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Accumulating evidence suggests that both the nature of oncogenic lesions and the cell-of-origin can strongly influence cancer histopathology, tumor aggressiveness and response to therapy. Although oncogenic Kras expression and loss of Trp53 tumor suppressor gene function have been demonstrated to initiate murine lung adenocarcinomas (LUADs) in alveolar type II (AT2) cells, clear evidence that Club cells, representing the second major subset of lung epithelial cells, can also act as cells-of-origin for LUAD is lacking. Equally, the exact anatomic location of Club cells that are susceptible to Kras transformation and the resulting tumor histotype remains to be established. Here, we provide definitive evidence for Club cells as progenitors for LUAD. Using in vivo lineage tracing, we find that a subset of Kras12V -expressing and Trp53-deficient Club cells act as precursors for LUAD and we define the stepwise trajectory of Club cell-initiated tumors leading to lineage marker conversion and aggressive LUAD. Our results establish Club cells as cells-of-origin for LUAD and demonstrate that Club cell-initiated tumors have the potential to develop aggressive LUAD.

A model for the prediction of the silage quality was tested in several large farms in northeast Germany. The model uses data and information on the fresh grass and the application of silage additives at ensiling to evaluate the “ensilability.” During clamp filling, the model analyses information on the filling performance, activity of compacting machines and hermitic covering of the clamp and evaluates the “ensiling technique.” Both “ensilability” and “ensiling technique” are assessed as “good,” “medium” or “bad” and pooled in “silage evaluation grades” 1–5. In the present model version, the predicted silage net energy lactation (NEL) and crude protein (CP) content is between 3% (for the best grade 1) and 15% (for the weakest grade 5) lower than the fresh grass NEL and CP content. In our experiments, all the grass silage production systems were characterized by “good” “ensilability” and “ensiling technique.” Under those circumstances, the experimental results indicated a closer numerical relation between fresh grass and measured silage NEL and CP content than between predicted silage and measured silage NEL and CP content. The results reveal that the model prediction calculation should be changed compared to the present version. If “ensilability” and “ensiling technique” are evaluated as “good,” the predicted silage NEL and CP content should be forecasted in a range between 0% and 3% decrease compared to fresh grass.

The TC48 drive is a low-cost, low-voltage integrated motor-drive solution suitable for mild hybrid electric vehicles, off-highway traction, and any application where a compact, highly torque-dense machine is required. Low-voltage solutions for electric vehicles are attractive to manufacturers due to lower insulation requirements, and hence lower cost. The package is based on a six-phase switched reluctance machine, which uses a novel stator topology and unique winding design to achieve high torque density. The power electronics converter hardware is integrated into the motor housing, giving a physically, electrically, and thermally optimised solution. The complete package has been designed to be suitable for manufacturing in high volumes. This study describes the electromagnetic design of the motor, the mechanical innovations used to physically realise this design, and the cooling system which makes the high power density possible. The integration of the power electronics and their control is also discussed. The project is the result of collaboration between Newcastle and Loughbosrough Universities, RDM Ltd., Productiv, Infineon, Tata Steel, and Libralato.

This paper proposes a solution to complement the insufficient voltage gain and voltage stress distribution of classical interleaved boost converter in high step-up application. An interleaved converter integrating coupled inductor and voltage multiplier cell, which provides an additional voltage gain is proposed. By stacking the secondary side of the interleaved coupled inductor to its primary side, a high step-up voltage gain and distributed voltage stress are realised. Low-voltage rated devices ultimately reduce the conduction losses. The principle of operation and the performance characteristic of the converter are presented and verified by an experimental prototype of 140 W, 12 V input, and 120 V output.

The aim of the investigation was to determine the water requirements of adult fallow deer (Dama dama), Skudde sheep (Ovis ammon) and mouflon (Ovis orientalis musimon) kept under the same conditions. This study was intended to allow the development of basic principles and recommendations for improving drinking water management in the production of fallow deer, sheep, and mouflon, taking into account the different reproductive statuses of these three species. At a fen, the water intake of the animals was recorded for three consecutive years (2011–2013) during the grazing period (1 May–31 October). The results were based on the regular measurement of the animals’ water intake under pasture management. Three herd repetitions were carried out per species during early and late summer and autumn. Each test group consisted of 10 adult female animals. To enable a comparison of the drinking water consumption among species of different weights, the water intake of each animal was converted into the water intake per kg of metabolic live weight (W0.75). During the early summer fallow deer and sheep consumed a similar amount of water. The mouflon had relatively low water consumption; in the late summer and autumn (September and October), these animals drank only sporadically. All three species consumed more water in the first 3 months of the grazing period than in the last 3 months. Daily water consumption by sheep and deer increased with heat stress caused by higher temperatures and relative humidity, whereas mouflon were relatively immune to such environmental influences. It is recommended that the small ruminant species investigated should be offered a constant supply of drinking water when under pasture management.

Interleaved boost converters IBCs are used when energy conversion is required at high current levels. Such converter systems may undergo various nonlinear phenomena which can affect their performance adversely. In this paper, we study an IBC and demonstrate the first instability through a Neimark-Sacker bifurcation, resulting in a torus. An analysis based on the calculation of the monodromy matrix reveals that the torus has a rather strange form as the complex Floquet multipliers that became unstable have a real value close to -1. We show that further variation in a parameter can result in novel nonlinear phenomena where the torus itself folds and grazes a switching manifold, resulting in a 'wobbling' of the closed loop that represents the torus in discrete time. Numerical and analytical results validate our work. Copyright © 2013 John Wiley & Sons, Ltd.

GTP cyclohydrolase (GCH1) is the key-enzyme to produce the essential enzyme cofactor, tetrahydrobiopterin. The byproduct, neopterin is increased in advanced human cancer and used as cancer-biomarker, suggesting that pathologically increased GCH1 activity may promote tumor growth. We found that inhibition or silencing of GCH1 reduced tumor cell proliferation and survival and the tube formation of human umbilical vein endothelial cells, which upon hypoxia increased GCH1 and endothelial NOS expression, the latter prevented by inhibition of GCH1. In nude mice xenografted with HT29-Luc colon cancer cells GCH1 inhibition reduced tumor growth and angiogenesis, determined by in vivo luciferase and near-infrared imaging of newly formed blood vessels. The treatment with the GCH1 inhibitor shifted the phenotype of tumor associated macrophages from the proangiogenic M2 towards M1, accompanied with a shift of plasma chemokine profiles towards tumor-attacking chemokines including CXCL10 and RANTES. GCH1 expression was increased in mouse AOM/DSS-induced colon tumors and in high grade human colon and skin cancer and oppositely, the growth of GCH1-deficient HT29-Luc tumor cells in mice was strongly reduced. The data suggest that GCH1 inhibition reduces tumor growth by (i) direct killing of tumor cells, (ii) by inhibiting angiogenesis, and (iii) by enhancing the antitumoral immune response.

Question: The role edges play in mediating the effects of disturbance is unclear. Bayhead tree islands, which experience above- and belowground fire, contain trees that recover from disturbance by seed (Pinus elliottii var. densa) and by sprouting (Gordonia lasianthus). How does distance-to-edge affect survival and post-fire response of trees with these contrasting life-history strategies? Location: Two bayhead tree islands at Archbold Biological Station, central Florida, North America. Methods: Stem diameter, depth of peat smoldering, char height, resprouting status, and location were recorded for all Pinus and Gordonia stems ≥8 cm. Distance to the edge of the tree island was quantified using GIS. Results: The focal species showed contrasting patterns of survival across the edge-to-interior gradient that reflected gradients of fire severity. Survival of Gordonia was lowest in the bayhead interior where peat smolder was deepest. Conversely, survival of Pinus was lowest near the edges where char heights were greatest. The distinct types of Gordonia resprouting (crown versus basal) also showed spatially contrasting patterns. Basal resprouting dominated near the edges and was positively influenced by char height, while crown resprouting was nearly constant across the edge-to-interior gradient and was negatively influenced by char height. Conclusions: The spatial patterns of tree survival and resprouting observed are likely due to gradients in intensity of peat smoldering and aboveground burning, coupled with differential susceptibility to these two types of fire. Despite the rarity of fire in wetland tree islands (compared to uplands) it may play an important role in structuring the spatial distribution of trees.

Formation of neurites and their differentiation into axons and dendrites requires precisely controlled changes in the cytoskeleton. While small GTPases of the Rho family appear to be involved in this regulation, it is still unclear how Rho function affects axonal and dendritic growth during development. Using hippocampal neurones at defined states of differentiation, we have dissected the function of RhoA in axonal and dendritic growth. Expression of a dominant negative RhoA variant inhibited axonal growth, whereas dendritic growth was promoted. The opposite phenotype was observed when a constitutively active RhoA variant was expressed. Inactivation of Rho by C3-catalysed ADP-ribosylation using C3 isoforms (Clostridium limosum, C3(lim) or Staphylococcus aureus, C3(stau2)), diminished axonal branching. By contrast, extracellularly applied nanomolar concentrations of C3 from C. botulinum (C3(bot)) or enzymatically dead C3(bot) significantly increased axon growth and axon branching. Taken together, axonal development requires activation of RhoA, whereas dendritic development benefits from its inactivation. However, extracellular application of enzymatically active or dead C3(bot) exclusively promotes axonal growth and branching suggesting a novel neurotrophic function of C3 that is independent from its enzymatic activity.

Despite an extensive research on the molecular basis of epilepsy, the essential players in the epileptogenic process leading to epilepsy are not known. Gene expression analysis is one strategy to enhance our understanding of the genes contributing to the functional neuronal changes underlying epileptogenesis. In the present study, we used the novel MPSS (massively parallel signature sequencing) method for analysis of gene expression in the rat kindling model of temporal lobe epilepsy. Kindling by repeated electrical stimulation of the amygdala resulted in the differential expression of 264 genes in the hippocampus compared to sham controls. The most strongly induced gene was Homer 1A, an immediate early gene involved in the modulation of glutamate receptor function. The overexpression of Homer 1A in the hippocampus of kindled rats was confirmed by RT-PCR. In order to evaluate the functional implications of Homer 1A overexpression for kindling, we used transgenic mice that permanently overexpress Homer 1A. Immunohistochemical characterization of these mice showed a marked Homer 1A overexpression in glutamatergic neurons of the hippocampus. Kindling of Homer 1A overexpressing mice resulted in a retardation of seizure generalization compared to wild-type controls. The data demonstrate that kindling-induced epileptogenesis leads to a striking overexpression of Homer 1A in the hippocampus, which may represent an intrinsic antiepileptogenic and anticonvulsant mechanism in the course of epileptogenesis that counteracts progression of the disease.

Quantitative Structure Activity-Relationships between the antituberculous activity of a series of 61 substituted xanthones and their 13C NMR chemical shifts, lipophilicity, and molar refractivities of the substituents were investigated. In addition to these structural parameters, the test concentrations of the compounds were considered because of the varying solubility. While the multiple linear regression-based Adaptive Least Squares analysis revealed only weak correlations between the antituberculous activity classes of the compounds and their physicochemical parameters, significantly better results were obtained by the Artificial Neural Network technique, which describes nonlinear relationships between the activity as dependent and the physicochemical parameters as independent variables.

A series or substituted xanthones was synthesized in order to prove the hypothesis that electron-withdrawing substituents enhance the antimycobacterial activity of these compounds, which is described by means of a QSAR equation with 13 C NMR chemical shifts as independent parameters. The key step of the synthesis is the formation of substituted 2-phenoxybenzoic acids by Ullmann reaction followed by intramolecular Friedel-Crafts acylation, leading to methyl-, carboxy-, nitro-, cyano-, and aminoxanthones as a test set for QSAR investigations. Spectroscopic data ( 1 H and 13 C chemical shifts, IR, UV) of these xanthones are presented and analyzed. Specific shift increments for xanthones depending on the substituent position and on the position of the respective proton/carbon atom as well as additivity rules were developed.

A series of substituted xanthones was tested for their activity against four mycobacterial strains (Mycobacterium tuberculosis, M. avium, M. lufu, M. smegmatis) by determination of the minimum inhibitory concentrations (MIC values). For the most active compounds, supplementary characterisation was performed by bacterial growth kinetics, which allows a more precise interpretation of their antimycobacterial effects. From the test set, 1-methyl-2,4,7-trinitroxanthone (8a) showed the highest antimycobacterial activity with a MIC value of 3 micrograms/mL against M. tuberculosis, which is comparable to the effect of well known drugs used in the treatment of tuberculosis. For all other compounds, the MIC values could not be determined, due to the comparatively low activity and to the poor solubility of the compounds, respectively. The semiquantitative evaluation of activity against the different strains of mycobacteria resulted in a classification into three activity classes, which will be used as dependent parameter in QSAR investigations, to be published in Part 3 of this series.

Bleeding is one of the most feared complications of veno-arterial (V-A) extracorporeal membrane oxygenation (ECMO), and is also a potential complication of flexible fiberoptic bronchoscopy (FFB). We retrospectively reviewed 14 patients who underwent FFB procedures with bronchial washings (BW) and bronchoalveolar lavage (BAL) to evaluate the safety of this procedure in children on ECMO. Standard FFB with BAUBW technique was used after stabilization on ECMO. Three patients underwent two procedures each, and one patient underwent three, for a total of 19 procedures. No significant complications, such as bleeding have occurred. Three patients required additional ECMO support shortly after FFB. After the 16 procedures done for atelectasis, seven patients improved radiographically, three had increased opacifications, and six were unchanged. The remaining three patients had suspected pulmonary infections, and in each, therapeutic decisions were guided by the BAL results. Lung compliance was unchanged or improved after 11 of 13 procedures. We conclude that FFB with BAUBW in children on ECMO is safe and may benefit certain patients. Pediatr Pulmonol. 1993; 16:215–218. © 1993 Wiley-Liss, Inc.

A series of substituted xanthones was tested for their activity against four mycobacterial strains (Mycobacterium tuberculosis, M. avium, M. lufu, M. smegmatis) by determination of the minimum inhibitory concentrations (MIC values). For the most active compounds, supplementary characterisation was performed by bacterial growth kinetics, which allows a more precise interpretation of their antimycobacterial effects. From the test set, 1-methyl-2,4,7-trinitroxanthone (8a) showed the highest antimycobacterial activity with a MIC value of 3 micrograms/mL against M. tuberculosis, which is comparable to the effect of well known drugs used in the treatment of tuberculosis. For all other compounds, the MIC values could not be determined, due to the comparatively low activity and to the poor solubility of the compounds, respectively. The semiquantitative evaluation of activity against the different strains of mycobacteria resulted in a classification into three activity classes, which will be used as dependent parameter in QSAR investigations, to be published in Part 3 of this series.

Different management regimes imposed on similar habitat types provide opportunities to investigate mechanisms driving community assembly and changes in species composition. We investigated the effect of pasture management on vegetation composition in wetlands with varying spatial isolation on a Florida cattle ranch. We hypothesized that increased pasture management intensity would dampen the expected negative effect of wetland isolation on native species richness due to a change from dispersal-driven community assembly to niche-driven assembly by accentuated environmental tolerance. We used native plant richness, exotic plant richness and mean coefficient of conservatism (CC) to assess wetland plant assemblage composition. Sixty wetlands were sampled, stratified by three levels of isolation across two pasture management intensities; semi-native (less intensely managed; mostly native grasses, never fertilized) and agronomically improved (intensely managed, planted with exotic grasses, and fertilized). Improved pasture wetlands had lower native richness and CC scores, and greater total soil phosphorus and exotic species coverage compared to seminative pasture wetlands. Increased wetland isolation was significantly associated with decreases in native species richness in

Laccase (E.C. 1.10.3.2) is slowly inhibited by lower fatty acids in a reversible reaction. The degree of inhibition depends on kind and concentration of the fatty acid, but not on the concentration of the enzyme itself. The degree of inhibition increases with the chain length of the fatty acids. The maximum inhibition was found with butyric acid.