2,721 research outputs found
Outer mitochondrial membrane localization of apoptosis-inducing factor: mechanistic implications for release
Poly(ADP-ribose) polymerase-1-dependent cell death (known as parthanatos) plays a pivotal role in many clinically important events including ischaemia/reperfusion injury and glutamate excitotoxicity. A recent study by us has shown that uncleaved AIF (apoptosis-inducing factor), but not calpain-hydrolysed truncated-AIF, was rapidly released from the mitochondria during parthanatos, implicating a second pool of AIF that might be present in brain mitochondria contributing to the rapid release. In the present study, a novel AIF pool is revealed in brain mitochondria by multiple biochemical analyses. Approx. 30% of AIF loosely associates with the outer mitochondrial membrane on the cytosolic side, in addition to its main localization in the mitochondrial intermembrane space attached to the inner membrane. Immunogold electron microscopic analysis of mouse brain further supports AIF association with the outer, as well as the inner, mitochondrial membrane in vivo. In line with these observations, approx. 20% of uncleaved AIF rapidly translocates to the nucleus and functionally causes neuronal death upon NMDA (N-methyl-d-aspartate) treatment. In the present study we show for the first time a second pool of AIF in brain mitochondria and demonstrate that this pool does not require cleavage and that it contributes to the rapid release of AIF. Moreover, these results suggest that this outer mitochondrial pool of AIF is sufficient to cause cell death during parthanatos. Interfering with the release of this outer mitochondrial pool of AIF during cell injury paradigms that use parthanatos hold particular promise for novel therapies to treat neurological disorders
Reward processing in autism: a thematic series
This thematic series presents theoretical and empirical papers focused on understanding autism from the perspective of reward processing deficits. Although the core symptoms of autism have not traditionally been conceptualized with respect to altered reward-based processes, it is clear that brain reward circuitry plays a critical role in guiding social and nonsocial learning and behavior throughout development. Additionally, brain reward circuitry may respond to social sources of information in ways that are similar to responses to primary rewards, and recent clinical data consistently suggest abnormal behavioral and neurobiologic responses to rewards in autism. This thematic series presents empirical data and review papers that highlight the utility of considering autism from the perspective of reward processing deficits. Our hope is that this novel framework may further elucidate autism pathophysiology, with the ultimate goal of yielding novel insights with potential therapeutic implications
Clinimetrics in rehabilitation medicine: current issues in developing and applying measurement instruments 1
Clinimetrics in rehabilitation medicine, i.e. the field of developing, evaluating and applying measurement instruments, has undergone considerable progress. Despite this progress, however, several issues remain. These include: (i) selection of an instrument out of the wide range available; (ii) using an instrument in a variety of diagnostic groups; (iii) using an instrument in individual patients, as opposed to a group of patients; and (iv) the use of instruments in clinical practice. This paper reviews these issues, as well as current attempts at resolving them. Illustrative examples are given. It is concluded that solutions seem to be available, but considerable research effort is required to make these a reality. Clinimetrics in rehabilitation medicine remains a field with challenging opportunities for researc
RELICS: The Reionization Lensing Cluster Survey and the Brightest High-z Galaxies
Massive foreground galaxy clusters magnify and distort the light of objects behind them, permitting a view into both the extremely distant and intrinsically faint galaxy populations. We present here the z ~ 6-8 candidate high-redshift galaxies from the Reionization Lensing Cluster Survey (RELICS), a Hubble and Spitzer Space Telescope survey of 41 massive galaxy clusters spanning an area of ≈200 arcmin². These clusters were selected to be excellent lenses, and we find similar high-redshift sample sizes and magnitude distributions as the Cluster Lensing And Supernova survey with Hubble (CLASH). We discover 257, 57, and eight candidate galaxies at z ~ 6, 7, and 8 respectively, (322 in total). The observed (lensed) magnitudes of the z ~ 6 candidates are as bright as AB mag ~23, making them among the brightest known at these redshifts, comparable with discoveries from much wider, blank-field surveys. RELICS demonstrates the efficiency of using strong gravitational lenses to produce high-redshift samples in the epoch of reionization. These brightly observed galaxies are excellent targets for follow-up study with current and future observatories, including the James Webb Space Telescope
The detection of the imprint of filaments on cosmic microwave background lensing
Galaxy redshift surveys, such as 2dF, SDSS, 6df, GAMA and VIPERS, have shown
that the spatial distribution of matter forms a rich web, known as the cosmic
web. The majority of galaxy survey analyses measure the amplitude of galaxy
clustering as a function of scale, ignoring information beyond a small number
of summary statistics. Since the matter density field becomes highly
non-Gaussian as structure evolves under gravity, we expect other statistical
descriptions of the field to provide us with additional information. One way to
study the non-Gaussianity is to study filaments, which evolve non-linearly from
the initial density fluctuations produced in the primordial Universe. In our
study, we report the first detection of CMB (Cosmic Microwave Background)
lensing by filaments and we apply a null test to confirm our detection.
Furthermore, we propose a phenomenological model to interpret the detected
signal and we measure how filaments trace the matter distribution on large
scales through filament bias, which we measure to be around 1.5. Our study
provides a new scope to understand the environmental dependence of galaxy
formation. In the future, the joint analysis of lensing and Sunyaev-Zel'dovich
observations might reveal the properties of `missing baryons', the vast
majority of the gas which resides in the intergalactic medium and has so far
evaded most observations
Hypercharge and the Cosmological Baryon Asymmetry
Stringent bounds on baryon and lepton number violating interactions have been
derived from the requirement that such interactions, together with electroweak
instantons, do not destroy a cosmological baryon asymmetry produced at an
extremely high temperature in the big bang. While these bounds apply in
specific models, we find that they are generically evaded. In particular, the
only requirement for a theory to avoid these bounds is that it contain charged
particles which, during a certain cosmological epoch, carry a non-zero
hypercharge asymmetry. Hypercharge neutrality of the universe then dictates
that the remaining particles must carry a compensating hypercharge density,
which is necessarily shared amongst them so as to give a baryon asymmetry.
Hence the generation of a hypercharge density in a sector of the theory forces
the universe to have a baryon asymmetry.Comment: 12 pages plus 1 Postscript figure available upon request. LBL 3482
Fructose transport-deficient Staphylococcus aureus reveals important role of epithelial glucose transporters in limiting sugar-driven bacterial growth in airway surface liquid.
Hyperglycaemia as a result of diabetes mellitus or acute illness is associated with increased susceptibility to respiratory infection with Staphylococcus aureus. Hyperglycaemia increases the concentration of glucose in airway surface liquid (ASL) and promotes the growth of S. aureus in vitro and in vivo. Whether elevation of other sugars in the blood, such as fructose, also results in increased concentrations in ASL is unknown and whether sugars in ASL are directly utilised by S. aureus for growth has not been investigated. We obtained mutant S. aureus JE2 strains with transposon disrupted sugar transport genes. NE768(fruA) exhibited restricted growth in 10Â mM fructose. In H441 airway epithelial-bacterial co-culture, elevation of basolateral sugar concentration (5-20Â mM) increased the apical growth of JE2. However, sugar-induced growth of NE768(fruA) was significantly less when basolateral fructose rather than glucose was elevated. This is the first experimental evidence to show that S. aureus directly utilises sugars present in the ASL for growth. Interestingly, JE2 growth was promoted less by glucose than fructose. Net transepithelial flux of D-glucose was lower than D-fructose. However, uptake of D-glucose was higher than D-fructose across both apical and basolateral membranes consistent with the presence of GLUT1/10 in the airway epithelium. Therefore, we propose that the preferential uptake of glucose (compared to fructose) limits its accumulation in ASL. Pre-treatment with metformin increased transepithelial resistance and reduced the sugar-dependent growth of S. aureus. Thus, epithelial paracellular permeability and glucose transport mechanisms are vital to maintain low glucose concentration in ASL and limit bacterial nutrient sources as a defence against infection
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Reduced preference for social rewards in a novel tablet based task in young children with Autism Spectrum Disorders
Atypical responsivity to social rewards has been observed in young children with or at risk of Autism Spectrum Disorders (ASD). These observations contributed to the hypothesis of reduced social motivation in ASD. In the current study we develop a novel task to test social reward preference using a tablet computer (iPad), where two differently coloured buttons were associated with a social and a nonsocial rewarding image respectively. 63 young children, aged 14–68 months, with and without a diagnosis of ASD took part in the study. The experimental sessions were also recorded on video, using an in-built webcam on the tablet as well as an external camera. Children with ASD were found to show a reduced relative preference for social rewards, indexed by a lower proportion of touches for the button associated with the social reward image. Greater social preference as measured using the tablet-based task was associated with increased use of social communicative behaviour such as eye contact with the experimenter and social smile in response to the social reward image. These results are consistent with earlier findings from eye-tracking studies, and provide novel empirical insights into atypical social reward responsivity in ASD
Voluminous lava flows at Oldoinyo Lengai in 2006: chronology of events and insights into the shallow magmatic system
Publisher Correction: Impact of alloy fluctuations and Coulomb effects on the electronic and optical properties of c-plane GaN/AlGaN quantum wells.
An amendment to this paper has been published and can be accessed via a link at the top of the paper
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