A major problem for human standing posture is a high centre of gravity (COG) maintained over a relatively small base of support. The body, therefore, has a high potential energy, leading to priority of equilibrium control during almost all motor tasks including quiet standing. Research on postural control has focused mainly on two types of study. One type evaluates balance with respect to external conditions. Unexpected external disturbances reveal centrally programmed stereotyped postural responses. Afferent feedback also influences posture when the initial setting is disturbed. The second type evaluates postural adjustments to anticipated internal disturbances of balance and reveals feedforward postural adjustments (for review, see Oddson, 1990;Dietz, 1992). By feedforward, we mean that the controller predicts an external input or behaves using higherorder processing rather than simple negative feedback of a variable. Fewer studies have dealt with the problem of maintaining balance during quiet relaxed stance. Hellebrandt (1938) introduced the concept of the stretch reflex strategy, or 'geotropic reflex' where the shift of the COG constantly stimulated stretch afferents of postural muscles that then contracted reflexively. This strategy was questioned since the angular motion at the ankle was less than necessary to elicit a stretch reflex (Kelton & Wright, 1949). Subsequent studies supported a central organization of posture that did not regulate the ankle angle or muscle length but a more global parameter such as the position of the COG (Gurfinkel et al. 1980;Dietz, 1992). Thus, the system strategy replaced the stretch reflex strategy whose role was then limited to Journal of Physiology (1999) 1. We studied quiet stance investigating strategies for maintaining balance. Normal subjects stood with natural stance and with feet together, with eyes open or closed. Kinematic, kinetic and EMG data were evaluated and cross-correlated. 2. Cross-correlation analysis revealed a high, positive, zero-phased correlation between anteroposterior motions of the centre of gravity (COG) and centre of pressure (COP), head and COG, and between linear motions of the shoulder and knee in both sagittal and frontal planes. There was a moderate, negative, zero-phased correlation between the anteroposterior motion of COP and ankle angular motion. 3. Narrow stance width increased ankle angular motion, hip angular motion, mediolateral sway of the COG, and the correlation between linear motions of the shoulder and knee in the frontal plane. Correlations between COG and COP and linear motions of the shoulder and knee in the sagittal plane were decreased. The correlation between the hip angular sway in the sagittal and frontal planes was dependent on interaction between support and vision. 4. Low, significant positive correlations with time lags of the maximum of cross-correlation of 250-300 ms were found between the EMG activity of the lateral gastrocnemius muscle and anteroposterior motions of the COG and COP during normal stance. Narrow ...

The liver is the most common site of metastatic disease1. While this metastatic tropism may reflect mechanical trapping of circulating tumor cells, liver metastasis is also dependent, at least in part, on formation of a “pro-metastatic” niche that supports tumor cell spread to the liver2,3. Mechanisms that direct formation of this niche, though, are poorly understood. Here, we show that hepatocytes coordinate myeloid cell accumulation and fibrosis within the liver, and in doing so, increase the susceptibility of the liver to metastatic seeding and outgrowth. Early during pancreatic tumorigenesis, hepatocytes demonstrate activation of Signal Transducer and Activator of Transcription 3 (STAT3) signaling and increased production of serum amyloid A1 and A2 (SAA). Overexpression of SAA by hepatocytes also occurs in pancreatic and colorectal cancer patients with liver metastases, and many patients with locally advanced and metastatic disease display elevated levels of circulating SAA. STAT3 activation in hepatocytes and the subsequent production of SAA are dependent on interleukin 6 (IL-6) that is released into the circulation by non-malignant cells. Genetic ablation or blockade of components of IL-6/STAT3/SAA signaling prevents establishment of a pro-metastatic niche and inhibits liver metastasis. Our data reveal an intercellular network underpinned by hepatocytes that forms the basis for a pro-metastatic niche in the liver and identify new therapeutic targets.

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SUMMARY Fas (CD95, Apo-1, TNFRSF6) is a prototypical apoptosis-inducing death receptor in the tumor necrosis factor receptor (TNFR) superfamily. While the extracellular domains of TNFRs form trimeric complexes with their ligands and the intracellular domains engage in higher-order oligomerization, the role of the transmembrane (TM) domains is unknown. Here, we determined the nuclear magnetic resonance (NMR) structures of mouse and human Fas-TM domains in bicelles that mimic lipid bilayers. Surprisingly, these domains use proline motifs to create optimal packing in homotrimer assembly distinct from classical trimeric coiled-coils in solution. Cancer-associated and structure-based mutations in Fas-TM disrupt trimerization in vitro and reduce apoptosis induction in vivo, indicating the essential role of intramembrane trimerization in receptor activity. Our data suggest that the structures represent the signaling-active conformation of Fas-TM, which appears to be different from the pre-ligand conformation. Analysis of other TNFR sequences suggests proline-containing sequences as common motifs for receptor TM trimerization.

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