julilili42/papers huggingface dataset:
A NanoLuc luciferase‐based assay enabling the real‐time analysis of protein secretion and injection by bacterial type III secretion systems
2020-02-18

Abstract The elucidation of the molecular mechanisms of secretion through bacterial protein secretion systems is impeded by a shortage of assays to quantitatively assess secretion kinetics. Also the analysis of the biological role of these secretion systems as well as the identification of inhibitors targeting these systems would greatly benefit from the availability of a simple, quick and quantitative assay to monitor principle secretion and injection into host cells. Here, we present a versatile solution to this need, utilizing the small and very bright NanoLuc luciferase to assess the function of the type III secretion system encoded by Salmonella pathogenicity island 1. Type III secretion substrate–NanoLuc fusions are readily secreted into the culture supernatant, where they can be quantified by luminometry after removal of bacteria. The NanoLuc‐based secretion assay features a very high signal‐to‐noise ratio and sensitivity down to the nanolitre scale. The assay enables monitoring of secretion kinetics and is adaptable to a high throughput screening format in 384‐well microplates. We further developed a split NanoLuc‐based assay that enables the real‐time monitoring of type III secretion‐dependent injection of effector–HiBiT fusions into host cells stably expressing the complementing NanoLuc–LgBiT.
Disclosing the Potential of the SARP-Type Regulator PapR2 for the Activation of Antibiotic Gene Clusters in Streptomycetes
2020-02-18

<i>Streptomyces</i> antibiotic regulatory protein (SARP) family regulators are well-known activators of antibiotic biosynthesis in streptomycetes. The respective genes occur in various types of antibiotic gene clusters encoding, e.g., for polyketides, ribosomally and non-ribosomally synthesized peptides, or β-lactam antibiotics. We found that overexpression of the SARP-type regulator gene <i>papR2</i> from <i>Streptomyces pristinaespiralis</i> in <i>Streptomyces lividans</i> leads to the activation of the silent undecylprodigiosin (Red) gene cluster. The activation happens upon the inducing function of PapR2, which takes over the regulatory role of RedD, the latter of which is the intrinsic SARP regulator of Red biosynthesis in <i>S. lividans</i>. Due to the broad abundance of SARP genes in different antibiotic gene clusters of various actinomycetes and the uniform activating principle of the encoded regulators, we suggest that this type of regulator is especially well suited to be used as an initiator of antibiotic biosynthesis in actinomycetes. Here, we report on a SARP-guided strategy to activate antibiotic gene clusters. As a proof of principle, we present the PapR2-driven activation of the amicetin/plicacetin gene cluster in the novel Indonesian strain isolate <i>Streptomyces</i> sp. SHP22-7.
Upregulation of SMYD3 and SMYD3 VNTR 3/3 polymorphism increase the risk of hepatocellular carcinoma
2020-02-18

Abstract SMYD3 (SET and MYND domain-containing protein 3) is involved in histone modification, which initiates oncogenesis by activating transcription of multiple downstream genes. To investigate associations of variable numbers of tandem repeats (VNTR) variants in the SMYD3 gene promoter, SMYD3 serum levels and SMYD3 mRNA expression in hepatitis B virus (HBV) infection and clinical progression of related liver disease. SMYD3 VNTRs were genotyped in 756 HBV patients and 297 healthy controls. SMYD3 serum levels were measured in 293 patients and SMYD3 mRNA expression was quantified in 48 pairs of hepatocellular tumor and adjacent non-tumor liver tissues. Genotype SYMD3 VNTR 3/3 was more frequent among HCC patients than in controls ( P adjusted = 0.037). SMYD3 serum levels increased according to clinical progression of liver diseases ( P = 0.01); HCC patients had higher levels than non-HCC patients ( P = 0.04). Among patients with SMYD3 VNTR 3/3, HCC patients had higher SMYD3 levels than others ( P &lt; 0.05). SMYD3 mRNA expression was up-regulated in HCC tumor tissues compared to other tissues ( P = 0.008). In conclusion, upregulation of SMYD3 correlates with the occurrence of HCC and SMYD3 VNTR 3/3 appears to increase the risk of HCC through increasing SMYD3 levels. SMYD3 may be an indicator for HCC development in HBV patients.
α2-Adrenergic Receptor in Liver Fibrosis: Implications for the Adrenoblocker Mesedin
2020-02-18

The noradrenergic system is proposed to play a prominent role in the pathogenesis of liver fibrosis. While α1- and β-adrenergic receptors (ARs) are suggested to be involved in a multitude of profibrogenic actions, little is known about α2-AR-mediated effects and their expression pattern during liver fibrosis and cirrhosis. We explored the expression of α2-AR in two models of experimental liver fibrosis. We further evaluated the capacity of the α2-AR blocker mesedin to deactivate hepatic stellate cells (HSCs) and to increase the permeability of human liver sinusoidal endothelial cells (hLSECs). The mRNA of α2a-, α2b-, and α2c-AR subtypes was uniformly upregulated in carbon tetrachloride-treated mice vs the controls, while in bile duct-ligated mice, only α2b-AR increased in response to liver injury. In murine HSCs, mesedin led to a decrease in α-smooth muscle actin, transforming growth factor-β and α2a-AR expression, which was indicated by RT-qPCR, immunocytochemistry, and Western blot analyses. In a hLSEC line, an increased expression of endothelial nitric oxide synthase was detected along with downregulated transforming growth factor-β. In conclusion, we suggest that the α2-AR blockade alleviates the activation of HSCs and may increase the permeability of liver sinusoids during liver injury.
Controlling photon bunching and antibunching of two quantum emitters near a core-shell sphere
2020-02-18

The collective spontaneous emission of two point-dipole emitters near a plasmonic core-shell nanosphere is theoretically investigated. Based on the expansion of mode functions in vector spherical harmonics, we derive closed analytical expressions for both the cooperative decay rate and the dipole-dipole interaction strength associated with two point dipoles close to a sphere. Considering a plasmonic nanoshell containing a linearly amplifying medium inside the core, the second-order correlation function for the two emitters shows that it is possible to tune the photon emission, selecting either photon bunching or antibunching as a function of the polarization and position of the sphere. This result opens vistas to applications involving tunable single-photon sources in engineered artificial media.
Using Transcriptomic Analysis to Assess Double-Strand Break Repair Activity: Towards Precise in Vivo Genome Editing
2020-02-18

Mutations in more than 200 retina-specific genes have been associated with inherited retinal diseases. Genome editing represents a promising emerging field in the treatment of monogenic disorders, as it aims to correct disease-causing mutations within the genome. Genome editing relies on highly specific endonucleases and the capacity of the cells to repair double-strand breaks (DSBs). As DSB pathways are cell-cycle dependent, their activity in postmitotic retinal neurons, with a focus on photoreceptors, needs to be assessed in order to develop therapeutic in vivo genome editing. Three DSB-repair pathways are found in mammalian cells: Non-homologous end joining (NHEJ); microhomology-mediated end joining (MMEJ); and homology-directed repair (HDR). While NHEJ can be used to knock out mutant alleles in dominant disorders, HDR and MMEJ are better suited for precise genome editing, or for replacing entire mutation hotspots in genomic regions. Here, we analyzed transcriptomic in vivo and in vitro data and revealed that HDR is indeed downregulated in postmitotic neurons, whereas MMEJ and NHEJ are active. Using single-cell RNA sequencing analysis, we characterized the dynamics of DSB repair pathways in the transition from dividing cells to postmitotic retinal cells. Time-course bulk RNA-seq data confirmed DSB repair gene expression in both in vivo and in vitro samples. Transcriptomic DSB repair pathway profiles are very similar in adult human, macaque, and mouse retinas, but not in ground squirrel retinas. Moreover, human-induced pluripotent stem-cell-derived neurons and retinal organoids can serve as well suited in vitro testbeds for developing genomic engineering approaches in photoreceptors. Our study provides additional support for designing precise in vivo genome-editing approaches via MMEJ, which is active in mature photoreceptors.
CB1 Receptor-Dependent and Independent Induction of Lipolysis in Primary Rat Adipocytes by the Inverse Agonist Rimonabant (SR141716A)
2020-02-18

(1) Background: Acute administration of the cannabinoid receptor 1 (CB1R) inverse agonist Rimonabant (SR141716A) to fed Wistar rats was shown to elicit a rapid and short-lasting elevation of serum free fatty acids. (2) Methods: The effect of Rimonabant on lipolysis in isolated primary rat adipocytes was studied to raise the possibility for direct mechanisms not involving the (hypothalamic) CB1R. (3) Results: Incubation of these cells with Rimonabant-stimulated lipolysis to up to 25% of the maximal isoproterenol effect, which was based on both CB1R-dependent and independent mechanisms. The CB1R-dependent one was already effective at Rimonabant concentrations of less than 1 μM and after short-term incubation, partially additive to β-adrenergic agonists and blocked by insulin and, in part, by adenosine deaminase, but not by propranolol. It was accompanied by protein kinase A (PKA)-mediated association of hormone-sensitive lipase (HSL) with lipid droplets (LD) and dissociation of perilipin-1 from LD. The CB1R-independent stimulation of lipolysis was observed only at Rimonabant concentrations above 1 μM and after long-term incubation and was not affected by insulin. It was recapitulated by a cell-free system reconstituted with rat adipocyte LD and HSL. Rimonabant-induced cell-free lipolysis was not affected by PKA-mediated phosphorylation of LD and HSL, but abrogated by phospholipase digestion or emulsification of the LD. Furthermore, LD isolated from adipocytes and then treated with Rimonabant (&gt;1 μM) were more efficient substrates for exogenously added HSL compared to control LD. The CB1R-independent lipolysis was also demonstrated in primary adipocytes from fed rats which had been treated with a single dose of Rimonabant (30 mg/kg). (4) Conclusions: These data argue for interaction of Rimonabant (at high concentrations) with both the LD surface and the CB1R of primary rat adipocytes, each leading to increased access of HSL to LD in phosphorylation-independent and dependent fashion, respectively. Both mechanisms may lead to direct and acute stimulation of lipolysis at peripheral tissues upon Rimonabant administration and represent targets for future obesity therapy which do not encompass the hypothalamic CB1R.
A Tactile Virtual Reality for the Study of Active Somatosensation
2020-02-18

Natural exploration of textures involves active sensing, i.e., voluntary movements of tactile sensors (e.g., human fingertips or rodent whiskers) across a target surface. Somatosensory input during moving tactile sensors varies according to both the movement and the surface texture. Combining motor and sensory information, the brain is capable of extracting textural features of the explored surface. Despite the ecological relevance of active sensing, psychophysical studies on active touch are largely missing. One reason for the lack of informative studies investigating active touch is the considerable challenge of assembling an appropriate experimental setup. A possible solution might be in the realm of virtual tactile reality that provides tactile finger stimulation depending on the position of the hand and the simulated texture of a target surface. In addition to rigorous behavioral studies, the investigation of the neuronal mechanisms of active tactile sensing in humans is highly warranted, requiring neurophysiological experiments using electroencephalography (EEG), magnetoencephalography (MEG) and/or functional magnetic resonance imaging (fMRI). However, current neuroimaging techniques impose specific requirements on the tactile stimulus delivery equipment in terms of compatibility with the neurophysiological methods being used. Here, we present a user-friendly, MEG compatible, tactile virtual reality simulator. The simulator consists of a piezo-electric tactile stimulator capable of independently protruding 16 plastic pistons of 1 mm diameter arranged in a 4 × 4 matrix. The stimulator delivers a spatial pattern of tactile stimuli to the tip of a finger depending on the position of the finger moving across a 2-dimensional plane. In order to demonstrate the functionality of the tactile virtual reality, we determined participants' detection thresholds in active and passive touch conditions. Thresholds in both conditions were higher than reported in the literature. It could well be that the processing of the piston-related stimulation was masked by the sensory input generated by placing the finger on the scanning probe. More so, the thresholds for both the active and passive tasks did not differ significantly. In further studies, the noise introduced by the stimulator in neuromagnetic recordings was quantified and somatosensory evoked fields for active and passive touch were recorded. Due to the compatibility of the stimulator with neuroimaging techniques such as MEG, and based on the feasibility to record somatosensory-related neuromagnetic brain activity the apparatus has immense potential for the exploration of the neural underpinnings of active tactile perception.
Dynamic absolutism and qualitative change
2020-02-18

Abstract According to Fine’s (Modality and tense: philosophical papers. Oxford University Press, Oxford, pp 261–320, 2005) famous take on the infamous McTaggartian paradox, realism about tensed facts is incompatible with the joint acceptence of three very general and seemingly plausible theses about reality. However, Correia and Rosenkranz (As time goes by: eternal facts in an ageing universe. Mentis, Paderborn, 2011) have recently objected that Fine’s argument depends on a crucial assumption about the nature of tensed facts; once that assumption is given up, they claim, realists can endorse the theses in question without further ado. They also argue that their novel version of tense realism, called dynamic absolutism, is to be preferred over its rivals. I argue in this paper that dynamic absolutism does not constitute a genuine alternative for realists about tense.
QUANTUM ALGEBRAIC SYMMETRIES IN NUCLEAR AND MOLECULAR PHYSICS
2020-02-18

The first realizations of quanttun algebraic symmetries in nuclear and molecular spectra are presented. Rotational spectra of even-even nuclei are described by the quantum algebra SUq(2). The two parameter formula given by the algebra is equivalent to an expan- sion in terms of powers of j(j + 1), similar to the expansion given by the Variable Moment of Inertia (VMI) model. The moment of inertia parameter in the two models, as well as the small parameter of the expansion, are found to have very similar numerical values. The same formalism is found to give very good results for superdeformed nuclear bands, which are closer to the classical SU(2) limit, as well as for rotational bands of diatomic molecules, in which a partial summation of the Dunham expansion for rotation-vibration spectra is achieved. Vibrational spectra of diatomic molecules can be described by the q-deformed anhannonic oscillator, having the symmetry Uq(2)&gt;Oq(2). An alternative de- scription is obtained in terms of the quantum algebra SUq(1,1). In both cases the energy formula obtained is equivalent to an expansion in terms of powers of (v+1⁄2) , where ν is the vibrational quantum number, while in the classical ST(1,1) case only the first two powers appear. In all cases the improved description of the empirical data is obtained with q being a phase (and not a real number). Further applications of quantum algebraic symmetries in nuclei and molecules are discussed.
Spatial Neuronal Integration Supports a Global Representation of Visual Numerosity in Primate Association Cortices
2020-02-19

Abstract Our sense of number rests on the activity of neurons that are tuned to the number of items and show great invariance across display formats and modalities. Whether numerosity coding becomes abstracted from local spatial representations characteristic of visual input is not known. We mapped the visual receptive fields (RFs) of numerosity-selective neurons in the pFC and ventral intraparietal area in rhesus monkeys. We found numerosity selectivity in pFC and ventral intraparietal neurons irrespective of whether they exhibited an RF and independent of the location of their RFs. RFs were not predictive of the preference of numerosity-selective neurons. Furthermore, the presence and location of RFs had no impact on tuning width and quality of the numerosity-selective neurons. These findings show that neurons in frontal and parietal cortices integrate abstract visuospatial stimuli to give rise to global and spatially released number representations as required for number perception.
Platelet Inhibition in Acute Coronary Syndrome and Percutaneous Coronary Intervention: Insights from the Past and Present
2020-02-19

Abstract Platelet activation and aggregation have a pivotal role in arterial thrombosis and in the pathogenesis of both acute coronary syndromes (ACS) and in the thrombotic complications that occur in patients undergoing percutaneous coronary intervention (PCI). The past 30 years has seen the progress from early trials of clopidogrel and glycoprotein IIb/IIIa inhibitors to the application of more potent P2Y12 inhibitors prasugrel and ticagrelor. Early enthusiasm for newer and more potent antiplatelet agents, which could reduce ischemic events, has led to the understanding of the importance of bleeding and a desire to individualize and optimize treatment. It has increasingly become apparent that the potency and duration of dual antiplatelet therapy (DAPT) has to reflect the balance between ischemic and bleeding risk. Recently, multiple strategies have been proposed to individualize DAPT intensity and duration to reduce the bleeding and ischemic risks. Strategies of de-escalation of DAPT intensity, as well as shorter (less than a year) or more prolonged (beyond a year) treatment have been proposed, as well as platelet function test and genotype guidance of P2Y12 inhibitor therapy. Herein, we provide an overview of the progress in the field of antiplatelet therapy for ACS and PCI over the years, showing the current directions of travel. Ongoing studies focusing on personalized antiplatelet treatment will hopefully yield further insight into ways of optimizing outcomes for the individual.
Digital visibility and the role of mutual interaction expectations: Reframing the journalist–audience relationship through the lens of interpersonal communication
2020-02-19

In the light of a new level of reciprocal visibility in the digital age, the journalist–audience relationship has fundamentally changed. Mutual expectations become visible or evolve anew. The question arises as to how these expectations and their (non-)fulfillment influence the journalist–audience relationship. Taking an interpersonal communication perspective by following expectancy violations theory, we focus on the level of interactions and propose a theoretical framework explaining how the interplay of journalists’ and audience’s mutual expectations affects their relationship. Our aim is to contribute to a better understanding of the journalist–audience relationship in digital media environments—and to provide indications for its functioning or failure.
Phase III study of perioperative pembrolizumab (pembro) plus neoadjuvant chemotherapy (chemo) versus placebo plus neoadjuvant chemo in cisplatin-eligible patients (pts) with muscle-invasive bladder cancer (MIBC): KEYNOTE-866.
2020-02-19

TPS599 Background: MIBC prognosis is poor, despite standard neoadjuvant cisplatin-based chemo. PD-1/PD-L1 pathway inhibition is an effective first-line option for cisplatin-ineligible pts and a second-line option for platinum-based chemo pretreated pts. Neoadjuvant chemo + pembro, a PD-1 inhibitor, recently showed encouraging pathologic complete response rates, in cisplatin-eligible patients with MIBC (NCT02365766), warranting further investigation. Methods: KEYNOTE-866 (NCT03924856) is a randomized phase 3 study to assess efficacy and safety of chemo+perioperative pembro versus chemo+perioperative placebo for pts with MIBC. An estimated 790 patients will be randomly assigned 1:1 to neoadjuvant pembro+chemo (4 cycles) followed by adjuvant pembro after radical cystectomy+pelvic lymph node dissection (RC+PLND, 13 cycles) or neoadjuvant placebo+chemo (4 cycles) followed by adjuvant placebo after RC+PLND (13 cycles). Pts will receive neoadjuvant and adjuvant pembro 200 mg IV Q3W; neoadjuvant chemo will be gemcitabine 1000 mg/m 2 +cisplatin 70 mg/m 2 IV Q3W. Pts will be stratified by tumor PD-L1 status (combined positive score [CPS] ≥10 vs CPS &lt;10), disease stage (T2 vs T3/4), and region of treatment (Unites States vs Europe vs most of world). Adults (≥18 y) with histologically confirmed MIBC (T2-T4aN0M0) who are cisplatin-eligible, are clinically nonmetastatic (N0M0), and have an ECOG PS 0 or 1 will be enrolled. Pts are required to provide tumor tissue for histology and PD-L1 analysis. Pts will not be permitted to have previously received systemic antineoplastic treatment for MIBC or radiotherapy to the bladder. Imaging by CT/MRI will be performed Q12W for up to 96 wk after cystectomy, at discontinuation, and during follow-up starting at 3 y (Q24W). Primary end points are pathologic complete response and event-free survival in all pts and pts with PD-L1 CPS ≥10. Secondary end points are OS, disease-free survival, and pathologic downstaging rate in all pts and pts with PD-L1 CPS ≥10, and safety. Accrual began June 13, 2019. Clinical trial information: NCT03924856.
Modeling the Fate of Pharmaceuticals in a Fourth‐Order River Under Competing Assumptions of Transient Storage
2020-02-19

Abstract Quantifying the degradation of micropollutants in streams is important for river‐water quality management. While biodegradation is believed to be enhanced in transient‐storage zones of rivers, it can also occur in the main channel. Photodegradation is restricted to the main channel and surface transient‐storage zones. In this study, we propose a transient‐storage model framework to address the transport and fate of micropollutants in different domains of a river. We fitted the model to nighttime and daytime measurements of a tracer and four pharmaceuticals in River Steinlach, Germany. We could separate the surface and subsurface fractions of the total transient‐storage zone by fitting fluorescein photodegradation at daytime versus conservative nighttime transport. In reactive transport, we tested two model variants, allowing biodegradation in the main channel or restricting it to the transient‐storage zones, obtaining similar model performances but different degradation rate coefficients. Carbamazepine is relatively conservative; photodegradation of metoprolol and venlafaxine can be quantitatively attributed to the main channel and surface transient‐storage zone; metoprolol, venlafaxine, and sulfamethoxazole undergo biodegradation. We projected a decrease of overall pollutant removal under higher flow conditions, regardless of attributing biodegradation to specific river compartments. Our study indicates that model‐based analysis of daytime and nighttime field experiments allows (1) distinguishing photodegradation and biodegradation, (2) reducing equifinality of surface and subsurface transient‐storage, and (3) estimating biodegradation in different domains under different assumptions. However, entirely reducing the equifinality of attributing biodegradation to different compartments is hardly possible in lowland rivers with only limited transient storage.