bluuebunny/crossref_metadata_2025_split huggingface dataset:
Potent and specific MTH1 inhibitors targeting gastric cancer
Authors: Zhou Wenjuan , Ma Liying , Yang Jing , Qiao Hui , Li Lingyu , Guo Qian , Ma Jinlian , Zhao Lijuan , Wang Junwei , Jiang Guozhong , Wan Xiangbin , Adam Goscinski Mariusz , Ding Lina , Zheng Yichao , Li Wencai , Liu Hongmin , Suo Zhenhe , Zhao Wen 
Published: June 2019

AbstractHuman mutT homolog 1(MTH1), the oxidized dNTP pool sanitizer enzyme, has been reported to be highly expressed in various malignant tumors. However, the oncogenic role of MTH1 in gastric cancer remains to be determined. In the current study, we found that MTH1 was overexpressed in human gastric cancer tissues and cells. Using an in vitro MTH1 inhibitor screening system, the compounds available in our laboratory were screened and the small molecules containing 5-cyano-6-phenylpyrimidine structure were firstly found to show potently and specifically inhibitory effect on MTH1, especially compound MI-743 with IC50 = 91.44 ± 1.45 nM. Both molecular docking and target engagement experiments proved that MI-743 can directly bind to MTH1. Moreover, MI-743 could not only inhibit cell proliferation in up to 16 cancer cell lines, especially gastric cancer cells HGC-27 and MGC-803, but also significantly induce MTH1-related 8-oxo-dG accumulation and DNA damage. Furthermore, the growth of xenograft tumours derived by injection of MGC-803 cells in nude mice was also significantly inhibited by MI-743 treatment. Importantly, MTH1 knockdown by siRNA in those two gastric cancer cells exhibited the similar findings. Our findings indicate that MTH1 is highly expressed in human gastric cancer tissues and cell lines. Small molecule MI-743 with 5-cyano-6-phenylpyrimidine structure may serve as a novel lead compound targeting the overexpressed MTH1 for gastric cancer treatment.
Detection of DNA base modifications by deep recurrent neural network on Oxford Nanopore sequencing data
Authors: Liu Qian , Fang Li , Yu Guoliang , Wang Depeng , Xiao Chuan-Le , Wang Kai 
Published: June 2019

AbstractDNA base modifications, such as C5-methylcytosine (5mC) and N6-methyldeoxyadenosine (6mA), are important types of epigenetic regulations. Short-read bisulfite sequencing and long-read PacBio sequencing have inherent limitations to detect DNA modifications. Here, using raw electric signals of Oxford Nanopore long-read sequencing data, we design DeepMod, a bidirectional recurrent neural network (RNN) with long short-term memory (LSTM) to detect DNA modifications. We sequence a human genome HX1 and a Chlamydomonas reinhardtii genome using Nanopore sequencing, and then evaluate DeepMod on three types of genomes (Escherichia coli, Chlamydomonas reinhardtii and human genomes). For 5mC detection, DeepMod achieves average precision up to 0.99 for both synthetically introduced and naturally occurring modifications. For 6mA detection, DeepMod achieves ~0.9 average precision on Escherichia coli data, and have improved performance than existing methods on Chlamydomonas reinhardtii data. In conclusion, DeepMod performs well for genome-scale detection of DNA modifications and will facilitate epigenetic analysis on diverse species.
Ultra-selective ligand-driven separation of strategic actinides
Authors: Deblonde Gauthier J.-P. , Ricano Abel , Abergel Rebecca J. 
Published: June 2019

AbstractMetal ion separations are critical to numerous fields, including nuclear medicine, waste recycling, space exploration, and fundamental research. Nonetheless, operational conditions and performance are limited, imposing compromises between recovery, purity, and cost. Siderophore-inspired ligands show unprecedented charge-based selectivity and compatibility with harsh industry conditions, affording excellent separation efficiency, robustness and process control. Here, we successfully demonstrate a general separation strategy on three distinct systems, for Ac, Pu, and Bk purification. Separation factors (SF) obtained with model compound 3,4,3-LI(1,2-HOPO) are orders of magnitude higher than with any other ligand currently employed: 106 between Ac and relevant metal impurities, and over 108 for redox-free Pu purification against uranyl ions and trivalent actinides or fission products. Finally, a one-step separation method (SF > 3 × 106 and radiopurity > 99.999%) enables the isolation of Bk from adjacent actinides and fission products. The proposed approach offers a paradigm change for the production of strategic elements.
Emergent bound states and impurity pairs in chemically doped Shastry-Sutherland system
Authors: Shi Zhenzhong , Steinhardt William , Graf David , Corboz Philippe , Weickert Franziska , Harrison Neil , Jaime Marcelo , Marjerrison Casey , Dabkowska Hanna A. , Mila Frédéric , Haravifard Sara 
Published: June 2019

AbstractImpurities often play a defining role in the ground states of frustrated quantum magnets. Studies of their effects are crucial in understanding of the phase diagram in these materials. SrCu2(BO3)2, an experimental realization of the Shastry-Sutherland (SS) lattice, provides a unique model system for such studies using both experimental and numerical approaches. Here we report effects of impurities on the crystals of bound states, and doping-induced emergent ground states in Mg-doped SrCu2(BO3)2, which remain stable in high magnetic fields. Using four complementary magnetometry techniques and theoretical simulations, a rich impurity-induced phenomenology at high fields is discovered. The results demonstrate a rare example in which even a small doping concentration interacts strongly with both triplets and bound states of triplets, and thus plays a significant role in the magnetization process even at high magnetic fields. Our findings provide insights into the study of impurity effects in geometrically frustrated quantum magnets.
Experimental study on removing heavy metals from the municipal solid waste incineration fly ash with the modified electrokinetic remediation device
Authors: Ji Hong , Huang Weiqiu , Xing Zhixiang , Zuo Jiaqi , Wang Zhuang , Yang Ke 
Published: June 2019

AbstractThe MSWI fly ash which contains a large number of heavy metal substances is a subsidiary product of waste incineration power generation technology. If the MSWI fly ash is disposed improperly, heavy metal pollutants will pose a great threat to environmental safety and human health. Based on the technology of electrokinetic remediation, the feasibility of removing heavy metal pollutants from the MSWI fly ash using a modified electrokinetic remediation device - cylinder device was evaluated in this study. Differing from the traditional cuboid device with the volume ratio of the cathode chamber to the anode chamber being 1:1, the volume ratio of the cathode chamber to the anode chamber of the cylinder device was 16:1. Changes in parameters, such as pH values and conductivity in the cathode and the anode chambers as well as current and voltage in the sample area were analysed under the voltage gradient of 2 V/cm. After the experiment, the average removal efficiencies for Zn, Pb, Cd and Cu in the sample area were 53.2%, 31.4%, 42.3% and 30.7%, respectively. It indicates that the cylinder device is effective in removing heavy metals from the MSWI fly ash. Adopting the cylinder device for the experimental study on the electrokinetic remediation technology could provide a better way of thinking for the future engineering practices and applications.
Surface modification of gold nanoparticles with neuron-targeted exosome for enhanced blood–brain barrier penetration
Authors: Khongkow Mattaka , Yata Teerapong , Boonrungsiman Suwimon , Ruktanonchai Uracha Rungsardthong , Graham Duncan , Namdee Katawut 
Published: June 2019

AbstractGold nanoparticles (AuNPs) have been extensively used as nanomaterials for theranostic applications due to their multifunctional characteristics in therapeutics, imaging, and surface modification. In this study, the unique functionalities of exosome-derived membranes were combined with synthetic AuNPs for targeted delivery to brain cells. Here, we report the surface modification of AuNPs with brain-targeted exosomes derived from genetically engineered mammalian cells by using the mechanical method or extrusion to create these novel nanomaterials. The unique targeting properties of the AuNPs after fabrication with the brain-targeted exosomes was demonstrated by their binding to brain cells under laminar flow conditions as well as their enhanced transport across the blood brain barrier. In a further demonstration of their ability to target brain cells, in vivo bioluminescence imaging revealed that targeted-exosome coated AuNPs accumulated in the mouse brain after intravenous injection. The surface modification of synthetic AuNPs with the brain-targeted exosome demonstrated in this work represents a highly novel and effective strategy to provide efficient brain targeting and shows promise for the future in using modified AuNPs to penetrate the brain.
Robust and accurate detection and sizing of repeats within the DMPK gene using a novel TP-PCR test
Authors: Leferink Maike , Wong Daphne P. W. , Cai Shiwei , Yeo Minli , Ho Jocelin , Lian Mulias , Kamsteeg Erik-Jan , Chong Samuel S. , Haer-Wigman Lonneke , Guan Ming 
Published: June 2019

AbstractMyotonic dystrophy type 1 is a multisystem disorder caused by the expansion of a trinucleotide repeat in the DMPK gene. In this study we evaluated the performance of the FastDM1TMDMPK sizing kit in myotonic dystrophy type 1 testing. This commercially available triplet repeat-primed PCR based kit was validated using reference and clinical samples. Based on testing with 19 reference samples, the assay yielded repeat sizes within three repeats from the consensus reference length, demonstrating an accuracy of 100%. Additionally, the assay generated consistent repeat size information with a concentration range of template-DNA, and upon repetition and reproduction (CV 0.36% to 0.41%). Clinical performance was established with 235 archived prenatal and postnatal clinical samples, yielding results of 100% sensitivity (95% CI, 97.29% to 100%) and 100% specificity (95% CI, 96.19% to 100%) in classifying the samples into the respective genotype groups of 5–35 (normal), 36–50 (non-pathogenic pre-expansion), 51–150 (unstable intermediate-sized pathogenic) or >150 (unstable pathogenic) CTG repeats, respectively. Furthermore, the assay identified interrupted repeat expansions in all samples known to have interruptions, and also identified interruptions in a subset of the clinical samples.
Prefrontal-posterior coupling mediates transitions between emotional states and influences executive functioning
Authors: Hao Yu , Yao Lin , Smith Derek M. , Sorel Edward , Anderson Adam K. , Schumacher Eric H. , Evans Gary W. 
Published: June 2019

AbstractEmotions often result from fluctuating experiences with self-regulation unfolding over time. However, most research has been focused on neural responses to static, affective stimuli. We studied emotion transitions, which correspond to dynamic conditions of varying affective valence or intensities. Functional coupling of prefrontal and posterior cortex (EEG coherence) was recorded during exposure to stable versus changing emotion-eliciting images (static vs. dynamic conditions). Prefrontal-posterior coupling was decreased in the dynamic conditions compared to the static conditions. A decrease in prefrontal-posterior coupling implies less control of the prefrontal cortex over perceptual information, which may allow the brain to become more affected by emotional fluctuations. We also assessed the aftereffect of EEG coherence on executive functioning, utilizing the flanker task. Among individuals reporting higher chronic stress, executive functioning decreased after dynamic conditions. This decrease in executive functioning was mediated by the decrease in prefrontal-posterior coupling in the dynamic conditions. These findings suggest that the strength of prefrontal-posterior coupling is not only related to emotional transitions but also to executive functioning. The deterioration of executive functioning after dynamic emotional processing may reflect the additional cognitive effort required to process dynamic shifts in affective stimuli, and this relationship is exacerbated by chronic stress.
Mapping the allosteric network within a SH3 domain
Authors: Malagrinò Francesca , Troilo Francesca , Bonetti Daniela , Toto Angelo , Gianni Stefano 
Published: June 2019

AbstractSH3 domains are very abundant protein-protein interactions modules, involved in the regulation of several cellular processes. Whilst they have been associated to allosteric communication pathways between contiguous domains in multi-domain proteins, there is lack of information regarding the intra-domain allosteric cross-talk within the SH3 moiety. Here we scrutinize the presence of an allosteric network in the C-terminal SH3 domain of Grb2 protein, upon binding the Grb2-associated binding 2 protein. To explore allostery, we performed double mutant cycle analysis, a powerful quantitative approach based on mutagenesis in conjunction with kinetic experiments. Data reveal the presence of an unexpected allosteric sparse network that modulates the affinity between the SH3 domain and its physiological partner.
Synchronization of megathrust earthquakes to periodic slow slip events in a single-degree-of-freedom spring-slider model
Authors: Ohtani Makiko , Kame Nobuki , Nakatani Masao 
Published: June 2019

AbstractRecently recognized slow slip events (SSEs) recurring in the deeper extensions of seismogenic zones along plate boundaries are drawing attention to their potential for triggering megathrust earthquakes that rupture the entire seismogenic zone. We describe how earthquakes simulated in a single-degree-of-freedom model are synchronized to the rhythm of imposed periodic SSEs. The time lag tQ from the one most recent SSE to a seismic event varies with system parameters and may take a broad range of eligible values between 0 and TSSE (SSE recurrence period). Earthquakes were found to synchronize with SSEs in various patterns depending on the proportion of SSE-driven loading within an SSE cycle, the recurrence period of the SSEs, and the duration of the SSEs, although synchronization itself remained a prevalent feature. Asynchrony was found only for long SSE durations.
Cultural variation between neighbouring communities of chimpanzees at Gombe, Tanzania
Authors: Pascual-Garrido Alejandra 
Published: June 2019

AbstractComparative animal studies have revealed the existence of inter-group differences in socially learned behaviours – so-called cultural variations. However, most research has drawn on geographically and thus environmentally separated populations, rendering it difficult to exclude genetic or ecological influences. To circumvent this problem, the behaviour of neighbouring groups from the same population can be juxtaposed - an approach which in wild chimpanzees (Pan troglodytes) has revealed cultural differences in the use of nut-cracking and ant-dipping tools. Here I apply archaeological methods to extend this approach to compare the qualities of termite fishing tools used by wild chimpanzees by comparing the neighbouring Kasekela and Mitumba communities at Gombe Stream National Park, Tanzania. While no identifiable differences existed between the available plant species and associated vegetal components, members of the Kasekela community selected a larger array of raw materials and manufactured significantly longer and wider tools compared with the Mitumba community. Thus, cultural knowledge is reflected in differentiated behaviour on a small spatial scale. This study emphasizes the use of archaeological methods to identify cultural variation among living chimpanzee communities, adding to the growing research operating within the new field of Primate Archaeology.
One-step procedure for the preparation of functional polysaccharide/fatty acid multilayered coatings
Authors: Micciulla Samantha , Hayward Dominic W. , Gerelli Yuri , Panzarella Alain , von Klitzing Regine , Gradzielski Michael , Chiappisi Leonardo 
Published: June 2019

AbstractSoft, stratified, amphiphilic systems are recurrent motifs in nature, e.g., in myelin sheaths or thylakoid stacks, and synthetic analogues are increasingly being exploited in the areas of biocatalysis, biosensing, and drug delivery. The synthesis of such complex multilayered systems usually requires lengthy preparation protocols. Here, we demonstrate the formation of multilayered fatty acid/polysaccharide thin films prepared via a single step protocol, which exploits the spontaneous self-assembly of the components into vesicular systems in aqueous solution. The solutions are characterized by light and neutron scattering experiments and the thin films by neutron reflectometry, optical ellipsometry, atomic force microscopy, and x-ray diffraction. The thin films exhibit structural features with sub-10 nm dimensions, stemming from the ordered sequence of hydrophilic and hydrophobic layers and respond strongly to changes in ambient humidity. Using this approach, films with a total thickness varying from tens to hundreds of nanometers can be easily prepared.
The histidine-rich loop in the extracellular domain of ZIP4 binds zinc and plays a role in zinc transport
Authors: Zhang Tuo , Kuliyev Eziz , Sui Dexin , Hu Jian 
Published: June 2019

Abstract
The Zrt-/Irt-like protein (ZIP) family mediates zinc influx from extracellular space or intracellular vesicles/organelles, playing a central role in systemic and cellular zinc homeostasis. Out of the 14 family members encoded in human genome, ZIP4 is exclusively responsible for zinc uptake from dietary food and dysfunctional mutations of ZIP4 cause a life-threatening genetic disorder, Acrodermatitis Enteropathica (AE). About half of the missense AE-causing mutations occur within the large N-terminal extracellular domain (ECD), and our previous study has shown that ZIP4–ECD is crucial for optimal zinc uptake but the underlying mechanism has not been clarified. In this work, we examined zinc binding to the isolated ZIP4–ECD from Pteropus Alecto (black fruit bat) and located zinc-binding sites with a low micromolar affinity within a histidine-rich loop ubiquitously present in ZIP4 proteins. Zinc binding to this protease-susceptible loop induces a small and highly localized structural perturbation. Mutagenesis and functional study on human ZIP4 by using an improved cell-based zinc uptake assay indicated that the histidine residues within this loop are not involved in preselection of metal substrate but play a role in promoting zinc transport. The possible function of the histidine-rich loop as a metal chaperone facilitating zinc binding to the transport site and/or a zinc sensor allosterically regulating the transport machinery was discussed. This work helps to establish the structure/function relationship of ZIP4 and also sheds light on other metal transporters and metalloproteins with clustered histidine residues.
JAK-Inhibitoren in der Rheumatologie
Authors: Witte Torsten 
Published: June 2019

„Was ist neu?“
Wirkmechanismen der JAK-Inhibitoren JAK-Inhibitoren wirken intrazellulär und hemmen im Gegensatz zu den Biologika viele Zytokine.
Pharmakokinetik JAK-Inhibitoren werden oral eingenommen. Angesichts der Halbwertzeit von einigen Stunden sind sie gut steuerbar.
Zulassungslage Die JAK-Inhibitoren Baricitinib und Tofacitinib sind zugelassen für die Therapie der mittelschweren bis schweren aktiven RA bei erwachsenen Patienten nach erfolgloser Therapie mit DMARDs. Tofacitinib ist auch bei Colitis ulcerosa und in der Kombination mit MTX auch bei der Psoriasis-Arthritis (PsA) zugelassen.
Wirksamkeit In der Kombination mit Methotrexat (MTX) ist Tofacitinib bei der rheumatoiden Arthritis (RA) so gut wirksam wie Adalimumab mit MTX, Baricitinib war in der Kombination mit MTX sogar bei einigen Endpunkten besser als Adalimumab mit MTX. Die JAK-Inhibitoren sind auch in der Monotherapie wirksam.
Nebenwirkungen Das Nebenwirkungsprofil der JAK-Inhibitoren unterscheidet sich nicht wesentlich von dem von TNF- oder IL6-Rezeptor-Inhibitoren. Nur das Auftreten eines Herpes zoster ist während der JAK-Inhibition etwas häufiger.
Perspektive JAK-Inhibitoren hemmen zahlreiche Zytokine, die auch bei verschiedenen anderen chronischen Krankheiten eine Rolle spielen. Daher ist mit Zulassungen für weitere Indikationen zu rechnen, z. B. Kollagenosen.
Erkrankungen der Aorta: von der Aortenklappe bis zur Aortenbifurkation
Authors: Quast Christine , Zimmer Sebastian , Adam Matti , Baldus Stephan , Nickenig Georg , Kelm Malte 
Published: June 2019

Was ist neu?
Stand der Dinge Sowohl im klinischen Bereich als auch in der Forschung etabliert sich zunehmend das Konzept, die Aorta als Gesamtorgan zu betrachten, das sich von der Aortenklappe bis zur Bifurkation erstreckt.
Aortenklappenstenose Aktuell laufen erste randomisierte Studien zur Ausweitung der Indikation zum interventionellen Aortenklappenersatz (TAVI, TAVR) hin zu einem Patientenkollektiv mit niedrigem OP-Risiko. Des Weiteren hat die interventionelle Versorgung der „Low flow, low gradient“-Aortenklappenstenose eine Aufwertung im Empfehlungsgrad erhalten und die interventionelle Valve-in-valve-Prozedur Eingang in den klinischen Alltag bei der individualisierten Patientenversorgung gefunden.
Aortenklappeninsuffizienz Kathetergestützt implantierte Klappenprothesen, die dediziert zur Behandlung der isolierten Aortenklappeninsuffizienz entwickelt werden, befinden sich für dieses Krankheitsbild in der klinischen Prüfung.
Erkrankungen der Aorta ascendens und descendens Während das Screening von Aortenaneurysmen zur ambulanten Routine wird, sind Studien zum risikostratifizierten Follow-up bei zunehmend endovaskulär versorgten Patienten notwendig, um eine bedarfsgerechte Nachsorge zu ermöglichen.