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Tumor-necrosis factor(TNF)-a inhibited in a dose-dependent fashion the proliferation of epidermalgrowth-factor(EGF)-stimulated MCF-7 breast cancer cells with an IC,, of 0.25 nM. A comparable TNFa-mediated inhibition of ~42144 mitogen-activated protein (MAP) kinase activity was observed in 10 nM EGF-stimulated cells. The MAP kinase activity dropped 50% within 3 min of TNF-a (1 nM) addition to EGF-stimulated MCF-7 cells. EGF and TNF-a, when added independently, led to a transient stimulation of MAP kinase activity with maximal activations within 6-8 min and 1-2 min, respectively. These observations suggest that MAP kinase activity in EGF-stimulated MCF-7 cells is modulated by the growth-inhibitory receptor pathways of TNF-a. Phosphorylation measurements on western blots determined the involvement of several individual MAP kinases, namely ~42144 MAP kinases, p38 MAP kinase and c-Jun N,-terminal kinase 1 (JNKI), in EGF and TNF-a-induced signalling. Phosphorylation of p42 and p38 MAP kinases only was observed after treatment with either TNF-a or EGF. A combination of both ligands inhibited p42 and p38 MAP kinase phosphorylation in MCF-7 cells. In contrast, no JNKI phosphorylation was detected in these cells. Simultaneous addition of okadaic acid, a potent inhibitor of phosphatases 1 and 2A, blocked the decay of EGF-stimulated MAP kinase activity over 40 min. TNF-a added to EGF-stimulated and okadaic-acid-treated cells increased the MAP kinase activity twofold within 1 rnin. Similarly, okadaic acid treatment partly reverted the TNF-a-inhibited growth of MCF-7 cells. These experiments suggest that phosphatases are involved in the rapid shut-down by TNF-a of p42 MAP kinase activity.Keywords: mitogen-activated protein kinase ; tumor-necrosis factor-a; breast cancer; signal transduction ; cross-talk Tumor-necrosis factor(TNF)-a is a pluripotent cytokine, which can modulate the growth of both normal and tumor cells in vitro [ l , 21. Several tumor cell lines have been shown to be sensitive to the cytotoxic or cytostatic effects of TNF-a, among them the hormone-dependent human breast cancer MCF-7 cells [3-51. MCF-7 cells respond to both epidermal-growth factor (EGF) and TNF-a, with EGF inducing accelerated growth in vitro and TNF-a inhibiting it. The antimitogenic effect of TNFa is dose dependent in EGF-stimulated MCF-7 cells [5]. However, the site and nature of the interaction between the stimulatory EGF-receptor signalling pathway and the inhibitory TNFreceptor pathway has not been elucidated. TNF-a has been shown to induce serinelthreonine or tyrosine phosphorylation of various cellular proteins including mitogen-activated protein (MAP) kinases [6, 71.MAP kinases are a class of serinelthreonine protein kinases believed to occupy a pivotal position in the phosphorylation cascades triggered by extracellular stimuli such as EGF [8-111.Correspondence to H. Mueller, Department of Research, University Women's Clinic, Schanzenstrasse 46, CH-4031 Basel, SwitzerlandAhbreviations. EGF, epidermal-growth factor; IMEM-20, improved mi...

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<p>Due to human intervention, many rivers worldwide exhibit sediment deficit as well as hydraulic and morphological degradation, resulting in the restoration of river habitat becoming a critical task. In Switzerland, the revised Waters Protection Act demands the restoration of 4,000 eco-morphologically impaired river kilometers by 2090. To meet this target, nature-based solutions such as engineered logjams are being implemented to increase flow heterogeneity and provide shelter and habitat for aquatic organisms. To optimize their design, it is crucial to improve our understanding of the physical and ecological interactions for habitat creation, while also considering the potential flood hazard.</p> <p>In this study, we performed a series of flume experiments on partially spanning logjams positioned in series. The experiments were conducted for different clearance distances between the installed logjams, logjam width, solid volume fraction, and flow Froude number. We analyzed the resulting flow velocity, water depth, and turbulent kinetic energy to quantify the flow heterogeneity and to evaluate the flood hazard.</p> <p>The results demonstrated that the backwater rise upstream of the first logjam was larger compared to the second logjam. Compared to previous experiments with single partially spanning logjams, the presence of the second logjam did not affect the backwater rise upstream of the first logjam. In addition, it was found that the backwater rise increased with increasing logjam width, resulting in a smaller logjam width being more beneficial from a flood hazard perspective. In contrast, a wider logjam led to a higher flow variability and the creation of two distinct flow regions downstream of the logjams. This result highlights the relevance to consider both flow variability and flood hazard aspects to design engineered logjams for river restoration projects.</p>