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

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

In search of ‘lost’ knowledge and outsourced expertise in flood risk management

This paper examines the parallel discourses of ‘lost’ local flood expertise and the growing use of commercial consultancies to outsource aspects of flood risk work. We critically examine the various claims and counter-claims about lost, local and external expertise in flood management, focusing on the aftermath of the 2007 floods in East Yorkshire, England. Drawing on interviews with consultants, drainage engineers and others, we caution against claims that privilege ‘local’ floods knowledge as ‘good’ and expert knowledge as somehow suspect. This paper urges carefulness in interpreting claims about local knowledge, arguing that it is important always to think instead of hybrid knowledge formations. We conclude by arguing that experiments in the co-production of flood risk knowledge need to be seen as part of a spectrum of ways for producing shared knowledge

A randomised trial evaluating Bevacizumab as adjuvant therapy following resection of AJCC stage IIB, IIC and III cutaneous melanoma : an update

At present, there are no standard therapies for the adjuvant treatment of malignant melanoma. Patients with primary tumours with a high-Breslow thickness (stages IIB and IIC) or with resected loco-regional nodal disease (stage III) are at high risk of developing metastasis and subsequent disease-related death. Given this, it is important that novel therapies are investigated in the adjuvant melanoma setting. Since angiogenesis is essential for primary tumour growth and the development of metastasis, anti-angiogenic agents are attractive potential therapeutic candidates for clinical trials in the adjuvant setting. Therefore, we initiated a phase II trial in resected high-risk cutaneous melanoma, assessing the efficacy of bevacizumab versus observation. In the interim safety data analysis, we demonstrate that bevacizumab is a safe therapy in the adjuvant melanoma setting with no apparent increase in the surgical complication rate after either primary tumour resection and/or loco-regional lymphadenectomy

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

Heights of one- and two-sided congruence lattices of semigroups

The height of a poset $P$ is the supremum of the cardinalities of chains in $P$. The exact formula for the height of the subgroup lattice of the symmetric group $\mathcal{S}_n$ is known, as is an accurate asymptotic formula for the height of the subsemigroup lattice of the full transformation monoid $\mathcal{T}_n$. Motivated by the related question of determining the heights of the lattices of left- and right congruences of $\mathcal{T}_n$, we develop a general method for computing the heights of lattices of both one- and two-sided congruences for semigroups. We apply this theory to obtain exact height formulae for several monoids of transformations, matrices and partitions, including: the full transformation monoid $\mathcal{T}_n$, the partial transformation monoid $\mathcal{PT}_n$, the symmetric inverse monoid $\mathcal{I}_n$, the monoid of order-preserving transformations $\mathcal{O}_n$, the full matrix monoid $\mathcal{M}(n,q)$, the partition monoid $\mathcal{P}_n$, the Brauer monoid $\mathcal{B}_n$ and the Temperley-Lieb monoid $\mathcal{TL}_n$

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

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)

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