julilili42/papers huggingface dataset:
Open-Minded Orthodox Bayesianism by Epsilon-Conditionalization
2018-12-04

Orthodox Bayesianism endorses revising by conditionalization. This paper investigates the zero-raising problem, or equivalently the certainty-dropping problem of orthodox Bayesianism: previously neglected possibilities remain neglected, although the new evidence might suggest otherwise. Yet, one may want to model open-minded agents, that is, agents capable of raising previously neglected possibilities. Different reasons can be given for open-mindedness, one of which is fallibilism. The paper proposes a family of open-minded propositional revisions depending on a parameter ε. The basic idea is this: first extend the prior to the newly suggested possibilities by mixing the prior with the uniform probability on these possibilities, then conditionalize. This may put the agent back on the right track when her beliefs or evidence happen to be false. The paper justifies this family of equivocal epsilon-conditionalizations as minimal non-biased open-minded modifications of conditionalization. Several variations are discussed, such as mixing with an ad hoc or silent prior instead of the uniform prior, and a generalization to probabilistic information is given. The approach is compared to other accounts, such as Jeffrey’s Bayesianism, Gärdenfors’s probabilistic revision, maximizing entropy, and minimal revision. 1 Introduction2 Downsides of Certainty Conservation3 Why Raise Zeros? 3.1 Accuracy defects 3.2 Fallibilism and dissolutions 3.3 Weak fallibilism and partial solutions4 Epsilon-Conditionalization 4.1 Definitions 4.2 Revision types and information assumptions 4.3 Epsilon interpretation and flavours5 Justifications 5.1 Open-minded orthodox Bayesianism 5.2 Minimal revision 5.3 Transitivity6 Conclusion Appendix
A Chromatin Immunoprecipitation Assay to Identify Novel NFAT2 Target Genes in Chronic Lymphocytic Leukemia
2018-12-04

Chronic lymphocytic leukemia (CLL) is characterized by the expansion of malignant B cell clones and represents the most common leukemia in western countries. The majority of CLL patients show an indolent course of the disease as well as an anergic phenotype of their leukemia cells, referring to a B cell receptor unresponsive to external stimulation. We have recently shown that the transcription factor NFAT2 is a crucial regulator of anergy in CLL. A major challenge in the analysis of the role of a transcription factor in different diseases is the identification of its specific target genes. This is of great significance for the elucidation of pathogenetic mechanisms and potential therapeutic interventions. Chromatin immunoprecipitation (ChIP) is a classic technique to demonstrate protein-DNA interactions and can, therefore, be used to identify direct target genes of transcription factors in mammalian cells. Here, ChIP was used to identify LCK as a direct target gene of NFAT2 in human CLL cells. DNA and associated proteins are crosslinked using formaldehyde and subsequently sheared by sonication into DNA fragments of approximately 200-500 base pairs (bp). Cross-linked DNA fragments associated with NFAT2 are then selectively immunoprecipitated from cell debris using an αNFAT2 antibody. After purification, associated DNA fragments are detected via quantitative real-time PCR (qRT-PCR). DNA sequences with evident enrichment represent regions of the genome which are targeted by NFAT2 in vivo. Appropriate shearing of the DNA and the selection of the required antibody are particularly crucial for the successful application of this method. This protocol is ideal for the demonstration of direct interactions of NFAT2 with target genes. Its major limitation is the difficulty to employ ChIP in large-scale assays analyzing the target genes of multiple transcription factors in intact organisms.
Tumor-draining lymph nodes are pivotal in PD-1/PD-L1 checkpoint therapy
2018-12-05

PD-1/PD-L1 checkpoint therapy for cancer is commonly considered to act by reactivating T cells in the tumor microenvironment. Here, we present data from 2 mouse tumor models demonstrating an essential involvement of tumor-draining lymph nodes in PD-1 and PD-L1 therapeutic efficacy. Immune activation induced by checkpoint treatment was predominantly observed in the tumor-draining, but not nondraining, lymph nodes and was reflected in local accumulation of CD8+ T cells. Surgical resection of these lymph nodes, but not contralateral lymph nodes, abolished therapy-induced tumor regressions and was associated with decreased immune infiltrate in the tumor microenvironment. Moreover, inhibitor FTY720, which locks lymphocytes in lymph organs, also abrogated checkpoint therapy, suggesting that the tumor-draining lymph nodes function as sites of T cell invigoration required for checkpoint blockade therapy. Now that PD-1/PD-L1 checkpoint treatment is applied in earlier clinical stages of cancer, our preclinical data advocate for enrolling patients with their tumor-draining lymph nodes still in place, to optimally engage the antitumor immune response and thereby enhance clinical benefit.
Efficacy of psychotherapies and pharmacotherapies for Bulimia nervosa
2018-12-05

Abstract Background Bulimia nervosa (BN), a mental disorder that causes significant impairment, can be treated with psychological, pharmacological, nutrition-based and self-help interventions. We conducted a pre-registered meta-analysis of randomized-controlled trials (RCTs) to assess the efficacy of these interventions in up to 19 different interventions. Methods Database search terms were combined for BN and RCTs from database inception to March 2017. Abstinence from binge eating episodes, compensatory behaviors, the absence of a BN diagnosis and reduction of symptom severity were considered as primary outcome variables, reduction of self-reported eating pathology and depression served as secondary outcome variables. Retrieved RCTs were meta-analyzed using fixed and random effects models. Results RCT (79 trials; 5775 participants) effects post-treatment revealed moderate to large intervention effects for psychotherapy [mostly cognitive-behavioral therapy (CBT)] for primary outcome variables. Slightly reduced effects were obtained for self-help and moderate effects for pharmacotherapy. Similarly, psychotherapy yielded large to very large effects in regard to secondary outcome variables, while moderate to large effects were observed for self-help, Pharmacotherapy and combined therapies. Meta-analyses for the pre to post changes within group confirmed these findings. Additionally, follow-up analyses revealed the sustainability of psychotherapies in terms of large effects in primary outcome criteria, while these effects were moderate for self-help, pharmacotherapy, and combined therapies. Conclusions Most psychological and pharmacological interventions revealed to be effective in BN treatment. Taking effect size, sustainability of the intervention, as well as the consistency of findings and available evidence into consideration, CBT can be recommended as the best intervention for the initial treatment of BN.
When (not) to Look for Contrastive Alternatives: The Role of Pitch Accent Type and Additive Particles
2018-12-05

This study investigates how pitch accent type and additive particles affect the activation of contrastive alternatives. In Experiment 1, German listeners heard declarative utterances (e.g., The swimmer wanted to put on flippers) and saw four printed words displayed on screen: one that was a contrastive alternative to the subject noun (e.g., diver), one that was non-contrastively related (e.g., pool), the object (e.g., flippers), and an unrelated distractor. Experiment 1 manipulated pitch accent type, comparing a broad focus control condition to two narrow focus conditions: with a contrastive or non-contrastive accent on the subject noun (nuclear L+H* vs. H+L*, respectively, followed by deaccentuation). In Experiment 2, the utterances in the narrow focus conditions were preceded by the unstressed additive particle auch (“also”), which may trigger alternatives itself. It associated with the accented subject. Results showed that, compared to the control condition, participants directed more fixations to the contrastive alternative when the subject was realized with a contrastive accent (nuclear L+H*) than when it was realized with non-contrastive H+L*, while additive particles had no effect. Hence, accent type is the primary trigger for signaling the presence of alternatives (i.e., contrast). Implications for theories of information structure and the processing of additive particles are discussed.
Belowground fungal community diversity and composition associated with Norway spruce along an altitudinal gradient
2018-12-05

Altitudinal gradients provide valuable information about the effects of environmental variables on changes in species richness and composition as well as the distribution of below ground fungal communities. Since most knowledge in this respect has been gathered on aboveground communities, we focused our study towards the characterization of belowground fungal communities associated with two different ages of Norway spruce (Picea abies) trees along an altitudinal gradient. By sequencing the internal transcribed spacer (ITS) region on the Illumina platform, we investigated the fungal communities in a floristically and geologically relatively well explored forest on the slope of Mt. Iseler of the Bavarian Alps. From fine roots and rhizosphere of a total of 90 of Norway spruce trees from 18 plots we detected 1285 taxa, with a range of 167 to 506 (average 377) taxa per plot. Fungal taxa are distributed over 96 different orders belonging to the phyla Ascomycota, Basidiomycota, Chrytridiomycota, Glomeromycota, and Mucoromycota. Overall the Agaricales (438 taxa) and Tremellales (81 taxa) belonging to the Basidiomycota and the Hypocreales (65 spp.) and Helotiales (61 taxa) belonging to the Ascomycota represented the taxon richest orders. The evaluation of our multivariate generalized mixed models indicate that the altitude has a significant influence on the composition of the fungal communities (p < 0.003) and that tree age determines community diversity (p < 0.05). A total of 47 ecological guilds were detected, of which the ectomycorrhizal and saprophytic guilds were the most taxon-rich. Our ITS amplicon Illumina sequencing approach allowed us to characterize a high fungal community diversity that would not be possible to capture with fruiting body surveys alone. We conclude that it is an invaluable tool for diverse monitoring tasks and inventorying biodiversity, especially in the detection of microorganisms developing very ephemeral and/or inconspicuous fruiting bodies or lacking them all together. Results suggest that the altitude mainly influences the community composition, whereas fungal diversity becomes higher in mature/older trees. Finally, we demonstrate that novel techniques from bacterial microbiome analyses are also useful for studying fungal diversity and community structure in a DNA metabarcoding approach, but that incomplete reference sequence databases so far limit effective identification.
Cellular-scale evaluation of induced photoreceptor degeneration in the living primate eye
2018-12-05

Progress is needed in developing animal models of photoreceptor degeneration and evaluating such models with longitudinal, noninvasive techniques. We employ confocal scanning laser ophthalmoscopy, optical coherence tomography (OCT) and high-resolution retinal imaging to noninvasively observe the retina of non-human primates with induced photoreceptor degeneration. Photoreceptors were imaged at the single-cell scale in three modalities of adaptive optics scanning light ophthalmoscopy: traditional confocal reflectance, indicative of waveguiding; a non-confocal offset aperture technique visualizing scattered light; and two-photon excited fluorescence, the time-varying signal of which, at 730 nm excitation, is representative of visual cycle function. Assessment of photoreceptor structure and function using these imaging modalities revealed a reduction in retinoid production in cone photoreceptor outer segments while inner segments appeared to remain present. Histology of one retina confirmed loss of outer segments and the presence of intact inner segments. This unique combination of imaging modalities can provide essential, clinically-relevant information on both the structural integrity and function of photoreceptors to not only validate models of photoreceptor degeneration but potentially evaluate the efficacy of future cell and gene-based therapies for vision restoration.
Difference hierarchies and duality with an application to formal\\n languages
2018-12-05

The notion of a difference hierarchy, first introduced by Hausdorff, plays an\\nimportant role in many areas of mathematics, logic and theoretical computer\\nscience such as descriptive set theory, complexity theory, and the theory of\\nregular languages and automata. From a lattice theoretic point of view, the\\ndifference hierarchy over a bounded distributive lattice stratifies the Boolean\\nalgebra generated by it according to the minimum length of difference chains\\nrequired to describe the Boolean elements. While each Boolean element is given\\nby a finite difference chain, there is no canonical such writing in general. We\\nshow that, relative to the filter completion, or equivalently, the lattice of\\nclosed upsets of the dual Priestley space, each Boolean element over the\\nlattice has a canonical minimum length decomposition into a Hausdorff\\ndifference. As a corollary each Boolean element over a (co-)Heyting algebra has\\na canonical difference chain. With a further generalization of this result\\ninvolving a directed family of adjunctions with meet-semilattices, we give an\\nelementary proof of the fact that a regular language is given by a Boolean\\ncombination of purely universal sentences using arbitrary numerical predicates\\nif and only if it is given by a Boolean combination of purely universal\\nsentences using only regular numerical predicates.\\n
Neuronal mechanisms of mutations in SCN8A causing epilepsy or intellectual disability
2018-12-06

Ion channel mutations can cause distinct neuropsychiatric diseases. We first studied the biophysical and neurophysiological consequences of four mutations in the human Na+ channel gene SCN8A causing either mild (E1483K) or severe epilepsy (R1872W), or intellectual disability and autism without epilepsy (R1620L, A1622D). Only combined electrophysiological recordings of transfected wild-type or mutant channels in both neuroblastoma cells and primary cultured neurons revealed clear genotype-phenotype correlations. The E1483K mutation causing mild epilepsy showed no significant biophysical changes, whereas the R1872W mutation causing severe epilepsy induced clear gain-of-function biophysical changes in neuroblastoma cells. However, both mutations increased neuronal firing in primary neuronal cultures. In contrast, the R1620L mutation associated with intellectual disability and autism-but not epilepsy-reduced Na+ current density in neuroblastoma cells and expectedly decreased neuronal firing. Interestingly, for the fourth mutation, A1622D, causing severe intellectual disability and autism without epilepsy, we observed a dramatic slowing of fast inactivation in neuroblastoma cells, which induced a depolarization block in neurons with a reduction of neuronal firing. This latter finding was corroborated by computational modelling. In a second series of experiments, we recorded three more mutations (G1475R, M1760I, G964R, causing intermediate or severe epilepsy, or intellectual disability without epilepsy, respectively) that revealed similar results confirming clear genotype-phenotype relationships. We found intermediate or severe gain-of-function biophysical changes and increases in neuronal firing for the two epilepsy-causing mutations and decreased firing for the loss-of-function mutation causing intellectual disability. We conclude that studies in neurons are crucial to understand disease mechanisms, which here indicate that increased or decreased neuronal firing is responsible for distinct clinical phenotypes.
Interfacing a Potential Purely Organic Molecular Quantum Bit with a Real-Life Surface
2018-12-06

By using a multidisciplinary and multitechnique approach, we have addressed the issue of attaching a molecular quantum bit to a real surface. First, we demonstrate that an organic derivative of the pyrene-Blatter radical is a potential molecular quantum bit. Our study of the interface of the pyrene-Blatter radical with a copper-based surface reveals that the spin of the interface layer is not canceled by the interaction with the surface and that the Blatter radical is resistant in presence of molecular water. Although the measured pyrene-Blatter derivative quantum coherence time is not the highest value known, this molecule is known as a "super stable" radical. Conversely, other potential qubits show poor thin film stability upon air exposure. Therefore, we discuss strategies to make molecular systems candidates as qubits competitive, bridging the gap between potential and real applications.
Combined Targeted Analysis of Metabolites and Proteins in Tear Fluid With Regard to Clinical Applications
2018-12-06

Our data about intra- and interindividual as well as intereye variation provide a valuable basis for the design of clinical studies, and for the applicability of multiplexed "omics" to well accessible tear fluid with regard to future routine use.
Understanding the Sensing Mechanism of Rh2O3 loaded In2O3
2018-12-06

The effect of Rh loading on CO sensing was studied for the case of In2O3. This was done by performing measurements with sensors based on loaded and unloaded materials that were performed at an operation temperature of 300 &amp;deg;C in the presence of low background oxygen concentration according to an experimental procedure that was demonstrated to help clarify the reception/transduction functions of loaded Semiconducting Metal Oxides (SMOX). The experimental investigation methods were DC resistance and Diffuse Reflectance Infrared Fourier Transform Spectroscopy (DRIFTS). The results indicate that in the case of Rh2O3 loaded In2O3 the reaction primary takes place on the Rh2O3 cluster and the electrical properties of the In2O3 are controlled by the pinning of the SMOX Fermi-level to the one of the Rh2O3 cluster.
Laughing Out Loud! Investigations on Different Types of Laughter
2018-12-06

This chapter summarizes findings on the production, perception, and cerebral processing of different types of laughter, such as friendly laughter, tickling laughter, ‘schadenfreude’ laughter (expressing the pleasure about somebody’s misfortune), and taunting laughter. It discusses the articulatory and acoustic patterns related to these different types of laughter. The majority of acoustic patterns specifically linked to distinct types of laugher are related to voice parameters, such as fundamental frequency, and the involvement of the oral and nasal cavities. This may result in coughing-like or snoring-like features of laughter. The chapter argues that this may constitute a link to the evolutionary progression of emotional expression. Regarding laughter perception, the chapter presents studies showing that different types of laughter can be classified by listeners based solely on acoustics. Moreover, it reports specific changes in laughter perception, such as in the case of gelotophobia (the fear of being laughed at) and social anxiety. Lastly, the chapter shows data on the neurobiological underpinnings of laughter perception in healthy subjects, as well as the neural correlates of the negative attention bias observed in patients with social anxiety. The identification of neurobiological correlates of cognitive biases during laughter perception may provide a promising target for evaluation of therapeutic interventions such as neuropsychological training, non-invasive brain stimulation, or neural feedbacktraining in further research projects. To conclude, laughter is a multi-faceted expression of both emotional and social interaction. Studies on how laughter can impact social interaction can be particularly helpful for future work on patients suffering from anxiety.
Voices in the Context of Human Faces and Bodies
2018-12-06

More often than not, emotion perception is a process guided by several sensory channels, accompanied by multimodal integration of emotional information. This process appears vital for effective social communication. This chapter provides an overview of recent studies describing the crossmodal integration of non-verbal emotional cues communicated via voices, faces, and bodies. The first parts of the chapter deal with the behavioural and neural correlates of multimodal integration in the healthy population using psychophysiological, electrophysiological, and neuroimaging measures, highlighting a network of brain areas involved in this process and discussing different methodological approaches. The final parts of the chapter, in contrast, are dedicated to the alterations of the multisensory integration of non-verbal emotional signals in states of psychiatric disease, with the main focus on schizophrenia and autism spectrum disorders.
Nil effects of μ-rhythm phase-dependent burst-rTMS on cortical excitability in humans: A resting-state EEG and TMS-EEG study
2018-12-07

Repetitive transcranial magnetic stimulation (rTMS) can induce excitability changes of a stimulated brain area through synaptic plasticity mechanisms. High-frequency (100 Hz) triplets of rTMS synchronized to the negative but not the positive peak of the ongoing sensorimotor μ-rhythm isolated with the concurrently acquired electroencephalography (EEG) resulted in a reproducible long-term potentiation like increase of motor evoked potential (MEP) amplitude, an index of corticospinal excitability (Zrenner et al. 2018, Brain Stimul 11:374-389). Here, we analyzed the EEG and TMS-EEG data from (Zrenner et al., 2018) to investigate the effects of μ-rhythm-phase-dependent burst-rTMS on EEG-based measures of cortical excitability. We used resting-state EEG to assess μ- and β-power in the motor cortex ipsi- and contralateral to the stimulation, and single-pulse TMS-evoked and induced EEG responses in the stimulated motor cortex. We found that μ-rhythm-phase-dependent burst-rTMS did not significantly change any of these EEG measures, despite the presence of a significant differential and reproducible effect on MEP amplitude. We conclude that EEG measures of cortical excitability do not reflect corticospinal excitability as measured by MEP amplitude. Most likely this is explained by the fact that rTMS induces complex changes at the molecular and synaptic level towards both excitation and inhibition that cannot be differentiated at the macroscopic level by EEG.