julilili42/papers huggingface dataset:
BTK operates a phospho-tyrosine switch to regulate NLRP3 inflammasome activity
2019-12-05

Abstract Activity of the NLRP3 inflammasome, a critical mediator of inflammation ( 1 ), is controlled by accessory proteins (2, 3) , post-translational modifications (4, 5) , cellular localization (6, 7) and oligomerization (8) . How these factors relate, is unclear. We show that the established drug target, Bruton’s Tyrosine Kinase (BTK) (2, 9) , integrates several levels of NLRP3 regulation: BTK phosphorylation of four conserved tyrosine residues, by neutralizing the charge of a polybasic linker region, weakens the interaction of NLRP3 with Golgi phospholipids and may thus guide NLRP3 cytosolic localization. BTK activity also promotes NLRP3 oligomerization and subsequent formation of inflammasomes. As NLRP3 tyrosine modification ultimately also impacts on IL-1β release, we propose BTK-mediated, charge-switch-based NLRP3 regulation as a novel and therapeutically tractable step in the control of inflammation. One Sentence Summary Multi-phosphorylation of NLRP3 by Bruton’s tyrosine kinase modulates NLRP3 cellular localization, inflammasome assembly, and IL-1β release.
Improvement of Fast Model-Based Acceleration of Parameter Look-Locker T1 Mapping
2019-12-05

Quantitative mapping is desirable in many scientific and clinical magneric resonance imaging (MRI) applications. Recent inverse recovery-look locker sequence enables single-shot T1 mapping with a time of a few seconds but the main computational load is directed into offline reconstruction, which can take from several minutes up to few hours. In this study we proposed improvement of model-based approach for T1-mapping by introduction of two steps fitting procedure. We provided analysis of further reduction of k-space data, which lead us to decrease of computational time and perform simulation of multi-slice development. The region of interest (ROI) analysis of human brain measurements with two different initial models shows that the differences between mean values with respect to a reference approach are in white matter—0.3% and 1.1%, grey matter—0.4% and 1.78% and cerebrospinal fluid—2.8% and 11.1% respectively. With further improvements we were able to decrease the time of computational of single slice to 6.5 min and 23.5 min for different initial models, which has been already not achieved by any other algorithm. In result we obtained an accelerated novel method of model-based image reconstruction in which single iteration can be performed within few seconds on home computer.
Determination of Dipole Polarization Effects in 7Li and 11Li
2019-12-05

The structure of 6Li, 7Li and 11Li nuclei is investigated in a model space which includes all configurations with oscillator energy up to 3hω above the ground state configuration. The energy spectra and electromagnetic properties of the low-lying states are determined with various two-body interactions, which are derived from the Bonn potential. In addition the calculation determines the dipole polarizability of7 Li and 11Li caused from virtual E1 excitations to the positive parity states of these nuclei.
Arabidopsis WRKY53, a Node of Multi-Layer Regulation in the Network of Senescence
2019-12-06

Leaf senescence is an integral part of plant development aiming at the remobilization of nutrients and minerals out of the senescing tissue into developing parts of the plant. Sequential as well as monocarpic senescence maximize the usage of nitrogen, mineral, and carbon resources for plant growth and the sake of the next generation. However, stress-induced premature senescence functions as an exit strategy to guarantee offspring under long-lasting unfavorable conditions. In order to coordinate this complex developmental program with all kinds of environmental input signals, complex regulatory cues have to be in place. Major changes in the transcriptome imply important roles for transcription factors. Among all transcription factor families in plants, the NAC and WRKY factors appear to play central roles in senescence regulation. In this review, we summarize the current knowledge on the role of WRKY factors with a special focus on WRKY53. In contrast to a holistic multi-omics view we want to exemplify the complexity of the network structure by summarizing the multilayer regulation of WRKY53 of Arabidopsis.
Antitumor astins originate from the fungal endophyte Cyanodermella asteris living within the medicinal plant Aster tataricus
2019-12-06

Significance Astins are natural products that bind to a crucial human regulatory protein, the stimulator of interferon genes (STING), which is a promising new therapeutic target for cancer and immune disorders. Astins have long been regarded as phytochemicals of a Chinese medicinal plant. Here, we show that they are produced by the newly identified fungal endophyte Cyanodermella asteris via a nonribosomal biosynthetic pathway. Moreover, we provide evidence that key astin variants are produced during symbiosis with the aster plant. The production of specific phytochemical variants during symbiotic interactions is poorly studied and might be more widespread than previously expected. These findings pave the way for a cost-effective biotechnological astin production.
Identification of Drug Resistance Determinants in a Clinical Isolate of Pseudomonas aeruginosa by High-Density Transposon Mutagenesis
2019-12-06

With the aim to identify potential new targets to restore antimicrobial susceptibility of multidrug-resistant (MDR) Pseudomonas aeruginosa isolates, we generated a high-density transposon (Tn) insertion mutant library in an MDR P. aeruginosa bloodstream isolate (isolate ID40). The depletion of Tn insertion mutants upon exposure to cefepime or meropenem was measured in order to determine the common resistome for these clinically important antipseudomonal β-lactam antibiotics.
Induction of NK Cell Reactivity against B-Cell Acute Lymphoblastic Leukemia by an Fc-Optimized FLT3 Antibody
2019-12-06

Antibody-dependent cellular cytotoxicity (ADCC) is a major mechanism by which antitumor antibodies mediate therapeutic efficacy. At present, we evaluate an Fc-optimized (amino acid substitutions S239D/I332E) FLT3 antibody termed 4G8-SDIEM (FLYSYN) in patients with acute myeloid leukemia (NCT02789254). Here we studied the possibility to induce NK cell ADCC against B-cell acute lymphoblastic leukemia (B-ALL) by Fc-optimized FLT3 antibody treatment. Flow cytometric analysis confirmed that FLT3 is widely expressed on B-ALL cell lines and leukemic cells of B-ALL patients. FLT3 expression did not correlate with that of CD20, which is targeted by Rituximab, a therapeutic monoclonal antibody (mAb) employed in B-ALL treatment regimens. Our FLT3 mAb with enhanced affinity to the Fc receptor CD16a termed 4G8-SDIE potently induced NK cell reactivity against FLT3-transfectants, the B-ALL cell line SEM and primary leukemic cells of adult B-ALL patients in a target-antigen dependent manner as revealed by analyses of NK cell activation and degranulation. This was mirrored by potent 4G8-SDIE mediated NK cell ADCC in experiments with FLT3-transfectants, the cell line SEM and primary cells as target cells. Taken together, the findings presented in this study provide evidence that 4G8-SDIE may be a promising agent for the treatment of B-ALL, particularly in CD20-negative cases.
Recombinant Modified Vaccinia Virus Ankara (MVA) Vaccines Efficiently Protect Cockatiels Against Parrot Bornavirus Infection and Proventricular Dilatation Disease
2019-12-06

Parrot bornaviruses (PaBVs) are the causative agents of proventricular dilatation disease (PDD), a chronic and often fatal neurologic disorder in Psittaciformes. The disease is widely distributed in private parrot collections and threatens breeding populations of endangered species. Thus, immunoprophylaxis strategies are urgently needed. In previous studies we demonstrated a prime-boost vaccination regime using modified vaccinia virus Ankara (MVA) and Newcastle disease virus (NDV) constructs expressing the nucleoprotein and phosphoprotein of PaBV-4 (MVA/PaBV-4 and NDV/PaBV-4, respectively) to protect cockatiels (Nymphicus hollandicus) against experimental challenge infection. Here we investigated the protective effect provided by repeated immunization with either MVA/PaBV-4, NDV/PaBV-4 or Orf virus constructs (ORFV/PaBV-4) individually. While MVA/PaBV-4-vaccinated cockatiels were completely protected against subsequent PaBV-2 challenge infection and PDD-associated lesions, the course of the challenge infection in NDV/PaBV-4- or ORFV/PaBV-4-vaccinated birds did not differ from the unvaccinated control group. We further investigated the effect of vaccination on persistently PaBV-4-infected cockatiels. Remarkably, subsequent immunization with MVA/PaBV-4 and NDV/PaBV-4 neither induced obvious immunopathogenesis exacerbating the disease nor reduced viral loads in the infected birds. In summary, we demonstrated that vaccination with MVA/PaBV-4 alone is sufficient to efficiently prevent PaBV-2 challenge infection in cockatiels, providing a suitable vaccine candidate against avian bornavirus infection and bornavirus-induced PDD.
Animal Rights and Robot Ethics
2019-12-06

This paper investigates challenges which anthropocentric and pathocentric ethics have to face when confronted with moral considerations about non-human animals, especially so-called disenhanced animals, and a new class of technological artifacts, namely social robots. Referring to the case of animal welfare, robot ethics emerges as a new discipline that has not yet reflected on the ideological biases that commonly underlie moral judgments toward animals and find expression in robot ethics, too. As a consequence, robot ethics perpetuates the “work of purification,” that is, the isolation and definition of a particular entity possessing a moral status. Whenever such an entity is defined, the definition excludes all those entities which could likewise possess a moral status but do not fit exactly to the pre-specified definition. The crucial question, then, is whether to seek an ethic of unconditional compassion that doesn't allow itself to be restricted by ideology and is therefore convenient for animal rights and robot ethics as well.
The Integrin Activating Protein Kindlin-3 Is Cleaved in Human Platelets during ST-Elevation Myocardial Infarction
2019-12-06

Kindlins are important proteins for integrin signaling and regulation of the cytoskeleton, but we know little about their precise function and regulation in platelets during acute ischemic events. In this work, we investigated kindlin-3 protein levels in platelets isolated from patients with ST-elevation myocardial infarction (STEMI) compared to patients with non-ischemic chest pain. Platelets from twelve patients with STEMI and twelve patients with non-ischemic chest pain were isolated and analyzed for kindlin-3 protein levels and intracellular localization by immunoblotting and two-dimensional gel electrophoresis. Platelet proteome analysis by two-dimensional gel electrophoresis and protein sequencing identified kindlin-3 as a protein that is cleaved in platelets from patients with myocardial infarction. Kindlin-3 full-length protein was significantly decreased in patients with STEMI compared to patients with non-ischemic chest pain (1.0 ± 0.2 versus 0.28 ± 0.2, p &lt; 0.05) by immunoblotting. Kindlin-3 showed a differential distribution and was primarily cleaved in the cytosolic and membrane compartment of platelets in myocardial infarction. Platelet activation with thrombin alone did not affect kindlin-3 protein levels. The present study demonstrates that kindlin-3 protein levels become significantly reduced in platelets of patients with myocardial infarction compared to controls. The results suggest that kindlin-3 cleavage in platelets is associated with the ischemic event of myocardial infarction.
Optimization in Detection of Antigen‐Specific T Cells Through Differentially Labeled MHC Multimers
2019-12-06

Abstract A large variety of fluorescent molecules are used on a regular basis to tag major histocompatibility complex (MHC) multimers for detection of antigen‐specific T cells. We have evaluated the way in which the choice of fluorescent label can impact the detection of MHC multimer binding T cells in an exploratory proficiency panel where detection of MHC multimer binding T cells was assessed across 16 different laboratories. We found that the staining index (SI) of the multimer reagent provided the best direct correlation with the value of a given fluorochrome for T cell detection studies. The SI is dependent on flow cytometer settings and chosen antibody panel; hence, the optimal fluorochrome selection may differ from lab to lab. Consequently, we describe a strategy to evaluate performance of the detection channels and optimize the SI for selected fluorescent molecules. This approach can easily be used to test and optimize fluorescence detection in relation to MHC multimer staining and in general, for antibody‐based identification of rare cell populations. © 2019 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.
Impact of tibial baseplate malposition on kinematics, contact forces and ligament tensions in TKA: A numerical analysis
2019-12-07

Tibial baseplate malposition effects ligament tensions, tibiofemoral contact forces and kinematics and has a risk of unfavorable clinical results due to postoperative pain, reduced range of motion, instability and a higher rate of early loosening. Therefore, surgeons should aim for a neutral position of the tibial baseplate.
Human mitochondrial DNA lineages in Iron-Age Fennoscandia suggest incipient admixture and eastern introduction of farming-related maternal ancestry
2019-12-07

Human ancient DNA studies have revealed high mobility in Europe’s past, and have helped to decode the human history on the Eurasian continent. Northeastern Europe, especially north of the Baltic Sea, however, remains less well understood largely due to the lack of preserved human remains. Finland, with a divergent population history from most of Europe, offers a unique perspective to hunter-gatherer way of life, but thus far genetic information on prehistoric human groups in Finland is nearly absent. Here we report 103 complete ancient mitochondrial genomes from human remains dated to AD 300–1800, and explore mtDNA diversity associated with hunter-gatherers and Neolithic farmers. The results indicate largely unadmixed mtDNA pools of differing ancestries from Iron-Age on, suggesting a rather late genetic shift from hunter-gatherers towards farmers in North-East Europe. Furthermore, the data suggest eastern introduction of farmer-related haplogroups into Finland, contradicting contemporary genetic patterns in Finns.
Ferroptotic pores induce Ca2+ fluxes and ESCRT-III activation to modulate cell death kinetics
2019-12-08

Summary Ferroptosis is an iron-dependent form of regulated necrosis associated with lipid peroxidation. Despite its key role in the inflammatory outcome of ferroptosis, little is known about the molecular events leading to the disruption of the plasma membrane during this type of cell death. Here we show that a sustained increase in cytosolic Ca 2+ is a hallmark of ferroptosis that precedes complete bursting of the cell. We report that plasma membrane damage leading to ferroptosis is associated with membrane nanopores of few nanometers in radius and that ferroptosis, but not lipid peroxidation, can be delayed by osmoprotectants. Importantly, Ca 2+ fluxes during ferroptosis correlate with the activation of ESCRT-III-mediated membrane repair, which counterbalances the kinetics of cell death and modulates the inflammatory signature of ferroptosis. Our findings with ferroptosis provide a unifying concept that sustained high levels of cytosolic Ca 2+ prior to plasma membrane disruption are a common feature of regulated necrosis and position ESCRT-III as a general protective mechanism in these inflammatory cell death pathways.
Inner Speech: New Voices
2019-12-09

In the last 10 years, inner speech – the little voice in the head – has started to become established as a topic in the philosophy of psychology. The two philosophers who have contributed most to this development are Agustín Vicente1 and Peter Langland-Hassan. Together, they have now edited the first largely philosophical anthology on the topic, Inner Speech: New Voices.2 In the first sentence of their introduction, Vicente and Langland-Hassan write that, ‘[i]n another possible world, not far from our own, inner speech occupies center stage in contemporary philosophical psychology’ (1).3 After all, the phenomenon lies at the meeting point of ‘intersecting “big ticket” questions about thought, language and consciousness’ (2). An example they offer of one such question: does inner speech merely express thoughts, or is inner speech itself actually a kind of thought? Readers who work through all of the contributions to the volume might well start to think that the philosophers and psychologists in this nearby world have fixed on something that we have neglected.
MERLIN: a novel BRET-based proximity biosensor for studying mitochondria–ER contact sites
2019-12-09

The contacts between the ER and mitochondria play a key role in cellular functions such as the exchange of lipids and calcium between both organelles, as well as in apoptosis and autophagy signaling. The molecular architecture and spatiotemporal regulation of these distinct contact regions remain obscure and there is a need for new tools that enable tackling these questions. Here, we present a new bioluminescence resonance energy transfer–based biosensor for the quantitative analysis of distances between the ER and mitochondria that we call MERLIN (Mitochondria–ER Length Indicator Nanosensor). The main advantages of MERLIN compared with available alternatives are that it does not rely on the formation of artificial physical links between the two organelles, which could lead to artifacts, and that it allows to study contact site reversibility and dynamics. We show the applicability of MERLIN by characterizing the role of the mitochondrial dynamics machinery on the contacts of this organelle with the ER.
The role of water and compression in the genesis of alkaline basalts: Inferences from the Carpathian-Pannonian region
2019-12-09

We present a new model for the formation of Plio-Pleistocene alkaline basalts in the central part of the Carpathian-Pannonian region (CPR). Based on the structural hydroxyl content of clinopyroxene megacrysts, the ‘water’ content of their host basalts is 2.0–2.5 wt.%, typical for island arc basalts. Likewise, the source region of the host basalts is ‘water’ rich (290–660 ppm), akin to the source of ocean island basalts. This high ‘water’ content could be the result of several subduction events from the Mesozoic onwards (e.g. Penninic, Vardar and Magura oceans), which have transported significant amounts of water back to the upper mantle, or hydrous plumes originating from the subduction graveyard beneath the Pannonian Basin. The asthenosphere with such a relatively high ‘water’ content beneath the CPR may have been above the ‘pargasite dehydration’ (90 km) solidi. This means that neither decompressional melting nor the presence of voluminous pyroxenite and eclogite lithologies are required to explain partial melting. While basaltic partial melts have been present in the asthenosphere for a long time, they were not extracted during the syn-rift phase, but were only emplaced at the onset of the subsequent tectonic inversion stage at ~8–5 Ma. We propose that the extraction has been facilitated by evolving vertical foliation in the asthenosphere as a response to the compression between the Adriatic indenter and the stable European platform. The vertical foliation and the prevailing compression effectively squeezed the partial basaltic melts from the asthenosphere. The overlying lithosphere may have been affected by buckling in response to compression, which was probably accompanied by formation of deep faults and deformation zones. These zones formed conduits towards the surface for melts squeezed out of the asthenosphere. This implies that basaltic partial melts could be present in the asthenosphere in cases where the bulk ‘water’ content is relatively high (&gt;~200 ppm) at temperatures exceeding ~1000–1100 °C. These melts could be extracted even under a compressional tectonic regime, where the combination of vertical foliation in the asthenosphere and deep fractures and deformation zones in the folded lithosphere provides pathways towards the surface. This model is also valid for deep seated transpressional or transtensional fault zones in the lithosphere.
Single Nucleotide Polymorphisms in Thyroid Hormone Transporter Genes MCT8, MCT10 and Deiodinase DIO2 Contribute to Inter-Individual Variance of Executive Functions and Personality Traits
2019-12-09

Abstract Thyroid hormones are modulators of cognitive functions, and changes in hormone levels affect intelligence, memory, attention and executive function. Single nucleotide polymorphisms (SNPs) of transporter proteins MCT8, MCT10 and deiodinase 2 (DIO2) influence thyroid metabolism and could therefore contribute to inter-individual variance of cognitive functions. This study investigates the influence of these SNPs using an extensive neuropsychological test battery. 656 healthy participants aged 18–39 years were genotyped for four SNPs: MCT8 (rs5937843 and rs6647476), MCT10 (rs14399) and DIO2 (rs225014) and underwent eleven different neuropsychological tests as well as four personality questionnaires. Test results were compared between homo- and heterozygous carriers and for the X-linked MCT8 additionally between men and women. Personality questionnaires revealed that Risk Seeking was reduced in homozygous T carriers and highest in homozygous C carriers of the DIO2 SNP and that both polymorphisms of MCT8 had an additive effect on Physical Aggression in men. Neuropsychological testing indicated that MCT10 affects nonverbal reasoning abilities, DIO2 influences working memory and verbal fluency and MCT8 influences attention, alertness and planning. This pilot study suggests an influence of polymorphisms in thyroid hormone transporter genes and deiodinase on cognitive domains and personality traits.
Mapping the Ethicality of Algorithmic Pricing: A Review of Dynamic and Personalized Pricing
2019-12-10

Abstract Firms increasingly deploy algorithmic pricing approaches to determine what to charge for their goods and services. Algorithmic pricing can discriminate prices both dynamically over time and personally depending on individual consumer information. Although legal, the ethicality of such approaches needs to be examined as often they trigger moral concerns and sometimes outrage. In this research paper, we provide an overview and discussion of the ethical challenges germane to algorithmic pricing. As a basis for our discussion, we perform a systematic interpretative review of 315 related articles on dynamic and personalized pricing as well as pricing algorithms in general. We then use this review to define the term algorithmic pricing and map its key elements at the micro-, meso-, and macro levels from a business and marketing ethics perspective. Thus, we can identify morally ambivalent topics that call for deeper exploration by future research.