PMI: A Delta Psi(m) Independent Pharmacological Regulator of Mitophagy

Mitophagy is central to mitochondrial and cellular homeostasis and operates via the PINK1/Parkin pathway targeting mitochondria devoid of membrane potential (ΔΨm) to autophagosomes. Although mitophagy is recognized as a fundamental cellular process, selective pharmacologic modulators of mitophagy are almost nonexistent. We developed a compound that increases the expression and signaling of the autophagic adaptor molecule P62/SQSTM1 and forces mitochondria into autophagy. The compound, P62-mediated mitophagy inducer (PMI), activates mitophagy without recruiting Parkin or collapsing ΔΨm and retains activity in cells devoid of a fully functional PINK1/Parkin pathway. PMI drives mitochondria to a process of quality control without compromising the bio-energetic competence of the whole network while exposing just those organelles to be recycled. Thus, PMI circumvents the toxicity and some of the nonspecific effects associated with the abrupt dissipation of ΔΨm by ionophores routinely used to induce mitophagy and represents a prototype pharmacological tool to investigate the molecular mechanisms of mitophagy

Is preparing for a language switch like preparing for a task switch? (article)

This is the author accepted manuscript. The final version is available from APA via the DOI in this recordThe dataset associated with this article is located in ORE at https://doi.org/10.24378/exe.403There is another ORE record for this publication: http://hdl.handle.net/10871/36569A key index of top-down control in task switching-preparation for a switch-is underexplored in language switching. The well-documented EEG "signature" of preparation for a task switch-a protracted positive-polarity modulation over the posterior scalp-has thus far not been reported in language switching, and the interpretation of previously reported effects of preparation on language switching performance is complicated by confounding factors. In an experiment using event-related potentials (ERPs) and an optimized picture-naming paradigm that addressed these confounds the language was specified by an auditory cue on every trial and changed unpredictably. There were two key manipulations. First, the cue-stimulus interval allowed either generous (1,500 ms) or little (100 ms) opportunity for preparation. Second, to explore the interplay between bottom-up and top-down language selection, we compared a highly transparent and familiar "supercue"-the name of the language spoken in that language to a relatively opaque cue (short speeded-up fragment of national anthem). Preparation for a switch elicited a brain potential strongly reminiscent of the posterior switch positivity documented in task switching. As previously shown in task switching, its amplitude inversely predicted the performance "switch cost," demonstrated by our ERP analyses contingent on reaction time (RT). This overlap in the electrophysiological correlates of preparing to switch tasks and languages suggests domain-general processes for top-down selection of task-set and language for production. But, the surprisingly small language switch cost following the supercue in the short CSI suggests that rapid and (possibly automatic) bottom-up selection-not typically observed in task switching-may also occur. (PsycINFO Database RecordThe research described in this paper was supported by a PhD scholarship to the second author from the Economic and Social Research Council (ESRC, UK)

Using machine learning to parametrize postmerger signals from binary neutron stars

There is growing interest in the detection and characterization of gravitational waves from postmerger oscillations of binary neutron stars. These signals contain information about the nature of the remnant and the high-density and out-of-equilibrium physics of the postmerger processes, which would complement any electromagnetic signal. However, the construction of binary neutron star postmerger waveforms is much more complicated than for binary black holes: (i) there are theoretical uncertainties in the neutron-star equation of state and other aspects of the high-density physics, (ii) numerical simulations are expensive and available ones only cover a small fraction of the parameter space with limited numerical accuracy, and (iii) it is unclear how to parametrize the theoretical uncertainties and interpolate across parameter space. In this work, we describe the use of a machine-learning method called a conditional variational autoencoder (CVAE) to construct postmerger models for hyper/massive neutron star remnant signals based on numerical-relativity simulations. The CVAE provides a probabilistic model, which encodes uncertainties in the training data within a set of latent parameters. We estimate that training such a model will ultimately require $\sim 10^4$ waveforms. However, using synthetic training waveforms as a proof-of-principle, we show that the CVAE can be used as an accurate generative model and that it encodes the equation of state in a useful latent representation

Perceived non-smoking norms and motivation to stop smoking, quit attempts, and cessation: a cross-sectional study in England

This study examined the prevalence of non-smoking norms in England and their associations with motivation to stop smoking, quit attempts, and cessation. Data were from a representative cross-sectional survey of 1,521 adults (301 combustible tobacco smokers). Descriptive non-smoking norms were endorsed, with just 16% of adults (12% of smokers) believing smoking was uncommon. Injunctive non-smoking norms were more prevalent, with 60–77% of adults (17–48% of smokers) viewing smoking as something of which others disapproved. Personal non-smoking norms were also prevalent among all adults (73% indicated they would prefer to live with a non-smoker) but not smokers (69% had no preference). Smokers who endorsed stronger descriptive non-smoking norms had increased odds of reporting high motivation to stop smoking (ORadj = 1.63, 95%CI 1.06–2.52). Female (but not male) past-year smokers who endorsed stronger injunctive (ORadj = 2.19, 95%CI 1.41–3.42) and personal (ORadj = 1.90, 95%CI 1.29–2.82) non-smoking norms had increased odds of having made a past-year quit attempt. In conclusion, perceived descriptive non-smoking norms are not held by the majority of adults in England. Injunctive and personal non-smoking norms are prevalent among all adults but lower among smokers. There is some evidence that smokers – in particular, women – who endorse stronger non-smoking norms are more likely to be motivated to stop smoking and to make a quit attempt

The Wisconsin H-Alpha Mapper Northern Sky Survey

The Wisconsin H-Alpha Mapper (WHAM) has surveyed the distribution and kinematics of ionized gas in the Galaxy above declination -30 degrees. The WHAM Northern Sky Survey (WHAM-NSS) has an angular resolution of one degree and provides the first absolutely-calibrated, kinematically-resolved map of the H-Alpha emission from the Warm Ionized Medium (WIM) within ~ +/-100 km/s of the Local Standard of Rest. Leveraging WHAM's 12 km/s spectral resolution, we have modeled and removed atmospheric emission and zodiacal absorption features from each of the 37,565 spectra. The resulting H-Alpha profiles reveal ionized gas detected in nearly every direction on the sky with a sensitivity of 0.15 R (3 sigma). Complex distributions of ionized gas are revealed in the nearby spiral arms up to 1-2 kpc away from the Galactic plane. Toward the inner Galaxy, the WHAM-NSS provides information about the WIM out to the tangent point down to a few degrees from the plane. Ionized gas is also detected toward many intermediate velocity clouds at high latitudes. Several new H II regions are revealed around early B-stars and evolved stellar cores (sdB/O). This work presents the details of the instrument, the survey, and the data reduction techniques. The WHAM-NSS is also presented and analyzed for its gross properties. Finally, some general conclusions are presented about the nature of the WIM as revealed by the WHAM-NSS.Comment: 42 pages, 14 figures (Fig 6-9 & 14 are full color); accepted for publication in 2003, ApJ, 149; Original quality figures (as well as data for the survey) are available at http://www.astro.wisc.edu/wham

Plasma Dynamics

Contains reports on four research projects

One along side the other : the collected letters of William Carlos Williams and Kenneth Burke

The collected letters of William Carlos Williams and Kenneth Burke from the Beineke Library at Yale, the Pattee Library at The Pennsylvania State University, and the Kenneth Burke estate, which span the entire forty-two years .of their relationship from 1921-1962, have been collected, collated, annotated, and introduced. The introduction describes their first meeting, offers a brief look at their lives and works, and contrasts their relationship with that of the attenuated image created by the John C. Thirlwall Selected Letters of William Carlos Williams (1957). The introduction goes on to examine the nature of their relationship as reflected by The Collected Letters and information gathered from interviews with Kenneth Burke, Michael Burke, and Bill Williams, Jr., as well as other sources and concludes with a brief characterization of the nature of their collaboration