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

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

Heating and Acceleration of Intracluster Medium Electrons by Turbulence

In this paper we investigate the feasibility of bremsstrahlung radiation from `nonthermal' electrons as a source of hard X-rays from the intracluster medium of clusters of galaxies. With an exact treatment of the Coulomb collisions in a Fokker-Planck analysis of the electron distribution we find that the severe difficulties with lifetimes of `nonthermal' particles found earlier by Petrosian (2001) using a cold target model remain problematic. We then address possible acceleration of background electrons into a nonthermal tail. We assume a simplified but generic acceleration rate and determine the expected evolution of an initially Maxwellian distribution of electrons. We find that strong nonthermal components arise only for rapid rate of acceleration which also heats up the entire plasma. These results confirm the conclusion that if the observed `nonthermal' excesses are due to some process accelerating the background thermal electrons this process must be short lived.Comment: 28 pages, 7 figures. Astrophysical Journal, in pres

Ranks of ideals in inverse semigroups of difunctional binary relations

The set Dn of all difunctional relations on an n element set is an inverse semigroup under a variation of the usual composition operation. We solve an open problem of Kudryavtseva and Maltcev (Publ Math Debrecen 78(2):253–282, 2011), which asks: What is the rank (smallest size of a generating set) of Dn? Specifically, we show that the rank of Dn is B(n)+n, where B(n) is the nth Bell number. We also give the rank of an arbitrary ideal of Dn. Although Dn bears many similarities with families such as the full transformation semigroups and symmetric inverse semigroups (all contain the symmetric group and have a chain of J-classes), we note that the fast growth of rank(Dn) as a function of n is a property not shared with these other families

The influence of left ventricular hypertrophyon survival in patients with coronaryartery disease: do race and gender matter?

AbstractObjectivesWe sought to determine the overall prognostic importance of left ventricular hypertrophy (LVH) among patients with coronary artery disease (CAD), as well as to determine whether this risk varies as a function of race or gender.BackgroundLeft ventricular hypertrophy is more prevalent among blacks and women than their counterparts. Blacks and women also have higher mortality with coronary disease.MethodsWe studied records of 2,461 patients (19% black, 42% women) diagnosed with CAD at cardiac catheterization between 1990 and 1998 from a single academic center. Left ventricular hypertrophy was defined using standard echocardiographic measures. Cox proportional hazards models were used for adjusted survival analyses. Mean patient follow-up was three years.ResultsPatients with LVH were older (68 vs. 65 years, p < 0.01), more often women (54% vs. 36%, p < 0.01), and black (25% vs. 16%, p < 0.01), and had higher unadjusted three-year mortality rates than patients without LVH (42% vs. 34%, p < 0.01). Left ventricular hypertrophy remained an independent predictor of mortality after adjusting for other clinical risk factors (hazard ratio 1.56, 95% confidence interval 1.35 to 1.80) with prognostic importance equivalent to that of left ventricular ejection fraction. Although the relative risk of LVH did not vary by race or gender, the attributable risk of LVH was greater in blacks and women.ConclusionsClinicians should consider the prognostic importance of LVH when assessing risk in patients with CAD. Because LVH is more common among black and women patients with CAD, it partially accounts for racial and gender differences in survival

Challenges and Solutions in the Development of Genomic Biomarker Panels: A Systematic Phased Approach

In the post-genome era, high throughput gene expression profiling has been successfully used to develop genomic biomarker panels (GBP) that can be integrated into clinical decision making. The development of GBPs in the context of personalized medicine is a scientifically challenging and resource-intense process. It needs to be accomplished in a systematic phased approach to address biological variation related to a clinical phenotype (e.g. disease etiology, gender, etc.) and minimize technical variation (noise). Here we present the methodological aspects of GBP development based on the experience of the Cardiac Allograft Rejection Gene Expression Observation (CARGO) study, a study that lead to the development of a molecular classifier for rejection screening in heart transplant patients