GEF-H1 Mediated Control of NOD1 Dependent NF-κB Activation by Shigella Effectors

Shigella flexneri has evolved the ability to modify host cell function with intracellular active effectors to overcome the intestinal barrier. The detection of these microbial effectors and the initiation of innate immune responses are critical for rapid mucosal defense activation. The guanine nucleotide exchange factor H1 (GEF-H1) mediates RhoA activation required for cell invasion by the enteroinvasive pathogen Shigella flexneri. Surprisingly, GEF-H1 is requisite for NF-κB activation in response to Shigella infection. GEF-H1 interacts with NOD1 and is required for RIP2 dependent NF-κB activation by H-Ala-D-γGlu-DAP (γTriDAP). GEF-H1 is essential for NF-κB activation by the Shigella effectors IpgB2 and OspB, which were found to signal in a NOD1 and RhoA Kinase (ROCK) dependent manner. Our results demonstrate that GEF-H1 is a critical component of cellular defenses forming an intracellular sensing system with NOD1 for the detection of microbial effectors during cell invasion by pathogens

Catching-up and falling behind knowledge spillover from American to German machine tool makers

In our days, German machine tool makers accuse their Chinese competitors of violating patent rights and illegally imitating German technology. A century ago, however, German machine tool makers used exactly the same methods to imitate American technology. To understand the dynamics of this catching-up process we use patent statistics to analyze firms? activities between 1877 and 1932. We show that German machine tool makers successfully deployed imitating and counterfeiting activities in the late 19th century and the 1920s to catchup to their American competitors. The German administration supported this strategy by stipulating a patent law that discriminated against foreign patent holders and probably also by delaying the granting of patents to foreign applicants. Parallel to the growing international competitiveness of German firms, however, the willingness to guarantee intellectual property rights of foreigners was also increasing because German firms had now to fear retaliatory measures in their own export markets when violating foreign property rights within Germany

Effect of added zinc in diets with ractopamine hydrochloride on growth performance, carcass characteristics, and ileal mucosal inflammation mRNA expression of finishing pigs

Citation: Paulk, C. B., Burnett, D. D., Tokach, M. D., Nelssen, J. L., Dritz, S. S., Derouchey, J. M., . . . Gonzalez, J. M. (2015). Effect of added zinc in diets with ractopamine hydrochloride on growth performance, carcass characteristics, and ileal mucosal inflammation mRNA expression of finishing pigs. Journal of Animal Science, 93(1), 185-196. doi:10.2527/jas2014-8286Two experiments were conducted to determine the effects of increasing the dietary Zn content on growth performance, carcass characteristics, plasma Zn, and ileal mucosal inflammation mRNA expression of finishing pigs fed diets containing ractopamine HCl (RAC; Elanco Animal Health, Greenfield, IN). In Exp. 1, 312 pigs (327 × 1050; PIC, Hendersonville, TN; 94 kg BW) were used in a 27-d study. There were 2 pigs per pen and 26 pens per treatment. Treatments included a corn–soybean meal diet (control; 0.66% standardized ileal digestible [SID] Lys); a diet (0.92% SID Lys) with 10 mg/kg RAC; and the RAC diet plus 50, 100, or 150 mg Zn/kg from ZnO or 50 mg Zn/kg from a Zn AA complex (ZnAA; Availa-Zn; Zinpro, Eden Prairie, MN). All diets also contained 83 mg Zn/kg from ZnSO4 in the trace mineral premix. Pigs fed the RAC diet without added Zn had increased (P < 0.05) ADG, G:F, HCW, carcass yield, and loin weight compared with pigs fed the control diet. Increasing Zn from ZnO in diets containing RAC tended to increase (linear, P = 0.067) G:F and loin weight (quadratic, P = 0.064). Pigs fed diets with 50 mg Zn/kg from ZnAA tended to have increased (P = 0.057) ADG compared with pigs fed the RAC diet. In Exp. 2, 320 pigs (327 × 1050; PIC; 98 kg BW) were used in a 35-d study. There were 2 pigs per pen and 20 pens per treatment. Treatments included a control diet (0.66% SID Lys); a diet (0.92% SID Lys) with 10 mg/ kg RAC; or the RAC diet plus 75, 150, and 225 mg Zn/ kg from ZnO or ZnAA. All diets also contained 55 mg Zn/kg from ZnSO4 from the trace mineral premix. Pigs fed the RAC diet had increased (P < 0.05) ADG, G:F, HCW, loin depth, percentage lean, and liver weight compared with pigs fed the control diet. No Zn level or source effects or level × source interactions were observed for growth performance. A Zn level × source interaction (quadratic, P = 0.007) was observed in liver Zn concentrations. This resulted from liver Zn concentrations plateauing at 150 mg Zn/kg when ZnO was supplemented, while there was a linear increase when using ZnAA. Increasing Zn in diets containing RAC increased (linear, P < 0.05) plasma Zn on d 18 and 32. The expression of IL-1? was increased (P = 0.014) in mucosa of pigs fed the RAC diet compared with those fed the control diet. Expression of IL-1? decreased (linear, P = 0.026) in the mucosa of pigs fed increasing added Zn. In conclusion, adding Zn to diets containing RAC resulted in a trend for improved growth performance of pigs in 1 of 2 experiments. Also, additional Zn increased plasma Zn and reduced IL-1?. © 2015 American Society of Animal Science. All rights reserved

Stress Field Interactions Between Overlapping Shield Volcanoes : Borehole Breakout Evidence From the Island of Hawai'i, USA

Acknowledgments: This PTA2 borehole investigation was funded by the International Continental Scientific Drilling Program (ICDP) and by VMAPP (Volcanic Margin Petroleum Prospectivity) project (VBPR/DougalEARTH/TGS) in collaboration with the Humu'ula Groundwater Research Project. D. A. J. and S. P. are partly funded through a Norwegian Research Council Centres of Excellence project (project number 223272, CEED). We thank Marco Groh for the logging operations. We thank two anonymous reviewers for the comments and suggestions. We are particularly grateful to the Associate Editor Mike Poland for his valuable comments and his critical review that greatly improved the manuscript.Peer reviewedPublisher PD

Genes of intestinal Escherichia coli and their relation to the inflammatory activity in patients with ulcerative colitis and Crohn’s disease

Escherichia coli gene fimA was the most frequent gene that occurred in the intestine of all investigated groups. All subjects with fimA gene had significantly higher values of tumor necrosis factor alpha (TNF-α) and CRP than those with other E. coli genes. There was also a tendency to increased serum interleukin (IL)-6 levels in patients carrying the fimA gene; however, no relation was observed to serum IL-8 and IL-10. Patients with Crohn’s disease had significantly higher IL-6 than those with ulcerative colitis (UC) and controls. The highest levels of TNF-α were detected in the UC group. There were no significant differences in serum IL-8 and IL-10 between all three groups. The presence of E. coli gene fimA in the large bowel of patients with IBD is related to the immunological activity of the disease which may be important from the aspect of therapeutical strategy

Wiskott-Aldrich syndrome protein deficiency in innate immune cells leads to mucosal immune dysregulation and colitis in mice

BACKGROUND & AIMS: Immunodeficiency and autoimmune sequelae, including colitis, develop in patients and mice deficient in Wiskott-Aldrich Syndrome protein (WASP), a hematopoietic-specific intracellular signaling molecule that regulates the actin cytoskeleton. Development of colitis in WASP-deficient mice requires lymphocytes; transfer of T cells is sufficient to induce colitis in immunodeficient mice. We investigated the interactions between innate and adaptive immune cells in mucosal regulation during development of T-cell-mediated colitis in mice with WASP-deficient cells of the innate immune system. METHODS: Naïve and/or regulatory CD4(+) T cells were transferred from 129 SvEv mice into RAG-2 deficient (RAG-2 KO) mice or mice lacking WASP and RAG-2 (WRDKO). Animals were observed for the development of colitis; effector and regulatory functions of innate immune and T cells were analyzed with in vivo and in vitro assays. RESULTS: Transfer of unfractionated CD4(+) T cells induced severe colitis in WRDKO, but not RAG-2 KO, mice. Naïve wild-type T cells had higher levels of effector activity and regulatory T cells had reduced suppressive function when transferred into WRDKO mice compared to RAG-2 KO mice. Regulatory T-cell proliferation, generation, and maintenance of FoxP3 expression were reduced in WRDKO recipients, and associated with reduced numbers of CD103(+) tolerogenic dendritic cells and levels of interleukin (IL)-10. Administration of IL-10 prevented induction of colitis following transfer of T cells into WRDKO mice. CONCLUSIONS: Defective interactions between WASP-deficient innate immune cells and normal T cells disrupt mucosal regulation, potentially by altering the functions of tolerogenic dendritic cells, production of IL-10, and homeostasis of regulatory T cells

Geokinematics of Central Europe: New insights from the CERGOP-2/Environment Project

The Central European Geodynamics Project CERGOP/2, funded by the European Union from 2003to 2006 under the 5th Framework Programme, benefited from repeated measurements of thecoordinates of epoch and permanent GPS stations of the Central European GPS Reference Network(CEGRN), starting in 1994. Here we report on the results of the systematic processing of availabledata up to 2005. The analysis has yielded velocities for some 60 sites, covering a variety of CentralEuropean tectonic provinces, from the Adria indenter to the Tauern window, the Dinarides, thePannonian Basin, the Vrancea seismic zone and the Carpathian Mountains. The estimated velocitiesdefine kinematical patterns which outline, with varying spatial resolution depending on the stationdensity and history, the present day surface kinematics in Central Europe. Horizontal velocities areanalyzed after removal from the ITRF2000 estimated velocities of a rigid rotation accounting forthe mean motion of Europe: a ~2.3 mm/yr north-south oriented convergence rate between Adria andthe Southern Alps that can be considered to be the present day velocity of the Adria indenterrelative to the European foreland. An eastward extrusion zone initiates at the Tauern Window. Thelateral eastward flow towards the Pannonian Basin exhibits a gentle gradient from 1-1.5 mm/yrimmediately east of the Tauern Window to zero in the Pannonian Basin. This kinematic continuityimplies that the Pannonian plate fragment recently suggested by seismic data does not require aspecific Eulerian pole. On the southeastern boundary of the Adria microplate, we report a velocitydrop from 4-4.5 mm/yr motion near Matera to ~1 mm/yr north of the Dinarides, in the southwesternpart of the Pannonian Basin. A positive velocity gradient as one moves south from West Ukraineacross Rumania and Bulgaria is estimated to be 2 mm/yr on a scale of 600-800 km, as if the crustwere dragged by the counterclockwise rotation along the North Anatolian Fault Zone. This regimeapparently does not interfere with the Vrancea seismic zone: earthquakes there are sufficiently deep(> 100 km) that the brittle deformation at depth can be considered as decoupled from the creep atthe surface. We conclude that models of the Quaternary tectonics of Central and Eastern Europeshould not neglect the long wavelength, nearly aseismic deformation affecting the upper crust in theRomanian and Bulgarian regions

Thermal history of the central Gotthard and Aar massifs, European Alps: Evidence for steady state, long-term exhumation

International audienceQuantifying long-term exhumation rates is a prerequisite for understanding the geodynamic evolution of orogens and their exogenic and endogenic driving forces. Here we reconstruct the exhumation history of the central Aar and Gotthard external crystalline massifs in the European Alps using apatite and zircon fission track and apatite (U-Th)/He data. Age-elevation relationships and time-temperature paths derived from thermal history modeling are interpreted to reflect nearly constant exhumation of ∼0.5 km/Ma since ∼14 Ma. A slightly accelerated rate (∼0.7 km/Ma) occurred from 16 to 14 Ma and again from 10 to 7 Ma. Faster exhumation between 16 and 14 Ma is most likely linked to indentation of the Adriatic wedge and related thrusting along the Alpine sole thrust, which, in turn, caused uplift and exhumation in the external crystalline massifs. The data suggest nearly steady, moderate exhumation rates since ∼14 Ma, regardless of major exogenic and endogenic forces such as a change to wetter climate conditions around 5 Ma or orogen-perpendicular extension initiated in Pliocene times. Recent uplift and denudation rates, interpreted to be the result of climate fluctuations and associated increase in erosional efficiency, are nearly twice this ∼0.5 km/Ma paleoexhumation rate

GEF-H1 Mediated Control of NOD1 Dependent NF-κB Activation by Shigella Effectors

Shigella flexneri has evolved the ability to modify host cell function with intracellular active effectors to overcome the intestinal barrier. The detection of these microbial effectors and the initiation of innate immune responses are critical for rapid mucosal defense activation. The guanine nucleotide exchange factor H1 (GEF-H1) mediates RhoA activation required for cell invasion by the enteroinvasive pathogen Shigella flexneri. Surprisingly, GEF-H1 is requisite for NF-κB activation in response to Shigella infection. GEF-H1 interacts with NOD1 and is required for RIP2 dependent NF-κB activation by H-Ala-D-γGlu-DAP (γTriDAP). GEF-H1 is essential for NF-κB activation by the Shigella effectors IpgB2 and OspB, which were found to signal in a NOD1 and RhoA Kinase (ROCK) dependent manner. Our results demonstrate that GEF-H1 is a critical component of cellular defenses forming an intracellular sensing system with NOD1 for the detection of microbial effectors during cell invasion by pathogens