Matrix Metalloproteinase 13 Is Induced in Fibroblasts in Polyomavirus Middle T Antigen-Driven Mammary Carcinoma without Influencing Tumor Progression

Matrix metalloproteinase (MMP) 13 (collagenase 3) is an extracellular matrix remodeling enzyme that is induced in myofibroblasts during the earliest invasive stages of human breast carcinoma, suggesting that it is involved in tumor progression. During progression of mammary carcinomas in the polyoma virus middle T oncogene mouse model (MMTV-PyMT), Mmp13 mRNA was strongly upregulated concurrently with the transition to invasive and metastatic carcinomas. As in human tumors, Mmp13 mRNA was found in myofibroblasts of invasive grade II and III carcinomas, but not in benign grade I and II mammary intraepithelial neoplasias. To determine if MMP13 plays a role in tumor progression, we crossed MMTV-PyMT mice with Mmp13 deficient mice. The absence of MMP13 did not influence tumor growth, vascularization, progression to more advanced tumor stages, or metastasis to the lungs, and the absence of MMP13 was not compensated for by expression of other MMPs or tissue inhibitor of metalloproteinases. However, an increased fraction of thin collagen fibrils was identified in MMTV-PyMT;Mmp13−/− compared to MMTV-PyMT;Mmp13+/+ tumors, showing that collagen metabolism was altered in the absence of MMP13. We conclude that the expression pattern of Mmp13 mRNA in myofibroblasts of invasive carcinomas in the MMTV-PyMT breast cancer model recapitulates the expression pattern observed in human breast cancer. Our results suggest that MMP13 is a marker of carcinoma-associated myofibroblasts of invasive carcinoma, even though it does not make a major contribution to tumor progression in the MMTV-PyMT breast cancer model

Bluegrass Covers of Bob Dylan Songs in the Sixties

Peu d’auteurs-compositeurs ont été autant repris que Bob Dylan. Bien que de nos jours, on l’associe spontanément aux traditions folk et rock/folk, son succès précoce le fit connaître au monde de la musique country et bluegrass, et il n’est pas si étonnant que certaines de ses premières chansons aient fait l’objet dans les années 1960 de reprises dans le style bluegrass, par des musiciens tels que les Dillars, les Country Gentlemen et Flatt and Scruggs. Certaines de ces premières reprises semblent avoir circulé dans les circuits secondaires de l’industrie du disque, et avoir été proposées aux interprètes sans aucun égard pour la cohérence avec le style ou le groupe en question. Certaines eurent du succès ; d’autres frisent la parodie musicale. Elles transformèrent l’œuvre originale de Dylan et changèrent, de nombreuses façons, les directions que le style bluegrass allait prendre par la suite.Few songwriters have had more of their songs covered by other artists than Bob Dylan. Although most commonly associated with the folk and folk/rock traditions today, his early listening included wide exposure to country music, including bluegrass, and it is not entirely surprising that some of his early works were covered in a bluegrass style by such artists as the Dillards, Country Gentlemen, and Flatt and Scruggs in the 1960s. Some of these early covers appear to have circulated in back channels of the recording industry and been pushed towards the performers regardless of the suitability for the style or the group in question. Some are quite successful; others border on musical parody. They changed not only the original work of Dylan but, in many ways, the future directions of the bluegrass style

Micro-optics for imaging.

This project investigates the fundamental imaging capability of an optic with a physical thickness substantially less than 1 mm. The analysis assumes that post-processing can overcome certain restrictions such as detector pixel size and image degradation due to aberrations. A first order optical analysis quickly reveals the limitations of even an ideal thin lens to provide sufficient image resolution and provides the justification for pursuing an annular design. Some straightforward examples clearly show the potential of this approach. The tradeoffs associated with annular designs, specifically field of view limitations and reduced mid-level spatial frequencies, are discussed and their impact on the imaging performance evaluated using several imaging examples. Additionally, issues such as detector acceptance angle and the need to balance aberrations with resolution are included in the analysis. With these restrictions, the final results present an excellent approximation of the expected performance of the lens designs presented

Evidence for the evolutionary steps leading to mecA-mediated ß-lactam resistance in staphylococci

The epidemiologically most important mechanism of antibiotic resistance in Staphylococcus aureus is associated with mecA–an acquired gene encoding an extra penicillin-binding protein (PBP2a) with low affinity to virtually all β-lactams. The introduction of mecA into the S. aureus chromosome has led to the emergence of methicillin-resistant S. aureus (MRSA) pandemics, responsible for high rates of mortality worldwide. Nonetheless, little is known regarding the origin and evolution of mecA. Different mecA homologues have been identified in species belonging to the Staphylococcus sciuri group representing the most primitive staphylococci. In this study we aimed to identify evolutionary steps linking these mecA precursors to the β-lactam resistance gene mecA and the resistance phenotype. We sequenced genomes of 106 S. sciuri, S. vitulinus and S. fleurettii strains and determined their oxacillin susceptibility profiles. Single-nucleotide polymorphism (SNP) analysis of the core genome was performed to assess the genetic relatedness of the isolates. Phylogenetic analysis of the mecA gene homologues and promoters was achieved through nucleotide/amino acid sequence alignments and mutation rates were estimated using a Bayesian analysis. Furthermore, the predicted structure of mecA homologue-encoded PBPs of oxacillin-susceptible and -resistant strains were compared. We showed for the first time that oxacillin resistance in the S. sciuri group has emerged multiple times and by a variety of different mechanisms. Development of resistance occurred through several steps including structural diversification of the non-binding domain of native PBPs; changes in the promoters of mecA homologues; acquisition of SCCmec and adaptation of the bacterial genetic background. Moreover, our results suggest that it was exposure to β-lactams in human-created environments that has driven evolution of native PBPs towards a resistance determinant. The evolution of β-lactam resistance in staphylococci highlights the numerous resources available to bacteria to adapt to the selective pressure of antibiotics

A Finite-Time Thermodynamics of Unsteady Fluid Flows

Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG geförderten) Allianz- bzw. Nationallizenz frei zugänglich.This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.Turbulent fluid has often been conceptualized as a transient thermodynamic phase. Here, a finite-time thermodynamics (FTT) formalism is proposed to compute mean flow and fluctuation levels of unsteady incompressible flows. The proposed formalism builds upon the Galerkin model framework, which simplifies a continuum 3D fluid motion into a finite-dimensional phase-space dynamics and, subsequently, into a thermodynamics energy problem. The Galerkin model consists of a velocity field expansion in terms of flow configuration dependent modes and of a dynamical system describing the temporal evolution of the mode coefficients. Each mode is treated as one thermodynamic degree of freedom, characterized by an energy level. The dynamical system approaches local thermal equilibrium (LTE) where each mode has the same energy if it is governed only by internal (triadic) mode interactions. However, in the generic case of unsteady flows, the full system approaches only partial LTE with unequal energy levels due to strongly mode-dependent external interactions. The FTT model is first illustrated by a traveling wave governed by a 1D Burgers equation. It is then applied to two flow benchmarks: the relatively simple laminar vortex shedding, which is dominated by two eigenmodes, and the homogeneous shear turbulence, which has been modeled with 1459 modes

Imprint of a dissolved cobalt basaltic source on the Kerguelen Plateau

International audienceProcesses of cobalt (Co) entrainment from shelf sediments over the Kerguelen Plateau were studied during the KEOPS (Kerguelen Ocean Plateau compared Study) in order to explain the exceptionally high dissolved cobalt concentrations that have been measured in the surface waters above the Kerguelen Plateau, and in intermediate and deep waters above its eastern slope. Lateral advection and dissolution of Co contained in basalt sediments around Heard Island, a main source of lithogenic Co in the study area, were shown to imprint the process of surface enrichment over the plateau. Dissolved Co enrichment was strongest at the intercept of the eastern slope with intermediate and deep waters, probably due to more efficient mobilisation of the sediments in the slope current, in addition to advection of Co-enriched and low-oxygenated ocean water masses. In surface waters, the strong sedimentary Co inputs were estimated to be much higher than biological Co uptake in phytoplankton blooms, underlining the potential use of dissolved cobalt as tracer of the natural iron fertilization above the Kerguelen Plateau. Based on a simple steady-state balance equation of the external input of dissolved iron over the plateau, the fertilization of iron inferred by using dissolved Co as a tracer of basalt sources is estimated to be 28 × 102 ± 21 × 102 t yr−1 in surface waters of the Kerguelen Plateau. This estimate is consistent with preceding ones (Zhang et al., 2008; Chever et al., 2010), and the calculated iron supply matches with the phytoplankton demand (Sarthou et al., 2008)

Results of D-IMPACT

Summary Aims:  Diagnosis IMprovement in PrimAry Care Trial (D-IMPACT) was a prospective, multicentre epidemiological study in three European countries to identify the optimal subset of simple tests applied in primary care to diagnose benign prostatic hyperplasia (BPH) in men who spontaneously present with lower urinary tract symptoms (LUTS). Methods:  Consecutive male patients aged ≥ 50 years who spontaneously attended their regular general practitioner (GP) office with LUTS were eligible for inclusion if they had not previously undergone BPH diagnostic tests or received treatment for BPH. Patients were assessed on three occasions, twice by their regular GP (visits 1 and 2) and once by a urologist (visit 3). The diagnostic accuracy of each variable was determined using the urologists' final BPH diagnosis (at visit 3) as gold-standard. Independent variables analysed were as follows: age; BPH diagnosis performed by GP in visit 1 (yes/no); probability of BPH diagnosis assessed by GP in visit 1; urinalysis (normal/abnormal); prostate-specific antigen (PSA); International Prostate Symptom Score (IPSS); diagnosis of BPH performed by GP in visit 2 (yes/no); and probability of BPH diagnosis assessed by GP in visit 2. Statistically significant variables (p 1.5 ng/ml and prostate volume ≥ 30 cm3). Among the independent variables analysed, only age, IPSS and PSA showed a statistically significant relationship with BPH diagnosis. In a logistic regression model including age, IPSS, PSA and probability of BPH (based on physical examination and symptoms), positive predictive value (PPV) was 77.1%. Exclusion of BPH probability resulted in a PPV of 75.7%. Conclusions:  A diagnostic algorithm including only objective variables (age, IPSS and PSA), easily implemented in any GP office, allows GPs to accurately diagnose BPH in approximately three-quarters of patients spontaneously reporting LUTS

Urinary tract obstruction induces transient accumulation of COX-2-derived prostanoids in kidney tissue

Inhibitors of cyclooxygenase (COX)-2 prevent suppression of aquaporin-2 and reduce polyuria in the acute phase after release of bilateral ureteral obstruction (BUO). We hypothesized that BUO leads to COX-2-mediated local accumulation of prostanoids in inner medulla (IM) tissue. To test this, rats were subjected to BUO and treated with selective COX-1 or COX-2 inhibitors. Tissue was examined at 2, 6, 12, and 24 h after BUO. COX-2 protein abundance increased in IM 12 and 24 h after onset of BUO but did not change in cortex. COX-1 did not change at any time points in any region. A full profile of all five primary prostanoids was obtained by mass spectrometric determination of PGE(2), PGF(2α), 6-keto-PGF(1α), PGD(2), and thromboxane (Tx) B(2) concentrations in kidney cortex/outer medulla and IM fractions. IM concentration of PGE(2), 6-keto-PGF(1α), and PGF(2α) was increased at 6 h BUO, and PGE(2) and PGF(2α) increased further at 12 h BUO. TxB(2) increased after 12 h BUO. 6-keto-PGF(1α) remained significantly increased after 24 h BUO. The COX-2 inhibitor parecoxib lowered IM PGE(2,) TxB(2), 6-keto-PGF(1α), and PGF(2α) below vehicle-treated BUO and sham rats at 6, 12 and, 24 h BUO. The COX-1 inhibitor SC-560 lowered PGE(2), PGF(2α), and PGD(2) in IM compared with untreated 12 h BUO, but levels remained significantly above sham. In cortex tissue, PGE(2) and 6-keto-PGF(1α) concentrations were elevated at 6 h only. In conclusion, COX-2 activity contributes to the transient increase in prostacyclin metabolite 6-keto-PGF(1α) and TxB(2) concentration in the kidney IM, and COX-2 is the predominant isoform that is responsible for accumulation of PGE(2) and PGF(2α) with minor, but significant, contributions from COX-1. PGD(2) synthesis is mediated exclusively by COX-1. In BUO, therapeutic interventions aimed at the COX-prostanoid pathway should target primarily COX-2