time during processing. Concrete words elicited an enhanced late going desynchronization of theta-band power (723-938 ms post stimulus onset) during associate generation. During mental imagery, abstract items elicited greater delta-band power from 800 to 1,000 ms following stimulus onset, theta-band power from 350 to 205 ms before response, and alpha-band power from 900 to 800 ms before response. Overall, the findings support DCT in suggesting that lexical concepts are not amodal and that concreteness effects are modulated by tasks that focus participants on verbal versus nonverbal, imagery-based knowledge.

  17. Rotor-generated unsteady aerodynamic interactions in a 1½ stage compressor

    NASA Astrophysics Data System (ADS)

    Papalia, John J.

    Because High Cycle Fatigue (HCF) remains the predominant surprise failure mode in gas turbine engines, HCF avoidance design systems are utilized to identify possible failures early in the engine development process. A key requirement of these analyses is accurate determination of the aerodynamic forcing function and corresponding airfoil unsteady response. The current study expands the limited experimental database of blade row interactions necessary for calibration of predictive HCF analyses, with transonic axial-flow compressors of particular interest due to the presence of rotor leading edge shocks. The majority of HCF failures in aircraft engines occur at off-design operating conditions. Therefore, experiments focused on rotor-IGV interactions at off-design are conducted in the Purdue Transonic Research Compressor. The rotor-generated IGV unsteady aerodynamics are quantified when the IGV reset angle causes the vane trailing edge to be nearly aligned with the rotor leading edge shocks. A significant vane response to the impulsive static pressure perturbation associated with a shock is evident in the point measurements at 90% span, with details of this complex interaction revealed in the corresponding time-variant vane-to-vane flow field data. Industry wide implementation of Controlled Diffusion Airfoils (CDA) in modern compressors motivated an investigation of upstream propagating CDA rotor-generated forcing functions. Whole field velocity measurements in the reconfigured Purdue Transonic Research Compressor along the design speedline reveal steady loading had a considerable effect on the rotor shock structure. A detached rotor leading edge shock exists at low loading, with an attached leading edge and mid-chord suction surface normal shock present at nominal loading. These CDA forcing functions are 3--4 times smaller than those generated by the baseline NACA 65 rotor at their respective operating points. However, the IGV unsteady aerodynamic response to the CDA forcing functions remains significant. The intra-vane transport of NACA 65 and CDA rotor wakes is also observed within the time-variant passage velocity data. In general, the wake width and decay rate increase with rotor speed and compressor steady loading respectively.

  18. Modeling Framework and Validation of a Smart Grid and Demand Response System for Wind Power Integration

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Broeer, Torsten; Fuller, Jason C.; Tuffner, Francis K.

    2014-01-31

    Electricity generation from wind power and other renewable energy sources is increasing, and their variability introduces new challenges to the power system. The emergence of smart grid technologies in recent years has seen a paradigm shift in redefining the electrical system of the future, in which controlled response of the demand side is used to balance fluctuations and intermittencies from the generation side. This paper presents a modeling framework for an integrated electricity system where loads become an additional resource. The agent-based model represents a smart grid power system integrating generators, transmission, distribution, loads and market. The model incorporates generatormore » and load controllers, allowing suppliers and demanders to bid into a Real-Time Pricing (RTP) electricity market. The modeling framework is applied to represent a physical demonstration project conducted on the Olympic Peninsula, Washington, USA, and validation simulations are performed using actual dynamic data. Wind power is then introduced into the power generation mix illustrating the potential of demand response to mitigate the impact of wind power variability, primarily through thermostatically controlled loads. The results also indicate that effective implementation of Demand Response (DR) to assist integration of variable renewable energy resources requires a diversity of loads to ensure functionality of the overall system.« less

  19. Relationship between Duration of Untreated Psychosis and Intrinsic Corticostriatal Connectivity in Patients with Early Phase Schizophrenia.

    PubMed

    Sarpal, Deepak K; Robinson, Delbert G; Fales, Christina; Lencz, Todd; Argyelan, Miklos; Karlsgodt, Katherine H; Gallego, Juan A; John, Majnu; Kane, John M; Szeszko, Philip R; Malhotra, Anil K

    2017-10-01

    Patients with first-episode psychosis experience psychotic symptoms for a mean of up to 2 years prior to initiation of treatment, and long duration of untreated psychosis (DUP) is associated with poor clinical outcomes. Meanwhile, evidence compiled from numerous studies suggests that longer DUP is not associated with structural brain abnormalities. To date, few studies have examined the relationship between DUP and functional neuroimaging measures. In the present study, we used seed-based resting-state functional connectivity to examine the impact of DUP on corticostriatal circuitry. We included 83 patients with early phase schizophrenia and minimal exposure to antipsychotic drugs (<2 years), who underwent resting state scanning while entering 12 weeks of prospective treatment with second-generation antipsychotic drugs. Functional connectivity maps of the striatum were generated and examined in relation to DUP as a covariate. Mediation analyses were performed on a composite measure of corticostriatal connectivity derived from the significant results of our DUP analysis. We found that longer DUP correlated with worse response to treatment as well as overall decreased functional connectivity between striatal nodes and specific regions within frontal and parietal cortices. Moreover, the relationship between DUP and treatment response was significantly mediated by corticostriatal connectivity. Our results indicate that variation in corticostriatal circuitry may play a role in the relationship between longer DUP and worsened response to treatment. Future prospective studies are necessary to further characterize potential causal links between DUP, striatal circuitry and clinical outcomes.

  20. The Use of Dispersion Relations For The Geomagnetic Transfer Functions

    NASA Astrophysics Data System (ADS)

    Marcuello, A.; Queralt, P.; Ledo, J. J.

    The magnetotelluric responses are complex magnitudes, where real and imaginary parts contain the same information on the geoelectrical structure. It seems possible, from very general hypotheses on the geoelectrical models (causality, stability and passivity), to apply the Kramers-Krönig dispersion relations to the magnetotelluric responses (impedance, geomagnetic transfer functions,...). In particular, the applica- bility of these relations to the impedance is a current point of discussion, but there are not many examples of their application to the geomagnetic transfer functions (tipper). The aim of this paper is to study how the relations of dispersion are applied to the real and imaginary part of the geomagnetic transfer functions, and to check its validity. For this reason, we have considered data (or responses) from two- and three-dimensional structures, and for these data, we have taken two situations: 1.- Responses that have been synthetically generated from numerical modelling, that allows us to control the quality of the data. 2.- Responses obtained from fieldwork, that are affected by exper- imental error. Additionally, we have also explored the use of these relations to extrap- olate the geomagnetic transfer functions outside the interval of measured frequencies, in order to obtain constrains on the values of these extrapolated data. The results have shown that the dispersion relations are accomplished for the geomag- netic transfer functions, and they can offer information about how these responses are behaved outside (but near) the range of measured frequencies.

  1. Blimp-1 controls plasma cell function through the regulation of immunoglobulin secretion and the unfolded protein response.

    PubMed

    Tellier, Julie; Shi, Wei; Minnich, Martina; Liao, Yang; Crawford, Simon; Smyth, Gordon K; Kallies, Axel; Busslinger, Meinrad; Nutt, Stephen L

    2016-03-01

    Plasma cell differentiation requires silencing of B cell transcription, while it establishes antibody-secretory function and long-term survival. The transcription factors Blimp-1 and IRF4 are essential for the generation of plasma cells; however, their function in mature plasma cells has remained elusive. We found that while IRF4 was essential for the survival of plasma cells, Blimp-1 was dispensable for this. Blimp-1-deficient plasma cells retained their transcriptional identity but lost the ability to secrete antibody. Blimp-1 regulated many components of the unfolded protein response (UPR), including XBP-1 and ATF6. The overlap in the functions of Blimp-1 and XBP-1 was restricted to that response, with Blimp-1 uniquely regulating activity of the kinase mTOR and the size of plasma cells. Thus, Blimp-1 was required for the unique physiological ability of plasma cells that enables the secretion of protective antibody.

  2. Altered Reward Function in Adolescent Depression: What, When, and How?

    PubMed Central

    Forbes, Erika E.; Dahl, Ronald E.

    2011-01-01

    Background Conceptual models and recent evidence indicate that neural response to reward is altered in depression. Taking a developmental approach to investigating reward function in adolescent depression can elucidate the etiology, pathophysiology, and course of depression, a disorder that typically begins during adolescence and has high rates of recurrence. Methods This conceptual review describes the what, when, and how of altered reward function in adolescent depression. With the goal of generating new, testable hypotheses within a developmental affective neuroscience framework, we critically review findings and suggest future directions. Peer-reviewed empirical papers for inclusion in this critical review were obtained by searching PubMed, PsycInfo, and ScienceDirect for the years 1990–2010. Results A pattern of low striatal response and high medial prefrontal response to reward is evident in adolescents and adults with depression. Given the salience of social stimuli for positive affect and depression, reward function might be especially disrupted in response to social rewards. Because of changes in the dopamine system and reward function with aging, altered reward function in depression might be more evident during adolescence than later in life; however, low reward function may also be a stable characteristic of people who experience depression. Mechanisms of altered reward function in depression could include disrupted balance of corticostriatal circuit function, with disruption occurring as aberrant adolescent brain development. Conclusions Future studies should examine responses to social rewards; employ longitudinal and prospective designs; and investigate patterns of functional connectivity in reward circuits. Understanding altered reward function in depression has potential implications for treatment development. A more rigorous approach to investigating anhedonia, threat-reward interactions, and comorbid anxiety will be valuable to future progress in describing the role of reward function in the pathophysiology of depression. PMID:22117893

  3. INCA- INTERACTIVE CONTROLS ANALYSIS

    NASA Technical Reports Server (NTRS)

    Bauer, F. H.

    1994-01-01

    The Interactive Controls Analysis (INCA) program was developed to provide a user friendly environment for the design and analysis of linear control systems, primarily feedback control systems. INCA is designed for use with both small and large order systems. Using the interactive graphics capability, the INCA user can quickly plot a root locus, frequency response, or time response of either a continuous time system or a sampled data system. The system configuration and parameters can be easily changed, allowing the INCA user to design compensation networks and perform sensitivity analysis in a very convenient manner. A journal file capability is included. This stores an entire sequence of commands, generated during an INCA session into a file which can be accessed later. Also included in INCA are a context-sensitive help library, a screen editor, and plot windows. INCA is robust to VAX-specific overflow problems. The transfer function is the basic unit of INCA. Transfer functions are automatically saved and are available to the INCA user at any time. A powerful, user friendly transfer function manipulation and editing capability is built into the INCA program. The user can do all transfer function manipulations and plotting without leaving INCA, although provisions are made to input transfer functions from data files. By using a small set of commands, the user may compute and edit transfer functions, and then examine these functions by using the ROOT_LOCUS, FREQUENCY_RESPONSE, and TIME_RESPONSE capabilities. Basic input data, including gains, are handled as single-input single-output transfer functions. These functions can be developed using the function editor or by using FORTRAN- like arithmetic expressions. In addition to the arithmetic functions, special functions are available to 1) compute step, ramp, and sinusoid functions, 2) compute closed loop transfer functions, 3) convert from S plane to Z plane with optional advanced Z transform, and 4) convert from Z plane to W plane and back. These capabilities allow the INCA user to perform block diagram algebraic manipulations quickly for functions in the S, Z, and W domains. Additionally, a versatile digital control capability has been included in INCA. Special plane transformations allow the user to easily convert functions from one domain to another. Other digital control capabilities include: 1) totally independent open loop frequency response analyses on a continuous plant, discrete control system with a delay, 2) advanced Z-transform capability for systems with delays, and 3) multirate sampling analyses. The current version of INCA includes Dynamic Functions (which change when a parameter changes), standard filter generation, PD and PID controller generation, incorporation of the QZ-algorithm (function addition, inverse Laplace), and describing functions that allow the user to calculate the gain and phase characteristics of a nonlinear device. The INCA graphic modes provide the user with a convenient means to document and study frequency response, time response, and root locus analyses. General graphics features include: 1) zooming and dezooming, 2) plot documentation, 3) a table of analytic computation results, 4) multiple curves on the same plot, and 5) displaying frequency and gain information for a specific point on a curve. Additional capabilities in the frequency response mode include: 1) a full complement of graphical methods Bode magnitude, Bode phase, Bode combined magnitude and phase, Bode strip plots, root contour plots, Nyquist, Nichols, and Popov plots; 2) user selected plot scaling; and 3) gain and phase margin calculation and display. In the time response mode, additional capabilities include: 1) support for inverse Laplace and inverse Z transforms, 2) support for various input functions, 3) closed loop response evaluation, 4) loop gain sensitivity analyses, 5) intersample time response for discrete systems using the advanced Z transform, and 6) closed loop time response using mixed plane (S, Z, W) operations with delay. A Graphics mode command was added to the current version of INCA, version 3.13, to produce Metafiles (graphic files) of the currently displayed plot. The metafile can be displayed and edited using the QPLOT Graphics Editor and Replotter for Metafiles (GERM) program included with the INCA package. The INCA program is written in Pascal and FORTRAN for interactive or batch execution and has been implemented on a DEC VAX series computer under VMS. Both source code and executable code are supplied for INCA. Full INCA graphics capabilities are supported for various Tektronix 40xx and 41xx terminals; DEC VT graphics terminals; many PC and Macintosh terminal emulators; TEK014 hardcopy devices such as the LN03 Laserprinter; and bit map graphics external hardcopy devices. Also included for the TEK4510 rasterizer users are a multiple copy feature, a wide line feature, and additional graphics fonts. The INCA program was developed in 1985, Version 2.04 was released in 1986, Version 3.00 was released in 1988, and Version 3.13 was released in 1989. An INCA version 2.0X conversion program is included.

  4. Generation and Nuclear Translocation of Sumoylated Transmembrane Fragment of Cell Adhesion Molecule L1

    PubMed Central

    Lutz, David; Wolters-Eisfeld, Gerrit; Joshi, Gunjan; Djogo, Nevena; Jakovcevski, Igor; Schachner, Melitta; Kleene, Ralf

    2012-01-01

    The functions of the cell adhesion molecule L1 in the developing and adult nervous system are triggered by homophilic and heterophilic interactions that stimulate signal transductions that activate cellular responses. Here, we show that stimulation of signaling by function-triggering L1 antibodies or L1-Fc leads to serine protease-dependent cleavage of full-length L1 at the plasma membrane and generation of a sumoylated transmembrane 70-kDa fragment comprising the intracellular and transmembrane domains and part of the extracellular domain. The 70-kDa transmembrane fragment is transported from the plasma membrane to a late endosomal compartment, released from endosomal membranes into the cytoplasm, and transferred from there into the nucleus by a pathway that depends on importin and chromatin-modifying protein 1. Mutation of the sumoylation site at Lys1172 or of the nuclear localization signal at Lys1147 abolished L1-stimulated generation or nuclear import of the 70-kDa fragment, respectively. Nuclear import of the 70-kDa fragment may activate cellular responses in parallel or in association with phosphorylation-dependent signaling pathways. Alterations in the levels of the 70-kDa fragment during development and in the adult after spinal cord injury or in a mouse model of Alzheimer disease suggest that this fragment is functionally implicated in development, regeneration, neurodegeneration, tumorigenesis, and possibly synaptic plasticity in the mature nervous system. PMID:22431726

  5. Nonlinear optical interactions in silicon waveguides

    NASA Astrophysics Data System (ADS)

    Kuyken, B.; Leo, F.; Clemmen, S.; Dave, U.; Van Laer, R.; Ideguchi, T.; Zhao, H.; Liu, X.; Safioui, J.; Coen, S.; Gorza, S. P.; Selvaraja, S. K.; Massar, S.; Osgood, R. M.; Verheyen, P.; Van Campenhout, J.; Baets, R.; Green, W. M. J.; Roelkens, G.

    2017-03-01

    The strong nonlinear response of silicon photonic nanowire waveguides allows for the integration of nonlinear optical functions on a chip. However, the detrimental nonlinear optical absorption in silicon at telecom wavelengths limits the efficiency of many such experiments. In this review, several approaches are proposed and demonstrated to overcome this fundamental issue. By using the proposed methods, we demonstrate amongst others supercontinuum generation, frequency comb generation, a parametric optical amplifier, and a parametric optical oscillator.

  6. The electrical conductivity of the Earth's upper mantle as estimated from satellite measured magnetic field variations. Ph.D. Thesis

    NASA Technical Reports Server (NTRS)

    Didwall, E. M.

    1981-01-01

    Low latitude magnetic field variations (magnetic storms) caused by large fluctuations in the equatorial ring current were derived from magnetic field magnitude data obtained by OGO 2, 4, and 6 satellites over an almost 5 year period. Analysis procedures consisted of (1) separating the disturbance field into internal and external parts relative to the surface of the Earth; (2) estimating the response function which related to the internally generated magnetic field variations to the external variations due to the ring current; and (3) interpreting the estimated response function using theoretical response functions for known conductivity profiles. Special consideration is given to possible ocean effects. A temperature profile is proposed using conductivity temperature data for single crystal olivine. The resulting temperature profile is reasonable for depths below 150-200 km, but is too high for shallower depths. Apparently, conductivity is not controlled solely by olivine at shallow depths.

  7. Mice with megabase humanization of their immunoglobulin genes generate antibodies as efficiently as normal mice.

    PubMed

    Murphy, Andrew J; Macdonald, Lynn E; Stevens, Sean; Karow, Margaret; Dore, Anthony T; Pobursky, Kevin; Huang, Tammy T; Poueymirou, William T; Esau, Lakeisha; Meola, Melissa; Mikulka, Warren; Krueger, Pamela; Fairhurst, Jeanette; Valenzuela, David M; Papadopoulos, Nicholas; Yancopoulos, George D

    2014-04-08

    Mice genetically engineered to be humanized for their Ig genes allow for human antibody responses within a mouse background (HumAb mice), providing a valuable platform for the generation of fully human therapeutic antibodies. Unfortunately, existing HumAb mice do not have fully functional immune systems, perhaps because of the manner in which their genetic humanization was carried out. Heretofore, HumAb mice have been generated by disrupting the endogenous mouse Ig genes and simultaneously introducing human Ig transgenes at a different and random location; KO-plus-transgenic humanization. As we describe in the companion paper, we attempted to make mice that more efficiently use human variable region segments in their humoral responses by precisely replacing 6 Mb of mouse Ig heavy and kappa light variable region germ-line gene segments with their human counterparts while leaving the mouse constant regions intact, using a unique in situ humanization approach. We reasoned the introduced human variable region gene segments would function indistinguishably in their new genetic location, whereas the retained mouse constant regions would allow for optimal interactions and selection of the resulting antibodies within the mouse environment. We show that these mice, termed VelocImmune mice because they were generated using VelociGene technology, efficiently produce human:mouse hybrid antibodies (that are rapidly convertible to fully human antibodies) and have fully functional humoral immune systems indistinguishable from those of WT mice. The efficiency of the VelocImmune approach is confirmed by the rapid progression of 10 different fully human antibodies into human clinical trials.

  8. An investigation into the probabilistic combination of quasi-static and random accelerations

    NASA Technical Reports Server (NTRS)

    Schock, R. W.; Tuell, L. P.

    1984-01-01

    The development of design load factors for aerospace and aircraft components and experiment support structures, which are subject to a simultaneous vehicle dynamic vibration (quasi-static) and acoustically generated random vibration, require the selection of a combination methodology. Typically, the procedure is to define the quasi-static and the random generated response separately, and arithmetically add or root sum square to get combined accelerations. Since the combination of a probabilistic and a deterministic function yield a probabilistic function, a viable alternate approach would be to determine the characteristics of the combined acceleration probability density function and select an appropriate percentile level for the combined acceleration. The following paper develops this mechanism and provides graphical data to select combined accelerations for most popular percentile levels.

  9. THE ENDOTHELIUM IN SEPSIS

    PubMed Central

    Ince, Can; Mayeux, Philip R.; Nguyen, Trung; Gomez, Hernando; Kellum, John A.; Ospina-Tascón, Gustavo A.; Hernandez, Glenn; Murray, Patrick; De Backer, Daniel

    2017-01-01

    Sepsis affects practically all aspects of endothelial cell (EC) function and is thought to be the key factor in the progression from sepsis to organ failure. Endothelial functions affected by sepsis include vasoregulation, barrier function, inflammation, and hemostasis. These are among other mechanisms often mediated by glycocalyx shedding, such as abnormal nitric oxide metabolism, up-regulation of reactive oxygen species generation due to down-regulation of endothelial-associated antioxidant defenses, transcellular communication, proteases, exposure of adhesion molecules, and activation of tissue factor. This review covers current insight in EC-associated hemostatic responses to sepsis and the EC response to inflammation. The endothelial cell lining is highly heterogeneous between different organ systems and consequently also in its response to sepsis. In this context, we discuss the response of the endothelial cell lining to sepsis in the kidney, liver, and lung. Finally, we discuss evidence as to whether the EC response to sepsis is adaptive or maladaptive. This study is a result of an Acute Dialysis Quality Initiative XIV Sepsis Workgroup meeting held in Bogota, Columbia, between October 12 and 15, 2014. PMID:26871664

  10. Neural signatures of cognitive and emotional biases in depression

    PubMed Central

    Fossati, Philippe

    2008-01-01

    Functional brain imaging studies suggest that depression is a system-level disorder affecting discrete but functionally linked cortical and limbic structures, with abnormalities in the anterior cingulate, lateral, ami medial prefrontal cortex, amygdala, ami hippocampus. Within this circuitry, abnormal corticolimbic interactions underlie cognitive deficits ami emotional impairment in depression. Depression involves biases toward processing negative emotional information and abnormal self-focus in response to emotional stimuli. These biases in depression could reflect excessive analytical self-focus in depression, as well as impaired cognitive control of emotional response to negative stimuli. By combining structural and functional investigations, brain imaging studies mav help to generate novel antidepressant treatments that regulate structural and factional plasticity within the neural network regulating mood and affective behavior.

  11. Cellular Links between Neuronal Activity and Energy Homeostasis.

    PubMed

    Shetty, Pavan K; Galeffi, Francesca; Turner, Dennis A

    2012-01-01

    Neuronal activity, astrocytic responses to this activity, and energy homeostasis are linked together during baseline, conscious conditions, and short-term rapid activation (as occurs with sensory or motor function). Nervous system energy homeostasis also varies during long-term physiological conditions (i.e., development and aging) and with adaptation to pathological conditions, such as ischemia or low glucose. Neuronal activation requires increased metabolism (i.e., ATP generation) which leads initially to substrate depletion, induction of a variety of signals for enhanced astrocytic function, and increased local blood flow and substrate delivery. Energy generation (particularly in mitochondria) and use during ATP hydrolysis also lead to considerable heat generation. The local increases in blood flow noted following neuronal activation can both enhance local substrate delivery but also provides a heat sink to help cool the brain and removal of waste by-products. In this review we highlight the interactions between short-term neuronal activity and energy metabolism with an emphasis on signals and factors regulating astrocyte function and substrate supply.

  12. Second and third harmonic generation associated to infrared transitions in a Morse quantum well under applied electric and magnetic fields

    NASA Astrophysics Data System (ADS)

    Restrepo, R. L.; Kasapoglu, E.; Sakiroglu, S.; Ungan, F.; Morales, A. L.; Duque, C. A.

    2017-09-01

    The effects of electric and magnetic fields on the second and third harmonic generation coefficients in a Morse potential quantum well are theoretically studied. The energy levels and corresponding wave functions are obtained by solving the Schrödinger equation for the electron in the parabolic band scheme and effective mass approximations and the envelope function approach. The results show that both the electric and the magnetic fields have significant influence on the magnitudes and resonant peak energy positions of the second and third harmonic generation responses. In general, the Morse potential profile becomes wider and shallower as γ -parameter increases and so the energies of the bound states will be functions of this parameter. Therefore, we can conclude that the effects of the electric and magnetic fields can be used to tune and control the optical properties of interest in the range of the infrared electromagnetic spectrum.

  13. AMP-activated protein kinase, stress responses and cardiovascular diseases

    PubMed Central

    WANG, Shaobin; SONG, Ping; ZOU, Ming-Hui

    2012-01-01

    AMPK (AMP-activated protein kinase) is one of the key players in maintaining intracellular homoeostasis. AMPK is well known as an energy sensor and can be activated by increased intracellular AMP levels. Generally, the activation of AMPK turns on catabolic pathways that generate ATP, while inhibiting cell proliferation and biosynthetic processes that consume ATP. In recent years, intensive investigations on the regulation and the function of AMPK indicates that AMPK not only functions as an intracellular energy sensor and regulator, but is also a general stress sensor that is important in maintaining intracellular homoeostasis during many kinds of stress challenges. In the present paper, we will review recent literature showing that AMPK functions far beyond its proposed energy sensor and regulator function. AMPK regulates ROS (reactive oxygen species)/redox balance, autophagy, cell proliferation, cell apoptosis, cellular polarity, mitochondrial function and genotoxic response, either directly or indirectly via numerous downstream pathways under physiological and pathological conditions. PMID:22390198

  14. Frequency-response identification of XV-15 tilt-rotor aircraft dynamics

    NASA Technical Reports Server (NTRS)

    Tischler, Mark B.

    1987-01-01

    The timely design and development of the next generation of tilt-rotor aircraft (JVX) depend heavily on the in-depth understanding of existing XV-15 dynamics and the availability of fully validated simulation models. Previous studies have considered aircraft and simulation trim characteristics, but analyses of basic flight vehicle dynamics were limited to qualitative pilot evaluation. The present study has the following objectives: documentation and evaluation of XV-15 bare-airframe dynamics; comparison of aircraft and simulation responses; and development of a validated transfer-function description of the XV-15 needed for future studies. A nonparametric frequency-response approach is used which does not depend on assumed model order or structure. Transfer-function representations are subsequently derived which fit the frequency responses in the bandwidth of greatest concern for piloted handling-qualities and control-system applications.

  15. Absolute calibration of optical streak cameras on picosecond time scales using supercontinuum generation

    DOE PAGES

    Patankar, S.; Gumbrell, E. T.; Robinson, T. S.; ...

    2017-08-17

    Here we report a new method using high stability, laser-driven supercontinuum generation in a liquid cell to calibrate the absolute photon response of fast optical streak cameras as a function of wavelength when operating at fastest sweep speeds. A stable, pulsed white light source based around the use of self-phase modulation in a salt solution was developed to provide the required brightness on picosecond timescales, enabling streak camera calibration in fully dynamic operation. The measured spectral brightness allowed for absolute photon response calibration over a broad spectral range (425-650nm). Calibrations performed with two Axis Photonique streak cameras using the Photonismore » P820PSU streak tube demonstrated responses which qualitatively follow the photocathode response. Peak sensitivities were 1 photon/count above background. The absolute dynamic sensitivity is less than the static by up to an order of magnitude. We attribute this to the dynamic response of the phosphor being lower.« less

  16. CK-2127107 amplifies skeletal muscle response to nerve activation in humans.

    PubMed

    Andrews, Jinsy A; Miller, Timothy M; Vijayakumar, Vipin; Stoltz, Randall; James, Joyce K; Meng, Lisa; Wolff, Andrew A; Malik, Fady I

    2018-05-01

    Three studies evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of CK-2127107 (CK-107), a next-generation fast skeletal muscle troponin activator (FSTA), in healthy participants. We tested the hypothesis that CK-107 would amplify the force-frequency response of muscle in humans. To assess the force-frequency response, participants received single doses of CK-107 and placebo in a randomized, double-blind, 4-period, crossover study. The force-frequency response of foot dorsiflexion following stimulation of the deep fibular nerve to activate the tibialis anterior muscle was assessed. CK-107 significantly increased tibialis anterior muscle response with increasing dose and plasma concentration in a frequency-dependent manner; the largest increase in peak force was ∼60% at 10 Hz. CK-107 appears more potent and produced larger increases in force than tirasemtiv-a first-generation FSTA-in a similar pharmacodynamic study, thereby supporting its development for improvement of muscle function of patients. Muscle Nerve 57: 729-734, 2018. © 2017 The Authors. Muscle & Nerve published by Wiley Periodicals, Inc.

  17. Student System, On-Line Admissions.

    ERIC Educational Resources Information Center

    White, Stephen R.

    This report provides technical information on an on-line admissions system developed by Montgomery College. Part I, Systems Development, describes the background, objectives and responsibilities, system design, and reports generated by the system. Part II, Operating Instructions, describes input forms and controls, admission system functions, file…

  18. Vestibular evoked myogenic potential (VEMP) with galvanic stimulation in normal subjects.

    PubMed

    Cunha, Luciana Cristina Matos; Labanca, Ludimila; Tavares, Maurício Campelo; Gonçalves, Denise Utsch

    2014-01-01

    The vestibular evoked myogenic potential (VEMP) generated by galvanic vestibular stimulation (GVS) is related to the vestibulo-spinal pathway. The response recorded from soleus muscle is biphasic with onset of short latency (SL) component around 60 ms and medium latency (ML) component around 100 ms. The first component reflects otolith function (sacule and utricle) and the last deals with semicircular canals. To describe VEMP generated by GVS. In this cross-sectional clinical study, VEMP was generated by 2 mA/400 ms binaural GVS, frequency of 5-6 ms that was recorded from soleus muscles of 13 healthy adults, mean age 56 years. The subjects remained standing, head turned contralateral to the GVS applied to the mastoid. Thirty GVS were applied to the mastoid in the position cathode right anode left, followed by 30 in inverted position. SL and ML were measured. SL and ML components were recorded from both legs of all participants and were similar. The average of SL component was 54 ms and of ML was 112 ms. The components SL and ML of the VEMP response in soleus were reproducible and are useful measures of vestibular-spinal function.

  19. Research on Aero-Thermodynamic Distortion Induced Structural Dynamic Response of Multistage Compressor Blading

    DTIC Science & Technology

    1992-03-01

    of realistic reduced frequency values for the ftost time. 14. SUIUECT TEIEMS IS. NUMBER OF PAGES Unsteady Aerodynamic, 143 Flow Induced Vibrations 16...Flat Plate APPENDIX X. Prediction of Turbulence Generated Random Vibrational 106 Response of Turbomachinery Blading 3 APPENDIX XI. Viscous Oscillating...failure is fatigue caused by vibrations at levels exceeding3 material endurance limits. These vibrations occur when a periodic forcing function, with

  20. Development of novel metabolite-responsive transcription factors via transposon-mediated protein fusion.

    PubMed

    Younger, Andrew K D; Su, Peter Y; Shepard, Andrea J; Udani, Shreya V; Cybulski, Thaddeus R; Tyo, Keith E J; Leonard, Joshua N

    2018-02-01

    Naturally evolved metabolite-responsive biosensors enable applications in metabolic engineering, ranging from screening large genetic libraries to dynamically regulating biosynthetic pathways. However, there are many metabolites for which a natural biosensor does not exist. To address this need, we developed a general method for converting metabolite-binding proteins into metabolite-responsive transcription factors-Biosensor Engineering by Random Domain Insertion (BERDI). This approach takes advantage of an in vitro transposon insertion reaction to generate all possible insertions of a DNA-binding domain into a metabolite-binding protein, followed by fluorescence activated cell sorting to isolate functional biosensors. To develop and evaluate the BERDI method, we generated a library of candidate biosensors in which a zinc finger DNA-binding domain was inserted into maltose binding protein, which served as a model well-studied metabolite-binding protein. Library diversity was characterized by several methods, a selection scheme was deployed, and ultimately several distinct and functional maltose-responsive transcriptional biosensors were identified. We hypothesize that the BERDI method comprises a generalizable strategy that may ultimately be applied to convert a wide range of metabolite-binding proteins into novel biosensors for applications in metabolic engineering and synthetic biology. © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  1. T inflammatory memory CD8 T cells participate to antiviral response and generate secondary memory cells with an advantage in XCL1 production.

    PubMed

    Jubin, Virginie; Ventre, Erwan; Leverrier, Yann; Djebali, Sophia; Mayol, Katia; Tomkowiak, Martine; Mafille, Julien; Teixeira, Marie; Teoh, Denise Y-L; Lina, Bruno; Walzer, Thierry; Arpin, Christophe; Marvel, Jacqueline

    2012-06-01

    Besides the classically described subsets of memory CD8 T cells generated under infectious conditions, are T inflammatory memory cells generated under sterile priming conditions, such as sensitization to allergens. Although not fully differentiated as pathogen-induced memory cells, they display memory properties that distinguish them from naive CD8 T cells. Given these memory cells are generated in an antigen-specific context that is devoid of pathogen-derived danger signals and CD4 T cell help, we herein questioned whether they maintained their activation and differentiation potential, could be recruited in an immune response directed against a pathogen expressing their cognate antigen and further differentiate in fully competent secondary memory cells. We show that T inflammatory memory cells can indeed take part to the immune response triggered by a viral infection, differentiate into secondary effectors and further generate typical central memory CD8 T cells and effector memory CD8 T cells. Furthermore, the secondary memory cells they generate display a functional advantage over primary memory cells in their capacity to produce TNF-α and the XCL1 chemokine. These results suggest that cross-reactive stimulations and differentiation of cells directed against allergens or self into fully competent pathogen-induced memory cells might have incidences in inflammatory immuno-pathologies.

  2. Analyzing Effects of Turbulence on Power Generation Using Wind Plant Monitoring Data: Preprint

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zhang, J.; Chowdhury, S.; Hodge, B. M.

    2014-01-01

    In this paper, a methodology is developed to analyze how ambient and wake turbulence affects the power generation of a single wind turbine within an array of turbines. Using monitoring data from a wind power plant, we selected two sets of wind and power data for turbines on the edge of the wind plant that resemble (i) an out-of-wake scenario (i.e., when the turbine directly faces incoming winds) and (ii) an in-wake scenario (i.e., when the turbine is under the wake of other turbines). For each set of data, two surrogate models were then developed to represent the turbine powermore » generation (i) as a function of the wind speed; and (ii) as a function of the wind speed and turbulence intensity. Support vector regression was adopted for the development of the surrogate models. Three types of uncertainties in the turbine power generation were also investigated: (i) the uncertainty in power generation with respect to the published/reported power curve, (ii) the uncertainty in power generation with respect to the estimated power response that accounts for only mean wind speed; and (iii) the uncertainty in power generation with respect to the estimated power response that accounts for both mean wind speed and turbulence intensity. Results show that (i) under the same wind conditions, the turbine generates different power between the in-wake and out-of-wake scenarios, (ii) a turbine generally produces more power under the in-wake scenario than under the out-of-wake scenario, (iii) the power generation is sensitive to turbulence intensity even when the wind speed is greater than the turbine rated speed, and (iv) there is relatively more uncertainty in the power generation under the in-wake scenario than under the out-of-wake scenario.« less

  3. Suction generation in white-spotted bamboo sharks Chiloscyllium plagiosum.

    PubMed

    Wilga, Cheryl D; Sanford, Christopher P

    2008-10-01

    After the divergence of chondrichthyans and teleostomes, the structure of the feeding apparatus also diverged leading to alterations in the suction mechanism. In this study we investigated the mechanism for suction generation during feeding in white-spotted bamboo sharks, Chiloscyllium plagiosum and compared it with that in teleosts. The internal movement of cranial elements and pressure in the buccal, hyoid and pharyngeal cavities that are directly responsible for suction generation was quantified using sonomicrometry and pressure transducers. Backward stepwise multiple linear regressions were used to explore the relationship between expansion and pressure, accounting for 60-96% of the variation in pressure among capture events. The progression of anterior to posterior expansion in the buccal, hyoid and pharyngeal cavities is accompanied by the sequential onset of subambient pressure in these cavities as prey is drawn into the mouth. Gape opening triggers the onset of subambient pressure in the oropharyngeal cavities. Peak gape area coincides with peak subambient buccal pressure. Increased velocity of hyoid area expansion is primarily responsible for generating peak subambient pressure in the buccal and hyoid regions. Pharyngeal expansion appears to function as a sink to receive water influx from the mouth, much like that of compensatory suction in bidirectional aquatic feeders. Interestingly, C. plagiosum generates large suction pressures while paradoxically compressing the buccal cavity laterally, delaying the time to peak pressure. This represents a fundamental difference from the mechanism used to generate suction in teleost fishes. Interestingly, pressure in the three cavities peaks in the posterior to anterior direction. The complex shape changes that the buccal cavity undergoes indicate that, as in teleosts, unsteady flow predominates during suction feeding. Several kinematic variables function together, with great variation over long gape cycles to generate the low subambient pressures used by C. plagiosum to capture prey.

  4. Linking EEG signals, brain functions and mental operations: Advantages of the Laplacian transformation.

    PubMed

    Vidal, Franck; Burle, Boris; Spieser, Laure; Carbonnell, Laurence; Meckler, Cédric; Casini, Laurence; Hasbroucq, Thierry

    2015-09-01

    Electroencephalography (EEG) is a very popular technique for investigating brain functions and/or mental processes. To this aim, EEG activities must be interpreted in terms of brain and/or mental processes. EEG signals being a direct manifestation of neuronal activity it is often assumed that such interpretations are quite obvious or, at least, straightforward. However, they often rely on (explicit or even implicit) assumptions regarding the structures supposed to generate the EEG activities of interest. For these assumptions to be used appropriately, reliable links between EEG activities and the underlying brain structures must be established. Because of volume conduction effects and the mixture of activities they induce, these links are difficult to establish with scalp potential recordings. We present different examples showing how the Laplacian transformation, acting as an efficient source separation method, allowed to establish more reliable links between EEG activities and brain generators and, ultimately, with mental operations. The nature of those links depends on the depth of inferences that can vary from weak to strong. Along this continuum, we show that 1) while the effects of experimental manipulation can appear widely distributed with scalp potentials, Laplacian transformation allows to reveal several generators contributing (in different manners) to these modulations, 2) amplitude variations within the same set of generators can generate spurious differences in scalp potential topographies, often interpreted as reflecting different source configurations. In such a case, Laplacian transformation provides much more similar topographies, evidencing the same generator(s) set, and 3) using the LRP as an index of response activation most often produces ambiguous results, Laplacian-transformed response-locked ERPs obtained over motor areas allow resolving these ambiguities. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. RF tumour ablation: computer simulation and mathematical modelling of the effects of electrical and thermal conductivity.

    PubMed

    Lobo, S M; Liu, Z-J; Yu, N C; Humphries, S; Ahmed, M; Cosman, E R; Lenkinski, R E; Goldberg, W; Goldberg, S N

    2005-05-01

    This study determined the effects of thermal conductivity on RF ablation tissue heating using mathematical modelling and computer simulations of RF heating coupled to thermal transport. Computer simulation of the Bio-Heat equation coupled with temperature-dependent solutions for RF electric fields (ETherm) was used to generate temperature profiles 2 cm away from a 3 cm internally-cooled electrode. Multiple conditions of clinically relevant electrical conductivities (0.07-12 S m-1) and 'tumour' radius (5-30 mm) at a given background electrical conductivity (0.12 S m-1) were studied. Temperature response surfaces were plotted for six thermal conductivities, ranging from 0.3-2 W m-1 degrees C (the range of anticipated clinical and experimental systems). A temperature response surface was obtained for each thermal conductivity at 25 electrical conductivities and 17 radii (n=425 temperature data points). The simulated temperature response was fit to a mathematical model derived from prior phantom data. This mathematical model is of the form (T=a+bRc exp(dR) s(f) exp(g)(s)) for RF generator-energy dependent situations and (T=h+k exp(mR)+n?exp(p)(s)) for RF generator-current limited situations, where T is the temperature (degrees C) 2 cm from the electrode and a, b, c, d, f, g, h, k, m, n and p are fitting parameters. For each of the thermal conductivity temperature profiles generated, the mathematical model fit the response surface to an r2 of 0.97-0.99. Parameters a, b, c, d, f, k and m were highly correlated to thermal conductivity (r2=0.96-0.99). The monotonic progression of fitting parameters permitted their mathematical expression using simple functions. Additionally, the effect of thermal conductivity simplified the above equation to the extent that g, h, n and p were found to be invariant. Thus, representation of the temperature response surface could be accurately expressed as a function of electrical conductivity, radius and thermal conductivity. As a result, the non-linear temperature response of RF induced heating can be adequately expressed mathematically as a function of electrical conductivity, radius and thermal conductivity. Hence, thermal conductivity accounts for some of the previously unexplained variance. Furthermore, the addition of this variable into the mathematical model substantially simplifies the equations and, as such, it is expected that this will permit improved prediction of RF ablation induced temperatures in clinical practice.

  6. Quantitative myocardial perfusion from static cardiac and dynamic arterial CT

    NASA Astrophysics Data System (ADS)

    Bindschadler, Michael; Branch, Kelley R.; Alessio, Adam M.

    2018-05-01

    Quantitative myocardial blood flow (MBF) estimation by dynamic contrast enhanced cardiac computed tomography (CT) requires multi-frame acquisition of contrast transit through the blood pool and myocardium to inform the arterial input and tissue response functions. Both the input and the tissue response functions for the entire myocardium are sampled with each acquisition. However, the long breath holds and frequent sampling can result in significant motion artifacts and relatively high radiation dose. To address these limitations, we propose and evaluate a new static cardiac and dynamic arterial (SCDA) quantitative MBF approach where (1) the input function is well sampled using either prediction from pre-scan timing bolus data or measured from dynamic thin slice ‘bolus tracking’ acquisitions, and (2) the whole-heart tissue response data is limited to one contrast enhanced CT acquisition. A perfusion model uses the dynamic arterial input function to generate a family of possible myocardial contrast enhancement curves corresponding to a range of MBF values. Combined with the timing of the single whole-heart acquisition, these curves generate a lookup table relating myocardial contrast enhancement to quantitative MBF. We tested the SCDA approach in 28 patients that underwent a full dynamic CT protocol both at rest and vasodilator stress conditions. Using measured input function plus single (enhanced CT only) or plus double (enhanced and contrast free baseline CT’s) myocardial acquisitions yielded MBF estimates with root mean square (RMS) error of 1.2 ml/min/g and 0.35 ml/min/g, and radiation dose reductions of 90% and 83%, respectively. The prediction of the input function based on timing bolus data and the static acquisition had an RMS error compared to the measured input function of 26.0% which led to MBF estimation errors greater than threefold higher than using the measured input function. SCDA presents a new, simplified approach for quantitative perfusion imaging with an acquisition strategy offering substantial radiation dose and computational complexity savings over dynamic CT.

  7. Test-Anchored Vibration Response Predictions for an Acoustically Energized Curved Orthogrid Panel with Mounted Components

    NASA Technical Reports Server (NTRS)

    Frady, Gregory P.; Duvall, Lowery D.; Fulcher, Clay W. G.; Laverde, Bruce T.; Hunt, Ronald A.

    2011-01-01

    rich body of vibroacoustic test data was recently generated at Marshall Space Flight Center for component-loaded curved orthogrid panels typical of launch vehicle skin structures. The test data were used to anchor computational predictions of a variety of spatially distributed responses including acceleration, strain and component interface force. Transfer functions relating the responses to the input pressure field were generated from finite element based modal solutions and test-derived damping estimates. A diffuse acoustic field model was applied to correlate the measured input sound pressures across the energized panel. This application quantifies the ability to quickly and accurately predict a variety of responses to acoustically energized skin panels with mounted components. Favorable comparisons between the measured and predicted responses were established. The validated models were used to examine vibration response sensitivities to relevant modeling parameters such as pressure patch density, mesh density, weight of the mounted component and model form. Convergence metrics include spectral densities and cumulative root-mean squared (RMS) functions for acceleration, velocity, displacement, strain and interface force. Minimum frequencies for response convergence were established as well as recommendations for modeling techniques, particularly in the early stages of a component design when accurate structural vibration requirements are needed relatively quickly. The results were compared with long-established guidelines for modeling accuracy of component-loaded panels. A theoretical basis for the Response/Pressure Transfer Function (RPTF) approach provides insight into trends observed in the response predictions and confirmed in the test data. The software developed for the RPTF method allows easy replacement of the diffuse acoustic field with other pressure fields such as a turbulent boundary layer (TBL) model suitable for vehicle ascent. Structural responses using a TBL model were demonstrated, and wind tunnel tests have been proposed to anchor the predictions and provide new insight into modeling approaches for this environment. Finally, design load factors were developed from the measured and predicted responses and compared with those derived from traditional techniques such as historical Mass Acceleration Curves and Barrett scaling methods for acreage and component-loaded panels.

  8. R package to estimate intracluster correlation coefficient with confidence interval for binary data.

    PubMed

    Chakraborty, Hrishikesh; Hossain, Akhtar

    2018-03-01

    The Intracluster Correlation Coefficient (ICC) is a major parameter of interest in cluster randomized trials that measures the degree to which responses within the same cluster are correlated. There are several types of ICC estimators and its confidence intervals (CI) suggested in the literature for binary data. Studies have compared relative weaknesses and advantages of ICC estimators as well as its CI for binary data and suggested situations where one is advantageous in practical research. The commonly used statistical computing systems currently facilitate estimation of only a very few variants of ICC and its CI. To address the limitations of current statistical packages, we developed an R package, ICCbin, to facilitate estimating ICC and its CI for binary responses using different methods. The ICCbin package is designed to provide estimates of ICC in 16 different ways including analysis of variance methods, moments based estimation, direct probabilistic methods, correlation based estimation, and resampling method. CI of ICC is estimated using 5 different methods. It also generates cluster binary data using exchangeable correlation structure. ICCbin package provides two functions for users. The function rcbin() generates cluster binary data and the function iccbin() estimates ICC and it's CI. The users can choose appropriate ICC and its CI estimate from the wide selection of estimates from the outputs. The R package ICCbin presents very flexible and easy to use ways to generate cluster binary data and to estimate ICC and it's CI for binary response using different methods. The package ICCbin is freely available for use with R from the CRAN repository (https://cran.r-project.org/package=ICCbin). We believe that this package can be a very useful tool for researchers to design cluster randomized trials with binary outcome. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Grapevine fatty acid hydroperoxide lyase generates actin-disrupting volatiles and promotes defence-related cell death

    PubMed Central

    Wang, Hao; Claudel, Patricia; Riemann, Michael; Hause, Bettina; Hugueney, Philippe; Nick, Peter

    2018-01-01

    Abstract Fatty acid hydroperoxides can generate short-chained volatile aldehydes that may participate in plant defence. A grapevine hydroperoxide lyase (VvHPL1) clustering to the CYP74B class was functionally characterized with respect to a role in defence. In grapevine leaves, transcripts of this gene accumulated rapidly to high abundance in response to wounding. Cellular functions of VvHPL1 were investigated upon heterologous expression in tobacco BY-2 cells. A C-terminal green fluorescent protein (GFP) fusion of VvHPL1 was located in plastids. The overexpression lines were found to respond to salinity stress or the bacterial elicitor harpin by increasing cell death. This signal-dependent mortality response was mitigated either by addition of exogenous jasmonic acid or by treatment with diphenyleneiodonium (DPI), an inhibitor of NADPH oxidases. By feeding different substrates to recombinantly expressed enzyme, VvHPL1 could also be functionally classified as true 13-HPL. The cognate products generated by this 13-HPL were cis-3-hexenal and trans-2-hexenal. Using a GFP-tagged actin marker line, one of these isomeric products, cis-3-hexenal, was found specifically to elicit a rapid disintegration of actin filaments. This response was not only observed in the heterologous system (tobacco BY-2), but also in a grapevine cell strain expressing this marker, as well as in leaf discs from an actin marker grape used as a homologous system. These results are discussed in the context of a role for VvHPL1 in a lipoxygenase-dependent signalling pathway triggering cell death-related defence that bifurcates from jasmonate-dependent basal immunity. PMID:29659985

  10. A preliminary quality of life questionnaire-bronchiectasis: a patient-reported outcome measure for bronchiectasis.

    PubMed

    Quittner, Alexandra L; Marciel, Kristen K; Salathe, Matthias A; O'Donnell, Anne E; Gotfried, Mark H; Ilowite, Jonathan S; Metersky, Mark L; Flume, Patrick A; Lewis, Sandra A; McKevitt, Matthew; Montgomery, A Bruce; O'Riordan, Thomas G; Barker, Alan F

    2014-08-01

    The Quality of Life Questionnaire-Bronchiectasis (QOL-B) is the first disease-specific, patient-reported outcome measure for patients with bronchiectasis. Content validity, cognitive testing, responsivity to open-label treatment, and psychometric analyses are presented. Reviews of literature, existing measures, and physician input were used to generate the initial QOL-B. Modifications following preliminary cognitive testing (N = 35 patients with bronchiectasis) generated version (V) 1.0. An open-ended patient interview study (N = 28) provided additional information and was content analyzed to derive saturation matrices, which summarized all disease-related topics mentioned by each participant. This resulted in QOL-B V2.0. Psychometric analyses were carried out using results from an open-label phase 2 trial, in which 89 patients were enrolled and treated with aztreonam for inhalation solution. Responsivity to open-label treatment was observed. Additional analyses generated QOL-B V3.0, with 37 items on eight scales: respiratory symptoms; physical, role, emotional, and social functioning; vitality; health perceptions; and treatment burden. For each scale, scores are standardized on a 0-to-100-point scale; higher scores indicate better health-related quality of life. No total score is calculated. A final cognitive testing study (N = 40) resulted in a minor change to one social functioning scale item (QOL-B V3.1). Content validity, cognitive testing, responsivity to open-label treatment, and initial psychometric analyses supported QOL-B items and structure. This interim QOL-B is a promising tool for evaluating the efficacy of new therapies for patients with bronchiectasis and for measuring symptoms, functioning, and quality of life in these patients on a routine basis. A final psychometric validation study is needed and is forthcoming. ClinicalTrials.gov; No.: NCT00805025; URL: www.clinicaltrials.gov.

  11. Airfoil gust response and the sound produced by airifoil-vortex interaction

    NASA Technical Reports Server (NTRS)

    Amiet, R. K.

    1986-01-01

    This paper contributes to the understanding of the noise generation process of an airfoil encountering an unsteady upwash. By using a fast Fourier transform together with accurate airfoil response functions, the lift-time waveform for an airfoil encountering a delta function gust (the indicial function) is calculated for a flat plate airfoil in a compressible flow. This shows the interesting property that the lift is constant until the generated acoustic wave reaches the trailing edge. Expressions are given for the magnitude of this constant and for the pressure distribution on the airfoil during this time interval. The case of an airfoil cutting through a line vortex is also analyzed. The pressure-time waveform in the far field is closely related to the left-time waveform for the above problem of an airfoil entering a delta function gust. The effects of varying the relevant parameters in the problem are studied, including the observed position, the core diameter of the vortex, the vortex orientation and the airfoil span. The far field sound varies significantly with observer position, illustrating the importance of non-compactness effects. Increasing the viscous core diameter tends to smooth the pressure-time waveform. For small viscous core radius and infinite span, changing the vortex orientation changes only the amplitude of the pressure-time waveform, and not the shape.

  12. NIP/DuoxA is essential for Drosophila embryonic development and regulates oxidative stress response.

    PubMed

    Xie, Xiaojun; Hu, Jack; Liu, Xiping; Qin, Hanjuan; Percival-Smith, Anthony; Rao, Yong; Li, Shawn S C

    2010-05-11

    NIP/DuoxA, originally cloned as a protein capable of binding to the cell fate determinant Numb in Drosophila, was recently identified as a modulator of reactive oxygen species (ROS) production in mammalian systems. Despite biochemical and cellular studies that link NIP/DuoxA to the generation of ROS through the dual oxidase (Duox) enzyme, the in vivo function of NIP/DuoxA has not been characterized to date. Here we report a genetic and functional characterization of nip in Drosophila melanogaster. We show that nip is essential for Drosophila development as nip null mutants die at the 1(st) larval instar. Expression of UAS-nip, but not UAS-Duox, rescued the lethality. To understand the function of nip beyond the early larval stage, we generated GAL4 inducible UAS-RNAi transgenes. da(G32)-GAL4 driven, ubiquitous RNAi-mediated silencing of nip led to profound abnormality in pre-adult development, crinkled wing and markedly reduced lifespan at 29 degrees C. Compared to wild type flies, da-GAL4 induced nip-RNAi transgenic flies exhibited significantly reduced ability to survive under oxidative stress and displayed impaired mitochondrial aconitase function. Our work provides in vivo evidence for a critical role for nip in the development and oxidative stress response in Drosophila.

  13. Functional plasticity of macrophages: in situ reprogramming of tumor-associated macrophages

    PubMed Central

    Stout, Robert D.; Watkins, Stephanie K.; Suttles, Jill

    2009-01-01

    The extent to which the functional heterogeneity of Mϕs is dependent on the differentiation of functional sublineages remains unresolved. One alternative hypothesis proposes that Mϕs are functionally plastic cells, which are capable of altering their functional activities progressively in response to progressively changing signaling molecules generated in their microenvironment. This “functional plasticity” hypothesis predicts that the functionally polarized Mϕs in chronic pathologies do not represent Mϕ sublineages but rather, are mutable phenotypes sustained by chronic signaling from the pathological environment. Solid TAMϕs are chronically polarized to provide activities that support tumor growth and metastasis and suppress adaptive immune responses. In support of the functional plasticity hypothesis, administration of slow-release microsphere-encapsulated IL-12 successfully reprogrammed TAMϕs in situ, reducing Mϕ support of tumor growth and metastasis and enhancing Mϕ proimmunogenic activities. Increased knowledge of how Mϕ function is regulated and how polarized Mϕs can be reprogrammed in situ will increase our ability to control Mϕ function in a variety of pathological states, including cancer and chronic inflammatory disease. PMID:19605698

  14. Cognitive deficit in patients with paranoid schizophrenia: Its clinical and laboratory correlates.

    PubMed

    Dorofeikova, Mariia; Neznanov, Nikolay; Petrova, Nataliia

    2018-04-01

    The aim of this study was to search for correlates of cognitive impairment in patients with paranoid schizophrenia among clinical, demographic, anamnestic and biochemical markers (NSE, S100B protein, BDNF, hs-CRP). Patients with paranoid schizophrenia (n=125) were examined using the Brief Assessment of Cognitive Function in Schizophrenia, the Rey-Osterrieth Complex Figure task, and a number of clinical scales including the Positive and Negative Syndrome Scale. The majority of patients demonstrated cognitive impairment. The type of impairment was highly heterogeneous and individual. Relationships were found between the degree of executive functioning and family history of mental illness; working memory and age of onset of schizophrenia; and visual memory and psychopathological symptomatology. Negative and affective symptoms were not significantly associated with cognitive functioning. Treatment with first generation antipsychotics was associated with a more frequent impairment of motor skills, and concomitant anticholinergic drugs, with reduced accuracy. Use of second-generation antipsychotics only was associated with better accuracy, working memory and speech fluency. Among the patients, 21.4% had signs of a systemic inflammatory response, indicating a possible role of inflammatory response in the development of schizophrenia. CRP, S100B and NSE levels reflected features of the course of illness and therapeutic response. Patients with lower concentrations of BDNF were characterized by lower processing speeds. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Immunomodulatory Role of Ocimum gratissimum and Ascorbic Acid against Nicotine-Induced Murine Peritoneal Macrophages In Vitro

    PubMed Central

    Mahapatra, Santanu Kar; Chakraborty, Subhankari Prasad; Roy, Somenath

    2011-01-01

    The aim of this present study was to evaluate the immune functions and immune responses in nicotine-induced (10 mM) macrophages and concurrently establish the immunomodulatory role of aqueous extract of Ocimum gratissimum (Ae-Og) and ascorbic acid. In this study, nitrite generations and some phenotype functions by macrophages were studied. Beside that, release of Th1 cytokines (TNF-α, IL-12) and Th2 cytokines (IL-10, TGF-β) was measured by ELISA, and the expression of these cytokines at mRNA level was analyzed by real-time PCR. Ae-Og, at a dose of 10 μg/mL, significantly reduced the nicotine-induced NO generation and iNOSII expression. Similar kinds of response were observed with supplementation of ascorbic acid (0.01 mM). The administration of Ae-Og and ascorbic acid increased the decreased adherence, chemotaxis, phagocytosis, and intracellular killing of bacteria in nicotine-treated macrophages. Ae-Og and ascorbic acid were found to protect the murine peritoneal macrophages through downregulation of Th1 cytokines in nicotine-treated macrophages with concurrent activation of Th2 responses. These findings strongly enhanced our understanding of the molecular mechanism leading to nicotine-induced suppression of immune functions and provide additional rationale for application of anti-inflammatory therapeutic approaches by O. gratissimum and ascorbic acid for different inflammatory disease prevention and treatment during nicotine toxicity. PMID:22220218

  16. Generation of kisspeptin-responsive GnRH neurons from human pluripotent stem cells.

    PubMed

    Poliandri, Ariel; Miller, Duncan; Howard, Sasha; Nobles, Muriel; Ruiz-Babot, Gerard; Harmer, Stephen; Tinker, Andrew; McKay, Tristan; Guasti, Leonardo; Dunkel, Leo

    2017-05-15

    GnRH neurons are fundamental for reproduction in all vertebrates, integrating all reproductive inputs. The inaccessibility of human GnRH-neurons has been a major impediment to studying the central control of reproduction and its disorders. Here, we report the efficient generation of kisspeptin responsive GnRH-secreting neurons by directed differentiation of human Embryonic Stem Cells and induced-Pluripotent Stem Cells derived from a Kallman Syndrome patient and a healthy family member. The protocol involves the generation of intermediate Neural Progenitor Cells (NPCs) through long-term Bone morphogenetic protein 4 inhibition, followed by terminal specification of these NPCs in media containing Fibroblast Growth Factor 8 and a NOTCH inhibitor. The resulting GnRH-expressing and -secreting neurons display a neuroendocrine gene expression pattern and present spontaneous calcium transients that can be stimulated by kisspeptin. These in vitro generated GnRH expressing cells provide a new resource for studying the molecular mechanisms underlying the development and function of GnRH neurons. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Emerging concepts in T follicular helper cell responses to malaria.

    PubMed

    Hansen, Diana S; Obeng-Adjei, Nyamekye; Ly, Ann; Ioannidis, Lisa J; Crompton, Peter D

    2017-02-01

    Antibody responses to malaria and candidate malaria vaccines are short-lived in children, leaving them susceptible to repeated malaria episodes. Because T follicular helper (T FH ) cells provide critical help to B cells to generate long-lived antibody responses, they have become the focus of recent studies of Plasmodium-infected mice and humans. The emerging data converge on common themes, namely, that malaria-induced T H1 cytokines are associated with the activation of (i) T-like memory T FH cells with impaired B cell helper function, and (ii) pre-T FH cells that acquire Th1-like features (T-bet expression, IFN-γ production), which impede their differentiation into fully functional T FH cells, thus resulting in germinal center dysfunction and suboptimal antibody responses. Deeper knowledge of T FH cells in malaria could illuminate strategies to improve vaccines through modulating T FH cell responses. This review summarizes emerging concepts in T FH cell responses to malaria. Copyright © 2016. Published by Elsevier Ltd.

  18. The evolving neurobiology of gut feelings.

    PubMed

    Mayer, E A; Naliboff, B; Munakata, J

    2000-01-01

    The bi-directional communication between limbic regions and the viscera play a central role in the generation and expression of emotional responses and associated emotional feelings. The response of different viscera to distinct, emotion-specific patterns of autonomic output is fed back to the brain, in particular to the cingulofrontal convergence region. Even though this process unfolds largely without conscious awareness, it plays an important role in emotional function and may influence rational decision making in the healthy individual. Alterations in this bi-directional process such as peripheral pathologies within the gut or alterations at the brain level may explain the close association between certain affective disorders and functional visceral syndromes.

  19. Acrolein inhalation alters myocardial synchrony and performance at and below exposure concentrations that cause ventilatory responses

    EPA Science Inventory

    Acrolein is an irritating aldehyde generated during combustion of organic compounds. Altered autonomic activity has been documented following acrolein inhalation, possibly impacting myocardial synchrony and function. Given the ubiquitous nature of acrolein in the environment, we ...

  20. Obstructions in Vascular Networks: Relation Between Network Morphology and Blood Supply

    PubMed Central

    Torres Rojas, Aimee M.; Meza Romero, Alejandro; Pagonabarraga, Ignacio; Travasso, Rui D. M.; Corvera Poiré, Eugenia

    2015-01-01

    We relate vascular network structure to hemodynamics after vessel obstructions. We consider tree-like networks with a viscoelastic fluid with the rheological characteristics of blood. We analyze the network hemodynamic response, which is a function of the frequencies involved in the driving, and a measurement of the resistance to flow. This response function allows the study of the hemodynamics of the system, without the knowledge of a particular pressure gradient. We find analytical expressions for the network response, which explicitly show the roles played by the network structure, the degree of obstruction, and the geometrical place in which obstructions occur. Notably, we find that the sequence of resistances of the network without occlusions strongly determines the tendencies that the response function has with the anatomical place where obstructions are located. We identify anatomical sites in a network that are critical for its overall capacity to supply blood to a tissue after obstructions. We demonstrate that relatively small obstructions in such critical sites are able to cause a much larger decrease on flow than larger obstructions placed in non-critical sites. Our results indicate that, to a large extent, the response of the network is determined locally. That is, it depends on the structure that the vasculature has around the place where occlusions are found. This result is manifest in a network that follows Murray’s law, which is in reasonable agreement with several mammalian vasculatures. For this one, occlusions in early generation vessels have a radically different effect than occlusions in late generation vessels occluding the same percentage of area available to flow. This locality implies that whenever there is a tissue irrigated by a tree-like in vivo vasculature, our model is able to interpret how important obstructions are for the irrigation of such tissue. PMID:26086774

  1. The forms of alkalis in the biochar produced from crop residues at different temperatures.

    PubMed

    Yuan, Jin-Hua; Xu, Ren-Kou; Zhang, Hong

    2011-02-01

    The forms of alkalis of the biochars produced from the straws of canola, corn, soybean and peanut at different temperatures (300, 500 and 700°C) were studied by means of oxygen-limited pyrolysis. The alkalinity and pH of the biochars increased with increased pyrolysis temperature. The X-ray diffraction spectra and the content of carbonates of the biochars suggested that carbonates were the major alkaline components in the biochars generated at the high temperature; they were also responsible for the strong buffer plateau-regions on the acid-base titration curves at 500 and 700°C. The data of FTIR-PAS and zeta potentials indicated that the functional groups such as -COO(-) (-COOH) and -O(-) (-OH) contained by the biochars contributed greatly to the alkalinity of the biochar samples tested, especially for those generated at the lower temperature. These functional groups were also responsible for the negative charges of the biochars. Copyright © 2010 Elsevier Ltd. All rights reserved.

  2. Functional Fixedness in Creative Thinking Tasks Depends on Stimulus Modality.

    PubMed

    Chrysikou, Evangelia G; Motyka, Katharine; Nigro, Cristina; Yang, Song-I; Thompson-Schill, Sharon L

    2016-11-01

    Pictorial examples during creative thinking tasks can lead participants to fixate on these examples and reproduce their elements even when yielding suboptimal creative products. Semantic memory research may illuminate the cognitive processes underlying this effect. Here, we examined whether pictures and words differentially influence access to semantic knowledge for object concepts depending on whether the task is close- or open-ended. Participants viewed either names or pictures of everyday objects, or a combination of the two, and generated common, secondary, or ad hoc uses for them. Stimulus modality effects were assessed quantitatively through reaction times and qualitatively through a novel coding system, which classifies creative output on a continuum from top-down-driven to bottom-up-driven responses. Both analyses revealed differences across tasks. Importantly, for ad hoc uses, participants exposed to pictures generated more top-down-driven responses than those exposed to object names. These findings have implications for accounts of functional fixedness in creative thinking, as well as theories of semantic memory for object concepts.

  3. Functional Fixedness in Creative Thinking Tasks Depends on Stimulus Modality

    PubMed Central

    Chrysikou, Evangelia G.; Motyka, Katharine; Nigro, Cristina; Yang, Song-I; Thompson-Schill, Sharon L.

    2015-01-01

    Pictorial examples during creative thinking tasks can lead participants to fixate on these examples and reproduce their elements even when yielding suboptimal creative products. Semantic memory research may illuminate the cognitive processes underlying this effect. Here, we examined whether pictures and words differentially influence access to semantic knowledge for object concepts depending on whether the task is close- or open-ended. Participants viewed either names or pictures of everyday objects, or a combination of the two, and generated common, secondary, or ad hoc uses for them. Stimulus modality effects were assessed quantitatively through reaction times and qualitatively through a novel coding system, which classifies creative output on a continuum from top-down-driven to bottom-up-driven responses. Both analyses revealed differences across tasks. Importantly, for ad hoc uses, participants exposed to pictures generated more top-down-driven responses than those exposed to object names. These findings have implications for accounts of functional fixedness in creative thinking, as well as theories of semantic memory for object concepts. PMID:28344724

  4. Spaceflight and immune responses of Rhesus monkeys

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, Gerald

    1994-01-01

    Evidence from both human and rodent studies indicates that alterations in immunological parameters occur after space flight. The objective of this project is to determine the effects of space flight on immune responses of Rhesus monkeys. The expected significance of the work is a determination of the range of immunological functions of the Rhesus monkey, a primate similar in many ways to man, affected by space flight. Changes in immune responses that could yield alterations in resistance to infection may be determined as well as the duration of alterations in immune responses. Additional information on the nature of cellular interactions for the generation of immune responses may also be obtained.

  5. First-Principles Framework to Compute Sum-Frequency Generation Vibrational Spectra of Semiconductors and Insulators.

    PubMed

    Wan, Quan; Galli, Giulia

    2015-12-11

    We present a first-principles framework to compute sum-frequency generation (SFG) vibrational spectra of semiconductors and insulators. The method is based on density functional theory and the use of maximally localized Wannier functions to compute the response to electric fields, and it includes the effect of electric field gradients at surfaces. In addition, it includes quadrupole contributions to SFG spectra, thus enabling the verification of the dipole approximation, whose validity determines the surface specificity of SFG spectroscopy. We compute the SFG spectra of ice I_{h} basal surfaces and identify which spectra components are affected by bulk contributions. Our results are in good agreement with experiments at low temperature.

  6. Experimental and theoretical study of Rayleigh-Lamb waves in a plate containing a surface-breaking crack

    NASA Technical Reports Server (NTRS)

    Paffenholz, Joseph; Fox, Jon W.; Gu, Xiaobai; Jewett, Greg S.; Datta, Subhendu K.

    1990-01-01

    Scattering of Rayleigh-Lamb waves by a normal surface-breaking crack in a plate has been studied both theoretically and experimentally. The two-dimensionality of the far field, generated by a ball impact source, is exploited to characterize the source function using a direct integration technique. The scattering of waves generated by this impact source by the crack is subsequently solved by employing a Green's function integral expression for the scattered field coupled with a finite element representation of the near field. It is shown that theoretical results of plate response, both in frequency and time, are similar to those obtained experimentally. Additionally, implication for practical applications are discussed.

  7. Investigation of ODE integrators using interactive graphics. [Ordinary Differential Equations

    NASA Technical Reports Server (NTRS)

    Brown, R. L.

    1978-01-01

    Two FORTRAN programs using an interactive graphic terminal to generate accuracy and stability plots for given multistep ordinary differential equation (ODE) integrators are described. The first treats the fixed stepsize linear case with complex variable solutions, and generates plots to show accuracy and error response to step driving function of a numerical solution, as well as the linear stability region. The second generates an analog to the stability region for classes of non-linear ODE's as well as accuracy plots. Both systems can compute method coefficients from a simple specification of the method. Example plots are given.

  8. Age differences in high frequency phasic heart rate variability and performance response to increased executive function load in three executive function tasks

    PubMed Central

    Byrd, Dana L.; Reuther, Erin T.; McNamara, Joseph P. H.; DeLucca, Teri L.; Berg, William K.

    2015-01-01

    The current study examines similarity or disparity of a frontally mediated physiological response of mental effort among multiple executive functioning tasks between children and adults. Task performance and phasic heart rate variability (HRV) were recorded in children (6 to 10 years old) and adults in an examination of age differences in executive functioning skills during periods of increased demand. Executive load levels were varied by increasing the difficulty levels of three executive functioning tasks: inhibition (IN), working memory (WM), and planning/problem solving (PL). Behavioral performance decreased in all tasks with increased executive demand in both children and adults. Adults’ phasic high frequency HRV was suppressed during the management of increased IN and WM load. Children’s phasic HRV was suppressed during the management of moderate WM load. HRV was not suppressed during either children’s or adults’ increasing load during the PL task. High frequency phasic HRV may be most sensitive to executive function tasks that have a time-response pressure, and simply requiring performance on a self-paced task requiring frontal lobe activation may not be enough to generate HRV responsitivity to increasing demand. PMID:25798113

  9. Topology optimized design of functionally graded piezoelectric ultrasonic transducers

    NASA Astrophysics Data System (ADS)

    Rubio, Wilfredo Montealegre; Buiochi, Flávio; Adamowski, Julio Cezar; Silva, Emílio C. N.

    2010-01-01

    This work presents a new approach to systematically design piezoelectric ultrasonic transducers based on Topology Optimization Method (TOM) and Functionally Graded Material (FGM) concepts. The main goal is to find the optimal material distribution of Functionally Graded Piezoelectric Ultrasonic Transducers, to achieve the following requirements: (i) the transducer must be designed to have a multi-modal or uni-modal frequency response, which defines the kind of generated acoustic wave, either short pulse or continuous wave, respectively; (ii) the transducer is required to oscillate in a thickness extensional mode or piston-like mode, aiming at acoustic wave generation applications. Two kinds of piezoelectric materials are mixed for producing the FGM transducer. Material type 1 represents a PZT-5A piezoelectric ceramic and material type 2 represents a PZT-5H piezoelectric ceramic. To illustrate the proposed method, two Functionally Graded Piezoelectric Ultrasonic Transducers are designed. The TOM has shown to be a useful tool for designing Functionally Graded Piezoelectric Ultrasonic Transducers with uni-modal or multi-modal dynamic behavior.

  10. In Vitro Tissue-Engineered Skeletal Muscle Models for Studying Muscle Physiology and Disease.

    PubMed

    Khodabukus, Alastair; Prabhu, Neel; Wang, Jason; Bursac, Nenad

    2018-04-25

    Healthy skeletal muscle possesses the extraordinary ability to regenerate in response to small-scale injuries; however, this self-repair capacity becomes overwhelmed with aging, genetic myopathies, and large muscle loss. The failure of small animal models to accurately replicate human muscle disease, injury and to predict clinically-relevant drug responses has driven the development of high fidelity in vitro skeletal muscle models. Herein, the progress made and challenges ahead in engineering biomimetic human skeletal muscle tissues that can recapitulate muscle development, genetic diseases, regeneration, and drug response is discussed. Bioengineering approaches used to improve engineered muscle structure and function as well as the functionality of satellite cells to allow modeling muscle regeneration in vitro are also highlighted. Next, a historical overview on the generation of skeletal muscle cells and tissues from human pluripotent stem cells, and a discussion on the potential of these approaches to model and treat genetic diseases such as Duchenne muscular dystrophy, is provided. Finally, the need to integrate multiorgan microphysiological systems to generate improved drug discovery technologies with the potential to complement or supersede current preclinical animal models of muscle disease is described. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Phylogeny of lymphocyte heterogeneity: the cellular requirements for the mixed leucocyte reaction with channel catfish.

    PubMed Central

    Miller, N W; Deuter, A; Clem, L W

    1986-01-01

    Vigorous mixed leucocyte reactions (MLR) were obtained using channel catfish peripheral blood leucocytes (PBL) when equal numbers of responder and stimulator cells (5 X 10(5) cells each) were cocultured. The use of 2000 rads of X-irradiation was sufficient to block subsequent proliferative responses of the stimulator cells. The cellular requirements for channel catfish MLR responses were assessed by using three functionally distinct leucocyte subpopulations isolated from the PBL. B cells (sIg+ lymphocytes) and T cells (sIg- lymphocytes) were isolated by an indirect panning procedure employing a monoclonal antibody specific for channel catfish Ig. A third population, monocytes, was isolated or depleted by adherence to baby hamster kidney cell microexudate-coated surfaces or adherence to Sephadex G-10, respectively. The results indicated that only the T cells were able to respond in the fish MLR, with monocytes being required as accessory cells. In contrast, all three cell types could function as stimulator cells. In addition, it was observed that low in vitro culture temperatures inhibited the generation of channel catfish MLRs, thereby supporting the contention that low temperature immunosuppression in fish results from a preferential inhibition of the generation of primary T-cell responses. PMID:2944817

  12. A High Throughput Protein Microarray Approach to Classify HIV Monoclonal Antibodies and Variant Antigens

    PubMed Central

    Dotsey, Emmanuel Y.; Gorlani, Andrea; Ingale, Sampat; Achenbach, Chad J.; Forthal, Donald N.; Felgner, Philip L.; Gach, Johannes S.

    2015-01-01

    In recent years, high throughput discovery of human recombinant monoclonal antibodies (mAbs) has been applied to greatly advance our understanding of the specificity, and functional activity of antibodies against HIV. Thousands of antibodies have been generated and screened in functional neutralization assays, and antibodies associated with cross-strain neutralization and passive protection in primates, have been identified. To facilitate this type of discovery, a high throughput-screening tool is needed to accurately classify mAbs, and their antigen targets. In this study, we analyzed and evaluated a prototype microarray chip comprised of the HIV-1 recombinant proteins gp140, gp120, gp41, and several membrane proximal external region peptides. The protein microarray analysis of 11 HIV-1 envelope-specific mAbs revealed diverse binding affinities and specificities across clades. Half maximal effective concentrations, generated by our chip analysis, correlated significantly (P<0.0001) with concentrations from ELISA binding measurements. Polyclonal immune responses in plasma samples from HIV-1 infected subjects exhibited different binding patterns, and reactivity against printed proteins. Examining the totality of the specificity of the humoral response in this way reveals the exquisite diversity, and specificity of the humoral response to HIV. PMID:25938510

  13. Test-Anchored Vibration Response Predictions for an Acoustically Energized Curved Orthogrid Panel with Mounted Components

    NASA Technical Reports Server (NTRS)

    Frady, Gregory P.; Duvall, Lowery D.; Fulcher, Clay W. G.; Laverde, Bruce T.; Hunt, Ronald A.

    2011-01-01

    A rich body of vibroacoustic test data was recently generated at Marshall Space Flight Center for a curved orthogrid panel typical of launch vehicle skin structures. Several test article configurations were produced by adding component equipment of differing weights to the flight-like vehicle panel. The test data were used to anchor computational predictions of a variety of spatially distributed responses including acceleration, strain and component interface force. Transfer functions relating the responses to the input pressure field were generated from finite element based modal solutions and test-derived damping estimates. A diffuse acoustic field model was employed to describe the assumed correlation of phased input sound pressures across the energized panel. This application demonstrates the ability to quickly and accurately predict a variety of responses to acoustically energized skin panels with mounted components. Favorable comparisons between the measured and predicted responses were established. The validated models were used to examine vibration response sensitivities to relevant modeling parameters such as pressure patch density, mesh density, weight of the mounted component and model form. Convergence metrics include spectral densities and cumulative root-mean squared (RMS) functions for acceleration, velocity, displacement, strain and interface force. Minimum frequencies for response convergence were established as well as recommendations for modeling techniques, particularly in the early stages of a component design when accurate structural vibration requirements are needed relatively quickly. The results were compared with long-established guidelines for modeling accuracy of component-loaded panels. A theoretical basis for the Response/Pressure Transfer Function (RPTF) approach provides insight into trends observed in the response predictions and confirmed in the test data. The software modules developed for the RPTF method can be easily adapted for quick replacement of the diffuse acoustic field with other pressure field models; for example a turbulent boundary layer (TBL) model suitable for vehicle ascent. Wind tunnel tests have been proposed to anchor the predictions and provide new insight into modeling approaches for this type of environment. Finally, component vibration environments for design were developed from the measured and predicted responses and compared with those derived from traditional techniques such as Barrett scaling methods for unloaded and component-loaded panels.

  14. Dual function of CD70 in viral infection: modulator of early cytokine responses and activator of adaptive responses1

    PubMed Central

    Allam, Atef; Swiecki, Melissa; Vermi, William; Ashwell, Jonathan D.; Colonna, Marco

    2014-01-01

    The role of the tumor necrosis factor family member CD70 in adaptive T cell responses has been intensively studied but its function in innate responses is still under investigation. Here we show that CD70 inhibits the early innate response to murine cytomegalovirus (MCMV) but is essential for the optimal generation of virus-specific CD8 T cells. CD70-/- mice reacted to MCMV infection with a robust type I interferon and proinflammatory cytokine response. This response was sufficient for initial control of MCMV, although at later time points, CD70-/- mice became more susceptible to MCMV infection. The heightened cytokine response during the early phase of MCMV infection in CD70-/- mice was paralleled by a reduction in regulatory T cells (Treg). Treg from naïve CD70-/- mice were not as efficient at suppressing T cell proliferation compared to Treg from naïve WT mice and depletion of Treg during MCMV infection in Foxp3-DTR mice or in WT mice recapitulated the phenotype observed in CD70-/- mice. Our study demonstrates that while CD70 is required for the activation of the antiviral adaptive response, it has a regulatory role in early cytokine responses to viruses such as MCMV, possibly through maintenance of Treg survival and function. PMID:24913981

  15. Enhanced microglial pro-inflammatory response to lipopolysaccharide correlates with brain infiltration and blood-brain barrier dysregulation in a mouse model of telomere shortening.

    PubMed

    Raj, Divya D A; Moser, Jill; van der Pol, Susanne M A; van Os, Ronald P; Holtman, Inge R; Brouwer, Nieske; Oeseburg, Hisko; Schaafsma, Wandert; Wesseling, Evelyn M; den Dunnen, Wilfred; Biber, Knut P H; de Vries, Helga E; Eggen, Bart J L; Boddeke, Hendrikus W G M

    2015-12-01

    Microglia are a proliferative population of resident brain macrophages that under physiological conditions self-renew independent of hematopoiesis. Microglia are innate immune cells actively surveying the brain and are the earliest responders to injury. During aging, microglia elicit an enhanced innate immune response also referred to as 'priming'. To date, it remains unknown whether telomere shortening affects the proliferative capacity and induces priming of microglia. We addressed this issue using early (first-generation G1 mTerc(-/-) )- and late-generation (third-generation G3 and G4 mTerc(-/-) ) telomerase-deficient mice, which carry a homozygous deletion for the telomerase RNA component gene (mTerc). Late-generation mTerc(-/-) microglia show telomere shortening and decreased proliferation efficiency. Under physiological conditions, gene expression and functionality of G3 mTerc(-/-) microglia are comparable with microglia derived from G1 mTerc(-/-) mice despite changes in morphology. However, after intraperitoneal injection of bacterial lipopolysaccharide (LPS), G3 mTerc(-/-) microglia mice show an enhanced pro-inflammatory response. Nevertheless, this enhanced inflammatory response was not accompanied by an increased expression of genes known to be associated with age-associated microglia priming. The increased inflammatory response in microglia correlates closely with increased peripheral inflammation, a loss of blood-brain barrier integrity, and infiltration of immune cells in the brain parenchyma in this mouse model of telomere shortening. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  16. Viral and cellular SOS-regulated motor proteins: dsDNA translocation mechanisms with divergent functions.

    PubMed

    Wolfe, Annie; Phipps, Kara; Weitao, Tao

    2014-01-01

    DNA damage attacks on bacterial cells have been known to activate the SOS response, a transcriptional response affecting chromosome replication, DNA recombination and repair, cell division and prophage induction. All these functions require double-stranded (ds) DNA translocation by ASCE hexameric motors. This review seeks to delineate the structural and functional characteristics of the SOS response and the SOS-regulated DNA translocases FtsK and RuvB with the phi29 bacteriophage packaging motor gp16 ATPase as a prototype to study bacterial motors. While gp16 ATPase, cellular FtsK and RuvB are similarly comprised of hexameric rings encircling dsDNA and functioning as ATP-driven DNA translocases, they utilize different mechanisms to accomplish separate functions, suggesting a convergent evolution of these motors. The gp16 ATPase and FtsK use a novel revolution mechanism, generating a power stroke between subunits through an entropy-DNA affinity switch and pushing dsDNA inward without rotation of DNA and the motor, whereas RuvB seems to employ a rotation mechanism that remains to be further characterized. While FtsK and RuvB perform essential tasks during the SOS response, their roles may be far more significant as SOS response is involved in antibiotic-inducible bacterial vesiculation and biofilm formation as well as the perspective of the bacteria-cancer evolutionary interaction.

  17. Primary Care Practices' Abilities And Challenges In Using Electronic Health Record Data For Quality Improvement.

    PubMed

    Cohen, Deborah J; Dorr, David A; Knierim, Kyle; DuBard, C Annette; Hemler, Jennifer R; Hall, Jennifer D; Marino, Miguel; Solberg, Leif I; McConnell, K John; Nichols, Len M; Nease, Donald E; Edwards, Samuel T; Wu, Winfred Y; Pham-Singer, Hang; Kho, Abel N; Phillips, Robert L; Rasmussen, Luke V; Duffy, F Daniel; Balasubramanian, Bijal A

    2018-04-01

    Federal value-based payment programs require primary care practices to conduct quality improvement activities, informed by the electronic reports on clinical quality measures that their electronic health records (EHRs) generate. To determine whether EHRs produce reports adequate to the task, we examined survey responses from 1,492 practices across twelve states, supplemented with qualitative data. Meaningful-use participation, which requires the use of a federally certified EHR, was associated with the ability to generate reports-but the reports did not necessarily support quality improvement initiatives. Practices reported numerous challenges in generating adequate reports, such as difficulty manipulating and aligning measurement time frames with quality improvement needs, lack of functionality for generating reports on electronic clinical quality measures at different levels, discordance between clinical guidelines and measures available in reports, questionable data quality, and vendors that were unreceptive to changing EHR configuration beyond federal requirements. The current state of EHR measurement functionality may be insufficient to support federal initiatives that tie payment to clinical quality measures.

  18. Primary Care Practices’ Abilities And Challenges In Using Electronic Health Record Data For Quality Improvement

    PubMed Central

    Cohen, Deborah J.; Dorr, David A.; Knierim, Kyle; DuBard, C. Annette; Hemler, Jennifer R.; Hall, Jennifer D.; Marino, Miguel; Solberg, Leif I.; McConnell, K. John; Nichols, Len M.; Nease, Donald E.; Edwards, Samuel T.; Wu, Winfred Y.; Pham-Singer, Hang; Kho, Abel N.; Phillips, Robert L.; Rasmussen, Luke V.; Duffy, F. Daniel; Balasubramanian, Bijal A.

    2018-01-01

    Federal value-based payment programs require primary care practices to conduct quality improvement activities, informed by the electronic reports on clinical quality measures that their electronic health records (EHRs) generate. To determine whether EHRs produce reports adequate to the task, we examined survey responses from 1,492 practices across twelve states, supplemented with qualitative data. Meaningful-use participation, which requires the use of a federally certified EHR, was associated with the ability to generate reports—but the reports did not necessarily support quality improvement initiatives. Practices reported numerous challenges in generating adequate reports, such as difficulty manipulating and aligning measurement time frames with quality improvement needs, lack of functionality for generating reports on electronic clinical quality measures at different levels, discordance between clinical guidelines and measures available in reports, questionable data quality, and vendors that were unreceptive to changing EHR configuration beyond federal requirements. The current state of EHR measurement functionality may be insufficient to support federal initiatives that tie payment to clinical quality measures. PMID:29608365

  19. A Feasibility Assessment of a Single Contracting Office for Common-User Transportation Services

    DTIC Science & Technology

    1990-09-01

    feasibility of consolidating the contracting functions that purchase common-user transportation services and occurs within the headquarters of the three...responsible for and the dollars spent in the procurement of those services. A complete breakdown of the services purchased is in chapter three. The...34 while contracting is the process a’contracting officer completes to satisfy a funded purchase request generated in response to a identified

  20. Responsive 3D microstructures from virus building blocks.

    PubMed

    Oh, Seungwhan; Kwak, Eun-A; Jeon, Seongho; Ahn, Suji; Kim, Jong-Man; Jaworski, Justyn

    2014-08-13

    Fabrication of 3D biological structures reveals dynamic response to external stimuli. A liquid-crystalline bridge extrusion technique is used to generate 3D structures allowing the capture of Rayleigh-like instabilities, facilitating customization of smooth, helical, or undulating periodic surface textures. By integrating intrinsic biochemical functionality and synthetic components into controlled structures, this strategy offers a new form of adaptable materials. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Dimorphous expressions of positive emotion: displays of both care and aggression in response to cute stimuli.

    PubMed

    Aragón, Oriana R; Clark, Margaret S; Dyer, Rebecca L; Bargh, John A

    2015-03-01

    Extremely positive experiences, and positive appraisals thereof, produce intense positive emotions that often generate both positive expressions (e.g., smiles) and expressions normatively reserved for negative emotions (e.g., tears). We developed a definition of these dimorphous expressions and tested the proposal that their function is to regulate emotions. We showed that individuals who express emotions in this dimorphous manner do so as a general response across a variety of emotionally provoking situations, which suggests that these expressions are responses to intense positive emotion rather than unique to one particular situation. We used cute stimuli (an elicitor of positive emotion) to demonstrate both the existence of these dimorphous expressions and to provide preliminary evidence of their function as regulators of emotion. © The Author(s) 2015.

  2. Immunoglobulin D (IgD)-deficient mice reveal an auxiliary receptor function for IgD in antigen-mediated recruitment of B cells

    PubMed Central

    1993-01-01

    To assess the role of immunoglobulin D (IgD) in vivo we generated IgD- deficient mice by gene targeting and studied B cell development and function in the absence of IgD expression. In the mutant animals, conventional and CD5-positive (B1) B cells are present in normal numbers, and the expression of the surface markers CD22 and CD23 in the compartment of conventional B cells indicates acquisition of a mature phenotype. As in wild-type animals, most of the peripheral B cells are resting cells. The IgD-deficient mice respond well to T cell- independent and -dependent antigens. However, in heterozygous mutant animals, B cells expressing the wild type IgH locus are overrepresented in the peripheral B cell pool, and T cell-dependent IgG1 responses are further dominated by B cells expressing the wild-type allele. Similarly, in homozygous mutant (IgD-deficient) animals, affinity maturation is delayed in the early primary response compared to control animals, although the mutants are capable of generating high affinity B cell memory. Thus, rather than being involved in major regulatory processes as had been suggested, IgD seems to function as an antigen receptor optimized for efficient recruitment of B cells into antigen- driven responses. The IgD-mediated acceleration of affinity maturation in the early phase of the T cell-dependent primary response may confer to the animal a critical advantage in the defense against pathogens. PMID:8418208

  3. Response diversity determines the resilience of ecosystems to environmental change.

    PubMed

    Mori, Akira S; Furukawa, Takuya; Sasaki, Takehiro

    2013-05-01

    A growing body of evidence highlights the importance of biodiversity for ecosystem stability and the maintenance of optimal ecosystem functionality. Conservation measures are thus essential to safeguard the ecosystem services that biodiversity provides and human society needs. Current anthropogenic threats may lead to detrimental (and perhaps irreversible) ecosystem degradation, providing strong motivation to evaluate the response of ecological communities to various anthropogenic pressures. In particular, ecosystem functions that sustain key ecosystem services should be identified and prioritized for conservation action. Traditional diversity measures (e.g. 'species richness') may not adequately capture the aspects of biodiversity most relevant to ecosystem stability and functionality, but several new concepts may be more appropriate. These include 'response diversity', describing the variation of responses to environmental change among species of a particular community. Response diversity may also be a key determinant of ecosystem resilience in the face of anthropogenic pressures and environmental uncertainty. However, current understanding of response diversity is poor, and we see an urgent need to disentangle the conceptual strands that pervade studies of the relationship between biodiversity and ecosystem functioning. Our review clarifies the links between response diversity and the maintenance of ecosystem functionality by focusing on the insurance hypothesis of biodiversity and the concept of functional redundancy. We provide a conceptual model to describe how loss of response diversity may cause ecosystem degradation through decreased ecosystem resilience. We explicitly explain how response diversity contributes to functional compensation and to spatio-temporal complementarity among species, leading to long-term maintenance of ecosystem multifunctionality. Recent quantitative studies suggest that traditional diversity measures may often be uncoupled from measures (such as response diversity) that may be more effective proxies for ecosystem stability and resilience. Certain conclusions and recommendations of earlier studies using these traditional measures as indicators of ecosystem resilience thus may be suspect. We believe that functional ecology perspectives incorporating the effects and responses of diversity are essential for development of management strategies to safeguard (and restore) optimal ecosystem functionality (especially multifunctionality). Our review highlights these issues and we envision our work generating debate around the relationship between biodiversity and ecosystem functionality, and leading to improved conservation priorities and biodiversity management practices that maximize ecosystem resilience in the face of uncertain environmental change. © 2012 The Authors. Biological Reviews © 2012 Cambridge Philosophical Society.

  4. H2S Regulates Hypobaric Hypoxia-Induced Early Glio-Vascular Dysfunction and Neuro-Pathophysiological Effects

    PubMed Central

    Kumar, Gaurav; Chhabra, Aastha; Mishra, Shalini; Kalam, Haroon; Kumar, Dhiraj; Meena, Ramniwas; Ahmad, Yasmin; Bhargava, Kalpana; Prasad, Dipti N.; Sharma, Manish

    2016-01-01

    Hypobaric Hypoxia (HH) is an established risk factor for various neuro-physiological perturbations including cognitive impairment. The origin and mechanistic basis of such responses however remain elusive. We here combined systems level analysis with classical neuro-physiological approaches, in a rat model system, to understand pathological responses of brain to HH. Unbiased ‘statistical co-expression networks’ generated utilizing temporal, differential transcriptome signatures of hippocampus—centrally involved in regulating cognition—implicated perturbation of Glio-Vascular homeostasis during early responses to HH, with concurrent modulation of vasomodulatory, hemostatic and proteolytic processes. Further, multiple lines of experimental evidence from ultra-structural, immuno-histological, substrate-zymography and barrier function studies unambiguously supported this proposition. Interestingly, we show a significant lowering of H2S levels in the brain, under chronic HH conditions. This phenomenon functionally impacted hypoxia-induced modulation of cerebral blood flow (hypoxic autoregulation) besides perturbing the strength of functional hyperemia responses. The augmentation of H2S levels, during HH conditions, remarkably preserved Glio-Vascular homeostasis and key neuro-physiological functions (cerebral blood flow, functional hyperemia and spatial memory) besides curtailing HH-induced neuronal apoptosis in hippocampus. Our data thus revealed causal role of H2S during HH-induced early Glio-Vascular dysfunction and consequent cognitive impairment. PMID:27211559

  5. Nanowire arrays restore vision in blind mice.

    PubMed

    Tang, Jing; Qin, Nan; Chong, Yan; Diao, Yupu; Yiliguma; Wang, Zhexuan; Xue, Tian; Jiang, Min; Zhang, Jiayi; Zheng, Gengfeng

    2018-03-06

    The restoration of light response with complex spatiotemporal features in retinal degenerative diseases towards retinal prosthesis has proven to be a considerable challenge over the past decades. Herein, inspired by the structure and function of photoreceptors in retinas, we develop artificial photoreceptors based on gold nanoparticle-decorated titania nanowire arrays, for restoration of visual responses in the blind mice with degenerated photoreceptors. Green, blue and near UV light responses in the retinal ganglion cells (RGCs) are restored with a spatial resolution better than 100 µm. ON responses in RGCs are blocked by glutamatergic antagonists, suggesting functional preservation of the remaining retinal circuits. Moreover, neurons in the primary visual cortex respond to light after subretinal implant of nanowire arrays. Improvement in pupillary light reflex suggests the behavioral recovery of light sensitivity. Our study will shed light on the development of a new generation of optoelectronic toolkits for subretinal prosthetic devices.

  6. Development of Vibrational Culture Model Mimicking Vocal Fold Tissues.

    PubMed

    Kim, Dongjoo; Lim, Jae-Yol; Kwon, Soonjo

    2016-10-01

    The vocal folds (VFs) are connective tissues with complex matrix structures that provide the required mechanical properties for voice generation. VF injury leads to changes in tissue structure and properties, resulting in reduced voice quality. However, injury-induced biochemical changes and repair in scarred VF tissues have not been well characterized to date. To treat scarred VFs, it is essential to understand how physiological characteristics of VFs tissue change in response to external perturbation. In this study, we designed a simple vibrational culture model to mimic vibratory microenvironments observed in vivo. This model consists of a flexible culture plate, three linear actuators, a stereo splitter, and a function generator. Human vocal fold fibroblast (hVFF) monolayers were established on the flexible membrane, to which normal phonatory vibrations were delivered from linear actuators and a function generator. The hVFF monolayers were exposed to the vibrational stresses at a frequency of 205 Hz for 2, 6, and 10 h with maximum displacement of 47.1 μm, followed by a 6 h rest. We then observed the changes in cell morphology, cell viability, and gene expression related to extracellular matrix components. In our dynamic culture device mimicking normal phonatory frequencies, cell proliferation increased and expression of hyaluronic acid synthase 2 was downregulated in response to vibrational stresses. The results presented herein will be useful for evaluating cellular responses following VF injuries in the presence or absence of vibrational stresses.

  7. Reactivity of hemodynamic responses and functional connectivity to different states of alpha synchrony: a concurrent EEG-fMRI study.

    PubMed

    Wu, Lei; Eichele, Tom; Calhoun, Vince D

    2010-10-01

    Concurrent EEG-fMRI studies have provided increasing details of the dynamics of intrinsic brain activity during the resting state. Here, we investigate a prominent effect in EEG during relaxed resting, i.e. the increase of the alpha power when the eyes are closed compared to when the eyes are open. This phenomenon is related to changes in thalamo-cortical and cortico-cortical synchronization. In order to investigate possible changes to EEG-fMRI coupling and fMRI functional connectivity during the two states we adopted a data-driven approach that fuses the multimodal data on the basis of parallel ICA decompositions of the fMRI data in the spatial domain and of the EEG data in the spectral domain. The power variation of a posterior alpha component was used as a reference function to deconvolve the hemodynamic responses from occipital, frontal, temporal, and subcortical fMRI components. Additionally, we computed the functional connectivity between these components. The results showed widespread alpha hemodynamic responses and high functional connectivity during eyes-closed (EC) rest, while eyes open (EO) resting abolished many of the hemodynamic responses and markedly decreased functional connectivity. These data suggest that generation of local hemodynamic responses is highly sensitive to state changes that do not involve changes of mental effort or awareness. They also indicate the localized power differences in posterior alpha between EO and EC in resting state data are accompanied by spatially widespread amplitude changes in hemodynamic responses and inter-regional functional connectivity, i.e. low frequency hemodynamic signals display an equivalent of alpha reactivity. Copyright 2010 Elsevier Inc. All rights reserved.

  8. A nonlinear filter-bank model of the guinea-pig cochlear nerve: Rate responses

    NASA Astrophysics Data System (ADS)

    Sumner, Christian J.; O'Mard, Lowel P.; Lopez-Poveda, Enrique A.; Meddis, Ray

    2003-06-01

    The aim of this study is to produce a functional model of the auditory nerve (AN) response of the guinea-pig that reproduces a wide range of important responses to auditory stimulation. The model is intended for use as an input to larger scale models of auditory processing in the brain-stem. A dual-resonance nonlinear filter architecture is used to reproduce the mechanical tuning of the cochlea. Transduction to the activity on the AN is accomplished with a recently proposed model of the inner-hair-cell. Together, these models have been shown to be able to reproduce the response of high-, medium-, and low-spontaneous rate fibers from the guinea-pig AN at high best frequencies (BFs). In this study we generate parameters that allow us to fit the AN model to data from a wide range of BFs. By varying the characteristics of the mechanical filtering as a function of the BF it was possible to reproduce the BF dependence of frequency-threshold tuning curves, AN rate-intensity functions at and away from BF, compression of the basilar membrane at BF as inferred from AN responses, and AN iso-intensity functions. The model is a convenient computational tool for the simulation of the range of nonlinear tuning and rate-responses found across the length of the guinea-pig cochlear nerve.

  9. Functional characterization of blue-light-induced responses and PHOTOTROPIN 1 gene in Welwitschia mirabilis.

    PubMed

    Ishishita, Kazuhiro; Suetsugu, Noriyuki; Hirose, Yuki; Higa, Takeshi; Doi, Michio; Wada, Masamitsu; Matsushita, Tomonao; Gotoh, Eiji

    2016-03-01

    The blue light (BL) receptor phototropin (phot) is specifically found in green plants; it regulates various BL-induced responses such as phototropism, chloroplast movement, stomatal opening, and leaf flattening. In Arabidopsis thaliana, two phototropins--phot1 and phot2--respond to blue light in overlapping but distinct ways. These BL-receptor-mediated responses enhance the photosynthetic activity of plants under weak light and minimize photodamage under strong light conditions. Welwitschia mirabilis Hook.f. found in the Namib Desert, and it has adapted to severe environmental stresses such as limiting water and strong sunlight. Although the plant has physiologically and ecologically unique features, it is unknown whether phototropin is functional in this plant. In this study, we assessed the functioning of phot-mediated BL responses in W. mirabilis. BL-dependent phototropism and stomatal opening was observed but light-dependent chloroplast movement was not detected. We performed a functional analysis of the PHOT1 gene of W. mirabilis, WmPHOT1, in Arabidopsis thaliana. We generated transgenic A. thaliana lines expressing WmPHOT1 in a phot1 phot2 double mutant background. Several Wmphot1 transgenic plants showed normal growth, although phot1 phot2 double mutant plants showed stunted growth. Furthermore, Wmphot1 transgenic plants showed normal phot1-mediated responses including phototropism, chloroplast accumulation, stomatal opening, and leaf flattening, but lacked the chloroplast avoidance response that is specifically mediated by phot2. Thus, our findings indicate that W. mirabilis possesses typical phot-mediated BL responses that were at least partially mediated by functional phototropin 1, an ortholog of Atphot1.

  10. Role of Hypomethylating Agents in the Treatment of Bone Marrow Failure

    DTIC Science & Technology

    2016-10-01

    functional studies, as proposed in Aim 2, to find that cells with cohesin gene mutations are sensitized to hypomethylating agents. We used CRISPR /Cas9...screen loss of function mutations in MDS for response to azacitidine. We used CRISPR /Cas9 genome engineering of primary human hematopoietic stem and...investigate whether sites of altered methylation occur at hydroxymethylated loci. We generated isogenic TF-1 cell line clones using CRISPR -Cas9

  11. Human platelet lysate is a successful alternative serum supplement for propagation of monocyte-derived dendritic cells.

    PubMed

    Švajger, Urban

    2017-04-01

    Clinical protocols for dendritic cell (DC) generation from monocytes require the use of animal serum-free supplements. Serum-free media can also require up to 1% of serum supplementation. In addition, recommendations based on the 3Rs (Refinement, Reduction, Replacement) principle also recommend the use of non-animal sera in in vitro studies. The aim of this study was to explore the potential use of platelet lysate (PL) for generation of optimally differentiated DCs from monocytes. Cells were isolated from buffy coats from healthy volunteers using immunomagnetic selection. DCs were differentiated in RPMI1640 supplemented with either 10% fetal bovine serum (FBS), 10% AB serum or 10% PL with the addition of granulocyte monocyte colony stimulating factor and interleukin-4. Generated DCs were assessed for their morphology, viability, endocytotic capacity, surface phenotype (immature, mature and tolerogenic DCs) and activation of important signaling pathways. DC function was evaluated on the basis of their allostimulatory capacity, cytokine profile and ability to induce different T-helper subsets. DCs generated with PL displayed normal viability, morphology and endocytotic capacity. Their differentiation and maturation phenotype was comparable to FBS-cultured DCs. They showed functional plasticity and up-regulated tolerogenic markers in response to their environment. PL-cultured mature DCs displayed unhindered allostimulatory potential and the capacity to induce Th1 responses. The use of PL allowed for activation of crucial signaling proteins associated with DC differentiation and maturation. This study demonstrates for the first time that human PL represents a successful alternative to FBS in differentiation of DCs from monocytes. DCs display the major phenotypic and functional characteristics compared with existing culture protocols. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  12. A Scalable System for Production of Functional Pancreatic Progenitors from Human Embryonic Stem Cells

    PubMed Central

    Schulz, Thomas C.; Young, Holly Y.; Agulnick, Alan D.; Babin, M. Josephine; Baetge, Emmanuel E.; Bang, Anne G.; Bhoumik, Anindita; Cepa, Igor; Cesario, Rosemary M.; Haakmeester, Carl; Kadoya, Kuniko; Kelly, Jonathan R.; Kerr, Justin; Martinson, Laura A.; McLean, Amanda B.; Moorman, Mark A.; Payne, Janice K.; Richardson, Mike; Ross, Kelly G.; Sherrer, Eric S.; Song, Xuehong; Wilson, Alistair Z.; Brandon, Eugene P.; Green, Chad E.; Kroon, Evert J.; Kelly, Olivia G.; D’Amour, Kevin A.; Robins, Allan J.

    2012-01-01

    Development of a human embryonic stem cell (hESC)-based therapy for type 1 diabetes will require the translation of proof-of-principle concepts into a scalable, controlled, and regulated cell manufacturing process. We have previously demonstrated that hESC can be directed to differentiate into pancreatic progenitors that mature into functional glucose-responsive, insulin-secreting cells in vivo. In this study we describe hESC expansion and banking methods and a suspension-based differentiation system, which together underpin an integrated scalable manufacturing process for producing pancreatic progenitors. This system has been optimized for the CyT49 cell line. Accordingly, qualified large-scale single-cell master and working cGMP cell banks of CyT49 have been generated to provide a virtually unlimited starting resource for manufacturing. Upon thaw from these banks, we expanded CyT49 for two weeks in an adherent culture format that achieves 50–100 fold expansion per week. Undifferentiated CyT49 were then aggregated into clusters in dynamic rotational suspension culture, followed by differentiation en masse for two weeks with a four-stage protocol. Numerous scaled differentiation runs generated reproducible and defined population compositions highly enriched for pancreatic cell lineages, as shown by examining mRNA expression at each stage of differentiation and flow cytometry of the final population. Islet-like tissue containing glucose-responsive, insulin-secreting cells was generated upon implantation into mice. By four- to five-months post-engraftment, mature neo-pancreatic tissue was sufficient to protect against streptozotocin (STZ)-induced hyperglycemia. In summary, we have developed a tractable manufacturing process for the generation of functional pancreatic progenitors from hESC on a scale amenable to clinical entry. PMID:22623968

  13. Thermo-responsive cell culture carrier: Effects on macrophage functionality and detachment efficiency.

    PubMed

    Rennert, Knut; Nitschke, Mirko; Wallert, Maria; Keune, Natalie; Raasch, Martin; Lorkowski, Stefan; Mosig, Alexander S

    2017-01-01

    Harvesting cultivated macrophages for tissue engineering purposes by enzymatic digestion of cell adhesion molecules can potentially result in unintended activation, altered function, or behavior of these cells. Thermo-responsive polymer is a promising tool that allows for gentle macrophage detachment without artificial activation prior to subculture within engineered tissue constructs. We therefore characterized different species of thermo-responsive polymers for their suitability as cell substrate and to mediate gentle macrophage detachment by temperature shift. Primary human monocyte- and THP-1-derived macrophages were cultured on thermo-responsive polymers and characterized for phagocytosis and cytokine secretion in response to lipopolysaccharide stimulation. We found that both cell types differentially respond in dependence of culture and stimulation on thermo-responsive polymers. In contrast to THP-1 macrophages, primary monocyte-derived macrophages showed no signs of impaired viability, artificial activation, or altered functionality due to culture on thermo-responsive polymers compared to conventional cell culture. Our study demonstrates that along with commercially available UpCell carriers, two other thermo-responsive polymers based on poly(vinyl methyl ether) blends are attractive candidates for differentiation and gentle detachment of primary monocyte-derived macrophages. In summary, we observed similar functionality and viability of primary monocyte-derived macrophages cultured on thermo-responsive polymers compared to standard cell culture surfaces. While this first generation of custom-made thermo-responsive polymers does not yet outperform standard culture approaches, our results are very promising and provide the basis for exploiting the unique advantages offered by custom-made thermo-responsive polymers to further improve macrophage culture and recovery in the future, including the covalent binding of signaling molecules and the reduction of centrifugation and washing steps. Optimizing these and other benefits of thermo-responsive polymers could greatly improve the culture of macrophages for tissue engineering applications.

  14. Gammadelta T cells: functional plasticity and heterogeneity.

    PubMed

    Carding, Simon R; Egan, Paul J

    2002-05-01

    Gammadelta T cells remain an enigma. They are capable of generating more unique antigen receptors than alphabeta T cells and B cells combined, yet their repertoire of antigen receptors is dominated by specific subsets that recognize a limited number of antigens. A variety of sometimes conflicting effector functions have been ascribed to them, yet their biological function(s) remains unclear. On the basis of studies of gammadelta T cells in infectious and autoimmune diseases, we argue that gammadelta T cells perform different functions according to their tissue distribution, antigen-receptor structure and local microenvironment; we also discuss how and at what stage of the immune response they become activated.

  15. Activity in the human brain predicting differential heart rate responses to emotional facial expressions.

    PubMed

    Critchley, Hugo D; Rotshtein, Pia; Nagai, Yoko; O'Doherty, John; Mathias, Christopher J; Dolan, Raymond J

    2005-02-01

    The James-Lange theory of emotion proposes that automatically generated bodily reactions not only color subjective emotional experience of stimuli, but also necessitate a mechanism by which these bodily reactions are differentially generated to reflect stimulus quality. To examine this putative mechanism, we simultaneously measured brain activity and heart rate to identify regions where neural activity predicted the magnitude of heart rate responses to emotional facial expressions. Using a forewarned reaction time task, we showed that orienting heart rate acceleration to emotional face stimuli was modulated as a function of the emotion depicted. The magnitude of evoked heart rate increase, both across the stimulus set and within each emotion category, was predicted by level of activity within a matrix of interconnected brain regions, including amygdala, insula, anterior cingulate, and brainstem. We suggest that these regions provide a substrate for translating visual perception of emotional facial expression into differential cardiac responses and thereby represent an interface for selective generation of visceral reactions that contribute to the embodied component of emotional reaction.

  16. Pericytes of the neurovascular unit: Key functions and signaling pathways

    PubMed Central

    Sweeney, Melanie D.; Ayyadurai, Shiva; Zlokovic, Berislav V.

    2017-01-01

    Pericytes are vascular mural cells embedded in the basement membrane of blood microvessels. They extend their processes along capillaries, pre-capillary arterioles, and post-capillary venules. The central nervous system (CNS) pericytes are uniquely positioned within the neurovascular unit between endothelial cells, astrocytes, and neurons. They integrate, coordinate, and process signals from their neighboring cells to generate diverse functional responses that are critical for CNS functions in health and disease including regulation of the blood-brain barrier permeability, angiogenesis, clearance of toxic metabolites, capillary hemodynamic responses, neuroinflammation, and stem cell activity. Here, we examine the key signaling pathways between pericytes and their neighboring endothelial cells, astrocytes, and neurons that control neurovascular functions. We also review the role of pericytes in different CNS disorders including rare monogenic diseases and complex neurological disorders such as Alzheimer's disease and brain tumors. Finally, we discuss directions for future studies. PMID:27227366

  17. Fish T cells: recent advances through genomics

    USGS Publications Warehouse

    Laing, Kerry J.; Hansen, John D.

    2011-01-01

    This brief review is intended to provide a concise overview of the current literature concerning T cells, advances in identifying distinct T cell functional subsets, and in distinguishing effector cells from memory cells. We compare and contrast a wealth of recent progress made in T cell immunology of teleost, elasmobranch, and agnathan fish, to knowledge derived from mammalian T cell studies. From genome studies, fish clearly have most components associated with T cell function and we can speculate on the presence of putative T cell subsets, and the ability to detect their differentiation to form memory cells. Some recombinant proteins for T cell associated cytokines and antibodies for T cell surface receptors have been generated that will facilitate studying the functional roles of teleost T cells during immune responses. Although there is still a long way to go, major advances have occurred in recent years for investigating T cell responses, thus phenotypic and functional characterization is on the near horizon.

  18. Towards integrated hygiene and food safety management systems: the Hygieneomic approach.

    PubMed

    Armstrong, G D

    1999-09-15

    Integrated hygiene and food safety management systems in food production can give rise to exceptional improvements in food safety performance, but require high level commitment and full functional involvement. A new approach, named hygieneomics, has been developed to assist management in their introduction of hygiene and food safety systems. For an effective introduction, the management systems must be designed to fit with the current generational state of an organisation. There are, broadly speaking, four generational states of an organisation in their approach to food safety. They comprise: (i) rules setting; (ii) ensuring compliance; (iii) individual commitment; (iv) interdependent action. In order to set up an effective integrated hygiene and food safety management system a number of key managerial requirements are necessary. The most important ones are: (a) management systems must integrate the activities of key functions from research and development through to supply chain and all functions need to be involved; (b) there is a critical role for the senior executive, in communicating policy and standards; (c) responsibilities must be clearly defined, and it should be clear that food safety is a line management responsibility not to be delegated to technical or quality personnel; (d) a thorough and effective multi-level audit approach is necessary; (e) key activities in the system are HACCP and risk management, but it is stressed that these are ongoing management activities, not once-off paper generating exercises; and (f) executive management board level review is necessary of audit results, measurements, status and business benefits.

  19. Second-harmonic generation from a positive-negative index material heterostructure.

    PubMed

    Mattiucci, Nadia; D'Aguanno, Giuseppe; Bloemer, Mark J; Scalora, Michael

    2005-12-01

    Resonant cavities have been widely used in the past to enhance material, nonlinear response. Traditional mirrors include metallic films and distributed Bragg reflectors. In this paper we propose negative index material mirrors as a third alternative. With the help of a rigorous Green function approach, we investigate second harmonic generation from single and coupled cavities, and theoretically prove that negative index material mirrors can raise the nonlinear conversion efficiency of a bulk material by at least four orders of magnitude compared to a bulk medium.

  20. CD70-deficiency impairs effector CD8 T cell generation and viral clearance but is dispensable for the recall response to LCMV

    PubMed Central

    Munitic, Ivana; Kuka, Mirela; Allam, Atef; Scoville, Jonathan P.; Ashwell, Jonathan D.

    2012-01-01

    CD27 interactions with its ligand, CD70, are thought to be necessary for optimal primary and memory adaptive immune responses to a variety of pathogens. Thus far all studies addressing the function of the CD27-CD70 axis have been performed either in mice lacking CD27, overexpressing CD70, or in which these receptors were blocked or mimicked by antibodies or recombinant soluble CD70. Because these methods have in some cases led to divergent results, we generated CD70-deficient mice to directly assess its role in vivo. We find that lack of CD70-mediated stimulation during primary responses to LCMV lowered the magnitude of CD8 antigen-specific T cell response, resulting in impaired viral clearance, without affecting CD4 T cell responses. Unexpectedly, CD70-CD27 costimulation was not needed for memory CD8 T cell generation or the ability to mount a recall response to LCMV. Adoptive transfers of wild type (WT) memory T cells into CD70−/− or WT hosts also showed no need for CD70-mediated stimulation during the course of the recall response. Moreover, CD70-expression by CD8 T cells could not rescue endogenous CD70−/− cells from defective expansion, arguing against a role for CD70-mediated T:T help in this model. Therefore, CD70 appears to be an important factor in the initiation of a robust and effective primary response but dispensable for CD8 T cell memory responses. PMID:23269247

  1. Phenotype and function of nasal dendritic cells

    PubMed Central

    Lee, Haekyung; Ruane, Darren; Law, Kenneth; Ho, Yan; Garg, Aakash; Rahman, Adeeb; Esterházy, Daria; Cheong, Cheolho; Goljo, Erden; Sikora, Andrew G.; Mucida, Daniel; Chen, Benjamin; Govindraj, Satish; Breton, Gaëlle; Mehandru, Saurabh

    2015-01-01

    Intranasal vaccination generates immunity across local, regional and distant sites. However, nasal dendritic cells (DC), pivotal for the induction of intranasal vaccine- induced immune responses, have not been studied in detail. Here, using a variety of parameters, we define nasal DCs in mice and humans. Distinct subsets of “classical” DCs, dependent on the transcription factor zbtb46 were identified in the murine nose. The murine nasal DCs were FLT3 ligand-responsive and displayed unique phenotypic and functional characteristics including the ability to present antigen, induce an allogeneic T cell response and migrate in response to LPS or live bacterial pathogens. Importantly, in a cohort of human volunteers, BDCA-1+ DCs were observed to be the dominant nasal DC population at steady state. During chronic inflammation, the frequency of both BDCA-1+ and BDCA-3hi DCs was reduced in the nasal tissue, associating the loss of these immune sentinels with chronic nasal inflammation. The present study is the first detailed description of the phenotypic, ontogenetic and functional properties of nasal DCs and will inform the design of preventative immunization strategies as well as therapeutic modalities against chronic rhinosinusitis. PMID:25669151

  2. Calculation of the static in-flight telescope-detector response by deconvolution applied to point-spread function for the geostationary earth radiation budget experiment.

    PubMed

    Matthews, Grant

    2004-12-01

    The Geostationary Earth Radiation Budget (GERB) experiment is a broadband satellite radiometer instrument program intended to resolve remaining uncertainties surrounding the effect of cloud radiative feedback on future climate change. By use of a custom-designed diffraction-aberration telescope model, the GERB detector spatial response is recovered by deconvolution applied to the ground calibration point-spread function (PSF) measurements. An ensemble of randomly generated white-noise test scenes, combined with the measured telescope transfer function results in the effect of noise on the deconvolution being significantly reduced. With the recovered detector response as a base, the same model is applied in construction of the predicted in-flight field-of-view response of each GERB pixel to both short- and long-wave Earth radiance. The results of this study can now be used to simulate and investigate the instantaneous sampling errors incurred by GERB. Also, the developed deconvolution method may be highly applicable in enhancing images or PSF data for any telescope system for which a wave-front error measurement is available.

  3. Polysensory response characteristics of dorsal root ganglion neurones that may serve sensory functions during myocardial ischaemia.

    PubMed

    Huang, M H; Horackova, M; Negoescu, R M; Wolf, S; Armour, J A

    1996-09-01

    To determine the response characteristics of dorsal root ganglion neurones that may serve sensory functions during myocardial ischaemia. Extracellular recordings were made from 54 spontaneously active and 5 normally quiescent dorsal root ganglion neurones (T2-T5) in 22 anaesthetized open-chest dogs under control conditions and during epicardial mechanical or chemical stimulation and myocardial ischaemia. The activity of 78% of spontaneously active and all quiescent neurones with left ventricular sensory fields was modified by left ventricular ischaemia. Forty-six spontaneously active neurones (85%) were polysensory with respect to mechanical and chemical stimuli. The 5 quiescent neurones responded only to chemical stimuli. Spontaneously active neurones associated with left ventricular mechanosensory endings (37 neurones) generated four different activity patterns in response to similar mechanical stimuli (high or low pressure active, high-low pressure active, high-low pressure inactive). A fifth group generated activity which was not related to chamber dynamics. Adenosine, adenosine 5'-triphosphate, substance P and bradykinin modified 72, 61, 65 and 63% of the spontaneously active neurones, respectively. Maximum local mechanical or chemical stimuli enhanced activity to similar degrees, as did ischaemia. Each ischaemia-sensitive neurone displayed unique activity patterns in response to similar mechanical or chemical stimuli. Most myocardial ischemia-sensitive dorsal root ganglion neurones associated with epicardial neurites sense mechanical and multiple chemical stimuli, a small population sensing only mechanical or chemical stimuli. Activity patterns generated by these neurones depend on their primary sensory characteristics or those of other neurones that may converge on them, as well as the type and magnitude of the stimuli that impinge upon their sensory fields, both normally and during ischaemia.

  4. Genome-wide analysis of alternative splicing during dendritic cell response to a bacterial challenge.

    PubMed

    Rodrigues, Raquel; Grosso, Ana Rita; Moita, Luís

    2013-01-01

    The immune system relies on the plasticity of its components to produce appropriate responses to frequent environmental challenges. Dendritic cells (DCs) are critical initiators of innate immunity and orchestrate the later and more specific adaptive immunity. The generation of diversity in transcriptional programs is central for effective immune responses. Alternative splicing is widely considered a key generator of transcriptional and proteomic complexity, but its role has been rarely addressed systematically in immune cells. Here we used splicing-sensitive arrays to assess genome-wide gene- and exon-level expression profiles in human DCs in response to a bacterial challenge. We find widespread alternative splicing events and splicing factor transcriptional signatures induced by an E. coli challenge to human DCs. Alternative splicing acts in concert with transcriptional modulation, but these two mechanisms of gene regulation affect primarily distinct functional gene groups. Alternative splicing is likely to have an important role in DC immunobiology because it affects genes known to be involved in DC development, endocytosis, antigen presentation and cell cycle arrest.

  5. Functional Genomics Using the Saccharomyces cerevisiae Yeast Deletion Collections.

    PubMed

    Nislow, Corey; Wong, Lai Hong; Lee, Amy Huei-Yi; Giaever, Guri

    2016-09-01

    Constructed by a consortium of 16 laboratories, the Saccharomyces genome-wide deletion collections have, for the past decade, provided a powerful, rapid, and inexpensive approach for functional profiling of the yeast genome. Loss-of-function deletion mutants were systematically created using a polymerase chain reaction (PCR)-based gene deletion strategy to generate a start-to-stop codon replacement of each open reading frame by homologous recombination. Each strain carries two molecular barcodes that serve as unique strain identifiers, enabling their growth to be analyzed in parallel and the fitness contribution of each gene to be quantitatively assessed by hybridization to high-density oligonucleotide arrays or through the use of next-generation sequencing technologies. Functional profiling of the deletion collections, using either strain-by-strain or parallel assays, provides an unbiased approach to systematically survey the yeast genome. The Saccharomyces yeast deletion collections have proved immensely powerful in contributing to the understanding of gene function, including functional relationships between genes and genetic pathways in response to diverse genetic and environmental perturbations. © 2016 Cold Spring Harbor Laboratory Press.

  6. Müller glia: Stem cells for generation and regeneration of retinal neurons in teleost fish

    PubMed Central

    Lenkowski, Jenny R.; Raymond, Pamela A.

    2014-01-01

    Adult zebrafish generate new neurons in the brain and retina throughout life. Growth-related neurogenesis allows a vigorous regenerative response to damage, and fish can regenerate retinal neurons, including photoreceptors, and restore functional vision following photic, chemical, or mechanical destruction of the retina. Müller glial cells in fish function as radial-glial-like neural stem cells. During adult growth, Müller glial nuclei undergo sporadic, asymmetric, self-renewing mitotic divisions in the inner nuclear layer to generate a rod progenitor that migrates along the radial fiber of the Müller glia into the outer nuclear layer, proliferates, and differentiates exclusively into rod photoreceptors. When retinal neurons are destroyed, Müller glia in the immediate vicinity of the damage partially and transiently dedifferentiate, re-express retinal progenitor and stem cell markers, re-enter the cell cycle, undergo interkinetic nuclear migration (characteristic of neuroepithelial cells), and divide once in an asymmetric, self-renewing division to generate a retinal progenitor. This daughter cell proliferates rapidly to form a compact neurogenic cluster surrounding the Müller glia; these multipotent retinal progenitors then migrate along the radial fiber to the appropriate lamina to replace missing retinal neurons. Some aspects of the injury-response in fish Müller glia resemble gliosis as observed in mammals, and mammalian Müller glia exhibit some neurogenic properties, indicative of a latent ability to regenerate retinal neurons. Understanding the specific properties of fish Müller glia that facilitate their robust capacity to generate retinal neurons will inform and inspire new clinical approaches for treating blindness and visual loss with regenerative medicine. PMID:24412518

  7. A novel function for the pineal organ in the control of swim depth in the Atlantic halibut larva

    NASA Astrophysics Data System (ADS)

    Novales Flamarique, Iñigo

    2002-02-01

    The pineal organ of vertebrates is a photo-sensitive structure that conveys photoperiod information to the brain. This information influences circadian rhythm and related metabolic processes such as thermoregulation, hatching time, body growth, and the timing of reproduction. This study demonstrates extra-ocular light responses that control swim depth in the larva of the Atlantic halibut, Hyppoglosus hyppoglosus. Young larvae without a functional eye (<29 days) swim upwards after an average delay of 5 s following the onset of a downwelling light stimulus, but sink downwards a few seconds later. Older larvae (>=29 days), which possess a functional eye, swim immediately downwards (microsecond delay) following the onset of the light stimulus, but proceed to swim upwards several seconds later. These two response patterns are thus opposite in polarity and have different time kinetics. Because the pineal organ of the Atlantic halibut develops during the embryonic stage, and because it is the only centre in the brain that expresses functional visual pigments (opsins) at early larval stages, it is the only photosensory organ capable of generating the extra-ocular responses observed.

  8. Temporal pattern changes in duodenal protein tyrosine nitration events in response to Eimeria acervulina infection in chickens

    USDA-ARS?s Scientific Manuscript database

    Intracellular generation of nitric oxide (NO) and superoxide anion (SOA) can result in the formation of 3'-nitrotyrosine proteins (NTp). Nitrated proteins usually are associated with significant perturbation in protein function, apoptosis, and cell death. We undertook the present study to establis...

  9. Significant modulation of mitochondrial electron transport system by nicotine in various rat brain regions

    USDA-ARS?s Scientific Manuscript database

    The mitochondrion is the organelle responsible for generation of most usable energy in a cell. It also plays an important role in a series of physiological processes such as apoptosis and proliferation. Although previous studies have demonstrated that nicotine modulates the morphology and function ...

  10. Analysis of complex samples using a portable multi-wavelength light emitting diode (LED) fluorescence spectrometer

    USDA-ARS?s Scientific Manuscript database

    Spectroscopic analysis of chemically complex samples often requires an increase n the dimensionality of the measured response surface. This often involves the measurement of emitted light intensities as functions of both wavelengths of excitation and emission resulting in the generation of an excita...

  11. Dreaming of a Better ILS

    ERIC Educational Resources Information Center

    Bahr, Ellen

    2007-01-01

    What would technological librarians like to see in the next generation of Integrated Library Systems (ILS)? This question was asked of several well- known library technology experts, and their responses are presented in this article. Survey respondents expressed a clear desire for the following features and functionality: (1) Direct, read-only…

  12. Peptides and peptidomimetics as immunomodulators

    PubMed Central

    Gokhale, Ameya S; Satyanarayanajois, Seetharama

    2014-01-01

    Peptides and peptidomimetics can function as immunomodulating agents by either blocking the immune response or stimulating the immune response to generate tolerance. Knowledge of B- or T-cell epitopes along with conformational constraints is important in the design of peptide-based immunomodulating agents. Work on the conformational aspects of peptides, synthesis and modified amino acid side chains have contributed to the development of a new generation of therapeutic agents for autoimmune diseases and cancer. The design of peptides/peptidomimetics for immunomodulation in autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, systemic lupus and HIV infection is reviewed. In cancer therapy, peptide epitopes are used in such a way that the body is trained to recognize and fight the cancer cells locally as well as systemically. PMID:25186605

  13. Aberrant in Vivo T Helper Type 2 Cell Response and Impaired Eosinophil Recruitment in Cc Chemokine Receptor 8 Knockout Mice

    PubMed Central

    Chensue, Stephen W.; Lukacs, Nicholas W.; Yang, Tong-Yuan; Shang, Xiaozhou; Frait, Kirsten A.; Kunkel, Steven L.; Kung, Ted; Wiekowski, Maria T.; Hedrick, Joseph A.; Cook, Donald N.; Zingoni, Alessandra; Narula, Satwant K.; Zlotnik, Albert; Barrat, Franck J.; O'Garra, Anne; Napolitano, Monica; Lira, Sergio A.

    2001-01-01

    Chemokine receptors transduce signals important for the function and trafficking of leukocytes. Recently, it has been shown that CC chemokine receptor (CCR)8 is selectively expressed by Th2 subsets, but its functional relevance is unclear. To address the biological role of CCR8, we generated CCR8 deficient (−/−) mice. Here we report defective T helper type 2 (Th2) immune responses in vivo in CCR8−/− mice in models of Schistosoma mansoni soluble egg antigen (SEA)-induced granuloma formation as well as ovalbumin (OVA)- and cockroach antigen (CRA)-induced allergic airway inflammation. In these mice, the response to SEA, OVA, and CRA showed impaired Th2 cytokine production that was associated with aberrant type 2 inflammation displaying a 50 to 80% reduction in eosinophils. In contrast, a prototypical Th1 immune response, elicited by Mycobacteria bovis purified protein derivative (PPD) was unaffected by CCR8 deficiency. Mechanistic analyses indicated that Th2 cells developed normally and that the reduction in eosinophil recruitment was likely due to systemic reduction in interleukin 5. These results indicate an important role for CCR8 in Th2 functional responses in vivo. PMID:11238588

  14. Estimation of Supersonic Stage Separation Aerodynamics of Winged-Body Launch Vehicles Using Response Surface Methods

    NASA Technical Reports Server (NTRS)

    Erickson, Gary E.

    2010-01-01

    Response surface methodology was used to estimate the longitudinal stage separation aerodynamic characteristics of a generic, bimese, winged multi-stage launch vehicle configuration at supersonic speeds in the NASA LaRC Unitary Plan Wind Tunnel. The Mach 3 staging was dominated by shock wave interactions between the orbiter and booster vehicles throughout the relative spatial locations of interest. The inference space was partitioned into several contiguous regions within which the separation aerodynamics were presumed to be well-behaved and estimable using central composite designs capable of fitting full second-order response functions. The underlying aerodynamic response surfaces of the booster vehicle in belly-to-belly proximity to the orbiter vehicle were estimated using piecewise-continuous lower-order polynomial functions. The quality of fit and prediction capabilities of the empirical models were assessed in detail, and the issue of subspace boundary discontinuities was addressed. Augmenting the central composite designs to full third-order using computer-generated D-optimality criteria was evaluated. The usefulness of central composite designs, the subspace sizing, and the practicality of fitting lower-order response functions over a partitioned inference space dominated by highly nonlinear and possibly discontinuous shock-induced aerodynamics are discussed.

  15. Curcumin prevents human dendritic cell response to immune stimulants

    PubMed Central

    Shirley, Shawna A.; Montpetit, Alison J.; Lockey, R.F.; Mohapatra, Shyam S.

    2012-01-01

    Curcumin, a compound found in the Indian spice turmeric, has anti-inflammatory and immunomodulatory properties, though the mechanism remains unclear. Dendritic cells (DCs) are important to generating an immune response and the effect of curcumin on human DCs has not been explored. The role curcumin in the DC response to bacterial and viral infection was investigated in vitro using LPS and Poly I:C as models of infection. CD14+ monocytes, isolated from human peripheral blood, were cultured in GM-CSF- and IL-4-supplemented medium to generate immature DCs. Cultures were incubated with curcumin, stimulated with LPS or Poly I:C and functional assays were performed. Curcumin prevents DCs from responding to immunostimulants and inducing naïve CD4+ T cell proliferation by blocking maturation marker, cytokine and chemokine expression and reducing both migration and endocytosis. These data suggest a therapeutic role for curcumin as an immune suppressant. PMID:18639521

  16. Curcumin prevents human dendritic cell response to immune stimulants

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Shirley, Shawna A.; Montpetit, Alison J.; Lockey, R.F.

    2008-09-26

    Curcumin, a compound found in the Indian spice turmeric, has anti-inflammatory and immunomodulatory properties, though the mechanism remains unclear. Dendritic cells (DCs) are important to generating an immune response and the effect of curcumin on human DCs has not been explored. The role curcumin in the DC response to bacterial and viral infection was investigated in vitro using LPS and Poly I:C as models of infection. CD14{sup +} monocytes, isolated from human peripheral blood, were cultured in GM-CSF- and IL-4-supplemented medium to generate immature DCs. Cultures were incubated with curcumin, stimulated with LPS or Poly I:C and functional assays weremore » performed. Curcumin prevents DCs from responding to immunostimulants and inducing CD4{sup +} T cell proliferation by blocking maturation marker, cytokine and chemokine expression and reducing both migration and endocytosis. These data suggest a therapeutic role for curcumin as an immune suppressant.« less

  17. [Formula: see text]Executive functions and social information processing in adolescents with severe behavior problems.

    PubMed

    Van Nieuwenhuijzen, M; Van Rest, M M; Embregts, P J C M; Vriens, A; Oostermeijer, S; Van Bokhoven, I; Matthys, W

    2017-02-01

    One tradition in research for explaining aggression and antisocial behavior has focused on social information processing (SIP). Aggression and antisocial behavior have also been studied from the perspective of executive functions (EFs), the higher-order cognitive abilities that affect other cognitive processes, such as social cognitive processes. The main goal of the present study is to provide insight into the relation between EFs and SIP in adolescents with severe behavior problems. Because of the hierarchical relation between EFs and SIP, we examined EFs as predictors of SIP. We hypothesized that, first, focused attention predicts encoding and interpretation, second, inhibition predicts interpretation, response generation, evaluation, and selection, and third, working memory predicts response generation and selection. The participants consisted of 94 respondents living in residential facilities aged 12-20 years, all showing behavior problems in the clinical range according to care staff. EFs were assessed using subtests from the Amsterdam Neuropsychological Test battery. Focused attention was measured by the Flanker task, inhibition by the GoNoGo task, and working memory by the Visual Spatial Sequencing task. SIP was measured by video vignettes and a structured interview. The results indicate that positive evaluation of aggressive responses is predicted by impaired inhibition and selection of aggressive responses by a combination of impaired focused attention and inhibition. It is concluded that different components of EFs as higher-order cognitive abilities affect SIP.

  18. Antimicrobial peptides and induced membrane curvature: geometry, coordination chemistry, and molecular engineering

    PubMed Central

    Schmidt, Nathan W.; Wong, Gerard C. L.

    2013-01-01

    Short cationic, amphipathic antimicrobial peptides are multi-functional molecules that have roles in host defense as direct microbicides and modulators of the immune response. While a general mechanism of microbicidal activity involves the selective disruption and permeabilization of cell membranes, the relationships between peptide sequence and membrane activity are still under investigation. Here, we review the diverse functions that AMPs collectively have in host defense, and show that these functions can be multiplexed with a membrane mechanism of activity derived from the generation of negative Gaussian membrane curvature. As AMPs preferentially generate this curvature in model bacterial cell membranes, the selective generation of negative Gaussian curvature provides AMPs with a broad mechanism to target microbial membranes. The amino acid constraints placed on AMPs by the geometric requirement to induce negative Gaussian curvature are consistent with known AMP sequences. This ‘saddle-splay curvature selection rule’ is not strongly restrictive so AMPs have significant compositional freedom to multiplex membrane activity with other useful functions. The observation that certain proteins involved in cellular processes which require negative Gaussian curvature contain domains with similar motifs as AMPs, suggests this rule may be applicable to other curvature-generating proteins. Since our saddle-splay curvature design rule is based upon both a mechanism of activity and the existing motifs of natural AMPs, we believe it will assist the development of synthetic antimicrobials. PMID:24778573

  19. B-cell activation with CD40L or CpG measures the function of B-cell subsets and identifies specific defects in immunodeficient patients.

    PubMed

    Marasco, Emiliano; Farroni, Chiara; Cascioli, Simona; Marcellini, Valentina; Scarsella, Marco; Giorda, Ezio; Piano Mortari, Eva; Leonardi, Lucia; Scarselli, Alessia; Valentini, Diletta; Cancrini, Caterina; Duse, Marzia; Grimsholm, Ola; Carsetti, Rita

    2017-01-01

    Around 65% of primary immunodeficiencies are antibody deficiencies. Functional tests are useful tools to study B-cell functions in vitro. However, no accepted guidelines for performing and evaluating functional tests have been issued yet. Here, we report our experience on the study of B-cell functions in infancy and throughout childhood. We show that T-independent stimulation with CpG measures proliferation and differentiation potential of memory B cells. Switched memory B cells respond better than IgM memory B cells. On the other hand, CD40L, a T-dependent stimulus, does not induce plasma cell differentiation, but causes proliferation of naïve and memory B cells. During childhood, the production of plasmablasts in response to CpG increases with age mirroring the development of memory B cells. The response to CD40L does not change with age. In patients with selective IgA deficiency (SIgAD), we observed that switched memory B cells are reduced due to the absence of IgA memory B cells. In agreement, IgA plasma cells are not generated in response to CpG. Unexpectedly, B cells from SIgAD patients show a reduced proliferative response to CD40L. Our results demonstrate that functional tests are an important tool to assess the functions of the humoral immune system. © 2016 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Engaging the CD40-CD40L pathway augments T-helper cell responses and improves control of Mycobacterium tuberculosis infection

    PubMed Central

    Bizzell, Erica; Madan-Lala, Ranjna

    2017-01-01

    Mycobacterium tuberculosis (Mtb) impairs dendritic cell (DC) functions and induces suboptimal antigen-specific CD4 T cell immune responses that are poorly protective. Mucosal T-helper cells producing IFN-γ (Th1) and IL-17 (Th17) are important for protecting against tuberculosis (TB), but the mechanisms by which DCs generate antigen-specific T-helper responses during Mtb infection are not well defined. We previously reported that Mtb impairs CD40 expression on DCs and restricts Th1 and Th17 responses. We now demonstrate that CD40-dependent costimulation is required to generate IL-17 responses to Mtb. CD40-deficient DCs were unable to induce antigen-specific IL-17 responses after Mtb infection despite the production of Th17-polarizing innate cytokines. Disrupting the interaction between CD40 on DCs and its ligand CD40L on antigen-specific CD4 T cells, genetically or via antibody blockade, significantly reduced antigen-specific IL-17 responses. Importantly, engaging CD40 on DCs with a multimeric CD40 agonist (CD40LT) enhanced antigen-specific IL-17 generation in ex vivo DC-T cell co-culture assays. Further, intratracheal instillation of Mtb-infected DCs treated with CD40LT significantly augmented antigen-specific Th17 responses in vivo in the lungs and lung-draining lymph nodes of mice. Finally, we show that boosting CD40-CD40L interactions promoted balanced Th1/Th17 responses in a setting of mucosal DC transfer, and conferred enhanced control of lung bacterial burdens following aerosol challenge with Mtb. Our results demonstrate that CD40 costimulation by DCs plays an important role in generating antigen-specific Th17 cells and targeting the CD40-CD40L pathway represents a novel strategy to improve adaptive immunity to TB. PMID:28767735

  1. A glance at subgenomic flavivirus RNAs and microRNAs in flavivirus infections.

    PubMed

    Bavia, Lorena; Mosimann, Ana Luiza Pamplona; Aoki, Mateus Nóbrega; Duarte Dos Santos, Claudia Nunes

    2016-05-28

    The family Flaviviridae comprises a wide variety of viruses that are distributed worldwide, some of which are associated with high rates of morbidity and mortality. There are neither vaccines nor antivirals for most flavivirus infections, reinforcing the importance of research on different aspects of the viral life cycle. During infection, cytoplasmic accumulation of RNA fragments mainly originating from the 3' UTRs, which have been designated subgenomic flavivirus RNAs (sfRNAs), has been detected. It has been shown that eukaryotic exoribonucleases are involved in viral sfRNA production. Additionally, viral and human small RNAs (sRNAs) have also been found in flavivirus-infected cells, especially microRNAs (miRNAs). miRNAs were first described in eukaryotic cells and in a mature and functional state present as single-stranded 18-24 nt RNA fragments. Their main function is the repression of translation through base pairing with cellular mRNAs, besides other functions, such as mRNA degradation. Canonical miRNA biogenesis involves Drosha and Dicer, however miRNA can also be generated by alternative pathways. In the case of flaviviruses, alternative pathways have been suggested. Both sfRNAs and miRNAs are involved in viral infection and host cell response modulation, representing interesting targets of antiviral strategies. In this review, we focus on the generation and function of viral sfRNAs, sRNAs and miRNAs in West Nile, dengue, Japanese encephalitis, Murray Valley encephalitis and yellow fever infections, as well as their roles in viral replication, translation and cell immune response evasion. We also give an overview regarding other flaviviruses and the generation of cellular miRNAs during infection.

  2. Hydrogen sulfide protects endothelial nitric oxide function under conditions of acute oxidative stress in vitro.

    PubMed

    Al-Magableh, Mohammad R; Kemp-Harper, Barbara K; Ng, Hooi H; Miller, Alyson A; Hart, Joanne L

    2014-01-01

    The aim of this study was to examine the ability of H2S, released from NaHS to protect vascular endothelial function under conditions of acute oxidative stress by scavenging superoxide anions (O2(-)) and suppressing vascular superoxide anion production. O2(-) was generated in Krebs' solution by reacting hypoxanthine with xanthine oxidase (Hx-XO) or with the O2(-) generator pyrogallol to model acute oxidative stress in vitro. O2(-) generation was measured by lucigenin-enhanced chemiluminescence. Functional responses in mouse aortic rings were assessed using a small vessel myograph. NaHS scavenged O2(-) in a concentration-dependent manner. Isolated aortic rings exposed to either Hx-XO or pyrogallol displayed significantly attenuated maximum vasorelaxation responses to the endothelium-dependent vasodilator acetylcholine, and significantly reduced NO bioavailability, which was completely reversed if vessels were pre-incubated with NaHS (100 μM). NADPH-stimulated aortic O2(-) production was significantly attenuated by the NADPH oxidase inhibitor diphenyl iodonium. Prior treatment of vessels with NaHS (100 nM-100 μM; 30 min) inhibited NADPH-stimulated aortic O2(-) production in a concentration-dependent manner. This effect persisted when NaHS was washed out prior to measuring NADPH-stimulated O2(-) production. These data show for the first time that NaHS directly scavenges O2(-) and suppresses vascular NADPH oxidase-derived O2(-) production in vitro. Furthermore, these properties protect endothelial function and NO bioavailability in an in vitro model of acute oxidative stress. These results suggest that H2S can elicit vasoprotection by both scavenging O2(-) and by reducing vascular NADPH oxidase-derived O2(-) production.

  3. Aging and Immune Function: Molecular Mechanisms to Interventions

    PubMed Central

    Ponnappan, Subramaniam

    2011-01-01

    Abstract The immune system of an organism is an essential component of the defense mechanism aimed at combating pathogenic stress. Age-associated immune dysfunction, also dubbed “immune senescence,” manifests as increased susceptibility to infections, increased onset and progression of autoimmune diseases, and onset of neoplasia. Over the years, extensive research has generated consensus in terms of the phenotypic and functional defects within the immune system in various organisms, including humans. Indeed, age-associated alterations such as thymic involution, T cell repertoire skewing, decreased ability to activate naïve T cells and to generate robust memory responses, have been shown to have a causative role in immune decline. Further, understanding the molecular mechanisms underlying the generation of proteotoxic stress, DNA damage response, modulation of ubiquitin proteasome pathway, and regulation of transcription factor NFκB activation, in immune decline, have paved the way to delineating signaling pathways that cross-talk and impact immune senescence. Given the role of the immune system in combating infections, its effectiveness with age may well be a marker of health and a predictor of longevity. It is therefore believed that a better understanding of the mechanisms underlying immune senescence will lead to an effective interventional strategy aimed at improving the health span of individuals. Antioxid. Redox Signal. 14, 1551–1585. PMID:20812785

  4. Cortical network reorganization guided by sensory input features.

    PubMed

    Kilgard, Michael P; Pandya, Pritesh K; Engineer, Navzer D; Moucha, Raluca

    2002-12-01

    Sensory experience alters the functional organization of cortical networks. Previous studies using behavioral training motivated by aversive or rewarding stimuli have demonstrated that cortical plasticity is specific to salient inputs in the sensory environment. Sensory experience associated with electrical activation of the basal forebrain (BasF) generates similar input specific plasticity. By directly engaging plasticity mechanisms and avoiding extensive behavioral training, BasF stimulation makes it possible to efficiently explore how specific sensory features contribute to cortical plasticity. This review summarizes our observations that cortical networks employ a variety of strategies to improve the representation of the sensory environment. Different combinations of receptive-field, temporal, and spectrotemporal plasticity were generated in primary auditory cortex neurons depending on the pitch, modulation rate, and order of sounds paired with BasF stimulation. Simple tones led to map expansion, while modulated tones altered the maximum cortical following rate. Exposure to complex acoustic sequences led to the development of combination-sensitive responses. This remodeling of cortical response characteristics may reflect changes in intrinsic cellular mechanisms, synaptic efficacy, and local neuronal connectivity. The intricate relationship between the pattern of sensory activation and cortical plasticity suggests that network-level rules alter the functional organization of the cortex to generate the most behaviorally useful representation of the sensory environment.

  5. Comparative metagenomic and metatranscriptomic analyses of microbial communities in acid mine drainage.

    PubMed

    Chen, Lin-xing; Hu, Min; Huang, Li-nan; Hua, Zheng-shuang; Kuang, Jia-liang; Li, Sheng-jin; Shu, Wen-sheng

    2015-07-01

    The microbial communities in acid mine drainage have been extensively studied to reveal their roles in acid generation and adaption to this environment. Lacking, however, are integrated community- and organism-wide comparative gene transcriptional analyses that could reveal the response and adaptation mechanisms of these extraordinary microorganisms to different environmental conditions. In this study, comparative metagenomics and metatranscriptomics were performed on microbial assemblages collected from four geochemically distinct acid mine drainage (AMD) sites. Taxonomic analysis uncovered unexpectedly high microbial biodiversity of these extremely acidophilic communities, and the abundant taxa of Acidithiobacillus, Leptospirillum and Acidiphilium exhibited high transcriptional activities. Community-wide comparative analyses clearly showed that the AMD microorganisms adapted to the different environmental conditions via regulating the expression of genes involved in multiple in situ functional activities, including low-pH adaptation, carbon, nitrogen and phosphate assimilation, energy generation, environmental stress resistance, and other functions. Organism-wide comparative analyses of the active taxa revealed environment-dependent gene transcriptional profiles, especially the distinct strategies used by Acidithiobacillus ferrivorans and Leptospirillum ferrodiazotrophum in nutrients assimilation and energy generation for survival under different conditions. Overall, these findings demonstrate that the gene transcriptional profiles of AMD microorganisms are closely related to the site physiochemical characteristics, providing clues into the microbial response and adaptation mechanisms in the oligotrophic, extremely acidic environments.

  6. Air shower simulation for WASAVIES: warning system for aviation exposure to solar energetic particles.

    PubMed

    Sato, T; Kataoka, R; Yasuda, H; Yashiro, S; Kuwabara, T; Shiota, D; Kubo, Y

    2014-10-01

    WASAVIES, a warning system for aviation exposure to solar energetic particles (SEPs), is under development by collaboration between several institutes in Japan and the USA. It is designed to deterministically forecast the SEP fluxes incident on the atmosphere within 6 h after flare onset using the latest space weather research. To immediately estimate the aircrew doses from the obtained SEP fluxes, the response functions of the particle fluxes generated by the incidence of monoenergetic protons into the atmosphere were developed by performing air shower simulations using the Particle and Heavy Ion Transport code system. The accuracy of the simulation was well verified by calculating the increase count rates of a neutron monitor during a ground-level enhancement, combining the response function with the SEP fluxes measured by the PAMELA spectrometer. The response function will be implemented in WASAVIES and used to protect aircrews from additional SEP exposure. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  7. Research Review: altered reward function in adolescent depression: what, when and how?

    PubMed

    Forbes, Erika E; Dahl, Ronald E

    2012-01-01

    Conceptual models and recent evidence indicate that neural response to reward is altered in depression. Taking a developmental approach to investigating reward function in adolescent depression can elucidate the etiology, pathophysiology and course of depression, a disorder that typically begins during adolescence and has high rates of recurrence. This conceptual review describes the what, when and how of altered reward function in adolescent depression. With the goal of generating new, testable hypotheses within a developmental affective neuroscience framework, we critically review findings and suggest future directions. Peer-reviewed empirical papers for inclusion in this critical review were obtained by searching PubMed, PsycInfo and ScienceDirect for the years 1990-2010. A pattern of low striatal response and high medial prefrontal response to reward is evident in adolescents and adults with depression. Given the salience of social stimuli for positive affect and depression, reward function might be especially disrupted in response to social rewards. Because of changes in the dopamine system and reward function with aging, altered reward function in depression might be more evident during adolescence than later in life; however, low reward function may also be a stable characteristic of people who experience depression. Mechanisms of altered reward function in depression could include disrupted balance of corticostriatal circuit function, with disruption occurring as aberrant adolescent brain development. Future studies should examine responses to social rewards; employ longitudinal and prospective designs; and investigate patterns of functional connectivity in reward circuits. Understanding altered reward function in depression has potential implications for treatment development. A more rigorous approach to investigating anhedonia, threat-reward interactions and comorbid anxiety will be valuable to future progress in describing the role of reward function in the pathophysiology of depression. © 2011 The Authors. Journal of Child Psychology and Psychiatry © 2011 Association for Child and Adolescent Mental Health.

  8. Local control theory using trajectory surface hopping and linear-response time-dependent density functional theory.

    PubMed

    Curchod, Basile F E; Penfold, Thomas J; Rothlisberger, Ursula; Tavernelli, Ivano

    2013-01-01

    The implementation of local control theory using nonadiabatic molecular dynamics within the framework of linear-response time-dependent density functional theory is discussed. The method is applied to study the photoexcitation of lithium fluoride, for which we demonstrate that this approach can efficiently generate a pulse, on-the-fly, able to control the population transfer between two selected electronic states. Analysis of the computed control pulse yields insights into the photophysics of the process identifying the relevant frequencies associated to the curvature of the initial and final state potential energy curves and their energy differences. The limitations inherent to the use of the trajectory surface hopping approach are also discussed.

  9. SNM1B/Apollo in the DNA damage response and telomere maintenance

    PubMed Central

    Schmiester, Maren; Demuth, Ilja

    2017-01-01

    hSNM1B/Apollo is a member of the highly conserved β-CASP subgroup within the MBL superfamily of proteins. It interacts with several DNA repair proteins and functions within the Fanconi anemia pathway in response to DNA interstrand crosslinks. As a shelterin accessory protein, hSNM1B/Apollo is also vital for the generation and maintenance of telomeric overhangs. In this review, we will summarize studies on hSNM1B/Apollo's function, including its contribution to DNA damage signaling, replication fork maintenance, control of topological stress and telomere protection. Furthermore, we will highlight recent studies illustrating hSNM1B/Apollo's putative role in human disease. PMID:28430596

  10. SNM1B/Apollo in the DNA damage response and telomere maintenance.

    PubMed

    Schmiester, Maren; Demuth, Ilja

    2017-07-18

    hSNM1B/Apollo is a member of the highly conserved β-CASP subgroup within the MBL superfamily of proteins. It interacts with several DNA repair proteins and functions within the Fanconi anemia pathway in response to DNA interstrand crosslinks. As a shelterin accessory protein, hSNM1B/Apollo is also vital for the generation and maintenance of telomeric overhangs. In this review, we will summarize studies on hSNM1B/Apollo's function, including its contribution to DNA damage signaling, replication fork maintenance, control of topological stress and telomere protection. Furthermore, we will highlight recent studies illustrating hSNM1B/Apollo's putative role in human disease.

  11. Immune-Modulating Perspectives for Low Frequency Electromagnetic Fields in Innate Immunity

    PubMed Central

    Rosado, Maria Manuela; Simkó, Myrtill; Mattsson, Mats-Olof; Pioli, Claudio

    2018-01-01

    In recent years, the effects of electromagnetic fields (EMFs) on the immune system have received a considerable interest, not only to investigate possible negative health impact but also to explore the possibility to favorably modulate immune responses. To generate beneficial responses, the immune system should eradicate pathogens while “respecting” the organism and tolerating irrelevant antigens. According to the current view, damage-associated molecules released by infected or injured cells, or secreted by innate immune cells generate danger signals activating an immune response. These signals are also relevant to the subsequent activation of homeostatic mechanisms that control the immune response in pro- or anti-inflammatory reactions, a feature that allows modulation by therapeutic treatments. In the present review, we describe and discuss the effects of extremely low frequency (ELF)-EMF and pulsed EMF on cell signals and factors relevant to the activation of danger signals and innate immunity cells. By discussing the EMF modulating effects on cell functions, we envisage the use of EMF as a therapeutic agent to regulate immune responses associated with wound healing. PMID:29632855

  12. Essential Role of Lymph Nodes in Contact Hypersensitivity Revealed in Lymphotoxin-α–Deficient Mice

    PubMed Central

    Rennert, Paul D.; Hochman, Paula S.; Flavell, Richard A.; Chaplin, David D.; Jayaraman, Sundararajan; Browning, Jeffrey L.; Fu, Yang-Xin

    2001-01-01

    Lymph nodes (LNs) are important sentinal organs, populated by circulating lymphocytes and antigen-bearing cells exiting the tissue beds. Although cellular and humoral immune responses are induced in LNs by antigenic challenge, it is not known if LNs are essential for acquired immunity. We examined immune responses in mice that lack LNs due to genetic deletion of lymphotoxin ligands or in utero blockade of membrane lymphotoxin. We report that LNs are absolutely required for generating contact hypersensitivity, a T cell–dependent cellular immune response induced by epicutaneous hapten. We show that the homing of epidermal Langerhans cells in response to hapten application is specifically directed to LNs, providing a cellular basis for this unique LN function. In contrast, the spleen cannot mediate contact hypersensitivity because antigen-bearing epidermal Langerhans cells do not access splenic white pulp. Finally, we formally demonstrate that LNs provide a unique environment essential for generating this acquired immune response by reversing the LN defect in lymphotoxin-α−/− mice, thereby restoring the capacity for contact hypersensitivity. PMID:11390430

  13. Immune-Modulating Perspectives for Low Frequency Electromagnetic Fields in Innate Immunity.

    PubMed

    Rosado, Maria Manuela; Simkó, Myrtill; Mattsson, Mats-Olof; Pioli, Claudio

    2018-01-01

    In recent years, the effects of electromagnetic fields (EMFs) on the immune system have received a considerable interest, not only to investigate possible negative health impact but also to explore the possibility to favorably modulate immune responses. To generate beneficial responses, the immune system should eradicate pathogens while "respecting" the organism and tolerating irrelevant antigens. According to the current view, damage-associated molecules released by infected or injured cells, or secreted by innate immune cells generate danger signals activating an immune response. These signals are also relevant to the subsequent activation of homeostatic mechanisms that control the immune response in pro- or anti-inflammatory reactions, a feature that allows modulation by therapeutic treatments. In the present review, we describe and discuss the effects of extremely low frequency (ELF)-EMF and pulsed EMF on cell signals and factors relevant to the activation of danger signals and innate immunity cells. By discussing the EMF modulating effects on cell functions, we envisage the use of EMF as a therapeutic agent to regulate immune responses associated with wound healing.

  14. An Aversive Response to Osmotic Upshift in Caenorhabditis elegans.

    PubMed

    Yu, Jingyi; Yang, Wenxing; Liu, He; Hao, Yingsong; Zhang, Yun

    2017-01-01

    Environmental osmolarity presents a common type of sensory stimulus to animals. While behavioral responses to osmotic changes are important for maintaining a stable intracellular osmolarity, the underlying mechanisms are not fully understood. In the natural habitat of Caenorhabditis elegans , changes in environmental osmolarity are commonplace. It is known that the nematode acutely avoids shocks of extremely high osmolarity. Here, we show that C. elegans also generates gradually increased aversion of mild upshifts in environmental osmolarity. Different from an acute avoidance of osmotic shocks that depends on the function of a transient receptor potential vanilloid channel, the slow aversion to osmotic upshifts requires the cGMP-gated sensory channel subunit TAX-2. TAX-2 acts in several sensory neurons that are exposed to body fluid to generate the aversive response through a motor network that underlies navigation. Osmotic upshifts activate the body cavity sensory neuron URX, which is known to induce aversion upon activation. Together, our results characterize the molecular and cellular mechanisms underlying a novel sensorimotor response to osmotic stimuli and reveal that C. elegans engages different behaviors and the underlying mechanisms to regulate responses to extracellular osmolarity.

  15. The VERRUN and VERNAL software systems for steady-state visual evoked response experimentation

    NASA Technical Reports Server (NTRS)

    Levison, W. H.; Zacharias, G. L.

    1984-01-01

    Two digital computer programs were developed for use in experiments involving steady-state visual evoked response (VER): VERRUN, whose primary functions are to generate a sum-of-sines (SOS) stimulus and to digitize and store electro-cortical response; and VERNAL, which provides both time- and frequency-domain metrics of the evoked response. These programs were coded in FORTRAN for operation on the PDP-11/34, using the RSX-11 Operating System, and the PDP-11/23, using the RT-11 Operating System. Users' and programmers' guides to these programs are provided, and guidelines for model analysis of VER data are suggested.

  16. Insights into distinct modulation of α7 and α7β2 nicotinic acetylcholine receptors by the volatile anesthetic isoflurane.

    PubMed

    Mowrey, David D; Liu, Qiang; Bondarenko, Vasyl; Chen, Qiang; Seyoum, Edom; Xu, Yan; Wu, Jie; Tang, Pei

    2013-12-13

    Nicotinic acetylcholine receptors (nAChRs) are targets of general anesthetics, but functional sensitivity to anesthetic inhibition varies dramatically among different subtypes of nAChRs. Potential causes underlying different functional responses to anesthetics remain elusive. Here we show that in contrast to the α7 nAChR, the α7β2 nAChR is highly susceptible to inhibition by the volatile anesthetic isoflurane in electrophysiology measurements. Isoflurane-binding sites in β2 and α7 were found at the extracellular and intracellular end of their respective transmembrane domains using NMR. Functional relevance of the identified β2 site was validated via point mutations and subsequent functional measurements. Consistent with their functional responses to isoflurane, β2 but not α7 showed pronounced dynamics changes, particularly for the channel gate residue Leu-249(9'). These results suggest that anesthetic binding alone is not sufficient to generate functional impact; only those sites that can modulate channel dynamics upon anesthetic binding will produce functional effects.

  17. Method of performing computational aeroelastic analyses

    NASA Technical Reports Server (NTRS)

    Silva, Walter A. (Inventor)

    2011-01-01

    Computational aeroelastic analyses typically use a mathematical model for the structural modes of a flexible structure and a nonlinear aerodynamic model that can generate a plurality of unsteady aerodynamic responses based on the structural modes for conditions defining an aerodynamic condition of the flexible structure. In the present invention, a linear state-space model is generated using a single execution of the nonlinear aerodynamic model for all of the structural modes where a family of orthogonal functions is used as the inputs. Then, static and dynamic aeroelastic solutions are generated using computational interaction between the mathematical model and the linear state-space model for a plurality of periodic points in time.

  18. Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress

    PubMed Central

    Picard, Martin; McManus, Meagan J.; Gray, Jason D.; Nasca, Carla; Moffat, Cynthia; Kopinski, Piotr K.; Seifert, Erin L.; McEwen, Bruce S.; Wallace, Douglas C.

    2015-01-01

    The experience of psychological stress triggers neuroendocrine, inflammatory, metabolic, and transcriptional perturbations that ultimately predispose to disease. However, the subcellular determinants of this integrated, multisystemic stress response have not been defined. Central to stress adaptation is cellular energetics, involving mitochondrial energy production and oxidative stress. We therefore hypothesized that abnormal mitochondrial functions would differentially modulate the organism’s multisystemic response to psychological stress. By mutating or deleting mitochondrial genes encoded in the mtDNA [NADH dehydrogenase 6 (ND6) and cytochrome c oxidase subunit I (COI)] or nuclear DNA [adenine nucleotide translocator 1 (ANT1) and nicotinamide nucleotide transhydrogenase (NNT)], we selectively impaired mitochondrial respiratory chain function, energy exchange, and mitochondrial redox balance in mice. The resulting impact on physiological reactivity and recovery from restraint stress were then characterized. We show that mitochondrial dysfunctions altered the hypothalamic–pituitary–adrenal axis, sympathetic adrenal–medullary activation and catecholamine levels, the inflammatory cytokine IL-6, circulating metabolites, and hippocampal gene expression responses to stress. Each mitochondrial defect generated a distinct whole-body stress-response signature. These results demonstrate the role of mitochondrial energetics and redox balance as modulators of key pathophysiological perturbations previously linked to disease. This work establishes mitochondria as stress-response modulators, with implications for understanding the mechanisms of stress pathophysiology and mitochondrial diseases. PMID:26627253

  19. The effect of fMRI task combinations on determining the hemispheric dominance of language functions.

    PubMed

    Niskanen, Eini; Könönen, Mervi; Villberg, Ville; Nissi, Mikko; Ranta-Aho, Perttu; Säisänen, Laura; Karjalainen, Pasi; Aikiä, Marja; Kälviäinen, Reetta; Mervaala, Esa; Vanninen, Ritva

    2012-04-01

    The purpose of this study is to establish the most suitable combination of functional magnetic resonance imaging (fMRI) language tasks for clinical use in determining language dominance and to define the variability in laterality index (LI) and activation power between different combinations of language tasks. Activation patterns of different fMRI analyses of five language tasks (word generation, responsive naming, letter task, sentence comprehension, and word pair) were defined for 20 healthy volunteers (16 right-handed). LIs and sums of T values were calculated for each task separately and for four combinations of tasks in predefined regions of interest. Variability in terms of activation power and lateralization was defined in each analysis. In addition, the visual assessment of lateralization of language functions based on the individual fMRI activation maps was conducted by an experienced neuroradiologist. A combination analysis of word generation, responsive naming, and sentence comprehension was the most suitable in terms of activation power, robustness to detect essential language areas, and scanning time. In general, combination analyses of the tasks provided higher overall activation levels than single tasks and reduced the number of outlier voxels disturbing the calculation of LI. A combination of auditory and visually presented tasks that activate different aspects of language functions with sufficient activation power may be a useful task battery for determining language dominance in patients.

  20. Calcium-dependent oligomerization of CAR proteins at cell membrane modulates ABA signaling

    PubMed Central

    Diaz, Maira; Sanchez-Barrena, Maria Jose; Gonzalez-Rubio, Juana Maria; Rodriguez, Lesia; Fernandez, Daniel; Antoni, Regina; Yunta, Cristina; Belda-Palazon, Borja; Gonzalez-Guzman, Miguel; Peirats-Llobet, Marta; Menendez, Margarita; Boskovic, Jasminka; Marquez, Jose A.; Rodriguez, Pedro L.; Albert, Armando

    2016-01-01

    Regulation of ion transport in plants is essential for cell function. Abiotic stress unbalances cell ion homeostasis, and plants tend to readjust it, regulating membrane transporters and channels. The plant hormone abscisic acid (ABA) and the second messenger Ca2+ are central in such processes, as they are involved in the regulation of protein kinases and phosphatases that control ion transport activity in response to environmental stimuli. The identification and characterization of the molecular mechanisms underlying the effect of ABA and Ca2+ signaling pathways on membrane function are central and could provide opportunities for crop improvement. The C2-domain ABA-related (CAR) family of small proteins is involved in the Ca2+-dependent recruitment of the pyrabactin resistance 1/PYR1-like (PYR/PYL) ABA receptors to the membrane. However, to fully understand CAR function, it is necessary to define a molecular mechanism that integrates Ca2+ sensing, membrane interaction, and the recognition of the PYR/PYL interacting partners. We present structural and biochemical data showing that CARs are peripheral membrane proteins that functionally cluster on the membrane and generate strong positive membrane curvature in a Ca2+-dependent manner. These features represent a mechanism for the generation, stabilization, and/or specific recognition of membrane discontinuities. Such structures may act as signaling platforms involved in the recruitment of PYR/PYL receptors and other signaling components involved in cell responses to stress. PMID:26719420

  1. Calcium-dependent oligomerization of CAR proteins at cell membrane modulates ABA signaling.

    PubMed

    Diaz, Maira; Sanchez-Barrena, Maria Jose; Gonzalez-Rubio, Juana Maria; Rodriguez, Lesia; Fernandez, Daniel; Antoni, Regina; Yunta, Cristina; Belda-Palazon, Borja; Gonzalez-Guzman, Miguel; Peirats-Llobet, Marta; Menendez, Margarita; Boskovic, Jasminka; Marquez, Jose A; Rodriguez, Pedro L; Albert, Armando

    2016-01-19

    Regulation of ion transport in plants is essential for cell function. Abiotic stress unbalances cell ion homeostasis, and plants tend to readjust it, regulating membrane transporters and channels. The plant hormone abscisic acid (ABA) and the second messenger Ca(2+) are central in such processes, as they are involved in the regulation of protein kinases and phosphatases that control ion transport activity in response to environmental stimuli. The identification and characterization of the molecular mechanisms underlying the effect of ABA and Ca(2+) signaling pathways on membrane function are central and could provide opportunities for crop improvement. The C2-domain ABA-related (CAR) family of small proteins is involved in the Ca(2+)-dependent recruitment of the pyrabactin resistance 1/PYR1-like (PYR/PYL) ABA receptors to the membrane. However, to fully understand CAR function, it is necessary to define a molecular mechanism that integrates Ca(2+) sensing, membrane interaction, and the recognition of the PYR/PYL interacting partners. We present structural and biochemical data showing that CARs are peripheral membrane proteins that functionally cluster on the membrane and generate strong positive membrane curvature in a Ca(2+)-dependent manner. These features represent a mechanism for the generation, stabilization, and/or specific recognition of membrane discontinuities. Such structures may act as signaling platforms involved in the recruitment of PYR/PYL receptors and other signaling components involved in cell responses to stress.

  2. Dynamic Interaction- and Phospho-Proteomics Reveal Lck as a Major Signaling Hub of CD147 in T Cells.

    PubMed

    Supper, Verena; Hartl, Ingrid; Boulègue, Cyril; Ohradanova-Repic, Anna; Stockinger, Hannes

    2017-03-15

    Numerous publications have addressed CD147 as a tumor marker and regulator of cytoskeleton, cell growth, stress response, or immune cell function; however, the molecular functionality of CD147 remains incompletely understood. Using affinity purification, mass spectrometry, and phosphopeptide enrichment of isotope-labeled peptides, we examined the dynamic of the CD147 microenvironment and the CD147-dependent phosphoproteome in the Jurkat T cell line upon treatment with T cell stimulating agents. We identified novel dynamic interaction partners of CD147 such as CD45, CD47, GNAI2, Lck, RAP1B, and VAT1 and, furthermore, found 76 CD147-dependent phosphorylation sites on 57 proteins. Using the STRING protein network database, a network between the CD147 microenvironment and the CD147-dependent phosphoproteins was generated and led to the identification of key signaling hubs around the G proteins RAP1B and GNB1, the kinases PKCβ, PAK2, Lck, and CDK1, and the chaperone HSPA5. Gene ontology biological process term analysis revealed that wound healing-, cytoskeleton-, immune system-, stress response-, phosphorylation- and protein modification-, defense response to virus-, and TNF production-associated terms are enriched within the microenvironment and the phosphoproteins of CD147. With the generated signaling network and gene ontology biological process term grouping, we identify potential signaling routes of CD147 affecting T cell growth and function. Copyright © 2017 by The American Association of Immunologists, Inc.

  3. Bottom-up and top-down emotion generation: implications for emotion regulation

    PubMed Central

    Misra, Supriya; Prasad, Aditya K.; Pereira, Sean C.; Gross, James J.

    2012-01-01

    Emotion regulation plays a crucial role in adaptive functioning and mounting evidence suggests that some emotion regulation strategies are often more effective than others. However, little attention has been paid to the different ways emotions can be generated: from the ‘bottom-up’ (in response to inherently emotional perceptual properties of the stimulus) or ‘top-down’ (in response to cognitive evaluations). Based on a process priming principle, we hypothesized that mode of emotion generation would interact with subsequent emotion regulation. Specifically, we predicted that top-down emotions would be more successfully regulated by a top-down regulation strategy than bottom-up emotions. To test this hypothesis, we induced bottom-up and top-down emotions, and asked participants to decrease the negative impact of these emotions using cognitive reappraisal. We observed the predicted interaction between generation and regulation in two measures of emotional responding. As measured by self-reported affect, cognitive reappraisal was more successful on top-down generated emotions than bottom-up generated emotions. Neurally, reappraisal of bottom-up generated emotions resulted in a paradoxical increase of amygdala activity. This interaction between mode of emotion generation and subsequent regulation should be taken into account when comparing of the efficacy of different types of emotion regulation, as well as when reappraisal is used to treat different types of clinical disorders. PMID:21296865

  4. Rapid phosphatidic acid accumulation in response to low temperature stress in Arabidopsis is generated through diacylglycerol kinase.

    PubMed

    Arisz, Steven A; van Wijk, Ringo; Roels, Wendy; Zhu, Jian-Kang; Haring, Michel A; Munnik, Teun

    2013-01-01

    Phosphatidic acid (PtdOH) is emerging as an important signaling lipid in abiotic stress responses in plants. The effect of cold stress was monitored using (32)P-labeled seedlings and leaf discs of Arabidopsis thaliana. Low, non-freezing temperatures were found to trigger a very rapid (32)P-PtdOH increase, peaking within 2 and 5 min, respectively. In principle, PtdOH can be generated through three different pathways, i.e., (1) via de novo phospholipid biosynthesis (through acylation of lyso-PtdOH), (2) via phospholipase D hydrolysis of structural phospholipids, or (3) via phosphorylation of diacylglycerol (DAG) by DAG kinase (DGK). Using a differential (32)P-labeling protocol and a PLD-transphosphatidylation assay, evidence is provided that the rapid (32)P-PtdOH response was primarily generated through DGK. A simultaneous decrease in the levels of (32)P-PtdInsP, correlating in time, temperature dependency, and magnitude with the increase in (32)P-PtdOH, suggested that a PtdInsP-hydrolyzing PLC generated the DAG in this reaction. Testing T-DNA insertion lines available for the seven DGK genes, revealed no clear changes in (32)P-PtdOH responses, suggesting functional redundancy. Similarly, known cold-stress mutants were analyzed to investigate whether the PtdOH response acted downstream of the respective gene products. The hos1, los1, and fry1 mutants were found to exhibit normal PtdOH responses. Slight changes were found for ice1, snow1, and the overexpression line Super-ICE1, however, this was not cold-specific and likely due to pleiotropic effects. A tentative model illustrating direct cold effects on phospholipid metabolism is presented.

  5. Rapid phosphatidic acid accumulation in response to low temperature stress in Arabidopsis is generated through diacylglycerol kinase

    PubMed Central

    Arisz, Steven A.; van Wijk, Ringo; Roels, Wendy; Zhu, Jian-Kang; Haring, Michel A.; Munnik, Teun

    2013-01-01

    Phosphatidic acid (PtdOH) is emerging as an important signaling lipid in abiotic stress responses in plants. The effect of cold stress was monitored using 32P-labeled seedlings and leaf discs of Arabidopsis thaliana. Low, non-freezing temperatures were found to trigger a very rapid 32P-PtdOH increase, peaking within 2 and 5 min, respectively. In principle, PtdOH can be generated through three different pathways, i.e., (1) via de novo phospholipid biosynthesis (through acylation of lyso-PtdOH), (2) via phospholipase D hydrolysis of structural phospholipids, or (3) via phosphorylation of diacylglycerol (DAG) by DAG kinase (DGK). Using a differential 32P-labeling protocol and a PLD-transphosphatidylation assay, evidence is provided that the rapid 32P-PtdOH response was primarily generated through DGK. A simultaneous decrease in the levels of 32P-PtdInsP, correlating in time, temperature dependency, and magnitude with the increase in 32P-PtdOH, suggested that a PtdInsP-hydrolyzing PLC generated the DAG in this reaction. Testing T-DNA insertion lines available for the seven DGK genes, revealed no clear changes in 32P-PtdOH responses, suggesting functional redundancy. Similarly, known cold-stress mutants were analyzed to investigate whether the PtdOH response acted downstream of the respective gene products. The hos1, los1, and fry1 mutants were found to exhibit normal PtdOH responses. Slight changes were found for ice1, snow1, and the overexpression line Super-ICE1, however, this was not cold-specific and likely due to pleiotropic effects. A tentative model illustrating direct cold effects on phospholipid metabolism is presented. PMID:23346092

  6. Unrecognized coral species diversity masks differences in functional ecology

    PubMed Central

    Boulay, Jennifer N.; Hellberg, Michael E.; Cortés, Jorge; Baums, Iliana B.

    2014-01-01

    Porites corals are foundation species on Pacific reefs but a confused taxonomy hinders understanding of their ecosystem function and responses to climate change. Here, we show that what has been considered a single species in the eastern tropical Pacific, Porites lobata, includes a morphologically similar yet ecologically distinct species, Porites evermanni. While P. lobata reproduces mainly sexually, P. evermanni dominates in areas where triggerfish prey on bioeroding mussels living within the coral skeleton, thereby generating asexual coral fragments. These fragments proliferate in marginal habitat not colonized by P. lobata. The two Porites species also show a differential bleaching response despite hosting the same dominant symbiont subclade. Thus, hidden diversity within these reef-builders has until now obscured differences in trophic interactions, reproductive dynamics and bleaching susceptibility, indicative of differential responses when confronted with future climate change. PMID:24335977

  7. T cell chronic lymphocytic leukaemia with suppressor phenotype.

    PubMed Central

    Hofman, F M; Smith, D; Hocking, W

    1982-01-01

    The peripheral blood cells from a patient with T cell chronic lymphocytic leukaemia were examined for surface marker and functional characteristics. Eighty-91% of the peripheral blood cells formed SRBC rosettes and 22-49% possessed Fc receptors; 73% of the peripheral blood cells were reactive with the OKT8 antiserum and 61% expressed DR antigens. Response to PHA stimulation was markedly reduced, whereas allogeneic responsiveness in mixed leucocyte culture was intact. The ability of Con A-stimulated peripheral blood cells to generate suppressor activity in a mixed leucocyte reaction was deficient, whereas suppression of in vitro immunoglobulin synthesis was greater than normal. The leukaemic peripheral blood cell population expressed a T suppressor phenotype. Functional studies suggest that these cells were derived from the subset of T lymphocytes with regulatory activity for immunoglobulin synthesis as opposed to mitogenic responsiveness. PMID:6215199

  8. Unrecognized coral species diversity masks differences in functional ecology.

    PubMed

    Boulay, Jennifer N; Hellberg, Michael E; Cortés, Jorge; Baums, Iliana B

    2014-02-07

    Porites corals are foundation species on Pacific reefs but a confused taxonomy hinders understanding of their ecosystem function and responses to climate change. Here, we show that what has been considered a single species in the eastern tropical Pacific, Porites lobata, includes a morphologically similar yet ecologically distinct species, Porites evermanni. While P. lobata reproduces mainly sexually, P. evermanni dominates in areas where triggerfish prey on bioeroding mussels living within the coral skeleton, thereby generating asexual coral fragments. These fragments proliferate in marginal habitat not colonized by P. lobata. The two Porites species also show a differential bleaching response despite hosting the same dominant symbiont subclade. Thus, hidden diversity within these reef-builders has until now obscured differences in trophic interactions, reproductive dynamics and bleaching susceptibility, indicative of differential responses when confronted with future climate change.

  9. Family matters: Intergenerational and interpersonal processes of executive function and attentive behavior

    PubMed Central

    Deater-Deckard, Kirby

    2014-01-01

    Individual differences in self-regulation include executive function (EF) components that serve self-regulation of attentive behavior by modulating reactive responses to the environment. These factors “run in families”. The purpose of this review is to summarize a program of research that addresses familial inter-generational transmission and inter-personal processes in development. Self-regulation of attentive behavior involves inter-related aspects of executive function (EF) including attention, inhibitory control, and working memory. Individual differences in EF skills develop in systematic ways over childhood, resulting in moderately stable differences between people by early adolescence. Through complex gene-environment transactions, EF is transmitted across generations within parent-child relationships that provide powerful socialization and experiential contexts in which EF and related attentive behavior are forged and practiced. Families matter as parents regulate home environments and themselves as best they can while also supporting cognitive self-regulation of attentive behavior in their children. PMID:25197171

  10. Orchestrating cytoskeleton and intracellular vesicle traffic to build functional immunological synapses.

    PubMed

    Soares, Helena; Lasserre, Rémi; Alcover, Andrés

    2013-11-01

    Immunological synapses are specialized cell-cell contacts formed between T lymphocytes and antigen-presenting cells. They are induced upon antigen recognition and are crucial for T-cell activation and effector functions. The generation and function of immunological synapses depend on an active T-cell polarization process, which results from a finely orchestrated crosstalk between the antigen receptor signal transduction machinery, the actin and microtubule cytoskeletons, and controlled vesicle traffic. Although we understand how some of these particular events are regulated, we still lack knowledge on how these multiple cellular elements are harmonized to ensure appropriate T-cell responses. We discuss here our view on how T-cell receptor signal transduction initially commands cytoskeletal and vesicle traffic polarization, which in turn sets the immunological synapse molecular design that regulates T-cell activation. We also discuss how the human immunodeficiency virus (HIV-1) hijacks some of these processes impairing immunological synapse generation and function. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. The ethological trap: functional and numerical responses of highly efficient invasive predators driving prey extinctions.

    PubMed

    Spencer, Ricky-John; Van Dyke, James U; Thompson, Michael B

    2016-10-01

    Ecological traps are threats to organisms, and exist in a range of biological systems. A subset of ecological trap theory is the "ethological trap," whereby behaviors canalized by past natural selection become traps when environments change rapidly. Invasive predators are major threats to imperiled species and their ability to exploit canalized behaviors of naive prey is particularly important for the establishment of the predator and the decline of the native prey. Our study uses ecological theory to demonstrate that invasive predator controls require shifts in management priorities. Total predation rate (i.e., total response) is the product of both the functional response and numerical response of predators to prey. Functional responses are the changes in the rate of prey consumption by individual predators, relative to prey abundance. Numerical responses are the aggregative rates of prey consumption by all predators relative to prey density, which change with predator density via reproduction or migration, in response to changes in prey density. Traditional invasive predator management methods focus on reducing predator populations, and thus manage for numerical responses. These management efforts fail to manage for functional responses, and may not eliminate impacts of highly efficient individual predators. We explore this problem by modeling the impacts of functional and numerical responses of invasive foxes depredating imperiled Australian turtle nests. Foxes exhibit exceptionally efficient functional responses. A single fox can destroy >95% of turtle nests in a nesting area, which eliminates juvenile recruitment. In this case, the ethological trap is the "Arribada" nesting strategy, an emergent behavior whereby most turtles in a population nest simultaneously in the same nesting grounds. Our models show that Arribada nesting events do not oversaturate foxes, and small numbers of foxes depredate all of the nests in a given Arribada. Widely scattering nests may reduce fox predation rates, but the long generation times of turtles combined with their rapid recent decline suggests that evolutionary responses in nesting strategy may be unlikely. Our study demonstrates that reducing populations of highly efficient invasive predators is insufficient for preserving native prey species. Instead, management must reduce individual predator efficiency, independent of reducing predator population size. © 2016 by the Ecological Society of America.

  12. Electromagnetic and neutral-weak response functions of 4He and 12C

    NASA Astrophysics Data System (ADS)

    Lovato, A.; Gandolfi, S.; Carlson, J.; Pieper, Steven C.; Schiavilla, R.

    2015-06-01

    Background: A major goal of nuclear theory is to understand the strong interaction in nuclei as it manifests itself in terms of two- and many-body forces among the nuclear constituents, the protons and neutrons, and the interactions of these constituents with external electroweak probes via one- and many-body currents. Purpose: The objective of the present work is to calculate the quasielastic electroweak response functions in light nuclei within the realistic dynamical framework outlined above. These response functions determine the inclusive cross section as function of the lepton momentum and energy transfers. Methods: Their ab initio calculation is a very challenging quantum many-body problem, since it requires summation over the entire excitation spectrum of the nucleus and inclusion in the electroweak currents of one- and many-body terms. Green's functions Monte Carlo methods allow one to circumvent both difficulties by computing the response in imaginary time (the so-called Euclidean response) and hence summing implicitly over the bound and continuum states of the nucleus, and by implementing specific algorithms designed to deal with the complicated spin-isospin structure of nuclear many-body operators. Results: Theoretical predictions for 4He and 12C, confirmed by experiment in the electromagnetic case, show that two-body currents generate excess transverse strength from threshold to the quasielastic to the dip region and beyond. Conclusions: These results challenge the conventional picture of quasielastic inclusive scattering as being largely dominated by single-nucleon knockout processes.

  13. Electromagnetic and neutral-weak response functions of 4He and 12C

    DOE PAGES

    Lovato, A.; Gandolfi, Stefano; Carlson, Joseph Allen; ...

    2015-06-04

    A major goal of nuclear theory is to understand the strong interaction in nuclei as it manifests itself in terms of two- and many-body forces among the nuclear constituents, the protons and neutrons, and the interactions of these constituents with external electroweak probes via one- and many-body currents. The objective of the present work is to calculate the quasielastic electroweak response functions in light nuclei within the realistic dynamical framework outlined above. These response functions determine the inclusive cross section as function of the lepton momentum and energy transfers. Their ab initio calculation is a very challenging quantum many-body problem,more » since it requires summation over the entire excitation spectrum of the nucleus and inclusion in the electroweak currents of one- and many-body terms. Green's functions Monte Carlo methods allow one to circumvent both difficulties by computing the response in imaginary time (the so-called Euclidean response) and hence summing implicitly over the bound and continuum states of the nucleus, and by implementing specific algorithms designed to deal with the complicated spin-isospin structure of nuclear many-body operators. Theoretical predictions for 4He and 12C, confirmed by experiment in the electromagnetic case, show that two-body currents generate excess transverse strength from threshold to the quasielastic to the dip region and beyond. In conclusion, these results challenge the conventional picture of quasielastic inclusive scattering as being largely dominated by single-nucleon knockout processes.« less

  14. Inflammatory responses to secondary organic aerosols (SOA) generated from biogenic and anthropogenic precursors

    NASA Astrophysics Data System (ADS)

    Tuet, Wing Y.; Chen, Yunle; Fok, Shierly; Champion, Julie A.; Ng, Nga L.

    2017-09-01

    Cardiopulmonary health implications resulting from exposure to secondary organic aerosols (SOA), which comprise a significant fraction of ambient particulate matter (PM), have received increasing interest in recent years. In this study, alveolar macrophages were exposed to SOA generated from the photooxidation of biogenic and anthropogenic precursors (isoprene, α-pinene, β-caryophyllene, pentadecane, m-xylene, and naphthalene) under different formation conditions (RO2 + HO2 vs. RO2 + NO dominant, dry vs. humid). Various cellular responses were measured, including reactive oxygen and nitrogen species (ROS/RNS) production and secreted levels of cytokines, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). SOA precursor identity and formation condition affected all measured responses in a hydrocarbon-specific manner. With the exception of naphthalene SOA, cellular responses followed a trend where TNF-α levels reached a plateau with increasing IL-6 levels. ROS/RNS levels were consistent with relative levels of TNF-α and IL-6, due to their respective inflammatory and anti-inflammatory effects. Exposure to naphthalene SOA, whose aromatic-ring-containing products may trigger different cellular pathways, induced higher levels of TNF-α and ROS/RNS than suggested by the trend. Distinct cellular response patterns were identified for hydrocarbons whose photooxidation products shared similar chemical functionalities and structures, which suggests that the chemical structure (carbon chain length and functionalities) of photooxidation products may be important for determining cellular effects. A positive nonlinear correlation was also detected between ROS/RNS levels and previously measured DTT (dithiothreitol) activities for SOA samples. In the context of ambient samples collected during summer and winter in the greater Atlanta area, all laboratory-generated SOA produced similar or higher levels of ROS/RNS and DTT activities. These results suggest that the health effects of SOA are important considerations for understanding the health implications of ambient aerosols.

  15. Molecular Steps in the Immune Signaling Pathway Evoked by Plant Elicitor Peptides: Ca2+-Dependent Protein Kinases, Nitric Oxide, and Reactive Oxygen Species Are Downstream from the Early Ca2+ Signal1[OPEN

    PubMed Central

    Ma, Yi; Zhao, Yichen; Walker, Robin K.; Berkowitz, Gerald A.

    2013-01-01

    Endogenous plant elicitor peptides (Peps) can act to facilitate immune signaling and pathogen defense responses. Binding of these peptides to the Arabidopsis (Arabidopsis thaliana) plasma membrane-localized Pep receptors (PEPRs) leads to cytosolic Ca2+ elevation, an early event in a signaling cascade that activates immune responses. This immune response includes the amplification of signaling evoked by direct perception of pathogen-associated molecular patterns by plant cells under assault. Work included in this report further characterizes the Pep immune response and identifies new molecular steps in the signal transduction cascade. The PEPR coreceptor BRASSINOSTEROID-INSENSITIVE1 Associated Kinase1 contributes to generation of the Pep-activated Ca2+ signal and leads to increased defense gene expression and resistance to a virulent bacterial pathogen. Ca2+-dependent protein kinases (CPKs) decode the Ca2+ signal, also facilitating defense gene expression and enhanced resistance to the pathogen. Nitric oxide and reduced nicotinamide adenine dinucleotide phosphate oxidase-dependent reactive oxygen species generation (due to the function of Respiratory Burst Oxidase Homolog proteins D and F) are also involved downstream from the Ca2+ signal in the Pep immune defense signal transduction cascade, as is the case with BRASSINOSTEROID-INSENSITIVE1 Associated Kinase1 and CPK5, CPK6, and CPK11. These steps of the pathogen defense response are required for maximal Pep immune activation that limits growth of a virulent bacterial pathogen in the plant. We find a synergism between function of the PEPR and Flagellin Sensing2 receptors in terms of both nitric oxide and reactive oxygen species generation. Presented results are also consistent with the involvement of the secondary messenger cyclic GMP and a cyclic GMP-activated Ca2+-conducting channel in the Pep immune signaling pathway. PMID:24019427

  16. Metabolomic and oxidative effects of quantum dots-indolicidin on three generations of Daphnia magna.

    PubMed

    Falanga, Annarita; Mercurio, Flavia A; Siciliano, Antonietta; Lombardi, Lucia; Galdiero, Stefania; Guida, Marco; Libralato, Giovanni; Leone, Marilisa; Galdiero, Emilia

    2018-05-01

    This study evaluated the effect of QDs functionalized with the antimicrobial peptide indolicidin on oxidative stress and metabolomics profiles of Daphnia magna across three generations (F0, F1, and F2). Exposing D. magna to sub-lethal concentrations of the complex QDs-indolicidin, a normal survival of daphnids was observed from F0 to F2, but a delay of first brood, fewer broods per female, a decrease of length of about 50% compared to control. In addition, QDs-indolicidin induced a significantly higher production of reactive oxygen species (ROS) gradually in each generation and an impairment of enzymes response to oxidative stress such as superoxide dismutase (SOD), catalase (CAT) and glutathione transferase (GST). Effects were confirmed by metabolomics profiles that pointed out a gradual decrease of metabolomics content over the three generations and a toxic effect of QDs-indolicidin likely related to the higher accumulation of ROS and decreased antioxidant capacity in F1 and F2 generations. Results highlighted the capability of metabolomics to reveal an early metabolic response to stress induced by environmental QDs-indolicidin complex. Copyright © 2018 Elsevier B.V. All rights reserved.

  17. Characterization of long-range functional connectivity in epileptic networks by neuronal spike-triggered local field potentials

    NASA Astrophysics Data System (ADS)

    Lopour, Beth A.; Staba, Richard J.; Stern, John M.; Fried, Itzhak; Ringach, Dario L.

    2016-04-01

    Objective. Quantifying the relationship between microelectrode-recorded multi-unit activity (MUA) and local field potentials (LFPs) in distinct brain regions can provide detailed information on the extent of functional connectivity in spatially widespread networks. These methods are common in studies of cognition using non-human animal models, but are rare in humans. Here we applied a neuronal spike-triggered impulse response to electrophysiological recordings from the human epileptic brain for the first time, and we evaluate functional connectivity in relation to brain areas supporting the generation of seizures. Approach. Broadband interictal electrophysiological data were recorded from microwires adapted to clinical depth electrodes that were implanted bilaterally using stereotactic techniques in six presurgical patients with medically refractory epilepsy. MUA and LFPs were isolated in each microwire, and we calculated the impulse response between the MUA on one microwire and the LFPs on a second microwire for all possible MUA/LFP pairs. Results were compared to clinical seizure localization, including sites of seizure onset and interictal epileptiform discharges. Main results. We detected significant interictal long-range functional connections in each subject, in some cases across hemispheres. Results were consistent between two independent datasets, and the timing and location of significant impulse responses reflected anatomical connectivity. However, within individual subjects, the spatial distribution of impulse responses was unique. In two subjects with clear seizure localization and successful surgery, the epileptogenic zone was associated with significant impulse responses. Significance. The results suggest that the spike-triggered impulse response can provide valuable information about the neuronal networks that contribute to seizures using only interictal data. This technique will enable testing of specific hypotheses regarding functional connectivity in epilepsy and the relationship between functional properties and imaging findings. Beyond epilepsy, we expect that the impulse response could be more broadly applied as a measure of long-range functional connectivity in studies of cognition.

  18. Characterization of long-range functional connectivity in epileptic networks by neuronal spike-triggered local field potentials

    PubMed Central

    Lopour, Beth A; Staba, Richard J; Stern, John M; Fried, Itzhak; Ringach, Dario L

    2017-01-01

    Objective Quantifying the relationship between microelectrode-recorded multi-unit activity (MUA) and local field potentials (LFPs) in distinct brain regions can provide detailed information on the extent of functional connectivity in spatially widespread networks. These methods are common in studies of cognition using non-human animal models, but are rare in humans. Here we applied a neuronal spike-triggered impulse response to electrophysiological recordings from the human epileptic brain for the first time, and we evaluate functional connectivity in relation to brain areas supporting the generation of seizures. Approach Broadband interictal electrophysiological data were recorded from microwires adapted to clinical depth electrodes that were implanted bilaterally using stereotactic techniques in six presurgical patients with medically refractory epilepsy. MUA and LFPs were isolated in each microwire, and we calculated the impulse response between the MUA on one microwire and the LFPs on a second microwire for all possible MUA/LFP pairs. Results were compared to clinical seizure localization, including sites of seizure onset and interictal epileptiform discharges. Main results We detected significant interictal long-range functional connections in each subject, in some cases across hemispheres. Results were consistent between two independent datasets, and the timing and location of significant impulse responses reflected anatomical connectivity. However, within individual subjects, the spatial distribution of impulse responses was unique. In two subjects with clear seizure localization and successful surgery, the epileptogenic zone was associated with significant impulse responses. Significance The results suggest that the spike-triggered impulse response can provide valuable information about the neuronal networks that contribute to seizures using only interictal data. This technique will enable testing of specific hypotheses regarding functional connectivity in epilepsy and the relationship between functional properties and imaging findings. Beyond epilepsy, we expect that the impulse response could be more broadly applied as a measure of long-range functional connectivity in studies of cognition. PMID:26975603

  19. Species Pool Functional Diversity Plays a Hidden Role in Generating β-Diversity.

    PubMed

    Patrick, Christopher J; Brown, Bryan L

    2018-05-01

    Functional trait diversity is used as a way to infer mechanistic processes that drive community assembly. While functional diversity within communities is often viewed as a response variable, here we present and test a framework for how functional diversity among taxa in the regional species pool drives the assembly of communities among habitats. We predicted that species pool functional diversity should work with environmental heterogeneity to drive β-diversity. We tested these predictions by modeling empirical patterns in invertebrate communities from 570 streams in 52 watersheds. Our analysis of the field data provided strong support for the inclusion of both functional diversity and environmental heterogeneity in the models, and our predictions were supported when the community was analyzed all together. However, analyses within individual functional feeding guilds revealed strong context dependency in the relative importance of functional diversity, γ-richness, and environmental heterogeneity to β-diversity. We interpret the results to mean that functional diversity can play an important role in driving β-diversity; however, within guilds the nature of interspecific interactions and species pool size complicate the relationship. Future research should test this conceptual model across different ecosystems and in experimental settings using metacommunity mesocosms to enhance our understanding of the role that functional variation plays in generating spatial biodiversity patterns.

  20. Circulating Th1 cell-type Tfh cells that exhibit impaired B cell help are preferentially activated during acute malaria in children

    PubMed Central

    Obeng-Adjei, Nyamekye; Portugal, Silvia; Tran, Tuan M.; Yazew, Takele B.; Skinner, Jeff; Li, Shanping; Jain, Aarti; Felgner, Philip L.; Doumbo, Ogobara K.; Kayentao, Kassoum; Ongoiba, Aissata; Traore, Boubacar; Crompton, Peter D.

    2015-01-01

    SUMMARY Malaria-specific antibody responses are short-lived in children, leaving them susceptible to repeated bouts of febrile malaria. The cellular and molecular mechanisms underlying this apparent immune deficiency are poorly understood. Recently, T follicular helper (Tfh) cells have been shown to play a critical role in generating long-lived antibody responses. We show that Malian children have resting PD-1+CXCR5+CD4+ Tfh cells in circulation that resemble germinal center Tfh cells phenotypically and functionally. Within this population PD-1+CXCR5+CXCR3− Tfh cells are superior to Th1-polarized PD-1+CXCR5+CXCR3+ Tfh cells in helping B cells. Longitudinally, we observed that malaria drives Th1 cytokine responses, and accordingly, the less functional Th1-polarized Tfh subset was preferentially activated and its activation did not correlate with antibody responses. These data provide insights into the Tfh cell biology underlying suboptimal antibody responses to malaria in children, and suggest that vaccine strategies that promote CXCR3− Tfh cell responses may improve malaria vaccine efficacy. PMID:26440897

  1. Data Comparisons and Summary of the Second Aeroelastic Prediction Workshop

    NASA Technical Reports Server (NTRS)

    Heeg, Jennifer; Wieseman, Carol D.; Chwalowski, Pawel

    2016-01-01

    This paper presents the computational results generated by participating teams of the second Aeroelastic Prediction Workshop and compare them with experimental data. Aeroelastic and rigid configurations of the Benchmark Supercritical Wing (BSCW) wind tunnel model served as the focus for the workshop. The comparison data sets include unforced ("steady") system responses, forced pitch oscillations and coupled fluid-structure responses. Integrated coefficients, frequency response functions, and flutter onset conditions are compared. The flow conditions studied were in the transonic range, including both attached and separated flow conditions. Some of the technical discussions that took place at the workshop are summarized.

  2. Taxonomic and functional diversity provides insight into microbial pathways and stress responses in the saline Qinghai Lake, China.

    PubMed

    Huang, Qiuyuan; Briggs, Brandon R; Dong, Hailiang; Jiang, Hongchen; Wu, Geng; Edwardson, Christian; De Vlaminck, Iwijn; Quake, Stephen

    2014-01-01

    Microbe-mediated biogeochemical cycles contribute to the global climate system and have sensitive responses and feedbacks to environmental stress caused by climate change. Yet, little is known about the effects of microbial biodiversity (i.e., taxonmic and functional diversity) on biogeochemical cycles in ecosytems that are highly sensitive to climate change. One such sensitive ecosystem is Qinghai Lake, a high-elevation (3196 m) saline (1.4%) lake located on the Tibetan Plateau, China. This study provides baseline information on the microbial taxonomic and functional diversity as well as the associated stress response genes. Illumina metagenomic and metatranscriptomic datasets were generated from lake water samples collected at two sites (B and E). Autotrophic Cyanobacteria dominated the DNA samples, while heterotrophic Proteobacteria dominated the RNA samples at both sites. Photoheterotrophic Loktanella was also present at both sites. Photosystem II was the most active pathway at site B; while, oxidative phosphorylation was most active at site E. Organisms that expressed photosystem II or oxidative phosphorylation also expressed genes involved in photoprotection and oxidative stress, respectively. Assimilatory pathways associated with the nitrogen cycle were dominant at both sites. Results also indicate a positive relationship between functional diversity and the number of stress response genes. This study provides insight into the stress resilience of microbial metabolic pathways supported by greater taxonomic diversity, which may affect the microbial community response to climate change.

  3. Taxonomic and Functional Diversity Provides Insight into Microbial Pathways and Stress Responses in the Saline Qinghai Lake, China

    PubMed Central

    Dong, Hailiang; Jiang, Hongchen; Wu, Geng; Edwardson, Christian; De Vlaminck, Iwijn; Quake, Stephen

    2014-01-01

    Microbe-mediated biogeochemical cycles contribute to the global climate system and have sensitive responses and feedbacks to environmental stress caused by climate change. Yet, little is known about the effects of microbial biodiversity (i.e., taxonmic and functional diversity) on biogeochemical cycles in ecosytems that are highly sensitive to climate change. One such sensitive ecosystem is Qinghai Lake, a high-elevation (3196 m) saline (1.4%) lake located on the Tibetan Plateau, China. This study provides baseline information on the microbial taxonomic and functional diversity as well as the associated stress response genes. Illumina metagenomic and metatranscriptomic datasets were generated from lake water samples collected at two sites (B and E). Autotrophic Cyanobacteria dominated the DNA samples, while heterotrophic Proteobacteria dominated the RNA samples at both sites. Photoheterotrophic Loktanella was also present at both sites. Photosystem II was the most active pathway at site B; while, oxidative phosphorylation was most active at site E. Organisms that expressed photosystem II or oxidative phosphorylation also expressed genes involved in photoprotection and oxidative stress, respectively. Assimilatory pathways associated with the nitrogen cycle were dominant at both sites. Results also indicate a positive relationship between functional diversity and the number of stress response genes. This study provides insight into the stress resilience of microbial metabolic pathways supported by greater taxonomic diversity, which may affect the microbial community response to climate change. PMID:25365331

  4. Mechanisms of information decoding in a cascade system of gene expression

    NASA Astrophysics Data System (ADS)

    Wang, Haohua; Yuan, Zhanjiang; Liu, Peijiang; Zhou, Tianshou

    2016-05-01

    Biotechnology advances have allowed investigation of heterogeneity of cellular responses to stimuli on the single-cell level. Functionally, this heterogeneity can compromise cellular responses to environmental signals, and it can also enlarge the repertoire of possible cellular responses and hence increase the adaptive nature of cellular behaviors. However, the mechanism of how this response heterogeneity is generated remains elusive. Here, by systematically analyzing a representative cellular signaling system, we show that (1) the upstream activator always amplifies the downstream burst frequency (BF) but the noiseless activator performs better than the noisy one, remarkably for small or moderate input signal strengths, and the repressor always reduces the downstream BF but the difference in the reducing effect between noiseless and noise repressors is very small; (2) both the downstream burst size and mRNA mean are a monotonically increasing function of the activator strength but a monotonically decreasing function of the repressor strength; (3) for repressor-type input, there is a noisy signal strength such that the downstream mRNA noise arrives at an optimal level, but for activator-type input, the output noise intensity is fundamentally a monotonically decreasing function of the input strength. Our results reveal the essential mechanisms of both signal information decoding and cellular response heterogeneity, whereas our analysis provides a paradigm for analyzing dynamics of noisy biochemical signaling systems.

  5. Functional Imaging of Sleep Vertex Sharp Transients

    PubMed Central

    Stern, John M.; Caporro, Matteo; Haneef, Zulfi; Yeh, Hsiang J.; Buttinelli, Carla; Lenartowicz, Agatha; Mumford, Jeanette A.; Parvizi, Josef; Poldrack, Russell A.

    2011-01-01

    Objective The vertex sharp transient (VST) is an electroencephalographic (EEG) discharge that is an early marker of non-REM sleep. It has been recognized since the beginning of sleep physiology research, but its source and function remain mostly unexplained. We investigated VST generation using functional MRI (fMRI). Methods Simultaneous EEG and fMRI were recorded from 7 individuals in drowsiness and light sleep. VST occurrences on EEG were modeled with fMRI using an impulse function convolved with a hemodynamic response function to identify cerebral regions correlating to the VSTs. A resulting statistical image was thresholded at Z>2.3. Results Two hundred VSTs were identified. Significantly increased signal was present bilaterally in medial central, lateral precentral, posterior superior temporal, and medial occipital cortex. No regions of decreased signal were present. Conclusion The regions are consistent with electrophysiologic evidence from animal models and functional imaging of human sleep, but the results are specific to VSTs. The regions principally encompass the primary sensorimotor cortical regions for vision, hearing, and touch. Significance The results depict a network comprising the presumed VST generator and its associated regions. The associated regions functional similarity for primary sensation suggests a role for VSTs in sensory experience during sleep. PMID:21310653

  6. Dissociation in undergraduate students: disruptions in executive functioning.

    PubMed

    Giesbrecht, Timo; Merckelbach, Harald; Geraerts, Elke; Smeets, Ellen

    2004-08-01

    The concept of dissociation refers to disruptions in attentional control. Attentional control is an executive function. Few studies have addressed the link between dissociation and executive functioning. Our study investigated this relationship in a sample of undergraduate students (N = 185) who completed the Dissociative Experiences Scale and the Random Number Generation Task. We found that minor disruptions in executive functioning were related to a subclass of dissociative experiences, notably dissociative amnesia and the Dissociative Experiences Scale Taxon. However, the two other subscales of the Dissociative Experiences Scale, measuring depersonalization and absorption, were unrelated to executive functioning. Our findings suggest that a failure to inhibit previous responses might contribute to the pathological memory manifestations of dissociation.

  7. Nanoparticle-coated micro-optofluidic ring resonator as a detector for microscale gas chromatographic vapor analysis.

    PubMed

    Scholten, K; Collin, W R; Fan, X; Zellers, E T

    2015-05-28

    A vapor sensor comprising a nanoparticle-coated microfabricated optofluidic ring resonator (μOFRR) is introduced. A multilayer film of polyether functionalized, thiolate-monolayer-protected gold nanoparticles (MPN) was solvent cast on the inner wall of the hollow cylindrical SiOxμOFRR resonator structure, and whispering gallery mode (WGM) resonances were generated with a 1550 nm tunable laser via an optical fiber taper. Reversible shifts in the WGM resonant wavelength upon vapor exposure were detected with a photodetector. The μOFRR chip was connected to a pair of upstream etched-Si chips containing PDMS-coated separation μcolumns and calibration curves were generated from the peak-area responses to five volatile organic compounds (VOCs). Calibration curves were linear, and the sensitivities reflected the influence of analyte volatility and analyte-MPN functional group affinity. Sorption-induced changes in film thickness apparently dominate over changes in the refractive index of the film as the determinant of responses for all VOCs. Peaks from the MPN-coated μOFRR were just 20-50% wider than those from a flame ionization detector for similar μcolumn separation conditions, reflecting the rapid response of the sensor for VOCs. The five VOCs were baseline separated in <1.67 min, with detection limits as low as 38 ng.

  8. Nanoparticle-coated micro-optofluidic ring resonator as a detector for microscale gas chromatographic vapor analysis

    NASA Astrophysics Data System (ADS)

    Scholten, K.; Collin, W. R.; Fan, X.; Zellers, E. T.

    2015-05-01

    A vapor sensor comprising a nanoparticle-coated microfabricated optofluidic ring resonator (μOFRR) is introduced. A multilayer film of polyether functionalized, thiolate-monolayer-protected gold nanoparticles (MPN) was solvent cast on the inner wall of the hollow cylindrical SiOx μOFRR resonator structure, and whispering gallery mode (WGM) resonances were generated with a 1550 nm tunable laser via an optical fiber taper. Reversible shifts in the WGM resonant wavelength upon vapor exposure were detected with a photodetector. The μOFRR chip was connected to a pair of upstream etched-Si chips containing PDMS-coated separation μcolumns and calibration curves were generated from the peak-area responses to five volatile organic compounds (VOCs). Calibration curves were linear, and the sensitivities reflected the influence of analyte volatility and analyte-MPN functional group affinity. Sorption-induced changes in film thickness apparently dominate over changes in the refractive index of the film as the determinant of responses for all VOCs. Peaks from the MPN-coated μOFRR were just 20-50% wider than those from a flame ionization detector for similar μcolumn separation conditions, reflecting the rapid response of the sensor for VOCs. The five VOCs were baseline separated in <1.67 min, with detection limits as low as 38 ng.

  9. Pushing the lipid envelope: using bio-inspired nanocomposites to understand and exploit lipid membrane limitations

    NASA Astrophysics Data System (ADS)

    Montano, Gabriel

    Lipids serve as the organizing matrix material for biological membranes, the site of interaction of cells with the external environment. . As such, lipids play a critical role in structure/function relationships of an extraordinary number of critical biological processes. In this talk, we will look at bio-inspired membrane assemblies to better understand the roles of lipids in biological systems as well as attempt to generate materials that can mimic and potentially advance upon biological membrane processes. First, we will investigate the response of lipids to adverse conditions. In particular, I will present data that demonstrates the response of lipids to harsh conditions and how such responses can be exploited to generate nanocomposite rearrangements. I will also show the effect of adding the endotoxin lipopolysaccharide (LPS) to lipid bilayer assemblies and describe implications on our understanding of LPS organization in biological systems as well as describe induced lipid modifications that can be exploited to organize membrane composites with precise, two-dimensional geometric control. Lastly, I will describe the use of amphiphilic block copolymers to create membrane nanocomposites capable of mimicking biological systems. In particular, I will describe the use of our polymer-based membranes in creating artificial photosynthetic assemblies that rival biological systems in function in a more flexible, dynamic matrix.

  10. Processor-Based Strong Physical Unclonable Functions with Aging-Based Response Tuning (Preprint)

    DTIC Science & Technology

    2013-01-01

    NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON GARRET S. ROSE a. REPORT U b . ABSTRACT U c. THIS PAGE U 19b. TELEPHONE NUMBER (Include area code...generated by quad-tree process variation model [1]. The number in the right side of the figures means Z value of Gaussian distribution. B . Delay model To...and B are technology dependent constants. As shown in Equation 2, the Vth shift heavily depends on temperature (T ) and stress time (t). By applying

  11. DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zhang, Jie; Jain, Rishabh; Hodge, Bri-Mathias

    A data-driven methodology is developed to analyze how ambient and wake turbulence affect the power generation of wind turbine(s). Using supervisory control and data acquisition (SCADA) data from a wind plant, we select two sets of wind velocity and power data for turbines on the edge of the plant that resemble (i) an out-of-wake scenario and (ii) an in-wake scenario. For each set of data, two surrogate models are developed to represent the turbine(s) power generation as a function of (i) the wind speed and (ii) the wind speed and turbulence intensity. Three types of uncertainties in turbine(s) power generationmore » are investigated: (i) the uncertainty in power generation with respect to the reported power curve; (ii) the uncertainty in power generation with respect to the estimated power response that accounts for only mean wind speed; and (iii) the uncertainty in power generation with respect to the estimated power response that accounts for both mean wind speed and turbulence intensity. Results show that (i) the turbine(s) generally produce more power under the in-wake scenario than under the out-of-wake scenario with the same wind speed; and (ii) there is relatively more uncertainty in the power generation under the in-wake scenario than under the out-of-wake scenario.« less

  12. Affective resonance in response to others' emotional faces varies with affective ratings and psychopathic traits in amygdala and anterior insula.

    PubMed

    Seara-Cardoso, Ana; Sebastian, Catherine L; Viding, Essi; Roiser, Jonathan P

    2016-01-01

    Despite extensive research on the neural basis of empathic responses for pain and disgust, there is limited data about the brain regions that underpin affective response to other people's emotional facial expressions. Here, we addressed this question using event-related functional magnetic resonance imaging to assess neural responses to emotional faces, combined with online ratings of subjective state. When instructed to rate their own affective response to others' faces, participants recruited anterior insula, dorsal anterior cingulate, inferior frontal gyrus, and amygdala, regions consistently implicated in studies investigating empathy for disgust and pain, as well as emotional saliency. Importantly, responses in anterior insula and amygdala were modulated by trial-by-trial variations in subjective affective responses to the emotional facial stimuli. Furthermore, overall task-elicited activations in these regions were negatively associated with psychopathic personality traits, which are characterized by low affective empathy. Our findings suggest that anterior insula and amygdala play important roles in the generation of affective internal states in response to others' emotional cues and that attenuated function in these regions may underlie reduced empathy in individuals with high levels of psychopathic traits.

  13. Community proteomics provides functional insight into polyhydroxyalkanoate production by a mixed microbial culture cultivated on fermented dairy manure.

    PubMed

    Hanson, Andrea J; Guho, Nicholas M; Paszczynski, Andrzej J; Coats, Erik R

    2016-09-01

    Polyhydroxyalkanoates (PHAs) are bio-based, biodegradable polyesters that can be produced from organic-rich waste streams using mixed microbial cultures (MMCs). To maximize PHA production, MMCs are enriched for bacteria with a high polymer storage capacity through the application of aerobic dynamic feeding (ADF) in a sequencing batch reactor (SBR), which consequently induces a feast-famine metabolic response. Though the feast-famine response is generally understood empirically at a macro-level, the molecular level is less refined. The objective of this study was to investigate the microbial community composition and proteome profile of an enriched MMC cultivated on fermented dairy manure. The enriched MMC exhibited a feast-famine response and was capable of producing up to 40 % (wt. basis) PHA in a fed-batch reactor. High-throughput 16S rRNA gene sequencing revealed a microbial community dominated by Meganema, a known PHA-producing genus not often observed in high abundance in enrichment SBRs. The application of the proteomic methods two-dimensional electrophoresis and LC-MS/MS revealed PHA synthesis, energy generation, and protein synthesis prominently occurring during the feast phase, corroborating bulk solution variable observations and theoretical expectations. During the famine phase, nutrient transport, acyl-CoA metabolism, additional energy generation, and housekeeping functions were more pronounced, informing previously under-determined MMC functionality under famine conditions. During fed-batch PHA production, acetyl-CoA acetyltransferase and PHA granule-bound phasin proteins were in increased abundance relative to the SBR, supporting the higher PHA content observed. Collectively, the results provide unique microbial community structural and functional insight into feast-famine PHA production from waste feedstocks using MMCs.

  14. Acidosis downregulates platelet haemostatic functions and promotes neutrophil proinflammatory responses mediated by platelets.

    PubMed

    Etulain, Julia; Negrotto, Soledad; Carestia, Agostina; Pozner, Roberto Gabriel; Romaniuk, María Albertina; D'Atri, Lina Paola; Klement, Giannoula Lakka; Schattner, Mirta

    2012-01-01

    Acidosis is one of the hallmarks of tissue injury such as trauma, infection, inflammation, and tumour growth. Although platelets participate in the pathophysiology of all these processes, the impact of acidosis on platelet biology has not been studied outside of the quality control of laboratory aggregation assays or platelet transfusion optimization. Herein, we evaluate the effect of physiologically relevant changes in extracellular acidosis on the biological function of platelets, placing particular emphasis on haemostatic and secretory functions. Platelet haemostatic responses such as adhesion, spreading, activation of αIIbβ3 integrin, ATP release, aggregation, thromboxane B2 generation, clot retraction and procoagulant activity including phosphatidilserine exposure and microparticle formation, showed a statistically significant inhibition of thrombin-induced changes at pH of 7.0 and 6.5 compared to the physiological pH (7.4). The release of alpha granule content was differentially regulated by acidosis. At low pH, thrombin or collagen-induced secretion of vascular endothelial growth factor and endostatin were dramatically reduced. The release of von Willebrand factor and stromal derived factor-1α followed a similar, albeit less dramatic pattern. In contrast, the induction of CD40L was not changed by low pH, and P-selectin exposure was significantly increased. While the generation of mixed platelet-leukocyte aggregates and the increased chemotaxis of neutrophils mediated by platelets were further augmented under acidic conditions in a P-selectin dependent manner, the increased neutrophil survival was independent of P-selectin expression. In conclusion, our results indicate that extracellular acidosis downregulates most of the haemostatic platelet functions, and promotes those involved in amplifying the neutrophil-mediated inflammatory response.

  15. Short Term, Low Dose Simvastatin Pretreatment Alters Memory Immune Function Following Secondary Staphylococcus aureus Infection.

    PubMed

    Smelser, Lisa K; Walker, Callum; Burns, Erin M; Curry, Michael; Black, Nathanael; Metzler, Jennifer A; McDowell, Susan A; Bruns, Heather A

    Statins are potent modulators of immune responses, resulting in their ability to enhance host survival from primary bacterial infections. Alterations in primary immune responses that may be beneficial for survival following infection may also result in alterations in the generation of the immunologic memory response and subsequently affect immune responses mounted during secondary bacterial infection. In this study, we report that levels of total serum IgG2c, following primary infection, were decreased in simvastatin pretreated mice, and investigate the effect of simvastatin treatment, prior to primary infection, on immune responses activated during secondary S. aureus infection. A secondary infection model was implemented whereby simvastatin pretreated and control mice were reinfected with S. aureus 14 days after primary infection, with no additional simvastatin treatment, and assessed for survival and alterations in immune function. While survivability to secondary S. aureus infection was not different between simvastatin pretreated and control mice, memory B and T lymphocyte functions were altered. Memory B cells, isolated 14 days after secondary infection, from simvastatin pretreated mice and stimulated ex vivo produced increased levels of IgG1 compared to memory B cells isolated from control mice, while levels of IgM and IgG2c remained similar. Furthermore, memory B and T lymphocytes from simvastatin pretreated mice exhibited a decreased proliferative response when stimulated ex vivo compared to memory cells isolated from control mice. These findings demonstrate the ability of a short term, low dose simvastatin treatment to modulate memory immune function.

  16. The Absence of Interleukin 1 Receptor–Related T1/St2 Does Not Affect T Helper Cell Type 2 Development and Its Effector Function

    PubMed Central

    Hoshino, Katsuaki; Kashiwamura, Shin-ichiro; Kuribayashi, Kozo; Kodama, Taku; Tsujimura, Tohru; Nakanishi, Kenji; Matsuyama, Tomohiro; Takeda, Kiyoshi; Akira, Shizuo

    1999-01-01

    T1/ST2, an orphan receptor with homology with the interleukin (IL)-1 receptor family, is expressed constitutively and stably on the surface of T helper type 2 (Th2) cells, but not on Th1 cells. T1/ST2 is also expressed on mast cells, which are critical for Th2-mediated effector responses. To evaluate whether T1/ST2 is required for Th2 responses and mast cell function, we have generated T1/ST2-deficient (T1/ST2−/−) mice and examined the roles of T1/ST2. Naive CD4+ T cells isolated from T1/ST2−/− mice developed to Th2 cells in response to IL-4 in vitro. T1/ST2−/− mice showed normal Th2 responses after infection with the helminthic parasite Nippostrongylus brasiliensis as well as in the mouse model of allergen-induced airway inflammation. In addition, differentiation and function of bone marrow–derived cultured mast cells were unaffected. These findings demonstrate that T1/ST2 does not play an essential role in development and function of Th2 cells and mast cells. PMID:10562328

  17. Autophagy Primes Neutrophils for Neutrophil Extracellular Trap Formation during Sepsis.

    PubMed

    Park, So Young; Shrestha, Sanjeeb; Youn, Young-Jin; Kim, Jun-Kyu; Kim, Shin-Yeong; Kim, Hyun Jung; Park, So-Hee; Ahn, Won-Gyun; Kim, Shin; Lee, Myung Goo; Jung, Ki-Suck; Park, Yong Bum; Mo, Eun-Kyung; Ko, Yousang; Lee, Suh-Young; Koh, Younsuck; Park, Myung Jae; Song, Dong-Keun; Hong, Chang-Won

    2017-09-01

    Neutrophils are key effectors in the host's immune response to sepsis. Excessive stimulation or dysregulated neutrophil functions are believed to be responsible for sepsis pathogenesis. However, the mechanisms regulating functional plasticity of neutrophils during sepsis have not been fully determined. We investigated the role of autophagy in neutrophil functions during sepsis in patients with community-acquired pneumonia. Neutrophils were isolated from patients with sepsis and stimulated with phorbol 12-myristate 13-acetate (PMA). The levels of reactive oxygen species generation, neutrophil extracellular trap (NET) formation, and granule release, and the autophagic status were evaluated. The effect of neutrophil autophagy augmentation was further evaluated in a mouse model of sepsis. Neutrophils isolated from patients who survived sepsis showed an increase in autophagy induction, and were primed for NET formation in response to subsequent PMA stimulation. In contrast, neutrophils isolated from patients who did not survive sepsis showed dysregulated autophagy and a decreased response to PMA stimulation. The induction of autophagy primed healthy neutrophils for NET formation and vice versa. In a mouse model of sepsis, the augmentation of autophagy improved survival via a NET-dependent mechanism. These results indicate that neutrophil autophagy primes neutrophils for increased NET formation, which is important for proper neutrophil effector functions during sepsis. Our study provides important insights into the role of autophagy in neutrophils during sepsis.

  18. Development of the Complex General Linear Model in the Fourier Domain: Application to fMRI Multiple Input-Output Evoked Responses for Single Subjects

    PubMed Central

    Rio, Daniel E.; Rawlings, Robert R.; Woltz, Lawrence A.; Gilman, Jodi; Hommer, Daniel W.

    2013-01-01

    A linear time-invariant model based on statistical time series analysis in the Fourier domain for single subjects is further developed and applied to functional MRI (fMRI) blood-oxygen level-dependent (BOLD) multivariate data. This methodology was originally developed to analyze multiple stimulus input evoked response BOLD data. However, to analyze clinical data generated using a repeated measures experimental design, the model has been extended to handle multivariate time series data and demonstrated on control and alcoholic subjects taken from data previously analyzed in the temporal domain. Analysis of BOLD data is typically carried out in the time domain where the data has a high temporal correlation. These analyses generally employ parametric models of the hemodynamic response function (HRF) where prewhitening of the data is attempted using autoregressive (AR) models for the noise. However, this data can be analyzed in the Fourier domain. Here, assumptions made on the noise structure are less restrictive, and hypothesis tests can be constructed based on voxel-specific nonparametric estimates of the hemodynamic transfer function (HRF in the Fourier domain). This is especially important for experimental designs involving multiple states (either stimulus or drug induced) that may alter the form of the response function. PMID:23840281

  19. Development of the complex general linear model in the Fourier domain: application to fMRI multiple input-output evoked responses for single subjects.

    PubMed

    Rio, Daniel E; Rawlings, Robert R; Woltz, Lawrence A; Gilman, Jodi; Hommer, Daniel W

    2013-01-01

    A linear time-invariant model based on statistical time series analysis in the Fourier domain for single subjects is further developed and applied to functional MRI (fMRI) blood-oxygen level-dependent (BOLD) multivariate data. This methodology was originally developed to analyze multiple stimulus input evoked response BOLD data. However, to analyze clinical data generated using a repeated measures experimental design, the model has been extended to handle multivariate time series data and demonstrated on control and alcoholic subjects taken from data previously analyzed in the temporal domain. Analysis of BOLD data is typically carried out in the time domain where the data has a high temporal correlation. These analyses generally employ parametric models of the hemodynamic response function (HRF) where prewhitening of the data is attempted using autoregressive (AR) models for the noise. However, this data can be analyzed in the Fourier domain. Here, assumptions made on the noise structure are less restrictive, and hypothesis tests can be constructed based on voxel-specific nonparametric estimates of the hemodynamic transfer function (HRF in the Fourier domain). This is especially important for experimental designs involving multiple states (either stimulus or drug induced) that may alter the form of the response function.

  20. Electro-Mechanical Resonance Curves

    ERIC Educational Resources Information Center

    Greenslade, Thomas B., Jr.

    2018-01-01

    Recently I have been investigating the frequency response of galvanometers. These are direct-current devices used to measure small currents. By using a low-frequency function generator to supply the alternating-current signal and a stopwatch smartphone app to measure the period, I was able to take data to allow a resonance curve to be drawn. This…

  1. Neurobehavioral and Neurophysiological Assessment of Healthy and "At-Risk" Full-Term Infants.

    ERIC Educational Resources Information Center

    Eldredge, Lynnette; Salamy, Alan

    1988-01-01

    Study evaluates the functioning of the central nervous system (CNS) of 15 neonates born at-risk for neurological sequelae and 15 healthy controls. CNS information was generated through the use of two measures: (1) the Neurological and Adaptive Capacity Score (NACS) and the auditory brainstem response (ABR). (Author/RWB)

  2. Theory of plasmonic effects in nonlinear optics: the case of graphene

    NASA Astrophysics Data System (ADS)

    Rostami, Habib; Katsnelson, Mikhail I.; Polini, Marco; Mikhail I. Katsnelson Collaboration; Habib Rostami; Marco Polini Collaboration

    The nonlinear optical properties of two-dimensional electronic systems are beginning to attract considerable interest both in the theoretical and experimental sectors. Recent experiments on the nonlinear optical properties of graphene reveal considerably strong third harmonic generation and four-wave mixing of this single-atomic-layer electronic system. We develop a large-N theory of electron-electron interaction corrections to multi-legged Feynman diagrams describing second- and third-order nonlinear response functions. Our theory is completely general and is useful to understand all second- and third-order nonlinear effects, including harmonic generation, wave mixing, and photon drag. We apply our theoretical framework to the case of graphene, by carrying out microscopic calculations of the second- and third-order nonlinear response functions of an interacting two-dimensional gas of massless Dirac fermions. We compare our results with recent measurements, where all-optical launching of graphene plasmons has been achieved. This work was supported by Fondazione Istituto Italiano di Tecnologia, the European Union's Horizon 2020 research and innovation programme under Grant agreement No. 696656 GrapheneCore, and the ERC Advanced Grant 338957 FEMTO/NANO (M.I.K.).

  3. Neurobiological Mechanisms for the Regulation of Mammalian Sleep-Wake Behavior: Reinterpretation of Historical Evidence and Inclusion of Contemporary Cellular and Molecular Evidence

    PubMed Central

    Datta, Subimal; MacLean, Robert Ross

    2007-01-01

    At its most basic level, the function of mammalian sleep can be described as a restorative process of the brain and body; recently, however, progressive research has revealed a host of vital functions to which sleep is essential. Although many excellent reviews on sleep behavior have been published, none have incorporated contemporary studies examining the molecular mechanisms that govern the various stages of sleep. Utilizing a holistic approach, this review is focused on the basic mechanisms involved in the transition from wakefulness, initiation of sleep and the subsequent generation of slow-wave sleep and rapid eye movement (REM) sleep. Additionally, using recent molecular studies and experimental evidence that provides a direct link to sleep as a behavior, we have developed a new model, the Cellular-Molecular-Network model, explaining the mechanisms responsible for regulating REM sleep. By analyzing the fundamental neurobiological mechanisms responsible for the generation and maintenance of sleep-wake behavior in mammals, we intend to provide a broader understanding of our present knowledge in the field of sleep research. PMID:17445891

  4. Analysis of tonal noise generating mechanisms in low-speed axial-flow fans

    NASA Astrophysics Data System (ADS)

    Canepa, Edward; Cattanei, Andrea; Zecchin, Fabio Mazzocut

    2016-08-01

    The present paper reports a comparison of experimental SPL spectral data related to the tonal noise generated by axial-flow fans. A nine blade rotor has been operated at free discharge conditions and in four geometrical configurations in which different kinds of tonal noise generating mechanisms are present: large-scale inlet turbulent structures, tip-gap flow, turbulent wakes, and rotor-stator interaction. The measurements have been taken in a hemi-anechoic chamber at constant rotational speed and, in order to vary the acoustic source strength, during low angular acceleration, linear speed ramps. In order to avoid erroneous quantitative evaluations if the acoustic propagation effects are not considered, the acoustic response functions of the different test configurations have been computed by means of the spectral decomposition method. Then, the properties of the tonal noise generating mechanisms have been studied. To this aim, the constant-Strouhal number SPL, obtained by means of measurements taken during the speed ramps, have been compared with the propagation function. Finally, the analysis of the phase of the acoustic pressure has allowed to distinguish between random and deterministic tonal noise generating mechanisms and to collect information about the presence of important propagation effects.

  5. A 120-kDa alkaline peptidase from Trypanosoma cruzi is involved in the generation of a novel Ca(2+)-signaling factor for mammalian cells.

    PubMed

    Burleigh, B A; Andrews, N W

    1995-03-10

    Trypomastigotes, the infective stages of the intracellular parasite Trypanosoma cruzi, induce rapid and repetitive cytosolic free Ca2+ transients in fibroblasts. Buffering or depletion of intracellular free Ca2+ inhibits cell entry by trypomastigotes, indicating a role for this signaling event in invasion. We show here that the majority of the Ca(2+)-signaling activity is associated with the soluble fraction of parasites disrupted by sonication. Distinct cell types from different species are responsive to this soluble factor, and intracellular free Ca2+ transients occur rapidly and reach concentrations comparable to responses induced by thrombin and bombesin. The Ca(2+)-signaling activity does not bind concanavalin A and is strongly inhibited by a specific subset of protease inhibitors. The only detectable protease in the fractions with Ca(2+)-signaling activity is an unusual alkaline peptidase of 120 kDa, to which no function had been previously assigned. The activity of the protease and cell invasion by trypomastigotes are blocked by the same specific inhibitors that impair Ca(2+)-signaling, suggesting that the enzyme is required for generating the response leading to infection. We demonstrate that the 120-kDa peptidase is not sufficient for triggering Ca(2+)-signaling, possibly being involved in the processing of precursors present only in infective trypomastigotes. These findings indicate a biological function for a previously identified unusual protozoan protease and provide the first example of a proteolytically generated parasite factor with characteristics of a mammalian hormone.

  6. 3,4-dichloropropionaniline suppresses normal macrophage function.

    PubMed

    Ustyugova, Irina V; Frost, Laura L; Van Dyke, Knox; Brundage, Kathleen M; Schafer, Rosana; Barnett, John B

    2007-06-01

    Macrophages are a critical part of the innate immune response and natural surveillance mechanisms. As such, proper macrophage function is crucial for engulfing bacterial pathogens through phagocytosis and destroying them by generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The production of a number of cytokines by macrophages, such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6, plays an important role in the initiation of the acquired immune response creating an inflammatory environment favorable for fighting a bacterial infection. 3,4-Dichloropropionaniline (DCPA) suppresses several inflammatory parameters, including TNF-alpha production through a mechanism where nuclear factor-kappaB (NF-kappaB)-DNA binding is inhibited but not entirely abrogated. The goal of the present study was to evaluate the effects of DCPA on the inflammatory mediators of macrophages, including ROS and RNS in both murine peritoneal exudate cells and the human monocytic cell line, THP-1. The ability to perform phagocytosis and directly kill Listeria monocytogenes was also assessed. The results indicate that DCPA decreases the ability of both types of macrophages to phagocytize beads and generate both types of reactive species, which was correlated with a decrement in listericidal activity. These results demonstrate that DCPA has profound effects on macrophage function and provide insight into the potential mechanisms of immunosuppression by DCPA.

  7. Schwann cell-specific JAM-C-deficient mice reveal novel expression and functions for JAM-C in peripheral nerves.

    PubMed

    Colom, Bartomeu; Poitelon, Yannick; Huang, Wenlong; Woodfin, Abigail; Averill, Sharon; Del Carro, Ubaldo; Zambroni, Desirée; Brain, Susan D; Perretti, Mauro; Ahluwalia, Amrita; Priestley, John V; Chavakis, Triantafyllos; Imhof, Beat A; Feltri, M Laura; Nourshargh, Sussan

    2012-03-01

    Junctional adhesion molecule-C (JAM-C) is an adhesion molecule expressed at junctions between adjacent endothelial and epithelial cells and implicated in multiple inflammatory and vascular responses. In addition, we recently reported on the expression of JAM-C in Schwann cells (SCs) and its importance for the integrity and function of peripheral nerves. To investigate the role of JAM-C in neuronal functions further, mice with a specific deletion of JAM-C in SCs (JAM-C SC KO) were generated. Compared to wild-type (WT) controls, JAM-C SC KO mice showed electrophysiological defects, muscular weakness, and hypersensitivity to mechanical stimuli. In addressing the underlying cause of these defects, nerves from JAM-C SC KO mice were found to have morphological defects in the paranodal region, exhibiting increased nodal length as compared to WTs. The study also reports on previously undetected expressions of JAM-C, namely on perineural cells, and in line with nociception defects of the JAM-C SC KO animals, on finely myelinated sensory nerve fibers. Collectively, the generation and characterization of JAM-C SC KO mice has provided unequivocal evidence for the involvement of SC JAM-C in the fine organization of peripheral nerves and in modulating multiple neuronal responses.

  8. Functional Mitochondria in Health and Disease.

    PubMed

    Herst, Patries M; Rowe, Matthew R; Carson, Georgia M; Berridge, Michael V

    2017-01-01

    The ability to rapidly adapt cellular bioenergetic capabilities to meet rapidly changing environmental conditions is mandatory for normal cellular function and for cancer progression. Any loss of this adaptive response has the potential to compromise cellular function and render the cell more susceptible to external stressors such as oxidative stress, radiation, chemotherapeutic drugs, and hypoxia. Mitochondria play a vital role in bioenergetic and biosynthetic pathways and can rapidly adjust to meet the metabolic needs of the cell. Increased demand is met by mitochondrial biogenesis and fusion of individual mitochondria into dynamic networks, whereas a decrease in demand results in the removal of superfluous mitochondria through fission and mitophagy. Effective communication between nucleus and mitochondria (mito-nuclear cross talk), involving the generation of different mitochondrial stress signals as well as the nuclear stress response pathways to deal with these stressors, maintains bioenergetic homeostasis under most conditions. However, when mitochondrial DNA (mtDNA) mutations accumulate and mito-nuclear cross talk falters, mitochondria fail to deliver critical functional outputs. Mutations in mtDNA have been implicated in neuromuscular and neurodegenerative mitochondriopathies and complex diseases such as diabetes, cardiovascular diseases, gastrointestinal disorders, skin disorders, aging, and cancer. In some cases, drastic measures such as acquisition of new mitochondria from donor cells occurs to ensure cell survival. This review starts with a brief discussion of the evolutionary origin of mitochondria and summarizes how mutations in mtDNA lead to mitochondriopathies and other degenerative diseases. Mito-nuclear cross talk, including various stress signals generated by mitochondria and corresponding stress response pathways activated by the nucleus are summarized. We also introduce and discuss a small family of recently discovered hormone-like mitopeptides that modulate body metabolism. Under conditions of severe mitochondrial stress, mitochondria have been shown to traffic between cells, replacing mitochondria in cells with damaged and malfunctional mtDNA. Understanding the processes involved in cellular bioenergetics and metabolic adaptation has the potential to generate new knowledge that will lead to improved treatment of many of the metabolic, degenerative, and age-related inflammatory diseases that characterize modern societies.

  9. Automatic generation of user material subroutines for biomechanical growth analysis.

    PubMed

    Young, Jonathan M; Yao, Jiang; Ramasubramanian, Ashok; Taber, Larry A; Perucchio, Renato

    2010-10-01

    The analysis of the biomechanics of growth and remodeling in soft tissues requires the formulation of specialized pseudoelastic constitutive relations. The nonlinear finite element analysis package ABAQUS allows the user to implement such specialized material responses through the coding of a user material subroutine called UMAT. However, hand coding UMAT subroutines is a challenge even for simple pseudoelastic materials and requires substantial time to debug and test the code. To resolve this issue, we develop an automatic UMAT code generation procedure for pseudoelastic materials using the symbolic mathematics package MATHEMATICA and extend the UMAT generator to include continuum growth. The performance of the automatically coded UMAT is tested by simulating the stress-stretch response of a material defined by a Fung-orthotropic strain energy function, subject to uniaxial stretching, equibiaxial stretching, and simple shear in ABAQUS. The MATHEMATICA UMAT generator is then extended to include continuum growth by adding a growth subroutine to the automatically generated UMAT. The MATHEMATICA UMAT generator correctly derives the variables required in the UMAT code, quickly providing a ready-to-use UMAT. In turn, the UMAT accurately simulates the pseudoelastic response. In order to test the growth UMAT, we simulate the growth-based bending of a bilayered bar with differing fiber directions in a nongrowing passive layer. The anisotropic passive layer, being topologically tied to the growing isotropic layer, causes the bending bar to twist laterally. The results of simulations demonstrate the validity of the automatically coded UMAT, used in both standardized tests of hyperelastic materials and for a biomechanical growth analysis.

  10. Impact of cercal air currents on singing motor pattern generation in the cricket (Gryllus bimaculatus DeGeer)

    PubMed Central

    2015-01-01

    The cercal system of crickets detects low-frequency air currents produced by approaching predators and self-generated air currents during singing, which may provide sensory feedback to the singing motor network. We analyzed the effect of cercal stimulation on singing motor pattern generation to reveal the response of a singing interneuron to predator-like signals and to elucidate the possible role of self-generated air currents during singing. In fictive singing males, we recorded an interneuron of the singing network while applying air currents to the cerci; additionally, we analyzed the effect of abolishing the cercal system in freely singing males. In fictively singing crickets, the effect of short air stimuli is either to terminate prematurely or to lengthen the interchirp interval, depending on their phase in the chirp cycle. Within our stimulation paradigm, air stimuli of different velocities and durations always elicited an inhibitory postsynaptic potential in the singing interneuron. Current injection in the singing interneuron elicited singing motor activity, even during the air current-evoked inhibitory input from the cercal pathway. The disruptive effects of air stimuli on the fictive singing pattern and the inhibitory response of the singing interneuron point toward the cercal system being involved in initiating avoidance responses in singing crickets, according to the established role of cerci in a predator escape pathway. After abolishing the activity of the cercal system, the timing of natural singing activity was not significantly altered. Our study provides no evidence that self-generated cercal sensory activity has a feedback function for singing motor pattern generation. PMID:26334014

  11. Effect of gel re-organization and tensional forces on alpha2beta1 integrin levels in dermal fibroblasts.

    PubMed

    Jenkins, G; Redwood, K L; Meadows, L; Green, M R

    1999-07-01

    Mechanical forces are known to play an important role in regulating cell function in a wide range of biological systems. This is of particular relevance to dermal fibroblast function, given that the skin is known to be held under an intrinsic natural tension. To understand more about the generation of force by dermal fibroblasts and their ability to respond to changes in it, we have studied the role of the beta1 integrin receptors expressed by dermal fibroblasts in their ability to generate tensional forces within a collagen type I matrix and the effect of altered tensional force on integrin expression by dermal fibroblasts. Using a purpose-built culture force monitor, function-blocking antibodies directed towards the beta1 receptors dramatically reduced the tensional forces generated by dermal fibroblasts in a 3D collagen I matrix. However, the specific involvement of alpha1 or alpha2 subunits could not be demonstrated. Analysis of cellular response demonstrated that cells isolated from contracting collagen gels expressed fourfold higher levels of alpha2 mRNA than cells isolated from fully restrained gels. The levels of beta1 messenger RNA were relatively unaffected by reductions in force. Cells exposed to single reductions in force, however, did not exhibit alterations in either alpha1 or beta1 mRNA levels. We propose, therefore that alpha2beta1 integrin receptor levels in dermal fibroblasts are not altered in response to single reductions of gel tension, but do change following a continual change in force and associated matrix re-organization

  12. TBGG- INTERACTIVE ALGEBRAIC GRID GENERATION

    NASA Technical Reports Server (NTRS)

    Smith, R. E.

    1994-01-01

    TBGG, Two-Boundary Grid Generation, applies an interactive algebraic grid generation technique in two dimensions. The program incorporates mathematical equations that relate the computational domain to the physical domain. TBGG has application to a variety of problems using finite difference techniques, such as computational fluid dynamics. Examples include the creation of a C-type grid about an airfoil and a nozzle configuration in which no left or right boundaries are specified. The underlying two-boundary technique of grid generation is based on Hermite cubic interpolation between two fixed, nonintersecting boundaries. The boundaries are defined by two ordered sets of points, referred to as the top and bottom. Left and right side boundaries may also be specified, and call upon linear blending functions to conform interior interpolation to the side boundaries. Spacing between physical grid coordinates is determined as a function of boundary data and uniformly spaced computational coordinates. Control functions relating computational coordinates to parametric intermediate variables that affect the distance between grid points are embedded in the interpolation formulas. A versatile control function technique with smooth cubic spline functions is also presented. The TBGG program is written in FORTRAN 77. It works best in an interactive graphics environment where computational displays and user responses are quickly exchanged. The program has been implemented on a CDC Cyber 170 series computer using NOS 2.4 operating system, with a central memory requirement of 151,700 (octal) 60 bit words. TBGG requires a Tektronix 4015 terminal and the DI-3000 Graphics Library of Precision Visuals, Inc. TBGG was developed in 1986.

  13. Searching for biomarkers of CDKL5 disorder: early-onset visual impairment in CDKL5 mutant mice

    PubMed Central

    Mazziotti, Raffaele; Lupori, Leonardo; Sagona, Giulia; Gennaro, Mariangela; Della Sala, Grazia; Putignano, Elena

    2017-01-01

    Abstract CDKL5 disorder is a neurodevelopmental disorder still without a cure. Murine models of CDKL5 disorder have been recently generated raising the possibility of preclinical testing of treatments. However, unbiased, quantitative biomarkers of high translational value to monitor brain function are still missing. Moreover, the analysis of treatment is hindered by the challenge of repeatedly and non-invasively testing neuronal function. We analyzed the development of visual responses in a mouse model of CDKL5 disorder to introduce visually evoked responses as a quantitative method to assess cortical circuit function. Cortical visual responses were assessed in CDKL5 null male mice, heterozygous females, and their respective control wild-type littermates by repeated transcranial optical imaging from P27 until P32. No difference between wild-type and mutant mice was present at P25-P26 whereas defective responses appeared from P27-P28 both in heterozygous and homozygous CDKL5 mutant mice. These results were confirmed by visually evoked potentials (VEPs) recorded from the visual cortex of a different cohort. The previously imaged mice were also analyzed at P60–80 using VEPs, revealing a persistent reduction of response amplitude, reduced visual acuity and defective contrast function. The level of adult impairment was significantly correlated with the reduction in visual responses observed during development. Support vector machine showed that multi-dimensional visual assessment can be used to automatically classify mutant and wt mice with high reliability. Thus, monitoring visual responses represents a promising biomarker for preclinical and clinical studies on CDKL5 disorder. PMID:28369421

  14. Measurements of farfield sound generation from a flow-excited cavity

    NASA Technical Reports Server (NTRS)

    Block, P. J. W.; Heller, H.

    1975-01-01

    Results of 1/3-octave-band spectral measurements of internal pressures and the external acoustic field of a tangentially blown rectangular cavity are compared. Proposed mechanisms for sound generation are reviewed, and spectra and directivity plots of cavity noise are presented. Directivity plots show a slightly modified monopole pattern. Frequencies of cavity response are calculated using existing predictions and are compared with those obtained experimentally. The effect of modifying the upstream boundary layer on the noise was investigated, and its effectiveness was found to be a function of cavity geometry and flow velocity.

  15. Engineering the Intracellular Micro- and Nano-environment via Magnetic Nanoparticles

    NASA Astrophysics Data System (ADS)

    Tseng, Peter

    Single cells, despite being the base unit of living organisms, possess a high degree of hierarchical structure and functional compartmentalization. This complexity exists for good reason: cells must respond efficiently and effectively to its surrounding environment by differentiating, moving, interacting, and more in order to survive or inhabit its role in the larger biological system. At the core of these responses is cellular decision-making. Cells process cues internally and externally from the environment and effect intracellular asymmetry in biochemistry and structure in order to carry out the proper biological responses. Functionalized magnetic particles have shown to be a powerful tool in interacting with biological matter, through either cell or biomolecule sorting, and the activation of biological processes. This dissertation reports on techniques utilizing manipulated magnetic nanoparticles (internalized by cells) to spatially and temporally localize intracellular cues, and examines the resulting asymmetry in biological processes generated by our methods. We first examine patterned micromagnetic elements as a simple strategy of rapidly manipulating magnetic nanoparticles throughout the intracellular space. Silicon or silicon dioxide substrates form the base for electroplated NiFe rods, which are repeated at varying size and pitch. A planarizing resin, initially SU-8, is used as the substrate layer for cellular adhesion. We demonstrate that through the manipulations of a simple external magnet, these micro-fabricated substrates can mediate rapid (under 2 s) and precise (submicron), reversible translation of magnetic nanoparticles through cellular space. Seeding cells on substrates composed of these elements allows simultaneous control of ensembles of nanoparticles over thousands of cells at a time. We believe such substrates could form the basis of magnetically based tools for the activation of biological matter. We further utilize these strategies to generate user-controllable (time-varying and localizable), massively parallel forces on arrays of cells mediated by coalesced ensembles of magnetic nanoparticles. The above process is simplified and adapted for single cell analysis by precisely aligning fibronectin patterned cells to a single flanking micromagnet. The cells are loaded with magnetic-fluorescent nanoparticles, which are then localized to uniform positions at the internal edge of the cell membrane over huge arrays of cells using large external fields, allowing us to conduct composed studies on cellular response to force. By applying forces approaching the yield tension (5 nN / mum) of single cells, we are able to generate highly coordinated responses in cellular behavior. We discover that increasing tension generates highly directed, PAK-dependent leading-edge type filopodia that increase in intensity with rising tension. In addition, we find that our generated forces can simulate cues created during cellular mitosis, as we are consistently able to generate significant (45 to 90 degree) biasing of the metaphase plate during cell division. Large sample size and rapid sample generation also allow us to analyze cells at an unprecedented rate---a single sample can simultaneously stimulate thousands of cells for high statistical accuracy in measurements. We believe these approaches have potential not just as a tool to study single-cell response, but as a means of cell control, potentially through modifying cell movement, division, or differentiation. More generally, once approaches to release nanoparticles from endosomes are implemented, the technique provides a platform to dynamically apply a range of localized stimuli arbitrarily within cells. Through the bioconjugation of proteins, nucleic acids, small molecules, or whole organelles a broad range of questions should be accessible concerning molecular localization and its importance in cell function.

  16. Modulation of ROS levels in fibroblasts by altering mitochondria regulates the process of wound healing.

    PubMed

    Janda, Jaroslav; Nfonsam, Valentine; Calienes, Fernanda; Sligh, James E; Jandova, Jana

    2016-05-01

    Mitochondria are the major source of reactive oxygen species (ROS) in fibroblasts which are thought to be crucial regulators of wound healing with a potential to affect the expression of nuclear genes involved in this process. ROS generated by mitochondria are involved in all stages of tissue repair process but the regulation of ROS-generating system in fibroblasts still remains poorly understood. The purpose of this study was to better understand molecular mechanisms of how the regulation of ROS levels generated by mitochondria may influence the process of wound repair. Cybrid model system of mtDNA variations was used to study the functional consequences of altered ROS levels on wound healing responses in a uniform nuclear background of cultured ρ(0) fibroblasts. Mitochondrial ROS in cybrids were modulated by antioxidants that quench ROS to examine their ability to close the wound. Real-time PCR arrays were used to investigate whether ROS generated by specific mtDNA variants have the ability to alter expression of some key nuclear-encoded genes central to the wound healing response and oxidative stress. Our data suggest levels of mitochondrial ROS affect expression of some nuclear encoded genes central to wound healing response and oxidative stress and modulation of mitochondrial ROS by antioxidants positively affects in vitro process of wound closure. Thus, regulation of mitochondrial ROS-generating system in fibroblasts can be used as effective natural redox-based strategy to help treat non-healing wounds.

  17. Human cell toxicogenomic analysis links reactive oxygen species to the toxicity of monohaloacetic acid drinking water disinfection byproducts

    PubMed Central

    Pals, Justin; Attene-Ramos, Matias S.; Xia, Menghang; Wagner, Elizabeth D.; Plewa, Michael J.

    2014-01-01

    Chronic exposure to drinking water disinfection byproducts has been linked to adverse health risks. The monohaloacetic acids (monoHAAs) are generated as byproducts during the disinfection of drinking water and are cytotoxic, genotoxic, mutagenic, and teratogenic. Iodoacetic acid toxicity was mitigated by antioxidants, suggesting the involvement of oxidative stress. Other monoHAAs may share a similar mode of action. Each monoHAA generated a significant concentration-response increase in the expression of a β-lactamase reporter under the control of the Antioxidant Response Element (ARE). The monoHAAs generated oxidative stress with a rank order of IAA > BAA >> CAA; this rank order was observed with other toxicological endpoints. Toxicogenomic analysis was conducted with a non-transformed human intestinal epithelial cell line (FHs 74 Int). Exposure to the monoHAAs altered the transcription levels of multiple oxidative stress responsive genes, indicating that each exposure generated oxidative stress. The transcriptome profiles showed an increase in TXNRD1 and SRXN1, suggesting peroxiredoxin proteins had been oxidized during monoHAA exposures. Three sources of reactive oxygen species were identified, the hypohalous acid generating peroxidase enzymes LPO and MPO, NADPH-dependent oxidase NOX5, and PTGS2 (COX-2) mediated arachidonic acid metabolism. Each monoHAA exposure caused an increase in COX-2 mRNA levels. These data provide a functional association between monoHAA exposure and adverse health outcomes such as oxidative stress, inflammation, and cancer. PMID:24050308

  18. Cardiovascular abnormalities with normal blood pressure in tissue kallikrein-deficient mice

    NASA Astrophysics Data System (ADS)

    Meneton, Pierre; Bloch-Faure, May; Hagege, Albert A.; Ruetten, Hartmut; Huang, Wei; Bergaya, Sonia; Ceiler, Debbie; Gehring, Doris; Martins, Isabelle; Salmon, Georges; Boulanger, Chantal M.; Nussberger, Jürg; Crozatier, Bertrand; Gasc, Jean-Marie; Heudes, Didier; Bruneval, Patrick; Doetschman, Tom; Ménard, Joël; Alhenc-Gelas, François

    2001-02-01

    Tissue kallikrein is a serine protease thought to be involved in the generation of bioactive peptide kinins in many organs like the kidneys, colon, salivary glands, pancreas, and blood vessels. Low renal synthesis and urinary excretion of tissue kallikrein have been repeatedly linked to hypertension in animals and humans, but the exact role of the protease in cardiovascular function has not been established largely because of the lack of specific inhibitors. This study demonstrates that mice lacking tissue kallikrein are unable to generate significant levels of kinins in most tissues and develop cardiovascular abnormalities early in adulthood despite normal blood pressure. The heart exhibits septum and posterior wall thinning and a tendency to dilatation resulting in reduced left ventricular mass. Cardiac function estimated in vivo and in vitro is decreased both under basal conditions and in response to βadrenergic stimulation. Furthermore, flow-induced vasodilatation is impaired in isolated perfused carotid arteries, which express, like the heart, low levels of the protease. These data show that tissue kallikrein is the main kinin-generating enzyme in vivo and that a functional kallikrein-kinin system is necessary for normal cardiac and arterial function in the mouse. They suggest that the kallikrein-kinin system could be involved in the development or progression of cardiovascular diseases.

  19. Platelets generated from human embryonic stem cells are functional in vitro and in the microcirculation of living mice

    PubMed Central

    Lu, Shi-Jiang; Li, Feng; Yin, Hong; Feng, Qiang; Kimbrel, Erin A; Hahm, Eunsil; Thon, Jonathan N; Wang, Wei; Italiano, Joseph E; Cho, Jaehyung; Lanza, Robert

    2011-01-01

    Platelets play an essential role in hemostasis and atherothrombosis. Owing to their short storage time, there is constant demand for this life-saving blood component. In this study, we report that it is feasible to generate functional megakaryocytes and platelets from human embryonic stem cells (hESCs) on a large scale. Differential-interference contrast and electron microscopy analyses showed that ultrastructural and morphological features of hESC-derived platelets were indistinguishable from those of normal blood platelets. In functional assays, hESC-derived platelets responded to thrombin stimulation, formed microaggregates, and facilitated clot formation/retraction in vitro. Live cell microscopy demonstrated that hESC-platelets formed lamellipodia and filopodia in response to thrombin activation, and tethered to each other as observed in normal blood. Using real-time intravital imaging with high-speed video microscopy, we have also shown that hESC-derived platelets contribute to developing thrombi at sites of laser-induced vascular injury in mice, providing the first evidence for in vivo functionality of hESC-derived platelets. These results represent an important step toward generating an unlimited supply of platelets for transfusion. Since platelets contain no genetic material, they are ideal candidates for early clinical translation involving human pluripotent stem cells. PMID:21221130

  20. Nonlinear Wavefront Control with All-Dielectric Metasurfaces

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wang, Lei; Kruk, Sergey; Koshelev, Kirill

    Metasurfaces, two-dimensional lattices of nanoscale resonators, offer unique opportunities for functional flat optics and allow the control of the transmission, reflection, and polarization of a wavefront of light. Recently, all-dielectric metasurfaces reached remarkable efficiencies, often matching or out-performing conventional optical elements. The exploitation of the nonlinear optical response of metasurfaces offers a paradigm shift in nonlinear optics, and dielectric nonlinear metasurfaces are expected to enrich subwavelength photonics by enhancing substantially nonlinear response of natural materials combined with the efficient control of the phase of nonlinear waves. Here, we suggest a novel and rather general approach for engineering the wavefront ofmore » parametric waves of arbitrary complexity generated by a nonlinear metasurface. We design all-dielectric nonlinear metasurfaces, achieve a highly efficient wavefront control of a third-harmonic field, and demonstrate the generation of nonlinear beams at a designed angle and the generation of nonlinear focusing vortex beams. Lastly, our nonlinear metasurfaces produce phase gradients over a full 0–2π phase range with a 92% diffraction efficiency.« less

  1. Reactive oxygen species, essential molecules, during plant-pathogen interactions.

    PubMed

    Camejo, Daymi; Guzmán-Cedeño, Ángel; Moreno, Alexander

    2016-06-01

    Reactive oxygen species (ROS) are continually generated as a consequence of the normal metabolism in aerobic organisms. Accumulation and release of ROS into cell take place in response to a wide variety of adverse environmental conditions including salt, temperature, cold stresses and pathogen attack, among others. In plants, peroxidases class III, NADPH oxidase (NOX) locates in cell wall and plasma membrane, respectively, may be mainly enzymatic systems involving ROS generation. It is well documented that ROS play a dual role into cells, acting as important signal transduction molecules and as toxic molecules with strong oxidant power, however some aspects related to its function during plant-pathogen interactions remain unclear. This review focuses on the principal enzymatic systems involving ROS generation addressing the role of ROS as signal molecules during plant-pathogen interactions. We described how the chloroplasts, mitochondria and peroxisomes perceive the external stimuli as pathogen invasion, and trigger resistance response using ROS as signal molecule. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  2. Nonlinear Wavefront Control with All-Dielectric Metasurfaces.

    PubMed

    Wang, Lei; Kruk, Sergey; Koshelev, Kirill; Kravchenko, Ivan; Luther-Davies, Barry; Kivshar, Yuri

    2018-06-13

    Metasurfaces, two-dimensional lattices of nanoscale resonators, offer unique opportunities for functional flat optics and allow the control of the transmission, reflection, and polarization of a wavefront of light. Recently, all-dielectric metasurfaces reached remarkable efficiencies, often matching or out-performing conventional optical elements. The exploitation of the nonlinear optical response of metasurfaces offers a paradigm shift in nonlinear optics, and dielectric nonlinear metasurfaces are expected to enrich subwavelength photonics by enhancing substantially nonlinear response of natural materials combined with the efficient control of the phase of nonlinear waves. Here, we suggest a novel and rather general approach for engineering the wavefront of parametric waves of arbitrary complexity generated by a nonlinear metasurface. We design all-dielectric nonlinear metasurfaces, achieve a highly efficient wavefront control of a third-harmonic field, and demonstrate the generation of nonlinear beams at a designed angle and the generation of nonlinear focusing vortex beams. Our nonlinear metasurfaces produce phase gradients over a full 0-2π phase range with a 92% diffraction efficiency.

  3. Nonlinear Wavefront Control with All-Dielectric Metasurfaces

    DOE PAGES

    Wang, Lei; Kruk, Sergey; Koshelev, Kirill; ...

    2018-05-11

    Metasurfaces, two-dimensional lattices of nanoscale resonators, offer unique opportunities for functional flat optics and allow the control of the transmission, reflection, and polarization of a wavefront of light. Recently, all-dielectric metasurfaces reached remarkable efficiencies, often matching or out-performing conventional optical elements. The exploitation of the nonlinear optical response of metasurfaces offers a paradigm shift in nonlinear optics, and dielectric nonlinear metasurfaces are expected to enrich subwavelength photonics by enhancing substantially nonlinear response of natural materials combined with the efficient control of the phase of nonlinear waves. Here, we suggest a novel and rather general approach for engineering the wavefront ofmore » parametric waves of arbitrary complexity generated by a nonlinear metasurface. We design all-dielectric nonlinear metasurfaces, achieve a highly efficient wavefront control of a third-harmonic field, and demonstrate the generation of nonlinear beams at a designed angle and the generation of nonlinear focusing vortex beams. Lastly, our nonlinear metasurfaces produce phase gradients over a full 0–2π phase range with a 92% diffraction efficiency.« less

  4. One-Step Generation of Multifunctional Polyelectrolyte Microcapsules via Nanoscale Interfacial Complexation in Emulsion (NICE)

    DOE PAGES

    Kim, Miju; Yeo, Seon Ju; Highley, Christopher B.; ...

    2015-07-14

    Polyelectrolyte microcapsules represent versatile stimuli-responsive structures that enable the encapsulation, protection, and release of active agents. Their conventional preparation methods, however, tend to be time-consuming, yield low encapsulation efficiency, and seldom allow for the dual incorporation of hydrophilic and hydrophobic materials, limiting their widespread utilization. In this work, we present a method to fabricate stimuli-responsive polyelectrolyte microcapsules in one step based on nanoscale interfacial complexation in emulsions (NICE) followed by spontaneous droplet hatching. NICE microcapsules can incorporate both hydrophilic and hydrophobic materials and also can be induced to trigger the release of encapsulated materials by changes in the solution pHmore » or ionic strength. We also show that NICE microcapsules can be functionalized with nanomaterials to exhibit useful functionality, such as response to a magnetic field and disassembly in response to light. NICE represents a potentially transformative method to prepare multifunctional nanoengineered polyelectrolyte microcapsules for various applications such as drug delivery and cell mimicry.« less

  5. Inverted-U Function Relating Cortical Plasticity and Task Difficulty

    PubMed Central

    Engineer, Navzer D.; Engineer, Crystal T.; Reed, Amanda C.; Pandya, Pritesh K.; Jakkamsetti, Vikram; Moucha, Raluca; Kilgard, Michael P.

    2012-01-01

    Many psychological and physiological studies with simple stimuli have suggested that perceptual learning specifically enhances the response of primary sensory cortex to task-relevant stimuli. The aim of this study was to determine whether auditory discrimination training on complex tasks enhances primary auditory cortex responses to a target sequence relative to non-target and novel sequences. We collected responses from more than 2,000 sites in 31 rats trained on one of six discrimination tasks that differed primarily in the similarity of the target and distractor sequences. Unlike training with simple stimuli, long-term training with complex stimuli did not generate target specific enhancement in any of the groups. Instead, cortical receptive field size decreased, latency decreased, and paired pulse depression decreased in rats trained on the tasks of intermediate difficulty while tasks that were too easy or too difficult either did not alter or degraded cortical responses. These results suggest an inverted-U function relating neural plasticity and task difficulty. PMID:22249158

  6. One-Step Generation of Multifunctional Polyelectrolyte Microcapsules via Nanoscale Interfacial Complexation in Emulsion (NICE).

    PubMed

    Kim, Miju; Yeo, Seon Ju; Highley, Christopher B; Burdick, Jason A; Yoo, Pil J; Doh, Junsang; Lee, Daeyeon

    2015-08-25

    Polyelectrolyte microcapsules represent versatile stimuli-responsive structures that enable the encapsulation, protection, and release of active agents. Their conventional preparation methods, however, tend to be time-consuming, yield low encapsulation efficiency, and seldom allow for the dual incorporation of hydrophilic and hydrophobic materials, limiting their widespread utilization. In this work, we present a method to fabricate stimuli-responsive polyelectrolyte microcapsules in one step based on nanoscale interfacial complexation in emulsions (NICE) followed by spontaneous droplet hatching. NICE microcapsules can incorporate both hydrophilic and hydrophobic materials and also can be induced to trigger the release of encapsulated materials by changes in the solution pH or ionic strength. We also show that NICE microcapsules can be functionalized with nanomaterials to exhibit useful functionality, such as response to a magnetic field and disassembly in response to light. NICE represents a potentially transformative method to prepare multifunctional nanoengineered polyelectrolyte microcapsules for various applications such as drug delivery and cell mimicry.

  7. One-Step Generation of Multifunctional Polyelectrolyte Microcapsules via Nanoscale Interfacial Complexation in Emulsion (NICE)

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kim, Miju; Yeo, Seon Ju; Highley, Christopher B.

    Polyelectrolyte microcapsules represent versatile stimuli-responsive structures that enable the encapsulation, protection, and release of active agents. Their conventional preparation methods, however, tend to be time-consuming, yield low encapsulation efficiency, and seldom allow for the dual incorporation of hydrophilic and hydrophobic materials, limiting their widespread utilization. In this work, we present a method to fabricate stimuli-responsive polyelectrolyte microcapsules in one step based on nanoscale interfacial complexation in emulsions (NICE) followed by spontaneous droplet hatching. NICE microcapsules can incorporate both hydrophilic and hydrophobic materials and also can be induced to trigger the release of encapsulated materials by changes in the solution pHmore » or ionic strength. We also show that NICE microcapsules can be functionalized with nanomaterials to exhibit useful functionality, such as response to a magnetic field and disassembly in response to light. NICE represents a potentially transformative method to prepare multifunctional nanoengineered polyelectrolyte microcapsules for various applications such as drug delivery and cell mimicry.« less

  8. Cysteine oxidation impairs systemic glucocorticoid responsiveness in children with difficult-to-treat asthma.

    PubMed

    Stephenson, Susan T; Brown, Lou Ann S; Helms, My N; Qu, Hongyan; Brown, Sheena D; Brown, Milton R; Fitzpatrick, Anne M

    2015-08-01

    The mechanisms underlying glucocorticoid responsiveness are largely unknown. Although redox regulation of the glucocorticoid receptor (GR) has been reported, it has not been studied in asthmatic patients. We characterized systemic cysteine oxidation and its association with inflammatory and clinical features in healthy children and children with difficult-to-treat asthma. We hypothesized that cysteine oxidation would be associated with increased markers of oxidative stress and inflammation, increased features of asthma severity, decreased clinically defined glucocorticoid responsiveness, and impaired GR function. PBMCs were collected from healthy children (n = 16) and children with asthma (n = 118) aged 6 to 17 years. Children with difficult-to-treat asthma underwent glucocorticoid responsiveness testing with intramuscular triamcinolone. Cysteine, cystine, and inflammatory chemokines and reactive oxygen species generation were quantified, and expression and activity of the GR were assessed. Cysteine oxidation was present in children with difficult-to-treat asthma and accompanied by increased reactive oxygen species generation and increased CCL3 and CXCL1 mRNA expression. Children with the greatest extent of cysteine oxidation had more features of asthma severity, including poorer symptom control, greater medication use, and less glucocorticoid responsiveness despite inhaled glucocorticoid therapy. Cysteine oxidation also modified the GR protein by decreasing available sulfhydryl groups and decreasing nuclear GR expression and activity. A highly oxidized cysteine redox state promotes a posttranslational modification of the GR that might inhibit its function. Given that cysteine oxidation is prevalent in children with difficult-to-treat asthma, the cysteine redox state might represent a potential therapeutic target for restoration of glucocorticoid responsiveness in this population. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  9. Plasmon-induced nonlinear response of silver atomic chains.

    PubMed

    Yan, Lei; Guan, Mengxue; Meng, Sheng

    2018-05-10

    Nonlinear response of a linear silver atomic chain upon ultrafast laser excitation has been studied in real time using the time-dependent density functional theory. We observe the presence of nonlinear responses up to the fifth order in tunneling current, which is ascribed to the excitation of high-energy electrons generated by Landau damping of plasmons. The nonlinear effect is enhanced after adsorption of polar molecules such as water due to the enhanced damping rates during plasmon decay. Increasing the length of atomic chains also increases the nonlinear response, favoring higher-order plasmon excitation. These findings offer new insights towards a complete understanding and ultimate control of plasmon-induced nonlinear phenomena to atomic precision.

  10. Selecting cockpit functions for speech I/O technology

    NASA Technical Reports Server (NTRS)

    Simpson, C. A.

    1985-01-01

    A general methodology for the initial selection of functions for speech generation and speech recognition technology is discussed. The SCR (Stimulus/Central-Processing/Response) compatibility model of Wickens et al. (1983) is examined, and its application is demonstrated for a particular cockpit display problem. Some limits of the applicability of that model are illustrated in the context of predicting overall pilot-aircraft system performance. A program of system performance measurement is recommended for the evaluation of candidate systems. It is suggested that no one measure of system performance can necessarily be depended upon to the exclusion of others. Systems response time, system accuracy, and pilot ratings are all important measures. Finally, these measures must be collected in the context of the total flight task environment.

  11. A preview of a modular surface light scattering instrument with autotracking optics

    NASA Technical Reports Server (NTRS)

    Meyer, William V.; Tin, Padetha; Mann, J. Adin, Jr.; Cheung, H. Michael; Rogers, Richard B.; Lading, Lars

    1994-01-01

    NASA's Advanced Technology Development (ATD) program is sponsoring the development of a new generation of surface light scattering hardware. This instrument is designed to non-invasively measure the surface response function of liquids over a wide range of operating conditions while automatically compensating for a sloshing surface. The surface response function can be used to compute surface tension, properties of monolayers present, viscosity, surface tension gradient and surface temperature. The instrument uses optical and electronic building blocks developed for the laser light scattering program at NASA Lewis along with several unique surface light scattering components. The emphasis of this paper is the compensation for bulk surface motion (slosh). Some data processing background information is also included.

  12. Influence of the Basset force on the resonant behavior of an oscillator with fluctuating frequency

    NASA Astrophysics Data System (ADS)

    Rekker, A.; Mankin, R.

    2015-10-01

    The influence of hydrodynamic interactions, such as Stokes and Basset forces, on the dynamics of a harmonically trapped Brownian tracer is considered. A generalized Langevin equation is used to describe the tracer's response to an external periodic force and to dichotomous fluctuations of the stiffness of the trapping potential. Relying on the Shapiro-Loginov formula, exact expressions for the complex susceptibility and for the response function are presented. On the basis of these exact formulas, it is demonstrated that interplay of a multiplicative colored noise and the Basset force induced memory effects can generate a variety of cooperation effects, such as multiresonance versus the driving frequency, as well as stochastic resonance versus noise parameters. In particular, in certain parameter regions the response function exhibits a resonance-like enhancement at intermediate values of the intensity of the Basset force. Conditions for the appearance of these effects are also discussed.

  13. Pathways connecting telomeres and p53 in senescence, apoptosis, and cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Artandi, Steven E.; Attardi, Laura D.

    2005-06-10

    The ends of eukaryotic chromosomes are protected by specialized structures termed telomeres that serve in part to prevent the chromosome end from activating a DNA damage response. However, this important function for telomeres in chromosome end protection can be lost as telomeres shorten with cell division in culture or in self-renewing tissues with advancing age. Impaired telomere function leads to induction of a DNA damage response and activation of the tumor suppressor protein p53. p53 serves a critical role in enforcing both senescence and apoptotic responses to dysfunctional telomeres. Loss of p53 creates a permissive environment in which critically shortmore » telomeres are inappropriately joined to generate chromosomal end-to-end fusions. These fused chromosomes result in cycles of chromosome fusion-bridge-breakage, which can fuel cancer initiation, especially in epithelial tissues, by facilitating changes in gene copy number.« less

  14. The epidermis coordinates auxin-induced stem growth in response to shade

    PubMed Central

    Procko, Carl; Burko, Yogev; Long, Jeff A.; Chory, Joanne

    2016-01-01

    Growth of a complex multicellular organism requires coordinated changes in diverse cell types. These cellular changes generate organs of the correct size, shape, and functionality. In plants, the growth hormone auxin induces stem elongation in response to shade; however, which cell types of the stem perceive the auxin signal and contribute to organ growth is poorly understood. Here, we blocked the transcriptional response to auxin within specific tissues to show that auxin signaling is required in many cell types for correct hypocotyl growth in shade, with a key role for the epidermis. Combining genetic manipulations in Arabidopsis thaliana with transcriptional profiling of the hypocotyl epidermis from Brassica rapa, we show that auxin acts in the epidermis in part by inducing activity of the locally acting, growth-promoting brassinosteroid pathway. Our findings clarify cell-specific auxin function in the hypocotyl and highlight the complexity of cell type interactions within a growing organ. PMID:27401556

  15. Self-powered enzyme micropumps

    NASA Astrophysics Data System (ADS)

    Sengupta, Samudra; Patra, Debabrata; Ortiz-Rivera, Isamar; Agrawal, Arjun; Shklyaev, Sergey; Dey, Krishna K.; Córdova-Figueroa, Ubaldo; Mallouk, Thomas E.; Sen, Ayusman

    2014-05-01

    Non-mechanical nano- and microscale pumps that function without the aid of an external power source and provide precise control over the flow rate in response to specific signals are needed for the development of new autonomous nano- and microscale systems. Here we show that surface-immobilized enzymes that are independent of adenosine triphosphate function as self-powered micropumps in the presence of their respective substrates. In the four cases studied (catalase, lipase, urease and glucose oxidase), the flow is driven by a gradient in fluid density generated by the enzymatic reaction. The pumping velocity increases with increasing substrate concentration and reaction rate. These rechargeable pumps can be triggered by the presence of specific analytes, which enables the design of enzyme-based devices that act both as sensor and pump. Finally, we show proof-of-concept enzyme-powered devices that autonomously deliver small molecules and proteins in response to specific chemical stimuli, including the release of insulin in response to glucose.

  16. Preliminary study of the Suomi NPP VIIRS detector-level spectral response function effects for the long-wave infrared bands M15 and M16

    NASA Astrophysics Data System (ADS)

    Padula, Francis; Cao, Changyong

    2014-09-01

    The Suomi NPP Visible Infrared Imaging Radiometer Suite (VIIRS) Sea Surface Temperature (SST) Environmental Data Record (EDR) team observed an anomalous striping pattern in the SST data. To assess possible causes due to the detector-level Spectral Response Functions (SRFs), a study was conducted to compare the radiometric response of the detector-level and operation band averaged SRFs of VIIRS bands M15 & M16 using simulated blackbody radiance data and clear-sky ocean radiances under different atmospheric conditions. It was concluded that the SST product is likely impacted by small differences in detector-level SRFs, and that if users require optimal system performance detector-level processing is recommended. Future work will investigate potential SDR product improvements through detector-level processing in support of the generation of Suomi NPP VIIRS climate quality SDRs.

  17. Selective adsorption of oppositely charged PNIPAAM on halloysite surfaces: a route to thermo-responsive nanocarriers.

    PubMed

    Cavallaro, Giuseppe; Lazzara, Giuseppe; Lisuzzo, Lorenzo; Milioto, Stefana; Parisi, Filippo

    2018-08-10

    Halloysite nanotubes were functionalized with stimuli-responsive macromolecules to generate smart nanohybrids. Poly(N-isopropylacrylamide)-co-methacrylic acid (PNIPAAM-co-MA) was selectively adsorbed into halloysite lumen by exploiting electrostatic interactions. Amine-terminated PNIPAAM polymer was also investigated that selectively interacts with the outer surface of the nanotubes. The adsorption site has a profound effect on the thermodynamic behavior and therefore temperature responsive features of the hybrid material. The drug release kinetics was investigated by using diclofenac as a non-steroidal anti-inflammatory drug model. The release kinetics depends on the nanoarchitecture of the PNIPAAM/halloysite based material. In particular, diclofenac release was slowed down above the LCST for PNIPAAM-co-MA/halloysite. Opposite trends occurred for halloysite functionalized with PNIPAAM at the outer surface. This work represents a further step toward the opportunity to extend and control the delivery conditions of active species, which represent a key point in technological applications.

  18. The habenula encodes negative motivational value associated with primary punishment in humans.

    PubMed

    Lawson, Rebecca P; Seymour, Ben; Loh, Eleanor; Lutti, Antoine; Dolan, Raymond J; Dayan, Peter; Weiskopf, Nikolaus; Roiser, Jonathan P

    2014-08-12

    Learning what to approach, and what to avoid, involves assigning value to environmental cues that predict positive and negative events. Studies in animals indicate that the lateral habenula encodes the previously learned negative motivational value of stimuli. However, involvement of the habenula in dynamic trial-by-trial aversive learning has not been assessed, and the functional role of this structure in humans remains poorly characterized, in part, due to its small size. Using high-resolution functional neuroimaging and computational modeling of reinforcement learning, we demonstrate positive habenula responses to the dynamically changing values of cues signaling painful electric shocks, which predict behavioral suppression of responses to those cues across individuals. By contrast, negative habenula responses to monetary reward cue values predict behavioral invigoration. Our findings show that the habenula plays a key role in an online aversive learning system and in generating associated motivated behavior in humans.

  19. Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation and functions in melanoma and ovarian cancer

    PubMed Central

    Gupta, Harshita B; Clark, Curtis A; Yuan, Bin; Sareddy, Gangadhara; Pandeswara, Srilakshmi; Padron, Alvaro S; Hurez, Vincent; Conejo-Garcia, José; Vadlamudi, Ratna; Li, Rong; Curiel, Tyler J

    2016-01-01

    As tumor PD-L1 provides signals to anti-tumor PD-1+ T cells that blunt their functions, αPD-1 and αPD-L1 antibodies have been developed as anti-cancer immunotherapies based on interrupting this signaling axis. However, tumor cell-intrinsic PD-L1 signals also regulate immune-independent tumor cell proliferation and mTOR signals, among other important effects. Tumor-initiating cells (TICs) generate carcinomas, resist treatments and promote relapse. We show here that in murine B16 melanoma and ID8agg ovarian carcinoma cells, TICs express more PD-L1 versus non-TICs. Silencing PD-L1 in B16 and ID8agg cells by shRNA (‘PD-L1lo’) reduced TIC numbers, the canonical TIC genes nanog and pou5f1 (oct4), and functions as assessed by tumorosphere development, immune-dependent and immune-independent tumorigenesis, and serial transplantability in vivo. Strikingly, tumor PD-L1 sensitized TIC to interferon-γ and rapamycin in vitro. Cell-intrinsic PD-L1 similarly drove functional TIC generation, canonical TIC gene expression and sensitivity to interferon-γ and rapamycin in human ES2 ovarian cancer cells. Thus, tumor-intrinsic PD-L1 signals promote TIC generation and virulence, possibly by promoting canonical TIC gene expression, suggesting that PD-L1 has novel signaling effects on cancer pathogenesis and treatment responses. PMID:28798885

  20. Modulation of innate immune responses by Yersinia type III secretion system translocators and effectors.

    PubMed

    Bliska, James B; Wang, Xiaoying; Viboud, Gloria I; Brodsky, Igor E

    2013-10-01

    The innate immune system of mammals responds to microbial infection through detection of conserved molecular determinants called 'pathogen-associated molecular patterns' (PAMPs). Pathogens use virulence factors to counteract PAMP-directed responses. The innate immune system can in turn recognize signals generated by virulence factors, allowing for a heightened response to dangerous pathogens. Many Gram-negative bacterial pathogens encode type III secretion systems (T3SSs) that translocate effector proteins, subvert PAMP-directed responses and are critical for infection. A plasmid-encoded T3SS in the human-pathogenic Yersinia species translocates seven effectors into infected host cells. Delivery of effectors by the T3SS requires plasma membrane insertion of two translocators, which are thought to form a channel called a translocon. Studies of the Yersinia T3SS have provided key advances in our understanding of how innate immune responses are generated by perturbations in plasma membrane and other signals that result from translocon insertion. Additionally, studies in this system revealed that effectors function to inhibit innateimmune responses resulting from insertion of translocons into plasma membrane. Here, we review these advances with the goal of providing insight into how a T3SS can activate and inhibit innate immune responses, allowing a virulent pathogen to bypass host defences. © 2013 John Wiley & Sons Ltd.

  1. Diels-Alder functionalized carbon nanotubes for bone tissue engineering: in vitro/in vivo biocompatibility and biodegradability

    NASA Astrophysics Data System (ADS)

    Mata, D.; Amaral, M.; Fernandes, A. J. S.; Colaço, B.; Gama, A.; Paiva, M. C.; Gomes, P. S.; Silva, R. F.; Fernandes, M. H.

    2015-05-01

    The risk-benefit balance for carbon nanotubes (CNTs) dictates their clinical fate. To take a step forward at this crossroad it is compulsory to modulate the CNT in vivo biocompatibility and biodegradability via e.g. chemical functionalization. CNT membranes were functionalised combining a Diels-Alder cycloaddition reaction to generate cyclohexene (-C6H10) followed by a mild oxidisation to yield carboxylic acid groups (-COOH). In vitro proliferation and osteogenic differentiation of human osteoblastic cells were maximized on functionalized CNT membranes (p,f-CNTs). The in vivo subcutaneously implanted materials showed a higher biological reactivity, thus inducing a slighter intense inflammatory response compared to non-functionalized CNT membranes (p-CNTs), but still showing a reduced cytotoxicity profile. Moreover, the in vivo biodegradation of CNTs was superior for p,f-CNT membranes, likely mediated by the oxidation-induced myeloperoxidase (MPO) in neutrophil and macrophage inflammatory milieus. This proves the biodegradability faculty of functionalized CNTs, which potentially avoids long-term tissue accumulation and triggering of acute toxicity. On the whole, the proposed Diels-Alder functionalization accounts for the improved CNT biological response in terms of the biocompatibility and biodegradability profiles. Therefore, CNTs can be considered for use in bone tissue engineering without notable toxicological threats.The risk-benefit balance for carbon nanotubes (CNTs) dictates their clinical fate. To take a step forward at this crossroad it is compulsory to modulate the CNT in vivo biocompatibility and biodegradability via e.g. chemical functionalization. CNT membranes were functionalised combining a Diels-Alder cycloaddition reaction to generate cyclohexene (-C6H10) followed by a mild oxidisation to yield carboxylic acid groups (-COOH). In vitro proliferation and osteogenic differentiation of human osteoblastic cells were maximized on functionalized CNT membranes (p,f-CNTs). The in vivo subcutaneously implanted materials showed a higher biological reactivity, thus inducing a slighter intense inflammatory response compared to non-functionalized CNT membranes (p-CNTs), but still showing a reduced cytotoxicity profile. Moreover, the in vivo biodegradation of CNTs was superior for p,f-CNT membranes, likely mediated by the oxidation-induced myeloperoxidase (MPO) in neutrophil and macrophage inflammatory milieus. This proves the biodegradability faculty of functionalized CNTs, which potentially avoids long-term tissue accumulation and triggering of acute toxicity. On the whole, the proposed Diels-Alder functionalization accounts for the improved CNT biological response in terms of the biocompatibility and biodegradability profiles. Therefore, CNTs can be considered for use in bone tissue engineering without notable toxicological threats. Electronic supplementary information (ESI) available: Experimental details on the preparation of HNO3 functionalized CNTs and supplementary analyses (μ-Raman, TG, EDS, acid-base titration, FTIR, roughness measurements, SEM and optical images) are shown. See DOI: 10.1039/c5nr01829c

  2. Synaptic vesicle pool‐specific modification of neurotransmitter release by intravesicular free radical generation

    PubMed Central

    Afuwape, Olusoji A. T.; Wasser, Catherine R.; Schikorski, Thomas

    2016-01-01

    Key points Synaptic transmission is mediated by the release of neurotransmitters from synaptic vesicles in response to stimulation or through the spontaneous fusion of a synaptic vesicle with the presynaptic plasma membrane.There is growing evidence that synaptic vesicles undergoing spontaneous fusion versus those fusing in response to stimuli are functionally distinct.In this study, we acutely probe the effects of intravesicular free radical generation on synaptic vesicles that fuse spontaneously or in response to stimuli.By targeting vesicles that preferentially release spontaneously, we can dissociate the effects of intravesicular free radical generation on spontaneous neurotransmission from evoked neurotransmission and vice versa.Taken together, these results further advance our knowledge of the synapse and the nature of the different synaptic vesicle pools mediating neurotransmission. Abstract Earlier studies suggest that spontaneous and evoked neurotransmitter release processes are maintained by synaptic vesicles which are segregated into functionally distinct pools. However, direct interrogation of the link between this putative synaptic vesicle pool heterogeneity and neurotransmission has been difficult. To examine this link, we tagged vesicles with horseradish peroxidase (HRP) – a haem‐containing plant enzyme – or antibodies against synaptotagmin‐1 (syt1). Filling recycling vesicles in hippocampal neurons with HRP and subsequent treatment with hydrogen peroxide (H2O2) modified the properties of neurotransmitter release depending on the route of HRP uptake. While strong depolarization‐induced uptake of HRP suppressed evoked release and augmented spontaneous release, HRP uptake during mild activity selectively impaired evoked release, whereas HRP uptake at rest solely potentiated spontaneous release. Expression of a luminal HRP‐tagged syt1 construct and subsequent H2O2 application resulted in a similar increase in spontaneous release and suppression as well as desynchronization of evoked release, recapitulating the canonical syt1 loss‐of‐function phenotype. An antibody targeting the luminal domain of syt1, on the other hand, showed that augmentation of spontaneous release and suppression of evoked release phenotypes are dissociable depending on whether the antibody uptake occurred at rest or during depolarization. Taken together, these findings indicate that vesicles that maintain spontaneous and evoked neurotransmitter release preserve their identity during recycling and syt1 function in suppression of spontaneous neurotransmission can be acutely dissociated from syt1 function to synchronize synaptic vesicle exocytosis upon stimulation. PMID:27723113

  3. Rapid Functional Decline of Activated and Memory Graft-vs-Host-Reactive T Cells Encountering Host Antigens in the Absence of Inflammation

    PubMed Central

    Li, Hao Wei; Andreola, Giovanna; Carlson, Alicia; Shao, Steven; Lin, Charles; Zhao, Guiling; Sykes, Megan

    2015-01-01

    Inflammation in the priming host environment has critical effects on the graft-vs-host (GVH) responses mediated by naïve donor T cells. However, it is unclear how a quiescent or inflammatory environment impacts the activity of GVH-reactive primed T and memory cells. We show here that GVH-reactive primed donor T cells generated in irradiated recipients had diminished ability compared to naïve T cells to increase donor chimerism when transferred to quiescent mixed allogeneic chimeras. GVH-reactive primed T cells showed marked loss of cytotoxic function and activation and delayed but not decreased proliferation or accumulation in lymphoid tissues when transferred to quiescent mixed chimeras compared to freshly irradiated secondary recipients. Primed CD4 and CD8 T cells provided mutual help to sustain these functions in both subsets. CD8 help for CD4 cells was largely IFN-γ-dependent. Toll-like receptor (TLR) stimulation following transfer of GVH-reactive primed T cells to mixed chimeras restored their cytotoxic effector function and permitted the generation of more effective T cell memory in association with reduced PD-1 expression on CD4 memory cells. Our data indicate that an inflammatory host environment is required for the maintenance of GVH-reactive primed T cell functions and the generation of memory T cells that can rapidly acquire effector functions. These findings have important implications for GVHD and T cell-mediated immunotherapies. PMID:26085679

  4. The adequate stimulus for avian short latency vestibular responses to linear translation

    NASA Technical Reports Server (NTRS)

    Jones, T. A.; Jones, S. M.; Colbert, S.

    1998-01-01

    Transient linear acceleration stimuli have been shown to elicit eighth nerve vestibular compound action potentials in birds and mammals. The present study was undertaken to better define the nature of the adequate stimulus for neurons generating the response in the chicken (Gallus domesticus). In particular, the study evaluated the question of whether the neurons studied are most sensitive to the maximum level of linear acceleration achieved or to the rate of change in acceleration (da/dt, or jerk). To do this, vestibular response thresholds were measured as a function of stimulus onset slope. Traditional computer signal averaging was used to record responses to pulsed linear acceleration stimuli. Stimulus onset slope was systematically varied. Acceleration thresholds decreased with increasing stimulus onset slope (decreasing stimulus rise time). When stimuli were expressed in units of jerk (g/ms), thresholds were virtually constant for all stimulus rise times. Moreover, stimuli having identical jerk magnitudes but widely varying peak acceleration levels produced virtually identical responses. Vestibular response thresholds, latencies and amplitudes appear to be determined strictly by stimulus jerk magnitudes. Stimulus attributes such as peak acceleration or rise time alone do not provide sufficient information to predict response parameter quantities. Indeed, the major response parameters were shown to be virtually independent of peak acceleration levels or rise time when these stimulus features were isolated and considered separately. It is concluded that the neurons generating short latency vestibular evoked potentials do so as "jerk encoders" in the chicken. Primary afferents classified as "irregular", and which traditionally fall into the broad category of "dynamic" or "phasic" neurons, would seem to be the most likely candidates for the neural generators of short latency vestibular compound action potentials.

  5. Deletion of BCG Hip1 protease enhances dendritic cell and CD4 T cell responses.

    PubMed

    Bizzell, Erica; Sia, Jonathan Kevin; Quezada, Melanie; Enriquez, Ana; Georgieva, Maria; Rengarajan, Jyothi

    2018-04-01

    Dendritic cells (DCs) play a key role in the generation of CD4 T cell responses to pathogens. Mycobacterium tuberculosis (Mtb) harbors immune evasion mechanisms that impair DC responses and prevent optimal CD4 T cell immunity. The vaccine strain Mycobacterium bovis Bacille Calmette-Guérin (BCG) shares many of the immune evasion proteins utilized by Mtb, but the role of these proteins in DC and T cell responses elicited by BCG is poorly understood. We previously reported that the Mtb serine protease, Hip1, promotes sub-optimal DC responses during infection. Here, we tested the hypothesis that BCG Hip1 modulates DC functions and prevents optimal antigen-specific CD4 T cell responses that limit the immunogenicity of BCG. We generated a strain of BCG lacking hip1 (BCGΔhip1) and show that it has superior capacity to induce DC maturation and cytokine production compared with the parental BCG. Furthermore, BCGΔhip1-infected DCs were more effective at driving the production of IFN-γ and IL-17 from antigen-specific CD4 T cells in vitro. Mucosal transfer of BCGΔhip1-infected DCs into mouse lungs induced robust CD4 T cell activation in vivo and generated antigen-specific polyfunctional CD4 T cell responses in the lungs. Importantly, BCGΔhip1-infected DCs enhanced control of pulmonary bacterial burden following Mtb aerosol challenge compared with the transfer of BCG-infected DCs. These results reveal that BCG employs Hip1 to impair DC activation, leading to attenuated lung CD4 T cell responses with limited capacity to control Mtb burden after challenge. ©2017 Society for Leukocyte Biology.

  6. Endothelinergic Contractile Hyperreactivity in Rat Contralateral Carotid to Balloon Injury: Integrated Role for ETB Receptors and Superoxide Anion

    PubMed Central

    Gimenes, Lilian R.; Gomes, Mayara S.; do Vale, Bruno N.; Cardoso, Cristina R. B.; de Oliveira, Ana M.; Moreira, Josimar D.

    2017-01-01

    Temporal consequences of neurocompensation to balloon injury on endothelinergic functionality in rat contralateral carotid were evaluated. Rats underwent balloon injury in left carotid and were treated with CP-96345 (NK1 antagonist). Concentration-response curves for endothelin-1 were obtained in contralateral (right) carotid at 2, 8, 16, 30, or 45 days after surgery in the absence or presence of BQ-123 (ETA antagonist), BQ-788 (ETB antagonist), or Tempol (superoxide-dismutase mimic). Endothelin-1-induced calcium mobilization was evaluated in functional assays carried out with BQ-123, BQ-788, or Tempol. Endothelin-1-induced NADPH oxidase-driven superoxide generation was measured by lucigenin chemiluminescence assays performed with BQ-123 or BQ-788. Endothelin-1-induced contraction was increased in contralateral carotid from the sixteenth day after surgery. This response was restored in CP-96345-treated rats. Endothelium removal or BQ-123 did not change endothelin-1-induced contraction in contralateral carotid. This response was restored by BQ-788 or Tempol. Contralateral carotid exhibited an increased endothelin-1-induced calcium mobilization, which was restored by BQ-788 or Tempol. Contralateral carotid exhibited an increased endothelin-1-induced lucigenin chemiluminescence, which was restored by BQ-788. We conclude that the NK1-mediated neurocompensatory response to balloon injury elicits a contractile hyperreactivity to endothelin-1 in rat contralateral carotid by enhancing the muscular ETB-mediated NADPH oxidase-driven generation of superoxide, which activates calcium channels. PMID:29062837

  7. DOE Office of Scientific and Technical Information (OSTI.GOV)

    Li, Hongyi; Sivapalan, Murugesu; Tian, Fuqiang

    Inspired by the Dunne diagram, the climatic and landscape controls on the partitioning of annual runoff into its various components (Hortonian and Dunne overland flow and subsurface stormflow) are assessed quantitatively, from a purely theoretical perspective. A simple distributed hydrologic model has been built sufficient to simulate the effects of different combinations of climate, soil, and topography on the runoff generation processes. The model is driven by a sequence of simple hypothetical precipitation events, for a large combination of climate and landscape properties, and hydrologic responses at the catchment scale are obtained through aggregation of grid-scale responses. It is found,more » first, that the water balance responses, including relative contributions of different runoff generation mechanisms, could be related to a small set of dimensionless similarity parameters. These capture the competition between the wetting, drying, storage, and drainage functions underlying the catchment responses, and in this way, provide a quantitative approximation of the conceptual Dunne diagram. Second, only a subset of all hypothetical catchment/climate combinations is found to be ‘‘behavioral,’’ in terms of falling sufficiently close to the Budyko curve, describing mean annual runoff as a function of climate aridity. Furthermore, these behavioral combinations are mostly consistent with the qualitative picture presented in the Dunne diagram, indicating clearly the commonality between the Budyko curve and the Dunne diagram. These analyses also suggest clear interrelationships amongst the ‘‘behavioral’’ climate, soil, and topography parameter combinations, implying these catchment properties may be constrained to be codependent in order to satisfy the Budyko curve.« less

  8. pigk Mutation underlies macho behavior and affects Rohon-Beard cell excitability

    PubMed Central

    Carmean, V.; Yonkers, M. A.; Tellez, M. B.; Willer, J. R.; Willer, G. B.; Gregg, R. G.; Geisler, R.; Neuhauss, S. C.

    2015-01-01

    The study of touch-evoked behavior allows investigation of both the cells and circuits that generate a response to tactile stimulation. We investigate a touch-insensitive zebrafish mutant, macho (maco), previously shown to have reduced sodium current amplitude and lack of action potential firing in sensory neurons. In the genomes of mutant but not wild-type embryos, we identify a mutation in the pigk gene. The encoded protein, PigK, functions in attachment of glycophosphatidylinositol anchors to precursor proteins. In wild-type embryos, pigk mRNA is present at times when mutant embryos display behavioral phenotypes. Consistent with the predicted loss of function induced by the mutation, knock-down of PigK phenocopies maco touch insensitivity and leads to reduced sodium current (INa) amplitudes in sensory neurons. We further test whether the genetic defect in pigk underlies the maco phenotype by overexpressing wild-type pigk in mutant embryos. We find that ubiquitous expression of wild-type pigk rescues the touch response in maco mutants. In addition, for maco mutants, expression of wild-type pigk restricted to sensory neurons rescues sodium current amplitudes and action potential firing in sensory neurons. However, expression of wild-type pigk limited to sensory cells of mutant embryos does not allow rescue of the behavioral touch response. Our results demonstrate an essential role for pigk in generation of the touch response beyond that required for maintenance of proper INa density and action potential firing in sensory neurons. PMID:26133798

  9. Memory T cells and vaccines.

    PubMed

    Esser, Mark T; Marchese, Rocio D; Kierstead, Lisa S; Tussey, Lynda G; Wang, Fubao; Chirmule, Narendra; Washabaugh, Michael W

    2003-01-17

    T lymphocytes play a central role in the generation of a protective immune response in many microbial infections. After immunization, dendritic cells take up microbial antigens and traffic to draining lymph nodes where they present processed antigens to naïve T cells. These naïve T cells are stimulated to proliferate and differentiate into effector and memory T cells. Activated, effector and memory T cells provide B cell help in the lymph nodes and traffic to sites of infection where they secrete anti-microbial cytokines and kill infected cells. At least two types of memory cells have been defined in humans based on their functional and migratory properties. T central-memory (T(CM)) cells are found predominantly in lymphoid organs and can not be immediately activated, whereas T effector-memory (T(EM)) cells are found predominantly in peripheral tissue and sites of inflammation and exhibit rapid effector function. Most currently licensed vaccines induce antibody responses capable of mediating long-term protection against lytic viruses such as influenza and small pox. In contrast, vaccines against chronic pathogens that require cell-mediated immune responses to control, such as malaria, Mycobacterium tuberculosis (TB), human immunodeficiency virus (HIV) and hepatitis C virus (HCV), are currently not available or are ineffective. Understanding the mechanisms by which long-lived cellular immune responses are generated following vaccination should facilitate the development of safe and effective vaccines against these emerging diseases. Here, we review the current literature with respect to memory T cells and their implications to vaccine development.

  10. Deterrence of device counterfeiting, cloning, and subversion by substitution using hardware fingerprinting

    DOEpatents

    Hamlet, Jason R; Bauer, Todd M; Pierson, Lyndon G

    2014-09-30

    Deterrence of device subversion by substitution may be achieved by including a cryptographic fingerprint unit within a computing device for authenticating a hardware platform of the computing device. The cryptographic fingerprint unit includes a physically unclonable function ("PUF") circuit disposed in or on the hardware platform. The PUF circuit is used to generate a PUF value. A key generator is coupled to generate a private key and a public key based on the PUF value while a decryptor is coupled to receive an authentication challenge posed to the computing device and encrypted with the public key and coupled to output a response to the authentication challenge decrypted with the private key.

  11. Generation of single domain antibody fragments derived from camelids and generation of manifold constructs.

    PubMed

    Vincke, Cécile; Gutiérrez, Carlos; Wernery, Ulrich; Devoogdt, Nick; Hassanzadeh-Ghassabeh, Gholamreza; Muyldermans, Serge

    2012-01-01

    Immunizing a camelid (camels and llamas) with soluble, properly folded proteins raises an affinity-matured immune response in the unique camelid heavy-chain only antibodies (HCAbs). The peripheral blood lymphocytes of the immunized animal are used to clone the antigen-binding antibody fragment from the HCAbs in a phage display vector. A representative aliquot of the library of these antigen-binding fragments is used to retrieve single domain antigen-specific binders by successive rounds of panning. These single domain antibody fragments are cloned in tandem to generate manifold constructs (bivalent, biparatopic or bispecific constructs) to increase their functional affinity, to increase specificity, or to connect two independent antigen molecules.

  12. The Individual and Population Genetics of Antibody Immunity.

    PubMed

    Watson, Corey T; Glanville, Jacob; Marasco, Wayne A

    2017-07-01

    Antibodies (Abs) produced by immunoglobulin (IG) genes are the most diverse proteins expressed in humans. While part of this diversity is generated by recombination during B-cell development and mutations during affinity maturation, the germ-line IG loci are also diverse across human populations and ethnicities. Recently, proof-of-concept studies have demonstrated genotype-phenotype correlations between specific IG germ-line variants and the quality of Ab responses during vaccination and disease. However, the functional consequences of IG genetic variation in Ab function and immunological outcomes remain underexplored. In this opinion article, we outline interconnections between IG genomic diversity and Ab-expressed repertoires and structure. We further propose a strategy for integrating IG genotyping with functional Ab profiling data as a means to better predict and optimize humoral responses in genetically diverse human populations, with immediate implications for personalized medicine. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Decreased rhythmic GABAergic septal activity and memory-associated theta oscillations after hippocampal amyloid-beta pathology in the rat.

    PubMed

    Villette, Vincent; Poindessous-Jazat, Frédérique; Simon, Axelle; Léna, Clément; Roullot, Elodie; Bellessort, Brice; Epelbaum, Jacques; Dutar, Patrick; Stéphan, Aline

    2010-08-18

    The memory deficits associated with Alzheimer's disease result to a great extent from hippocampal network dysfunction. The coordination of this network relies on theta (symbol) oscillations generated in the medial septum. Here, we investigated in rats the impact of hippocampal amyloid beta (Abeta) injections on the physiological and cognitive functions that depend on the septohippocampal system. Hippocampal Abeta injections progressively impaired behavioral performances, the associated hippocampal theta power, and theta frequency response in a visuospatial recognition test. These alterations were associated with a specific reduction in the firing of the identified rhythmic bursting GABAergic neurons responsible for the propagation of the theta rhythm to the hippocampus, but without loss of medial septal neurons. Such results indicate that hippocampal Abeta treatment leads to a specific functional depression of inhibitory projection neurons of the medial septum, resulting in the functional impairment of the temporal network.

  14. Armc5 deletion causes developmental defects and compromises T-cell immune responses

    PubMed Central

    Hu, Yan; Lao, Linjiang; Mao, Jianning; Jin, Wei; Luo, Hongyu; Charpentier, Tania; Qi, Shijie; Peng, Junzheng; Hu, Bing; Marcinkiewicz, Mieczyslaw Martin; Lamarre, Alain; Wu, Jiangping

    2017-01-01

    Armadillo repeat containing 5 (ARMC5) is a cytosolic protein with no enzymatic activities. Little is known about its function and mechanisms of action, except that gene mutations are associated with risks of primary macronodular adrenal gland hyperplasia. Here we map Armc5 expression by in situ hybridization, and generate Armc5 knockout mice, which are small in body size. Armc5 knockout mice have compromised T-cell proliferation and differentiation into Th1 and Th17 cells, increased T-cell apoptosis, reduced severity of experimental autoimmune encephalitis, and defective immune responses to lymphocytic choriomeningitis virus infection. These mice also develop adrenal gland hyperplasia in old age. Yeast 2-hybrid assays identify 16 ARMC5-binding partners. Together these data indicate that ARMC5 is crucial in fetal development, T-cell function and adrenal gland growth homeostasis, and that the functions of ARMC5 probably depend on interaction with multiple signalling pathways. PMID:28169274

  15. Multi-factor authentication

    DOEpatents

    Hamlet, Jason R; Pierson, Lyndon G

    2014-10-21

    Detection and deterrence of spoofing of user authentication may be achieved by including a cryptographic fingerprint unit within a hardware device for authenticating a user of the hardware device. The cryptographic fingerprint unit includes an internal physically unclonable function ("PUF") circuit disposed in or on the hardware device, which generates a PUF value. Combining logic is coupled to receive the PUF value, combines the PUF value with one or more other authentication factors to generate a multi-factor authentication value. A key generator is coupled to generate a private key and a public key based on the multi-factor authentication value while a decryptor is coupled to receive an authentication challenge posed to the hardware device and encrypted with the public key and coupled to output a response to the authentication challenge decrypted with the private key.

  16. Streamlining genomes: toward the generation of simplified and stabilized microbial systems.

    PubMed

    Leprince, Audrey; van Passel, Mark W J; dos Santos, Vitor A P Martins

    2012-10-01

    At the junction between systems and synthetic biology, genome streamlining provides a solid foundation both for increased understanding of cellular circuitry, and for the tailoring of microbial chassis towards innovative biotechnological applications. Iterative genomic deletions (targeted and random) helps to generate simplified, stabilized and predictable genomes, whereas multiplexing genome engineering reveals a broad functional genetic diversity. The decrease in oligo and gene synthesis costs promises effective combinatorial tools for the generation of chassis based on streamlined and tractable genomes. Here we review recent progresses in streamlining genomes through recombineering techniques aiming to generate insights into cellular mechanisms and responses towards the design and assembly of streamlined genome chassis together with new cellular modules in diverse biotechnological applications. Copyright © 2012 Elsevier Ltd. All rights reserved.

  17. Functional imaging of the human brain using a modular, fibre-less, high-density diffuse optical tomography system.

    PubMed

    Chitnis, Danial; Cooper, Robert J; Dempsey, Laura; Powell, Samuel; Quaggia, Simone; Highton, David; Elwell, Clare; Hebden, Jeremy C; Everdell, Nicholas L

    2016-10-01

    We present the first three-dimensional, functional images of the human brain to be obtained using a fibre-less, high-density diffuse optical tomography system. Our technology consists of independent, miniaturized, silicone-encapsulated DOT modules that can be placed directly on the scalp. Four of these modules were arranged to provide up to 128, dual-wavelength measurement channels over a scalp area of approximately 60 × 65 mm 2 . Using a series of motor-cortex stimulation experiments, we demonstrate that this system can obtain high-quality, continuous-wave measurements at source-detector separations ranging from 14 to 55 mm in adults, in the presence of hair. We identify robust haemodynamic response functions in 5 out of 5 subjects, and present diffuse optical tomography images that depict functional haemodynamic responses that are well-localized in all three dimensions at both the individual and group levels. This prototype modular system paves the way for a new generation of wearable, wireless, high-density optical neuroimaging technologies.

  18. Melanocortin 1 Receptor: Structure, Function, and Regulation

    PubMed Central

    Wolf Horrell, Erin M.; Boulanger, Mary C.; D’Orazio, John A.

    2016-01-01

    The melanocortin 1 receptor (MC1R) is a melanocytic Gs protein coupled receptor that regulates skin pigmentation, UV responses, and melanoma risk. It is a highly polymorphic gene, and loss of function correlates with a fair, UV-sensitive, and melanoma-prone phenotype due to defective epidermal melanization and sub-optimal DNA repair. MC1R signaling, achieved through adenylyl cyclase activation and generation of the second messenger cAMP, is hormonally controlled by the positive agonist melanocortin, the negative agonist agouti signaling protein, and the neutral antagonist β-defensin 3. Activation of cAMP signaling up-regulates melanin production and deposition in the epidermis which functions to limit UV penetration into the skin and enhances nucleotide excision repair (NER), the genomic stability pathway responsible for clearing UV photolesions from DNA to avoid mutagenesis. Herein we review MC1R structure and function and summarize our laboratory’s findings on the molecular mechanisms by which MC1R signaling impacts NER. PMID:27303435

  19. Calcium signalling in the acinar environment of the exocrine pancreas: physiology and pathophysiology.

    PubMed

    Gryshchenko, Oleksiy; Gerasimenko, Julia V; Peng, Shuang; Gerasimenko, Oleg V; Petersen, Ole H

    2018-02-09

    Ca 2+ signalling in different cell types in exocrine pancreatic lobules was monitored simultaneously and signalling responses to various stimuli were directly compared. Ca 2+ signals evoked by K + -induced depolarization were recorded from pancreatic nerve cells. Nerve cell stimulation evoked Ca 2+ signals in acinar but not in stellate cells. Stellate cells are not electrically excitable as they, like acinar cells, did not generate Ca 2+ signals in response to membrane depolarization. The responsiveness of the stellate cells to bradykinin was markedly reduced in experimental alcohol-related acute pancreatitis, but they became sensitive to stimulation with trypsin. Our results provide fresh evidence for an important role of stellate cells in acute pancreatitis. They seem to be a critical element in a vicious circle promoting necrotic acinar cell death. Initial trypsin release from a few dying acinar cells generates Ca 2+ signals in the stellate cells, which then in turn damage more acinar cells causing further trypsin liberation. Physiological Ca 2+ signals in pancreatic acinar cells control fluid and enzyme secretion, whereas excessive Ca 2+ signals induced by pathological agents induce destructive processes leading to acute pancreatitis. Ca 2+ signals in the peri-acinar stellate cells may also play a role in the development of acute pancreatitis. In this study, we explored Ca 2+ signalling in the different cell types in the acinar environment of the pancreatic tissue. We have, for the first time, recorded depolarization-evoked Ca 2+ signals in pancreatic nerves and shown that whereas acinar cells receive a functional cholinergic innervation, there is no evidence for functional innervation of the stellate cells. The stellate, like the acinar, cells are not electrically excitable as they do not generate Ca 2+ signals in response to membrane depolarization. The principal agent evoking Ca 2+ signals in the stellate cells is bradykinin, but in experimental alcohol-related acute pancreatitis, these cells become much less responsive to bradykinin and then acquire sensitivity to trypsin. Our new findings have implications for our understanding of the development of acute pancreatitis and we propose a scheme in which Ca 2+ signals in stellate cells provide an amplification loop promoting acinar cell death. Initial release of the proteases kallikrein and trypsin from dying acinar cells can, via bradykinin generation and protease-activated receptors, induce Ca 2+ signals in stellate cells which can then, possibly via nitric oxide generation, damage more acinar cells and thereby cause additional release of proteases, generating a vicious circle. © 2018 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

  20. Segmental duplications and evolutionary acquisition of UV damage response in the SPATA31 gene family of primates and humans.

    PubMed

    Bekpen, Cemalettin; Künzel, Sven; Xie, Chen; Eaaswarkhanth, Muthukrishnan; Lin, Yen-Lung; Gokcumen, Omer; Akdis, Cezmi A; Tautz, Diethard

    2017-03-06

    Segmental duplications are an abundant source for novel gene functions and evolutionary adaptations. This mechanism of generating novelty was very active during the evolution of primates particularly in the human lineage. Here, we characterize the evolution and function of the SPATA31 gene family (former designation FAM75A), which was previously shown to be among the gene families with the strongest signal of positive selection in hominoids. The mouse homologue for this gene family is a single copy gene expressed during spermatogenesis. We show that in primates, the SPATA31 gene duplicated into SPATA31A and SPATA31C types and broadened the expression into many tissues. Each type became further segmentally duplicated in the line towards humans with the largest number of full-length copies found for SPATA31A in humans. Copy number estimates of SPATA31A based on digital PCR show an average of 7.5 with a range of 5-11 copies per diploid genome among human individuals. The primate SPATA31 genes also acquired new protein domains that suggest an involvement in UV response and DNA repair. We generated antibodies and show that the protein is re-localized from the nucleolus to the whole nucleus upon UV-irradiation suggesting a UV damage response. We used CRISPR/Cas mediated mutagenesis to knockout copies of the gene in human primary fibroblast cells. We find that cell lines with reduced functional copies as well as naturally occurring low copy number HFF cells show enhanced sensitivity towards UV-irradiation. The acquisition of new SPATA31 protein functions and its broadening of expression may be related to the evolution of the diurnal life style in primates that required a higher UV tolerance. The increased segmental duplications in hominoids as well as its fast evolution suggest the acquisition of further specific functions particularly in humans.

  1. Reticular formation responses to magnetic brain stimulation of primary motor cortex

    PubMed Central

    Fisher, Karen M; Zaaimi, Boubker; Baker, Stuart N

    2012-01-01

    Transcranial magnetic stimulation (TMS) of cerebral cortex is a popular technique for the non-invasive investigation of motor function. TMS is often assumed to influence spinal circuits solely via the corticospinal tract. We were interested in possible trans-synaptic effects of cortical TMS on the ponto-medullary reticular formation in the brainstem, which is the source of the reticulospinal tract and could also generate spinal motor output. We recorded from 210 single units in the reticular formation of three anaesthetized macaque monkeys whilst TMS was performed over primary motor cortex. Short latency responses were observed consistent with activation of a cortico-reticular pathway. However, we also demonstrated surprisingly powerful responses at longer latency, which often appeared at lower threshold than the earlier effects. These late responses seemed to be generated partly as a consequence of the sound click made by coil discharge, and changed little with coil location. This novel finding has implications for the design of future studies using TMS, as well as suggesting a means of non-invasively probing an otherwise inaccessible important motor centre. PMID:22674723

  2. Reticular formation responses to magnetic brain stimulation of primary motor cortex.

    PubMed

    Fisher, Karen M; Zaaimi, Boubker; Baker, Stuart N

    2012-08-15

    Transcranial magnetic stimulation (TMS) of cerebral cortex is a popular technique for the non-invasive investigation of motor function. TMS is often assumed to influence spinal circuits solely via the corticospinal tract. We were interested in possible trans-synaptic effects of cortical TMS on the ponto-medullary reticular formation in the brainstem, which is the source of the reticulospinal tract and could also generate spinal motor output. We recorded from 210 single units in the reticular formation of three anaesthetized macaque monkeys whilst TMS was performed over primary motor cortex. Short latency responses were observed consistent with activation of a cortico-reticular pathway. However, we also demonstrated surprisingly powerful responses at longer latency, which often appeared at lower threshold than the earlier effects. These late responses seemed to be generated partly as a consequence of the sound click made by coil discharge, and changed little with coil location. This novel finding has implications for the design of future studies using TMS, as well as suggesting a means of non-invasively probing an otherwise inaccessible important motor centre.

  3. Response Functions for Neutron Skyshine Analyses

    NASA Astrophysics Data System (ADS)

    Gui, Ah Auu

    Neutron and associated secondary photon line-beam response functions (LBRFs) for point monodirectional neutron sources and related conical line-beam response functions (CBRFs) for azimuthally symmetric neutron sources are generated using the MCNP Monte Carlo code for use in neutron skyshine analyses employing the internal line-beam and integral conical-beam methods. The LBRFs are evaluated at 14 neutron source energies ranging from 0.01 to 14 MeV and at 18 emission angles from 1 to 170 degrees. The CBRFs are evaluated at 13 neutron source energies in the same energy range and at 13 source polar angles (1 to 89 degrees). The response functions are approximated by a three parameter formula that is continuous in source energy and angle using a double linear interpolation scheme. These response function approximations are available for a source-to-detector range up to 2450 m and for the first time, give dose equivalent responses which are required for modern radiological assessments. For the CBRF, ground correction factors for neutrons and photons are calculated and approximated by empirical formulas for use in air-over-ground neutron skyshine problems with azimuthal symmetry. In addition, a simple correction procedure for humidity effects on the neutron skyshine dose is also proposed. The approximate LBRFs are used with the integral line-beam method to analyze four neutron skyshine problems with simple geometries: (1) an open silo, (2) an infinite wall, (3) a roofless rectangular building, and (4) an infinite air medium. In addition, two simple neutron skyshine problems involving an open source silo are analyzed using the integral conical-beam method. The results obtained using the LBRFs and the CBRFs are then compared with MCNP results and results of previous studies.

  4. Functional significance of the electrocorticographic auditory responses in the premotor cortex.

    PubMed

    Tanji, Kazuyo; Sakurada, Kaori; Funiu, Hayato; Matsuda, Kenichiro; Kayama, Takamasa; Ito, Sayuri; Suzuki, Kyoko

    2015-01-01

    Other than well-known motor activities in the precentral gyrus, functional magnetic resonance imaging (fMRI) studies have found that the ventral part of the precentral gyrus is activated in response to linguistic auditory stimuli. It has been proposed that the premotor cortex in the precentral gyrus is responsible for the comprehension of speech, but the precise function of this area is still debated because patients with frontal lesions that include the precentral gyrus do not exhibit disturbances in speech comprehension. We report on a patient who underwent resection of the tumor in the precentral gyrus with electrocorticographic recordings while she performed the verb generation task during awake brain craniotomy. Consistent with previous fMRI studies, high-gamma band auditory activity was observed in the precentral gyrus. Due to the location of the tumor, the patient underwent resection of the auditory responsive precentral area which resulted in the post-operative expression of a characteristic articulatory disturbance known as apraxia of speech (AOS). The language function of the patient was otherwise preserved and she exhibited intact comprehension of both spoken and written language. The present findings demonstrated that a lesion restricted to the ventral precentral gyrus is sufficient for the expression of AOS and suggest that the auditory-responsive area plays an important role in the execution of fluent speech rather than the comprehension of speech. These findings also confirm that the function of the premotor area is predominantly motor in nature and its sensory responses is more consistent with the "sensory theory of speech production," in which it was proposed that sensory representations are used to guide motor-articulatory processes.

  5. Exploring novel objective functions for simulating muscle coactivation in the neck.

    PubMed

    Mortensen, J; Trkov, M; Merryweather, A

    2018-04-11

    Musculoskeletal modeling allows for analysis of individual muscles in various situations. However, current techniques to realistically simulate muscle response when significant amounts of intentional coactivation is required are inadequate. This would include stiffening the neck or spine through muscle coactivation in preparation for perturbations or impacts. Muscle coactivation has been modeled previously in the neck and spine using optimization techniques that seek to maximize the joint stiffness by maximizing total muscle activation or muscle force. These approaches have not sought to replicate human response, but rather to explore the possible effects of active muscle. Coactivation remains a challenging feature to include in musculoskeletal models, and may be improved by extracting optimization objective functions from experimental data. However, the components of such an objective function must be known before fitting to experimental data. This study explores the effect of components in several objective functions, in order to recommend components to be used for fitting to experimental data. Four novel approaches to modeling coactivation through optimization techniques are presented, two of which produce greater levels of stiffness than previous techniques. Simulations were performed using OpenSim and MATLAB cooperatively. Results show that maximizing the moment generated by a particular muscle appears analogous to maximizing joint stiffness. The approach of optimizing for maximum moment generated by individual muscles may be a good candidate for developing objective functions that accurately simulate muscle coactivation in complex joints. This new approach will be the focus of future studies with human subjects. Copyright © 2018 Elsevier Ltd. All rights reserved.

  6. Multiple components of surround modulation in primary visual cortex: multiple neural circuits with multiple functions?

    PubMed Central

    Nurminen, Lauri; Angelucci, Alessandra

    2014-01-01

    The responses of neurons in primary visual cortex (V1) to stimulation of their receptive field (RF) are modulated by stimuli in the RF surround. This modulation is suppressive when the stimuli in the RF and surround are of similar orientation, but less suppressive or facilitatory when they are cross-oriented. Similarly, in human vision surround stimuli selectively suppress the perceived contrast of a central stimulus. Although the properties of surround modulation have been thoroughly characterized in many species, cortical areas and sensory modalities, its role in perception remains unknown. Here we argue that surround modulation in V1 consists of multiple components having different spatio-temporal and tuning properties, generated by different neural circuits and serving different visual functions. One component arises from LGN afferents, is fast, untuned for orientation, and spatially restricted to the surround region nearest to the RF (the near-surround); its function is to normalize V1 cell responses to local contrast. Intra-V1 horizontal connections contribute a slower, narrowly orientation-tuned component to near-surround modulation, whose function is to increase the coding efficiency of natural images in manner that leads to the extraction of object boundaries. The third component is generated by topdown feedback connections to V1, is fast, broadly orientation-tuned, and extends into the far-surround; its function is to enhance the salience of behaviorally relevant visual features. Far- and near-surround modulation, thus, act as parallel mechanisms: the former quickly detects and guides saccades/attention to salient visual scene locations, the latter segments object boundaries in the scene. PMID:25204770

  7. Ex vivo PD-L1/PD-1 pathway blockade reverses dysfunction of circulating CEA specific T cells in pancreatic cancer patients

    PubMed Central

    Chen, Y; Xue, SA; Behboudi, S; Mohammad, GH; Pereira, SP; Morris, EC

    2017-01-01

    Carcinoembryonic antigen (CEA) is a candidate target for cellular immunotherapy of pancreatic cancer (PC). In this study, we have characterised the antigen-specific function of autologous cytotoxic T lymphocytes (CTL) specific for the HLA-A2 restricted peptide, pCEA691–699, isolated from the peripheral T cell repertoire of PC patients and sought to determine if ex vivo PD-L1 & TIM3 blockade could enhance CTL function. CD8+ T cell lines were generated from peripheral blood mononuclear cells (PBMCs) of 18 HLA-A2+ patients with PC and from 15 healthy controls. In vitro peptide specific responses were evaluated by flow cytometry after staining for intracellular cytokine production and CSFE cytotoxicity assays using pancreatic cancer cell lines as targets. Cytokine secreting functional CEA691-specific CTL lines were successfully generated from 10 of 18PC patients, with two CTL lines able to recognise and kill both CEA691 peptide-loaded T2 cells and CEA+ HLA-A2+ pancreatic cancer cell lines. In the presence of ex vivo PD-L1 blockade, functional CEA691-specific CD8+ T cell responses, including IFN-γ secretion and proliferation, were enhanced and this effect was more pronounced on Ag-specific T cells isolated from tumor draining lymph nodes. These data demonstrate that CEA691-specific CTL can be readily expanded from the self-restricted T cell repertoire of PC patients and that their function can be enhanced by PD-L1 blockade. PMID:28710313

  8. ATM directs DNA damage responses and proteostasis via genetically separable pathways

    PubMed Central

    Lee, Ji-Hoon; Mand, Michael R.; Kao, Chung-Hsuan; Zhou, Yi; Ryu, Seung W.; Richards, Alicia L.; Coon, Joshua J.; Paull, Tanya T.

    2018-01-01

    The protein kinase ATM is a master regulator of the DNA damage response but also responds directly to oxidative stress. Loss of ATM causes Ataxia telangiectasia, a neurodegenerative disorder with pleiotropic symptoms that include cerebellar dysfunction, cancer, diabetes, and premature aging. Here, we genetically separated DNA damage activation of ATM from oxidative activation using separation-of-function mutations. We found that deficiency in ATM activation by Mre11-Rad50-Nbs1 and DNA double-strand breaks resulted in loss of cell viability, checkpoint activation, and DNA end resection in response to DNA damage. In contrast, loss of oxidative activation of ATM had minimal effects on DNA damage-related outcomes but blocked ATM-mediated initiation of checkpoint responses after oxidative stress and resulted in deficiencies in mitochondrial function and autophagy. In addition, expression of ATM lacking oxidative activation generates widespread protein aggregation. These results indicate a direct relationship between the mechanism of ATM activation and its effects on cellular metabolism and DNA damage responses in human cells and implicates ATM in the control of protein homeostasis. PMID:29317520

  9. Linking runoff response to burn severity after a wildfire

    USGS Publications Warehouse

    Moody, J.A.; Martin, D.A.; Haire, S.L.; Kinner, D.A.

    2008-01-01

    Extreme floods often follow wildfire in mountainous watersheds. However, a quantitative relation between the runoff response and burn severity at the watershed scale has not been established. Runoff response was measured as the runoff coefficient C, which is equal to the peak discharge per unit drainage area divided by the average maximum 30 min rainfall intensity during each rain storm. The magnitude of the bum severity was expressed as the change in the normalized burn ratio. A new burn severity variable, hydraulic functional connectivity ?? was developed and incorporates both the magnitude of the burn severity and the spatial sequence of the bum severity along hillslope flow paths. The runoff response and the burn severity were measured in seven subwatersheds (0.24 to 0.85 km2) in the upper part of Rendija Canyon burned by the 2000 Cerro Grande Fire Dear Los Alamos, New Mexico, USA. A rainfall-discharge relation was determined for four of the subwatersheds with nearly the same bum severity. The peak discharge per unit drainage area Qupeak was a linear function of the maximum 30 min rainfall intensity I30. This function predicted a rainfall intensity threshold of 8.5 mm h-1 below which no runoff was generated. The runoff coefficient C = Qupeak/I30 was a linear function of the mean hydraulic functional connectivity of the subwatersheds. Moreover, the variability of the mean hydraulic functional connectivity was related to the variability of the mean runoff coefficient, and this relation provides physical insight into why the runoff response from the same subwatershed can vary for different rainstorms with the same rainfall intensity. Published in 2007 by John Wiley & Sons, Ltd.

  10. Systematic Analysis of γ-Aminobutyric Acid (GABA) Metabolism and Function in the Social Amoeba Dictyostelium discoideum*

    PubMed Central

    Wu, Yuantai; Janetopoulos, Chris

    2013-01-01

    While GABA has been suggested to regulate spore encapsulation in the social amoeba Dictyostelium discoideum, the metabolic profile and other potential functions of GABA during development remain unclear. In this study, we investigated the homeostasis of GABA metabolism by disrupting genes related to GABA metabolism and signaling. Extracellular levels of GABA are tightly regulated during early development, and GABA is generated by the glutamate decarboxylase, GadB, during growth and in early development. However, overexpression of the prespore-specific homologue, GadA, in the presence of GadB reduces production of extracellular GABA. Perturbation of extracellular GABA levels delays the process of aggregation. Cytosolic GABA is degraded by the GABA transaminase, GabT, in the mitochondria. Disruption of a putative vesicular GABA transporter (vGAT) homologue DdvGAT reduces secreted GABA. We identified the GABAB receptor-like family member GrlB as the major GABA receptor during early development, and either disruption or overexpression of GrlB delays aggregation. This delay is likely the result of an abolished pre-starvation response and late expression of several “early” developmental genes. Distinct genes are employed for GABA generation during sporulation. During sporulation, GadA alone is required for generating GABA and DdvGAT is likely responsible for GABA secretion. GrlE but not GrlB is the GABA receptor during late development. PMID:23548898

  11. Enhanced Vertical Perception through Head-Related Impulse Response Customization Based on Pinna Response Tuning in the Median Plane

    NASA Astrophysics Data System (ADS)

    Shin, Ki Hoon; Park, Youngjin

    Human's ability to perceive elevation of a sound and distinguish whether a sound is coming from the front or rear strongly depends on the monaural spectral features of the pinnae. In order to realize an effective virtual auditory display by HRTF (head-related transfer function) customization, the pinna responses were isolated from the median HRIRs (head-related impulse responses) of 45 individual HRIRs in the CIPIC HRTF database and modeled as linear combinations of 4 or 5 basic temporal shapes (basis functions) per each elevation on the median plane by PCA (principal components analysis) in the time domain. By tuning the weight of each basis function computed for a specific height to replace the pinna response in the KEMAR HRIR at the same height with the resulting customized pinna response and listening to the filtered stimuli over headphones, 4 individuals with normal hearing sensitivity were able to create a set of HRIRs that outperformed the KEMAR HRIRs in producing vertical effects with reduced front/back ambiguity in the median plane. Since the monaural spectral features of the pinnae are almost independent of azimuthal variation of the source direction, similar vertical effects could also be generated at different azimuthal directions simply by varying the ITD (interaural time difference) according to the direction as well as the size of each individual's own head.

  12. Lung pathology in response to repeated exposure to Staphylococcus aureus in congenic residual function cystic fibrosis mice does not increase in response to decreased CFTR levels or increased bacterial load.

    PubMed

    Davidson, Donald J; Webb, Sheila; Teague, Peter; Govan, John R W; Dorin, Julia R

    2004-01-01

    To establish the role of defects in murine Cftr in the susceptibility to Staphylococcus aureus lung disease using mouse models of cystic fibrosis (CF), congenic or inbred strains. We describe the histopathological analyses of CF mice repeatedly exposed by aerosolisation to a CF isolate of S. aureus, using residual function Cftr mice and compound heterozygotes generated by intercrossing these with Cftr 'null' mice, all congenic on the C57Bl6/N background. We demonstrate that mice congenic on the C57Bl/6 background develop significantly more severe lung pathology than non-CF littermates in response to repeated exposure to the most frequent early CF lung pathogen S. aureus. Furthermore, reducing the level of Cftr by half in compound heterozygote mice does not impact upon disease severity, even in response to an increased bacterial dose. These results are consistent with an airway clearance defect, or abnormal inflammatory response secondary to Cftr mutation. These studies confirm the primary role for Cftr mutation in the development of this lung phenotype. In addition, these results demonstrate that a further 50% decrease in residual wild-type Cftr mRNA levels in this model does not impact the severity of the histopathological response to S. aureus, suggesting a critical threshold level for functional CFTR. Copyright 2004 S. Karger AG, Basel

  13. Developmental Changes in Information Central to Artifact Representation: Evidence from "Functional Fluency" Tasks

    ERIC Educational Resources Information Center

    Defeyter, Margaret Anne; Avons, S. E.; German, Tamsin C.

    2007-01-01

    Research suggests that while information about design is a central feature of older children's artifact representations it may be less important in the artifact representations of younger children. Three experiments explore the pattern of responses that 5- and 7-year-old children generate when asked to produce multiple uses for familiar…

  14. An analysis of transient flow in upland watersheds: interactions between structure and process

    Treesearch

    David Lawrence Brown

    1995-01-01

    The physical structure and hydrological processes of upland watersheds interact in response to forcing functions such as rainfall, leading to storm runoff generation and pore pressure evolution. Transient fluid flow through distinct flow paths such as the soil matrix, macropores, saprolite, and bedrock may be viewed as a consequence of such interactions. Field...

  15. Cumulative watershed effects: a research perspective

    Treesearch

    Leslie M. Reid; Robert R. Ziemer

    1989-01-01

    A cumulative watershed effect (CWE) is any response to multiple land-use activities that is caused by, or results in, altered watershed function. The CWE issue is politically defined, as is the significance of particular impacts. But the processes generating CWEs are the traditional focus of geomorphology and ecology, and have thus been studied for decades. The CWE...

  16. Towards More Precise Design Guidance: Specifying and Testing the Functions of Assigned Student Roles in Online Discussions

    ERIC Educational Resources Information Center

    Wise, Alyssa Friend; Saghafian, Marzieh; Padmanabhan, Poornima

    2012-01-01

    While assigning student roles is a popular technique in online discussions, roles and the responsibilities allocated to them have not been consistently assigned. This makes it difficult to compare implementations and generate principled guidance for role design. This study critically examined frequently assigned student roles and identified a set…

  17. Divergent Task Performance in Older Adults: Declarative Memory or Creative Potential?

    ERIC Educational Resources Information Center

    Leon, Susan A.; Altmann, Lori J. P.; Abrams, Lise; Gonzalez Rothi, Leslie J.; Heilman, Kenneth M.

    2014-01-01

    Divergent thinking is a process or method used to generate creative ideas by exploring many possible solutions or responses, and is a critical element of creativity. Lesion and imaging studies have shown that the frontal lobes are important in mediating divergent thinking, and frontal lobe function is highly dependent on white matter connections…

  18. Dietary glutamine supplementation partly reverses impaired macrophage function resulting from overload training in rats.

    PubMed

    Xiao, Weihua; Chen, Peijie; Dong, Jingmei; Wang, Ru; Luo, Beibei

    2015-04-01

    The aim of this study was to evaluate the effect of overload training on the function of peritoneal macrophages in rats, and to test the hypothesis that glutamine in vivo supplementation would partly reverse the eventual functional alterations induced by overload training in these cells. Forty male Wistar rats were randomly divided into 5 groups: control group (C), overload training group (E1), overload training and restore one week group (E2), glutamine-supplementation group (EG1), and glutamine-supplementation and restore 1-week group (EG2). All rats, except those placed on sedentary control were subjected to 11 weeks of overload training protocol. Blood hemoglobin, serum testosterone, and corticosterone of rats were measured. Moreover, the functions (chemotaxis, phagocytosis, cytokines synthesis, reactive oxygen species generation) of peritoneal macrophages were determined. Data showed that blood hemoglobin, serum testosterone, corticosterone and body weight in the overload training group decreased significantly as compared with the control group. Meanwhile, the chemotaxis capacity (decreased by 31%, p = .003), the phagocytosis capacity (decreased by 27%, p = .005), the reactive oxygen species (ROS) generation (decreased by 35%, p = .003) and the cytokines response capability of macrophages were inhibited by overload training. However, the hindering of phagocytosis and the cytokines response capability of macrophages induced by overload training could be ameliorated and reversed respectively, by dietary glutamine supplementation. These results suggest that overload training impairs the function of peritoneal macrophages, which is essential for the microbicidal actions of macrophages. This may represent a novel mechanism of immunodepression induced by overload training. Nonetheless, dietary glutamine supplementation could partly reverse the impaired macrophage function resulting from overload training.

  19. Peripheral self-reactivity regulates antigen-specific CD8 T-cell responses and cell division under physiological conditions.

    PubMed

    Swee, Lee Kim; Tan, Zhen Wei; Sanecka, Anna; Yoshida, Nagisa; Patel, Harshil; Grotenbreg, Gijsbert; Frickel, Eva-Maria; Ploegh, Hidde L

    2016-11-01

    T-cell identity is established by the expression of a clonotypic T-cell receptor (TCR), generated by somatic rearrangement of TCRα and β genes. The properties of the TCR determine both the degree of self-reactivity and the repertoire of antigens that can be recognized. For CD8 T cells, the relationship between TCR identity-hence reactivity to self-and effector function(s) remains to be fully understood and has rarely been explored outside of the H-2 b haplotype. We measured the affinity of three structurally distinct CD8 T-cell-derived TCRs that recognize the identical H-2 L d -restricted epitope, derived from the Rop7 protein of Toxoplasma gondii We used CD8 T cells obtained from mice generated by somatic cell nuclear transfer as the closest approximation of primary T cells with physiological TCR rearrangements and TCR expression levels. First, we demonstrate the common occurrence of secondary rearrangements in endogenously rearranged loci. Furthermore, we characterized and compared the response of Rop7-specific CD8 T-cell clones upon Toxoplasma gondii infection as well as effector function and TCR signalling upon antigenic stimulation in vitro Antigen-independent TCR cross-linking in vitro uncovered profound intrinsic differences in the effector functions between T-cell clones. Finally, by assessing the degree of self-reactivity and comparing the transcriptomes of naive Rop7 CD8 T cells, we show that lower self-reactivity correlates with lower effector capacity, whereas higher self-reactivity is associated with enhanced effector function as well as cell cycle entry under physiological conditions. Altogether, our data show that potential effector functions and basal proliferation of CD8 T cells are set by self-reactivity thresholds. © 2016 The Authors.

  20. Transient Receptor Potential Vanilloid 4 Ion Channel Functions as a Pruriceptor in Epidermal Keratinocytes to Evoke Histaminergic Itch*

    PubMed Central

    Chen, Yong; Fang, Quan; Wang, Zilong; Zhang, Jennifer Y.; MacLeod, Amanda S.; Hall, Russell P.; Liedtke, Wolfgang B.

    2016-01-01

    TRPV4 ion channels function in epidermal keratinocytes and in innervating sensory neurons; however, the contribution of the channel in either cell to neurosensory function remains to be elucidated. We recently reported TRPV4 as a critical component of the keratinocyte machinery that responds to ultraviolet B (UVB) and functions critically to convert the keratinocyte into a pain-generator cell after excess UVB exposure. One key mechanism in keratinocytes was increased expression and secretion of endothelin-1, which is also a known pruritogen. Here we address the question of whether TRPV4 in skin keratinocytes functions in itch, as a particular form of “forefront” signaling in non-neural cells. Our results support this novel concept based on attenuated scratching behavior in response to histaminergic (histamine, compound 48/80, endothelin-1), not non-histaminergic (chloroquine) pruritogens in Trpv4 keratinocyte-specific and inducible knock-out mice. We demonstrate that keratinocytes rely on TRPV4 for calcium influx in response to histaminergic pruritogens. TRPV4 activation in keratinocytes evokes phosphorylation of mitogen-activated protein kinase, ERK, for histaminergic pruritogens. This finding is relevant because we observed robust anti-pruritic effects with topical applications of selective inhibitors for TRPV4 and also for MEK, the kinase upstream of ERK, suggesting that calcium influx via TRPV4 in keratinocytes leads to ERK-phosphorylation, which in turn rapidly converts the keratinocyte into an organismal itch-generator cell. In support of this concept we found that scratching behavior, evoked by direct intradermal activation of TRPV4, was critically dependent on TRPV4 expression in keratinocytes. Thus, TRPV4 functions as a pruriceptor-TRP in skin keratinocytes in histaminergic itch, a novel basic concept with translational-medical relevance. PMID:26961876

  1. An Aversive Response to Osmotic Upshift in Caenorhabditis elegans

    PubMed Central

    Yu, Jingyi; Liu, He

    2017-01-01

    Abstract Environmental osmolarity presents a common type of sensory stimulus to animals. While behavioral responses to osmotic changes are important for maintaining a stable intracellular osmolarity, the underlying mechanisms are not fully understood. In the natural habitat of Caenorhabditis elegans, changes in environmental osmolarity are commonplace. It is known that the nematode acutely avoids shocks of extremely high osmolarity. Here, we show that C. elegans also generates gradually increased aversion of mild upshifts in environmental osmolarity. Different from an acute avoidance of osmotic shocks that depends on the function of a transient receptor potential vanilloid channel, the slow aversion to osmotic upshifts requires the cGMP-gated sensory channel subunit TAX-2. TAX-2 acts in several sensory neurons that are exposed to body fluid to generate the aversive response through a motor network that underlies navigation. Osmotic upshifts activate the body cavity sensory neuron URX, which is known to induce aversion upon activation. Together, our results characterize the molecular and cellular mechanisms underlying a novel sensorimotor response to osmotic stimuli and reveal that C. elegans engages different behaviors and the underlying mechanisms to regulate responses to extracellular osmolarity. PMID:28451641

  2. Fluidic Energy Harvester Optimization in Grid Turbulence

    NASA Astrophysics Data System (ADS)

    Danesh-Yazdi, Amir; Elvin, Niell; Andreopoulos, Yiannis

    2017-11-01

    Even though it is omnipresent in nature, there has not been a great deal of research in the literature involving turbulence as an energy source for piezoelectric fluidic harvesters. In the present work, a grid-generated turbulence forcing function model which we derived previously is employed in the single degree-of-freedom electromechanical equations to find the power output and tip displacement of piezoelectric cantilever beams. Additionally, we utilize simplified, deterministic models of the turbulence forcing function to obtain closed-form expressions for the power output. These theoretical models are studied using experiments that involve separately placing a hot-wire anemometer probe and a short PVDF beam in flows where turbulence is generated by means of passive and semi-passive grids. From a parametric study on the deterministic models, we show that the white noise forcing function best mimics the experimental data. Furthermore, our parametric study of the response spectrum of a generic fluidic harvester in grid-generated turbulent flow shows that optimum power output is attained for beams placed closer to the grid with a low natural frequency and damping ratio and a large electromechanical coupling coefficient. NSF Grant No. CBET 1033117.

  3. Impairment of cognitive functioning during Sunitinib or Sorafenib treatment in cancer patients: a cross sectional study

    PubMed Central

    2014-01-01

    Background Impairment of cognitive functioning has been reported in several studies in patients treated with chemotherapy. So far, no studies have been published on the effects of the vascular endothelial growth factor receptor (VEGFR) inhibitors on cognitive functioning. We investigated the objective and subjective cognitive function of patients during treatment with VEGFR tyrosine kinase inhibitors (VEGFR TKI). Methods Three groups of participants, matched on age, sex and education, were enrolled; 1. metastatic renal cell cancer (mRCC) or GIST patients treated with sunitinib or sorafenib (VEGFR TKI patients n = 30); 2. patients with mRCC not receiving systemic treatment (patient controls n = 20); 3. healthy controls (n = 30). Sixteen neuropsychological tests examining the main cognitive domains (intelligence, memory, attention and concentration, executive functions and abstract reasoning) were administered by a neuropsychologist. Four questionnaires were used to assess subjective cognitive complaints, mood, fatigue and psychological wellbeing. Results No significant differences in mean age, sex distribution, education level or IQ were found between the three groups. Both patient groups performed significantly worse on the cognitive domains Learning & Memory and Executive Functions (Response Generation and Problem Solving) compared to healthy controls. However only the VEGFR TKI patients showed impairments on the Executive subdomain Response Generation. Effect sizes of cognitive dysfunction in patients using VEGFR TKI were larger on the domains Learning & Memory and Executive Functions, compared to patient controls. Both patients groups performed on the domain Attention & Concentration the same as the healthy controls. Longer duration of treatment on VEGFR TKI was associated with a worse score on Working Memory tasks. Conclusions Our data suggest that treatment with VEGFR TKI has a negative impact on cognitive functioning, specifically on Learning & Memory, and Executive Functioning. We propose that patients who are treated with VEGFR TKI are monitored and informed for possible signs or symptoms associated with cognitive impairment. Trial registration ClinicalTrials.gov Identifier: NCT01246843. PMID:24661373

  4. Human Cardiomyocytes Prior to Birth by Integration-Free Reprogramming of Amniotic Fluid Cells

    PubMed Central

    Jiang, Guihua; Herron, Todd J.; Di Bernardo, Julie; Walker, Kendal A.; O’Shea, K. Sue

    2016-01-01

    The establishment of an abundant source of autologous cardiac progenitor cells would represent a major advance toward eventual clinical translation of regenerative medicine strategies in children with prenatally diagnosed congenital heart disease. In support of this concept, we sought to examine whether functional, transgene-free human cardiomyocytes (CMs) with potential for patient-specific and autologous applications could be reliably generated following routine amniocentesis. Under institutional review board approval, amniotic fluid specimens (8–10 ml) at 20 weeks gestation were expanded and reprogrammed toward pluripotency using nonintegrating Sendai virus (SeV) expressing OCT4, SOX2, cMYC, and KLF4. Following exposure of these induced pluripotent stem cells to cardiogenic differentiation conditions, spontaneously beating amniotic fluid-derived cardiomyocytes (AF-CMs) were successfully generated with high efficiency. After 6 weeks, quantitative gene expression revealed a mixed population of differentiated atrial, ventricular, and nodal AF-CMs, as demonstrated by upregulation of multiple cardiac markers, including MYH6, MYL7, TNNT2, TTN, and HCN4, which were comparable to levels expressed by neonatal dermal fibroblast-derived CM controls. AF-CMs had a normal karyotype and demonstrated loss of NANOG, OCT4, and the SeV transgene. Functional characterization of SIRPA+ AF-CMs showed a higher spontaneous beat frequency in comparison with dermal fibroblast controls but revealed normal calcium transients and appropriate chronotropic responses after β-adrenergic agonist stimulation. Taken together, these data suggest that somatic cells present within human amniotic fluid can be used to generate a highly scalable source of functional, transgene-free, autologous CMs before a child is born. This approach may be ideally suited for patients with prenatally diagnosed cardiac anomalies. Significance This study presents transgene-free human amniotic fluid-derived cardiomyocytes (AF-CMs) for potential therapy in tissue engineering and regenerative medicine applications. Using 8–10 ml of amniotic fluid harvested at 20 weeks gestation from normal pregnancies, a mixed population of atrial, ventricular, and nodal AF-CMs were reliably generated after Sendai virus reprogramming toward pluripotency. Functional characterization of purified populations of beating AF-CMs revealed normal calcium transients and appropriate chronotropic responses after β-adrenergic agonist stimulation in comparison with dermal fibroblast controls. Because AF-CMs can be generated in fewer than 16 weeks, this approach may be ideally suited for eventual clinical translation at birth in children with prenatally diagnosed cardiac anomalies. PMID:27465073

  5. Seasonal dynamics alter taxonomical and functional microbial profiles in Pampa biome soils under natural grasslands

    PubMed Central

    Barboza, Anthony Diego Muller; Pylro, Victor Satler; Jacques, Rodrigo Josemar Seminot; Gubiani, Paulo Ivonir; de Quadros, Fernando Luiz Ferreira; da Trindade, Júlio Kuhn; Triplett, Eric W.

    2018-01-01

    Soil microbial communities’ assembly is strongly tied to changes in temperature and moisture. Although microbial functional redundancy seems to overcome taxonomical composition changes, the sensitivity and resilience of soil microbial communities from subtropical regions in response to seasonal variations are still poorly understood. Thus, the development of new strategies for biodiversity conservation and sustainable management require a complete understanding of the soil abiotic process involved in the selection of microbial taxa and functions. In this work, we used state of the art molecular methodologies (Next Generation Sequencing) to compare the taxonomic (metataxonomics) and functional (metatranscriptomics) profiles among soil samples from two subtropical natural grasslands located in the Pampa biome, Brazil, in response to short-term seasonal variations. Our data suggest that grasslands maintained a stable microbial community membership along the year with oscillation in abundance. Apparently soil microbial taxa are more susceptible to natural climatic disturbances while functions are more stable and change with less intensity along the year. Finally, our data allow us to conclude that the most abundant microbial groups and functions were shared between seasons and locations reflecting the existence of a stable taxonomical and functional core microbiota.

  6. Analysis and selection of optimal function implementations in massively parallel computer

    DOEpatents

    Archer, Charles Jens [Rochester, MN; Peters, Amanda [Rochester, MN; Ratterman, Joseph D [Rochester, MN

    2011-05-31

    An apparatus, program product and method optimize the operation of a parallel computer system by, in part, collecting performance data for a set of implementations of a function capable of being executed on the parallel computer system based upon the execution of the set of implementations under varying input parameters in a plurality of input dimensions. The collected performance data may be used to generate selection program code that is configured to call selected implementations of the function in response to a call to the function under varying input parameters. The collected performance data may be used to perform more detailed analysis to ascertain the comparative performance of the set of implementations of the function under the varying input parameters.

  7. Genomic Enzymology: Web Tools for Leveraging Protein Family Sequence-Function Space and Genome Context to Discover Novel Functions.

    PubMed

    Gerlt, John A

    2017-08-22

    The exponentially increasing number of protein and nucleic acid sequences provides opportunities to discover novel enzymes, metabolic pathways, and metabolites/natural products, thereby adding to our knowledge of biochemistry and biology. The challenge has evolved from generating sequence information to mining the databases to integrating and leveraging the available information, i.e., the availability of "genomic enzymology" web tools. Web tools that allow identification of biosynthetic gene clusters are widely used by the natural products/synthetic biology community, thereby facilitating the discovery of novel natural products and the enzymes responsible for their biosynthesis. However, many novel enzymes with interesting mechanisms participate in uncharacterized small-molecule metabolic pathways; their discovery and functional characterization also can be accomplished by leveraging information in protein and nucleic acid databases. This Perspective focuses on two genomic enzymology web tools that assist the discovery novel metabolic pathways: (1) Enzyme Function Initiative-Enzyme Similarity Tool (EFI-EST) for generating sequence similarity networks to visualize and analyze sequence-function space in protein families and (2) Enzyme Function Initiative-Genome Neighborhood Tool (EFI-GNT) for generating genome neighborhood networks to visualize and analyze the genome context in microbial and fungal genomes. Both tools have been adapted to other applications to facilitate target selection for enzyme discovery and functional characterization. As the natural products community has demonstrated, the enzymology community needs to embrace the essential role of web tools that allow the protein and genome sequence databases to be leveraged for novel insights into enzymological problems.

  8. Genomic Enzymology: Web Tools for Leveraging Protein Family Sequence–Function Space and Genome Context to Discover Novel Functions

    PubMed Central

    2017-01-01

    The exponentially increasing number of protein and nucleic acid sequences provides opportunities to discover novel enzymes, metabolic pathways, and metabolites/natural products, thereby adding to our knowledge of biochemistry and biology. The challenge has evolved from generating sequence information to mining the databases to integrating and leveraging the available information, i.e., the availability of “genomic enzymology” web tools. Web tools that allow identification of biosynthetic gene clusters are widely used by the natural products/synthetic biology community, thereby facilitating the discovery of novel natural products and the enzymes responsible for their biosynthesis. However, many novel enzymes with interesting mechanisms participate in uncharacterized small-molecule metabolic pathways; their discovery and functional characterization also can be accomplished by leveraging information in protein and nucleic acid databases. This Perspective focuses on two genomic enzymology web tools that assist the discovery novel metabolic pathways: (1) Enzyme Function Initiative-Enzyme Similarity Tool (EFI-EST) for generating sequence similarity networks to visualize and analyze sequence–function space in protein families and (2) Enzyme Function Initiative-Genome Neighborhood Tool (EFI-GNT) for generating genome neighborhood networks to visualize and analyze the genome context in microbial and fungal genomes. Both tools have been adapted to other applications to facilitate target selection for enzyme discovery and functional characterization. As the natural products community has demonstrated, the enzymology community needs to embrace the essential role of web tools that allow the protein and genome sequence databases to be leveraged for novel insights into enzymological problems. PMID:28826221

  9. A simple theoretical framework for understanding heterogeneous differentiation of CD4+ T cells

    PubMed Central

    2012-01-01

    Background CD4+ T cells have several subsets of functional phenotypes, which play critical yet diverse roles in the immune system. Pathogen-driven differentiation of these subsets of cells is often heterogeneous in terms of the induced phenotypic diversity. In vitro recapitulation of heterogeneous differentiation under homogeneous experimental conditions indicates some highly regulated mechanisms by which multiple phenotypes of CD4+ T cells can be generated from a single population of naïve CD4+ T cells. Therefore, conceptual understanding of induced heterogeneous differentiation will shed light on the mechanisms controlling the response of populations of CD4+ T cells under physiological conditions. Results We present a simple theoretical framework to show how heterogeneous differentiation in a two-master-regulator paradigm can be governed by a signaling network motif common to all subsets of CD4+ T cells. With this motif, a population of naïve CD4+ T cells can integrate the signals from their environment to generate a functionally diverse population with robust commitment of individual cells. Notably, two positive feedback loops in this network motif govern three bistable switches, which in turn, give rise to three types of heterogeneous differentiated states, depending upon particular combinations of input signals. We provide three prototype models illustrating how to use this framework to explain experimental observations and make specific testable predictions. Conclusions The process in which several types of T helper cells are generated simultaneously to mount complex immune responses upon pathogenic challenges can be highly regulated, and a simple signaling network motif can be responsible for generating all possible types of heterogeneous populations with respect to a pair of master regulators controlling CD4+ T cell differentiation. The framework provides a mathematical basis for understanding the decision-making mechanisms of CD4+ T cells, and it can be helpful for interpreting experimental results. Mathematical models based on the framework make specific testable predictions that may improve our understanding of this differentiation system. PMID:22697466

  10. ZSCAN10 expression corrects the genomic instability of iPSCs from aged donors.

    PubMed

    Skamagki, Maria; Correia, Cristina; Yeung, Percy; Baslan, Timour; Beck, Samuel; Zhang, Cheng; Ross, Christian A; Dang, Lam; Liu, Zhong; Giunta, Simona; Chang, Tzu-Pei; Wang, Joye; Ananthanarayanan, Aparna; Bohndorf, Martina; Bosbach, Benedikt; Adjaye, James; Funabiki, Hironori; Kim, Jonghwan; Lowe, Scott; Collins, James J; Lu, Chi-Wei; Li, Hu; Zhao, Rui; Kim, Kitai

    2017-09-01

    Induced pluripotent stem cells (iPSCs), which are used to produce transplantable tissues, may particularly benefit older patients, who are more likely to suffer from degenerative diseases. However, iPSCs generated from aged donors (A-iPSCs) exhibit higher genomic instability, defects in apoptosis and a blunted DNA damage response compared with iPSCs generated from younger donors. We demonstrated that A-iPSCs exhibit excessive glutathione-mediated reactive oxygen species (ROS) scavenging activity, which blocks the DNA damage response and apoptosis and permits survival of cells with genomic instability. We found that the pluripotency factor ZSCAN10 is poorly expressed in A-iPSCs and addition of ZSCAN10 to the four Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC) during A-iPSC reprogramming normalizes ROS-glutathione homeostasis and the DNA damage response, and recovers genomic stability. Correcting the genomic instability of A-iPSCs will ultimately enhance our ability to produce histocompatible functional tissues from older patients' own cells that are safe for transplantation.

  11. The neurovascular unit, matrix proteases, and innate inflammation.

    PubMed

    del Zoppo, Gregory J

    2010-10-01

    In the central nervous system, microvessel-neuron interactions appear highly coordinated. The rapid simultaneous responses of the microvasculature, neurons, and glia to focal ischemia in experimental ischemic stroke suggest that these responses could be viewed in a unitary fashion, rather than as individual components. The "neurovascular unit" consists of microvessels (endothelial cells-basal lamina matrix-astrocyte end-feet [and pericytes]), astrocytes, neurons and their axons, and other supporting cells that are likely to modulate the function of the "unit." Each cell component generates an inflammatory response to ischemia. Matrix metalloproteinase (MMP)-9 was first associated with hemorrhagic transformation following focal ischemia in an experimental model. A series of studies of ischemic stroke patients also suggests a relationship between MMP-9 levels and several consequences of ischemic injury, including hemorrhagic transformation. Recent experimental work suggests specific cell sources for MMP-9 generation and for matrix proteases from four distinct families that could impact neurovascular unit integrity. © 2010 New York Academy of Sciences.

  12. New activity pattern in human interactive dynamics

    NASA Astrophysics Data System (ADS)

    Formentin, Marco; Lovison, Alberto; Maritan, Amos; Zanzotto, Giovanni

    2015-09-01

    We investigate the response function of human agents as demonstrated by written correspondence, uncovering a new pattern for how the reactive dynamics of individuals is distributed across the set of each agent’s contacts. In long-term empirical data on email, we find that the set of response times considered separately for the messages to each different correspondent of a given writer, generate a family of heavy-tailed distributions, which have largely the same features for all agents, and whose characteristic times grow exponentially with the rank of each correspondent. We furthermore show that this new behavioral pattern emerges robustly by considering weighted moving averages of the priority-conditioned response-time probabilities generated by a basic prioritization model. Our findings clarify how the range of priorities in the inputs from one’s environment underpin and shape the dynamics of agents embedded in a net of reactive relations. These newly revealed activity patterns might be universal, being present in other general interactive environments, and constrain future models of communication and interaction networks, affecting their architecture and evolution.

  13. Multi-Beam Approach for Accelerating Alignment and Calibration of HyspIRI-Like Imaging Spectrometers

    NASA Technical Reports Server (NTRS)

    Eastwood, Michael L.; Green, Robert O.; Mouroulis, Pantazis; Hochberg, Eric B.; Hein, Randall C.; Kroll, Linley A.; Geier, Sven; Coles, James B.; Meehan, Riley

    2012-01-01

    A paper describes an optical stimulus that produces more consistent results, and can be automated for unattended, routine generation of data analysis products needed by the integration and testing team assembling a high-fidelity imaging spectrometer system. One key attribute of the system is an arrangement of pick-off mirrors that provides multiple input beams (five in this implementation) to simultaneously provide stimulus light to several field angles along the field of view of the sensor under test, allowing one data set to contain all the information that previously required five data sets to be separately collected. This stimulus can also be fed by quickly reconfigured sources that ultimately provide three data set types that would previously be collected separately using three different setups: Spectral Response Function (SRF), Cross-track Response Function (CRF), and Along-track Response Function (ARF), respectively. This method also lends itself to expansion of the number of field points if less interpolation across the field of view is desirable. An absolute minimum of three is required at the beginning stages of imaging spectrometer alignment.

  14. Sex versus parthenogenesis; immune function in a facultatively parthenogenetic phasmatid (Extatosoma tiaratum).

    PubMed

    Alavi, Yasaman; Elgar, Mark Adrian; Jones, Therésa Melanie

    2017-07-01

    Facultative parthenogenetic species, in which females can alternate between sex and parthenogenesis, are useful models to investigate the costs and benefits of sex and parthenogenesis, an ongoing issue in biology. The necessary empirical studies comparing the outcomes of alternative reproductive modes on life history traits are rare and focus mainly on traits directly associated with reproductive fitness. Immune function determines the ability of individuals to defend themselves against injury and disease and is therefore likely to have a significant impact on fitness. Here, we used the facultatively parthenogenetic Australian phasmatid, Extatosoma tiaratum, to investigate the effect of both maternal and offspring mode of conception (sexual or parthenogenetic) on offspring immune function (haemocyte concentration, lytic activity and phenoloxidase activity). We show that when parthenogenesis persists beyond one generation, it has negative effects on immune response in terms of haemocyte concentration and lytic activity. Phenoloxidase activity positively correlates with the level of microsatellite heterozygosity. Moreover, immune response decreases across consecutive sampling weeks, suggesting there are physiological constraints with respect to mounting immune responses in close time intervals. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Design of robust flow processing networks with time-programmed responses

    NASA Astrophysics Data System (ADS)

    Kaluza, P.; Mikhailov, A. S.

    2012-04-01

    Can artificially designed networks reach the levels of robustness against local damage which are comparable with those of the biochemical networks of a living cell? We consider a simple model where the flow applied to an input node propagates through the network and arrives at different times to the output nodes, thus generating a pattern of coordinated responses. By using evolutionary optimization algorithms, functional networks - with required time-programmed responses - were constructed. Then, continuing the evolution, such networks were additionally optimized for robustness against deletion of individual nodes or links. In this manner, large ensembles of functional networks with different kinds of robustness were obtained, making statistical investigations and comparison of their structural properties possible. We have found that, generally, different architectures are needed for various kinds of robustness. The differences are statistically revealed, for example, in the Laplacian spectra of the respective graphs. On the other hand, motif distributions of robust networks do not differ from those of the merely functional networks; they are found to belong to the first Alon superfamily, the same as that of the gene transcription networks of single-cell organisms.

  16. Acid sphingomyelinase mediates human CD4+ T-cell signaling: potential roles in T-cell responses and diseases

    PubMed Central

    Bai, Aiping; Guo, Yuan

    2017-01-01

    Acid sphingomyelinase (ASM) is a lipid hydrolase. By generating ceramide, ASM had been reported to have an important role in regulating immune cell functions inclusive of macrophages, NK cells, and CD8+ T cells, whereas the role of ASM bioactivity in regulation of human CD4+ T-cell functions remained uncertain. Recent studies have provided novel findings in this field. Upon stimulation of CD3 and/or CD28, ASM-dependent ceramide signaling mediates intracellular downstream signal cascades of CD3 and CD28, and regulates CD4+ T-cell activation and proliferation. Meanwhile, CD39 and CD161 have direct interactions with ASM, which mediates downstream signals inclusive of STAT3 and mTOR and thus defines human Th17 cells. Intriguingly, ASM mediates Th1 responses, but negatively regulates Treg functions. In this review, we summarized the pivotal roles of ASM in regulation of human CD4+ T-cell activation and responses. ASM/sphingolipid signaling may be a novel target for the therapy of human autoimmune diseases. PMID:28749465

  17. Transonic buffet behavior of Northrop F-5A aircraft

    NASA Technical Reports Server (NTRS)

    Hwang, C.; Pi, W. S.

    1974-01-01

    Flight tests were performed on an F-5A aircraft to investigate the dynamic buffet pressure distribution on the wing surfaces and the responses during a series of transonic maneuvers called wind-up turns. The conditions under which the tests were conducted are defined. The fluctuating buffet pressure data on the right wing of the aircraft were acquired by miniaturized semiconductor-type pressure transducers flush mounted on the wing. Processing of the fluctuating pressures and responses included the generation of the auto- and cross-power spectra, and of the spatial correlation functions. An analytical correlation procedure was introduced to compute the aircraft response spectra based on the measured buffet pressures.

  18. Dynamic visualization of data streams

    DOEpatents

    Wong, Pak Chung [Richalnd, WA; Foote, Harlan P [Richland, WA; Adams, Daniel R [Kennewick, WA; Cowley, Wendy E [Richland, WA; Thomas, James J [Richland, WA

    2009-07-07

    One embodiment of the present invention includes a data communication subsystem to receive a data stream, and a data processing subsystem responsive to the data communication subsystem to generate a visualization output based on a group of data vectors corresponding to a first portion of the data stream. The processing subsystem is further responsive to a change in rate of receipt of the data to modify the visualization output with one or more other data vectors corresponding to a second portion of the data stream as a function of eigenspace defined with the group of data vectors. The system further includes a display device responsive to the visualization output to provide a corresponding visualization.

  19. Variation analysis of transcriptome changes reveals cochlear genes and their associated functions in cochlear susceptibility to acoustic overstimulation.

    PubMed

    Yang, Shuzhi; Cai, Qunfeng; Bard, Jonathan; Jamison, Jennifer; Wang, Jianmin; Yang, Weiping; Hu, Bo Hua

    2015-12-01

    Individual variation in the susceptibility of the auditory system to acoustic overstimulation has been well-documented at both the functional and structural levels. However, the molecular mechanism responsible for this variation is unclear. The current investigation was designed to examine the variation patterns of cochlear gene expression using RNA-seq data and to identify the genes with expression variation that increased following acoustic trauma. This study revealed that the constitutive expressions of cochlear genes displayed diverse levels of gene-specific variation. These variation patterns were altered by acoustic trauma; approximately one-third of the examined genes displayed marked increases in their expression variation. Bioinformatics analyses revealed that the genes that exhibited increased variation were functionally related to cell death, biomolecule metabolism, and membrane function. In contrast, the stable genes were primarily related to basic cellular processes, including protein and macromolecular syntheses and transport. There was no functional overlap between the stable and variable genes. Importantly, we demonstrated that glutamate metabolism is related to the variation in the functional response of the cochlea to acoustic overstimulation. Taken together, the results indicate that our analyses of the individual variations in transcriptome changes of cochlear genes provide important information for the identification of genes that potentially contribute to the generation of individual variation in cochlear responses to acoustic overstimulation. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Long-term functional plasticity in plant hydraulic architecture in response to supplemental moisture.

    PubMed

    von Arx, Georg; Archer, Steven R; Hughes, Malcolm K

    2012-05-01

    Plasticity in structural and functional traits related to water balance may determine plant performance and survival in ecosystems characterized by water limitation or high levels of rainfall variability, particularly in perennial herbaceous species with long generation cycles. This paper addresses whether and the extent to which several such seasonal to long-term traits respond to changes in moisture availability. Using a novel approach that integrates ecology, physiology and anatomy, a comparison was made of lifetime functional traits in the root xylem of a long-lived perennial herb (Potentilla diversifolia, Rosaceae) growing in dry habitats with those of nearby individuals growing where soil moisture had been supplemented for 14 years. Traditional parameters such as specific leaf area (SLA) and above-ground growth were also assessed. Individuals from the site receiving supplemental moisture consistently showed significant responses in all considered traits related to water balance: SLA was greater by 24 %; roots developed 19 % less starch storing tissue, an indicator for drought-stress tolerance; and vessel size distributions shifted towards wider elements that collectively conducted water 54 % more efficiently - but only during the years for which moisture was supplemented. In contrast, above-ground growth parameters showed insignificant or inconsistent responses. The phenotypic changes documented represent consistent, dynamic responses to increased moisture availability that should increase plant competitive ability. The functional plasticity of xylem anatomy quantified in this study constitutes a mechanistic basis for anticipating the differential success of plant species in response to climate variability and change, particularly where water limitation occurs.

  1. Guinea Pig Oxygen-Sensing and Carotid Body Functional Properties

    PubMed Central

    Gonzalez-Obeso, Elvira; Docio, Inmaculada; Olea, Elena; Cogolludo, Angel; Obeso, Ana; Rocher, Asuncion; Gomez-Niño, Angela

    2017-01-01

    Mammals have developed different mechanisms to maintain oxygen supply to cells in response to hypoxia. One of those mechanisms, the carotid body (CB) chemoreceptors, is able to detect physiological hypoxia and generate homeostatic reflex responses, mainly ventilatory and cardiovascular. It has been reported that guinea pigs, originally from the Andes, have a reduced ventilatory response to hypoxia compared to other mammals, implying that CB are not completely functional, which has been related to genetically/epigenetically determined poor hypoxia-driven CB reflex. This study was performed to check the guinea pig CB response to hypoxia compared to the well-known rat hypoxic response. These experiments have explored ventilatory parameters breathing different gases mixtures, cardiovascular responses to acute hypoxia, in vitro CB response to hypoxia and other stimuli and isolated guinea pig chemoreceptor cells properties. Our findings show that guinea pigs are hypotensive and have lower arterial pO2 than rats, probably related to a low sympathetic tone and high hemoglobin affinity. Those characteristics could represent a higher tolerance to hypoxic environment than other rodents. We also find that although CB are hypo-functional not showing chronic hypoxia sensitization, a small percentage of isolated carotid body chemoreceptor cells contain tyrosine hydroxylase enzyme and voltage-dependent K+ currents and therefore can be depolarized. However hypoxia does not modify intracellular Ca2+ levels or catecholamine secretion. Guinea pigs are able to hyperventilate only in response to intense acute hypoxic stimulus, but hypercapnic response is similar to rats. Whether other brain areas are also activated by hypoxia in guinea pigs remains to be studied. PMID:28533756

  2. Guinea Pig Oxygen-Sensing and Carotid Body Functional Properties.

    PubMed

    Gonzalez-Obeso, Elvira; Docio, Inmaculada; Olea, Elena; Cogolludo, Angel; Obeso, Ana; Rocher, Asuncion; Gomez-Niño, Angela

    2017-01-01

    Mammals have developed different mechanisms to maintain oxygen supply to cells in response to hypoxia. One of those mechanisms, the carotid body (CB) chemoreceptors, is able to detect physiological hypoxia and generate homeostatic reflex responses, mainly ventilatory and cardiovascular. It has been reported that guinea pigs, originally from the Andes, have a reduced ventilatory response to hypoxia compared to other mammals, implying that CB are not completely functional, which has been related to genetically/epigenetically determined poor hypoxia-driven CB reflex. This study was performed to check the guinea pig CB response to hypoxia compared to the well-known rat hypoxic response. These experiments have explored ventilatory parameters breathing different gases mixtures, cardiovascular responses to acute hypoxia, in vitro CB response to hypoxia and other stimuli and isolated guinea pig chemoreceptor cells properties. Our findings show that guinea pigs are hypotensive and have lower arterial pO 2 than rats, probably related to a low sympathetic tone and high hemoglobin affinity. Those characteristics could represent a higher tolerance to hypoxic environment than other rodents. We also find that although CB are hypo-functional not showing chronic hypoxia sensitization, a small percentage of isolated carotid body chemoreceptor cells contain tyrosine hydroxylase enzyme and voltage-dependent K + currents and therefore can be depolarized. However hypoxia does not modify intracellular Ca 2+ levels or catecholamine secretion. Guinea pigs are able to hyperventilate only in response to intense acute hypoxic stimulus, but hypercapnic response is similar to rats. Whether other brain areas are also activated by hypoxia in guinea pigs remains to be studied.

  3. Preparing for adulthood: thousands upon thousands of new cells are born in the hippocampus during puberty, and most survive with effortful learning

    PubMed Central

    Curlik, Daniel M.; DiFeo, Gina; Shors, Tracey J.

    2014-01-01

    The dentate gyrus of the hippocampal formation generates new granule neurons throughout life. The number of neurons produced each day is inversely related to age, with thousands more produced during puberty than during adulthood, and many fewer produced during senescence. In adulthood, approximately half of these cells undergo apoptosis shortly after they are generated. Most of these cells can be rescued from death by effortful and successful learning experiences (Gould et al., 1999; Waddell and Shors, 2008; Curlik and Shors, 2011). Once rescued, the newly-generated cells differentiate into neurons, and remain in the hippocampus for at least several months (Leuner et al., 2004). Here, we report that many new hippocampal cells also undergo cell death during puberty. Because the juvenile brain is more plastic than during adulthood, and because many experiences are new, we hypothesized that a great number of cells would be rescued by learning during puberty. Indeed, adolescent rats that successfully acquired the trace eyeblink response retained thousands more cells than animals that were not trained, and those that failed to learn. Because the hippocampus generates thousands more cells during puberty than during adulthood, these results support the idea that the adolescent brain is especially responsive to learning. This enhanced response can have significant consequences for the functional integrity of the hippocampus. Such a massive increase in cell proliferation is likely an adaptive response as the young animal must emerge from the care of its mother to face the dangers, challenges, and opportunities of adulthood. PMID:24795549

  4. Use of antigen-primed dendritic cells for inducing antitumor immune responses in vitro in patients with non-small cell lung cancer

    PubMed Central

    Obleukhova, Irina; Kiryishina, Nataliya; Falaleeva, Svetlana; Lopatnikova, Julia; Kurilin, Vasiliy; Kozlov, Vadim; Vitsin, Aleksander; Cherkasov, Andrey; Kulikova, Ekaterina; Sennikov, Sergey

    2018-01-01

    Cancer is associated with a reduction in immature and mature circulating dendritic cells (DCs), and with an impaired migratory capacity, compared with healthy donors. Therefore, modern approaches to the in vitro generation of DCs loaded with tumor antigens and their use for inducing antitumor immune responses in vivo are being investigated. The purpose of the present study was to investigate the phenotypic and functional characteristics of peripheral blood DC subsets in patients with non-small cell lung cancer (NSCLC), and the development of an antitumor cytotoxic response by mononuclear cells (MNCs) from patients using in vitro generated antigen-primed DCs. Heparinized peripheral venous blood samples were obtained from 10 healthy donors and 20 patients with a histologically verified diagnosis of NSCLC. The ability of antigen-activated DCs to stimulate the activity of MNCs against autologous tumor cells was evaluated using a cytotoxic test. Peripheral blood DC subsets from patients with NSCLC were identified to be decreased and to exhibit an impaired ability to mature, compared with healthy donors. Furthermore, DCs generated from MNCs from patients with NSCLC were able to stimulate a specific cytotoxic response when loaded with autologous tumor lysates or RNA and matured, in vitro. A perforin and granzyme B-dependent mode of cytotoxicity was primarily induced. The ability of DCs loaded with tumor antigens to increase the cytotoxic activity of MNCs against NSCLC cells in vitro indicates the effective induction and co-stimulation of T lymphocytes by the generated DCs. PMID:29399182

  5. The effects of session length on demand functions generated using FR schedules.

    PubMed

    Foster, T Mary; Kinloch, Jennifer; Poling, Alan

    2011-05-01

    In comparing open and closed economies, researchers often arrange shorter sessions under the former condition than under the latter. Several studies indicate that session length per se can affect performance and there are some data that indicate that this variable can influence demand functions. To provide further data, the present study exposed domestic hens to series of increasing fixed-ratio schedules with the length of the open-economy sessions varied over 10, 40, 60, and 120 min. Session time affected the total-session response rates and pause lengths. The shortest session gave the greatest response rates and shortest pauses and the longest gave the lowest response rates and longest pauses. The total-session demand functions also changed with session length: The shortest session gave steeper initial slopes (i.e., the functions were more elastic at small ratios) and smaller rates of change of elasticity than the longest session. Response rates, pauses, and demand functions were, however, similar for equivalent periods of responding taken from within sessions of different overall lengths (e.g., total-session data for 10-min sessions and the data for the first 10 min of 120-min sessions). These findings suggest that differences in session length can confound the results of studies comparing open and closed economies when those economies are arranged in sessions that differ substantially in length, hence data for equivalent-length periods of responding, rather than total-session data, should be of primary interest under these conditions.

  6. Pathogen Proliferation Governs the Magnitude but Compromises the Function of CD8 T Cells1

    PubMed Central

    Sad, Subash; Dudani, Renu; Gurnani, Komal; Russell, Marsha; van Faassen, Henk; Finlay, Brett; Krishnan, Lakshmi

    2014-01-01

    CD8+ T cell memory is critical for protection against many intracellular pathogens. However, it is not clear how pathogen virulence influences the development and function of CD8+ T cells. Salmonella typhimurium (ST) is an intracellular bacterium that causes rapid fatality in susceptible mice and chronic infection in resistant strains. We have constructed recombinant mutants of ST, expressing the same immunodominant Ag OVA, but defective in various key virulence genes. We show that the magnitude of CD8+ T cell response correlates directly to the intracellular proliferation of ST. Wild-type ST displayed efficient intracellular proliferation and induced increased numbers of OVA-specific CD8+ T cells upon infection in mice. In contrast, mutants with defective Salmonella pathogenicity island II genes displayed poor intracellular proliferation and induced reduced numbers of OVA-specific CD8+ T cells. However, when functionality of the CD8+ T cell response was measured, mutants of ST induced a more functional response compared with the wild-type ST. Infection with wild-type ST, in contrast to mutants defective in pathogenicity island II genes, induced the generation of mainly effector-memory CD8+ T cells that expressed little IL-2, failed to mediate efficient cytotoxicity, and proliferated poorly in response to Ag challenge in vivo. Taken together, these results indicate that pathogens that proliferate rapidly and chronically in vivo may evoke functionally inferior memory CD8+ T cells which may promote the survival of the pathogen. PMID:18424704

  7. jSynthesizer: A Java based first-motion synthetic seismogram tool

    NASA Astrophysics Data System (ADS)

    Sullivan, Mark

    2009-10-01

    Both researchers and educators need software tools to create synthetic seismograms to model earthquake sources. We have developed a program that generates first-motion synthetic seismograms that is highly interactive and suited to the needs of both research and education audiences. Implemented in the Java programming language, our program is available for use on Windows, Mac OS X and Linux operating systems. Our program allows the user to input the fault parameters strike, dip and slip angle, numerically or graphically using a lower hemisphere equal-area stereographic projection of the focal sphere of the earthquake. This representation is familiar to geologists and seismologists as the standard way of displaying the orientation of a fault in space. The user is also able to enter the relative location of the seismograph and the depth and crustal velocity structure in the vicinity of the earthquake. The direct P wave along with reflections off of layer boundaries near the source are generated using a constant ray-parameter approximation. The instrument response functions used by the Worldwide Standardized Seismogram Network and the attenuation response of the Earth's mantle are generated in the frequency domain and applied to generate the synthetic seismogram. Planned enhancements to this program will allow the simultaneous generation of seismograms at many stations as well as more complicated crustal structures.

  8. Neural and cognitive face-selective markers: An integrative review.

    PubMed

    Yovel, Galit

    2016-03-01

    Faces elicit robust and selective neural responses in the primate brain. These neural responses have been investigated with functional MRI and EEG in numerous studies, which have reported face-selective activations in the occipital-temporal cortex and an electrophysiological face-selective response that peaks 170 ms after stimulus onset at occipital-temporal sites. Evidence for face-selective processes has also been consistently reported in cognitive studies, which investigated the face inversion effect, the composite face effect and the left visual field (LVF) superiority. These cognitive effects indicate that the perceptual representation that we generate for faces differs from the representation that is generated for inverted faces or non-face objects. In this review, I will show that the fMRI and ERP face-selective responses are strongly associated with these three well-established behavioral face-selective measures. I will further review studies that examined the relationship between fMRI and EEG face-selective measures suggesting that they are strongly linked. Taken together these studies imply that a holistic representation of a face is generated at 170 ms after stimulus onset over the right hemisphere. These findings, which reveal a strong link between the various and complementary cognitive and neural measures of face processing, allow to characterize where, when and how faces are represented during the first 200 ms of face processing. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. A heating-superfusion platform technology for the investigation of protein function in single cells.

    PubMed

    Xu, Shijun; Ainla, Alar; Jardemark, Kent; Jesorka, Aldo; Jeffries, Gavin D M

    2015-01-06

    Here, we report on a novel approach for the study of single-cell intracellular enzyme activity at various temperatures, utilizing a localized laser heating probe in combination with a freely positionable microfluidic perfusion device. Through directed exposure of individual cells to the pore-forming agent α-hemolysin, we have controlled the membrane permeability, enabling targeted delivery of the substrate. Mildly permeabilized cells were exposed to fluorogenic substrates to monitor the activity of intracellular enzymes, while adjusting the local temperature surrounding the target cells, using an infrared laser heating system. We generated quantitative estimates for the intracellular alkaline phosphatase activity at five different temperatures in different cell lines, constructing temperature-response curves of enzymatic activity at the single-cell level. Enzymatic activity was determined rapidly after cell permeation, generating five-point temperature-response curves within just 200 s.

  10. The effects of stress hormones on immune function may be vital for the adaptive reconfiguration of the immune system during fight-or-flight behavior.

    PubMed

    Adamo, Shelley A

    2014-09-01

    Intense, short-term stress (i.e., robust activation of the fight-or-flight response) typically produces a transient decline in resistance to disease in animals across phyla. Chemical mediators of the stress response (e.g., stress hormones) help induce this decline, suggesting that this transient immunosuppression is an evolved response. However, determining the function of stress hormones on immune function is difficult because of their complexity. Nevertheless, evidence suggests that stress hormones help maintain maximal resistance to disease during the physiological changes needed to optimize the body for intense physical activity. Work on insects demonstrates that stress hormones both shunt resources away from the immune system during fight-or-flight responses as well as reconfigure the immune system. Reconfiguring the immune system minimizes the impact of the loss of these resources and reduces the increased costs of some immune functions due to the physiological changes demanded by the fight-or-flight response. For example, during the stress response of the cricket Gryllus texensis, some molecular resources are shunted away from the immune system and toward lipid transport, resulting in a reduction in resistance to disease. However, insects' immune cells (hemocytes) have receptors for octopamine (the insect stress neurohormone). Octopamine increases many hemocyte functions, such as phagocytosis, and these changes would tend to mitigate the decline in immunity due to the loss of molecular resources. Moreover, because the stress response generates oxidative stress, some immune responses are probably more costly when activated during a stress response (e.g., those that produce reactive molecules). Some of these immune responses are depressed during stress in crickets, while others, whose costs are probably not increased during a stress response, are enhanced. Some effects of stress hormones on immune systems may be better understood as examples of reconfiguration rather than as mediating a trade-off. © The Author 2014. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.

  11. Functional imaging of sleep vertex sharp transients.

    PubMed

    Stern, John M; Caporro, Matteo; Haneef, Zulfi; Yeh, Hsiang J; Buttinelli, Carla; Lenartowicz, Agatha; Mumford, Jeanette A; Parvizi, Josef; Poldrack, Russell A

    2011-07-01

    The vertex sharp transient (VST) is an electroencephalographic (EEG) discharge that is an early marker of non-REM sleep. It has been recognized since the beginning of sleep physiology research, but its source and function remain mostly unexplained. We investigated VST generation using functional MRI (fMRI). Simultaneous EEG and fMRI were recorded from seven individuals in drowsiness and light sleep. VST occurrences on EEG were modeled with fMRI using an impulse function convolved with a hemodynamic response function to identify cerebral regions correlating to the VSTs. A resulting statistical image was thresholded at Z>2.3. Two hundred VSTs were identified. Significantly increased signal was present bilaterally in medial central, lateral precentral, posterior superior temporal, and medial occipital cortex. No regions of decreased signal were present. The regions are consistent with electrophysiologic evidence from animal models and functional imaging of human sleep, but the results are specific to VSTs. The regions principally encompass the primary sensorimotor cortical regions for vision, hearing, and touch. The results depict a network comprising the presumed VST generator and its associated regions. The associated regions functional similarity for primary sensation suggests a role for VSTs in sensory experience during sleep. Copyright © 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  12. Optimized Reduction of Unsteady Radial Forces in a Singlechannel Pump for Wastewater Treatment

    NASA Astrophysics Data System (ADS)

    Kim, Jin-Hyuk; Cho, Bo-Min; Choi, Young-Seok; Lee, Kyoung-Yong; Peck, Jong-Hyeon; Kim, Seon-Chang

    2016-11-01

    A single-channel pump for wastewater treatment was optimized to reduce unsteady radial force sources caused by impeller-volute interactions. The steady and unsteady Reynolds- averaged Navier-Stokes equations using the shear-stress transport turbulence model were discretized by finite volume approximations and solved on tetrahedral grids to analyze the flow in the single-channel pump. The sweep area of radial force during one revolution and the distance of the sweep-area center of mass from the origin were selected as the objective functions; the two design variables were related to the internal flow cross-sectional area of the volute. These objective functions were integrated into one objective function by applying the weighting factor for optimization. Latin hypercube sampling was employed to generate twelve design points within the design space. A response-surface approximation model was constructed as a surrogate model for the objectives, based on the objective function values at the generated design points. The optimized results showed considerable reduction in the unsteady radial force sources in the optimum design, relative to those of the reference design.

  13. Clonazepam responsive opsoclonus myoclonus syndrome: additional evidence in favour of fastigial nucleus disinhibition hypothesis?

    PubMed

    Paliwal, Vimal Kumar; Chandra, Satish; Verma, Ritu; Kalita, Jayantee; Misra, Usha K

    2010-05-01

    Opsoclonus myoclonus syndrome is a rare paraneoplastic syndrome seen in 50% of children with neuroblastoma. Neural generator of opsoclonus and myoclonus is not known but evidences suggest the role of fastigial nucleus disinhibition from the loss of function of inhibitory (GABAergic) Purkinje cells in the cerebellum. We present a child with paraneoplastic opsoclonus myoclonus syndrome who responded well to clonazepam. Response to clonazepam is an evidence for the involvement of GABAergic neural circuits in the genesis of opsoclonus myoclonus syndrome and is in agreement with fastigial nucleus disinhibition hypothesis.

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

    PubMed Central

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

    2017-01-01

    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

  15. In-Vitro Induced Immunosuppression in a Rotary Cell Culture System

    NASA Technical Reports Server (NTRS)

    Grimm, Elizabeth A.

    1998-01-01

    The function of the innate immune system is to provide a first-line of defense against infectious organisms, via control of bacterial and viral growth using antigen nonspecific means. These nonspecific immune effectors include macrophages and Natural Killing (NK) cells, and certain cytokines elicited in response to "super antigens" on the infectious agents. This innate system usually keeps most infectious agents from rapidly growing while the adaptive immune system is generating a specific response complete with immunologic memory. Compelling evidence suggests that space flight results in various immunosuppressive effects, including reduced innate and adaptive immune responses. We were particularly concerned with reduced NK activity at landing, and have asked whether the microgravity component of space flight could be responsible for the previously observed NK defect. We have conclusively demonstrated that simulated microgravity as provided by the Synthecon bioreactors does not inhibit the NK function nor the IL-2 activation of lymphokine-activated killing (LAK). Interleukin-2 is the key cytokine responsible for activation of NK cells to express LAK, as well as to support differentiation of lymphocytes during adaptive immune responses. Therefore, we have disproved our original hypothesis based on poor NK in many of the astronauts upon landing.

  16. Gene Deletions in Mycobacterium bovis BCG Stimulate Increased CD8+ T Cell Responses

    PubMed Central

    Panas, Michael W.; Sixsmith, Jaimie D.; White, KeriAnn; Korioth-Schmitz, Birgit; Shields, Shana T.; Moy, Brian T.; Lee, Sunhee; Schmitz, Joern E.; Jacobs, William R.; Porcelli, Steven A.; Haynes, Barton F.; Letvin, Norman L.

    2014-01-01

    Mycobacteria, the etiological agents of tuberculosis and leprosy, have coevolved with mammals for millions of years and have numerous ways of suppressing their host's immune response. It has been suggested that mycobacteria may contain genes that reduce the host's ability to elicit CD8+ T cell responses. We screened 3,290 mutant Mycobacterium bovis bacillus Calmette Guerin (BCG) strains to identify genes that decrease major histocompatibility complex (MHC) class I presentation of mycobacterium-encoded epitope peptides. Through our analysis, we identified 16 mutant BCG strains that generated increased transgene product-specific CD8+ T cell responses. The genes disrupted in these mutant strains had disparate predicted functions. Reconstruction of strains via targeted deletion of genes identified in the screen recapitulated the enhanced immunogenicity phenotype of the original mutant strains. When we introduced the simian immunodeficiency virus (SIV) gag gene into several of these novel BCG strains, we observed enhanced SIV Gag-specific CD8+ T cell responses in vivo. This study demonstrates that mycobacteria carry numerous genes that act to dampen CD8+ T cell responses and suggests that genetic modification of these genes may generate a novel group of recombinant BCG strains capable of serving as more effective and immunogenic vaccine vectors. PMID:25287928

  17. Gene deletions in Mycobacterium bovis BCG stimulate increased CD8+ T cell responses.

    PubMed

    Panas, Michael W; Sixsmith, Jaimie D; White, KeriAnn; Korioth-Schmitz, Birgit; Shields, Shana T; Moy, Brian T; Lee, Sunhee; Schmitz, Joern E; Jacobs, William R; Porcelli, Steven A; Haynes, Barton F; Letvin, Norman L; Gillard, Geoffrey O

    2014-12-01

    Mycobacteria, the etiological agents of tuberculosis and leprosy, have coevolved with mammals for millions of years and have numerous ways of suppressing their host's immune response. It has been suggested that mycobacteria may contain genes that reduce the host's ability to elicit CD8(+) T cell responses. We screened 3,290 mutant Mycobacterium bovis bacillus Calmette Guerin (BCG) strains to identify genes that decrease major histocompatibility complex (MHC) class I presentation of mycobacterium-encoded epitope peptides. Through our analysis, we identified 16 mutant BCG strains that generated increased transgene product-specific CD8(+) T cell responses. The genes disrupted in these mutant strains had disparate predicted functions. Reconstruction of strains via targeted deletion of genes identified in the screen recapitulated the enhanced immunogenicity phenotype of the original mutant strains. When we introduced the simian immunodeficiency virus (SIV) gag gene into several of these novel BCG strains, we observed enhanced SIV Gag-specific CD8(+) T cell responses in vivo. This study demonstrates that mycobacteria carry numerous genes that act to dampen CD8(+) T cell responses and suggests that genetic modification of these genes may generate a novel group of recombinant BCG strains capable of serving as more effective and immunogenic vaccine vectors. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  18. Emotion and the Cardiovascular System: Postulated Role of Inputs From the Medial Prefrontal Cortex to the Dorsolateral Periaqueductal Gray.

    PubMed

    Dampney, Roger

    2018-01-01

    The midbrain periaqueductal gray (PAG) plays a major role in generating different types of behavioral responses to emotional stressors. This review focuses on the role of the dorsolateral (dl) portion of the PAG, which on the basis of anatomical and functional studies, appears to have a unique and distinctive role in generating behavioral, cardiovascular and respiratory responses to real and perceived emotional stressors. In particular, the dlPAG, but not other parts of the PAG, receives direct inputs from the primary auditory cortex and from the secondary visual cortex. In addition, there are strong direct inputs to the dlPAG, but not other parts of the PAG, from regions within the medial prefrontal cortex that in primates correspond to cortical areas 10 m, 25 and 32. I first summarise the evidence that the inputs to the dlPAG arising from visual, auditory and olfactory signals trigger defensive behavioral responses supported by appropriate cardiovascular and respiratory effects, when such signals indicate the presence of a real external threat, such as the presence of a predator. I then consider the functional roles of the direct inputs from the medial prefrontal cortex, and propose the hypothesis that these inputs are activated by perceived threats, that are generated as a consequence of complex cognitive processes. I further propose that the inputs from areas 10 m, 25 and 32 are activated under different circumstances. The input from cortical area 10 m is of special interest, because this cortical area exists only in primates and is much larger in the brain of humans than in all other primates.

  19. Emotion and the Cardiovascular System: Postulated Role of Inputs From the Medial Prefrontal Cortex to the Dorsolateral Periaqueductal Gray

    PubMed Central

    Dampney, Roger

    2018-01-01

    The midbrain periaqueductal gray (PAG) plays a major role in generating different types of behavioral responses to emotional stressors. This review focuses on the role of the dorsolateral (dl) portion of the PAG, which on the basis of anatomical and functional studies, appears to have a unique and distinctive role in generating behavioral, cardiovascular and respiratory responses to real and perceived emotional stressors. In particular, the dlPAG, but not other parts of the PAG, receives direct inputs from the primary auditory cortex and from the secondary visual cortex. In addition, there are strong direct inputs to the dlPAG, but not other parts of the PAG, from regions within the medial prefrontal cortex that in primates correspond to cortical areas 10 m, 25 and 32. I first summarise the evidence that the inputs to the dlPAG arising from visual, auditory and olfactory signals trigger defensive behavioral responses supported by appropriate cardiovascular and respiratory effects, when such signals indicate the presence of a real external threat, such as the presence of a predator. I then consider the functional roles of the direct inputs from the medial prefrontal cortex, and propose the hypothesis that these inputs are activated by perceived threats, that are generated as a consequence of complex cognitive processes. I further propose that the inputs from areas 10 m, 25 and 32 are activated under different circumstances. The input from cortical area 10 m is of special interest, because this cortical area exists only in primates and is much larger in the brain of humans than in all other primates. PMID:29881334

  20. Noise adaptation in integrate-and fire neurons.

    PubMed

    Rudd, M E; Brown, L G

    1997-07-01

    The statistical spiking response of an ensemble of identically prepared stochastic integrate-and-fire neurons to a rectangular input current plus gaussian white noise is analyzed. It is shown that, on average, integrate-and-fire neurons adapt to the root-mean-square noise level of their input. This phenomenon is referred to as noise adaptation. Noise adaptation is characterized by a decrease in the average neural firing rate and an accompanying decrease in the average value of the generator potential, both of which can be attributed to noise-induced resets of the generator potential mediated by the integrate-and-fire mechanism. A quantitative theory of noise adaptation in stochastic integrate-and-fire neurons is developed. It is shown that integrate-and-fire neurons, on average, produce transient spiking activity whenever there is an increase in the level of their input noise. This transient noise response is either reduced or eliminated over time, depending on the parameters of the model neuron. Analytical methods are used to prove that nonleaky integrate-and-fire neurons totally adapt to any constant input noise level, in the sense that their asymptotic spiking rates are independent of the magnitude of their input noise. For leaky integrate-and-fire neurons, the long-run noise adaptation is not total, but the response to noise is partially eliminated. Expressions for the probability density function of the generator potential and the first two moments of the potential distribution are derived for the particular case of a nonleaky neuron driven by gaussian white noise of mean zero and constant variance. The functional significance of noise adaptation for the performance of networks comprising integrate-and-fire neurons is discussed.

  1. Searching for biomarkers of CDKL5 disorder: early-onset visual impairment in CDKL5 mutant mice.

    PubMed

    Mazziotti, Raffaele; Lupori, Leonardo; Sagona, Giulia; Gennaro, Mariangela; Della Sala, Grazia; Putignano, Elena; Pizzorusso, Tommaso

    2017-06-15

    CDKL5 disorder is a neurodevelopmental disorder still without a cure. Murine models of CDKL5 disorder have been recently generated raising the possibility of preclinical testing of treatments. However, unbiased, quantitative biomarkers of high translational value to monitor brain function are still missing. Moreover, the analysis of treatment is hindered by the challenge of repeatedly and non-invasively testing neuronal function. We analyzed the development of visual responses in a mouse model of CDKL5 disorder to introduce visually evoked responses as a quantitative method to assess cortical circuit function. Cortical visual responses were assessed in CDKL5 null male mice, heterozygous females, and their respective control wild-type littermates by repeated transcranial optical imaging from P27 until P32. No difference between wild-type and mutant mice was present at P25-P26 whereas defective responses appeared from P27-P28 both in heterozygous and homozygous CDKL5 mutant mice. These results were confirmed by visually evoked potentials (VEPs) recorded from the visual cortex of a different cohort. The previously imaged mice were also analyzed at P60-80 using VEPs, revealing a persistent reduction of response amplitude, reduced visual acuity and defective contrast function. The level of adult impairment was significantly correlated with the reduction in visual responses observed during development. Support vector machine showed that multi-dimensional visual assessment can be used to automatically classify mutant and wt mice with high reliability. Thus, monitoring visual responses represents a promising biomarker for preclinical and clinical studies on CDKL5 disorder. © The Author 2017. Published by Oxford University Press.

  2. Toll-Like Receptor-Mediated Free Radical Generation in Clonorchis sinensis Excretory-Secretory Product-Treated Cholangiocarcinoma Cells.

    PubMed

    Bahk, Young Yil; Pak, Jhang Ho

    2016-10-01

    Clonorchiasis, caused by direct contact with Clonorchis sinensis worms and their excretory-secretory products (ESPs), is associated with chronic inflammation, malignant changes in bile ducts, and even cholangiocarcinogenesis. Our previous report revealed that intracellular free radicals enzymatically generated by C. sinensis ESPs cause NF-κB-mediated inflammation in human cholangiocarcinoma cells (HuCCT1). Therefore, the present study was conducted to examine the role of upstream Toll-like receptors (TLRs) on the initial host innate immune responses to infection. We found that treatment of HuCCT1 cells with native ESPs induced changes in TLR mRNA levels in a time-dependent manner, concomitant with the generation of free radicals. ESP-mediated free radical generation was markedly attenuated by preincubation of the cells with TLR1-4-neutralizing antibodies, indicating that at least TLR1 through 4 participate in stimulation of the host innate immune responses. These findings indicate that free radicals triggered by ESPs are critically involved in TLR signal transduction. Continuous signaling by this pathway may function in initiating C. sinensis infection-associated inflammation cascades, a detrimental event leading to progression to more severe hepatobiliary diseases.

  3. Random number generation in bilingual Balinese and German students: preliminary findings from an exploratory cross-cultural study.

    PubMed

    Strenge, Hans; Lesmana, Cokorda Bagus Jaya; Suryani, Luh Ketut

    2009-08-01

    Verbal random number generation is a procedurally simple task to assess executive function and appears ideally suited for the use under diverse settings in cross-cultural research. The objective of this study was to examine ethnic group differences between young adults in Bali (Indonesia) and Kiel (Germany): 50 bilingual healthy students, 30 Balinese and 20 Germans, attempted to generate a random sequence of the digits 1 to 9. In Balinese participants, randomization was done in Balinese (native language L1) and Indonesian (first foreign language L2), in German subjects in the German (L1) and English (L2) languages. 10 of 30 Balinese (33%), but no Germans, were unable to inhibit habitual counting in more than half of the responses. The Balinese produced significantly more nonrandom responses than the Germans with higher rates of counting and significantly less occurrence of the digits 2 and 3 in L1 compared with L2. Repetition and cycling behavior did not differ between the four languages. The findings highlight the importance of taking into account culture-bound psychosocial factors for Balinese individuals when administering and interpreting a random number generation test.

  4. Schizotypal thinking and associative processing: a response commonality analysis of verbal fluency.

    PubMed Central

    Duchêne, A; Graves, R E; Brugger, P

    1998-01-01

    OBJECTIVE: To determine whether people with high scores for schizotypal thinking generate more uncommon words in a letter fluency task than people with low scores. DESIGN: Prospective study. SETTING: University psychology department. PATIENTS: Forty healthy, right-handed students. INTERVENTIONS: Students were administered the Magical Ideation (MI) Scale and a 2-minute letter fluency task in which they named as many nouns as possible beginning with "A" or "F," in any order. OUTCOME MEASURES: Total number of words produced and percentage of unique, rare and common words (as determined by the responses of the whole group); scores on MI scale. RESULTS: Participants with high scores (above the median) on the MI scale generated as many words as those who had low scores. People in both groups also generated a comparable number of unique words (named by only 1 person) and common words (named by 6 or more people). As hypothesized, people with high scores on the MI scale generated more rare words (named by fewer than 6 people) than those with low scores. CONCLUSIONS: These findings support the view of a disinhibition of semantic network functioning as the neuropsychological basis of creative thought, magical ideation and thought disorder. PMID:9505061

  5. Electrophysiological Evidence for the Sources of the Masking Level Difference.

    PubMed

    Fowler, Cynthia G

    2017-08-16

    The purpose of this review article is to review evidence from auditory evoked potential studies to describe the contributions of the auditory brainstem and cortex to the generation of the masking level difference (MLD). A literature review was performed, focusing on the auditory brainstem, middle, and late latency responses used in protocols similar to those used to generate the behavioral MLD. Temporal coding of the signals necessary for generating the MLD occurs in the auditory periphery and brainstem. Brainstem disorders up to wave III of the auditory brainstem response (ABR) can disrupt the MLD. The full MLD requires input to the generators of the auditory late latency potentials to produce all characteristics of the MLD; these characteristics include threshold differences for various binaural signal and noise conditions. Studies using central auditory lesions are beginning to identify the cortical effects on the MLD. The MLD requires auditory processing from the periphery to cortical areas. A healthy auditory periphery and brainstem codes temporal synchrony, which is essential for the ABR. Threshold differences require engaging cortical function beyond the primary auditory cortex. More studies using cortical lesions and evoked potentials or imaging should clarify the specific cortical areas involved in the MLD.

  6. Oxidative stress and vascular inflammation in aging.

    PubMed

    El Assar, Mariam; Angulo, Javier; Rodríguez-Mañas, Leocadio

    2013-12-01

    Vascular aging, a determinant factor for cardiovascular disease and health status in the elderly, is now viewed as a modifiable risk factor. Impaired endothelial vasodilation is a early hallmark of arterial aging that precedes the clinical manifestations of vascular dysfunction, the first step to cardiovascular disease and influencing vascular outcomes in the elderly. Accordingly, the preservation of endothelial function is thought to be an essential determinant of healthy aging. With special attention on the effects of aging on the endothelial function, this review is focused on the two main mechanisms of aging-related endothelial dysfunction: oxidative stress and inflammation. Aging vasculature generates an excess of the reactive oxygen species (ROS), superoxide and hydrogen peroxide, that compromise the vasodilatory activity of nitric oxide (NO) and facilitate the formation of the deleterious radical, peroxynitrite. Main sources of ROS are mitochondrial respiratory chain and NADPH oxidases, although NOS uncoupling could also account for ROS generation. In addition, reduced antioxidant response mediated by erythroid-2-related factor-2 (Nrf2) and downregulation of mitochondrial manganese superoxide dismutase (SOD2) contributes to the establishment of chronic oxidative stress in aged vessels. This is accompanied by a chronic low-grade inflammatory phenotype that participates in defective endothelial vasodilation. The redox-sensitive transcription factor, nuclear factor-κB (NF-κB), is upregulated in vascular cells from old subjects and drives a proinflammatory shift that feedbacks oxidative stress. This chronic NF-κB activation is contributed by increased angiotensin-II signaling and downregulated sirtuins and precludes adequate cellular response to acute ROS generation. Interventions targeted to recover endogenous antioxidant capacity and cellular stress response rather than exogenous antioxidants could reverse oxidative stress-inflammation vicious cycle in vascular aging. Lifestyle attitudes such as caloric restriction and exercise training appear as effective ways to overcome defective antioxidant response and inflammation, favoring successful vascular aging and decreasing the risk for cardiovascular disease. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Alternative Splicing Control of Abiotic Stress Responses.

    PubMed

    Laloum, Tom; Martín, Guiomar; Duque, Paula

    2018-02-01

    Alternative splicing, which generates multiple transcripts from the same gene, is an important modulator of gene expression that can increase proteome diversity and regulate mRNA levels. In plants, this post-transcriptional mechanism is markedly induced in response to environmental stress, and recent studies have identified alternative splicing events that allow rapid adjustment of the abundance and function of key stress-response components. In agreement, plant mutants defective in splicing factors are severely impaired in their response to abiotic stress. Notably, mounting evidence indicates that alternative splicing regulates stress responses largely by targeting the abscisic acid (ABA) pathway. We review here current understanding of post-transcriptional control of plant stress tolerance via alternative splicing and discuss research challenges for the near future. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. TCR revision generates functional CD4+ T cells1

    PubMed Central

    Hale, J. Scott; Wubeshet, Maramawit; Fink, Pamela J.

    2010-01-01

    CD4+Vβ5+ peripheral T cells in B6 mice respond to encounter with a peripherally-expressed endogenous superantigen by undergoing either deletion or TCR revision. In this latter process, cells lose surface Vβ5 expression and undergo RAG-dependent rearrangement of endogenous TCRβ genes, driving surface expression of novel TCRs. While post-revision CD4+Vβ5−TCRβ+ T cells accumulate with age in Vβ5 transgenic mice and bear a diverse TCR Vβ repertoire, it is unknown whether they respond to homeostatic and antigenic stimuli, and thus may benefit the host. We now demonstrate that post-revision cells are functional. These cells have a high rate of steady-state homeostatic proliferation in situ and they undergo extensive MHC class II-dependent lymphopenia-induced proliferation. Importantly, post-revision cells do not proliferate in response to the tolerizing superantigen, implicating TCR revision as a mechanism of tolerance induction and demonstrating that TCR-dependent activation of post-revision cells is not driven by the transgene-encoded receptor. Post-revision cells proliferate extensively to commensal bacterial Ags and can generate I-Ab-restricted responses to Ag by producing IFNγ following Listeria monocytogenes challenge. These data show that rescued post-revision T cells are responsive to homeostatic signals and recognize self and foreign peptides in the context of self MHC, and are thus useful to the host. PMID:20971922

  9. TCR revision generates functional CD4+ T cells.

    PubMed

    Hale, J Scott; Wubeshet, Maramawit; Fink, Pamela J

    2010-12-01

    CD4(+)Vβ5(+) peripheral T cells in C57BL/6 mice respond to encounter with a peripherally expressed endogenous superantigen by undergoing either deletion or TCR revision. In this latter process, cells lose surface Vβ5 expression and undergo RAG-dependent rearrangement of endogenous TCRβ genes, driving surface expression of novel TCRs. Although postrevision CD4(+)Vβ5(-)TCRβ(+) T cells accumulate with age in Vβ5 transgenic mice and bear a diverse TCR Vβ repertoire, it is unknown whether they respond to homeostatic and antigenic stimuli and thus may benefit the host. We demonstrate in this study that postrevision cells are functional. These cells have a high rate of steady-state homeostatic proliferation in situ, and they undergo extensive MHC class II-dependent lymphopenia-induced proliferation. Importantly, postrevision cells do not proliferate in response to the tolerizing superantigen, implicating TCR revision as a mechanism of tolerance induction and demonstrating that TCR-dependent activation of postrevision cells is not driven by the transgene-encoded receptor. Postrevision cells proliferate extensively to commensal bacterial Ags and can generate I-A(b)-restricted responses to Ag by producing IFN-γ following Listeria monocytogenes challenge. These data show that rescued postrevision T cells are responsive to homeostatic signals and recognize self- and foreign peptides in the context of self-MHC and are thus useful to the host.

  10. Social re-orientation and brain development: An expanded and updated view.

    PubMed

    Nelson, Eric E; Jarcho, Johanna M; Guyer, Amanda E

    2016-02-01

    Social development has been the focus of a great deal of neuroscience based research over the past decade. In this review, we focus on providing a framework for understanding how changes in facets of social development may correspond with changes in brain function. We argue that (1) distinct phases of social behavior emerge based on whether the organizing social force is the mother, peer play, peer integration, or romantic intimacy; (2) each phase is marked by a high degree of affect-driven motivation that elicits a distinct response in subcortical structures; (3) activity generated by these structures interacts with circuits in prefrontal cortex that guide executive functions, and occipital and temporal lobe circuits, which generate specific sensory and perceptual social representations. We propose that the direction, magnitude and duration of interaction among these affective, executive, and perceptual systems may relate to distinct sensitive periods across development that contribute to establishing long-term patterns of brain function and behavior. Published by Elsevier Ltd.

  11. Functional tooth restoration by next-generation bio-hybrid implant as a bio-hybrid artificial organ replacement therapy

    PubMed Central

    Oshima, Masamitsu; Inoue, Kaoru; Nakajima, Kei; Tachikawa, Tetsuhiko; Yamazaki, Hiromichi; Isobe, Tomohide; Sugawara, Ayaka; Ogawa, Miho; Tanaka, Chie; Saito, Masahiro; Kasugai, Shohei; Takano-Yamamoto, Teruko; Inoue, Takashi; Tezuka, Katsunari; Kuboki, Takuo; Yamaguchi, Akira; Tsuji, Takashi

    2014-01-01

    Bio-hybrid artificial organs are an attractive concept to restore organ function through precise biological cooperation with surrounding tissues in vivo. However, in bio-hybrid artificial organs, an artificial organ with fibrous connective tissues, including muscles, tendons and ligaments, has not been developed. Here, we have enveloped with embryonic dental follicle tissue around a HA-coated dental implant, and transplanted into the lower first molar region of a murine tooth-loss model. We successfully developed a novel fibrous connected tooth implant using a HA-coated dental implant and dental follicle stem cells as a bio-hybrid organ. This bio-hybrid implant restored physiological functions, including bone remodelling, regeneration of severe bone-defect and responsiveness to noxious stimuli, through regeneration with periodontal tissues, such as periodontal ligament and cementum. Thus, this study represents the potential for a next-generation bio-hybrid implant for tooth loss as a future bio-hybrid artificial organ replacement therapy. PMID:25116435

  12. Gelatin promotes murine fibrosarcoma L929 cell detachment and protects the cells from TNFα-induced cytotoxicity.

    PubMed

    Wang, Hong-Ju; Li, Meng-Qi; Liu, Wei; Yao, Guo-Dong; Xia, Ming-Yu; Hayashi, Toshihiko; Fujisaki, Hitomi; Hattori, Shunji; Tashiro, Shin-Ichi; Onodera, Satoshi; Ikejima, Takashi

    2016-07-01

    Gelatin has been considered to exist as intermediate substance of collagen catabolism in tissue remodeling or under inflammatory conditions. We have initiated the study on possible biological functions of gelatin that can exist temporally and locally under the conditions of remodeling and inflammation Materials and methods: To this purpose, we investigated cell proliferation and survival on gelatin-coated dishes and the response to tumor necrosis factor α (TNFα)-induced cytotoxicity in L929 cells. Autophagy level, ATP level, and ROS generation are examined. L929 cells detached from the gelatin-coated dishes and formed multicellular aggregates. TNFα-induced cytotoxicity in L929 cells was inhibited by gelatin-coating culture. The cells on gelatin-coated dishes showed reduced cellular ATP levels and increased adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) phosphorylation, leading to increased ROS generation and autophagy. This study showed that gelatin-coated culture protected L929 cells from TNFα-induced cytotoxicity and suggested for a possible pathophysiological function of gelatin in regulating cellular functions.

  13. Parallel Fixed Point Implementation of a Radial Basis Function Network in an FPGA

    PubMed Central

    de Souza, Alisson C. D.; Fernandes, Marcelo A. C.

    2014-01-01

    This paper proposes a parallel fixed point radial basis function (RBF) artificial neural network (ANN), implemented in a field programmable gate array (FPGA) trained online with a least mean square (LMS) algorithm. The processing time and occupied area were analyzed for various fixed point formats. The problems of precision of the ANN response for nonlinear classification using the XOR gate and interpolation using the sine function were also analyzed in a hardware implementation. The entire project was developed using the System Generator platform (Xilinx), with a Virtex-6 xc6vcx240t-1ff1156 as the target FPGA. PMID:25268918

  14. The cross-tissue metabolic response of abalone (Haliotis midae) to functional hypoxia.

    PubMed

    Venter, Leonie; Loots, Du Toit; Mienie, Lodewyk J; Jansen van Rensburg, Peet J; Mason, Shayne; Vosloo, Andre; Lindeque, Jeremie Z

    2018-03-23

    Functional hypoxia is a stress condition caused by the abalone itself as a result of increased muscle activity, which generally necessitates the employment of anaerobic metabolism if the activity is sustained for prolonged periods. With that being said, abalone are highly reliant on anaerobic metabolism to provide partial compensation for energy production during oxygen-deprived episodes. However, current knowledge on the holistic metabolic response for energy metabolism during functional hypoxia, and the contribution of different metabolic pathways and various abalone tissues towards the overall accumulation of anaerobic end-products in abalone are scarce. Metabolomics analysis of adductor muscle, foot muscle, left gill, right gill, haemolymph and epipodial tissue samples indicated that South African abalone ( Haliotis midae) subjected to functional hypoxia utilises predominantly anaerobic metabolism, and depends on all of the main metabolite classes (proteins, carbohydrates and lipids) for energy supply. Functional hypoxia caused increased levels of anaerobic end-products: lactate, alanopine, tauropine, succinate and alanine. Also, elevation in arginine levels was detected, confirming that abalone use phosphoarginine to generate energy during functional hypoxia. Different tissues showed varied metabolic responses to hypoxia, with functional hypoxia showing excessive changes in the adductor muscle and gills. From this metabolomics investigation, it becomes evident that abalone are metabolically able to produce sufficient amounts of energy when functional hypoxia is experienced. Also, tissue interplay enables the adjustment of H. midae energy requirements as their metabolism shifts from aerobic to anaerobic respiration during functional hypoxia.This article has an associated First Person interview with the first author of the paper. © 2018. Published by The Company of Biologists Ltd.

  15. The cross-tissue metabolic response of abalone (Haliotis midae) to functional hypoxia

    PubMed Central

    Venter, Leonie; Loots, Du Toit; Mienie, Lodewyk J.; Jansen van Rensburg, Peet J.; Mason, Shayne; Vosloo, Andre

    2018-01-01

    ABSTRACT Functional hypoxia is a stress condition caused by the abalone itself as a result of increased muscle activity, which generally necessitates the employment of anaerobic metabolism if the activity is sustained for prolonged periods. With that being said, abalone are highly reliant on anaerobic metabolism to provide partial compensation for energy production during oxygen-deprived episodes. However, current knowledge on the holistic metabolic response for energy metabolism during functional hypoxia, and the contribution of different metabolic pathways and various abalone tissues towards the overall accumulation of anaerobic end-products in abalone are scarce. Metabolomics analysis of adductor muscle, foot muscle, left gill, right gill, haemolymph and epipodial tissue samples indicated that South African abalone (Haliotis midae) subjected to functional hypoxia utilises predominantly anaerobic metabolism, and depends on all of the main metabolite classes (proteins, carbohydrates and lipids) for energy supply. Functional hypoxia caused increased levels of anaerobic end-products: lactate, alanopine, tauropine, succinate and alanine. Also, elevation in arginine levels was detected, confirming that abalone use phosphoarginine to generate energy during functional hypoxia. Different tissues showed varied metabolic responses to hypoxia, with functional hypoxia showing excessive changes in the adductor muscle and gills. From this metabolomics investigation, it becomes evident that abalone are metabolically able to produce sufficient amounts of energy when functional hypoxia is experienced. Also, tissue interplay enables the adjustment of H. midae energy requirements as their metabolism shifts from aerobic to anaerobic respiration during functional hypoxia. This article has an associated First Person interview with the first author of the paper. PMID:29572259

  16. Application of genetic algorithms to tuning fuzzy control systems

    NASA Technical Reports Server (NTRS)

    Espy, Todd; Vombrack, Endre; Aldridge, Jack

    1993-01-01

    Real number genetic algorithms (GA) were applied for tuning fuzzy membership functions of three controller applications. The first application is our 'Fuzzy Pong' demonstration, a controller that controls a very responsive system. The performance of the automatically tuned membership functions exceeded that of manually tuned membership functions both when the algorithm started with randomly generated functions and with the best manually-tuned functions. The second GA tunes input membership functions to achieve a specified control surface. The third application is a practical one, a motor controller for a printed circuit manufacturing system. The GA alters the positions and overlaps of the membership functions to accomplish the tuning. The applications, the real number GA approach, the fitness function and population parameters, and the performance improvements achieved are discussed. Directions for further research in tuning input and output membership functions and in tuning fuzzy rules are described.

  17. The pharmacology of second-generation chimeric antigen receptors.

    PubMed

    van der Stegen, Sjoukje J C; Hamieh, Mohamad; Sadelain, Michel

    2015-07-01

    Second-generation chimeric antigen receptors (CARs) retarget and reprogramme T cells to augment their antitumour efficacy. The combined activating and co-stimulatory domains incorporated in these CARs critically determine the function, differentiation, metabolism and persistence of engineered T cells. CD19-targeted CARs that incorporate CD28 or 4-1BB signalling domains are the best known to date. Both have shown remarkable complete remission rates in patients with refractory B cell malignancies. Recent data indicate that CD28-based CARs direct a brisk proliferative response and boost effector functions, whereas 4-1BB-based CARs induce a more progressive T cell accumulation that may compensate for less immediate potency. These distinct kinetic features can be exploited to further develop CAR-based T cell therapies for a variety of cancers. A new field of immunopharmacology is emerging.

  18. Construction of CRISPR Libraries for Functional Screening.

    PubMed

    Carstens, Carsten P; Felts, Katherine A; Johns, Sarah E

    2018-01-01

    Identification of gene function has been aided by the ability to generate targeted gene knockouts or transcriptional repression using the CRISPR/CAS9 system. Using pooled libraries of guide RNA expression vectors that direct CAS9 to a specific genomic site allows identification of genes that are either enriched or depleted in response to a selection scheme, thus linking the affected gene to the chosen phenotype. The quality of the data generated by the screening is dependent on the quality of the guide RNA delivery library with regards to error rates and especially evenness of distribution of the guides. Here, we describe a method for constructing complex plasmid libraries based on pooled designed oligomers with high representation and tight distributions. The procedure allows construction of plasmid libraries of >60,000 members with a 95th/5th percentile ratio of less than 3.5.

  19. The Functional Measurement Experiment Builder suite: two Java-based programs to generate and run functional measurement experiments.

    PubMed

    Mairesse, Olivier; Hofmans, Joeri; Theuns, Peter

    2008-05-01

    We propose a free, easy-to-use computer program that does not requires prior knowledge of computer programming to generate and run experiments using textual or pictorial stimuli. Although the FM Experiment Builder suite was initially programmed for building and conducting FM experiments, it can also be applied for non-FM experiments that necessitate randomized, single, or multifactorial designs. The program is highly configurable, allowing multilingual use and a wide range of different response formats. The outputs of the experiments are Microsoft Excel compatible .xls files that allow easy copy-paste of the results into Weiss's FM CalSTAT program (2006) or any other statistical package. Its Java-based structure is compatible with both Windows and Macintosh operating systems, and its compactness (< 1 MB) makes it easily distributable over the Internet.

  20. In vitro effects of 4-hydroperoxycyclophosphamide on human immunoregulatory T subset function. I. Selective effects on lymphocyte function in T-B cell collaboration.

    PubMed

    Ozer, H; Cowens, J W; Colvin, M; Nussbaum-Blumenson, A; Sheedy, D

    1982-01-01

    The alkylating agent cyclophosphamide may suppress or enhance immune responses in vivo but is inactive in vitro unless metabolized by microsomal enzyme activation. 4-hydroperoxycyclophosphamide (4-HC) is a synthetic compound that is spontaneously converted in aqueous solution to the active metabolites. In this report, we examined the in vitro sensitivity of functional human T cell subsets to 4-HC in a polyclonal B cell differentiation assay and in the generation of mitogen-induced suppressor cells for effector B cell function. Con A-induced T suppression of B cell differentiation is completely abrogated by a 1-h pretreatment of T cells at very low concentrations of between 10(-2) and 20 nmol/ml, whereas inducer T cell function is sensitive only to concentrations in greater than 40 nmol/ml. The effects of 4-HC on suppressor T cells appear to occur at concentrations that do not result in DNA cross-linking or decreased blastogenesis. Con A-induced T suppressors are generated from within the OKT4+, OKT8- subset and are sensitive to low-dose 4-HC only before activation, whereas differentiated suppressor cells are resistant to concentrations in greater than 80 nmol/ml. Low-dose 4-HC pretreatment of the B cell population results in abrogation of immunoglobulin secretion when treated B cells are cocultured with unfractionated T cells, however, this effect is completely reversible if pretreated B cells are cocultured with T cells devoid of suppressor activity. These results demonstrate that human presuppressor cells for B-effector function differentiate in response to Con A from the OKT4+, OKT8- subset and are exquisitely sensitive to low concentrations of CYP whereas mature suppressor and inducer functions are resistant to all but very high concentrations in vitro. The differential sensitivity of functional T and B cell subsets to 4-HC in vitro can be a very useful probe in dissecting immunoregulatory interactions with man.

  1. Nanoparticle heterodimers: The role of size and interparticle gap distance on the optical response

    NASA Astrophysics Data System (ADS)

    Mokkath, Junais Habeeb

    2018-05-01

    Composite plasmonic nanostructures with controlled size, shape and relative arrangement is a subject of significant current research interest. Much of this is stimulated by the prospects by generating enormous near-field enhancements of the surface and interparticle gap regions for potential applications in surface-enhanced spectroscopies. In this manuscript, using time-dependent density functional theory (TDDFT) calculations, we investigate how the optical response in size matched homodimers and size mismatched heterodimers composed of Aluminum modify while varying the size and interparticle gap distances in the sub-nanometer range. Both systems show interesting optical response evolution. In particular, the size mismatched heterodimers show even more complex optical response evolution due to a symmetry-breaking in the system.

  2. Cognitive functioning and social problem-solving skills in schizophrenia.

    PubMed

    Hatashita-Wong, Michi; Smith, Thomas E; Silverstein, Steven M; Hull, James W; Willson, Deborah F

    2002-05-01

    This study examined the relationships between symptoms, cognitive functioning, and social skill deficits in schizophrenia. Few studies have incorporated measures of cognitive functioning and symptoms in predictive models for social problem solving. For our study, 44 participants were recruited from consecutive outpatient admissions. Neuropsychological tests were given to assess cognitive function, and social problem solving was assessed using structured vignettes designed to evoke the participant's ability to generate, evaluate, and apply solutions to social problems. A sequential model-fitting method of analysis was used to incorporate social problem solving, symptom presentation, and cognitive impairment into linear regression models. Predictor variables were drawn from demographic, cognitive, and symptom domains. Because this method of analysis was exploratory and not intended as hierarchical modelling, no a priori hypotheses were proposed. Participants with higher scores on tests of cognitive flexibility were better able to generate accurate, appropriate, and relevant responses to the social problem-solving vignettes. The results suggest that cognitive flexibility is a potentially important mediating factor in social problem-solving competence. While other factors are related to social problem-solving skill, this study supports the importance of cognition and understanding how it relates to the complex and multifaceted nature of social functioning.

  3. A Mitochondrial Superoxide Signal Triggers Increased Longevity in Caenorhabditis elegans

    PubMed Central

    Yang, Wen; Hekimi, Siegfried

    2010-01-01

    The nuo-6 and isp-1 genes of C. elegans encode, respectively, subunits of complex I and III of the mitochondrial respiratory chain. Partial loss-of-function mutations in these genes decrease electron transport and greatly increase the longevity of C. elegans by a mechanism that is distinct from that induced by reducing their level of expression by RNAi. Electron transport is a major source of the superoxide anion (O⋅ –), which in turn generates several types of toxic reactive oxygen species (ROS), and aging is accompanied by increased oxidative stress, which is an imbalance between the generation and detoxification of ROS. These observations have suggested that the longevity of such mitochondrial mutants might result from a reduction in ROS generation, which would be consistent with the mitochondrial oxidative stress theory of aging. It is difficult to measure ROS directly in living animals, and this has held back progress in determining their function in aging. Here we have adapted a technique of flow cytometry to directly measure ROS levels in isolated mitochondria to show that the generation of superoxide is elevated in the nuo-6 and isp-1 mitochondrial mutants, although overall ROS levels are not, and oxidative stress is low. Furthermore, we show that this elevation is necessary and sufficient to increase longevity, as it is abolished by the antioxidants NAC and vitamin C, and phenocopied by mild treatment with the prooxidant paraquat. Furthermore, the absence of effect of NAC and the additivity of the effect of paraquat on a variety of long- and short-lived mutants suggest that the pathway triggered by mitochondrial superoxide is distinct from previously studied mechanisms, including insulin signaling, dietary restriction, ubiquinone deficiency, the hypoxic response, and hormesis. These findings are not consistent with the mitochondrial oxidative stress theory of aging. Instead they show that increased superoxide generation acts as a signal in young mutant animals to trigger changes of gene expression that prevent or attenuate the effects of subsequent aging. We propose that superoxide is generated as a protective signal in response to molecular damage sustained during wild-type aging as well. This model provides a new explanation for the well-documented correlation between ROS and the aged phenotype as a gradual increase of molecular damage during aging would trigger a gradually stronger ROS response. PMID:21151885

  4. TRPC Channel Structure and Properties.

    PubMed

    Feng, Shengjie

    2017-01-01

    TRPC channels are the first identified members in the TRP family. They function as either homo- or heterotetramers regulating intracellular Ca 2+ concentration in response to numerous physiological or pathological stimuli. TRPC channels are nonselective cation channels permeable to Ca 2+ . The properties and the functional domains of TRPC channels have been identified by electrophysiological and biochemical methods. However, due to the large size, instability, and flexibility of their complexes, the structures of the members in TRPC family remain unrevealed. More efforts should be made on structure analysis and generating good tools, including specific antibodies, agonist, and antagonist.

  5. Development of CMOS Active Pixel Image Sensors for Low Cost Commercial Applications

    NASA Technical Reports Server (NTRS)

    Gee, R.; Kemeny, S.; Kim, Q.; Mendis, S.; Nakamura, J.; Nixon, R.; Ortiz, M.; Pain, B.; Staller, C.; Zhou, Z; hide

    1994-01-01

    JPL, under sponsorship from the NASA Office of Advanced Concepts and Technology, has been developing a second-generation solid-state image sensor technology. Charge-coupled devices (CCD) are a well-established first generation image sensor technology. For both commercial and NASA applications, CCDs have numerous shortcomings. In response, the active pixel sensor (APS) technology has been under research. The major advantages of APS technology are the ability to integrate on-chip timing, control, signal-processing and analog-to-digital converter functions, reduced sensitivity to radiation effects, low power operation, and random access readout.

  6. Making sense out of spinal cord somatosensory development

    PubMed Central

    Seal, Rebecca P.

    2016-01-01

    The spinal cord integrates and relays somatosensory input, leading to complex motor responses. Research over the past couple of decades has identified transcription factor networks that function during development to define and instruct the generation of diverse neuronal populations within the spinal cord. A number of studies have now started to connect these developmentally defined populations with their roles in somatosensory circuits. Here, we review our current understanding of how neuronal diversity in the dorsal spinal cord is generated and we discuss the logic underlying how these neurons form the basis of somatosensory circuits. PMID:27702783

  7. A Recombinant Antibody with the Antigen-Specific, Major Histocompatibility Complex-Restricted Specificity of T Cells

    NASA Astrophysics Data System (ADS)

    Andersen, Peter S.; Stryhn, Anette; Hansen, Bjarke E.; Fugger, Lars; Engberg, Jan; Buus, Soren

    1996-03-01

    Specific recognition of peptide/major histocompatibility complex (MHC) molecule complexes by the T-cell receptor is a key reaction in the specific immune response. Antibodies against peptide/MHC complexes would therefore be valuable tools in studying MHC function and T-cell recognition and might lead to novel approaches in immunotherapy. However, it has proven difficult to generate antibodies with the specificity of T cells by conventional hybridoma techniques. Here we report that the phage display technology is a feasible alternative to generate antibodies recognizing specific, predetermined peptide/MHC complexes.

  8. Convexity of Energy-Like Functions: Theoretical Results and Applications to Power System Operations

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Dvijotham, Krishnamurthy; Low, Steven; Chertkov, Michael

    2015-01-12

    Power systems are undergoing unprecedented transformations with increased adoption of renewables and distributed generation, as well as the adoption of demand response programs. All of these changes, while making the grid more responsive and potentially more efficient, pose significant challenges for power systems operators. Conventional operational paradigms are no longer sufficient as the power system may no longer have big dispatchable generators with sufficient positive and negative reserves. This increases the need for tools and algorithms that can efficiently predict safe regions of operation of the power system. In this paper, we study energy functions as a tool to designmore » algorithms for various operational problems in power systems. These have a long history in power systems and have been primarily applied to transient stability problems. In this paper, we take a new look at power systems, focusing on an aspect that has previously received little attention: Convexity. We characterize the domain of voltage magnitudes and phases within which the energy function is convex in these variables. We show that this corresponds naturally with standard operational constraints imposed in power systems. We show that power of equations can be solved using this approach, as long as the solution lies within the convexity domain. We outline various desirable properties of solutions in the convexity domain and present simple numerical illustrations supporting our results.« less

  9. The mitochondrial alternative oxidase Aox1 is needed to cope with respiratory stress but dispensable for pathogenic development in Ustilago maydis

    PubMed Central

    Piñón-Zárate, Gabriela; Matus-Ortega, Genaro; Guerra, Guadalupe; Feldbrügge, Michael; Pardo, Juan Pablo

    2017-01-01

    The mitochondrial alternative oxidase is an important enzyme that allows respiratory activity and the functioning of the Krebs cycle upon disturbance of the respiration chain. It works as a security valve in transferring excessive electrons to oxygen, thereby preventing potential damage by the generation of harmful radicals. A clear biological function, besides the stress response, has so far convincingly only been shown for plants that use the alternative oxidase to generate heat to distribute volatiles. In fungi it was described that the alternative oxidase is needed for pathogenicity. Here, we investigate expression and function of the alternative oxidase at different stages of the life cycle of the corn pathogen Ustilago maydis (Aox1). Interestingly, expression of Aox1 is specifically induced during the stationary phase suggesting a role at high cell density when nutrients become limiting. Studying deletion strains as well as overexpressing strains revealed that Aox1 is dispensable for normal growth, for cell morphology, for response to temperature stress as well as for filamentous growth and plant pathogenicity. However, during conditions eliciting respiratory stress yeast-like growth as well as hyphal growth is strongly affected. We conclude that Aox1 is dispensable for the normal biology of the fungus but specifically needed to cope with respiratory stress. PMID:28273139

  10. Human cell toxicogenomic analysis linking reactive oxygen species to the toxicity of monohaloacetic acid drinking water disinfection byproducts.

    PubMed

    Pals, Justin; Attene-Ramos, Matias S; Xia, Menghang; Wagner, Elizabeth D; Plewa, Michael J

    2013-01-01

    Chronic exposure to drinking water disinfection byproducts has been linked to adverse health risks. The monohaloacetic acids (monoHAAs) are generated as byproducts during the disinfection of drinking water and are cytotoxic, genotoxic, mutagenic, and teratogenic. Iodoacetic acid toxicity was mitigated by antioxidants, suggesting the involvement of oxidative stress. Other monoHAAs may share a similar mode of action. Each monoHAA generated a significant concentration-response increase in the expression of a β-lactamase reporter under the control of the antioxidant response element (ARE). The monoHAAs generated oxidative stress with a rank order of iodoacetic acid (IAA) > bromoacetic acid (BAA) ≫ chloroacetic acid (CAA); this rank order was observed with other toxicological end points. Toxicogenomic analysis was conducted with a nontransformed human intestinal epithelial cell line (FHs 74 Int). Exposure to the monoHAAs altered the transcription levels of multiple oxidative stress responsive genes, indicating that each exposure generated oxidative stress. The transcriptome profiles showed an increase in thioredoxin reductase 1 (TXNRD1) and sulfiredoxin (SRXN1), suggesting peroxiredoxin proteins had been oxidized during monoHAA exposures. Three possible sources of reactive oxygen species were identified, the hypohalous acid generating peroxidase enzymes lactoperoxidase (LPO) and myeloperoxidase (MPO), nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxidase 5 (NOX5), and PTGS2 (COX-2) mediated arachidonic acid metabolism. Each monoHAA exposure caused an increase in COX-2 mRNA levels. These data provide a functional association between monoHAA exposure and adverse health outcomes such as oxidative stress, inflammation, and cancer.

  11. Characterisation of the immune response to type I collagen in scleroderma

    PubMed Central

    Warrington, Kenneth J; Nair, Usha; Carbone, Laura D; Kang, Andrew H; Postlethwaite, Arnold E

    2006-01-01

    This study was conducted to examine the frequency, phenotype, and functional profile of T lymphocytes that proliferate in response to type I collagen (CI) in patients with scleroderma (SSc). Peripheral blood mononuclear cells (PBMCs) from SSc patients, healthy controls, and rheumatoid arthritis disease controls were labeled with carboxy-fluorescein diacetate, succinimidyl ester (CFSE), cultured with or without antigen (bovine CI) for 14 days, and analysed by flow cytometry. Surface markers of proliferating cells were identified by multi-color flow cytometry. T-cell lines were derived after sorting for proliferating T cells (CFSElow). Cytokine expression in CI-responsive T cells was detected by intracellular staining/flow cytometry and by multiplex cytokine bead assay (Bio-Plex). A T-cell proliferative response to CI was detected in 8 of 25 (32%) SSc patients, but was infrequent in healthy or disease controls (3.6%; p = 0.009). The proliferating T cells expressed a CD4+, activated (CD25+), memory (CD45RO+) phenotype. Proliferation to CI did not correlate with disease duration or extent of skin involvement. T-cell lines were generated using in vitro CI stimulation to study the functional profile of these cells. Following activation of CI-reactive T cells, we detected intracellular interferon (IFN)-γ but not interleukin (IL)-4 by flow cytometry. Supernatants from the T-cell lines generated in vitro contained IL-2, IFN-γ, GM-CSF (granulocyte macrophage-colony-stimulating factor), and tumour necrosis factor-α, but little or no IL-4 and IL-10, suggesting that CI-responsive T cells express a predominantly Th1 cytokine pattern. In conclusion, circulating memory CD4 T cells that proliferate to CI are present in a subset of patients with SSc, but are infrequent in healthy or disease controls. PMID:16879746

  12. Transcriptomic Responses to Salinity Stress in the Pacific Oyster Crassostrea gigas

    PubMed Central

    Zhao, Xuelin; Yu, Hong; Kong, Lingfeng; Li, Qi

    2012-01-01

    Background Low salinity is one of the main factors limiting the distribution and survival of marine species. As a euryhaline species, the Pacific oyster Crassostrea gigas is considered to be tolerant to relative low salinity. The genes that regulate C. gigas responses to osmotic stress were monitored using the next-generation sequencing of whole transcriptome with samples taken from gills. By RNAseq technology, transcript catalogs of up- and down-regulated genes were generated from the oysters exposed to low and optimal salinity seawater. Methodology/Principal Findings Through Illumina sequencing, we reported 1665 up-regulated transcripts and 1815 down-regulated transcripts. A total of 45771 protein-coding contigs were identified from two groups based on sequence similarities with known proteins. As determined by GO annotation and KEGG pathway mapping, functional annotation of the genes recovered diverse biological functions and processes. The genes that changed expression significantly were highly represented in cellular process and regulation of biological process, intracellular and cell, binding and protein binding according to GO annotation. The results highlighted genes related to osmoregulation, signaling and interactions of osmotic stress response, anti-apoptotic reactions as well as immune response, cell adhesion and communication, cytoskeleton and cell cycle. Conclusions/Significance Through more than 1.5 million sequence reads and the expression data of the two libraries, the study provided some useful insights into signal transduction pathways in oysters and offered a number of candidate genes as potential markers of tolerance to hypoosmotic stress for oysters. In addition, the characterization of C. gigas transcriptome will not only provide a better understanding of the molecular mechanisms about the response to osmotic stress of the oysters, but also facilitate research into biological processes to find underlying physiological adaptations to hypoosmotic shock for marine invertebrates. PMID:23029449

  13. Unravelling Responses for the Canadian National Seismic Network

    NASA Astrophysics Data System (ADS)

    Mulder, T. L.

    2009-12-01

    There are a number of attendant difficulties any network must deal with that range from defining the transfer function to instrument naming conventions to choices of final local file format representation. These choices ultimately result in the ease of conversion to other data formats and therefore directly impact useability. In particular, the ease of data exhange and use of established software that is dependent on standard data types is impacted. This becomes particularly critical with large (terabyte) dataset processing and when integrating external datasets into analysis procedures. Transfer functions, often referred to as instrument responses, are a key component in describing instrumentation. The transfer function describes the complete response of the seismic system. The seismic system is designed to be a linear system that can be decomposed into discrete components. Analogue or digital convolution can be represented as multiplication in the frequency domain. The two basic elements of a seismic system are the sensor and datalogger. The analogue sensor can be represented mathmatically as poles and zeroes. The datalogger can be further broken down into its discrete analogue and digital components: the preamp, A/D converter, and fir filters. The Canadian seismic network (CNSN) digitizers have an additional complication. To save telemetry band-width, the 32 bit signal from the digitizer has a transmission gain removed. The transmission gain (txgain) represents the number of the least significant bits truncated from the sample (2^txgain) after which the data is compressed and transmitted. While telemetry band-width is not the issue it was, now that many sites have ip connectivity, this user programmable transmission gain is still in use and can vary from station to station. The processes receiving the transmitted data do not restore the pre-transmission scaling, consequently the archived waveform files can vary in bit weight over time from station to station depending on the value of the transmission gain. Consequently the transmission gain must be factored into the transfer function. This presentation describes the process for generating the transfer function based on the constituent components discussed here. A matlab routine run on the database generates the transfer function plots for the network.

  14. Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo

    PubMed Central

    Najm, Fadi J.; Madhavan, Mayur; Zaremba, Anita; Shick, Elizabeth; Karl, Robert T.; Factor, Daniel C.; Miller, Tyler E.; Nevin, Zachary S.; Kantor, Christopher; Sargent, Alex; Quick, Kevin L.; Schlatzer, Daniela M.; Tang, Hong; Papoian, Ruben; Brimacombe, Kyle R.; Shen, Min; Boxer, Matthew B.; Jadhav, Ajit; Robinson, Andrew P.; Podojil, Joseph R.; Miller, Stephen D.; Miller, Robert H.; Tesar, Paul J.

    2015-01-01

    Multiple sclerosis (MS) involves an aberrant autoimmune response and progressive failure of remyelination in the central nervous system (CNS). Prevention of neural degeneration and subsequent disability requires remyelination through the generation of new oligodendrocytes, but current treatments exclusively target the immune system. Oligodendrocyte progenitor cells (OPCs) are stem cells in the CNS and the principal source of myelinating oligodendrocytes1. OPCs are abundant in demyelinated regions of MS patients, yet fail to differentiate, thereby representing a cellular target for pharmacological intervention2. To discover therapeutic compounds for enhancing myelination from endogenous OPCs, we screened a library of bioactive small molecules on mouse pluripotent epiblast stem cell (EpiSC)-derived OPCs3–5. We identified seven drugs that functioned at nanomolar doses to selectively enhance the generation of mature oligodendrocytes from OPCs in vitro. Two drugs, miconazole and clobetasol, were effective in promoting precocious myelination in organotypic cerebellar slice cultures, and in vivo in early postnatal mouse pups. Systemic delivery of each of the two drugs significantly increased the number of new oligodendrocytes and enhanced remyelination in a lysolecithin-induced mouse model of focal demyelination. Administering each of the two drugs at the peak of disease in the experimental autoimmune encephalomyelitis (EAE) mouse model of chronic progressive MS resulted in striking reversal of disease severity. Immune response assays showed that miconazole functioned directly as a remyelinating drug with no effect on the immune system, whereas clobetasol was a potent immunosuppressant as well as a remyelinating agent. Mechanistic studies showed that miconazole and clobetasol functioned in OPCs through mitogen-activated protein kinase (MAPK) and glucocorticoid receptor (GR) signaling, respectively. Furthermore, both drugs enhanced the generation of human oligodendrocytes from human OPCs in vitro. Collectively, our results provide a rationale for testing miconazole and clobetasol, or structurally-modified derivatives, to enhance remyelination in patients. PMID:25896324

  15. CO2/HCO3−- and Calcium-regulated Soluble Adenylyl Cyclase as a Physiological ATP Sensor*

    PubMed Central

    Zippin, Jonathan H.; Chen, Yanqiu; Straub, Susanne G.; Hess, Kenneth C.; Diaz, Ana; Lee, Dana; Tso, Patrick; Holz, George G.; Sharp, Geoffrey W. G.; Levin, Lonny R.; Buck, Jochen

    2013-01-01

    The second messenger molecule cAMP is integral for many physiological processes. In mammalian cells, cAMP can be generated from hormone- and G protein-regulated transmembrane adenylyl cyclases or via the widely expressed and structurally and biochemically distinct enzyme soluble adenylyl cyclase (sAC). sAC activity is uniquely stimulated by bicarbonate ions, and in cells, sAC functions as a physiological carbon dioxide, bicarbonate, and pH sensor. sAC activity is also stimulated by calcium, and its affinity for its substrate ATP suggests that it may be sensitive to physiologically relevant fluctuations in intracellular ATP. We demonstrate here that sAC can function as a cellular ATP sensor. In cells, sAC-generated cAMP reflects alterations in intracellular ATP that do not affect transmembrane AC-generated cAMP. In β cells of the pancreas, glucose metabolism generates ATP, which corresponds to an increase in cAMP, and we show here that sAC is responsible for an ATP-dependent cAMP increase. Glucose metabolism also elicits insulin secretion, and we further show that sAC is necessary for normal glucose-stimulated insulin secretion in vitro and in vivo. PMID:24100033

  16. Efficient generation of dopaminergic-like neurons by overexpression of Nurr1 and Pitx3 in mouse induced Pluripotent Stem Cells.

    PubMed

    Salemi, Salemeh; Baktash, Parvaneh; Rajaei, Bahareh; Noori, Mehri; Amini, Hossein; Shamsara, Mehdi; Massumi, Mohammad

    2016-07-28

    Parkinson's disease (PD) is a neurodegenerative disorder, in which the nigro-striatal Dopaminergic (DAergic) neurons are selectively lost. Treatment of neurodegenerative diseases with Pluripotent Stem Cells (PSCs) is a big interest in cell therapy. Here, we used induced Pluripotent Stem Cells (iPSCs) expressing two master Dopaminergic (DAergic) transcription factors, i.e. Nurr1 and Pitx3, to generate functional in vitro DAergic-like neurons. After establishment and characterization of Doxycycline-inducible iPSCs from mouse fibroblasts, the cells were transduced by NURR1- and PITX3-harboring lentiviruses. The Nurr1/Pitx3 -iPSCs were differentiated through a five-stage protocol to generate DAergic-like neurons. The results confirmed the efficient expression of DAergic neuron markers in the end of protocol. Beside, the generated cells could exclusively synthesize and secrete Dopamine in response to secretagogues. In conclusion, overexpression of Nurr1 and Pitx3 in iPSCs could efficiently program iPSCs into functional DAergic-like neurons. This finding may have an impact on future stem cell therapy of PD. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  17. The forkhead domain gene unc-130 generates chemosensory neuron diversity in C. elegans

    PubMed Central

    Sarafi-Reinach, Trina R.; Sengupta, Piali

    2000-01-01

    Caenorhabditis elegans responds to its complex chemical environment using a small number of chemosensory neurons. Each of these neurons exhibits a unique sensory response repertoire. The developmental mechanisms that generate this diversity of function are largely unknown. Many C. elegans chemosensory neurons, including the AWA and ASG neurons, arise as lineal sisters of an asymmetric division. Here we describe the gene unc-130, which plays a role in the generation of the AWA and ASG neurons. In unc-130 mutants, the ASG neurons adopt the fate of the AWA neurons. unc-130 encodes a member of the forkhead domain family of transcription factors, and is expressed in the precursors to AWA and ASG neurons. Misexpression of unc-130 in the AWA neurons is partly sufficient to repress the AWA fate, but not to promote ASG fate. unc-130 also plays a role in the development of additional chemosensory neurons. Our experiments show that the ASG neurons share a developmental default state in common with three types of olfactory neurons. We propose that distinct cell fates and hence diversity of function in the chemosensory neurons of C. elegans are generated in a hierarchical manner, utilizing both lineage-dependent and independent mechanisms. PMID:11018015

  18. Development tests for the 2.5 megawatt Mod-2 wind turbine generator

    NASA Technical Reports Server (NTRS)

    Andrews, J. S.; Baskin, J. M.

    1982-01-01

    The 2.5 megawatt MOD-2 wind turbine generator test program is discussed. The development of the 2.5 megawatt MOD-2 wind turbine generator included an extensive program of testing which encompassed verification of analytical procedures, component development, and integrated system verification. The test program was to assure achievement of the thirty year design operational life of the wind turbine system as well as to minimize costly design modifications which would otherwise have been required during on site system testing. Computer codes were modified, fatigue life of structure and dynamic components were verified, mechanical and electrical component and subsystems were functionally checked and modified where necessary to meet system specifications, and measured dynamic responses of coupled systems confirmed analytical predictions.

  19. A new response matrix for a 6LiI scintillator BSS system

    NASA Astrophysics Data System (ADS)

    Lacerda, M. A. S.; Méndez-Villafañe, R.; Lorente, A.; Ibañez, S.; Gallego, E.; Vega-Carrillo, H. R.

    2017-10-01

    A new response matrix was calculated for a Bonner Sphere Spectrometer (BSS) with a 6 LiI(Eu) scintillator, using the Monte Carlo N-Particle radiation transport code MCNPX. Responses were calculated for 6 spheres and the bare detector, for energies varying from 1.059E(-9) MeV to 105.9 MeV, with 20 equal-log(E)-width bins per energy decade, totalizing 221 energy groups. A comparison was done among the responses obtained in this work and other published elsewhere, for the same detector model. The calculated response functions were inserted in the response input file of the MAXED code and used to unfold the total and direct neutron spectra generated by the 241Am-Be source of the Universidad Politécnica de Madrid (UPM). These spectra were compared with those obtained using the same unfolding code with the Mares and Schraube matrix response.

  20. Noun and knowledge retrieval for biological and non-biological entities following right occipitotemporal lesions.

    PubMed

    Bruffaerts, Rose; De Weer, An-Sofie; De Grauwe, Sophie; Thys, Miek; Dries, Eva; Thijs, Vincent; Sunaert, Stefan; Vandenbulcke, Mathieu; De Deyne, Simon; Storms, Gerrit; Vandenberghe, Rik

    2014-09-01

    We investigated the critical contribution of right ventral occipitotemporal cortex to knowledge of visual and functional-associative attributes of biological and non-biological entities and how this relates to category-specificity during confrontation naming. In a consecutive series of 7 patients with lesions confined to right ventral occipitotemporal cortex, we conducted an extensive assessment of oral generation of visual-sensory and functional-associative features in response to the names of biological and nonbiological entities. Subjects also performed a confrontation naming task for these categories. Our main novel finding related to a unique case with a small lesion confined to right medial fusiform gyrus who showed disproportionate naming impairment for nonbiological versus biological entities, specifically for tools. Generation of visual and functional-associative features was preserved for biological and non-biological entities. In two other cases, who had a relatively small posterior lesion restricted to primary visual and posterior fusiform cortex, retrieval of visual attributes was disproportionately impaired compared to functional-associative attributes, in particular for biological entities. However, these cases did not show a category-specific naming deficit. Two final cases with the largest lesions showed a classical dissociation between biological versus nonbiological entities during naming, with normal feature generation performance. This is the first lesion-based evidence of a critical contribution of the right medial fusiform cortex to tool naming. Second, dissociations along the dimension of attribute type during feature generation do not co-occur with category-specificity during naming in the current patient sample. Copyright © 2014 Elsevier Ltd. All rights reserved.

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