julilili42/papers huggingface dataset:
The Resazurin‐Resorufin System: Insights From a Decade of “Smart” Tracer Development for Hydrologic Applications
2018-08-07

Abstract The resazurin‐resorufin tracer system has been used to quantify surface water‐sediment interactions and microbial metabolic activity in stream ecosystems for one decade. This review describes the evolution of the tracer technique and summarizes how it has been used by the hydrologic and stream ecology communities. We highlight major hydrologic applications and milestones in the advancement of the reactive tracer system on scales ranging from cells to river reaches and catchments. We discuss the advantages and limitations of the resazurin‐resorufin system for hydrologic applications and suggest new directions of research, including how to address existing knowledge gaps. Beyond the goal of summarizing information that is specific to the development of the resazurin‐resorufin system, this review seeks to inform on the development of new “smart” tracer techniques as they, very likely, will face the same or similar challenges and opportunities encountered in the development of the resazurin‐resorufin system. The supporting information furthermore contains a detailed manual for the application of the resazurin‐resorufin system as hydrologic tracer and MATLAB codes for the analysis of their reactive transport.
Recent advances and emerging therapies in the non-surgical management of ulcerative colitis
2018-08-07

<ns4:p>The so-called “biologicals” (monoclonal antibodies to various inflammatory targets like tumor necrosis factor or integrins) have revolutionized the treatment of inflammatory bowel diseases. In ulcerative colitis, they have an established role in inducing remission in steroid-refractory disease and, thereafter, maintaining remission with or without azathioprine. Nevertheless, their limitations are also obvious: lack of primary response or loss of response during maintenance as well as various, in part severe, side effects. The latter are less frequent in anti-integrin treatment, but efficacy, especially during induction, is delayed. New antibodies as well as small molecules have also demonstrated clinical efficacy and are soon to be licensed for ulcerative colitis. None of these novel drugs seems to be much more effective overall than the competition, but they provide new options in otherwise refractory patients. This increasing complexity requires new algorithms, but it is still premature to outline each drug’s role in future treatment paradigms.</ns4:p>
Characterization of the breast cancer resistance protein (BCRP/ABCG2) in clear cell renal cell carcinoma
2018-08-07

The efflux transporter breast cancer resistance protein BCRP/ ABCG2 is well‐known for its contribution to multi‐drug resistance in cancer. Its relevance in cancer biology independent from drug efflux remains largely elusive. Our study aimed at elucidating the biological relevance and regulatory mechanisms of BCRP/ ABCG2 in clear cell renal cell carcinoma (ccRCC) and disease progression. Two independent ccRCC‐cohorts [Cohort 1 (KIRC/TCGA): n = 453, Cohort 2: n = 64] were investigated to elucidate BCRP/ ABCG2 mRNA and protein expression and their association with survival. The impact of BCRP/ ABCG2 on response to sunitinib treatment was investigated in two independent sunitinib‐treated ccRCC‐cohorts based on mRNA levels. Moreover, underlying regulatory mechanisms for interindividual variability of BCRP/ ABCG2 expression were systematically assessed. Owing to redundant functional properties, mRNA and protein expression of the multidrug resistance protein MDR1/ ABCB1 were additionally evaluated in these cohorts. In independent ccRCC‐cohorts, low BCRP/ ABCG2 and MDR1/ ABCB1 mRNA and protein expression were associated with severity (e.g., tumor stage) of ccRCC and poor cancer‐specific survival. BCRP/ ABCG2 and MDR1/ ABCB1 mRNA expression were linked to decreased progression‐free survival after sunitinib treatment. Germline and somatic variants influenced interindividual variability of BCRP/ ABCG2 expression only moderately. miR‐212‐3p and miR‐132‐3p were identified to regulate BCRP/ ABCG2 posttranscriptionally by interaction with the ABCG2 3′UTR as confirmed through reporter gene assays in RCC cell lines. In summary, BCRP/ ABCG2 expression in ccRCC underlies considerable interindividual variability with impact on patient survival and response to sunitinib treatment. While germline or somatic genetic variants and DNA methylation cannot explain aberrant BCRP/ ABCG2 expression, miR‐212‐3p and miR‐132‐3p were identified to contribute to posttranscriptional regulation of BCRP/ ABCG2 .
Are diffuse and limited juvenile systemic sclerosis different in clinical presentation? Clinical characteristics of a juvenile systemic sclerosis cohort
2018-08-07

Introduction: Juvenile systemic sclerosis is an orphan disease. Currently, the majority of juvenile systemic sclerosis cohort studies are retrospective in design without standardized assessment. This study was conducted prospectively to investigate the difference in manifestations of limited cutaneous juvenile systemic sclerosis and diffuse cutaneous juvenile systemic sclerosis subtypes. An additional aim was to compare these data to other juvenile systemic sclerosis cohorts and a large adult systemic sclerosis cohort. Methods: Patients fulfilling the Paediatric Rheumatology European Society juvenile systemic sclerosis classification criteria were included. Clinical characteristics and patient-related outcomes were assessed. Results: In all, 88 patients with a mean disease duration of 3.5 years were enrolled, 72.5% with diffuse cutaneous juvenile systemic sclerosis with a mean modified Rodnan Skin score of 18 and 27.5% with limited cutaneous juvenile systemic sclerosis with mean modified Rodnan Skin score of 9. The mean age at the onset of Raynaud’s and first non-Raynaud’s symptoms was similar in both groups, approximately 9 and 10.5 years. Active digital tip ulcerations were present in 29% diffuse cutaneous juvenile systemic sclerosis and none in the limited cutaneous juvenile systemic sclerosis subjects (p = 0.005). Of those with cardiopulmonary testing, 3% of diffuse cutaneous juvenile systemic sclerosis and 23% of limited cutaneous juvenile systemic sclerosis group had cardiac involvement (p = 0.015), and 41% diffuse cutaneous juvenile systemic sclerosis and 22% of the limited cutaneous juvenile systemic sclerosis group had pulmonary involvement (p = 0.009). Physician global disease damage assessment was higher in the diffuse cutaneous juvenile systemic sclerosis group compared to the limited cutaneous juvenile systemic sclerosis group: 35 and 15 (p = 0.021). Discussion: The majority of this international juvenile systemic sclerosis cohort had diffuse cutaneous juvenile systemic sclerosis (72.5%) with more frequent vascular and pulmonary involvement compared to the limited cutaneous group, who had increased cardiac involvement. Our cohort reflects prior findings of published juvenile systemic sclerosis cohorts and emphasizes a difference in the presentation compared to adult-onset systemic sclerosis.
Identification of neurophysiological biotypes in attention deficit hyperactivity disorder
2018-08-07

Aim Findings on neurophysiological alterations in attention deficit hyperactivity disorder (ADHD) have been proposed to underlie ADHD symptoms, with different etiological pathways for different patient biotypes. We aimed at determining whether neurophysiological deviations confirm distinct neurophysiological profiles in ADHD, thus providing direct evidence for the endophenotype concept. Methods Neurophysiological biotypes were investigated in 87 adult patients with ADHD using cluster analysis. Parameters fed into the analysis comprised both hemodynamic and electrophysiological data. To validate results, the independent variables of the clusters were compared with healthy controls. Results Cluster analysis yielded three neurophysiologically based ADHD biotypes showing: (i) above‐average functioning in attention allocation; (ii) difficulties in attention allocation and inhibitory control but elevated frontal activation during a working memory task; and (iii) functional impairments in state regulation. Conclusion Classifying patients with ADHD into neurophysiological biotypes sheds light on etiological pathways, with implications for diagnostics and (individualized) treatment options.
Reactivating the Dormant Motor Cortex After Spinal Cord Injury With EEG Neurofeedback: A Case Study With a Chronic, Complete C4 Patient
2018-08-07

Chronic spinal cord injury (SCI) patients present poor motor cortex activation during movement attempts. The reactivation of this brain region can be beneficial for them, for instance, allowing them to use brain-machine interfaces for motor rehabilitation or restoration. These brain-machine interfacess generally use electroencephalography (EEG) to measure the cortical activation during the attempts of movement, quantifying it as the event-related desynchronization (ERD) of the alpha/mu rhythm. Based on previous evidence showing that higher tonic EEG alpha power is associated with higher ERD, we hypothesized that artificially increasing the alpha power over the motor cortex of these patients could enhance their ERD (ie, motor cortical activation) during movement attempts. We used EEG neurofeedback (NF) to enhance the tonic EEG alpha power, providing real-time visual feedback of the alpha oscillations measured over the motor cortex. This approach was evaluated in a C4, ASIA A, SCI patient (9 months after the injury) who did not present ERD during the movement attempts of his paralyzed hands. The patient performed 4 NF sessions (in 4 consecutive days) and screenings of his EEG activity before and after each session. After the intervention, the patient presented a significant increase in the alpha power over the motor cortex, and a significant enhancement of the mu ERD in the contralateral motor cortex when he attempted to close the assessed right hand. As a proof of concept investigation, this article shows how a short NF intervention might be used to enhance the motor cortical activation in patients with chronic tetraplegia.
Breast cancer patients suggestive of Li-Fraumeni syndrome: mutational spectrum, candidate genes, and unexplained heredity
2018-08-07

Our study details the mutational spectrum in breast cancer patients suggestive of Li-Fraumeni syndrome and indicates the need for intensified research on monoallelic variants in Fanconi pathway and RECQ family genes. Notably, this study further reveals a large portion of still unexplained Li-Fraumeni(-like) cases, warranting comprehensive investigation of recently described candidate genes as well as noncoding regions of the TP53 gene in patients with Li-Fraumeni(-like) syndrome lacking TP53 variants in coding regions.
cGMP Imaging in Brain Slices Reveals Brain Region-Specific Activity of NO-Sensitive Guanylyl Cyclases (NO-GCs) and NO-GC Stimulators
2018-08-07

Impaired NO-cGMP signaling has been linked to several neurological disorders. NO-sensitive guanylyl cyclase (NO-GC), of which two isoforms—NO-GC1 and NO-GC2—are known, represents a promising drug target to increase cGMP in the brain. Drug-like small molecules have been discovered that work synergistically with NO to stimulate NO-GC activity. However, the effects of NO-GC stimulators in the brain are not well understood. In the present study, we used Förster/fluorescence resonance energy transfer (FRET)-based real-time imaging of cGMP in acute brain slices and primary neurons of cGMP sensor mice to comparatively assess the activity of two structurally different NO-GC stimulators, IWP-051 and BAY 41-2272, in the cerebellum, striatum and hippocampus. BAY 41-2272 potentiated an elevation of cGMP induced by the NO donor DEA/NO in all tested brain regions. Interestingly, IWP-051 potentiated DEA/NO-induced cGMP increases in the cerebellum and striatum, but not in the hippocampal CA1 area or primary hippocampal neurons. The brain-region-selective activity of IWP-051 suggested that it might act in a NO-GC isoform-selective manner. Results of mRNA in situ hybridization indicated that the cerebellum and striatum express NO-GC1 and NO-GC2, while the hippocampal CA1 area expresses mainly NO-GC2. IWP-051-potentiated DEA/NO-induced cGMP signals in the striatum of NO-GC2 knockout mice but was ineffective in the striatum of NO-GC1 knockout mice. These results indicate that IWP-051 preferentially stimulates NO-GC1 signaling in brain slices. Interestingly, no evidence for an isoform-specific effect of IWP-051 was observed when the cGMP-forming activity of whole brain homogenates was measured. This apparent discrepancy suggests that the method and conditions of cGMP measurement can influence results with NO-GC stimulators. Nevertheless, it is clear that NO-GC stimulators enhance cGMP signaling in the brain and should be further developed for the treatment of neurological diseases.
Mystical Foundations of Politics? Luther on God’s Presence and the Place of Human Beings
2018-08-07

This article opens up a dialogue between two strands of Luther research, which until now have had limited contact: a German strand interested in the influence of Luther’s mystical education on his Reformation theology, and a German and Anglo-American strand concerned with Luther’s doctrine of the three estates and understanding of politics, emphasising in particular God’s constant activity in our daily life. This article has a twofold aim: first, to undertake a historical reconstruction of the influence of mysticism on the late Luther, and second to draw some systematic conclusions for our contemporary situation. The conclusion emphasises that the mystical tradition helps us to gain a better understanding of God’s manifold present activities, namely, because it helps us to perceive that God does not work through spoken words alone, but also through gestures, gazes and other embodied activities.
Complement 5a Receptor Polymorphisms Are Associated With Panton-Valentine Leukocidin–positive Staphylococcus aureus Colonization in African Pygmies
2018-08-07

Panton-Valentine leukocidin (PVL) is common in African Staphylococcus aureus and can be associated with skin and soft tissue infection. PVL-positive S. aureus colonization is associated with a variant of complement receptor 5a, the cellular target of the lukS PVL subunit.
Bacterial type III secretion systems: a complex device for the delivery of bacterial effector proteins into eukaryotic host cells
2018-08-08

Virulence-associated type III secretion systems (T3SS) serve the injection of bacterial effector proteins into eukaryotic host cells. They are able to secrete a great diversity of substrate proteins in order to modulate host cell function, and have evolved to sense host cell contact and to inject their substrates through a translocon pore in the host cell membrane. T3SS substrates contain an N-terminal signal sequence and often a chaperone-binding domain for cognate T3SS chaperones. These signals guide the substrates to the machine where substrates are unfolded and handed over to the secretion channel formed by the transmembrane domains of the export apparatus components and by the needle filament. Secretion itself is driven by the proton motive force across the bacterial inner membrane. The needle filament measures 20-150 nm in length and is crowned by a needle tip that mediates host-cell sensing. Secretion through T3SS is a highly regulated process with early, intermediate and late substrates. A strict secretion hierarchy is required to build an injectisome capable of reaching, sensing and penetrating the host cell membrane, before host cell-acting effector proteins are deployed. Here, we review the recent progress on elucidating the assembly, structure and function of T3SS injectisomes.
Systematic discovery of uncharacterized transcription factors in Escherichia coli K-12 MG1655
2018-08-08

Abstract Transcriptional regulation enables cells to respond to environmental changes. Of the estimated 304 candidate transcription factors (TFs) in Escherichia coli K-12 MG1655, 185 have been experimentally identified, but ChIP methods have been used to fully characterize only a few dozen. Identifying these remaining TFs is key to improving our knowledge of the E. coli transcriptional regulatory network (TRN). Here, we developed an integrated workflow for the computational prediction and comprehensive experimental validation of TFs using a suite of genome-wide experiments. We applied this workflow to (i) identify 16 candidate TFs from over a hundred uncharacterized genes; (ii) capture a total of 255 DNA binding peaks for ten candidate TFs resulting in six high-confidence binding motifs; (iii) reconstruct the regulons of these ten TFs by determining gene expression changes upon deletion of each TF and (iv) identify the regulatory roles of three TFs (YiaJ, YdcI, and YeiE) as regulators of l-ascorbate utilization, proton transfer and acetate metabolism, and iron homeostasis under iron-limited conditions, respectively. Together, these results demonstrate how this workflow can be used to discover, characterize, and elucidate regulatory functions of uncharacterized TFs in parallel.
Xylem functioning, dysfunction and repair: a physical perspective and implications for phloem transport
2018-08-08

Xylem and phloem are the two main conveyance systems in plants allowing exchanges of water and carbohydrates between roots and leaves. While each system has been studied in isolation for well over a century, the coupling and coordination between them remains the subject of inquiry and active research and frames the scope of the review here. Using a set of balance equations, hazards of bubble formation and their role in shaping xylem pressure and its corollary impact on phloem pressure and sugar transport are featured. The behavior of an isolated and freely floating air bubble within the xylem is first analyzed so as to introduce key principles such as the Helmholtz free energy and its links to embryonic bubble sizes. These principles are extended by considering bubbles filled with water vapor and air arising from air seeding. Using this framework, key results about stability and hazards of bubbles in contact with xylem walls are discussed. A chemical equilibrium between phloem and xylem systems is then introduced to link xylem and osmotic pressures. The consequences of such a link for sugar concentration needed to sustain efficient phloem transport by osmosis in the loading zone is presented. Catastrophic cases where phloem dysfunction occurs are analyzed in terms of xylem function and its vulnerability to cavitation. A link between operating pressures in the soil system bounded by field capacity and wilting points and maintenance of phloem functioning are discussed as conjectures to be tested in the future.
Developing Small‐Molecule Inhibitors of HECT‐Type Ubiquitin Ligases for Therapeutic Applications: Challenges and Opportunities
2018-08-08

Abstract The ubiquitin system regulates countless physiological and disease‐associated processes and has emerged as an attractive entryway for therapeutic efforts. With over 600 members in the human proteome, ubiquitin ligases are the most diverse class of ubiquitylation enzymes and pivotal in encoding specificity in ubiquitin signaling. Although considerable progress has been made in the identification of small molecules targeting RING ligases, relatively little is known about the “druggability” of HECT ( h omologous to E 6AP C t erminus) ligases, many of which are critically implicated in human pathologies. A major obstacle to optimizing the few available ligands is our incomplete understanding of their inhibitory mechanisms and the structural basis of catalysis in HECT ligases. Here, we survey recent approaches to manipulate the activities of HECT ligases with small molecules to showcase the particular challenges and opportunities these enzymes hold as therapeutic targets.
D-Fructose-based spiro-fused PHOX ligands: synthesis and application in enantioselective allylic alkylation
2018-08-08

Phosphinooxazoline (PHOX) ligands are an important class of ligands in asymmetric catalysis. We synthesized ten novel D-fructose-derived spiro-fused PHOX ligands with different steric and electronic demand. The application of two of them was tested in asymmetric allylic alkylation. The ligands are prepared in two steps from readily available 1,2- O -isopropylidene protected β-D-fructopyranoses by the BF 3 ·OEt 2 -promoted Ritter reaction with 2-bromobenzonitrile to construct the oxazoline moiety followed by Ullmann coupling of the resulting aryl bromides with diphenylphosphine. Both steps proceeded mostly in good to high yields (57–86% for the Ritter reaction and 35–89% for the Ullmann coupling). The Ritter reaction gave two anomers, which could be separated by column chromatography. The prepared ligands showed promising results (er of up to 84:16) in Tsuji–Trost reactions with diphenylallyl acetate as model substrate.
The effect of layout and pacing on learning from diagrams with unnecessary text
2018-08-08

Summary Although the presentation of extraneous (i.e., irrelevant or unnecessary) information hinders learning, it is unclear whether and how layout and pacing influence this effect. In two experiments, participants learned how the heart functions using four different layouts: a diagram presented without unnecessary text (diagram only), with unnecessary text separated from the diagram (separated) or integrated into the diagram (integrated), or with separated unnecessary text and the instruction to integrate (integration instruction). In Experiment 1, study time was self‐paced for half of the participants and system paced for the other half. There were no effects of layout and of pacing on learning, although system pacing was more effortful than self‐pacing. In Experiment 2, which was system paced and employed eye tracking, the integrated condition showed worse learning outcomes than the separated condition. Moreover, in the integrated condition, participants made more integration attempts between the unnecessary text and the diagram than in the separated condition.
Antiplatelet Treatment for Catheter-Based Interventions in High-Risk Patients: Current Guidelines and Expert Opinion
2018-08-08

Abstract Catheter-based interventions have revolutionized treatment of both coronary artery disease and aortic valve disease. Yet, these procedures are accompanied by thromboembolic and bleeding complications. Antiplatelet agents and anticoagulants with tolerable risk of bleeding complications are required to protect from recurrent thromboembolic events. Although guidelines for antithrombotic treatment in patients undergoing percutaneous coronary intervention (PCI) and transcatheter aortic valve replacement (TAVR) are available, scarce evidence exists regarding therapeutic recommendations for patients at high risk for thromboembolic events or major bleeding. The choice of optimal antiplatelet therapy after PCI in patients with complex coronary artery disease and concomitant atrial fibrillation often poses a clinical challenge. The antiplatelet therapy in patients undergoing TAVR is so far based mostly on expert consensus. The present review addresses state-of-the-art antithrombotic therapy, particularly focusing on patients at high risk of thromboembolic and bleeding events, and aims to provide recommendations for clinical practice.