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

Information systems for development planning

In this paper the changing approaches to development planning are described, from the economic-growth oriented strategies of the 1950s and the 1960s to the contemporary emphasis on alleviating poverty and meeting basic needs. The process of development planning includes several phases; the identification of aims, analysis, plan formulation and detailed design, Implementation, controls, updating, and feedback and adjustment. This process has become much more sophisticated in recent years, but in general, the comprehensiveness and refinement of a development plan depends on the type and scope of the data available. At the same time, the very process of planning may reveal deficiencies In data and thus act as an incentive to improved information gathering. Three information systems are needed for development planning: a resources information system, whose importance has been recognised for some time but which has frequently consisted of a series of isolated and uncoordinated inventories and studies; a scientific and technological information system' and a management information system, whose Importance has frequently been neglected. Information in these areas must be collected, communicated to government policy makers and administrators to meet their immediate needs, and stored in a convenient and coordinated form so that it will be accessible in the future. More global surveys and inventories will be needed during the eiarly stages of development planning, and detailed project and programme surveys will be needed during the design and implementation stages

Infinitely many states and stochastic symmetry in a Gaussian Potts-Hopfield model

We study a Gaussian Potts-Hopfield model. Whereas for Ising spins and two disorder variables per site the chaotic pair scenario is realized, we find that for q-state Potts spins [{q(q-1} \over 2]-tuples occur. Beyond the breaking of a continous stochastic symmetry, we study the fluctuations and obtain the Newman-Stein metastate description for our model.Comment: latex, 17 page

CDI/THREDDS interoperability in the SeaDataNet framework

Abstract. SeaDataNet is an EU funded project aiming to create and operate a pan-European, marine data infrastructure for managing the large and diverse datasets (i.e. temperature, salinity current, sea level, chemical, physical and biological properties) collected by the oceanographic fleets and the new automatic observation systems. In order to make the SeaDataNet system compliant with the INSPIRE Implementing Rules for discovery service, an ISO 19139 encoding of the SeaDataNet Common Data Index (CDI) metadata model was defined. Moreover, the problem of heterogeneous data sources has been addressed. In fact, a widely used system of SeaDataNet partners and oceanographic-marine community is THREDDS/OPeNDAP; this raises up the problem of federating into SeaDataNet framework THREDDS/OPeNDAP systems as well. In this paper we describe an interoperability framework to access resources (i.e. data and services) that are available through CDI and THREDDS/OPeNDAP services. The proposed solution implements a common catalog interface to discover and access the two heterogeneous resources in a common way. This catalog service is fully distributed and implements international standards as far as geospatial information discovery and query are concerned. The developed solution is called GI-cat and was experimented in the framework of the SeaDataNet European project

Parameterization of oceanic whitecap fraction based on satellite observations

In this study, the utility of satellite-based white-cap fraction (W) data for the prediction of sea spray aerosol (SSA) emission rates is explored. More specifically, the study aims at evaluating how an account for natural variability of whitecaps in the W parameterization would affect SSA mass flux predictions when using a sea spray source function (SSSF) based on the discrete whitecap method. The starting point is a data set containing W data for 2006 together with matching wind speed U-10 and sea surface temperature (SST) T. Whitecap fraction W was estimated from observations of the ocean surface brightness temperature T-B by satellite-borne radiometers at two frequencies (10 and 37 GHz). A global-scale assessment of the data set yielded approximately quadratic correlation between W and U-10. A new global W(U-10) parameterization was developed and used to evaluate an intrinsic correlation between W and U-10 that could have been introduced while estimating W from T B. A regional-scale analysis over different seasons indicated significant differences of the coefficients of regional W(U-10) relationships. The effect of SST on W is explicitly accounted for in a new W(U-10, T) parameterization. The analysis of W values obtained with the new W(U-10) and W(U-10, T) parameterizations indicates that the influence of secondary factors on W is for the largest part embedded in the exponent of the wind speed dependence. In addition, the W(U-10, T) parameterization is able to partially model the spread (or variability) of the satellite-based W data. The satellite-based parameterization W(U-10, T) was applied in an SSSF to estimate the global SSA emission rate. The thus obtained SSA production rate for 2006 of 4.4 x 10(12) kg year(-1) is within previously reported estimates, however with distinctly different spatial distribution.Peer reviewe

Smoothing Algorithms and High-order Singularities in Gravitational Lensing

We propose a new smoothing method for obtaining surface densities from discrete particle positions from numerical simulations. This is an essential step for many applications in gravitational lensing. This method is based on the ``scatter'' interpretation of the discrete density field in the Smoothed Particle Hydrodynamics. We use Monte Carlo simulations of uniform density fields and one isothermal ellipsoid to empirically derive the noise properties, and best smoothing parameters (such as the number of nearest neighbors used). A cluster from high-resolution simulations is then used to assess the reality of high-order singularities such as swallowtails and butterflies in caustics, which are important for the interpretation of substructures in gravitational lenses. We also compare our method with the Delaunay tesselation field estimator using the galaxy studied by Bradac et al. (2004), and find good agreements. We show that higher order singularities are not only connected with bound subhaloes but also with the satellite streams. However, the presence of high-order singularities are sensitive to not only the fluctuation amplitude of the surface density, but also the detailed form of the underlying smooth lensing potential (such as ellipticity and external shear).Comment: ApJ, Accepted,(Released November 1st). The high resolution figures are availabel at http://202.127.29.4/mppg/english/data

Spin alignment of dark matter haloes in filaments and walls

The MMF technique is used to segment the cosmic web as seen in a cosmological N-body simulation into wall-like and filament-like structures. We find that the spins and shapes of dark matter haloes are significantly correlated with each other and with the orientation of their host structures. The shape orientation is such that the halo minor axes tend to lie perpendicular to the host structure, be it a wall or filament. The orientation of the halo spin vector is mass dependent. Low mass haloes in walls and filaments have a tendency to have their spins oriented within the parent structure, while higher mass haloes in filaments have spins that tend to lie perpendicular to the parent structure.Comment: 4 pages, 2 figure

High-Latitude HI in the Low Surface Brightness Galaxy UGC7321

From the analysis of sensitive HI 21-cm line observations, we find evidence for vertically extended HI emission (|z|<~2.4 kpc) in the edge-on, low surface brightness spiral galaxy UGC7321. Three-dimensional modelling suggests that the HI disk of UGC7321 is both warped and flared, but that neither effect can fully reproduce the spatial distribution and kinematics of the highest z-height gas. We are able to model the high-latitude emission as an additional HI component in the form of a ``thick disk'' or ``halo'' with a FWHM~3.3 kpc. We find tentative evidence that the vertically extended gas declines in rotational velocity as a function of z, although we are unable to completely rule out models with constant V(z). In spite of the low star formation rate of UGC7321, energy from supernovae may be sufficient to sustain this high-latitude gas. However, alternative origins for this material, such as slow, sustained infall, cannot yet be excluded.Comment: to appear in the August 20 Astrophysical Journal; 17 pages; version with full resolution figures available at http://cfa-www.harvard.edu/~lmatthew

Proteomics of Syntrophomonas zehnderi and Methanobacterium formicicum growing on long-chain fatty acids

Background: Conversion of long-chain fatty acids (LCFA) in anaerobic digesters relies on syntrophic relationship between acetogenic bacteria and methanogenic archaea. Conversion of unsaturated- and saturated-LCFA has been previously shown by a coculture of Syntrophomonas zehnderi and Methanobacterium formicium. Degradation of unsaturated-LCFA is rare among Syntrophomonas species; the best studied fatty acid oxidizer, S. wolfei, can only grow on saturated-LCFA. Objectives: Major differences are expected in the pathways and enzymes involved in the degradation of unsaturated-LCFA. In this work we used proteogenomic approach to study these differences. Methods: A draft genome of S. zehnderi was obtained by Illumina HiSeq sequencing. Genomes of S. zehnderi and S. wolfei (available at NCBI) were compared. S. zehnderi and M. formicicum co-cultures grown on oleate (unsaturated LCFA, C18:1) and on stearate (saturated LCFA, C18:0) were further studied using a proteomics approach. Conclusions: Genomic comparison of S. zehnderi and S. wolfei revealed approximately 900 different proteins and 1200 common proteins. In the genome of S. zehnderi, two replicates of the unsaturated acyl-CoA dehydrogenase genes were identified, one of which differs considerably from the acyl-CoA gene found in S. wolfei. Proteomic analysis of S. zehnderi and M. formicium co-cultures revealed high expression levels of proteins related to the -oxidation of LCFA (up to 30% of total proteins identified). Different protein expression levels were observed during the degradation of oleate (44% unique proteins) and stearate (23% unique proteins). In addition, proteins involved in electron transfer were highly expressed, including electron transfer flavoproteins, ATP synthases and a number of hydrogenases and formate dehydrogenases

Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers

Contains fulltext : 89346.pdf (publisher's version ) (Open Access)BACKGROUND: Colorectal, endometrial and upper urinary tract tumours are characteristic for Lynch syndrome (hereditary non-polyposis colon carcinoma, HNPCC). The aim of the present study was to establish whether carriers of mutations in mismatch repair genes MLH1, MSH2 or MSH6 are at increased risk of urinary bladder cancer. METHODS: Carriers and first degree relatives of 95 families with a germline mutation in the MLH1 (n=26), MSH2 (n=43), or MSH6 (n=26) gene were systematically questioned about the occurrence of carcinoma. The cumulative risk of cancer occurring before the age of 70 years (CR70) was compared to the CR70 of the general Dutch population. Microsatellite instability (MSI) testing and/or immunohistochemistry (IHC) for mismatch repair proteins was performed on bladder tumour tissue. RESULTS: Bladder cancer was diagnosed in 21 patients (90% men) from 19 Lynch syndrome families (2 MLH1, 15 MSH2, and 4 MSH6). CR70 for bladder cancer was 7.5% (95% CI 3.1% to 11.9%) for men and 1.0% (95% CI 0% to 2.4%) for women, resulting in relative risks for mutation carriers and first degree relatives of 4.2 (95% CI 2.2 to 7.2) for men and 2.2 (95% CI 0.3 to 8.0) for women. Men carrying an MSH2 mutation and their first degree relatives were at highest risks: CR70 for bladder and upper urinary tract cancer being 12.3% (95% CI 4.3% to 20.3%) and 5.9% (95% CI 0.7% to 11.1%). Bladder cancer tissue was MSI positive in 6/7 tumours and loss of IHC staining was found in 14/17 tumours, indicating Lynch syndrome aetiology. CONCLUSION: Patients with Lynch syndrome carrying an MSH2 mutation are at increased risk of urinary tract cancer including bladder cancer. In these cases surveillance should be considered.01 juli 201