julilili42/papers huggingface dataset:
Mereology in Aristotle's Assertoric Syllogistic
2018-06-01

How does Aristotle think about sentences like 'Every x is y' in the Prior Analytics? A recently popular answer conceives of these sentences as expressing a mereological relationship between x and y: the sentence is true just in case x is, in some sense, a part of y. I argue that the motivations for this interpretation have so far not been compelling. I provide a new justification for the mereological interpretation. First, I prove a very general algebraic soundness and completeness result that unifies the most important soundness and completeness results to date. Then I argue that this result vindicates the mereological interpretation. In contrast to previous interpretations, this argument shows how Aristotle's conception of predication in mereological terms can do important logical work.
Algorithms and Bounds for L-Drawings of Directed Graphs
2018-06-01

We introduce L-drawings, a novel paradigm for representing directed graphs aiming at combining the readability features of orthogonal drawings with the expressive power of adjacency matrix representations. In an L-drawing, vertices have exclusive [Formula: see text]- and [Formula: see text]-coordinates and edges consist of two segments, one exiting the source vertically and one entering the destination horizontally. We study the problem of computing L-drawings using minimum ink. We prove its NP-hardness and provide a heuristic based on a polynomial-time algorithm that adds a vertex to a drawing using the minimum additional ink. We performed an experimental analysis of the heuristic which confirms its effectiveness.
Hegels Begriff der Gewohnheit
2018-06-01

Abstract In his Encyclopedia of Philosophical Sciences , Hegel states that the essential characteristic of spirit is to exhibit the structure of manifestation. This paper argues that for Hegel the structure of manifestation is actualized in habituated bodily actions, which sheds light on Hegel’s understanding of the relation between body and soul. Furthermore, the paper shows that there is an intrinsic relation between Hegel’s theory of habit and his aesthetics. Insofar as it exemplifies the structure of manifestation, habit has an expressive dimension for Hegel, and is therefore essentially complemented by its portrayal in classical works of art by virtue of the specific relation between form and content that such works exhibit. According to the interpretation presented here, Hegel’s philosophy of mind and his philosophy of aesthetics mutually complement and illuminate each other.
Further evidence for complex inheritance of holoprosencephaly: Lessons learned from pre‐ and postnatal diagnostic testing in Germany
2018-06-01

Holoprosencephaly (HPE) has been defined as a distinct clinical entity with characteristic facial gestalt, which may—or may not—be associated with the true brain malformation observed postmortem in autopsy or in pre‐ or postnatal imaging. Affected families mainly show autosomal dominant inheritance with markedly reduced penetrance and extremely broad clinical variability even between mutation carriers within the same families. We here present advances in prenatal imaging over the last years, increasing the proportion of individuals with HPE identified prenatally including milder HPE forms and more frequently allowing to detect more severe forms already in early gestation. We report the results of diagnostic genetic testing of 344 unrelated patients for HPE at our lab in Germany since the year 2000, which currently with the application of next generation sequencing (NGS) panel sequencing identifies causal mutations for about 31% (12/38) of unrelated individuals with normal chromosomes when compared to about 15% (46/306) using conventional Sanger sequencing and Multiplex Ligation‐dependent Probe Amplification (MLPA). More comprehensive genetic testing by our in house NGS panel sequencing of 10 HPE associated genes (MiSeqTM and NextSeqTM500, Illumina, Inc., San Diego, CA) not only allowed to include genes with smaller contribution to the phenotype, but may also unravel additional low frequency or more common genetic variants potentially contributing to the observed large intrafamiliar variability and may ultimately guide our understanding of the individual clinical manifestation of this complex developmental disorder.
Prognostic Value of Atrial Fibrillation Inducibility in Patients Without History of Clinical Atrial Fibrillation
2018-06-01

AF inducibility was found more often in an older population with cardiac comorbidities. While inducibility was associated with an increased rate of diagnosed new-onset clinical AF in the months after testing, non-inducibility seemed to be associated with freedom from AF at least in the short to medium term. However, there was no significant difference in the long term follow-up.
LGG-20. MOLECULARLY-DEFINED DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR (DLGNT) COMPRISES TWO SUBGROUPS WITH DISTINCT CLINICAL AND GENETIC FEATURES
2018-06-01

Diffuse leptomeningeal glioneuronal tumors (DLGNT) represent a rare CNS neoplasm included in the latest WHO classification update from 2016. The wide spectrum of histological and radiological features can make this enigmatic tumor entity difficult to diagnose. In recent years, large-scale genomic and epigenomic analyses have provided insight into key genetic alterations in pediatric brain tumors. Through genome-wide DNA methylation screening of >25,000 tumors, we discovered a distinct class comprising 31 tumors, mostly diagnosed as DLGNTs. Copy number profiles derived from the methylation arrays revealed unifying characteristics, including loss of chromosomal arm 1p in 100% of cases. Furthermore, this molecular DLGNT class could be subdivided into two subgroups (DLGNT-pediatric and DLGNT-adult), with all DLGNT-adult additionally displaying gain of chromosomal arm 1q. Co-deletion of 1p/19q was frequently observed in both subgroups, especially in DLGNT-pediatric cases. Both subgroups also displayed recurrent genetic alterations leading to an aberrant MAPK/ERK pathway, with KIAA1549:BRAF fusion being the most frequent event. Other alterations included fusions of NTRK1/2/3 and TRIM33:RAF1. Age at diagnosis was significantly lower (median 5 vs 14 years, p<0.005) and clinical course less aggressive, in the DLGNT-pediatric group (5-yr OS 100%, vs 50% in DLGNT-adult). Our study proposes an additional molecular layer to the current histopathological classification of DLGNT, of particular use for cases not displaying typical morphological or radiological characteristics. Recurrent 1p deletion and MAPK/ERK pathway activation represent diagnostic and therapeutic biomarkers, laying the foundation for future clinical trials with e.g. MEK inhibitors that may improve the clinical outcome of patients with DLGNT.
Characterization of new anti-IL-6 antibodies revealed high potency candidates for intracellular cytokine detection and specific targeting of IL-6 receptor binding sites
2018-06-01

Interleukin-6 (IL-6) expression and secretion, induced by inflammatory processes, stimulate the acute phase response cascade. The overexpression of IL-6 contributes to a variety of inflammatory diseases, e.g. rheumatoid arthritis, Castleman's disease, multiple myeloma, and prostate cancer. Screening for high amounts of IL-6 in the patients' blood serum can be crucial for an adequate treatment. In this study, five novel murine monoclonal antibodies (mAbs) reactive to human IL-6 were generated. The mAbs were characterized for potential diagnostic purposes and recombinant antibodies were derived thereof. Initial epitope mapping using a combination of blocking experiments and Hyper-IL-6, a fusion protein consisting of IL-6 and the soluble IL-6 receptor revealed distinct but overlapping binding sites. At least one of the mAbs was found to interact with the region of IL-6/ IL-R complex formation. Three mAbs were applied successfully in intracellular staining by flow cytometry, whereas one of the mAbs showed comparable binding as a reference reagent. Furthermore, the mAbs were tested for applications in various immunological assays such as ELISA, Western blot and surface plasmon resonance spectroscopy (SPR), using IL-6 from commercial sources as well as in-house produced protein (IL-6_IME). The limit of detection was determined by sandwich ELISA (0.5 ng/mL, SD ±0.005). Our results also demonstrated that the recombinant IL-6 produced was functional and correctly folded. These findings support the use of the generated mAb clones as promising candidates for application in various immunological assays for diagnostic and scientific purposes.
Beta-Screen: Non-invasive and easy to use MEA-based parallelized screening system for intact islets of Langerhans
2018-06-01

The increase in blood glucose concentration leads to glucose-induced electrical activity of pancreatic beta-cells resulting in insulin secretion. This electrical activity manifests in glucose concentration-dependent oscillations which can easily be recorded by micro-electrode arrays (MEA). To increase the throughput of the measurements to an extent suitable for drug development we developed a MEA-based parallelized recording system for primary rodent, human or stem cell derived islets of Langerhans called Beta-Screen.
NFM-11. PEDIATRIC MENINGIOMAS ARE MOLECULARLY DISTINCT FROM ADULT COUNTERPARTS
2018-06-01

In contrast to adulthood, meningiomas are rare among children and adolescents. Although recent papers have characterized the genomics of adult meningiomas, the molecular profiles of childhood meningiomas have not been elucidated in detail. We analyzed 41 tumor samples from 37 pediatric meningioma patients (female: 17, male: 20; age range: 1-21 years). Atypical meningioma WHO grade II was the most frequent histological subtype (N=14, 38%). Most tumors were located at the convexity (N=18) or the skull base (N=15). Lack of SMO, AKT, KLF4/TRAF7 mutations by Sanger sequencing (n=22) prompted whole genome sequencing of a subset (n=7). All seven cases exhibited bi-allelic inactivation of NF2 (combined large deletion and germline (5/7) or somatic (2/7) base exchanges/frameshifts). Subsequently, tumor samples from all 37 patients were subjected to 450K DNA methylation profiling and targeted DNA sequencing using brain tumor specific gene panel. Loss of chromosome 22 was frequent (N=28, 76%), followed by loss of chromosome 1 (N=12, 32%) and chromosome 18 (N=7, 19%). Moreover, separation into three groups was evident: One encompassing all clear-cell meningiomas with enrichment for SMARCE1 mutations, a second dominated by atypical meningiomas, and a third group composed of benign meningiomas, as well as rare subtypes such as rhabdoid meningiomas. When analyzed with 105 adult tumors, most of pediatric meningiomas (28/37) clustered into a separate methylation group both by unsupervised hierarchical clustering and t-stochastic nearest neighbor embedding (t-SNE). Four recurrences were similar to the primary tumor. These data suggest that pediatric meningiomas are genetically distinct from adult counterparts.
Reactivity of Trivalent Ate Complex (thf)LiCe[N(SiHMe2)2]4 toward 1,1,3,3‐N,N,N′,N′‐Tetramethylguanidine
2018-06-01

The ate complex (thf)LiCe[N(SiHMe 2 ) 2 ] 4 reacts readily with 2–4 equiv. 1,1,3,3‐ N,N,N ′, N ′‐tetramethylguanidine (HTMG) via a tandem protonolysis/HTMG monoinsertion/HNMe 2 elimination reaction, affording [Ce{N(SiHMe 2 ) 2 } 2 (μ‐L TMG )] 2 [L TMG = N=C(NMe 2 )N=C(NMe 2 ) 2 ]. Reaction of (thf)LiCe[N(SiHMe 2 ) 2 ] with 1 equiv. HTMG gave a silylamido/guanidine mono‐exchange, leading to the isolation of the dimeric compound [Ce{N(SiHMe 2 ) 2 } 2 (μ‐TMG)] 2 , which could be converted further into [Ce{N(SiHMe 2 ) 2 } 2 (μ‐L TMG )] 2 by addition of another equiv. of HTMG. The mechanism of formation of complex [Ce{N(SiHMe 2 ) 2 } 2 (μ‐L TMG )] 2 are discussed.
Altered global brain-network properties as trait marker in restrictive eating disorders
2018-06-01

Introduction: Resting state fMRI (rs-fMRI) studies have identified functional connectivity patterns associated with obesity (Kullmann et al., 2012; Garcia-Garcia et al., 2013), but few have investigated in individuals with restrictive eating disorders (RED). Moreover, the majority of previous studies have employed traditional analysis procedures which fail to appreciate the complex nature of brain network organization. One previous rs-fMRI study in underweight patient employing graph-theoretic metrics revealed changes in global and intermediate brain network architecture possibly driven by local degradations in a thalamo-insular network (Geisler et al., 2016). Here we study individuals with restrictive eating disorders (RED) who present with a normal weight. Methods: The study includes fMRI resting state data of 30 individuals with RED and 30 healthy controls (HC). FMRI data were preprocessed within the nipype framework (Gorgolewski et al., 2011) using SPM8 including the artifact detection (ART), DARTEL toolbox for generating a group template and spatial normalization. Then by using the DPARSFA toolbox (Chao-Gan et al., 2010) we parcellated the volumes were into 160 spherical regions of interest (ROIs) as defined by Dosenbach (Dosenbach et al., 2010). The extracted time courses of these ROIs were used to create symmetric correlation matrices with pair-wise Pearson correlation coefficients. Based on these matrices, we constructed weighted, undirected graph networks with 160 nodes on individual subject level. We computed well-established global metrics (clustering coefficient, characteristic pathlength, small-worldness index, efficiency, degree correlation) and local graph metrics (degree, strength, average pathlength, betweenness centrality, participation index, local efficiency, normalized local efficiency) across a range of network densities (Sporns et al., 2004; Rubinov et al., 2010). Results: Indicative of an altered global network structure, RED individuals showed an increased degree correlation between linked pairs of nodes and reduced global clustering as well as small-worldness compared to HC, while no group differences at an intermediate or local network level were evident. Conclusions: This pattern of results suggests that normal-weight RED individuals have a global brain network configuration characterized by an affinity for nodes of a similar degree to connect preferably. Moreover, the network topology of RED was characterized by a reduced presence of highly interconnected groups of nodes.
IMMU-28. DECIPHERING THE AT/RT LIGANDOME
2018-06-01

Atypical teratoid/rhabdoid tumors (AT/RTs) are commonly regarded as immunologically cold tumors, as they rank among malignancies with the lowest mutational load. However, low mutational burden is not necessarily correlated with poor immunogenicity, as tumor-exclusive peptides bound in the tumor cell’s MHC represent potential targets for immune responses. Indeed, in a first set of n=17 AT/RT samples we could determine by immunohistochemistry that 1.8% of all cells within the tumors were T-cells. MHC class I, class II, and PD-L1 was expressed on 12.9%, 3%, and 5.1% of the tumor cells, respectively. To investigate whether the ligandome of AT/RTs contained tumor-exclusive peptides we then analyzed 23 centrally reviewed AT/RTs using LC-MS and subsequent bioinformatical validation. In 14 (61%) and 21 (91%) of the 23 patients, tumor-exclusive peptides were identified (59 MHC class I and 153 class II peptides in total). Of these, 47/109 peptides were exclusive for one tumor, demonstrating the high individuality of the AT/RT ligandome. Representative examples of these ligandome peptides proved to be immunogenic in T-cell priming assays. Mutation analysis revealed a median of 11 (range 1-166) tumor-specific mutations dispersed over the entire genome. In silico MHC-binding prediction showed that these neoantigenic peptides had a similar binding affinity compared to their ligandome counterparts. In conclusion, tumor-exclusive ligandome peptides can be identified in the vast majority of AT/RT patients. In silico and in vitro analyses qualify them as suitable candidates for personalized cancer vaccines.
PO-348 The other 98%: making sense of non-coding variation
2018-06-01

Introduction Despite the ever-increasing availability of whole genome sequencing datasets, our ability to understand functional impact of genetic variation remains largely restricted to the coding portion of the genome. Although a selection of methods exist to estimate variant damage potential, these methods are heavily biassed towards coding variation and have limited ability to detect potentially functional variants in non-coding regions. Furthermore, these methods either ignore tissue context of the variant or combine epigenetic annotations from multiple tissues, often dominated by blood cell lines, and are therefore poorly suited for predicting functional impact of variants in regulatory elements that act in a tissue-specific manner. Material and methods In order to address these limitations, we have developed a machine learning classifier aimed at prioritising non-coding variants while taking into account relevant tissue context. We defined ’functional impact’ as the propensity of a variant to cause allele-specific chromatin accessibility. DNase Hypersensitive Site (DHS) variants found to display preferential accessibility, as well as a matched set of negative variants, were annotated with a range of features including a set of core epigenetic marks from the ROADMAP Epigenomics project matched to the tissue of origin of the positive variant set. We then combined several machine learning algorithms to train an ensemble classifier. On a balanced test set (equal number of positive and negative variants) our model achieved area under curve (AUC) of ~75%. On a realistic dataset, where the negative variants outnumbered the positive ones 100:1, we achieved AUC of 90%. Results and discussions To demonstrate the importance of tissue context when estimating functional impact of non-coding variants, we compared the classifier’s performance on the same set of variants annotated with epigenetic information from either a closely matched or an unrelated tissue. We observed a notable drop in performance when using epigenetic context from a mismatched tissue. We show that our method drastically outperforms existing damage estimation tools in its ability to predict allele-specific chromatin accessibility. Finally, we demonstrate the utility of our method by successfully prioritising experimentally validated regulatory variants among the large number of variants within the same linkage disequilibrium block. Conclusion The above method will aid in interpretation of whole genome sequencing datasets generated in cancer and rare disease studies.
Evaluating Optical Flow Vectors Under Varying Computer-Generated Snow Intensities and Pixel Density for Autonomous Vehicles
2018-06-01

The success of Advanced Driver Assistance Systems (ADAS) in self-driving vehicles depends on the accuracy of underlying algorithms used for vision and range-based sensors. In this paper, we present an evaluation model, that measures the performance of optical flow algorithms in noisy conditions and different data processing methods used to determine a mean flow vector of objects. To validate the evaluation model, we run the dense polynomial expansion Farneback [1] algorithm and then perform the evaluation (i) under light, mild and heavy snow intensities, (ii) pixel densities of 0.5, 0.16 and 0.1 pixels/pixel and (iii) data processing methods: Moving Average, Voted Mean and Weighted Mean on Edges. We provide experimental evidence about the quality of robustness of algorithms through Jaccard Index and deviation of displacement vectors from their expected value under different practical criteria that are relevant for the automotive domain.
Noradrenergic primary and secondary reward processing in healthy subjects
2018-06-01

Introduction: We recently investigated the effects of the noradrenergic antidepressant reboxetine (REB) and the antipsychotic amisulpride (AMS) compared to placebo (PLA) on neural correlates of primary reinforcers by visual erotic stimulation in healthy subjects (Graf et al. 2017). Whereas AMS left subjective sexual function and corresponding neural activations unimpaired, attenuated neural activations were observed within the nucleus accumbens (Nacc) along with diminished behavioural sexual functioning under REB. However, a global dampening of the reward system under REB seems not intuitive considering the complementary role of the noradrenergic to the dopamine system in reinforced learning as coded in prediction error processing. Methods: We therefore investigated the sample of 17 healthy males in a mean age of 23.8 years again by functional magnetic resonance imaging (fMRI) to explore the noradrenergic effects on neural prediction error signalling. Participants took REB (4mg/d), AMS (200mg/d) and PLA each for 7 days within a randomized, double-blind, within-subject cross-over design. During fMRI, we used an established monetary incentive task to assess neural prediction error signals within the bilateral Nacc using an independent anatomical mask for a region of interest (ROI) analysis. Activations within the same ROI were also assessed for the erotic picture paradigm. Results: We could confirm our previous results from the whole brain analysis for the selected ROI by significant (p&lt;0.05 FWE-corrected) attenuated Nacc-activations during visual sexual stimulation under REB compared to PLA. However, neural activations concerning prediction error processing and monetary reward expectation were unimpaired or even increased under REB compared to PLA along with unimpaired reaction times in the reward task. For both tasks, neural activations and behavioural processing were not altered by AMS compared to PLA. Conclusions: With attenuated neural activations within the Nacc during visual erotic stimulation and otherwise unimpaired or even increased neural prediction error and monetary reward expectancy processing, our results provide evidence regarding a differential modulation of the neural reward system by the noradrenergic agent REB according to the presence of primary reinforcers such as erotic stimuli in contrast to secondary such as monetary rewards.
Senescence mirrors the extent of liver fibrosis in chronic hepatitis C virus infection
2018-06-04

Summary Background Chronic viral hepatitis is linked to fibrotic liver injury that can progress to liver cirrhosis with its associated complications. Recent evidence suggests a role of senescence in liver fibrosis, although the senescence regulators contributing to fibrosis progression remain unclear. Aim To investigate the role of senescence and different senescence markers for fibrosis progression in patients with chronic hepatitis C virus ( HCV ) infection. Methods The expression of the cell cycle inhibitors p21, p27 and p16 as well as the senescence markers p‐ HP 1γ and γ‐H2 AX was analysed in liver tissue with different fibrosis stages. Senescence‐associated chitotriosidase activity was measured in sera of HCV patients (n = 61) and age‐matched healthy individuals (n = 22). Results We found a remarkable up‐regulation of the cell cycle inhibitors and senescence markers in chronic HCV infection compared to healthy liver tissue. Liver tissue with relevant fibrosis stages (F2‐3) or cirrhosis (F4) revealed a significant increase in senescent cells compared to livers with no or minimal fibrosis (F0‐1). In cirrhotic livers, a significantly higher number of p‐ HP 1γ, p21 and p27 positive cells was detected compared to liver tissue with F2‐3 fibrosis. Importantly, we identified T‐cells as the dominant cell type contributing to increased senescence during fibrosis progression. Compared to healthy individuals, serum chitotriosidase was significantly elevated and correlated with histological fibrosis stages and liver stiffness as assessed by transient elastography. Conclusions Senescence of hepatic T‐cells is enhanced in chronic viral hepatitis and increases with fibrosis progression. Serological detection of senescence‐associated chitotriosidase might allow for the non‐invasive detection of relevant fibrosis stages.