A Novel Convex Relaxation for Non-Binary Discrete Tomography

We present a novel convex relaxation and a corresponding inference algorithm for the non-binary discrete tomography problem, that is, reconstructing discrete-valued images from few linear measurements. In contrast to state of the art approaches that split the problem into a continuous reconstruction problem for the linear measurement constraints and a discrete labeling problem to enforce discrete-valued reconstructions, we propose a joint formulation that addresses both problems simultaneously, resulting in a tighter convex relaxation. For this purpose a constrained graphical model is set up and evaluated using a novel relaxation optimized by dual decomposition. We evaluate our approach experimentally and show superior solutions both mathematically (tighter relaxation) and experimentally in comparison to previously proposed relaxations

LSD1 controls metastasis of androgen-independent prostate cancer cells through PXN and LPAR6

Lysine-specific demethylase 1 (LSD1) was shown to control gene expression and cell proliferation of androgen-dependent prostate cancer (PCa) cells, whereas the role of LSD1 in androgen-independent metastatic prostate cancer remains elusive. Here, we show that depletion of LSD1 leads to increased migration and invasion of androgen-independent PCa cells. Transcriptome and cistrome analyses reveal that LSD1 regulates expression of lysophosphatidic acid receptor 6 (LPAR6) and cytoskeletal genes including the focal adhesion adaptor protein paxillin (PXN). Enhanced LPAR6 signalling upon LSD1 depletion promotes migration with concomitant phosphorylation of PXN. In mice LPAR6 overexpression enhances, whereas knockdown of LPAR6 abolishes metastasis of androgen-independent PCa cells. Taken together, we uncover a novel mechanism of how LSD1 controls metastasis and identify LPAR6 as a promising therapeutic target to treat metastatic prostate cancer

The Combined Dexamethasone/CRH Test (DEX/CRH Test) and Prediction of Acute Treatment Response in Major Depression

In this study the predictive value of the combined dexamethasone/CRH test (DEX/CRH test) for acute antidepressant response was investigated. In 114 depressed inpatients suffering from unipolar or bipolar depression (sample 1) the DEX/CRH test was performed at admission and shortly before discharge. During their stay in the hospital patients received different antidepressant treatment regimens. At admission, the rate of nonsuppression (basal cortisol levels >75.3 nmol/l) was 24.6% and was not related to the later therapeutic response. Moreover, 45 out of 114 (39.5%) patients showed an enhancement of HPA axis function at discharge in spite of clinical improvement. In a second sample, 40 depressed patients were treated either with reboxetine or mirtazapine for 5 weeks. The DEX/CRH test was performed before, after 1 week, and after 5 weeks of pharmacotherapy. Attenuation of HPA axis activity after 1 week was associated with a more pronounced alleviation of depressive symptoms after 5-week mirtazapine treatment, whereas downregulation of HPA system activity after 5 weeks was related to clinical response to reboxetine. However, early improvement of HPA axis dysregulation was not necessarily followed by a beneficial treatment outcome. Taken together, performance of a single DEX/CRH test does not predict the therapeutic response. The best predictor for response seems to be an early attenuation of HPA axis activity within 1 or 2 weeks. However, early improvement of HPA system dysfunction is not a sufficient condition for a favourable response. Since a substantial part of depressive patients display a persistence of HPA axis hyperactivity at discharge, downregulation of HPA system function is not a necessary condition for acute clinical improvement either. Our data underline the importance of HPA axis dysregulation for treatment outcome in major depression, although restoration of HPA system dysfunction seems to be neither a necessary nor a sufficient determinant for acute treatment response

Hookworm Infection and Environmental Factors in Mbeya Region, Tanzania: A Cross-sectional, Population-based study.

Hookworm disease is one of the most common infections and cause of a high disease burden in the tropics and subtropics. Remotely sensed ecological data and model-based geostatistics have been used recently to identify areas in need for hookworm control. Cross-sectional interview data and stool samples from 6,375 participants from nine different sites in Mbeya region, south-western Tanzania, were collected as part of a cohort study. Hookworm infection was assessed by microscopy of duplicate Kato-Katz thick smears from one stool sample from each participant. A geographic information system was used to obtain remotely sensed environmental data such as land surface temperature (LST), vegetation cover, rainfall, and elevation, and combine them with hookworm infection data and with socio-demographic and behavioral data. Uni- and multivariable logistic regression was performed on sites separately and on the pooled dataset. Univariable analyses yielded significant associations for all ecological variables. Five ecological variables stayed significant in the final multivariable model: population density (odds ratio (OR) = 0.68; 95% confidence interval (CI) = 0.63-0.73), mean annual vegetation density (OR = 0.11; 95% CI = 0.06-0.18), mean annual LST during the day (OR = 0.81; 95% CI = 0.75-0.88), mean annual LST during the night (OR = 1.54; 95% CI = 1.44-1.64), and latrine coverage in household surroundings (OR = 1.02; 95% CI = 1.01-1.04). Interaction terms revealed substantial differences in associations of hookworm infection with population density, mean annual enhanced vegetation index, and latrine coverage between the two sites with the highest prevalence of infection. This study supports previous findings that remotely sensed data such as vegetation indices, LST, and elevation are strongly associated with hookworm prevalence. However, the results indicate that the influence of environmental conditions can differ substantially within a relatively small geographic area. The use of large-scale associations as a predictive tool on smaller scales is therefore problematic and should be handled with care

Economic and environmental assessment of seed and rhizome propagated Miscanthus in the UK

Growth in planted areas of Miscanthus for biomass in Europe has stagnated since 2010 due to technical challenges, economic barriers and environmental concerns. These limitations need to be overcome before biomass production from Miscanthus can expand to several million hectares. In this paper we consider the economic and environmental effects of introducing seed based hybrids as an alternative to clonal M. x giganteus (Mxg). The impact of seed based propagation and novel agronomy was compared with current Mxg cultivation and used in ten commercially relevant, field scale experiments planted between 2012 and 2014 in the UK, Germany and Ukraine. Economic and greenhouse gas (GHG) emissions costs were quantified for the following production chain: propagation, establishment, harvest, transportation, storage and fuel preparation (excluding soil carbon changes). The production and utilisation efficiency of seed and rhizome propagation were compared. Results show that new hybrid seed propagation significantly reduces establishment cost to below ?900 ha-1. Calculated GHG emission costs for the seeds established via plugs, though relatively small, was higher than rhizomes because fossil fuels were assumed to heat glasshouses for raising seedling plugs (5.3 and 1.5 kg CO2 eq. C Mg (dry matter (DM))-1), respectively. Plastic mulch film reduced establishment time, improving crop economics. The breakeven yield was calculated to be 6 Mg DM ha-1 y-1, which is about half average UK yield for Mxg; with newer seeded hybrids reaching 16 Mg DM ha-1 in second year UK trials. These combined improvements will significantly increase crop profitability. The trade-offs between costs of production for the preparation of different feedstock formats show that bales are the best option for direct firing with the lowest transport costs (?0.04 Mg -1 km-1) and easy on-farm storage. However if pelleted fuel is required then chip harvesting is more economic. We show how current seed based propagation methods can increase the rate at which Miscanthus can be scaled up; ~x100 those of current rhizome propagation. These rapid ramp rates for biomass production are required to deliver a scalable and economic Miscanthus biomass fuel whose GHG emissions are ~1/20th those of natural gas per unit of heatpublishersversionPeer reviewe

Neuroactive steroids in depression and anxiety disorders: Clinical studies

Certain neuroactive steroids modulate ligand-gated ion channels via non-genomic mechanisms. Especially 3 alpha-reduced pregnane steroids are potent positive allosteric modulators of the gamma-aminobutyric acid type A (GABA(A)) receptor. During major depression, there is a disequilibrium of 3 alpha-reduced neuroactive steroids, which is corrected by clinically effective pharmacological treatment. To investigate whether these alterations are a general principle of successful antidepressant treatment, we studied the impact of nonpharmacological treatment options on neuroactive steroid concentrations during major depression. Neither partial sleep deprivation, transcranial magnetic stimulation, nor electroconvulsive therapy affected neuroactive steroid levels irrespectively of the response to these treatments. These studies suggest that the changes in neuroactive steroid concentrations observed after antidepressant pharmacotherapy more likely reflect distinct pharmacological properties of antidepressants rather than the clinical response. In patients with panic disorder, changes in neuroactive steroid composition have been observed opposite to those seen in depression. However, during experimentally induced panic induction either with cholecystokinine-tetrapeptide or sodium lactate, there was a pronounced decline in the concentrations of 3 alpha-reduced neuroactive steroids in patients with panic disorder, which might result in a decreased GABAergic tone. In contrast, no changes in neuroactive steroid concentrations could be observed in healthy controls with the exception of 3 alpha,5 alpha-tetrahydrodeoxycorticosterone. The modulation of GABA(A) receptors by neuroactive steroids might contribute to the pathophysiology of depression and anxiety disorders and might offer new targets for the development of novel anxiolytic compounds. Copyright (c) 2006 S. Karger AG, Basel

Mechanistic basis of an epistatic interaction reducing age at onset in hereditary spastic paraplegia

Many genetic neurological disorders exhibit variable expression within affected families, often exemplified by variations in disease age at onset. Epistatic effects (i.e. effects of modifier genes on the disease gene) may underlie this variation, but the mechanistic basis for such epistatic interactions is rarely understood. Here we report a novel epistatic interaction between SPAST and the contiguous gene DPY30, which modifies age at onset in hereditary spastic paraplegia, a genetic axonopathy. We found that patients with hereditary spastic paraplegia caused by genomic deletions of SPAST that extended into DPY30 had a significantly younger age at onset. We show that, like spastin, the protein encoded by SPAST, the DPY30 protein controls endosomal tubule fission, traffic of mannose 6-phosphate receptors from endosomes to the Golgi, and lysosomal ultrastructural morphology. We propose that additive effects on this pathway explain the reduced age at onset of hereditary spastic paraplegia in patients who are haploinsufficient for both genes.This work was supported by grants to E.R.; Project Grant from United States Spastic Paraplegia Foundation, UK Medical Research Council Project Grant [MR/M00046X/1], Project grant from NIHR Biomedical Research Centre at Addenbrooke’s Hospital, Wellcome Trust Senior Research Fellowship in Clinical Science [082381], Project Grant from Tom Wahlig Stiftung (project 33). J.E. and P.M. are supported by a Wellcome Trust Principal Research Fellowship Grant to Margaret S. Robinson [086598]. T.M.N. was supported by an MRC PhD studentship [G0800117]. B.W. is supported by the Tom Wahlig Advanced Fellowship, the German Federal Ministry of Education and Research (BMBF, 01GQ113), the Bavarian Ministry of Education and Culture, Sciences and Arts in the framework of the Bavarian Molecular Biosystems Research Network and ForIPS, and the Interdisciplinary Centre for Clinical Research (IZKF, University Hospital of Erlangen, N3 and F3). T.R. was supported by research grant DFG GRK2162/1 of the Deutsche Forschungsgemeinschaft. The study was also supported by the European Union within the 7th European Community Framework Program for Research and Technological Development through funding for the NEUROMICS network (F5-2012-305121 to L.S. and A.D.), the E-Rare Network NEUROLIPID (01GM1408B to R.S. and ANR-13-RARE-0003-02 to G.S.), and a Marie Curie International Outgoing Fellowship (grant PIOF-GA-2012-326681 to R.S. and L.S.). This work was further supported by the US National Institutes of Health (NIH) (grant 5R01NS072248 to R.S.), the German HSP-Selbsthilfegruppe e.V. (grant to R.S. and L.S.), and grants to C.B.: Project Grant from Tom Wahlig Stiftung (project 20), grant from the Stiftung für Pathobiochemie und Molekulare Diagnostik. CIMR is supported by a Wellcome Trust Strategic Award [100140] and Equipment Grant [093026]

Thermodynamics of impurity-enhanced vacancy formation in metals

Hydrogen induced vacancy formation in metals and metal alloys has been of great interest during the past couple of decades. The main reason for this phenomenon, often referred to as the superabundant vacancy formation, is the lowering of vacancy formation energy due to the trapping of hydrogen. By means of thermodynamics, we study the equilibrium vacancy formation in fcc metals (Pd, Ni, Co, and Fe) in correlation with the H amounts. The results of this study are compared and found to be in good agreement with experiments. For the accurate description of the total energy of the metal-hydrogen system, we take into account the binding energies of each trapped impurity, the vibrational entropy of defects, and the thermodynamics of divacancy formation. We demonstrate the effect of vacancy formation energy, the hydrogen binding, and the divacancy binding energy on the total equilibrium vacancy concentration. We show that the divacancy fraction gives the major contribution to the total vacancy fraction at high H fractions and cannot be neglected when studying superabundant vacancies. Our results lead to a novel conclusion that at high hydrogen fractions, superabundant vacancy formation takes place regardless of the binding energy between vacancies and hydrogen. We also propose the reason of superabundant vacancy formation mainly in the fcc phase. The equations obtained within this work can be used for any metal-impurity system, if the impurity occupies an interstitial site in the lattice. Published by AIP Publishing.Peer reviewe

FAHN/SPG35 : a narrow phenotypic spectrum across disease classifications

The endoplasmic reticulum enzyme fatty acid 2-hydroxylase (FA2H) plays a major role in the formation of 2-hydroxy glycosphingolipids, main components of myelin. FA2H deficiency in mice leads to severe central demyelination and axon loss. In humans it has been associated with phenotypes from the neurodegeneration with brain iron accumulation (fatty acid hydroxylase-associated neurodegeneration, FAHN), hereditary spastic paraplegia (HSP type SPG35) and leukodystrophy (leukodystrophy with spasticity and dystonia) spectrum. We performed an in-depth clinical and retrospective neurophysiological and imaging study in a cohort of 19 cases with biallelic FA2H mutations. FAHN/SPG35 manifests with early childhood onset predominantly lower limb spastic tetraparesis and truncal instability, dysarthria, dysphagia, cerebellar ataxia, and cognitive deficits, often accompanied by exotropia and movement disorders. The disease is rapidly progressive with loss of ambulation after a median of 7 years after disease onset and demonstrates little interindividual variability. The hair of FAHN/SPG35 patients shows a bristle-like appearance; scanning electron microscopy of patient hair shafts reveals deformities (longitudinal grooves) as well as plaque-like adhesions to the hair, likely caused by an abnormal sebum composition also described in a mouse model of FA2H deficiency. Characteristic imaging features of FAHN/SPG35 can be summarized by the WHAT' acronym: white matter changes, hypointensity of the globus pallidus, ponto-cerebellar atrophy, and thin corpus callosum. At least three of four imaging features are present in 85% of FA2H mutation carriers. Here, we report the first systematic, large cohort study in FAHN/SPG35 and determine the phenotypic spectrum, define the disease course and identify clinical and imaging biomarkers