Lysyl oxidase enzymatic function increases stiffness to drive colorectal cancer progression through FAK.

The extracellular, matrix-modifying enzyme lysyl oxidase (LOX) has recently been linked to colorectal cancer (CRC) progression, in particular to the stages of invasion and metastasis. In this report, we use cell lines expressing a catalytically inactive mutant form of LOX to show that catalytic activity is required for LOX-mediated effects on proliferation and invasion in both in vitro and in vivo models of CRC. Furthermore, we use rheology to measure the relative stiffness of modified collagen matrices and subcutaneous tumors, and show that LOX-induced collagen cross-linking results in stiffening of the matrix both in vitro and in vivo. We observe a strong association between matrix stiffness and activation of the FAK (focal adhesion kinase)/SRC-signaling pathway, with a stiffer environment resulting in increased FAK/SRC phosphorylation and a more proliferative and invasive phenotype. We are the first to show a direct relationship between LOX enzymatic activity and tissue stiffness, and to demonstrate a role for stiffness in driving CRC progression. Our findings provide significant evidence to suggest that therapeutic inhibition of LOX activity may provide a novel effective treatment option for patients with metastatic CRC.

Bid, a widely expressed proapoptotic protein of the Bcl-2 family, displays lipid transfer activity.

Bid is an abundant proapoptotic protein of the Bcl-2 family that is crucial for the induction of death receptor-mediated apoptosis in primary tissues such as liver. Bid action has been proposed to involve the relocation of its truncated form, tBid, to mitochondria to facilitate the release of apoptogenic cytochrome c. The mechanism of Bid relocation to mitochondria was unclear. We report here novel biochemical evidence indicating that Bid has lipid transfer activity between mitochondria and other intracellular membranes, thereby explaining its dynamic relocation to mitochondria. First, physiological concentrations of phospholipids such as phosphatidic acid and phosphatidylglycerol induced an accumulation of full-length Bid in mitochondria when incubated with light membranes enriched in endoplasmic reticulum. Secondly, native and recombinant Bid, as well as tBid, displayed lipid transfer activity under the same conditions and at the same nanomolar concentrations leading to mitochondrial relocation and release of cytochrome c. Thus, Bid is likely to be involved in the transport and recycling of mitochondrial phospholipids. We discuss how this new role of Bid may relate to its proapoptotic action.

Hadronic loop corrections to the muon anomalous magnetic moment.

The dominant theoretical uncertainties in both the anomalous magnetic moment of the muon and the value of the electromagnetic coupling at the Z scale, M(Z), arise from their hadronic contributions. Since these will ultimately dominate the experimental errors, we study the correlation between them, as well as with other fundamental parameters. To this end we present analytical formulas for the QCD contribution from higher energies and from heavy quarks. Including these correlations affects the Higgs boson mass extracted from precision data.

Indications for an extra neutral gauge boson in electroweak precision data

A new analysis of the hadronic peak cross section at LEP 1 implies a small amount of missing invisible width in Z decays, while the effective weak charge in atomic parity violation has been determined recently to 0.6% accuracy, indicating a significantly negative S parameter. As a consequence, the data are described well if the presence of an extra Z' boson, such as predicted in grand unified theories, is assumed. Moreover, the data are now rich enough to study an arbitrary extra Z' boson and to determine its couplings in a model independent way. An excellent fit to the data is obtained in this case, suggestive of a family nonuniversal Z' similar to those predicted in a class of superstring theories.

Tacrolimus in acute renal failure: does L-arginine-infusion prevent changes in renal hemodynamics?

Nephrotoxicity is one of the main side effects of calcineurin-inhibitors. The influence of tacrolimus on the renal vasculature has not been well described. We have therefore examined the effects of tacrolimus on renal functional parameters as well as the contribution of the NO-system in a model of ischemic acute renal failure (ARF). Induction of ARF was achieved by clamping both renal arteries of female Sprague-Dawley rats. During the experiment, RBF, GFR, MAP, RVR and FENa were determined during infusion of vehicle, TAC, TAC and the NOS-activator L-arginine, and TAC and NOS-inhibition due to L-NMMA. TAC induced a significant rise in RVR with further decrease of RBF and GFR. Simultaneous L-arginine-infusion could reverse these effects during the infusion without complete restoration to preischemic levels. NOS-inhibition increased MAP and RBF without any effect on GFR. FENa did not differ significantly between the groups. Tacrolimus in the situation of ischemic acute renal failure causes vasoconstriction of pre- and postglomerular vessels with a further deterioration of renal function. L-arginine abolishes the functional deterioration, most likely due to increased NO-liberation.

Experimental model of lead nephropathy. IV. Correlation between renal functional changes and hematological indices of lead toxicity.

Adverse effects on hematopoiesis and renal function have been reported in both animals and humans exposed to high doses of lead for a protracted period of time, but little is known about the interrelationship between these two target organ systems. The present study examines rats exposed via drinking water to high dose (5000 mg/L) or low dose (100 mg/L) lead, either continuously or discontinuously, for periods ranging from 1 to 12 months. In addition to blood lead, indices of hematological abnormalities included hematocrit, zinc protoporphyrin (ZPP) and red blood cell (RBC) membrane sodium-potassium-activated adenosine triphosphatase (Na-K-ATPase). Renal function abnormalities were assessed by measurements of glomerular filtration rate (GFR) by the single injection 125-I-iothalamate technique and urinary excretion of the proximal renal tubular enzyme, ligandin. Blood lead and GFR correlated positively during the first 6 months of lead administration, reflecting a stimulatory effect of lead on renal hypertrophy and GFR during this time period. When this distorting effect was factored out, there were few residual correlations between renal and hematological abnormalities. The only significant relationship between GFR and hematological parameters of lead toxicity was a negative correlation between GFR and RBC membrane Na-K-ATPase in animals treated with high dose lead for 6 months and observed at the end of 12 months (discontinuous group).(ABSTRACT TRUNCATED AT 250 WORDS)

Chemical Varieties of Essential Oils from Elsholtzia polystachya from Two Different Locations in India1.

Capillary GC, GC-MS, IR, GC-IR, (1)H- and (13)C-NMR studies of the essential oil from the leaves and cones of ELSHOLTZIA POLYSTACHYA collected from two different locations in India revealed that one oil contained 1,8-cineol (37.3%), the other one perillene (61.2%) as the main constituent.

[Quantitative value of the hallux pattern: mother-child correlation]. / Zum quantitativen Wert des Grosszehenballenmusters: Mutter-Kind-Korrelationen.

Mother-child correlations based upon the ridge-counts of the patterns of the hallucal areas of the soles were computed and compared with the results from finger-tips and palms. The results which are to be found in the hallucal areas of the sole join seamless to those known from finger and hand characters and show that the ridge-count of the hallucal pattern is in the same way suitable for quantitative genetic analysis of dermatoglyphics as the generally accepted dermatoglyphic counts.

Infrared hot carrier diode mixer.

Detection of a 54.3-GHz beatnote at 10.6 microm has been observed with a hot carrier diode mixer. The diode consists of a "cat whisker" antenna, which forms an ohmic point contact to n-InAs. The mechanism of this room-temperature detector is described as the "thermoelectric effect" of hot carriers.