Computational Modelling of Metastasis Development in Renal Cell Carcinoma

The biology of the metastatic colonization process remains a poorly understood phenomenon. To improve our knowledge of its dynamics, we conducted a modelling study based on multi-modal data from an orthotopic murine experimental system of metastatic renal cell carcinoma. The standard theory of metastatic colonization usually assumes that secondary tumours, once established at a distant site, grow independently from each other and from the primary tumour. Using a mathematical model that translates this assumption into equations, we challenged this theory against our data that included: 1) dynamics of primary tumour cells in the kidney and metastatic cells in the lungs, retrieved by green fluorescent protein tracking, and 2) magnetic resonance images (MRI) informing on the number and size of macroscopic lesions. Critically, when calibrated on the growth of the primary tumour and total metastatic burden, the predicted theoretical size distributions were not in agreement with the MRI observations. Moreover, tumour expansion only based on proliferation was not able to explain the volume increase of the metastatic lesions. These findings strongly suggested rejection of the standard theory, demonstrating that the time development of the size distribution of metastases could not be explained by independent growth of metastatic foci. This led us to investigate the effect of spatial interactions between merging metastatic tumours on the dynamics of the global metastatic burden. We derived a mathematical model of spatial tumour growth, confronted it with experimental data of single metastatic tumour growth, and used it to provide insights on the dynamics of multiple tumours growing in close vicinity. Together, our results have implications for theories of the metastatic process and suggest that global dynamics of metastasis development is dependent on spatial interactions between metastatic lesions.     

Analyse der schlagauslösenden Bewegungsparameter einer punktförmigen Beuteattrappe bei der Aeschnalarve

Zusammenfassung Bei der Libellenlarve Aeschna cyanea M. werden die einzelnen, für die Auslösung des Fangschlags relevanten Bewegungsparameter einer punktförmigen Beuteattrappe und die wirksamste Kombination dieser Parameter bestimmt.Als Beiz dient der beliebig bewegbare Leuchtpunkt eines Oszillographen, der auf die ebene Mattscheibe eines Versuchsaquariums projiziert wird. Die Schläge der frei beweglichen Larve werden vom Beobachter gezählt oder elektrisch registriert.Die Bahngeschwindigkeit von kontinuierlich gebotenen Bewegungsreizen wirkt sich stark auf die Schlagzahl aus: Die Schläge nehmen von 0,005–2,5 cm/sec zu, nehmen von 5,1 cm/sec an wieder ab und hören bei 41,0 cm/sec ganz auf. Die Veränderung der mittleren Geschwindigkeit von Sinusschwingungen und Zufallsbewegungen bewirkt ähnliche Reaktionskurven wie die Veränderung der gleichmäigen Geschwindigkeit von Dreiecksschwingungen und kreisförmigen Bewegungen; eine gleichförmige Optimalgesohwindigkeit wird jedoch stärker beantwortet als eine periodisch schwankende.Bietet man eine Folge von diskontinuierlichen Bewegungsreizen, die nach einer einmaligen Durchquerung eines begrenzten Feldes der Projektionsfläche verschwinden, so spielt die Dauer einer Einzelbewegung eine Rolle. Um die Schläge voll in Gang zu bringen, müssen eindimensionale Schwingungen 3–6 sec dauern, ein viel intensiver wirkender zweidimensionaler Reiz (Zickzackbewegung) jedoch nur 0,8 sec.Im optimalen, relativ hohen Geschwindigkeitsbereich läßt die Erhöhung der Bewegungsamplitude von 0,25 auf 2,0 cm die Schlagzahl progressiv absinken. Der Vergleich zwischen diesen Amplituden und dem Öffnungswinkel des frontalen, die Beute fixierenden Ommatidienfeldes zeigt, daß der Leuchtpunkt nur bei sehr kleinen Ablenkungen die frontalen Rezeptoren kontinuierlich reizt. — Die Bevorzugung von raschen Bewegungsreizen mit kleiner Amplitude besteht nicht bei Larven, die durch prompte Fixier- und Folgereaktionen den Leuchtpunkt in ihrer frontalen Fixierebene bewahren.Der Vergleich zwischen den 4 in dieser Untersuchung erzeugten Bewegungsmustern (ein- und zweidimensionale Schwingungen, Kreis- und Zufallsbewegungen) zeigt, daß eine Bewegung um so mehr Schläge auslöst, je vollständiger sie auf dicht aneinanderliegenden, zweidimensionalen Bahnen das frontale Ommatidienfeld abtastet.Die optimale Reizkombination (Zickzackbewegung) besteht aus einer kleinen (0,2–0,4 cm) Vertikalschwingung mit optimaler Geschwindigkeit, die sich langsam (0,32 cm/sec) seitlich verschiebt. Dieser Reiz stellt die Verbindung der optimalen Werte aller Bewegungsparameter dar und bewirkt, daß pro Zeiteinheit eine möglichst große Zahl frontaler Rezeptoren mit der optimalen Bahngeschwindigkeit gereizt wird.

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Analysis of the parameters of a moving lightspot which release the predatory strike in dragonfly larvae

Summary This study analyses the predatory strike response of the dragonfly larva Aeschna cyanea M. towards a moving spot of light. Its aim is to determine the single parameters of movement of the spot which release the strike and the most effective combination of these parameters.As the velocity of a continuously moving lightspot is increased the number of strikes rises to a maximum (at 2.5 cm/sec) and then declines to 0 (at 41.0 cm/sec). Both uniform and non uniform velocities give curves of similar shape but different magnitudes.In the presentation of a sequence of discontinuous movements (where the spot moves across a part of the screen and then disappears) the duration of a single movement is important: Unidimensional oscillations must last 3 to 6 sec in order to release predatory strikes; twodimensional zigzag movements, much more effective, need last only 0.8 sec.In the optimal velocity range, increasing the amplitude of a movement from 0.25 to 2.00 cm produces a progressive decrease of the response rate. The comparison between these amplitudes and the size of the field of the frontal ommatidia, which fixate the prey, suggests that the spot stimulates these receptors continuously only when it moves with small amplitudes. — However, this preference for small amplitudes does not exist in those individuals which have rapid fixation- and following-reactions and which thus can track the stimulus.Comparison between the four patterns of movement which have been presented (one- and two-dimensional oscillations, circular and random movements) suggests that the spot releases more strikes the more exactly its movement covers the frontal fixation plane.The most effective stimulus for eliciting strikes was found to be a twodimensional zigzag oscillation. This movement consists of a small (0.2–0.4 cm), rapid (2.5 cm/ sec), vertical oscillation, which progresses slowly (0.3 cm/sec) sideways. This movement combines the optimal values of all parameters and stimulates with the optimal velocity the greatest possible number of frontal receptors in a given time.

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Diese Arbeit wurde in Seewiesen mit Dr. H. C. Howland begonnen und dank der fortwährenden, großzügigen Unterstützung von Herrn Dr. H. Mittelstaedt beendet. Frau L. Dinnendahl fertigte die Zeichnungen an und durchsah das Manuskript, Dr. E. Kramer und Herr P. Heinecke standen mir ständig in technischen Fragen bei, Herr E. Butenandt leistete wertvolle Kritik am Manuskript. — In Genf gewährte mir Prof. J. Piaget vollkommene Freiheit in der Gestaltung meiner Arbeit. — Ihnen allen sei an dieser Stelle herzlichst gedankt.     

Fanconi DNA repair pathway is required for survival and long-term maintenance of neural progenitors

Although brain development abnormalities and brain cancer predisposition have been reported in some Fanconi patients, the possible role of Fanconi DNA repair pathway during neurogenesis is unclear. We thus addressed the role of fanca and fancg, which are involved in the activation of Fanconi pathway, in neural stem and progenitor cells during brain development and adult neurogenesis. Fanca(-/-) and fancg(-/-) mice presented with microcephalies and a decreased neuronal production in developing cortex and adult brain. Apoptosis of embryonic neural progenitors, but not that of postmitotic neurons, was increased in the neocortex of fanca(-/-) and fancg(-/-) mice and was correlated with chromosomal instability. In adult Fanconi mice, we showed a reduced proliferation of neural progenitor cells related to apoptosis and accentuated neural stem cells exhaustion with ageing. In addition, embryonic and adult Fanconi neural stem cells showed a reduced capacity to self-renew in vitro. Our study demonstrates a critical role for Fanconi pathway in neural stem and progenitor cells during developmental and adult neurogenesis.     

A focused antibody library for selecting scFvs expressed at high levels in the cytoplasm

Background  

Intrabodies are defined as antibody molecules which are ectopically expressed inside the cell. Such intrabodies can be used to visualize or inhibit the targeted antigen in living cells. However, most antibody fragments cannot be used as intrabodies because they do not fold under the reducing conditions of the cell cytosol and nucleus.     

Horizontal Gene Transfer of “Prototype” Nramp in Bacteria

Eukaryotic Nramp genes encode divalent metal ion permeases important for nutrition and resistance to microbial infection. Bacterial homologs encode proton-dependent transporters of manganese (MntH), and other divalent metal ions. Bacterial MntH were classified in three homology groups (A, B, C) and MntH C further subdivided in C, C, C. The proteins from C. tepidum (MntH B) and E. faecalis (MntH C1, 2), divergent in sequence and hydropathy profile, conferred increased metal sensitivity when expressed in E. coli, suggesting conservation of divalent metal transport function in MntH B and C. Several genomic evidence suggest horizontal gene transfer (HGT) of mntH C genes: (i) The enterobacteria Wigglesworthia mntH C gene is linked to an Asn t-RNA, and its sequence most conserved with Gram positive bacteria homologs; (ii) all the C genes identified in oral streptococcaceae are associated with different potentially mobile DNA elements; (iii) Lactococcus lactis and Burkholderia mallei genomes contain an mntH gene prematurely terminated and a novel full-length mntH C gene; (iv) remarkable sequence relatedness between the unicellular alga C. reinhardtii prototype Nramp and some MntH C (e.g., Nostoc spp., Listeria spp.) suggests HGT between Eukarya and Bacteria. Other prototype Nramp genes (intronless, encoding proteins strongly conserved with MntH A and B proteins) identified in invertebrates represent a possible source for transfer of Nramp genes toward opportunistic bacteria. This study demonstrates complex evolution of MntH in Bacteria. It is proposed that prototype Nramp are ancestors of bacterial MntH C proteins, which could facilitate bacterial infection. Equally contributing authors (Etienne Richer and Pascal Courville).     

Digital transformation—life cycle assessment of digital services,multifunctional devices and cloud computing

The International Journal of Life Cycle Assessment -     

The trypanolytic factor of human serum: many ways to enter the parasite,a single way to kill

Humans have developed a particular innate immunity system against African trypanosomes, and only two Trypanosoma brucei clones (T. b. gambiense, T. b. rhodesiense) can resist this defence and cause sleeping sickness. The main players of this immunity are the primate‐specific apolipoprotein L‐I (apoL1) and haptoglobin‐related protein (Hpr). These proteins are both associated with two serum complexes, a minor subfraction of HDLs and an IgM/apolipoprotein A‐I (apoA1) complex, respectively, termed trypanosome lytic factor (TLF) 1 and TLF2. Although the two complexes appear to lyse trypanosomes by the same mechanism, they enter the parasite through various modes of uptake. In case of TLF1 one uptake process was characterized. When released in the circulation, haemoglobin (Hb) binds to Hpr, hence to TLF1. In turn the TLF1–Hpr–Hb complex binds to the trypanosome haptoglobin (Hp)–Hb receptor, whose original function is to ensure haem uptake for optimal growth of the parasite. This binding triggers efficient uptake of TLF1 and subsequent trypanosome lysis. While Hpr is involved as TLF ligand, the lytic activity is due to apoL1, a Bcl‐2‐like pore‐forming protein. We discuss the in vivo relevance of this uptake pathway in the context of other potentially redundant delivery routes.