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

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

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 $\mathcal{TL}_n$

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

Eccentric black hole-neutron star mergers: effects of black hole spin and equation of state

There is a high level of interest in black hole-neutron star binaries, not only because their mergers may be detected by gravitational wave observatories in the coming years, but also because of the possibility that they could explain a class of short duration gamma-ray bursts. We study black hole-neutron star mergers that occur with high eccentricity as may arise from dynamical capture in dense stellar regions such as nuclear or globular clusters. We perform general relativistic simulations of binaries with a range of impact parameters, three different initial black hole spins (zero, aligned and anti-aligned with the orbital angular momentum), and neutron stars with three different equations of state. We find a rich diversity across these parameters in the resulting gravitational wave signals and matter dynamics, which should also be reflected in the consequent electromagnetic emission. Before tidal disruption, the gravitational wave emission is significantly larger than perturbative predictions suggest for periapsis distances close to effective innermost stable separations, exhibiting features reflecting the zoom-whirl dynamics of the orbit there. Guided by the simulations, we develop a simple model for the change in orbital parameters of the binary during close encounters. Depending upon the initial parameters of the system, we find that mass transfer during non-merging close encounters can range from essentially zero to a sizable fraction of the initial neutron star mass. The same holds for the amount of material outside the black hole post-merger, and in some cases roughly half of this material is estimated to be unbound. We also see that non-merging close encounters generically excite large oscillations in the neutron star that are qualitatively consistent with f-modes.Comment: 19 pages, 13 figures, revised according to referee comment

Glycemic Control Patterns and Kidney Disease Progression among Primary Care Patients with Diabetes Mellitus

Background: Reducing glycosylated hemoglobin (HbA1c) to near or less than 7% in patients with diabetes is associated with diminished microvascular complications, but this level is not consistently achieved. The purpose of this study was to examine the relationship between fluctuations in HbA1c and changes in estimated glomerular filtration rate (eGFR) and estimated stage of chronic kidney disease (CKD) in an academic primary care practice. Methods: We analyzed data from 791 diabetic primary care patients (25% white; 75% African American) enrolled between 1998 to 2002 and followed through 2008 (mean follow-up, 7.6 1.9 years). We calculated baseline and final follow-up eGFR using the Modification of Diet in Renal Disease equation. We examined the relationship between fluctuations in HbA1c and changes in eGFR and stage of CKD using multivariable linear and logistic regression models that controlled for demographic and clinical variables associated with CKD progression. Results: From baseline to follow-up, mean eGFR in African Americans declined to a greater extent and more rapidly than in whites. Age, mean systolic blood pressure, initial HbA1c, initial eGFR, and number of HbA1c values (all P 7% (P < .02); however, this contributed little to explaining model variance. Conclusion: These data suggest that traditional demographic and clinical risk factors remain significantly associated with changes in eGFR and that the pattern of variability in HbA1c is only modestly important in contributing to changes in eGFR among African-American and white diabetic patients in primary care

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)

Circular Single-Stranded DNA Virus (Microviridae: Gokushovirinae: Jodiemicrovirus) Associated with the Pathobiome of the Flat-Back Mud Crab, Eurypanopeus depressus

A single-stranded DNA (ssDNA) virus is presented from a metagenomic data set derived from Alphaproteobacteria-infected hepatopancreatic tissues of the crab Eurypanopeus depressus. The circular virus genome (4,768 bp) encodes 14 hypothetical proteins, some similar to other bacteriophages (Microviridae). Based on its relatedness to other Microviridae, this virus represents a member of a novel genus.Joyner Open Access Publishing Support Fun