Expression of a catalytically inactive mutant form of glutathione peroxidase 4 (Gpx4) confers a dominant-negative effect in male fertility.

The selenoenzyme Gpx4 is essential for early embryogenesis and cell viability for its unique function to prevent phospholipid oxidation. Recently, the cytosolic form of Gpx4 was identified as an upstream regulator of a novel form of non-apoptotic cell death, called ferroptosis, whereas the mitochondrial isoform of Gpx4 (mGpx4) was previously shown to be crucial for male fertility. Here, we generated and analyzed mice with targeted mutation of the active site selenocysteine (Sec) of Gpx4 (Gpx4_U46S). Mice homozygous for Gpx4_U46S died at the same embryonic stage (E7.5) as Gpx4-/- embryos as expected. Surprisingly, male mice heterozygous for Gpx4_U46S presented subfertility. Subfertility was manifested in a reduced number of litters from heterozygous breedings and an impairment of spermatozoa to fertilize oocytes in vitro. Morphologically, sperm isolated from heterozygous Gpx4_U46S mice revealed many structural abnormalities particularly in the spermatozoan midpiece due to improper oxidation and polymerization of sperm capsular proteins and malformation of the mitochondrial capsule surrounding and stabilizing sperm mitochondria. These findings are reminiscent of sperm isolated from selenium-deprived rodents or from mice specifically lacking mGpx4. Due to a strongly facilitated incorporation of Ser in the polypeptide chain as compared to Sec at the UGA codon, expression of the catalytically inactive Gpx4_U46S was found to be strongly increased. Since the stability of the mitochondrial capsule of mature spermatozoa depends on the moonlighting function of Gpx4 both as an enzyme oxidizing capsular protein thiols and being a structural protein, tightly controlled expression of functional Gpx4 emerges being key for full male fertility

Surface acoustic waves induced micropatterning of cells in gelatin methacryloyl (GelMA) hydrogels

Acoustic force patterning is an emerging technology that provides a platform to control the spatial location of cells in a rapid, accurate, yet contactless manner. However, very few studies have been reported on the usage of acoustic force patterning for the rapid arrangement of biological objects, such as cells, in a three-dimensional (3D) environment. In this study, we report on a bio-acoustic force patterning technique, which uses surface acoustic waves (SAWs) for the rapid arrangement of cells within an extracellular matrix-based hydrogel such as gelatin methacryloyl (GelMA). A proof-of-principle was achieved through both simulations and experiments based on the in-house fabricated piezoelectric SAW transducers, which enabled us to explore the effects of various parameters on the performance of the built construct. The SAWs were applied in a fashion that generated standing SAWs (SSAWs) on the substrate, the energy of which subsequently was transferred into the gel, creating a rapid, and contactless alignment of the cells (<10 s, based on the experimental conditions). Following ultraviolet radiation induced photo-crosslinking of the cell encapsulated GelMA pre-polymer solution, the patterned cardiac cells readily spread after alignment in the GelMA hydrogel and demonstrated beating activity in 5–7 days. The described acoustic force assembly method can be utilized not only to control the spatial distribution of the cells inside a 3D construct, but can also preserve the viability and functionality of the patterned cells (e.g. beating rates of cardiac cells). This platform can be potentially employed in a diverse range of applications, whether it is for tissue engineering, in vitro cell studies, or creating 3D biomimetic tissue structures

Protoplanetary disc evolution affected by star-disc interactions in young stellar clusters

This article has been accepted for publication in Monthly Notices of the Royal Astronomical Society. © 2014 The Authors. Published by Oxford University Press on behalf of the Royal Astronomical Society.Most stars form in a clustered environment. Therefore, it is important to assess how this environment influences the evolution of protoplanetary discs around young stars. In turn, this affects their ability to produce planets and ultimately life. We present here for the first time 3D smoothed particle hydrodynamics/N-body simulations that include both the hydrodynamical evolution of the discs around their natal stars, as well as the dynamics of the stars themselves. The discs are viscously evolving, accreting mass on to the central star and spreading. We find penetrating encounters to be very destructive for the discs as in previous studies, although the frequency of such encounters is low. We also find, however, that encounter influence the disc radii more strongly than other disc properties such as the disc mass. The disc sizes are set by the competition between viscous spreading and the disruptive effect of encounters. As discs spread, encounters become more and more important. In the regime of rapid spreading, encounters simply truncate the discs, stripping the outer portions. In the opposite regime, we find that the effect of many distant encounters is able to limit the disc size. Finally, we predict from our simulations that disc sizes are limited by encounters at stellar densities exceeding ∼2–3 × 103 pc−2.Peer reviewe

Molecular Aspects of Secretory Granule Exocytosis by Neurons and Endocrine Cells

Neuronal communication and endocrine signaling are fundamental for integrating the function of tissues and cells in the body. Hormones released by endocrine cells are transported to the target cells through the circulation. By contrast, transmitter release from neurons occurs at specialized intercellular junctions, the synapses. Nevertheless, the mechanisms by which signal molecules are synthesized, stored, and eventually secreted by neurons and endocrine cells are very similar. Neurons and endocrine cells have in common two different types of secretory organelles, indicating the presence of two distinct secretory pathways. The synaptic vesicles of neurons contain excitatory or inhibitory neurotransmitters, whereas the secretory granules (also referred to as dense core vesicles, because of their electron dense content) are filled with neuropeptides and amines. In endocrine cells, peptide hormones and amines predominate in secretory granules. The function and content of vesicles, which share antigens with synaptic vesicles, are unknown for most endocrine cells. However, in B cells of the pancreatic islet, these vesicles contain GABA, which may be involved in intrainsular signaling.' Exocytosis of both synaptic vesicles and secretory granules is controlled by cytoplasmic calcium. However, the precise mechanisms of the subsequent steps, such as docking of vesicles and fusion of their membranes with the plasma membrane, are still incompletely understood. This contribution summarizes recent observations that elucidate components in neurons and endocrine cells involved in exocytosis. Emphasis is put on the intracellular aspects of the release of secretory granules that recently have been analyzed in detail

Water formation on bare grains: When the chemistry on dust impacts interstellar gas

Context. Water together with O2 are important gas phase ingredients to cool dense gas in order to form stars. On dust grains, H2 O is an important constituent of the icy mantle in which a complex chemistry is taking place, as revealed by hot core observations. The formation of water can occur on dust grain surfaces, and can impact gas phase composition. Aims. The formation of molecules such as OH, H2 O, HO2, H2 O2, as well as their deuterated forms and O2 and O3 is studied in order to assess how the chemistry varies in different astrophysical environments, and how the gas phase is affected by grain surface chemistry. Methods. We use Monte Carlo simulations to follow the formation of molecules on bare grains as well as the fraction of molecules released into the gas phase. We consider a surface reaction network, based on gas phase reactions, as well as UV photo-dissociation of the chemical species. Results. We show that grain surface chemistry has a strong impact on gas phase chemistry, and that this chemistry is very different for different dust grain temperatures. Low temperatures favor hydrogenation, while higher temperatures favor oxygenation. Also, UV photons dissociate the molecules on the surface, that can reform subsequently. The formation-destruction cycle increases the amount of species released into the gas phase. We also determine the time scales to form ices in diffuse and dense clouds, and show that ices are formed only in shielded environments, as supported by observations.Comment: Accepted in A&

Soft X-ray absorption excess in gamma-ray burst afterglow spectra: Absorption by turbulent ISM

This is the accepted manuscript version of the following article: M. Tanga, P. Schady, A. Gatto, J. Greiner, M. G. H. Krause, R. Diehl, S. Savaglio, and S. Walch, ‘Soft X-ray absorption excess in gamma-ray burst afterglow spectra: Absorption by turbulent ISM’ Astronomy & Astrophysics, Vol 595, November 2016, A24. The final, published version is available online at doi: http://dx.doi.org/10.1051/0004-6361/201527961 Reproduced with permission from Astronomy & Astrophysics. © 2018 ESO.Two-thirds of long duration gamma-ray bursts (GRBs) show soft X-ray absorption in excess of the Milky Way. The column densities of metals inferred from UV and optical spectra differ from those derived from soft X-ray spectra, at times by an order of magnitude, with the latter being higher. The origin of the soft X-ray absorption excess observed in GRB X-ray afterglow spectra remains a heavily debated issue, which has resulted in numerous investigations on the effect of hot material both internal and external to the GRB host galaxy on our X-ray afterglow observations. Nevertheless, all models proposed so far have either only been able to account for a subset of our observations (i.e. at z > 2), or they have required fairly extreme conditions to be present within the absorbing material. In this paper, we investigate the absorption of the GRB afterglow by a collisionally ionised and turbulent interstellar medium (ISM). We find that a dense (3 per cubic centimeters) collisionally ionised ISM could produce UV/optical and soft X-ray absorbing column densities that differ by a factor of 10, however the UV/optical and soft X-ray absorbing column densities for such sightlines and are 2-3 orders of magnitude lower in comparison to the GRB afterglow spectra. For those GRBs with a larger soft X-ray excess of up to an order of magnitude, the contribution in absorption from a turbulent ISM as considered here would ease the required conditions of additional absorbing components, such as the GRB circumburst medium and intergalactic medium.Peer reviewedFinal Accepted Versio

Protostellar discs formed from turbulent cores

We investigate the collapse and fragmentation of low-mass, trans-sonically turbulent prestellar cores, using SPH simulations. The initial conditions are slightly supercritical Bonnor-Ebert spheres, all with the same density profile, the same mass (M_O=6.1 Msun) and the same radius (R_O=17,000 AU), but having different initial turbulent velocity fields. Four hundred turbulent velocity fields have been generated, all scaled so that the mean Mach number is M=1. Then a subset of these, having a range of net angular momenta, j, has been evolved. The evolution of these turbulent cores is not strongly correlated with j. Instead it is moderated by the formation of filamentary structures due to converging turbulent flows. A high fraction (~ 82%) of the protostars forming from turbulent cores are attended by protostellar accretion discs, but only a very small fraction (~16%) of these discs is sufficiently cool and extended to develop non-linear gravitational instabilities and fragment.Comment: 10 pages, 8 figures, submitte

Impact of magnetic fields on ram pressure stripping in disk galaxies

(abridged) Ram pressure can remove significant amounts of gas from galaxies in clusters, and thus has a large impact on the evolution of cluster galaxies. Recent observations have shown that key properties of ram pressure stripped tails of galaxies are in conflict with predictions by simulations. To increase the realism of existing simulations, we simulated for the first time a disk galaxy exposed to a uniformly magnetized wind including radiative cooling and self-gravity of the gas. We find that B-fields have a strong effect on the morphology of the gas in the tail of the galaxy. While in the pure hydro case the tail is very clumpy, the MHD case shows very filamentary structures in the tail. The filaments can be strongly supported by magnetic pressure and, when this is the case, the B-field vectors tend to be aligned with the filaments. The ram pressure stripping may lead to the formation of magnetized density tails that appear as bifurcated in the plane of the sky and resemble the double tails observed in ESO 137-001 and ESO 137-002. Such tails can be formed under a variety of situations, both for the disks oriented face-on with respect to the ICM wind and for the tilted ones. While this bifurcation is due to the generic tendency for the B-fields to produce very filamentary tail morphology, the tail properties are further shaped by the combination of the B-field orientation and the sliding of the field past the disk surface exposed to the wind. Magnetic draping does not strongly change the rate of gas stripping. For a face-on galaxy, the field tends to reduce the amount of stripping compared to the pure hydro case, and is associated with the formation of a magnetic draping layer on the side of the galaxy exposed to the ICM wind. For significantly tilted disks, the stripping rate may be enhanced by the ``scraping'' of the disk surface by the B-fields sliding past the ISM/ICM interface.Comment: ApJ in press. arXiv admin note: text overlap with arXiv:0909.3097 by other author

Immunotherapeutic targeting of membrane Hsp70-expressing tumors using recombinant human granzyme B

Background: We have previously reported that human recombinant granzyme B (grB) mediates apoptosis in membrane heat shock protein 70 (Hsp70)-positive tumor cells in a perforin-independent manner