Abstract In neurological disorders, both acute and chronic neural stress can disrupt cellular proteostasis, resulting in the generation of pathological protein. However in most cases, neurons adapt ...to these proteostatic perturbations by activating a range of cellular protective and repair responses, thus maintaining cell function. These interconnected adaptive mechanisms comprise a ‘proteostasis network’ and include the unfolded protein response, the ubiquitin proteasome system and autophagy. Interestingly, several recent studies have shown that these adaptive responses can be stimulated by preconditioning treatments, which confer resistance to a subsequent toxic challenge – the phenomenon known as hormesis. In this review we discuss the impact of adaptive stress responses stimulated in diverse human neuropathologies including Parkinson׳s disease, Wolfram syndrome, brain ischemia, and brain cancer. Further, we examine how these responses and the molecular pathways they recruit might be exploited for therapeutic gain. This article is part of a Special Issue entitled SI:ER stress.
Interstellar dust and starlight are modeled for the galaxies of the project "Key Insights on Nearby Galaxies: A Far-Infrared Survey with Herschel." The galaxies were observed by the Infrared Array ...Camera and the Multiband Imaging Photometer for Spitzer on Spitzer Space Telescope, and the Photodetector Array Camera and Spectrometer and the Spectral and Photometric Imaging Receiver on Herschel Space Observatory. With data from 3.6 to 500 m, dust models are strongly constrained. Using a physical dust model, for each pixel in each galaxy we estimate (1) dust surface density, (2) dust mass fraction in polycyclic aromatic hydrocarbons (PAHs), (3) distribution of starlight intensities heating the dust, (4) total infrared (IR) luminosity emitted by the dust, and (5) IR luminosity originating in subregions with high starlight intensity. The dust models successfully reproduce the observed global and resolved spectral energy distributions. With the angular resolution of Herschel, we obtain well-resolved maps (available online) for the dust properties. As in previous studies, we find the PAH fraction to be an increasing function of metallicity, with a threshold oxygen abundance Z/Z 0.1, but we find the data to be fitted best with increasing linearly with above a threshold value of 0.15(O/H) . We obtain total dust masses for each galaxy by summing the dust mass over the individual map pixels; these "resolved" dust masses are consistent with the masses inferred from a model fit to the global photometry. The global dust-to-gas ratios obtained from this study are found to correlate with galaxy metallicities. Systems with Z/Z 0.5 have most of their refractory elements locked up in dust, whereas in systems with Z/Z 0.3 most of these elements tend to remain in the gas phase. Within galaxies, we find that is suppressed in regions with unusually warm dust with . With knowledge of one long-wavelength flux density ratio (e.g., f160/f500), the minimum starlight intensity heating the dust ( ) can be estimated to within ∼50%, despite a variation in of more than two orders of magnitude. For the adopted dust model, dust masses can be estimated to within ∼0.2 dex accuracy using the f160/f500 flux ratio and the integrated dust luminosity, and to ∼0.07 dex accuracy using the 500 m luminosity alone. There are additional systematic errors arising from the choice of dust model, but these are hard to estimate. These calibrated prescriptions for estimating starlight heating intensity and dust mass may be useful for studies of high-redshift galaxies.
When combined with infrared observations with the Spitzer telescope (3 to 160 μm), the Herschel
Space Observatory now fully samples the thermal dust emission up to 500 μm and enables us to better ...estimate the total infrared-submm energy budget (L
TIR) of nearby galaxies. We present new empirical calibrations to estimate resolved and integrated total infrared luminosities from Spitzer and Herschel bands used as monochromatic or combined tracers. We base our calibrations on resolved elements of nearby galaxies (3 to 30 Mpc) observed with Herschel. We perform a resolved spectral energy distribution (SED) modelling of these objects using the Draine & Li dust models and investigate the influence of the addition of Spectral and Photometric Imaging Receiver (SPIRE) measurements in the estimation of L
TIR. We find that using data up to 250 μm leads to local L
TIR values consistent with those obtained with a complete coverage (up to 500 μm) within ±10 per cent for most of our resolved elements. We then study the distribution of energy in the resolved SEDs of our galaxies. The bulk of energy (30-50 per cent) is contained in the 70-160 μm band. The 24-70 μm fraction decreases with increasing metallicity. The 160-1100 μmsubmillimetre band can account for up to 25 per cent of the L
TIR in metal-rich galaxies. We investigate the correlation between the total infrared (TIR) surface brightnesses/luminosities and monochromatic Spitzer and Herschel surface brightnesses/luminosities. The three Photodetector Array Camera and Spectrometer (PACS) bands can be used as reliable monochromatic estimators of the L
TIR, the 100 μm band being the most reliable monochromatic tracer. There is also a strong correlation between the SPIRE 250 μm and L
TIR, although with more scatter than for the PACS relations. We also study the ability of our monochromatic relations to reproduce integrated L
TIR of nearby galaxies as well as L
TIR of z ∼ 1-3 sources. Finally, we provide calibration coefficients that can be used to derive TIR surface brightnesses/luminosities from a combination of Spitzer and Herschel surface brightnesses/fluxes and analyse the associated uncertainties.
The physical state of interstellar gas and dust is dependent on the processes which heat and cool this medium. To probe heating and cooling of the interstellar medium over a large range of infrared ...surface brightness, on sub-kiloparsec scales, we employ line maps of CII 158 mu m, OI 63 mu m, and NII 122 mu m in NGC 1097 and NGC 4559, obtained with the Photodetector Array Camera & Spectrometer on board Herschel. We matched new observations to existing Spitzer Infrared Spectrograph data that trace the total emission of polycyclic aromatic hydrocarbons (PAHs). We confirm at small scales in these galaxies that the canonical measure of photoelectric heating efficiency, (CII + OI)/TIR, decreases as the far-infrared (far-IR) color, nufunctionof sub(nu)(70 mu m) nufunctionof sub(nu)(100 mu m), increases. In contrast, the ratio of far-IR cooling to total PAH emission, (CII + OI)/PAH, is a near constant ~6% over a wide range of far-IR color, 0.5 < nufunctionof sub(nu)(70 mu m) nufunctionof sub(nu)(100 mu m) <, ~0.95. In the warmest regions, where nufunctionof sub(nu)(70 mu m) nufunctionof sub(nu)(100 mu m) > ~0.95, the ratio (CII + OII)/PAH drops rapidly to 4%. We derived representative values of the local ultraviolet radiation density, G sub(0), and the gas density, n sub(H), by comparing our observations to models of photodissociation regions. The ratio G sub(0)/n sub(H), derived from fine-structure lines, is found to correlate with the mean dust-weighted starlight intensity, left angle bracketUright angle bracket, derived from models of the IR spectral energy distribution. Emission from regions that exhibit a line deficit is characterized by an intense radiation field, indicating that small grains are susceptible to ionization effects. We note that there is a shift in the 7.7/11.3 mu m PAH ratio in regions that exhibit a deficit in (CII + OI)/PAH, suggesting that small grains are ionized in these environments.
New far-infrared and submillimeter photometry from the Herschel Space Observatory is presented for 61 nearby galaxies from the Key Insights on Nearby Galaxies: A Far-Infrared Survey with Herschel ...(KINGFISH) sample. The spatially integrated fluxes are largely consistent with expectations based on Spitzer far-infrared photometry and extrapolations to longer wavelengths using popular dust emission models. Dwarf irregular galaxies are notable exceptions, as already noted by other authors, as their 500 mu m emission shows evidence for a submillimeter excess. In addition, the fraction of dust heating attributed to intense radiation fields associated with photodissociation regions is found to be (21 + or - 4)% larger when Herschel data are included in the analysis. Dust masses obtained from the dust emission models of Draine & Li are found to be on average nearly a factor of two higher than those based on single-temperature modified blackbodies, as single blackbody curves do not capture the full range of dust temperatures inherent to any galaxy. The discrepancy is largest for galaxies exhibiting the coolest far-infrared colors.
Reverse transcription quantitative-polymerase chain reaction (RT-qPCR) has become a routine method in many laboratories. Normalization of data from experimental conditions is critical for data ...processing and is usually achieved by the use of a single reference gene. Nevertheless, as pointed by the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines, several reference genes should be used for reliable normalization. Ageing is a physiological process that results in a decline of many expressed genes. Reliable normalization of RT-qPCR data becomes crucial when studying ageing. Here, we propose a RT-qPCR study from four mouse brain regions (cortex, hippocampus, striatum and cerebellum) at different ages (from 8 weeks to 22 months) in which we studied the expression of nine commonly used reference genes. With the use of two different algorithms, we found that all brain structures need at least two genes for a good normalization step. We propose specific pairs of gene for efficient data normalization in the four brain regions studied. These results underline the importance of reliable reference genes for specific brain regions in ageing.
We characterize the dust in NGC 628 and NGC 6946, two nearby spiral galaxies in the KINGFISH sample. With data from 3.6 mu m to 500 mu m, dust models are strongly constrained. Using the Draine & Li ...dust model (amorphous silicate and carbonaceous grains), for each pixel in each galaxy we estimate (1) dust mass surface density, (2) dust mass fraction contributed by polycyclic aromatic hydrocarbons, (3) distribution of starlight intensities heating the dust, (4) total infrared (IR) luminosity emitted by the dust, and (5) IR luminosity originating in regions with high starlight intensity. We obtain maps for the dust properties, which trace the spiral structure of the galaxies. The dust models successfully reproduce the observed global and resolved spectral energy distributions (SEDs). The overall dust/H mass ratio is estimated to be 0.0082 + or - 0.0017 for NGC 628, and 0.0063 + or - 0.0009 for NGC 6946, consistent with what is expected for galaxies of near-solar metallicity. Our derived dust masses are larger (by up to a factor of three) than estimates based on single-temperature modified blackbody fits. We show that the SED fits are significantly improved if the starlight intensity distribution includes a (single intensity) "delta function" component. We find no evidence for significant masses of cold dust (T <, ~ 12 K). Discrepancies between PACS and MIPS photometry in both low and high surface brightness areas result in large uncertainties when the modeling is done at PACS resolutions, in which case SPIRE, MIPS70, and MIPS160 data cannot be used. We recommend against attempting to model dust at the angular resolution of PACS.
Thrombolysis with tissue-type plasminogen activator (tPA) is used for the treatment of patients with acute ischemic stroke. However, a growing body of evidence indicates that, besides the ...unquestionable benefit from its thrombolytic activity, tPA also has a deleterious effect on the ischemic brain including cytotoxicity and increased permeability of the neurovascular unit with the development of cerebral edema. Because an increasing number of acute stroke patients are treated with tPA, it is important to know the mechanisms of harmful effects of tPA on the ischemic brain. Here, the best studied pathways of tPA neurotoxicity are discussed along with future directions for a safer use of tPA as a thrombolytic agent in the setting of acute ischemic stroke.
Alpha-1 antitrypsin (α1-AT) is the most abundant circulating protease inhibitor. The common severe Z allele of α1-AT (Glu342Lys) causes the protein to form ordered polymers that are retained within ...the endoplasmic reticulum of hepatocytes. These polymers form the periodic acid-Schiff positive inclusions that are associated with cirrhosis. The lack of circulating α1-AT predisposes the Z α1-AT homozygote to early onset emphysema. We review here the molecular basis of α1-AT deficiency and show how understanding the liver disease provides new insights in the pathobiology of the associated emphysema. The mechanism of α1-AT deficiency provides a paradigm for a wider group of conditions that we have termed the serpinopathies. We also examine the strategies that are being pursued to develop novel therapies for α1-AT deficiency. This review considers our understanding of the pathobiology of α1-AT deficiency and then illustrate the therapeutic possibilities that can ensue once we understand basic mechanisms of disease.
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