Induction, characterization, and cell transfer of autoimmune tubulointerstitial nephritis

Induction, characterization, and cell transfer of autoimmune tubulointerstitial nephritis. Autoimmune tubulointerstitial nephritis (TIN) was induced in Lewis (LEW) rats by immunization with homologous Brown–Norway (BN) rat renal basement membrane (RBM), complete Freund's adjuvant and Bordetella pertussis vaccine. The BN strain has a tubular basement membrane (TBM) antigen (Ag+) detectable by immunofluorescence which is lacking in unmodified LEW rat TBM. Development of TIN in LEW rats correlated with TBM Ag+ immunogens from homologous and heterologous RBM preparations. By day 14 after immunization TIN developed characterized by elevated serum creatinine levels and by tubular destruction with focal, circumscribed lesions containing epithelioid cells, giant cells and mononuclear cell infiltrates. Approximately 60% of the mononuclear cells bore T cell antigens with most cells expressing la markers. Immunofluorescence and elution studies revealed no selective IgG fixation to TBM at day 14 despite high titers of circulating alloantibody reactive with the immunizing TBM. Intravenous transfer of LNC and/or splenic cells (3.5 to 7 × 108) to naive LEW rats resulted in less severe but histologically identical TIN in seven days with T cell subpopulations similar to those seen in the active model. This model strongly suggests an initiating role for cell–mediated immunity in TIN in the rat and may provide a parallel to human TIN

A-CHAIM: Near-Real-Time Data Assimilation of the High Latitude Ionosphere With a Particle Filter

The Assimilative Canadian High Arctic Ionospheric Model (A-CHAIM) is an operational ionospheric data assimilation model that provides a 3D representation of the high latitude ionosphere in Near-Real-Time (NRT). A-CHAIM uses low-latency observations of slant Total Electron Content (sTEC) from ground-based Global Navigation Satellite System (GNSS) receivers, ionosondes, and vertical TEC from the JASON-3 altimeter satellite to produce an updated electron density model above 45° geomagnetic latitude. A-CHAIM is the first operational use of a particle filter data assimilation for space environment modeling, to account for the nonlinear nature of sTEC observations. The large number (>104 ) of simultaneous observations creates significant problems with particle weight degeneracy, which is addressed by combining measurements to form new composite observables. The performance of A-CHAIM is assessed by comparing the model outputs to unassimilated ionosonde observations, as well as to in-situ electron density observations from the SWARM and DMSP satellites. During moderately disturbed conditions from 21 September 2021 through 29 September 2021, A-CHAIM demonstrates a 40%–50% reduction in error relative to the background model in the F2-layer critical frequency (foF2) at midlatitude and auroral reference stations, and little change at higher latitudes. The height of the F2-layer (hmF2) shows a small 5%–15% improvement at all latitudes. In the topside, A-CHAIM demonstrates a 15%–20% reduction in error for the Swarm satellites, and a 23%–28% reduction in error for the DMSP satellites. The reduction in error is distributed evenly over the assimilation region, including in data-sparse regions

Long-term determination of energetic electron precipitation into the atmosphere from AARDDVARK subionospheric VLF observations

We analyze observations of subionospherically propagating very low frequency (VLF) radio waves to determine outer radiation belt energetic electron precipitation (EEP) flux magnitudes. The radio wave receiver in Sodankylä, Finland (Sodankylä Geophysical Observatory) observes signals from the transmitter with call sign NAA (Cutler, Maine). The receiver is part of the Antarctic-Arctic Radiation-belt Dynamic Deposition VLF Atmospheric Research Konsortia (AARDDVARK). We use a near-continuous data set spanning November 2004 until December 2013 to determine the long time period EEP variations. We determine quiet day curves over the entire period and use these to identify propagation disturbances caused by EEP. Long Wave Propagation Code radio wave propagation modeling is used to estimate the precipitating electron flux magnitudes from the observed amplitude disturbances, allowing for solar cycle changes in the ambient D region and dynamic variations in the EEP energy spectra. Our method performs well during the summer months when the daylit ionosphere is most stable but fails during the winter. From the summer observations, we have obtained 693 days worth of hourly EEP flux magnitudes over the 2004–2013 period. These AARDDVARK-based fluxes agree well with independent satellite precipitation measurements during high-intensity events. However, our method of EEP detection is 10–50 times more sensitive to low flux levels than the satellite measurements. Our EEP variations also show good agreement with the variation in lower band chorus wave powers, providing some confidence that chorus is the primary driver for the outer belt precipitation we are monitoring

Mars Riometer System

A riometer (relative ionospheric opacity meter) measures the intensity of cosmic radio noise at the surface of a planet. When an electromagnetic wave passes through the ionosphere collisions between charged particles (usually electrons) and neutral gases remove energy from the wave. By measuring the received signal intensity at the planet's surface and comparing it to the expected value (the quietday curve) a riometer can deduce the absorption (attenuation) of the trans-ionospheric signal. Thus the absorption measurements provide an indication of ionisation changes occurring in the ionosphere. To avoid the need for orbiting sounders riometers use the cosmic noise background as a signal source. Earth-based systems are not subject to the challenging power, volume and mass restriction that would apply to a riometer for Mars. Some Earth-based riometers utilise phased-array antennas in order to provide an imaging capability

Ground-based estimates of outer radiation belt energetic electron precipitation fluxes into the atmosphere

AARDDVARK data from a radio wave receiver in Sodankyla, Finland have been used to monitor transmissions across the auroral oval and just into the polar cap from the very low frequency communications transmitter, call sign NAA (24.0 kHz, 44 degrees N, 67 degrees W, L = 2.9), in Maine, USA, since 2004. The transmissions are influenced by outer radiation belt (L = 3-7) energetic electron precipitation. In this study, we have been able to show that the observed transmission amplitude variations can be used to determine routinely the flux of energetic electrons entering the upper atmosphere along the total path and between 30 and 90 km. Our analysis of the NAA observations shows that electron precipitation fluxes can vary by 3 orders of magnitude during geomagnetic storms. Typically when averaging over L = 3-7 we find that the >100 keV POES "trapped" fluxes peak at about 10(6) el. cm(-2) s(-1) sr(-1) during geomagnetic storms, with the DEMETER >100 keV drift loss cone showing peak fluxes of 105 el. cm(-2) s(-1) sr(-1), and both the POES >100 keV "loss" fluxes and the NAA ground-based >100 keV precipitation fluxes showing peaks of similar to 10(4) el. cm(-2) s(-1) sr(-1). During a geomagnetic storm in July 2005, there were systematic MLT variations in the fluxes observed: electron precipitation flux in the midnight sector (22-06 MLT) exceeded the fluxes from the morning side (0330-1130 MLT) and also from the afternoon sector (1130-1930 MLT). The analysis of NAA amplitude variability has the potential of providing a detailed, near real-time, picture of energetic electron precipitation fluxes from the outer radiation belts

Intratracheal administration of endotoxin and cytokines: VIII. LPS induces E-selectin expression; anti-E-selectin and soluble E-selectin inhibit acute inflammation

E-selectin is an inducible endothelial adhesion molecule that binds neutrophils. E-selectin mRNA is not constitutively detectable in the lungs of rats. Intratracheal injection of LPS induces pulmonary E-selectin mRNA expression at 2–4 h. Intratracheal injection of LPS followed at 2 and 4 h by intravenous injection of mouse F(ab′) 2 or F(ab′)) anti-E-selectin monoclonal antibody inhibits the emigration of neutrophils into the bronchoalveolar space at 6 h by 50–70%. TNF and IL-6 bioactivity are not decreased in bronchoalveolar lavage fluid after treatment with anti-E-selectin antibody as compared to controls, suggesting that the anti-E-selectin does not affect the magnitude of the LPS-initiated cytokine cascade. Intratracheal injection of LPS followed at 2 and 4 h by intravenous injection of soluble E-selectin inhibits neutrophilic emigration at 6 h by 64%, suggesting that endogenous soluble E-selectin shed from activated endothelium may play a role in the endogenous down-regulation of acute inflammation. E-selectin-mediated adhesion of neutrophils to endothelium appears crucial to the full development of the acute inflammation response.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44513/1/10753_2005_Article_BF01534436.pd

Radiation-induced lung injury in vivo: Expression of transforming growth factor—Beta precedes fibrosis

Cytokine release from irradiated cells has been postulated to start soon after irradiation preceding detectable clinical and pathological manifestation of lung injury. The expression of transforming growth factor beta (TGF β ), a fibrogenic and radiation-inducible cytokine, was studied from 1–16 weeks after the 15 and 30 Gray (Gy) of thoracic irradiation to rats. Thoracic irradiation caused an increase in TGF β protein in bronchoalveolar lavage (BAL) fluid peaking at 3–6 weeks as compared to sham-irradiated control rats. Steady state TGF β mRNA expression as shown by whole lung northern blot assay paralleled the TGF β protein expression in BAL fluid. The peak of TGF β protein increase in BAL fluid between 3 and 6 weeks coincided with the initial influx of inflammatory cells in BAL fluid, but preceded histologically discernable pulmonary fibrosis that was not apparent until 8–10 weeks after irradiation. In conclusion, TGF β and mRNA and protein upregulation preceded the radiation-induced pulmonary fibrosis, suggesting a pathogenetic role in the development of radiation fibrosis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44516/1/10753_2005_Article_BF01486737.pd

Effect of intraperitoneally administered recombinant murine granulocyte-macrophage colony-stimulating factor (rmGM-CSF) on the cytotoxic potential of murine peritoneal cells

We studied the effect of recombinant murine granulocyte–macrophage colony-stimulating factor(rmGM-CSF) on the cytotoxic potential of murine peritoneal cells. Mice received rmGM-CSF intraperitoneally using different dosages and injection schemes. At different time points after the last injection, mice were sacrificed, peritoneal cells isolated and their tumour cytotoxicity was determined by a cytotoxicity assay using syngeneic [methyl-3H]thymidine-labelled colon carcinoma cells. Also, the cytotoxic response to a subsequent in vitro stimulation with lipopolysaccharide was determined. Upon daily injection of 6000–54 000 U rmGM-CSF over a 6-day period, the number of peritoneal cells increased over ten fold with the highest rmGM-CSF dose. Increases in cell numbers was mainly due to increases in macrophage numbers. Upon injection of three doses of 3000 U rmGM-CSF per day for 3 consecutive days, the number of macrophages remained elevated for minimally 6 days. Although the peritoneal cells from rmGM-CSF-treated mice were not activated to a tumoricidal state, they could be activated to high levels of cytotoxicity with an additional in vitro stimulation of lipopolysaccharide. Resident cells isolated from control mice could be activated only to low levels of tumour cytotoxicity with lipopolysaccharide. Tumour cytotoxicity strongly correlated with nitric oxide secretion. When inhibiting nitric oxide synthase, tumour cell lysis decreased. Thus, the expanded peritoneal cell population induced by multiple injections of rmGM-CSF has a strong tumour cytotoxic potential and might provide a favourable condition for immunotherapeutic treatment of peritoneal neoplasms. © 1999 Cancer Research Campaig

Identification of Keratinocyte Growth Factor as a Target of microRNA-155 in Lung Fibroblasts: Implication in Epithelial-Mesenchymal Interactions

International audienceBACKGROUND: Epithelial-mesenchymal interactions are critical in regulating many aspects of vertebrate embryo development, and for the maintenance of homeostatic equilibrium in adult tissues. The interactions between epithelium and mesenchyme are believed to be mediated by paracrine signals such as cytokines and extracellular matrix components secreted from fibroblasts that affect adjacent epithelia. In this study, we sought to identify the repertoire of microRNAs (miRNAs) in normal lung human fibroblasts and their potential regulation by the cytokines TNF-alpha, IL-1beta and TGF-beta. METHODOLOGY/PRINCIPAL FINDINGS: MiR-155 was significantly induced by inflammatory cytokines TNF-alpha and IL-1beta while it was down-regulated by TGF-beta. Ectopic expression of miR-155 in human fibroblasts induced modulation of a large set of genes related to "cell to cell signalling", "cell morphology" and "cellular movement". This was consistent with an induction of caspase-3 activity and with an increase in cell migration in fibroblasts tranfected with miR-155. Using different miRNA bioinformatic target prediction tools, we found a specific enrichment for miR-155 predicted targets among the population of down-regulated transcripts. Among fibroblast-selective targets, one interesting hit was keratinocyte growth factor (KGF, FGF-7), a member of the fibroblast growth factor (FGF) family, which owns two potential binding sites for miR-155 in its 3'-UTR. Luciferase assays experimentally validated that miR-155 can efficiently target KGF 3'-UTR. Site-directed mutagenesis revealed that only one out of the 2 potential sites was truly functional. Functional in vitro assays experimentally validated that miR-155 can efficiently target KGF 3'-UTR. Furthermore, in vivo experiments using a mouse model of lung fibrosis showed that miR-155 expression level was correlated with the degree of lung fibrosis. CONCLUSIONS/SIGNIFICANCE: Our results strongly suggest a physiological function of miR-155 in lung fibroblasts. Altogether, this study implicates this miRNA in the regulation by mesenchymal cells of surrounding lung epithelium, making it a potential key player during tissue injury

Cancer Genomics Identifies Regulatory Gene Networks Associated with the Transition from Dysplasia to Advanced Lung Adenocarcinomas Induced by c-Raf-1

Background: Lung cancer is a leading cause of cancer morbidity. To improve an understanding of molecular causes of disease a transgenic mouse model was investigated where targeted expression of the serine threonine kinase c-Raf to respiratory epithelium induced initialy dysplasia and subsequently adenocarcinomas. This enables dissection of genetic events associated with precancerous and cancerous lesions. Methodology/Principal Findings: By laser microdissection cancer cell populations were harvested and subjected to whole genome expression analyses. Overall 473 and 541 genes were significantly regulated, when cancer versus transgenic and non-transgenic cells were compared, giving rise to three distinct and one common regulatory gene network. At advanced stages of tumor growth predominately repression of gene expression was observed, but genes previously shown to be upregulated in dysplasia were also up-regulated in solid tumors. Regulation of developmental programs as well as epithelial mesenchymal and mesenchymal endothelial transition was a hall mark of adenocarcinomas. Additionaly, genes coding for cell adhesion, i.e. the integrins and the tight and gap junction proteins were repressed, whereas ligands for receptor tyrosine kinase such as epi- and amphiregulin were up-regulated. Notably, Vegfr- 2 and its ligand Vegfd, as well as Notch and Wnt signalling cascades were regulated as were glycosylases that influence cellular recognition. Other regulated signalling molecules included guanine exchange factors that play a role in an activation of the MAP kinases while several tumor suppressors i.e. Mcc, Hey1, Fat3, Armcx1 and Reck were significantly repressed. Finally, probable molecular switches forcing dysplastic cells into malignantly transformed cells could be identified. Conclusions/Significance: This study provides insight into molecular pertubations allowing dysplasia to progress further to adenocarcinoma induced by exaggerted c-Raf kinase activity