julilili42/papers huggingface dataset:
The action-sentence compatibility effect (ACE) a benchmark finding for embodiment - A meta-analysis
2022-01-07

The embodied account of language comprehension has been one of the most influentialtheoretical developments in the recent decades addressing the question how humanscomprehend and represent language. To examine its assumptions, many studies havemade use of behavioral paradigms involving basic compatibility effects. Theaction–sentence compatibility effect (ACE) is one of the most influential of thesecompatibility effects and is the most widely cited evidence for the assumptions of theembodied account of language comprehension. However, recently there have beendifficulties to extend or even to reliably replicate the ACE. The conflicting findingsconcerning the ACE and its extensions lead to the discussion whether the ACE isindeed a reliable effect or whether it might be the product of publication bias or otherdistorting research practices. In a first step we conducted a meta-analysis using arandom-effects model. This analysis revealed a small but significant effect size of theACE (d = .129, p = .007). A second meta-analytic approach supports these findings ofthe existence of an ACE (Fisher’s method: χ2 = 124.379, p &amp;lt; .001). Furthermore, thetask-parameter Delay occurred as a factor of interest in whether the ACE appears withpositive or negative effect direction. This meta-analysis further assessed for potentialpublication bias and suggests that there is bias in the ACE literature.
Continuous, non-invasive monitoring of oxygen consumption in a parallelized microfluidic in vitro system provides novel insight into the response to nutrients and drugs of primary human hepatocytes
2022-01-07

Oxygen plays a fundamental role in cellular energy metabolism, differentiation and cell biology in general. Consequently, in vitro oxygen sensing can be used to assess cell vitality and detect specific mechanisms of toxicity. In 2D in vitro models currently used, the oxygen supply provided by diffusion is generally too low, especially for cells having a high oxygen demand. In organ-on-chip systems, a more physiologic oxygen supply can be generated by establishing unidirectional perfusion. We established oxygen sensors in an easy-to-use and parallelized organ-on-chip system. We demonstrated the applicability of this system by analyzing the influence of fructose (40 mM, 80 mM), ammonium chloride (100 mM) and Na-diclofenac (50 μM, 150 μM, 450 μM, 1500 μM) on primary human hepatocytes (PHH). Fructose treatment for two hours showed an immediate drop of oxygen consumption (OC) with subsequent increase to nearly initial levels. Treatment with 80 mM glucose, 20 mM lactate or 20 mM glycerol did not result in any changes in OC which demonstrates a specific effect of fructose. Application of ammonium chloride for two hours did not show any immediate effects on OC, but qualitatively changed the cellular response to FCCP treatment. Na-diclofenac treatment for 24 hours led to a decrease of the maximal respiration and reserve capacity. We also demonstrated the stability of our system by repeatedly treating cells with 40 mM fructose, which led to similar cell responses on the same day as well as on subsequent days. In conclusion, our system enables in depth analysis of cellular respiration after substrate treatment in an unidirectional perfused organ-on-chip system.
Proof Compression and NP Versus PSPACE II: Addendum
2022-01-07

In our previous work we proved the conjecture NP = PSPACE by advanced proof theoretic methods that combined Hudelmaier’s cut-free sequent calculus for minimal logic (HSC) with the horizontal compressing in the corresponding minimal Prawitz-style natural deduction (ND). In this Addendum we show how to prove a weaker result NP = coNP without referring to HSC. The underlying idea (due to the second author) is to omit full minimal logic and compress only “naive” normal tree-like ND refutations of the existence of Hamiltonian cycles in given non-Hamiltonian graphs, since the Hamiltonian graph problem in NPcomplete. Thus, loosely speaking, the proof of NP = coNP can be obtained by HSC-elimination from our proof of NP = PSPACE.
"DYT6 mutated THAP1 is a cell type dependent regulator of the SP1 family"
2022-01-07

&lt;p&gt;DYT6 dystonia is caused by mutations in the transcription factor THAP1. THAP1 knock-out or knock-in mouse models revealed complex gene expression changes which are potentially responsible for the pathogenesis of DYT6 dystonia. However, how THAP1 mutations lead to these gene expression alterations and whether the gene expression changes are also reflected in the brain of THAP1 patients are still unclear. In this study we used epigenetic and transcriptomic approaches combined with multiple model systems (THAP1 patients&#39; frontal cortex, THAP1 patients&#39; iPSCs derived midbrain dopaminergic neurons, THAP1 heterozygous knock-out rat model, and THAP1 heterozygous knock-out SH-SY5Y cell lines) to uncover a novel function of THAP1 and the potential pathogenesis of DYT6 dystonia. We observed that THAP1 targeted only a minority of differentially expressed genes caused by its mutation. THAP1 mutations lead to dysregulation of genes mainly through regulation of SP1 family members, SP1 and SP4, in a cell type dependent manner. Comparing global differentially expressed genes detected in THAP1 patients&#39; iPSCs derived midbrain dopaminergic neurons and THAP1 heterozygous knock-out rat striatum, we observed many common dysregulated genes and 61 of them are involved in dystonic syndromes related pathways, like synaptic transmission, nervous system development, and locomotor behavior. Further behavioral and electrophysiological studies confirmed the involvement of these pathways in THAP1 knock-out rats. Taking together, our study characterized the function of THAP1 and contributes to the understanding of the pathogenesis of primary dystonia in human and rat. As SP1 family members are dysregulated in some neurodegenerative diseases, our data may link THAP1 dystonia to multiple neurological diseases and may thus provide common treatment targets.&lt;/p&gt;
Identifying the Steps Required to Effectively Implement Next-Generation Sequencing in Oncology at a National Level in Europe
2022-01-08

Next-generation sequencing (NGS) may enable more focused and highly personalized cancer treatment, with the National Comprehensive Cancer Network and European Society for Medical Oncology guidelines now recommending NGS for daily clinical practice for several tumor types. However, NGS implementation, and therefore patient access, varies across Europe; a multi-stakeholder collaboration is needed to establish the conditions required to improve this discrepancy. In that regard, we set up European Alliance for Personalised Medicine (EAPM)-led expert panels during the first half of 2021, including key stakeholders from across 10 European countries covering medical, economic, patient, industry, and governmental expertise. We describe the outcomes of these panels in order to define and explore the necessary conditions for NGS implementation into routine clinical care to enable patient access, identify specific challenges in achieving them, and make short- and long-term recommendations. The main challenges identified relate to the demand for NGS tests (governance, clinical standardization, and awareness and education) and supply of tests (equitable reimbursement, infrastructure for conducting and validating tests, and testing access driven by evidence generation). Recommendations made to resolve each of these challenges should aid multi-stakeholder collaboration between national and European initiatives, to complement, support, and mutually reinforce efforts to improve patient care.
Dairy Intake and Parkinson's Disease: A Mendelian Randomization Study
2022-01-08

Abstract Background Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding. Objective The aim is to examine the association between genetically predicted dairy intake and PD using two‐sample Mendelian randomization (MR). Methods We genotyped a well‐established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage‐PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry). Results Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% confidence interval = 1.12–2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37–4.56], P = 0.003; P ‐difference with women = 0.029). Conclusions Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society
Biomarkers Associated with Immune-Related Adverse Events under Checkpoint Inhibitors in Metastatic Melanoma
2022-01-08

Immune checkpoint inhibitors (ICI) have revolutionized the therapeutic landscape of metastatic melanoma. However, ICI are often associated with immune-related adverse events (IRAE) such as colitis, hepatitis, pancreatitis, hypophysitis, pneumonitis, thyroiditis, exanthema, nephritis, myositis, encephalitis, or myocarditis. Biomarkers associated with the occurrence of IRAE would be desirable. In the literature, there is only little data available and furthermore mostly speculative, especially in view of genetic alterations. Our major aim was to check for possible associations between NGS-based genetic alterations and IRAE. We therefore analyzed 95 melanoma patients with ICI and evaluated their NGS results. We checked the data in view of potential associations between copy number variations (CNVs), small variations (VARs), human leucocyte antigen (HLA), sex, blood count parameters, pre-existing autoimmune diseases and the occurrence of IRAE. We conducted a literature research on genetic alterations hypothesized to be associated with the occurrence of IRAE. In total, we identified 39 genes that have been discussed as hypothetical biomarkers. We compared the list of these 39 genes with the tumor panel that our patients had received and focused our study on those 16 genes that were also included in the tumor panel used for NGS. Therefore, we focused our analyses on the following genes: AIRE, TERT, SH2B3, LRRK2, IKZF1, SMAD3, JAK2, PRDM1, CTLA4, TSHR, FAN1, SLCO1B1, PDCD1, IL1RN, CD274, UNG. We obtained relevant results: female sex was significantly associated with the development of hepatitis, combined immunotherapy with colitis, increased total and relative monocytes at therapy initiation were significantly associated with the development of pancreatitis, the same, pre-existing autoimmune diseases. Further significant associations were as follows: HLA homozygosity (hepatitis), and VARs on SMAD3 (pancreatitis). Regarding CNVs, significant markers included PRDM1 deletions and IL1RN (IRAE), CD274 duplications and SLCO1B1 (hepatitis), PRDM1 and CD274 (encephalitis), and PRDM1, CD274, TSHR, and FAN1 (myositis). Myositis and encephalitis, both, were associated with alterations of PRDM1 and CD274, which might explain their joined appearance in clinical practice. The association between HLA homozygosity and IRAE was clarified by finding HLA-A homozygosity as determining factor. We identified several genetic alterations hypothesized in the literature to be associated with the development of IRAE and found significant results concerning pre-existing autoimmune diseases and specific blood count parameters. Our findings can help to better understand the development of IRAE in melanoma patients. NGS might be a useful screening tool, however, our findings have yet to be confirmed in larger studies.
Targeted protein degradation: from small molecules to complex organelles—a Keystone Symposia report
2022-01-08

Abstract Targeted protein degradation is critical for proper cellular function and development. Protein degradation pathways, such as the ubiquitin proteasomes system, autophagy, and endosome–lysosome pathway, must be tightly regulated to ensure proper elimination of misfolded and aggregated proteins and regulate changing protein levels during cellular differentiation, while ensuring that normal proteins remain unscathed. Protein degradation pathways have also garnered interest as a means to selectively eliminate target proteins that may be difficult to inhibit via other mechanisms. On June 7 and 8, 2021, several experts in protein degradation pathways met virtually for the Keystone eSymposium “Targeting protein degradation: from small molecules to complex organelles.” The event brought together researchers working in different protein degradation pathways in an effort to begin to develop a holistic, integrated vision of protein degradation that incorporates all the major pathways to understand how changes in them can lead to disease pathology and, alternatively, how they can be leveraged for novel therapeutics.
How paediatric drug development and use could benefit from OMICs: A c4c expert group white paper
2022-01-08

The safety and efficacy of pharmacotherapy in children, particularly preterms, neonates and infants, is limited by a paucity of good‐quality data from prospective clinical drug trials. A specific challenge is the establishment of valid biomarkers. OMICs technologies may support these efforts by complementary information about targeted and nontargeted molecules through systematic characterization and quantitation of biological samples. OMICs technologies comprise at least genomics, epigenomics, transcriptomics, proteomics, metabolomics and microbiomics in addition to the patient's phenotype. OMICs technologies are in part hypothesis‐generating, allowing an in depth understanding of disease pathophysiology and pharmacological mechanisms. Application of OMICs technologies in paediatrics faces major challenges before routine adoption. First, developmental processes need to be considered, including a subdivision into specific age groups as developmental changes clearly impact OMICs data. Second, compared to the adult population, the number of patients is limited as are the type and amount of necessary biomaterial, especially in neonates and preterms. Thus, advanced trial designs and biostatistical methods, noninvasive biomarkers, innovative biobanking concepts including data and samples from healthy children, as well as analytical approaches (eg liquid biopsies) should be addressed to overcome these obstacles. The ultimate goal is to link OMICs technologies with innovative analysis tools, such as artificial intelligence at an early stage. The use of OMICs data based on a feasible approach will contribute to the identification complex phenotypes and subpopulations of patients to improve the development of medicines for children with potential economic advantages.
Placing Arrows in Directed Graph Layouts: Algorithms and Experiments
2022-01-08

Abstract We study how to place arrow heads in directed graph drawings aiming at minimizing their overlaps and avoiding intersections between arrow heads and edges. The objective is to support users to correctly and quickly recognize edge orientations, i.e. to deduce unambiguously the edge orientations. Our contribution is two‐fold: (i) We present exact and heuristic algorithms for this arrow placement problem, along with an extensive experimental analysis of these techniques; and (ii) we report on a user study aimed to understand the impact of different arrow placement strategies on performing global and local analysis tasks on directed graph layouts.
Endometrial hyperplasia as a risk factor of endometrial cancer
2022-01-10

Abstract Endometrial hyperplasia (EH) is the precursor lesion for endometrioid adenocarcinoma of the endometrium (EC), which represents the most common malignancy of the female reproductive tract in industrialized countries. The most important risk factor for the development of EH is chronic exposure to unopposed estrogen. Histopathologically, EH can be classified into EH without atypia (benign EH) and atypical EH/endometrial intraepithelial neoplasia (EIN). Clinical management ranges from surveillance or progestin therapy through to hysterectomy, depending on the risk of progression to or concomitant EC and the patient ́s desire to preserve fertility. Multiple studies support the efficacy of progestins in treating both benign and atypical EH. This review summarizes the evidence base regarding risk factors and management of EH. Additionally, we performed a systematic literature search of the databases PubMed and Cochrane Controlled Trials register for studies analyzing the efficacy of progestin treatment in women with EH.
Changes in CD163+, CD11b+, and CCR2+ peripheral monocytes relate to Parkinson’s disease and cognition
2022-01-10

Alpha-synuclein pathology is associated with immune activation and neurodegeneration in Parkinson's disease. The immune activation involves not only microglia but also peripheral immune cells, such as mononuclear phagocytes found in blood and infiltrated in the brain. Understanding peripheral immune involvement is essential for developing immunomodulatory treatment. Therefore, we aimed to study circulating mononuclear phagocytes in early- and late-stage Parkinson's disease, defined by disease duration of less or more than five years, respectively, and analyze their association with clinical phenotypes. We performed a cross-sectional multi-color flow cytometry study on 78 sex-balanced individuals with sporadic Parkinson's disease, 28 controls, and longitudinal samples from seven patients and one control. Cell frequencies and surface marker expressions on natural killer cells, monocyte subtypes, and dendritic cells were compared between groups and correlated with standardized clinical scores. We found elevated frequencies and surface levels of migration- (CCR2, CD11b) and phagocytic- (CD163) markers, particularly on classical and intermediate monocytes in early Parkinson's disease. HLA-DR expression was increased in advanced stages of the disease, whereas TLR4 expression was decreased in women with Parkinson's Disease. The disease-associated immune changes of CCR2 and CD11b correlated with worse cognition. Increased TLR2 expression was related to worse motor symptoms. In conclusion, our data highlights the TLR2 relevance in the symptomatic motor presentation of the disease and a role for peripheral CD163<sup>+</sup> and migration-competent monocytes in Parkinson's disease cognitive defects. Our study suggests that the peripheral immune system is dynamically altered in Parkinson's disease stages and directly related to both symptoms and the sex bias of the disease.
Pleomorphic xanthoastrocytoma is a heterogeneous entity with pTERT mutations prognosticating shorter survival
2022-01-10

Abstract Pleomorphic xanthoastrocytoma (PXA) in its classic manifestation exhibits distinct morphological features and is assigned to CNS WHO grade 2 or grade 3. Distinction from glioblastoma variants and lower grade glial and glioneuronal tumors is a common diagnostic challenge. We compared a morphologically defined set of PXA (histPXA) with an independent set, defined by DNA methylation analysis (mcPXA). HistPXA encompassed 144 tumors all subjected to DNA methylation array analysis. Sixty-two histPXA matched to the methylation class mcPXA. These were combined with the cases that showed the mcPXA signature but had received a histopathological diagnosis other than PXA. This cohort constituted a set of 220 mcPXA. Molecular and clinical parameters were analyzed in these groups. Morphological parameters were analyzed in a subset of tumors with FFPE tissue available. HistPXA revealed considerable heterogeneity in regard to methylation classes, with methylation classes glioblastoma and ganglioglioma being the most frequent mismatches. Similarly, the mcPXA cohort contained tumors of diverse histological diagnoses, with glioblastoma constituting the most frequent mismatch. Subsequent analyses demonstrated the presence of canonical pTERT mutations to be associated with unfavorable prognosis among mcPXA. Based on these data, we consider the tumor type PXA to be histologically more varied than previously assumed. Histological approach to diagnosis will predominantly identify cases with the established archetypical morphology. DNA methylation analysis includes additional tumors in the tumor class PXA that share similar DNA methylation profile but lack the typical morphology of a PXA. DNA methylation analysis also assist in separating other tumor types with morphologic overlap to PXA. Our data suggest the presence of canonical pTERT mutations as a robust indicator for poor prognosis in methylation class PXA.
Upregulation of cAMP prevents antibody-mediated thrombus formation in COVID-19
2022-01-10

Abstract Thromboembolic events are frequently reported in patients infected with the SARS-CoV-2 virus. The exact mechanisms of COVID-19-associated hypercoagulopathy, however, remain elusive. Recently, we observed that platelets (PLTs) from patients with severe COVID-19 infection express high levels of procoagulant markers, which were found to be associated with increased risk for thrombosis. In the current study, we investigated the time course as well as the mechanisms leading to procoagulant PLTs in COVID-19. Our study demonstrates the presence of PLT-reactive IgG antibodies that induce marked changes in PLTs in terms of increased inner-mitochondrial transmembrane potential (Δψ) depolarization, phosphatidylserine (PS) externalization, and P-selectin expression. The IgG-induced procoagulant PLTs and increased thrombus formation were mediated by ligation of PLT Fc-γ RIIA (FcγRIIA). In addition, contents of calcium and cyclic-adenosine-monophosphate (cAMP) in PLTs were identified to play a central role in antibody-induced procoagulant PLT formation. Most importantly, antibody-induced procoagulant events, as well as increased thrombus formation in severe COVID-19, were inhibited by Iloprost, a clinically approved therapeutic agent that increases the intracellular cAMP levels in PLTs. Our data indicate that upregulation of cAMP could be a potential therapeutic target to prevent antibody-mediated coagulopathy in COVID-19 disease.
A new method for birch tar making with materials available in the Stone Age
2022-01-10

Abstract The use of birch tar can be traced back to the European Middle Palaeolithic and is relevant for our understanding of the technical skills and cognitive abilities of Neanderthals. Due to the lack of archaeological evidence, it remains unknown what techniques were used for birch tar making. Efficiency was recently used as a proxy to determine the method most likely used in the Middle Palaeolithic. Todtenhaupt et al. have proposed a technique employing a groove-like structure that is comparable with the recently presented condensation method. The groove method resulted in higher tar yields compared to other experimental aceramic production processes. However, the implications for Palaeolithic tar making remain unclear because some of the materials used in the experiment were not available then (polished granite slabs). To approach this problem, we replicated the groove with river cobbles and, in a second experiment with flint fragments, to evaluate whether similar results can be obtained. We were successful in producing birch tar in multiple runs with the cobble- and flint-grooves, which, in addition, proved to be more efficient than the condensation method in terms of tar yield per bark input. Our experimental study provides an additional possibility to make prehistoric birch tar.