Collective tumor cell migration in the presence of fibroblasts.

In this work we investigate fibroblast-enhanced tumor cell migration in an idealized tumor setting through a computational model based on a multiphase approach consisting of three phases, namely tumor cells, fibroblasts and interstitial fluid. The interaction between fibroblasts and tumor cells has previously been investigated through this model (Urdal et al., 2019) to comply with reported in vitro experimental results (Shieh et al., 2011). Using the information gained from in vitro single-cell behavior, what will the effect of fibroblast-enhanced tumor cell migration be in a tumor setting? In particular, how will tumor cells migrate in a heterogeneous tumor environment compared to controlled in vitro microfluidic-based experiments? From what we know about the behavior of a tumor, is that collective invasion into adjacent tissue is frequently observed. Here, we want to elucidate how fibroblasts may guide tumor cells towards draining lymphatics to which tumor cells may subsequently intravasate and thus spread to other parts of the body. Fibroblasts can act as leader cells, where they create tracks within the extracellular matrix (ECM) by matrix remodeling and contraction. In addition, a heterotypic mechanical adhesion between fibroblasts and tumor cells also assist the fibroblasts to act as leader cells. Our simulation results show how the interaction between the two cell types yields collective migration of tumor cells outwards from the tumor where fibroblasts dictate the direction of migration. The model also describes how this well-orchestrated invasive behavior is the result of a proper combination of different interaction forces between cell-ECM, fibroblast-ECM, fluid-ECM and cell-fibroblast.

Competing tumor cell migration mechanisms caused by interstitial fluid flow.

In the seminal work by Swartz and collaborators (Shields et al., 2007) it was discovered that autologously secreted or activated (ECM-bound) chemokine forms local pericellular diffusion gradients skewed by fluid convection, and the cells subsequently chemotact up the flow-directed gradient. However, in (Polacheck et al., 2011) Kamm and collaborators found that there is a competing downstream and upstream migration transport mechanism. Their study showed that both mechanisms are present at the same time and the relative strength of these two stimuli governs the directional bias in migration for a cell population and is a function of cell density, interstitial flow rate, and CCR7 receptor availability. The main objective of this work is to give a possible explanation of these two different concurrent cell migration mechanisms by means of a theoretical model. Relying on multiphase modelling, separate momentum balance equations are formulated, respectively, for the cell phase and the interstitial fluid (IF) phase. In order to represent proteolytic activity and autologous chemotaxis a non-moving ECM component is included, as well as proteases secreted by the cancer cells and chemokine that can be released from ECM. The cell and IF momentum balance equations include cell-ECM and fluid-ECM resistance force terms (i.e., classical Darcy's equation terms), but also a cell-fluid interaction term that can account for a more indirect effect that fluid-generated stress may have on cancer cells. We illustrate how the cancer cells can work through this term and effectively avoid being pushed in the flow direction, and even create upstream migration by controlling its magnitude and sign. We think of this as the mathematical interpretation of the experimental observation by Kamm and collaborators that the fluid generated matrix adhesion tension on the upstream side of cells activates integrin adhesion complexes, resulting in activation of focal adhesion (FA) proteins. The model predicts that generally the strength of the upstream migration mechanism is sensitive to the cell volume fraction: a lower density of cells is subject to a weaker upstream migration effect; a higher density of cancer cells can more effectively generate upstream migration. This behavior is a result of the nonlinear coupling between cell-ECM, fluid-ECM, and cell-fluid interaction terms that naturally are involved in the mathematical expression for the net cell velocity.

Regulation of neuronal survival and morphology by the E3 ubiquitin ligase RNF157.

Neuronal health is essential for the long-term integrity of the brain. In this study, we characterized the novel E3 ubiquitin ligase ring finger protein 157 (RNF157), which displays a brain-dominant expression in mouse. RNF157 is a homolog of the E3 ligase mahogunin ring finger-1, which has been previously implicated in spongiform neurodegeneration. We identified RNF157 as a regulator of survival in cultured neurons and established that the ligase activity of RNF157 is crucial for this process. We also uncovered that independently of its ligase activity, RNF157 regulates dendrite growth and maintenance. We further identified the adaptor protein APBB1 (amyloid beta precursor protein-binding, family B, member 1 or Fe65) as an interactor and proteolytic substrate of RNF157 in the control of neuronal survival. Here, the nuclear localization of Fe65 together with its interaction partner RNA-binding protein SART3 (squamous cell carcinoma antigen recognized by T cells 3 or Tip110) is crucial to trigger apoptosis. In summary, we described that the E3 ligase RNF157 regulates important aspects of neuronal development.

N(1520) 3/2(-) helicity amplitudes from an energy-independent multipole analysis based on new polarization data on photoproduction of neutral pions.

New data on the polarization observables T, P, and H for the reaction γp→pπ(0) are reported. The results are extracted from azimuthal asymmetries when a transversely polarized butanol target and a linearly polarized photon beam are used. The data were taken at the Bonn electron stretcher accelerator ELSA using the CBELSA/TAPS detector. These and earlier data are used to perform a truncated energy-independent partial wave analysis in sliced-energy bins. This energy-independent analysis is compared to the results from energy-dependent partial wave analyses.

Neutron skin of (208)pb from coherent pion photoproduction.

Information on the size and shape of the neutron skin on (208)Pb is extracted from coherent pion photoproduction cross sections measured using the Crystal Ball detector together with the Glasgow tagger at the MAMI electron beam facility. On exploitation of an interpolated fit of a theoretical model to the measured cross sections, the half-height radius and diffuseness of the neutron distribution are found to be c(n)=6.70±0.03(stat.) fm and a(n)=0.55±0.01(stat.)(-0.03)(+0.02)(sys.) fm, respectively, corresponding to a neutron skin thickness Δr(np)=0.15±0.03(stat.)(-0.03)(+0.01)(sys.) fm. The results give the first successful extraction of a neutron skin thickness with an electromagnetic probe and indicate that the skin of (208)Pb has a halo character. The measurement provides valuable new constraints on both the structure of nuclei and the equation of state for neutron-rich matter.

Photoproduction of π0 mesons off neutrons in the nucleon resonance region.

Precise angular distributions have been measured for the first time for the photoproduction of π0 mesons off neutrons bound in the deuteron. The effects from nuclear Fermi motion have been eliminated by a complete kinematic reconstruction of the final state. The influence of final-state-interaction effects has been estimated by a comparison of the reaction cross section for quasifree protons bound in the deuteron to the results for free protons and then applied as a correction to the quasifree neutron data. The experiment was performed at the tagged photon facility of the Mainz Microtron MAMI with the Crystal Ball and TAPS detector setup for incident photon energies between 0.45 and 1.4 GeV. The results are compared to the predictions from reaction models and partial-wave analyses based on data from other isospin channels. The model predictions show large discrepancies among each other and the present data will provide much tighter constraints. This is demonstrated by the results of a new analysis in the framework of the Bonn-Gatchina coupled-channel analysis which included the present data.

Measurement of the 1H(γ, p)π0 reaction using a novel nucleon spin polarimeter.

We report the first large-acceptance measurement of polarization transfer from a polarized photon beam to a recoiling nucleon. The measurement pioneers a novel polarimetry technique, which can be applied to many other nuclear and hadron physics experiments. The commissioning reaction of 1H(γ, p)π0 in the range 0.4

Accurate test of chiral dynamics in the γp→π0p reaction.

A precision measurement of the differential cross sections dσ/dΩ and the linearly polarized photon asymmetry Σ≡(dσ⊥-dσ∥)/(dσ⊥+dσ∥) for the γp→π0p reaction in the near-threshold region has been performed with a tagged photon beam and almost 4π detector at the Mainz Microtron. The Glasgow-Mainz photon tagging facility along with the Crystal Ball/TAPS multiphoton detector system and a cryogenic liquid hydrogen target were used. These data allowed for a precise determination of the energy dependence of the real parts of the S- and all three P-wave amplitudes for the first time and provide the most stringent test to date of the predictions of chiral perturbation theory and its energy region of agreement with experiment.

[Preventive bone mineral density measurement in postmenopausal women. Differentiation of treatment of recommendations Guidelines of the Umbrella Organization for Osteology ("Dachverband Osteologie")]. / Präventive Knochendichtemessung bei postmenopausalen Frauen. Differenzierung der Therapieempfehlungen der Leitlinien des Dachverbandes Osteologie (DVO).

BACKGROUND: Osteopenia (OP) or osteoporosis (OST) was diagnosed by bone densitometry (DXA) in postmenopausal women free of known skeletal disorders and without acute fracture. DVO guidelines were applied to define therapeutic indication. METHODS: The study included 94 women aged 59-81 years. Fracture or operation ≤12 months, malignant tumor, ovariectomy, and drugs such as cortisone, strontium, fluorides, bisphosphonates, SERMs, estrogens, and steroids were exclusion criteria. The lowest T-score at the spine, femoral neck, or total hip was decisive. The indication for therapy was determined by evaluating age, BMD, and other risk factors. RESULTS: Using the WHO criteria 22.3% (n=21) had normal BMD, 52.1% (n=49) had OP, and 25.6% (n=24) had OST. According to "Dachverband Osteologie" (DVO) guidelines, 28 women (29.8%) of the whole group needed therapy. Of the 28 women receiving therapy, 9 had OP and 19 had OST. Therapy was indicated in 18.4% for OP and 79.2% for OST. CONCLUSION: A preventive measurement of BMD with DXA provides a benefit for postmenopausal women. Combinatory assessment and consideration of other risk factors allows identification of women who might benefit from early treatment.

Narrow structure in the excitation function of η photoproduction off the neutron.

The photoproduction of η mesons off nucleons bound in 2H and 3He has been measured in coincidence with recoil protons and recoil neutrons for incident photon energies from threshold up to 1.4 GeV. The experiments were performed at the Mainz MAMI accelerator, using the Glasgow tagged photon facility. Decay photons from the η→2γ and η→3π0 decays and the recoil nucleons were detected with an almost 4π electromagnetic calorimeter combining the Crystal Ball and TAPS detectors. The data from both targets are of excellent statistical quality and show a narrow structure in the excitation function of γn→nη. The results from the two measurements are consistent, taking into account the expected effects from nuclear Fermi motion. The best estimates for position and intrinsic width of the structure are W=(1670±5) MeV and Γ=(30±15) MeV. For the first time precise results for the angular dependence of this structure have been extracted.

Beam-helicity asymmetries in double-pion photoproduction off the proton.

Beam-helicity asymmetries have been measured at the MAMI accelerator in Mainz in the three isospin channels gamma[over -->]p-->pi(+)pi(0)n, gamma[over -->]p-->pi(0)pi(0)p, and gamma[over -->]p-->pi(+)pi(-)p. The circularly polarized photons, produced from bremsstrahlung of longitudinally polarized electrons, were tagged with the Glasgow magnetic spectrometer. Charged pions and the decay photons of pi(0) mesons were detected in a 4pi electromagnetic calorimeter which combined the Crystal Ball detector with the TAPS detector. The precisely measured asymmetries are very sensitive to details of the production processes and are thus key observables in the modeling of the reaction dynamics.

Incoherent neutral pion photoproduction on 12C.

We present the first detailed measurement of incoherent photoproduction of neutral pions to a discrete state of a residual nucleus. The 12C(gamma,pi(0))(12)C*(4.4 MeV) reaction has been studied with the Glasgow photon tagger at MAMI employing a new technique which uses the large solid angle Crystal Ball detector both as a pi(0) spectrometer and to detect decay photons from the excited residual nucleus. The technique has potential applications to a broad range of future nuclear measurements with the Crystal Ball and similar detector systems elsewhere. Such data are sensitive to the propagation of the Delta in the nuclear medium and will give the first information on matter transition form factors from measurements with an electromagnetic probe. The incoherent cross sections are compared to two theoretical predictions including a Delta-hole model.

Measurement of the Gerasimov-Drell-Hearn Integrand for 2H from 200 to 800 MeV.

A measurement of the helicity dependence of the total inclusive photoabsorption cross section on the deuteron was carried out at MAMI (Mainz) in the energy range 200

Helicity amplitudes A1/2 and A3/2 for the D13(1520) resonance obtained from the gamma-->p-->-->ppi(0) Reaction.

The helicity dependence of the gamma-->p-->-->ppi(0) reaction has been measured for the first time in the photon-energy range from 550 to 790 MeV. The experiment, performed at the Mainz microtron MAMI, used a 4pi-detector system, a circularly polarized, tagged photon beam, and a longitudinally polarized frozen-spin target. These data are predominantly sensitive to the D13(1520) resonance and are used to determine its helicity amplitudes.

Neutron polarizabilities investigated by quasifree Compton scattering from the deuteron.

Measuring Compton scattered photons and recoil neutrons in coincidence, quasifree Compton scattering by the neutron has been investigated at MAMI (Mainz) at theta(lab)(gamma) = 136 degrees in an energy range from 200 to 400 MeV. From the data a polarizability difference of alpha(n)-beta(n) = 9.8+/-3.6(stat)+2.1-1.1(syst)+/-2.2(model) in units of 10(-4) fm(3) has been determined. In combination with the polarizability sum alpha(n)+beta(n) = 15.2+/-0.5 deduced from photoabsorption data, the first precise results for the neutron electric and magnetic polarizabilities, alpha(n) = 12.5+/-1.8(stat)+1.1-0.6(syst)+/-1.1(model) and beta(n) = 2.7-/+1.8(stat)+0.6-1.1(syst)-/+1.1(model), are obtained.

Pharmacology and biology of corticotropin-releasing factor (CRF) receptors.

The biology of corticotropin-releasing factor (CRF) finds increasing interest in the scientific community because of the neuromodulatory actions of CRF on brain functions such as learning, anxiety, feeding, and locomotion. Additional actions on immunumodulation and apoptosis have recently been discovered. All actions of CRF are mediated by G protein-coupled receptors, which trigger different, sometimes opposite actions in different regions of the central nervous system. The CRF system exhibits considerable plasticity by the involvement of numerous different ligands, splice variants, and transductional couplings. The generation of multiple splice variants is facilitated by the intron exon structure of the CRF receptor genes.

Functional and protein chemical characterization of the N-terminal domain of the rat corticotropin-releasing factor receptor 1.

Rat corticotropin-releasing factor receptor 1 (rCRFR1) was produced either in transfected HEK 293 cells as a complex glycosylated protein or in the presence of the mannosidase I inhibitor kifunensine as a high mannose glycosylated protein. The altered glycosylation did not influence the biological function of rCRFR1 as demonstrated by competitive binding of rat urocortin (rUcn) or human/rat corticotropin-releasing factor (h/rCRF) and agonist-induced cAMP accumulation. The low production rate of the N-terminal domain of rCRFR1 (rCRFR1-NT) by transfected HEK 293 cells, was increased by a factor of 100 in the presence of kifunensine. The product, rCRFR1-NT-Kif, bound rUcn specifically (K(D) = 27 nM) and astressin (K(I) = 60 nM). This affinity was 10-fold lower than the affinity of full length rCRFR1. However, it was sufficiently high for rCRFR1-NT-Kif to serve as a model for the N-terminal domain of rCRFR1. With protein fragmentation, Edman degradation, and mass spectrometric analysis, evidence was found for the signal peptide cleavage site C-terminally to Thr(23) and three disulfide bridges between precursor residues 30 and 54, 44 and 87, and 68 and 102. Of all putative N-glycosylation sites in positions 32, 38, 45, 78, 90, and 98, all Asn residues except for Asn(32) were glycosylated to a significant extent. No O-glycosylation was observed.

A single amino acid serves as an affinity switch between the receptor and the binding protein of corticotropin-releasing factor: implications for the design of agonists and antagonists.

In view of the observation that corticotropin-releasing factor (CRF) affects several brain functions through at least two subtypes of G protein-dependent receptors and a binding protein (CRFBP), we have developed synthetic strategies to provide enhanced binding specificity. Human/rat CRF (h/rCRF) and the CRF-like peptide sauvagine (Svg), differing in their affinities to CRFBP by two orders of magnitude, were used to identify the residues determining binding to CRFBP. By amino acid exchanges, it was found that Ala(22) of h/rCRF was responsible for this peptide's high affinity to CRFBP, whereas Glu(21) located in the equivalent position of Svg prevented high affinity binding to CRFBP. Accordingly, [Glu(22)]h/rCRF was not bound with high affinity to CRFBP in contrast to [Ala(21)]Svg, which exhibited such high affinity. Furthermore, the affinity of both peptides to either CRF receptor (CRFR) subtype was not reduced by these replacements, and their subtype preference was not changed. Thus, exchange of Ala and Glu and vice versa in positions 22 and 21 of h/rCRF and Svg, respectively, serves as a switch discriminating between CRFBP and CRFR. On the basis of this switch function, development of new specific CRF agonists and antagonists is expected to be facilitated. One application was the modification of the CRF antagonist astressin (Ast), whose employment in animal experiments is limited by its low solubility in cerebrospinal fluid. Introduction of Glu residues into Ast generated with [Glu(11,16)]Ast an acidic astressin, which efficiently antagonized in vivo the CRFR1-dependent reduction of locomotion induced by ovine CRF without detectable binding to CRFBP.

Pharmacological characterization of recombinant rat corticotropin releasing factor binding protein using different sauvagine analogs.

Little is known on the structural ligand requirements for corticotropin-releasing factor binding protein (CRFBP) of the rat used as an important experimental animal. To obtain such information recombinant rat CRFBP was produced in stably transfected HEK 293 cells. The primary structure and posttranslational processing of purified rat CRFBP was established by peptide mapping using HPLC combined with mass spectrometric analysis. Rat CRFBP was pharmacologically characterized employing a competition binding assay with tritium-labeled rat urocortin. The rank order of declining affinity of various CRF analogs was urotensin-I, human/rat CRF (h/rCRF), rat urocortin, sauvagine (Svg), and ovine CRF in agreement with the rank order found for human CRFBP. In contrast to astressin, the CRF receptor 2-selective antagonist anti-sauvagine-30 did not show any detectable specific binding to rat CRFBP. The significance of residues 10 to 12 and 21 to 24 of Svg for its low affinity binding was established by changing these residues of Svg to those of h/rCRF. The corresponding residues 22 to 25 of h/rCRF represented the ARAE motif determined to be crucial for binding in agreement with reported data on human CRFBP. Residues 11 to 13 of CRF introduced into Svg also enhanced the affinity to rat CRFBP.

Electromagnetic compatibility of electronic implants--review of the literature.

The aim of the article was to provide an overview of published studies regarding the electromagnetic compatibility (EMC) of electronic implants. The available literature was sorted according to combinations of implant types and sources of interference. Several experiments concerning the susceptibility of pacemakers to mobile phones have been performed. The results of these experiments suggest measures that may be used to prevent the disturbance of pacemakers. For instance, instead of carrying the activated mobile phone in the breast pocket it is recommended that a distance of 30 cm be maintained between the pacemaker and the mobile phone, and that the mobile phone be used on the contralateral side of the pacemaker's location. Similar measures may be recommended for patients with implantable cardioverter defibrillators when using mobile phones. Patients with electronic implants should walk rapidly through anti theft-devices because some of these devices are liable to disturb implants. Patients with cardiac pacemakers should not be subjected to magnetic resonance imaging as far as possible. For a variety of combinations of implants and interference sources, e.g. cardiac pacemakers and base station antennas, no studies were found in the literature. It is strongly recommended that trials be carried out to evaluate the potential risk for patients in these settings.