Hyperoxia Causes Mitochondrial Fragmentation in Pulmonary Endothelial Cells by Increasing Expression of Pro-Fission Proteins

Objective—We explored mechanisms that alter mitochondrial structure and function in pulmonary endothelial cells (PEC) function after hyperoxia. Approach and Results—Mitochondrial structures of PECs exposed to hyperoxia or normoxia were visualized and mitochondrial fragmentation quantified. Expression of pro-fission or fusion proteins or autophagy-related proteins were assessed by Western blot. Mitochondrial oxidative state was determined using mito-roGFP. Tetramethylrhodamine methyl ester estimated mitochondrial polarization in treatment groups. The role of mitochondrially derived reactive oxygen species in mt-fragmentation was investigated with mito-TEMPOL and mitochondrial DNA (mtDNA) damage studied by using ENDO III (mt-tat-endonuclease III), a protein that repairs mDNA damage. Drp-1 (dynamin-related protein 1) was overexpressed or silenced to test the role of this protein in cell survival or transwell resistance. Hyperoxia increased fragmentation of PEC mitochondria in a time-dependent manner through 48 hours of exposure. Hyperoxic PECs exhibited increased phosphorylation of Drp-1 (serine 616), decreases in Mfn1 (mitofusion protein 1), but increases in OPA-1 (optic atrophy 1). Pro-autophagy proteins p62 (LC3 adapter–binding protein SQSTM1/p62), PINK-1 (PTEN-induced putative kinase 1), and LC3B (microtubule-associated protein 1A/1B-light chain 3) were increased. Returning cells to normoxia for 24 hours reversed the increased mt-fragmentation and changes in expression of pro-fission proteins. Hyperoxia-induced changes in mitochondrial structure or cell survival were mitigated by antioxidants mito-TEMPOL, Drp-1 silencing, or inhibition or protection by the mitochondrial endonuclease ENDO III. Hyperoxia induced oxidation and mitochondrial depolarization and impaired transwell resistance. Decrease in resistance was mitigated by mito-TEMPOL or ENDO III and reproduced by overexpression of Drp-1. Conclusions—Because hyperoxia evoked mt-fragmentation, cell survival and transwell resistance are prevented by ENDO III and mito-TEMPOL and Drp-1 silencing, and these data link hyperoxia-induced mt-DNA damage, Drp-1 expression, mt-fragmentation, and PEC dysfunction

The K-band luminosity function at z=1: a powerful constraint on galaxy formation theory

There are two major approaches to modelling galaxy evolution. The traditional view is that the most massive galaxies were assembled early and have evolved with steeply declining star formation rates since a redshift of 2 or higher. According to hierarchical theories, massive galaxies were assembled much more recently from mergers of smaller subunits. Here we present a simple observational test designed to differentiate between the two. The observed K-band flux from a galaxy is a good measure of its stellar mass even at high redshift. It is probably only weakly affected by dust extinction. We compute the evolution of the observed K-band luminosity function for traditional, pure luminosity evolution (PLE) models and for hierarchical models. At z=0, both models can fit the observed local K-band luminosity function. By redshift 1, they differ greatly in the predicted abundance of bright galaxies. We calculate the redshift distributions of K-band selected galaxies and compare these with available data. We show that the number of K<19 galaxies with redshifts greater than 1 is well below the numbers predicted by the PLE models. In the Songaila et al (1994) redshift sample of 118 galaxies with 16<K<18, 33 galaxies are predicted to lie at z>1. Only 2 are observed. In the Cowie et al. (1996) redshift sample of 52 galaxies with 18<K<19, 28 galaxies are predicted to lie at at z>1. Only 5 are observed. Both these samples are more than 90% complete. We conclude that there is already strong evidence that the abundance of massive galaxies at z=1 is well below the local value. This is inconsistent with the traditional model, but similar to the expectations of hierarchical models.Comment: 13 pages, Latex, 4 figures included in text, submitted to MNRAS pink page

Estimating the mass density of neutral gas at z<1z < 1

We use the relationships between galactic HI mass and B-band luminosity determined by Rao & Briggs to recalculate the mass density of neutral gas at the present epoch based on more recent measures of the galaxy luminosity function than were available to those authors. We find $\Omega_{gas}(z=0) \simeq 5 \times 10^{-4}$ in good agreement with the original Rao & Briggs value, suggesting that this quantity is now reasonably secure. We then show that, if the scaling between H I mass and B-band luminosity has remained approximately constant since $z = 1$, the evolution of the luminosity function found by the Canada-France redshift survey translates to an increase of $\Omega_{gas}$ by a factor of $\approx 3$ at $z = 0.5 - 1$ . A similar value is obtained quite independently from consideration of the luminosity function of Mg II absorbers at $z = 0.65$. By combining these new estimates with data from damped \lya systems at higher redshift, it is possible to assemble a rough sketch of the evolution of $\Omega_{gas}$ over the last 90% of the age of the universe. The consumption of H I gas with time is in broad agreement with models of chemical evolution which include the effects of dust, although more extensive samples of damped \lya systems at low and intermediate redshift are required for a quantitative assessment of the dust bias.Comment: LaTeX file, 11 pages, 1 figure, accepted MNRAS pink page

A frequency-selective feedback model of auditory efferent suppression and its implications for the recognition of speech in noise

The potential contribution of the peripheral auditory efferent system to our understanding of speech in a background of competing noise was studied using a computer model of the auditory periphery and assessed using an automatic speech recognition system. A previous study had shown that a fixed efferent attenuation applied to all channels of a multi-channel model could improve the recognition of connected digit triplets in noise [G. J. Brown, R. T. Ferry, and R. Meddis, J. Acoust. Soc. Am. 127, 943?954 (2010)]. In the current study an anatomically justified feedback loop was used to automatically regulate separate attenuation values for each auditory channel. This arrangement resulted in a further enhancement of speech recognition over fixed-attenuation conditions. Comparisons between multi-talker babble and pink noise interference conditions suggest that the benefit originates from the model?s ability to modify the amount of suppression in each channel separately according to the spectral shape of the interfering sounds

On the category of Euclidean configuration spaces and associated fibrations

We calculate the Lusternik-Schnirelmann category of the k-th ordered configuration spaces F(R^n,k) of R^n and give bounds for the category of the corresponding unordered configuration spaces B(R^n,k) and the sectional category of the fibrations pi^n_k: F(R^n,k) --> B(R^n,k). We show that secat(pi^n_k) can be expressed in terms of subspace category. In many cases, eg, if n is a power of 2, we determine cat(B(R^n,k)) and secat(pi^n_k) precisely.Comment: This is the version published by Geometry & Topology Monographs on 19 March 200