TY - JOUR AB - A Ge–Si core–shell nanowire is used to realize a Josephson field‐effect transistor with highly transparent contacts to superconducting leads. By changing the electric field, access to two distinct regimes, not combined before in a single device, is gained: in the accumulation mode the device is highly transparent and the supercurrent is carried by multiple subbands, while near depletion, the supercurrent is carried by single‐particle levels of a strongly coupled quantum dot operating in the few‐hole regime. These results establish Ge–Si nanowires as an important platform for hybrid superconductor–semiconductor physics and Majorana fermions. AU - Ridderbos, Joost AU - Brauns, Matthias AU - Shen, Jie AU - de Vries, Folkert K. AU - Li, Ang AU - Bakkers, Erik P. A. M. AU - Brinkman, Alexander AU - Zwanenburg, Floris A. ID - 5990 IS - 44 JF - Advanced Materials SN - 0935-9648 TI - Josephson effect in a few-hole quantum dot VL - 30 ER - TY - JOUR AB - Genome amplification and cellular senescence are commonly associated with pathological processes. While physiological roles for polyploidization and senescence have been described in mouse development, controversy exists over their significance in humans. Here, we describe tetraploidization and senescence as phenomena of normal human placenta development. During pregnancy, placental extravillous trophoblasts (EVTs) invade the pregnant endometrium, termed decidua, to establish an adapted microenvironment required for the developing embryo. This process is critically dependent on continuous cell proliferation and differentiation, which is thought to follow the classical model of cell cycle arrest prior to terminal differentiation. Strikingly, flow cytometry and DNAseq revealed that EVT formation is accompanied with a genome-wide polyploidization, independent of mitotic cycles. DNA replication in these cells was analysed by a fluorescent cell-cycle indicator reporter system, cell cycle marker expression and EdU incorporation. Upon invasion into the decidua, EVTs widely lose their replicative potential and enter a senescent state characterized by high senescence-associated (SA) β-galactosidase activity, induction of a SA secretory phenotype as well as typical metabolic alterations. Furthermore, we show that the shift from endocycle-dependent genome amplification to growth arrest is disturbed in androgenic complete hydatidiform moles (CHM), a hyperplastic pregnancy disorder associated with increased risk of developing choriocarinoma. Senescence is decreased in CHM-EVTs, accompanied by exacerbated endoreduplication and hyperploidy. We propose induction of cellular senescence as a ploidy-limiting mechanism during normal human placentation and unravel a link between excessive polyploidization and reduced senescence in CHM. AU - Velicky, Philipp AU - Meinhardt, Gudrun AU - Plessl, Kerstin AU - Vondra, Sigrid AU - Weiss, Tamara AU - Haslinger, Peter AU - Lendl, Thomas AU - Aumayr, Karin AU - Mairhofer, Mario AU - Zhu, Xiaowei AU - Schütz, Birgit AU - Hannibal, Roberta L. AU - Lindau, Robert AU - Weil, Beatrix AU - Ernerudh, Jan AU - Neesen, Jürgen AU - Egger, Gerda AU - Mikula, Mario AU - Röhrl, Clemens AU - Urban, Alexander E. AU - Baker, Julie AU - Knöfler, Martin AU - Pollheimer, Jürgen ID - 5998 IS - 10 JF - PLOS Genetics SN - 1553-7404 TI - Genome amplification and cellular senescence are hallmarks of human placenta development VL - 14 ER - TY - JOUR AB - Motivation Computational prediction of the effect of mutations on protein stability is used by researchers in many fields. The utility of the prediction methods is affected by their accuracy and bias. Bias, a systematic shift of the predicted change of stability, has been noted as an issue for several methods, but has not been investigated systematically. Presence of the bias may lead to misleading results especially when exploring the effects of combination of different mutations. Results Here we use a protocol to measure the bias as a function of the number of introduced mutations. It is based on a self-consistency test of the reciprocity the effect of a mutation. An advantage of the used approach is that it relies solely on crystal structures without experimentally measured stability values. We applied the protocol to four popular algorithms predicting change of protein stability upon mutation, FoldX, Eris, Rosetta and I-Mutant, and found an inherent bias. For one program, FoldX, we manage to substantially reduce the bias using additional relaxation by Modeller. Authors using algorithms for predicting effects of mutations should be aware of the bias described here. AU - Usmanova, Dinara R AU - Bogatyreva, Natalya S AU - Ariño Bernad, Joan AU - Eremina, Aleksandra A AU - Gorshkova, Anastasiya A AU - Kanevskiy, German M AU - Lonishin, Lyubov R AU - Meister, Alexander V AU - Yakupova, Alisa G AU - Kondrashov, Fyodor AU - Ivankov, Dmitry ID - 5995 IS - 21 JF - Bioinformatics SN - 1367-4803 TI - Self-consistency test reveals systematic bias in programs for prediction change of stability upon mutation VL - 34 ER - TY - JOUR AB - Lamellipodia are flat membrane protrusions formed during mesenchymal motion. Polymerization at the leading edge assembles the actin filament network and generates protrusion force. How this force is supported by the network and how the assembly rate is shared between protrusion and network retrograde flow determines the protrusion rate. We use mathematical modeling to understand experiments changing the F-actin density in lamellipodia of B16-F1 melanoma cells by modulation of Arp2/3 complex activity or knockout of the formins FMNL2 and FMNL3. Cells respond to a reduction of density with a decrease of protrusion velocity, an increase in the ratio of force to filament number, but constant network assembly rate. The relation between protrusion force and tension gradient in the F-actin network and the density dependency of friction, elasticity, and viscosity of the network explain the experimental observations. The formins act as filament nucleators and elongators with differential rates. Modulation of their activity suggests an effect on network assembly rate. Contrary to these expectations, the effect of changes in elongator composition is much weaker than the consequences of the density change. We conclude that the force acting on the leading edge membrane is the force required to drive F-actin network retrograde flow. AU - Dolati, Setareh AU - Kage, Frieda AU - Mueller, Jan AU - Müsken, Mathias AU - Kirchner, Marieluise AU - Dittmar, Gunnar AU - Sixt, Michael K AU - Rottner, Klemens AU - Falcke, Martin ID - 5992 IS - 22 JF - Molecular Biology of the Cell TI - On the relation between filament density, force generation, and protrusion rate in mesenchymal cell motility VL - 29 ER - TY - JOUR AB - The optic tectum (TeO), or superior colliculus, is a multisensory midbrain center that organizes spatially orienting responses to relevant stimuli. To define the stimulus with the highest priority at each moment, a network of reciprocal connections between the TeO and the isthmi promotes competition between concurrent tectal inputs. In the avian midbrain, the neurons mediating enhancement and suppression of tectal inputs are located in separate isthmic nuclei, facilitating the analysis of the neural processes that mediate competition. A specific subset of radial neurons in the intermediate tectal layers relay retinal inputs to the isthmi, but at present it is unclear whether separate neurons innervate individual nuclei or a single neural type sends a common input to several of them. In this study, we used in vitro neural tracing and cell-filling experiments in chickens to show that single neurons innervate, via axon collaterals, the three nuclei that comprise the isthmotectal network. This demonstrates that the input signals representing the strength of the incoming stimuli are simultaneously relayed to the mechanisms promoting both enhancement and suppression of the input signals. By performing in vivo recordings in anesthetized chicks, we also show that this common input generates synchrony between both antagonistic mechanisms, demonstrating that activity enhancement and suppression are closely coordinated. From a computational point of view, these results suggest that these tectal neurons constitute integrative nodes that combine inputs from different sources to drive in parallel several concurrent neural processes, each performing complementary functions within the network through different firing patterns and connectivity. AU - Garrido-Charad, Florencia AU - Vega Zuniga, Tomas A AU - Gutiérrez-Ibáñez, Cristián AU - Fernandez, Pedro AU - López-Jury, Luciana AU - González-Cabrera, Cristian AU - Karten, Harvey J. AU - Luksch, Harald AU - Marín, Gonzalo J. ID - 6010 IS - 32 JF - Proceedings of the National Academy of Sciences SN - 0027-8424 TI - “Shepherd’s crook” neurons drive and synchronize the enhancing and suppressive mechanisms of the midbrain stimulus selection network VL - 115 ER -