An incremental algorithm for uncapacitated facility location problem

We study the incremental facility location problem, wherein we are given an instance of the uncapacitated facility location problem (UFLP) and seek an incremental sequence of opening facilities and an incremental sequence of serving customers along with their fixed assignments to facilities open in the partial sequence. We say that a sequence has a competitive ratio of k, if the cost of serving the first ℓ customers in the sequence is at most k times the optimal solution for serving any ℓ customers for all possible values of ℓ. We provide an incremental framework that computes a sequence with a competitive ratio of at most eight and a worst-case instance that provides a lower bound of three for any incremental sequence. We also present the results of our computational experiments carried out on a set of benchmark instances for the UFLP. The problem has applications in multistage network planning

Lagrangian Decompositions for the Two-Level FTTx Network Design Problem

We consider the design of a passive optical telecommunication access network, where clients have to be connected to an intermediate level of distribution points (DPs) and further on to some central offices (COs) in a tree-like fashion. Each client demands a given number of fiber connections to its CO. Passive optical splitters installed at the DPs allow k connections to share a single common fiber between the DP and the CO. We consider fixed charge costs for the use of an edge of the underlying street network, of a DP, and of a CO and variable costs for installing fibers along the street edges and for installing splitters at the DPs. We present two Lagrangian decomposition approaches that decompose the problem based on the network structure and on the cost structure, respectively. The subproblems are solved using MIP techniques. We report computational results for realistic instances and compare the efficiency of the Lagrangian approaches to the solutions of an integrated MIP model

Neural mechanism underlying preview effects and masked priming effects in visual word processing

Two classic experimental paradigms – masked repetition priming and the boundary paradigm – have played a pivotal role in understanding the process of visual word recognition. Traditionally, these paradigms have often been employed by different communities of researchers, with their own long-standing research traditions. Nevertheless, a review of the literature suggests that the brain-electric correlates of word processing established with both paradigms may show interesting similarities, in particular with regard to the location, timing, and direction of N1 and N250 effects. However, as of yet, no direct comparison has been undertaken between both paradigms. In the current study, we used combined eye-tracking/EEG to perform such a within-subject comparison using the same materials (single Chinese characters) as stimuli. Our results show the typical early repetition effects of N1 and N250 for both paradigms. However, repetition effects in N250 (i.e., a reduced negativity following identical-word primes/previews as compared to different-word primes/previews) were larger in the boundary paradigm than with masked priming. For N1 effects, repetition effects were similar across the two paradigms showing a larger N1 after repetitions as compared to alternations. Therefore, the results indicate that at the neural level, a briefly presented and masked foveal prime produces qualitatively similar facilitatory effects on visual word recognition as a parafoveal preview before a saccade, although such effects appear to be stronger in the latter case

How the dominant reading direction changes parafoveal processing:A combined EEG/eye-tracking study

Reading directions vary across writing systems. Through long-term experience readers adjust their visual systems to the dominant reading direction in their writing systems. However, little is known about the neural correlates underlying these adjustments because different writing systems do not just differ in reading direction, but also regarding visual and linguistic properties. Here, we took advantage that Chinese is read to different degrees in left-right or top-down directions in different regions. We investigated visual word processing in participants from Taiwan (both top-down and left-right directions) and from mainland China (only left-right direction). Combined EEG/eye tracking was used together with a saccade-contingent parafoveal preview manipulation to investigate neural correlates, while participants read 5-word lists. Fixation-related potentials (FRPs) showed a reduced late N1 effect (preview positivity), but this effect was modulated by the prior experience with a specific reading direction. Results replicate previous findings that valid previews facilitate visual word processing, as indicated by reduced FRP activation. Critically, the results indicate that this facilitation effect depends on experience with a given reading direction, suggesting a specific mechanism how cultural experience shapes the way people process visual information

Continuous monitoring of the temporal evolution of the snowpack using upward-looking ground penetrating radar technology

Snow stratigraphy and water percolation are key parameters in avalanche forecasting. It is, however, difficult to model or measure stratigraphy and water flow in a sloping snowpack. Numerical modeling results depend highly on the type and availability of input data and the parameterization of the physical processes. Furthermore, the sensors themselves may influence the snowpack or be destroyed due to snow gliding and avalanches. Radar technology allows non-destructive scanning of the snowpack and deducing internal snow properties. If the radar system is buried in the ground, it cannot be destroyed by avalanche impacts or snow creep. During the winter seasons 2010-2011 and 2011-2012 we recorded continuous data with upward-looking pulsed radar systems (upGPR) at two test sites. We demonstrate that it is possible to determine the snow height with an accuracy comparable to conventional snow depth measuring devices. We determined the bulk volumetric liquid water content and tracked the position of the first stable wetting front. Wet-snow avalanche activity increased, when melt water penetrated deeper into the snowpack

Reduced Basal Autophagy and Impaired Mitochondrial Dynamics Due to Loss of Parkinson's Disease-Associated Protein DJ-1

BACKGROUND: Mitochondrial dysfunction and degradation takes a central role in current paradigms of neurodegeneration in Parkinson's disease (PD). Loss of DJ-1 function is a rare cause of familial PD. Although a critical role of DJ-1 in oxidative stress response and mitochondrial function has been recognized, the effects on mitochondrial dynamics and downstream consequences remain to be determined. METHODOLOGY/PRINCIPAL FINDINGS: Using DJ-1 loss of function cellular models from knockout (KO) mice and human carriers of the E64D mutation in the DJ-1 gene we define a novel role of DJ-1 in the integrity of both cellular organelles, mitochondria and lysosomes. We show that loss of DJ-1 caused impaired mitochondrial respiration, increased intramitochondrial reactive oxygen species, reduced mitochondrial membrane potential and characteristic alterations of mitochondrial shape as shown by quantitative morphology. Importantly, ultrastructural imaging and subsequent detailed lysosomal activity analyses revealed reduced basal autophagic degradation and the accumulation of defective mitochondria in DJ-1 KO cells, that was linked with decreased levels of phospho-activated ERK2. CONCLUSIONS/SIGNIFICANCE: We show that loss of DJ-1 leads to impaired autophagy and accumulation of dysfunctional mitochondria that under physiological conditions would be compensated via lysosomal clearance. Our study provides evidence for a critical role of DJ-1 in mitochondrial homeostasis by connecting basal autophagy and mitochondrial integrity in Parkinson's disease

Molecular Epidemiology of Mycobacterium abscessus Isolates Recovered from German Cystic Fibrosis Patients

Infections due to Mycobacterium abscessus are a major cause of mortality and morbidity in cystic fibrosis (CF) patients. Furthermore, M. abscessus has been suspected to be involved in person-to-person transmissions. In 2016, dominant global clonal complexes (DCCs) that occur worldwide among CF patients have been described. To elucidate the epidemiological situation of M. abscessus among CF patients in Germany and to put these data into a global context, we performed whole-genome sequencing of a set of 154 M. abscessus isolates from 123 German patients treated in 14 CF centers. We used MTBseq pipeline to identify clusters of closely related isolates and correlate those with global findings. Genotypic drug susceptibility for macrolides and aminoglycosides was assessed by characterization of the erm(41), rrl, and rrs genes. By this approach, we could identify representatives of all major DCCs (Absc 1, Absc 2, and Mass 1) in our cohort. Intrapersonal isolates showed higher genetic relatedness than interpersonal isolates (median 3 SNPs versus 16 SNPs; P < 0.001). We further identified four clusters with German patients from same centers clustering with less than 25 SNPs distance (range 3 to 18 SNPs) but did not find any hint for in-hospital person-to-person transmission. This is the largest study investigating phylogenetic relations of M. abscessus isolates in Germany. We identified representatives of all reported DCCs but evidence for nosocomial transmission remained inconclusive. Thus, the occurrence of genetically closely related isolates of M. abscessus has to be interpreted with care, as a direct interhuman transmission cannot be directly deduced.Peer Reviewe

Quinpramine Ameliorates Rat Experimental Autoimmune Neuritis and Redistributes MHC Class II Molecules

Activation of inflammatory cells is central to the pathogenesis of autoimmune demyelinating diseases of the peripheral nervous system. The novel chimeric compound quinpramine—generated from imipramine and quinacrine—redistributes cholesterol rich membrane domains to intracellular compartments. We studied the immunological and clinical effects of quinpramine in myelin homogenate induced Lewis rat experimental autoimmune neuritis (EAN), a model system for acute human inflammatory neuropathies, such as the Guillain-Barré syndrome. EAN animals develop paresis of all limbs due to autoimmune inflammation of peripheral nerves. Quinpramine treatment ameliorated clinical disease severity of EAN and infiltration of macrophages into peripheral nerves. It reduced expression of MHC class II molecules on antigen presenting cells and antigen specific T cell proliferation both in vitro and in vivo. Quinpramine exerted its anti-proliferatory effect on antigen presenting cells, but not on responder T cells. Our data suggest that quinpramine represents a candidate pharmaceutical for inflammatory neuropathies

Benchmarking whole exome sequencing in the German Network for Personalized Medicine

Introduction Whole Exome Sequencing (WES) has emerged as an efficient tool in clinical cancer diagnostics to broaden the scope from panel-based diagnostics to screening of all genes and enabling robust determination of complex biomarkers in a single analysis. Methods To assess concordance, six formalin-fixed paraffin-embedded (FFPE) tissue specimens and four commercial reference standards were analyzed by WES as matched tumor-normal DNA at 21 NGS centers in Germany, each employing local wet-lab and bioinformatics investigating somatic and germline variants, copy-number alteration (CNA), and different complex biomarkers. Somatic variant calling was performed in 494 diagnostically relevant cancer genes. In addition, all raw data were re-analyzed with a central bioinformatic pipeline to separate wet- and dry-lab variability. Results The mean positive percentage agreement (PPA) of somatic variant calling was 76% and positive predictive value (PPV) 89% compared a consensus list of variants found by at least five centers. Variant filtering was identified as the main cause for divergent variant calls. Adjusting filter criteria and re-analysis increased the PPA to 88% for all and 97% for clinically relevant variants. CNA calls were concordant for 82% of genomic regions. Calls of homologous recombination deficiency (HRD), tumor mutational burden (TMB), and microsatellite instability (MSI) status were concordant for 94%, 93%, and 93% respectively. Variability of CNAs and complex biomarkers did not increase considerably using the central pipeline and was hence attributed to wet-lab differences. Conclusion Continuous optimization of bioinformatic workflows and participating in round robin tests are recommend