bluuebunny/crossref_metadata_2025 huggingface dataset:
Pd/Cu‐Catalyzed Enantioselective Sequential Heck/Sonogashira Coupling: Asymmetric Synthesis of Oxindoles Containing Trifluoromethylated Quaternary Stereogenic Centers
Authors: Bai Xingfeng , Wu Caizhi , Ge Shaozhong , Lu Yixin
Published: October 2019

An asymmetric palladium and copper co‐catalyzed Heck/Sonogashira reaction between o‐iodoacrylanilides and terminal alkynes to synthesize chiral oxindoles was developed. In particular, a wide range of CF3‐substituted o‐iodoacrylanilides reacted with terminal alkynes, affording the corresponding chiral oxindoles containing trifluoromethylated quaternary stereogenic centers in high yields with excellent enantioselectivities (94–98 % ee). This asymmetric Heck/Sonogashira reaction provides a general approach to access oxindole derivatives containing quaternary stereogenic centers including CF3‐substituted ones.
Peri‐operative brachial plexus injury following self‐positioning for stereotactic radiofrequency ablation
Authors: Hoerner E. , Bale R. , Gasteiger L. , Putzer D.
Published: October 2019

A 71‐year‐old woman with a known accessory cervical rib and distinct scoliosis was scheduled for elective, percutaneous stereotactic radiofrequency ablation of a non‐resectable intrahepatic cholangiocellular carcinoma. Patient positioning and fixation using a Bluebag fixation system (Medical Intelligence, Schwabmünchen, Germany) and a dedicated adjustable armrest were customised in the patient while awake. In order to provide safe conditions for mask ventilation and tracheal intubation, the patient was returned to standard supine positioning without changing the position of the armrest. Following the induction of general anaesthesia, the patient's arm was returned to the previously defined position. Upon completion of the procedure and emergence from anaesthesia, the patient immediately reported symptoms of severe brachial plexus damage. Therefore, we suggest that awake positioning according to current recommendations does not completely preclude the possibility of neurologic injury.
Coupled Genomic Evolutionary Histories as Signatures of Organismal Innovations in Cephalopods
Authors: Ritschard Elena A. , Whitelaw Brooke , Albertin Caroline B. , Cooke Ira R. , Strugnell Jan M. , Simakov Oleg
Published: October 2019

How genomic innovation translates into organismal organization remains largely unanswered. Possessing the largest invertebrate nervous system, in conjunction with many species‐specific organs, coleoid cephalopods (octopuses, squids, cuttlefishes) provide exciting model systems to investigate how organismal novelties evolve. However, dissecting these processes requires novel approaches that enable deeper interrogation of genome evolution. Here, the existence of specific sets of genomic co‐evolutionary signatures between expanded gene families, genome reorganization, and novel genes is posited. It is reasoned that their co‐evolution has contributed to the complex organization of cephalopod nervous systems and the emergence of ecologically unique organs. In the course of reviewing this field, how the first cephalopod genomic studies have begun to shed light on the molecular underpinnings of morphological novelty is illustrated and their impact on directing future research is described. It is argued that the application and evolutionary profiling of evolutionary signatures from these studies will help identify and dissect the organismal principles of cephalopod innovations. By providing specific examples, the implications of this approach both within and beyond cephalopod biology are discussed.
In‐situ SHINERS Study of the Size and Composition Effect of Pt‐based Nanocatalysts in Catalytic Hydrogenation
Authors: Wang Chen , Chen Xing , Chen Tian‐Ming , Wei Jie , Qin S.‐N. , Zheng Ju‐Fang , Zhang Hua , Tian Zhong‐Qun , Li Jian‐Feng
Published: October 2019

Understanding the structure‐activity relationship of catalytic reactions at a molecular level still remains a great challenge. Herein, shell‐isolated nanoparticle‐enhanced Raman spectroscopy (SHINERS) is employed to in‐situ study the catalytic hydrogenation of para‐nitrothiophenol (pNTP) on Pt‐based nanocatalysts with different size and composition. The nanocatalysts are assembled on pinhole‐free shell‐isolate nanoparticles (SHINs), which work as Raman amplifiers to enhance the Raman signals of species on the catalysts, allowing the in‐situ monitoring of catalytic reactions carried out on the catalysts. Using this strategy, we find that the catalytic activity of the Pt nanocatalysts shows a volcanic trend with the Pt size, and that PtM (M=Ni or Cu) bimetallic nanocatalysts display much higher performance compared with Pt due to better activation of the nitro group. This work demonstrates that SHINERS is a promising technique for in‐situ study of nanocatalysis thus can deepen the understanding of the behaviors of different catalysts.
Chemistry Escape – Finde den Weg
Authors: Groß Katharina , Schumacher Andrea
Published: October 2019

Der außerschulische Lernort ELKE für Schülerinnen und Schüler zeichnet sich durch curricular anbindungsfähige Inhalte und eine kompetenzorientierte Gestaltung aus und zielt darauf ab, eine lernwirksame Vernetzung des Schülerlabors mit dem Chemieunterricht zu erreichen. In dem Beitrag wird die Konzeption eines neuen Experimentiertages „Chemistry escape – Finde den Weg“, der in Form eines escape room aufgebaut wurde, für das Schülerlabor ELKEOberstufe sowohl inhaltlich als auch in seiner didaktischen Ausgestaltung vorgestellt.
A fine‐grained loop‐level parallel approach to efficient fuzzy community detection in complex networks
Authors: Muñoz‐Caro Camelia , Niño Alfonso , Reyes Sebastián
Published: October 2019

Determining the inner organizational structure of sets of networked elements is of paramount importance to analyze real‐world systems such as social, biological, or economic networks. To such an end, it is necessary to identify communities of interrelated nodes within the networks. Recently, a fuzzy community detection approach based on the minimization of a topological error functional has been proposed in the form of a gradient‐based algorithm design pattern. However, the intrinsic quadratic algorithmic complexity of the procedure limits the problem size that can be efficiently treated. Here, we extend the ability of this approach to analyze larger networks resorting to parallelism. Thus, we identify the concurrency sources in the gradient‐based algorithm design pattern. To determine the parallelization limits, we develop a two‐dimensional performance model as a function of the number of processors and network size. The model permits to compute the maximum possible speedup. Another model is presented to find the maximum problem size tractable in a given amount of time. Application of the previous models to a set of benchmark networks shows that parallelization enhances the proposed fuzzy community detection approach in more than an order of magnitude. This allows treatment of networks with several hundred thousand nodes in a time frame of hours.
Differential gene expression in chronic wasting disease‐positive white‐tailed deer (Odocoileus virginianus)
Authors: Trone‐Launer Emma K. , Wang Jun , Lu Guoqing , Mateus‐Pinilla Nohra E. , Zick Paige R. , Lamer James T. , Shelton Paul A. , Jacques Christopher N.
Published: October 2019

Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSE) that affects cervid species throughout North America. We evaluated gene expression in white‐tailed deer collected by Illinois Department of Natural Resource wildlife managers during annual population reduction (e.g., sharpshooting) and disease monitoring efforts throughout the CWD‐endemic area of northcentral Illinois. We conducted comparative transcriptomic analysis of liver and retropharyngeal lymph node tissue samples between CWD‐positive (n = 5) and CWD‐not detected (n = 5) deer. A total of 74,479 transcripts were assembled, and 51,661 (69.36%) transcripts were found to have matched proteins in NCBI‐NR and UniProt. Our analysis of functional categories showed 40,308 transcripts were assigned to at least one Gene Ontology term and 37,853 transcripts were involved in at least one pathway. We identified a total of 59 differentially expressed genes (DEGs) in CWD‐positive deer, of which 36 and 23 were associated with liver and retropharyngeal lymph node tissues, respectively. Functions of DEGs lend support to previous relationships between misfolded PrP and cellular membranes (e.g., STXBP5), and internal cellular components. We identified several genes that suggest a link between CWD and retroviruses and identified the gene ADIPOQ that acts as a tumor necrosis factor (TNF) antagonist. This gene may lead to reduced production of TNF and impact disease progression and clinical symptoms associated with CWD (i.e., wasting syndrome). Use of candidate genes identified in this study suggests the activation of endogenous processes in CWD‐positive deer, which in turn may enable earlier detection of the disease.
Chiral Modification of the Tetrakis(pentafluorophenyl)borate Anion with Myrtanyl Groups
Authors: Pommerening Phillip , Oestreich Martin
Published: October 2019

The synthesis and characterization of chiral [B(C6F5)4]– derivatives bearing a myrtanyl group instead of a fluoro substituent in the para position are described. These new chiral borates were isolated as their bench‐stable lithium, sodium, and cesium salts. The corresponding trityl salts were prepared and tested as catalysts in representative counteranion‐directed Diels–Alder reactions and Mukaiyama aldol additions but no enantioselectivity was obtained. Preformation of a chalcone‐derived silylcarboxonium ion with the chiral borate as counteranion did not lead to any asymmetric induction in a reaction with cyclohexa‐1,3‐diene.
Fear in dreams and in wakefulness: Evidence for day/night affective homeostasis
Authors: Sterpenich Virginie , Perogamvros Lampros , Tononi Giulio , Schwartz Sophie
Published: October 2019

Recent neuroscientific theories have proposed that emotions experienced in dreams contribute to the resolution of emotional distress and preparation for future affective reactions. We addressed one emerging prediction, namely that experiencing fear in dreams is associated with more adapted responses to threatening signals during wakefulness. Using a stepwise approach across two studies, we identified brain regions activated when experiencing fear in dreams and showed that frightening dreams modulated the response of these same regions to threatening stimuli during wakefulness. Specifically, in Study 1, we performed serial awakenings in 18 participants recorded throughout the night with high‐density electroencephalography (EEG) and asked them whether they experienced any fear in their dreams. Insula and midcingulate cortex activity increased for dreams containing fear. In Study 2, we tested 89 participants and found that those reporting higher incidence of fear in their dreams showed reduced emotional arousal and fMRI response to fear‐eliciting stimuli in the insula, amygdala and midcingulate cortex, while awake. Consistent with better emotion regulation processes, the same participants displayed increased medial prefrontal cortex activity. These findings support that emotions in dreams and wakefulness engage similar neural substrates, and substantiate a link between emotional processes occurring during sleep and emotional brain functions during wakefulness.
A novel platform to evaluate the dampening of water and solute transport in an experimental channel under unsteady flow conditions
Authors: Majdalani Samer , Moussa Roger , Chazarin Jean‐Philippe
Published: October 2019

This paper presents a novel platform to study the dampening of water and solute transport in an experimental channel under unsteady flow conditions, where literature data are scarce. We address the question about what could be the smallest size of experimental platform that is useful for research, project studies, and teaching activities and that allows to do rational experiments characterized by small space occupation, short experimental duration, high measurement precision, high quality and reproducible experimental curves, low water and energy consumption, and the possibility to test a large variety of hydrograph scenarios. Whereas large scale hydraulic laboratories have focused their studies on sediment transport, our platform deals with solute transport. The objectives of our study are (a) building a platform that allows to do rational experiments, (b) enriching the lack of experimental data concerning water and solute transport under unsteady state conditions, and (c) studying the dampening of water and solute transport. We studied solute transport in a channel with lateral gain and lateral loss under different experimental configurations, and we show how the same lateral loss flow event can lead to different lateral loss mass repartitions under different configurations. In order to characterize water and solute dampening between the input and the output of the channel, we calculate dampening ratios based on peak coordinates of time flow curves and time mass curves and that express the decrease of peak amplitude and the increase of peak occurrence time between the input and output curves. Finally, we use a solute transport model coupling the diffusive wave equation for water transfer and the advection–diffusion equation for solute transport in order to simulate the experimental data. The simulations are quite good with a Nash–Sutcliffe efficiency NSE > 0.98 for water transfer and 0.84 < NSE < 0.97 for solute transport. This platform could serve hydrological modellers because it offers a variety of measured parameters (flow, water height, and solute concentration), at a fine time step under unsteady flow conditions.
Gut microbiome and cancer immunotherapy
Authors: Sun Jin‐Yu , Yin Tai‐Lang , Zhou Jianhua , Xu Jiang , Lu Xiao‐Jie
Published: October 2019

Gut microbiome has received significant attention for its influences on a variety of host functions, especially immune modulation. With the next‐generation sequencing methodologies, more knowledge is gathered about gut microbiome and its irreplaceable role in keeping the balance between human health and diseases is figured out. Immune checkpoint inhibitors (ICIs) are one of the most innovational cancer immunotherapies across cancer types and significantly expand the therapeutic options of cancer patients. However, a proportion of patients show no effective responses or develop immune‐related adverse events when responses do occur. More important, it is demonstrated that the therapeutic response or treatment‐limiting toxicity of cancer immunotherapy can be ameliorated or diminished by gut microbiome modulation. In this review, we first introduce the relationship between gut microbiome and cancer immunotherapy. And then, we expound the impact of gut microbiome on efficacy and toxicity of cancer immunotherapy. Further, we review approaches to manipulating gut microbiome to regulate response to ICIs. Finally, we discuss the current challenges and propose future directions to improve cancer immunotherapy via gut microbiome manipulation.
Knowledge and attitudes of Parkinson’s disease risk in the Gaucher population
Authors: Zaretsky Leah , Zeid Natasha , Naik Hetanshi , Alcalay Roy N. , Balwani Manisha
Published: October 2019

Individuals with Gaucher disease have an increased risk of developing Parkinson's disease as compared to the general population. Though the association is well‐known in the scientific community, it is unclear if individuals with Gaucher disease are being counseled on the increased risk. To date, no studies have been performed assessing whether Gaucher disease patients are aware of the increased risk of developing Parkinson's disease. Furthermore, it is unknown how and when individuals with Gaucher disease wish to learn of the increased risk. To assess this, an online survey was administered to Gaucher disease patients. We hypothesized that most individuals with Gaucher disease have been informed of the risk, and that they wish to be told of the risk by their health care provider at the time of diagnosis. Study results revealed that of 125 individuals with Gaucher disease, 80% previously knew about the association with Parkinson's disease, 83.7% preferred to find out about the increased risk from a health care provider, and 71.0% wanted to find out at the time of Gaucher disease diagnosis. These results suggest that health care providers should counsel Gaucher disease patients about the increased Parkinson's disease risk, and they should do so at the time of diagnosis.
Prospective Multicenter Study of the Safety of Gadoteridol in 6163 Patients
Authors: Cho Sung Bum , Lee A‐Leum , Chang Hyuk Won , Kim Kyeong Ah , Yoo Won Jong , Yeom Jeong A. , Rho Myung Ho , Kim Sung Jin , Lim Yun‐jung , Han Miran
Published: October 2019

Background

The safety of gadolinium‐based contrast agents is of fundamental importance.

Purpose

To determine the frequency and severity of immediate‐type adverse reactions to approved doses of gadoteridol in patients referred for routine gadoteridol‐enhanced MRI in actual clinical practice settings.

Study Type

Prospective, observational.

Population

In all, 6163 subjects were enrolled (mean age: 56.7 ± 15.4 years; range: 6–93 years).

Field Strength/Sequence

1.5T and 3.0T.

Assessment

Assessment was of immediate adverse reactions by the investigating radiologist using the MedDRA System Organ Class and preferred term.

Statistical Tests

Summary statistics for continuous variables, descriptive statistics for demographic characteristics.

Results

Overall, 19 adverse events occurred in 13 (0.21%) patients, of which 15 in 10 (0.16%) patients were considered related to gadoteridol administration. These events were evenly distributed between male and female subjects and all occurred in adults. Twelve of the 15 related events in eight (0.13%) patients were considered mild in intensity (rapidly self‐resolving), while the remaining three events in two patients (0.03%) were considered moderate in intensity. None were of severe intensity and no serious adverse events occurred.

Data Conclusion

The rate of immediate‐type adverse events following exposure to approved doses of gadoteridol is extremely low, and mostly limited to transient and self‐resolving symptoms.

Level of Evidence: 2

Technical Efficacy Stage: 5

J. Magn. Reson. Imaging 2020;51:861–868.
Using spectral matching to interpret LC‐MS/MS data during RNA modification mapping
Authors: Paulines Mellie June , Wetzel Collin , Limbach Patrick A.
Published: October 2019

While a number of approaches have been developed to analyze liquid chromatography tandem mass spectrometry (LC‐MS/MS) data obtained from modified oligonucleotides, the majority of these methods require analyzing every MS/MS spectrum de novo to sequence the oligonucleotide and place the modification. Spectral matching is an alternative approach for analyzing MS/MS data that is based on creating a library of annotated MS/MS spectra against which individual MS/MS data can be searched. Here, we have adapted the existing NIST spectral matching software to enable its use in the interpretation of MS/MS data obtained from modified oligonucleotides. In particular, we demonstrate the utility of this approach to identify specific post‐transcriptionally modified nucleosides in particular transfer RNAs (tRNAs) obtained through a conventional RNA modification mapping experimental protocol. Spectral matching was found to be an efficient approach for screening for known modified tRNAs by using the experimental data as the library and previously annotated RNase T1 digestion products of tRNAs as the reference spectra. The utility of spectral matching for rapid analysis of multiple LC‐MS/MS analyses was demonstrated by screening mutant strains of Streptococcus mutans to identify the enzyme(s) responsible for synthesizing the tRNA position 37 modification threonylcarbamoyladenosine (t6A).
Lipase of Pseudomonas guariconesis as an additive in laundry detergents and transesterification biocatalysts
Authors: Devi Rajan , Madhavan Nampoothiri Kesavan , Sukumaran Rajeev Kumar , Sindhu Raveendran , Arumugam Muthu
Published: October 2019

A newly isolated culture, Pseudomonas guariconesis, is reported for the first time for lipase production. Various process parameters affecting enzyme production were optimized through statistical design experiments. The Plackett–Burman experimental design was used for screening 10 parameters for lipase production, which was further optimized using the central composite design of response surface methodology. Maximum lipase activity of 220 U/ml was obtained after 24 h of incubation in shake‐flask cultures with an inoculum concentration of 0.6% v/v, incubation temperature of 30°C, and medium pH 9.0. Castor oil (0.5% v/v) was used as the inducer for lipase production. The enzyme was found to be compatible with five different commercial detergents, indicating its potential to be used in detergent formulations. It also acted as a biocatalyst in a transesterification process. The alkaline enzyme was found to be stable in the presence of bleaching agents, metal ions, and organic solvents as well.
A Robust and High Self‐Healing Efficiency Poly(Urea‐Urethane) Based on Disulfide Bonds with Cost‐Effective Strategy
Authors: Wang Yulong , Li Yaqiong , Bai Jingjing , Li Zhenzhong , Hu Guosheng
Published: October 2019

The development of self‐healing poly(urea‐urethane)s with remarkable mechanical properties as well as self‐healing capability is an important challenge through a low‐cost approach. In this study, cystine dimethyl ester (CDE) is synthesized cost‐effectively using cystine from bio‐based sources as raw material, and a novel self‐healing poly(urea‐urethane) is successfully prepared using synthesized CDE as a disulfide‐containing chain extender through a two‐step approach. The as‐prepared disulfide‐containing poly(urea‐urethane) (SPU) presents an excellent self‐healing capability with self‐healing efficiency of 95.3% at a moderate healing temperature (≈60 °C). Meanwhile, the SPU exhibits robust mechanical properties possessing a maximum tensile strength of 25.80 MPa and a high elongation at break of over 460% simultaneously. The compromise between self‐healing capability and mechanical performance can be responsible for the exchange of dynamic disulfide bonds and the existence of quadruple hydrogen bonding. This strategy provides an available idea to develop robust self‐healing polymer materials cost‐effectively.
Superconvergent patch recovery with constraints for three‐dimensional contact problems within the Cartesian grid Finite Element Method
Authors: Navarro‐Jiménez José M. , Navarro‐García Héctor , Tur Manuel , Ródenas Juan J.
Published: October 2019

The superconvergent patch recovery technique with constraints (SPR‐C) consists in improving the accuracy of the recovered stresses obtained with the original SPR technique by considering known information about the exact solution, like the internal equilibrium equation, the compatibility equation or the Neumann boundary conditions, during the recovery process. In this paper the SPR‐C is extended to consider the equilibrium around the contact area when solving contact problems with the Cartesian grid Finite Element Method. In the proposed method, the Finite Element stress fields of both bodies in contact are considered during the recovery process and the equilibrium is enforced by means of the continuity of tractions along the contact surface.
Synthesis and Properties of Polycarbosilanes Having Lactose‐Derived Structures
Authors: Matsumoto Kozo , Miyano Tatsuya , Kotake Yojiro
Published: October 2019

A polycarbosilane having lactose‐derived structures was synthesized, and its thermal property, cytotoxicity, chemical crosslinking, and protein adsorption properties were investigated. The polycarbosilane (PSB‐Lac) was prepared by a thiol‐ene reaction between precursor poly(1‐(3‐butenyl)‐1‐methylsilacyclubane) (PSB) and heptaacetyl lactose that carried a thiol group at the anomeric position, and the successive deprotection of the acetyl groups. The lactose introduction efficiency determined by 1H NMR measurement was 75%. TGA and DSC revealed that the polymer had a 5 wt% decomposition temperature of 260 °C and glass transition temperature (Tg) of 84 °C, which indicated that PSB‐Lac was a thermally stable polymer. PSB‐Lac had no significant cytotoxicity, which was evaluated by human liver cancer cell line HepG2 cultivation on the polystyrene dishes coated with the polymer. Urethane‐crosslinked PSB‐Lac films were prepared by casting solutions of PSB‐Lac and hexamethylene diisocyanate and heating at 120 °C after evaporation of the solvent. The crosslinked PSB‐Lac showed higher adsorption of bovine serum albumin than the similarly crosslinked polycarbosilane that had a glucose structure (PSB‐Glc). © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 2420–2425
Nonlinear mixed‐effects models with misspecified random‐effects distribution
Authors: Drikvandi Reza
Published: October 2019

Nonlinear mixed‐effects models are being widely used for the analysis of longitudinal data, especially from pharmaceutical research. They use random effects which are latent and unobservable variables so the random‐effects distribution is subject to misspecification in practice. In this paper, we first study the consequences of misspecifying the random‐effects distribution in nonlinear mixed‐effects models. Our study is focused on Gauss‐Hermite quadrature, which is now the routine method for calculation of the marginal likelihood in mixed models. We then present a formal diagnostic test to check the appropriateness of the assumed random‐effects distribution in nonlinear mixed‐effects models, which is very useful for real data analysis. Our findings show that the estimates of fixed‐effects parameters in nonlinear mixed‐effects models are generally robust to deviations from normality of the random‐effects distribution, but the estimates of variance components are very sensitive to the distributional assumption of random effects. Furthermore, a misspecified random‐effects distribution will either overestimate or underestimate the predictions of random effects. We illustrate the results using a real data application from an intensive pharmacokinetic study.
Predictions of Pattern Formation in Amino Acid Adlayers at the In Vacuo Graphene Interface: Influence of Termination State
Authors: Awuah Joel B. , Walsh Tiffany R.
Published: October 2019

Controlled self‐assembly of biomolecules on graphene offers a pathway for realizing its full potential in biological applications. Microscopy has revealed the self‐assembly of amino acid adlayers into dimer rows on nonreactive substrates. However, neither the spontaneous formation of these patterns, nor the influence of amino acid termination state on the formation of patterns has been directly resolved to date. Molecular dynamics simulations, with the ability to reveal atomic level details and exert full control over the termination state, are used here to model initially disordered adlayers of neutral, zwitterionic, and neutral–zwitterionic mixtures for two types of amino acids, tryptophan and methionine, adsorbed on graphene in vacuo. The simulations of the zwitterion‐containing adlayers exhibit the spontaneous emergence of dimer row ordering, mediated by charge‐driven intermolecular interactions. In contrast, adlayers containing only neutral species do not assemble into ordered patterns. It is also found that the presence of trace amounts of water reduces the interamino acid interactions in the adlayers, but does not induce or disrupt pattern formation. Overall, the findings reveal the balance between the lateral interamino acid interactions and amino acid–graphene interactions, providing foundational insights for ultimately realizing the predictable pattern formation of biomolecules adsorbed on unreactive surfaces.
Trends in mental health, non‐suicidal self‐harm and suicide attempts in 16–24-year old students and non-students in England, 2000–2014
Authors: McManus S. , Gunnell D.
Published: October 2019

There are concerns about high levels of mental ill-health amongst university students, but little is known about the mental health of students compared to non-students over time. Using data on young people (16–24) from three UK National Psychiatric Morbidity Surveys (2000, 2007, and 2014), we found no evidence that the overall prevalence of common mental disorder (CMD), suicide attempts, or non-suicidal self-harm (NSSH) differed between students and non-students, although there was an indication that CMDs rose markedly in female students between 2007 and 2014. A rise in NSSH is apparent in both students and non-students.
The prognostic value of serum erythropoietin in patients with lower-risk myelodysplastic syndromes: a review of the literature and expert opinion
Authors: Park Sophie , Kelaidi Charikleia , Meunier Mathieu , Casadevall Nicole , Gerds Aaron T. , Platzbecker Uwe
Published: October 2019

Myelodysplastic syndromes (MDS) are hematopoietic stem cell malignancies associated with an erythroid maturation defect, resulting in anemia. Treatments for MDS include erythropoiesis-stimulating agents (ESAs). The identification of prognostic markers is important to help predict response and improve outcomes. Various scoring systems have been developed to help predict response to ESAs. Despite limitations in its assessment, serum erythropoietin (sEPO) level is an important predictor of hematologic response to ESAs in patients with lower-risk MDS. Numerous studies have reported significantly lower sEPO levels among responders versus non-responders. Furthermore, treatment response is significantly more likely among those with sEPO levels below versus those above various cutoffs. Other prognostic indicators for response to ESAs include lower transfusion requirement, fewer bone marrow blasts, higher hemoglobin, lower serum ferritin, lower-risk MDS, and more normal cytogenetics. Studies of other MDS therapies (e.g., lenalidomide and luspatercept) have also reported that lower sEPO levels are indicative of hematologic response. In addition, lower sEPO levels (up to 500 IU/L) have been included in treatment algorithms for patients with lower-risk MDS to define whether ESAs are indicated. Lower sEPO levels are predictive of hematologic response—particularly to ESAs. Further, clinical trials should use sEPO thresholds to ensure more homogeneous cohorts.
Efficacy and safety of kaolin-based hemostatic pad vs. standard mechanical compression following transradial and transulnar access for elective coronary angiography and PCI: RAUL trial substudy
Authors: Pawel Lewandowski , Dagmara Gralak-Lachowska , Pawel Maciejewski , Bogumil Ramotowski , Andrzej Budaj , Sebastian Stec
Published: October 2019

Hemostatic devices used in the transradial approach (TRA) and transulnar approach (TUA) are limited. This study compared the efficacy and safety of hemostasis using the QuikClot Radial hemostatic pad (QC) vs. standard mechanical compression (SC) after coronary angiography (CAG). This prospective single-center randomized trial included CAG patients. The primary and secondary endpoints were efficacy (successful hemostasis) and safety (total artery occlusion [TAO], pseudoaneurysm, hematoma), respectively. A visual analog scale (VAS) evaluated patient pain during compression. In 2013–2017, 200 patients were randomized 2 × 2 into the: (1) TRA and TUA groups and (2) QC and SC groups. Successful hemostasis was achieved in 92 (92%) patients in the QC group and 100 (100%) patients in the SC group (p < 0.006). The TRA SC subgroup showed significantly better results than the TRA QC subgroup (100% vs. 90.0%; p < 0.03). Similar results were obtained in the TUA QC and TUA SC subgroups (95% vs. 100%; p = 0.5). The secondary endpoint was achieved in the QC and SC groups (8% vs. 9%; p = 0.8). Patients reported significantly less pain during QC application than during SC (VAS: 2.6 ± 2.6 vs. 3.4 ± 2.9; p < 0.03). In patients undergoing CAG with TRA or TUA, QC was associated with lower efficacy, less discomfort, and similar safety compared to SC.
Predominant cleavage of proteins N-terminal to serines and threonines using scandium(III) triflate
Authors: Koehler Christian J. , Thiede Bernd
Published: October 2019

Proteolytic digestion prior to LC–MS analysis is a key step for the identification of proteins. Digestion of proteins is typically performed with trypsin, but certain proteins or important protein sequence regions might be missed using this endoproteinase. Only few alternative endoproteinases are available and chemical cleavage of proteins is rarely used. Recently, it has been reported that some metal complexes can act as artificial proteases. In particular, the Lewis acid scandium(III) triflate has been shown to catalyze the cleavage of peptide bonds to serine and threonine residues. Therefore, we investigated if this compound can also be used for the cleavage of proteins. For this purpose, several single proteins, the 20S immune-proteasome (17 proteins), and the Universal Proteomics Standard UPS1 (48 proteins) were analyzed by MALDI–MS and/or LC–MS. A high cleavage specificity N-terminal to serine and threonine residues was observed, but also additional peptides with deviating cleavage specificity were found. Scandium(III) triflate can be a useful tool in protein analysis as no other reagent has been reported yet which showed cleavage specificity within proteins to serines and threonines.

Graphic abstract
Cancer-associated fibroblast-derived WNT2 increases tumor angiogenesis in colon cancer
Authors: Unterleuthner Daniela , Neuhold Patrick , Schwarz Katharina , Janker Lukas , Neuditschko Benjamin , Nivarthi Harini , Crncec Ilija , Kramer Nina , Unger Christine , Hengstschläger Markus , Eferl Robert , Moriggl Richard , Sommergruber Wolfgang , Gerner Christopher , Dolznig Helmut
Published: October 2019

WNT2 acts as a pro-angiogenic factor in placental vascularization and increases angiogenesis in liver sinusoidal endothelial cells (ECs) and other ECs. Increased WNT2 expression is detectable in many carcinomas and participates in tumor progression. In human colorectal cancer (CRC), WNT2 is selectively elevated in cancer-associated fibroblasts (CAFs), leading to increased invasion and metastasis. However, if there is a role for WNT2 in colon cancer, angiogenesis was not addressed so far. We demonstrate that WNT2 enhances EC migration/invasion, while it induces canonical WNT signaling in a small subset of cells. Knockdown of WNT2 in CAFs significantly reduced angiogenesis in a physiologically relevant assay, which allows precise assessment of key angiogenic properties. In line with these results, expression of WNT2 in otherwise WNT2-devoid skin fibroblasts led to increased angiogenesis. In CRC xenografts, WNT2 overexpression resulted in enhanced vessel density and tumor volume. Moreover, WNT2 expression correlates with vessel markers in human CRC. Secretome profiling of CAFs by mass spectrometry and cytokine arrays revealed that proteins associated with pro-angiogenic functions are elevated by WNT2. These included extracellular matrix molecules, ANG-2, IL-6, G-CSF, and PGF. The latter three increased angiogenesis. Thus, stromal-derived WNT2 elevates angiogenesis in CRC by shifting the balance towards pro-angiogenic signals.
Understanding the influence of teacher–learner relationships on learners’ assessment perception
Authors: Schut Suzanne , van Tartwijk Jan , Driessen Erik , van der Vleuten Cees , Heeneman Sylvia
Published: October 2019

Low-stakes assessments are theorised to stimulate and support self-regulated learning. They are feedback-, not decision-oriented, and should hold little consequences to a learner based on their performance. The use of low-stakes assessment as a learning opportunity requires an environment in which continuous improvement is encouraged. This may be hindered by learners’ perceptions of assessment as high-stakes. Teachers play a key role in learners’ assessment perceptions. By investigating assessment perceptions through an interpersonal theory-based perspective of teacher–learner relationships, we aim to better understand the mechanisms explaining the relationship between assessment and learning within medical education. First, twenty-six purposefully selected learners, ranging from undergraduates to postgraduates in five different settings of programmatic assessment, were interviewed about their assessment task perception. Next, we conducted a focussed analysis using sensitising concepts from interpersonal theory to elucidate the influence of the teacher–learner relationship on learners’ assessment perceptions. The study showed a strong relation between learners’ perceptions of the teacher–learner relationship and their assessment task perception. Two important sources for the perception of teachers’ agency emerged from the data: positional agency and expert agency. Together with teacher’s communion level, both types of teachers’ agency are important for understanding learners’ assessment perceptions. High levels of teacher communion had a positive impact on the perception of assessment for learning, in particular in relations in which teachers’ agency was less dominantly exercised. When teachers exercised these sources of agency dominantly, learners felt inferior to their teachers, which could hinder the learning opportunity. To utilise the learning potential of low-stakes assessment, teachers are required to stimulate learner agency in safe and trusting assessment relationships, while carefully considering the influence of their own agency on learners’ assessment perceptions. Interpersonal theory offers a useful lens for understanding assessment relationships. The Interpersonal Circumplex provides opportunities for faculty development that help teachers develop positive and productive relationships with learners in which the potential of low-stakes assessments for self-regulated learning is realised.
Wilson disease missense mutations in ATP7B affect metal-binding domain structural dynamics
Authors: Shanmugavel Kumaravel Ponnandai , Kumar Ranjeet , Li Yaozong , Wittung-Stafshede Pernilla
Published: October 2019

Wilson disease (WD) is caused by mutations in the gene for ATP7B, a copper transport protein that regulates copper levels in cells. A large number of missense mutations have been reported to cause WD but genotype–phenotype correlations are not yet established. Since genetic screening for WD may become reality in the future, it is important to know how individual mutations affect ATP7B function, with the ultimate goal to predict pathophysiology of the disease. To begin to assess mechanisms of dysfunction, we investigated four proposed WD-causing missense mutations in metal-binding domains 5 and 6 of ATP7B. Three of the four variants showed reduced ATP7B copper transport ability in a traditional yeast assay. To probe mutation-induced structural dynamic effects at the atomic level, molecular dynamics simulations (1.5 μs simulation time for each variant) were employed. Upon comparing individual metal-binding domains with and without mutations, we identified distinct differences in structural dynamics via root-mean square fluctuation and secondary structure content analyses. Most mutations introduced distant effects resulting in increased dynamics in the copper-binding loop. Taken together, mutation-induced long-range alterations in structural dynamics provide a rationale for reduced copper transport ability.
An Improved Surface Boundary Condition for Large-Eddy Simulations Based on Monin–Obukhov Similarity Theory: Evaluation and Consequences for Grid Convergence in Neutral and Stable Conditions
Authors: Maronga Björn , Knigge Christoph , Raasch Siegfried
Published: October 2019

Monin–Obukhov similarity theory is used in large-eddy simulation (LES) models as a surface boundary condition to predict the surface shear stress and scalar fluxes based on the gradients between the surface and the first grid level above the surface. We outline deficiencies of this methodology, such as the systematical underestimation of the surface shear stress, and propose a modified boundary condition to correct for this issue. The proposed boundary condition is applied to a set of LES for both neutral and stable boundary layers with successively decreasing grid spacing. The results indicate that the proposed boundary condition reliably corrects the surface shear stress and the sensible heat flux, and improves grid convergence of these quantities. The LES data indicate improved grid convergence for the surface shear stress, more so than for the surface heat flux. This is either due to a limited performance of the Monin–Obukhov similarity functions or due to problems in the LES model in representing stable conditions. Furthermore, we find that the correction achieved using the proposed boundary condition does not lead to improved grid convergence of the wind-speed and temperature profiles. From this we conclude that the sensitivity of the wind-speed and temperature profiles in the LES model to the grid spacing is more likely related to under-resolved near-surface gradients and turbulent mixing at the boundary-layer top, to the SGS model formulation, and/or to numerical issues, and not to deficiencies due to the use of improper surface boundary conditions.
Twenty-five years of adaptation finance through a climate justice lens
Authors: Khan Mizan , Robinson Stacy-ann , Weikmans Romain , Ciplet David , Roberts J. Timmons
Published: October 2019

How much finance should be provided to support climate change adaptation and by whom? How should it be allocated, and on what basis? Over the years, various actors have expressed different normative expectations on climate finance. Which of these expectations are being met and which are not; why, and with what consequences? Have new norms and rules emerged, which remain contested? This article takes stock of the first 25+ years of adaptation finance under the United Nations Framework Convention on Climate Change (UNFCCC) and seeks to understand whether adaptation finance has become more justly governed and delivered over the past quarter century. We distinguish among three “eras” of adaptation finance: (1) the early years under the UNFCCC (1992–2008); (2) the Copenhagen shift (2009–2015); and (3) the post-Paris era (2016–2018). For each era, we systematically review the justice issues raised by evolving expectations and rules over the provision, distribution, and governance of adaptation finance. We conclude by outlining future perspectives for adaptation finance and their implications for climate justice.
The Adaptation and Feasibility of Narrative Enhancement and Cognitive Therapy (NECT) for Late-Onset Psychosis
Authors: Ching Elaine Y. N. , Smyth Lucy , De Souza Tanisha , Charlesworth Georgina
Published: October 2019

The aim of this study is to adapt and feasibility test the narrative component of Narrative Enhancement and Cognitive Therapy (NECT) for late-onset psychosis. This study followed the development and feasibility phases of the Medical Research Council framework. The original NECT intervention was adapted based on consultations with service users, experts, and clinicians. The evaluation of the feasibility test of the adapted intervention was guided by Orsmond and Cohn (Occup Particip Health 35(3):169–177, 2015)’s model for feasibility studies. The final adaptations consist of language, readability, and delivery. The adapted intervention was tested for feasibility and acceptability with one group of five patients recruited from a National Health Service (NHS) Trust in UK Results were mixed in participant outcomes and a likelihood of acceptability of the intervention. This indicates the need for a larger scale feasibility test to explore the identified benefits and challenges of implementing NECT in NHS or community settings for late-onset psychosis.
Evolving graphs with semantic neutral drift
Authors: Atkinson Timothy , Plump Detlef , Stepney Susan
Published: October 2019

We introduce the concept of Semantic Neutral Drift (SND) for genetic programming (GP), where we exploit equivalence laws to design semantics preserving mutations guaranteed to preserve individuals’ fitness scores. A number of digital circuit benchmark problems have been implemented with rule-based graph programs and empirically evaluated, demonstrating quantitative improvements in evolutionary performance. Analysis reveals that the benefits of the designed SND reside in more complex processes than simple growth of individuals, and that there are circumstances where it is beneficial to choose otherwise detrimental parameters for a GP system if that facilitates the inclusion of SND.
Evaluations as a decent knowledge base? Describing and explaining the quality of the European Commission’s ex-post legislative evaluations
Authors: van Voorst Stijn , Mastenbroek Ellen
Published: October 2019

Evaluations are a potentially important tool for democratic governments: they provide a basis for accountability and policy learning. To contribute to these key functions, evaluations must be of sufficient methodological quality. However, this quality is threatened by both political influences and technical complexities. This article describes and explains the variance in the quality of ex-post legislative (EPL) evaluations conducted by the European Commission, which is a frontrunner in this realm. A number of potential political and technical explanations of evaluation quality are tested with a unique, self-constructed dataset of 153 EPL evaluations. The results show that the Commission’s EPL evaluations usually apply a robust methodology, while the clarity of their scope, the accuracy of their data and the foundations of their conclusions are problematic. The variance in this quality is mainly explained by the type of evaluator: EPL evaluations conducted by external actors are of higher quality than evaluations conducted internally by the Commission.
The use of recovery time in timetables: rail passengers’ preferences and valuation relative to travel time and delays
Authors: Ojeda-Cabral Manuel , Shires Jeremy , Wardman Mark , Teklu Fitsum , Harris Nigel
Published: October 2019

Recovery time in the rail industry is the additional time that is included in train timetables over and above the minimum journey time necessary often with the explicit aim of improving punctuality. Recovery time is widely used in railways in a number of countries but prior to this study there has been no investigation of the rail users’ point of view. Perceived recovery time, such as being held outside stations and prolonged stops at stations, might have some premium valuation due to the frustration caused. If perceived recovery time in train timetables does carry a premium, then the benefits of improved punctuality achieved by it will be reduced. This paper is the first to investigate passengers’ views and preferences on the use of recovery time. We summarise the findings of a large study and provide estimates of passengers’ valuations of recovery time, both relative to in-vehicle time and late time, that can be used for economic appraisal purposes. Overall, we find most passengers support the use of recovery time but the context is important. Only 13% of users disapprove of its use as a tool to reduce lateness. The estimated premia vary by demand characteristics and are significant in some contexts, although on average are of a small magnitude. The applicability of the estimates is demonstrated through the appraisal of an actual scheme in the UK. We observe that the introduction of more recovery time along with the subsequent improvement in reliability can lead to significant reductions in generalised journey time, even when recovery time carries a valuation premium. We must however strike a word of caution since we note that there were higher than expected proportions of non-traders in the survey which may have affected the results; future studies into the topic should look to minimise the proportion of non-traders. This study provides valuable and necessary first steps in this challenging topic.