julilili42/papers huggingface dataset:
Bile Microinfarcts in Cholestasis Are Initiated by Rupture of the Apical Hepatocyte Membrane and Cause Shunting of Bile to Sinusoidal Blood
2018-08-13

Bile duct ligation (BDL) is an experimental procedure that mimics obstructive cholestatic disease. One of the early consequences of BDL in rodents is the appearance of so‐called bile infarcts that correspond to Charcot‐Gombault necrosis in human cholestasis. The mechanisms causing bile infarcts and their pathophysiological relevance are unclear. Therefore, intravital two photon–based imaging of BDL mice was performed with fluorescent bile salts (BS) and non‐BS organic anion analogues. Key findings were followed up by matrix‐assisted laser desorption ionization imaging, clinical chemistry, immunostaining, and gene expression analyses. In the acute phase, 1‐3 days after BDL, BS concentrations in bile increased and single‐cell bile microinfarcts occurred in dispersed hepatocytes throughout the liver caused by the rupture of the apical hepatocyte membrane. This rupture occurred after loss of mitochondrial membrane potential, followed by entry of bile, cell death, and a “domino effect” of further death events of neighboring hepatocytes. Bile infarcts provided a trans‐epithelial shunt between bile canaliculi and sinusoids by which bile constituents leaked into blood. In the chronic phase, ≥21 days after BDL, uptake of BS tracers at the sinusoidal hepatocyte membrane was reduced. This contributes to elevated concentrations of BS in blood and decreased concentrations in the biliary tract. Conclusion: Bile microinfarcts occur in the acute phase after BDL in a limited number of dispersed hepatocytes followed by larger infarcts involving neighboring hepatocytes, and they allow leakage of bile from the BS‐overloaded biliary tract into blood, thereby protecting the liver from BS toxicity; in the chronic phase after BDL, reduced sinusoidal BS uptake is a dominant protective factor, and the kidney contributes to the elimination of BS until cholemic nephropathy sets in.
Salmonella Typhimurium effector SseI inhibits chemotaxis and increases host cell survival by deamidation of heterotrimeric Gi proteins
2018-08-13

Salmonella enterica serotype Typhimurium (S. Typhimurium) is one of the most frequent causes of food-borne illness in humans and usually associated with acute self-limiting gastroenteritis. However, in immunocompromised patients, the pathogen can disseminate and lead to severe systemic diseases. S. Typhimurium are facultative intracellular bacteria. For uptake and intracellular life, Salmonella translocate numerous effector proteins into host cells using two type-III secretion systems (T3SS), which are encoded within Salmonella pathogenicity islands 1 (SPI-1) and 2 (SPI-2). While SPI-1 effectors mainly promote initial invasion, SPI-2 effectors control intracellular survival and proliferation. Here, we elucidate the mode of action of Salmonella SPI-2 effector SseI, which is involved in control of systemic dissemination of S. Typhimurium. SseI deamidates a specific glutamine residue of heterotrimeric G proteins of the Gαi family, resulting in persistent activation of the G protein. Gi activation inhibits cAMP production and stimulates PI3-kinase γ by Gαi-released Gβγ subunits, resulting in activation of survival pathways by phosphorylation of Akt and mTOR. Moreover, SseI-induced deamidation leads to non-polarized activation of Gαi and, thereby, to loss of directed migration of dendritic cells.
Genotype-Phenotype Association and Impact on Outcomes following Guided De-Escalation of Anti-Platelet Treatment in Acute Coronary Syndrome Patients: The TROPICAL-ACS Genotyping Substudy
2018-08-13

Background Phenotype-guided de-escalation (PGDE) of P2Y12-inhibitor treatment with an early switch from prasugrel to clopidogrel was identified as an effective alternative treatment strategy in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). The Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment for Acute Coronary Syndromes (TROPICAL-ACS) Genotyping Substudy aimed to investigate whether CYP2C19 genotypes correlate with on-treatment platelet reactivity (PR) in ACS patients treated with clopidogrel or prasugrel and thus might be useful for guidance of early de-escalation of anti-platelet treatment. Methods and Results A total of 603 ACS consecutive patients were enrolled in four centres (23.1% of the overall TROPICAL-ACS population). Rapid genotyping (Spartan RX) for CYP2C19*2, *3 and *17 alleles was performed. Associations between PR and the primary and secondary endpoints of the TROPICAL-ACS trial and CYP2C19*2 and CYP2C19*17 carrier status were evaluated. For the PGDE group, the on-clopidogrel PR significantly differed across CYP2C19*2 (p &lt; 0.001) and CYP2C19*17 genotypes (p = 0.05). Control group patients were not related (p = 0.90, p = 0.74) to on-prasugrel PR. For high PR versus non-high PR patients within the PGDE group, significant differences were observed for the rate of CYP2C19*2 allele carriers (43% vs. 28%, p = 0.007). Conclusion CYP2C19*2 and CYP2C19*17 carrier status correlates with PR in ACS patients treated with clopidogrel and thus might be useful for pre-selecting patients who will and who may not be suitable for PGDE of anti-platelet treatment. Regarding phenotype-guided treatment, we did not observe added benefit of genotyping to predict ischaemic and bleeding risk in patients who underwent a PGDE approach. Clinical Trial Registration URL: https//www.clinicaltrials.gov. Unique Identifier: NCT: 01959451.
Formation of a planetary Laplace resonance through migration in an eccentric disk
2018-08-13

Context. Orbital mean motion resonances in planetary systems originate from dissipative processes in disk-planet interactions that lead to orbital migration. In multi-planet systems that host giant planets, the perturbation of the protoplanetary disk strongly affects the migration of companion planets. Aims. By studying the well-characterized resonant planetary system around GJ 876 we aim to explore which effects shape disk-driven migration in such a multi-planet system to form resonant chains. Methods. We modelled the orbital migration of three planets embedded in a protoplanetary disk using two-dimensional locally isothermal hydrodynamical simulations. In order to explore the effect of several disk characteristics, we performed a parameter study by varying the disk thickness, α viscosity, mass as well as the initial position of the planets. Moreover, we have carefully analysed and compared simulations with various boundary conditions at the disk’s inner rim. Results. We find that due to the high masses of the giant planets in this system, substantial eccentricity can be excited in the disk. This results in large variations of the torque acting on the outer lower mass planet, which we attribute to a shift of Lindblad and corotation resonances as it approaches the eccentric gap that the giants create. Depending on disk parameters, the migration of the outer planet can be stopped at the gap edge in a non-resonant state. In other models, the outer planet is able to open a partial gap and to circularize the disk again, later entering a 2:1 resonance with the most massive planet in the system to complete the observed 4:2:1 Laplace resonance. Conclusions. Disk-mediated interactions between planets due to spiral waves and excitation of disk eccentricity by massive planets cause deviations from smooth inward migration of exterior lower mass planets. Self-consistent modelling of the disk-driven migration of multi-planet systems is thus mandatory. Constraints can be placed on the properties of the disk during the migration phase, based on the observed resonant state of the system. Our results are compatible with a late migration of the outermost planet into the resonant chain, when the giant planet pair already is in resonance.
Oral Versus Written Recall of Long-Term Memory Items: Replicating and Extending the Writing Superiority Effect Across Knowledge Domains
2018-08-13

Abstract Although language production offers a commonly used window into individuals’ knowledge, it remains questionable whether oral or written language production allows better diagnostic content validity, for example, in educational or legal settings. Existing results vary with respect to empirical evidence in favor of the oral or the written modality in knowledge assessment. However, for list-like organized knowledge domains (i.e., domains consisting of a definite number of uniform items), a writing superiority effect (WSE) has been consistently observed. We present 3 experiments in which the WSE is replicated and generalized to hitherto untested knowledge domains and participant pools. To estimate the content validity of the verbal recall modes, free recall performance is analyzed as a function of modality, taking into account cued recall performance, which is known to allow more complete knowledge recollection. Throughout all experiments, free recall performance was better in the written than in the oral diagnosis of list-like knowledge. The results recommend written diagnosis at least for similarly structured knowledge domains. Future research should investigate to which degree writing superiority also holds for other kinds of knowledge domains and which language production and retrieval processes are responsible for the effect.
Brain-based ranking of cognitive domains to predict schizophrenia
2018-08-13

Abstract Schizophrenia is a devastating brain disorder that disturbs sensory perception, motor action, and abstract thought. Its clinical phenotype implies dysfunction of various mental domains, which has motivated a series of theories regarding the underlying pathophysiology. Aiming at a predictive benchmark of a catalogue of cognitive functions, we developed a bottom-up machine-learning strategy and provide a proof of principle in a multi-site clinical dataset (n=324). Existing neuroscientific knowledge on diverse cognitive domains was first condensed into neuro-topographical maps. We then examined how the ensuing meta-analytic cognitive priors can distinguish patients and controls using brain morphology and intrinsic functional connectivity. Some affected cognitive domains supported well-studied directions of research on auditory evaluation and social cognition. However, rarely suspected cognitive domains also emerged as disease-relevant, including self-oriented processing of bodily sensations in gustation and pain. Such algorithmic charting of the cognitive landscape can be used to make targeted recommendations for future mental health research.
Microscopic density functional theory for monolayers of diblock copolymers
2018-08-13

We propose density functional theory for diblock copolymers in two dimensions. Our theoretical framework is based on Wertheim’s first order thermodynamic perturbation theory. Using the proposed approach, we investigate the structure and phase behavior of monolayers of symmetric diblock copolymers. We find that the phase behavior of symmetric diblock copolymer monolayers is similar to that in 3D. This includes the scaling of the equilibrium lamellar width with chain length. We find that the topology of the resulting phase diagrams depends on the chain length and the unlike segment interaction incompatibility and involves either one, two, or three triple points (one of them being the peritectic point). We expect that a similar phase behavior could be obtained for monolayers of colloidal suspensions with carefully tuned interparticle interactions.
Cyanophycin Synthesis Optimizes Nitrogen Utilization in the Unicellular Cyanobacterium Synechocystis sp. Strain PCC 6803
2018-08-14

We clarified the elusive biological function of cyanophycin in the nondiazotrophic cyanobacterium Synechocystis sp. PCC 6803. Cyanophycin is a dynamic carbon/nitrogen storage polymer (multi-arginyl- l -polyaspartate) that is conditionally present in most cyanobacteria and a few heterotrophic bacteria as cellular inclusion granules. Here, we show that the cyanophycin-synthesizing enzyme CphA in the nonactive state localizes diffusely in the cytoplasm. When cyanophycin synthesis is triggered, active CphA first aggregates into foci and then covers the surface of mature cyanophycin granules, which in vitro requires Mg 2+ as a cofactor. Cyanophycin accumulation enables Synechocystis sp. to optimize nitrogen assimilation under nitrogen-poor conditions, in particular when the nitrogen supply fluctuates and during day/night cycles, by allowing continuous nitrogen assimilation and storage. Therefore, cyanophycin provides the wild-type cyanobacterium with a clear fitness advantage over non-cyanophycin-producing cells in natural environments with fluctuating nitrogen supply.
Contribution of BH3-domain and Transmembrane-domain to the Activity and Interaction of the Pore-forming Bcl-2 Proteins Bok, Bak, and Bax
2018-08-14

Abstract Central to intrinsic apoptosis signaling is the release of cytochrome c from mitochondria, which depends on the pro-apoptotic effector proteins Bax, Bak or Bok. These pore-forming effector proteins share four Bcl-2 homology (BH) domains, a functionally essential and conserved sequence of hydrophobic amino acids in their BH3-domain and a C-terminal transmembrane-domain whose specific function remains rather unknown. To elucidate the molecular basis of Bok-mediated apoptosis we analyzed apoptosis induction by transmembrane-domain deficient BokΔTM compared to the respective Bax and Bak proteins and proteins in which the first leucine in the BH3-stretch was mutated to glutamic acid. We show that deletion of the C-terminal transmembrane-domain reduces the pro-apoptotic function of each protein. Mutation of the first leucine in the BH3-domain (L78E) blocks activity of Bak, while mutation of the homologue residues in Bax or Bok (L63E and L70E respectively) does not affect apoptosis induction. Unexpectedly, combined mutation of the BH3-domain and deletion of the transmembrane-domain enhances the pro-apoptotic activity of Bok(L70E)ΔTM by abolishing the interaction with anti-apoptotic proteins, especially the primary Bok-inhibitory protein Mcl-1. These results therefore suggest a specific contribution of the transmembrane-domain to the pro-apoptotic function and interaction of Bok.
Nanosecond Tracer Diffusion as a Probe of the Solution Structure and Molecular Mobility of Protein Assemblies: The Case of Ovalbumin
2018-08-14

Protein diffusion is not only an important process ensuring biological function but can also be used as a probe to obtain information on structural properties of protein assemblies in liquid solutions. Here, we explore the oligomerization state of ovalbumin at high protein concentrations by means of its short-time self-diffusion. We employ high-resolution incoherent quasielastic neutron scattering to access the self-diffusion on nanosecond timescales, on which interparticle contacts are not altered. Our results indicate that ovalbumin in aqueous (D<sub>2</sub>O) solutions occurs in increasingly large assemblies of its monomeric subunits with rising protein concentration. It changes from nearly monomeric toward dimeric and ultimately larger than tetrameric complexes. Simultaneously, we access information on the internal molecular mobility of ovalbumin on the nanometer length scale and compare it with results obtained for bovine serum albumin, immunoglobulin, and β-lactoglobulin.
Pentamethylcyclopentadienyl-Supported Rare-Earth-Metal Benzyl, Amide, and Imide Complexes
2018-08-14

The half-sandwich diiodide complexes [Cp*LnI2]x (Ln = Y, Lu), obtained in high yields from Cp*Ln(AlMe4)2 (Cp*= C5Me5) and 2 equiv of ISiMe3, reacted with 2 equiv of potassium benzyl KCH2Ph in THF to afford complexes Cp*Ln(CH2Ph)2(thf). Protonolysis of Cp*Ln(CH2Ph)2(thf) with 3,5-bis(trifluoromethyl)aniline (H2NC6H3(CF3)2-3,5 = H2NArCF3) in toluene gave rare-earth-metal imide complexes [Cp*Ln(NC6H3(CF3)2-3,5)(thf)x]2 (Ln = Y (x = 2), Lu (x = 1)). The dimeric structure of [Cp*Ln(NC6H3(CF3)2-3,5)(thf)x]2 with two bridging imido ligands forming a planar Ln2N2 core was analyzed by X-ray crystallography. Treatment of Cp*Y(CH2Ph)2(thf) with H2NC6H3(CF3)2-3,5 in THF led to the monomeric bis(amide) complex Cp*Y(NHC6H3(CF3)2-3,5)2(thf)2. The reaction of Cp*Y(CH2Ph)2(thf) with 2,6-diisopropylaniline in toluene gave also the bis(amide) complex Cp*Y(NHC6H3iPr2-2,6)2(thf), whereas, in a THF solution, the formation of the labile mixed benzyl amide complex Cp*Y(HNC6H3iPr2-2,6)(CH2Ph)(thf) was observed.
Iron line spectroscopy of black holes in vector-tensor Galileon modified gravity
2018-08-14

Recently, a rotating black hole solution was found in Vector-Tensor Galileons\\nmodified gravity that has some significant differences from the Kerr black hole\\nsolution. We study the iron line shape that is part of the reflection spectrum\\nof accretion disks around black holes in this new black hole solution. We\\nsimulate and compare the iron lines of this solution with those of the Kerr\\nsolution to see if the technique of iron line spectroscopy can be used as a\\ntool to test Vector-Tensor Galileons modified gravity. Our analysis shows that\\ncurrent X-ray facilities can, in principle, be used to test and place\\nconstraints on Vector-Tensor Galileons modified gravity in the strong coupling\\nand ultraspinning regimes.\\n
Contingency Contracts for Weight Gain of Patients with Anorexia Nervosa in Inpatient Therapy: Practice Styles of Specialized Centers
2018-08-14

The treatment of patients with anorexia nervosa (AN) is often challenging, due to a high degree of ambivalence towards recovery and weight gain these patients often express. One part of the multimodal treatment is the utilization of treatment contracts (i.e., contingency contracts) that aim to motivate patients to gain weight by applying positive and negative consequences for the (non-)achievement of weight goals. The main aim of this study is to assess and analyze current standards of contingency contracts’ utilization in German eating disorder centers. n = 76 mental health professionals of twelve specialized university centers in Germany that are currently or were formerly treating patients with AN in an inpatient setting participated. Most experts use contingency contracts in their clinic with weekly weight goals ranging between 500 and 700 g. Overall effectiveness and significance of contingency contracts for the inpatient treatment of patients with AN was rated high. Typical characteristics of a contingency contract in specialized German university hospital centers, such as the most frequent consequences, are described. The survey results assist the planning of further studies aiming to improve the multimodal treatment of patients with AN. For clinical practice, using external motivators such as contingency contracts as well as targeting internal motivation (e.g., by using motivational interviewing) is proposed.
Growth of films with anisotropic particles: Simulations and rate equations
2018-08-14

By means of computer simulations and kinetic rate equations, we study the formation of a film of rod-like particles which are deposited on a substrate. The rod-rod interactions are hard with a short-range attraction of variable strength and width, and the rod-substrate interactions favor lying rods with a variable strength. For a rod aspect ratio of 5 and deposition of up to an equivalent of one monolayer of standing rods, we demonstrate a rich variety of growth modes upon variation of the three interaction parameters. We formulate rate equations for the time evolution of densities of islands composed of standing, lying, and mixed rods. Input parameters such as diffusion constants, island capture numbers, and rod reorientation free energies are extracted from simulations, while rod reorientation attempt frequencies remain as free parameters. Numerical solutions of the rate equations in a simple truncation show rough qualitative agreement with the simulations for the early stage of film growth but an extension to later stages requires to go significantly beyond this simple truncation.
Abstract A098: Whole blood assay for rapid detection of AR-v7 in metastatic castration-resistant prostate cancer: No correlation with response to androgen-axis targeting agents
2018-08-14

Abstract Background: The expression of AR-v7 in circulating tumor cells (CTCs) of mCRPC patients potentially confers treatment resistance to AR-axis targeting agents, though recent data from the ARMOR3-SV study as well as other publications challenge this hypothesis. Due to the potential barriers of developing a reliable CTC platform, our aim was to develop a rapid assay for AR-v7 detection in patient whole blood samples. Method: We created and optimized a whole blood quantitative real-time polymerase chain reaction assay to correlate outcomes of patients on AR-axis targeting agents with expression of AR-v7. The expression of AR-v7 mRNA in whole blood from 47 patients with mCRPC was obtained prior to commencing therapy. Each sample was run in triplicate; positivity was defined as at least two replicates reaching cycle threshold within a standard deviation between cycles of ≤ 0.25. Gene expression was correlated with PSA response rate using Fisher’s exact test. Results: In our cohort, 10 of 47 patients (21%) were AR-v7+. Of patients commencing abiraterone or enzalutamide (37/47 patients, 79%), we observed similar response rates in the AR-v7+ (4/7) patients, compared to the AR-v7 (20/30) patients (57% vs. 66%, P=0.63; Fisher’s exact test). In two patients, early onset of acquired resistance was associated with conversion from AR-v7 to AR-v7+. AR-v7 was not detected in any of the 13 normal male controls. Conclusion: We developed a specific assay for AR-v7 detection in whole blood from mCRPC patients. Similar PSA response rates were seen in AR-v7+ and AR-v7 patients, inconsistent with literature characterizing AR-v7 as a predictive biomarker, but in support of ARMOR3-SV data demonstrating moderate response rates to an AR-axis targeting agent in AR-v7+ patients. Future directions will include cohort expansion, interrogation of other AR variants, and examination of other clinically meaningful endpoints. Citation Format: Sarah To, Edmond Kwan, Heidi Fettke, Maria Docanto, Nicole Ng, Andrew Mant, Phillip Parente, Carmel Pezaro, Lisa Horvath, Lisa Graham, Tilman Todenhofer, Arun Azad. Whole blood assay for rapid detection of AR-v7 in metastatic castration-resistant prostate cancer: No correlation with response to androgen-axis targeting agents [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A098.