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

A role for TSPO in mitochondrial Ca2+ homeostasis and redox stress signaling

The 18 kDa translocator protein TSPO localizes on the outer mitochondrial membrane (OMM). Systematically overexpressed at sites of neuroinflammation it is adopted as a biomarker of brain conditions. TSPO inhibits the autophagic removal of mitochondria by limiting PARK2-mediated mitochondrial ubiquitination via a peri-organelle accumulation of reactive oxygen species (ROS). Here we describe that TSPO deregulates mitochondrial Ca2+ signaling leading to a parallel increase in the cytosolic Ca2+ pools that activate the Ca2+-dependent NADPH oxidase (NOX) thereby increasing ROS. The inhibition of mitochondrial Ca2+ uptake by TSPO is a consequence of the phosphorylation of the voltage-dependent anion channel (VDAC1) by the protein kinase A (PKA), which is recruited to the mitochondria, in complex with the Acyl-CoA binding domain containing 3 (ACBD3). Notably, the neurotransmitter glutamate, which contributes neuronal toxicity in age-dependent conditions, triggers this TSPO-dependent mechanism of cell signaling leading to cellular demise. TSPO is therefore proposed as a novel OMM-based pathway to control intracellular Ca2+ dynamics and redox transients in neuronal cytotoxicity

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

New Measurements of the Motion of the Zodiacal Dust

Using the Wisconsin H-Alpha Mapper (WHAM), we have measured at high spectral resolution and high signal-to-noise the profile of the scattered solar Mg I 5184 absorption line in the zodiacal light. The observations were carried out toward 49 directions that sampled the ecliptic equator from solar elongations of 48\dg (evening sky) to 334\dg (morning sky) plus observations near +47\dg and +90\dg ecliptic latitude. The spectra show a clear prograde kinematic signature that is inconsistent with dust confined to the ecliptic plane and in circular orbits influenced only by the sun's gravity. In particular, the broadened widths of the profiles, together with large amplitude variations in the centroid velocity with elongation angle, indicate that a significant population of dust is on eccentric orbits. In addition, the wide, flat-bottomed line profile toward the ecliptic pole indicates a broad distribution of orbital inclinations extending up to about 30\dg - 40\dg with respect to the ecliptic plane. The absence of pronounced asymmetries in the shape of the profiles limits the retrograde population to less than 10% of the prograde population and also places constraints on the scattering phase function of the particles. These results do not show the radial outflow or evening--morning velocity amplitude asymmetry reported in some earlier investigations. The reduction of the spectra included the discovery and removal of extremely faint, unidentified terrestrial emission lines that contaminate and distort the underlying Mg I profile. This atmospheric emission is too weak to have been seen in earlier, lower signal-to-noise observations, but it probably affected the line centroid measurements of previous investigations.Comment: 24 pages, 8 figures, 1 table, to appear in ApJ v612; figures appear low-res only on scree

Measured g factors and the tidal-wave description of transitional nuclei near A = 100

The transient-field technique has been used in both conventional kinematics and inverse kinematics to measure the g factors of the 2+ states in the stable even isotopes of Ru, Pd and Cd. The statistical precision of the g(2+) values has been significantly improved, allowing a critical comparison with the tidal-wave version of the cranking model recently proposed for transitional nuclei in this region.Comment: Accepted for publication in Physical Review C, April 201

Microwave dielectric spectrum of rocks

A combination of several measurement techniques was used to investigate the dielectric properties of 80 rock samples in the microwave region. The real part of the dielectric constant, epsilon', was measured in 0.1 GHz steps from 0.5 to 18 GHz, and the imaginary part, epsilon'', was measured at five frequencies extending between 1.6 and 16 GHz. In addition to the dielectric measurements, the bulk density was measured for all the samples and the bulk chemical composition was determined for 56 of the samples. The study shows that epsilon' is frequency-dependent over the 0.5 to 18 GHz range for all rock samples, and that the bulk density rho accounts for about 50 percent of the observed variance of epsilon'. For individual rock types (by genesis), about 90 percent of the observed variance may be explained by the combination of density and the fractional contents of SiO2, Fe2O3, MgO, and TiO2. For the loss factor epsilon'', it was not possible to establish statistically significant relationships between it and the measured properties of the rock samples (density and chemical composition)

Schizophrenia trials in China: a survey

OBJECTIVE: China's biomedical research activity is increasing and this literature is becoming more accessible online. Our aim was to survey all randomized control schizophrenia trials (RCTs) in one Chinese bibliographic database. METHOD: Chinese Academic Journals was electronically searched for RCTs and all relevant citations were also sought on PubMed to ascertain global accessibility. RESULTS: The search identified 3275 records, of which 982 were RCTs relevant to schizophrenia. A total of 71% (699) could be found by using English phrases. All the main body of text of the 982 papers was in Mandarin. On average, these trials involved about 100 people, with interventions and outcome measures familiar to schizophrenia trialists worldwide. Four of the 982 records (<1%) were identified on PubMed. CONCLUSION: Those undertaking systematic reviews should search the Chinese literature for relevant material. Failing to do this will leave the results of systematic reviews prone to random error or bias, or both

The DLV System for Knowledge Representation and Reasoning

This paper presents the DLV system, which is widely considered the state-of-the-art implementation of disjunctive logic programming, and addresses several aspects. As for problem solving, we provide a formal definition of its kernel language, function-free disjunctive logic programs (also known as disjunctive datalog), extended by weak constraints, which are a powerful tool to express optimization problems. We then illustrate the usage of DLV as a tool for knowledge representation and reasoning, describing a new declarative programming methodology which allows one to encode complex problems (up to $\Delta^P_3$-complete problems) in a declarative fashion. On the foundational side, we provide a detailed analysis of the computational complexity of the language of DLV, and by deriving new complexity results we chart a complete picture of the complexity of this language and important fragments thereof. Furthermore, we illustrate the general architecture of the DLV system which has been influenced by these results. As for applications, we overview application front-ends which have been developed on top of DLV to solve specific knowledge representation tasks, and we briefly describe the main international projects investigating the potential of the system for industrial exploitation. Finally, we report about thorough experimentation and benchmarking, which has been carried out to assess the efficiency of the system. The experimental results confirm the solidity of DLV and highlight its potential for emerging application areas like knowledge management and information integration.Comment: 56 pages, 9 figures, 6 table

Population pharmacokinetics-based recommendations for a single delayed or missed dose of nusinersen

Nusinersen is an antisense oligonucleotide approved for the treatment of spinal muscular atrophy. The drug is given intrathecally at 12 mg, beginning with 3 loading doses at 2-week intervals, a fourth loading dose 30 days thereafter, and maintenance doses at 4-month intervals. This population pharmacokinetic model was developed to clarify how to maintain targeted nusinersen exposure after an unforeseen one-time delay or missed dose. Simulations demonstrated that the impact of a one-time delay in dosing or a missed dose on median cerebrospinal fluid exposures depended on duration of interruption and the regimen phase in which it occurred. Delays in loading doses delayed reaching the peak trough concentration by approximately the duration of the interruption. Resumption of the regimen as soon as possible resulted in achieving steady state trough concentration upon completion of the loading phase. A short delay (30-90 days) during the maintenance phase led to prolonged lower median cerebrospinal fluid concentration if all subsequent doses were shifted by the same 4-month interval. However, administration of the delayed dose, followed by the subsequent dose as originally scheduled, rapidly restored trough concentration. If a dose must be delayed, patients should return to the original dosing schedule as soon as possible

A Content Analysis of Psychological Resilience Among First Responders and the General Population

The current study examined how first responders and the general population described the concept of resilience. Categories of resilience were coded a priori using Stemler’s content analysis. For the general population, positive coping was the most frequently occurring category followed by social support and adaptability. The next most frequently occurring terms were societal resources and personal competence. Consistent with the general population, first responders described resilience most frequently with positive coping. Social support was the next most frequently occurring category, followed by personal competence, perseverance, emotional regulation, and physical fitness. Although both the general population and first responder participants highlighted the importance of having a support network, first responders suggested that dealing with traumatic experiences was more of an individual process, and seeking professional help was not common practice. Implications for mental health professionals and future directions for research are offered.ECU Open Access Publishing Support Fun