bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efflux pump activity potentiates the evolution of antibiotic resistance across S. aureus isolates
Authors: Papkou Andrei , Hedge Jessica , Kapel Natalia , Young Bernadette , MacLean R. Craig 
Published: August 2020

AbstractThe rise of antibiotic resistance in many bacterial pathogens has been driven by the spread of a few successful strains, suggesting that some bacteria are genetically pre-disposed to evolving resistance. Here, we test this hypothesis by challenging a diverse set of 222 isolates ofStaphylococcus aureuswith the antibiotic ciprofloxacin in a large-scale evolution experiment. We find that a single efflux pump,norA, causes widespread variation in evolvability across isolates. ElevatednorAexpression potentiates evolution by increasing the fitness benefit provided by DNA topoisomerase mutations under ciprofloxacin treatment. Amplification ofnorAprovides a further mechanism of rapid evolution in isolates from the CC398 lineage. Crucially, chemical inhibition of NorA effectively prevents the evolution of resistance in all isolates. Our study shows that pre-existing genetic diversity plays a key role in shaping resistance evolution, and it may be possible to predict which strains are likely to evolve resistance and to optimize inhibitor use to prevent this outcome.
Quantitative evaluation of protective antibody response induced by hepatitis E vaccine in humans
Authors: Wen Gui-Ping , He Linling , Tang Zi-Min , Wang Si-Ling , Zhang Xu , Chen Yuan-Zhi , Lin Xiaohe , Liu Chang , Chen Jia-Xin , Ying Dong , Chen Zi-Hao , Wang Ying-Bin , Luo Wen-Xin , Huang Shou-Jie , Li Shao-Wei , Zhang Jun , Zheng Zi-Zheng , Zhu Jiang , Xia Ning-Shao 
Published: August 2020

AbstractEfficacy evaluation through human trials is crucial for advancing a vaccine candidate to clinics. Next-generation sequencing (NGS) can be used to quantify B cell repertoire response and trace antibody lineages during vaccination. Here, we demonstrate this application with a case study of Hecolin®, the licensed vaccine for hepatitis E virus (HEV). Four subjects are administered the vaccine following a standard three-dose schedule. Vaccine-induced antibodies exhibit a high degree of clonal diversity, recognize five conformational antigenic sites of the genotype 1 HEV p239 antigen, and cross-react with other genotypes. Unbiased repertoire sequencing is performed for seven time points over six months of vaccination, with maturation pathways characterize for a set of vaccine-induced antibodies. In addition to dynamic repertoire profiles, NGS analysis reveals differential patterns of HEV-specific antibody lineages and highlights the necessity of the long vaccine boost. Together, our study presents a quantitative strategy for vaccine evaluation in small-scale human studies.
Structure-based evolution of a promiscuous inhibitor to a selective stabilizer of protein–protein interactions
Authors: Sijbesma Eline , Visser Emira , Plitzko Kathrin , Thiel Philipp , Milroy Lech-Gustav , Kaiser Markus , Brunsveld Luc , Ottmann Christian 
Published: August 2020

AbstractThe systematic stabilization of protein–protein interactions (PPI) has great potential as innovative drug discovery strategy to target novel and hard-to-drug protein classes. The current lack of chemical starting points and focused screening opportunities limits the identification of small molecule stabilizers that engage two proteins simultaneously. Starting from our previously described virtual screening strategy to identify inhibitors of 14-3-3 proteins, we report a conceptual molecular docking approach providing concrete entries for discovery and rational optimization of stabilizers for the interaction of 14-3-3 with the carbohydrate-response element-binding protein (ChREBP). X-ray crystallography reveals a distinct difference in the binding modes between weak and general inhibitors of 14-3-3 complexes and a specific, potent stabilizer of the 14-3-3/ChREBP complex. Structure-guided stabilizer optimization results in selective, up to 26-fold enhancement of the 14-3-3/ChREBP interaction. This study demonstrates the potential of rational design approaches for the development of selective PPI stabilizers starting from weak, promiscuous PPI inhibitors.
Enhancing myocardial repair with CardioClusters
Authors: Monsanto Megan M. , Wang Bingyan J. , Ehrenberg Zach R. , Echeagaray Oscar , White Kevin S. , Alvarez Roberto , Fisher Kristina , Sengphanith Sharon , Muliono Alvin , Gude Natalie A. , Sussman Mark A. 
Published: August 2020

AbstractCellular therapy to treat heart failure is an ongoing focus of intense research, but progress toward structural and functional recovery remains modest. Engineered augmentation of established cellular effectors overcomes impediments to enhance reparative activity. Such ‘next generation’ implementation includes delivery of combinatorial cell populations exerting synergistic effects. Concurrent isolation and expansion of three distinct cardiac-derived interstitial cell types from human heart tissue, previously reported by our group, prompted design of a 3D structure that maximizes cellular interaction, allows for defined cell ratios, controls size, enables injectability, and minimizes cell loss. Herein, mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs) and c-Kit+cardiac interstitial cells (cCICs) when cultured together spontaneously form scaffold-free 3D microenvironments termed CardioClusters. scRNA-Seq profiling reveals CardioCluster expression of stem cell-relevant factors, adhesion/extracellular-matrix molecules, and cytokines, while maintaining a more native transcriptome similar to endogenous cardiac cells. CardioCluster intramyocardial delivery improves cell retention and capillary density with preservation of cardiomyocyte size and long-term cardiac function in a murine infarction model followed 20 weeks. CardioCluster utilization in this preclinical setting establish fundamental insights, laying the framework for optimization in cell-based therapeutics intended to mitigate cardiomyopathic damage.
A nature-inspired hydrogen-bonded supramolecular complex for selective copper ion removal from water
Authors: Bui Ngoc T. , Kang Hyungmook , Teat Simon J. , Su Gregory M. , Pao Chih-Wen , Liu Yi-Sheng , Zaia Edmond W. , Guo Jinghua , Chen Jeng-Lung , Meihaus Katie R. , Dun Chaochao , Mattox Tracy M. , Long Jeffrey R. , Fiske Peter , Kostecki Robert , Urban Jeffrey J. 
Published: August 2020

AbstractHerein, we present a scalable approach for the synthesis of a hydrogen-bonded organic–inorganic framework via coordination-driven supramolecular chemistry, for efficient remediation of trace heavy metal ions from water. In particular, using copper as our model ion of interest and inspired by nature’s use of histidine residues within the active sites of various copper binding proteins, we design a framework featuring pendant imidazole rings and copper-chelating salicylaldoxime, known as zinc imidazole salicylaldoxime supramolecule. This material is water-stable and exhibits unprecedented adsorption kinetics, up to 50 times faster than state-of-the-art materials for selective copper ion capture from water. Furthermore, selective copper removal is achieved using this material in a pH range that was proven ineffective with previously reported metal–organic frameworks. Molecular dynamics simulations show that this supramolecule can reversibly breathe water through lattice expansion and contraction, and that water is initially transported into the lattice through hopping between hydrogen-bond sites.
Artificial van der Waals hybrid synapse and its application to acoustic pattern recognition
Authors: Seo Seunghwan , Kang Beom-Seok , Lee Je-Jun , Ryu Hyo-Jun , Kim Sungjun , Kim Hyeongjun , Oh Seyong , Shim Jaewoo , Heo Keun , Oh Saeroonter , Park Jin-Hong 
Published: August 2020

AbstractBrain-inspired parallel computing, which is typically performed using a hardware neural-network platform consisting of numerous artificial synapses, is a promising technology for effectively handling large amounts of informational data. However, the reported nonlinear and asymmetric conductance-update characteristics of artificial synapses prevent a hardware neural-network from delivering the same high-level training and inference accuracies as those delivered by a software neural-network. Here, we developed an artificial van-der-Waals hybrid synapse that features linear and symmetric conductance-update characteristics. Tungsten diselenide and molybdenum disulfide channels were used selectively to potentiate and depress conductance. Subsequently, via training and inference simulation, we demonstrated the feasibility of our hybrid synapse toward a hardware neural-network and also delivered high recognition rates that were comparable to those delivered using a software neural-network. This simulation involving the use of acoustic patterns was performed with a neural network that was theoretically formed with the characteristics of the hybrid synapses.
Neuronal adenosine A2A receptors signal ergogenic effects of caffeine
Authors: Aguiar Aderbal S. , Speck Ana Elisa , Canas Paula M. , Cunha Rodrigo A. 
Published: August 2020

AbstractCaffeine is one of the most used ergogenic aid for physical exercise and sports. However, its mechanism of action is still controversial. The adenosinergic hypothesis is promising due to the pharmacology of caffeine, a nonselective antagonist of adenosine A1 and A2A receptors. We now investigated A2AR as a possible ergogenic mechanism through pharmacological and genetic inactivation. Forty-two adult females (20.0 ± 0.2 g) and 40 male mice (23.9 ± 0.4 g) from a global and forebrain A2AR knockout (KO) colony ran an incremental exercise test with indirect calorimetry (V̇O2 and RER). We administered caffeine (15 mg/kg, i.p., nonselective) and SCH 58261 (1 mg/kg, i.p., selective A2AR antagonist) 15 min before the open field and exercise tests. We also evaluated the estrous cycle and infrared temperature immediately at the end of the exercise test. Caffeine and SCH 58621 were psychostimulant. Moreover, Caffeine and SCH 58621 were ergogenic, that is, they increased V̇O2max, running power, and critical power, showing that A2AR antagonism is ergogenic. Furthermore, the ergogenic effects of caffeine were abrogated in global and forebrain A2AR KO mice, showing that the antagonism of A2AR in forebrain neurons is responsible for the ergogenic action of caffeine. Furthermore, caffeine modified the exercising metabolism in an A2AR-dependent manner, and A2AR was paramount for exercise thermoregulation.
Modeling and scale-bridging using machine learning: nanoconfinement effects in porous media
Authors: Lubbers Nicholas , Agarwal Animesh , Chen Yu , Son Soyoun , Mehana Mohamed , Kang Qinjun , Karra Satish , Junghans Christoph , Germann Timothy C. , Viswanathan Hari S. 
Published: August 2020

AbstractFine-scale models that represent first-principles physics are challenging to represent at larger scales of interest in many application areas. In nanoporous media such as tight-shale formations, where the typical pore size is less than 50 nm, confinement effects play a significant role in how fluids behave. At these scales, fluids are under confinement, affecting key properties such as density, viscosity, adsorption, etc. Pore-scale Lattice Boltzmann Methods (LBM) can simulate flow in complex pore structures relevant to predicting hydrocarbon production, but must be corrected to account for confinement effects. Molecular dynamics (MD) can model confinement effects but is computationally expensive in comparison. The hurdle to bridging MD with LBM is the computational expense of MD simulations needed to perform this correction. Here, we build a Machine Learning (ML) surrogate model that captures adsorption effects across a wide range of parameter space and bridges the MD and LBM scales using a relatively small number of MD calculations. The model computes upscaled adsorption parameters across varying density, temperature, and pore width. The ML model is 7 orders of magnitude faster than brute force MD. This workflow is agnostic to the physical system and could be generalized to further scale-bridging applications.
Understanding the spatial–temporal variation of human footprint in Jiangsu Province, China, its anthropogenic and natural drivers and potential implications
Authors: Shen Feixue , Yang Lin , He Xianglin , Zhou Chenghu , Adams Jonathan M. 
Published: August 2020

AbstractUnderstanding the spatial and temporal patterns of human pressures provides a foundation for understanding interactions between human and environment and managing human activities for a sustainable development. This study is the first attempt focused within China at calculating the spatial–temporal human footprint and its driving forces in a highly urbanized area with intensive human activities. Population, land use, night-time lights, and road impacts were used to generate human footprint maps of Jiangsu Province for 2000, 2010 and 2015 with a resolution of 1 km * 1 km. Five natural drivers and four anthropogenic drivers were employed to construct generalized additive models for explaining the spatial variation of human footprint and its change. It shows that a large difference is between the human footprint in northern and southern Jiangsu, and the pattern of human pressures conforms to the “Matthew effect”, with spatial aggregation of high human footprint areas accelerating. Slope, industrialization level are significant in explaining the spatial variation of human footprint in 2000, 2010 and 2015. The effect of natural drivers decreases for explaining the human footprint over time. Furthermore, annual precipitation, mean annual temperature and urban per capita disposable income are also significant drivers for human footprint in 2010 and 2015. And the increasing of human footprint slows with increasing of industrialization level. The difference of industrialization level and urban income between northern and southern Jiangsu mainly caused different driving pattern for human footprint and its change. Our study has generated new insights on the interaction pattern between human and nature in highly developed regions based on the human footprint concept, and can provide references for managing human activities in similar regions rapid socioeconomic development.
Validation of a patient-specific system for mandible-first bimaxillary surgery: ramus and implant positioning precision assessment and guide design comparison
Authors: Badiali Giovanni , Bevini Mirko , Ruggiero Federica , Cercenelli Laura , Lovero Elisa , De Simone Elisabetta , Rucci Paola , Bianchi Alberto , Marchetti Claudio 
Published: August 2020

AbstractIn orthognathic surgery, the use of patient-specific osteosynthesis devices is a novel approach used to transfer the virtual surgical plan to the patient. The aim of this study is to analyse the quality of mandibular anatomy reproduction using a mandible-first mandibular-PSI guided procedure on 22 patients. Three different positioning guide designs were compared in terms of osteosynthesis plate positioning and mandibular anatomical outcome. PSIs and positioning guides were designed according to virtual surgical plan and 3D printed using biocompatible materials. A CBCT scan was performed 1 month after surgery and postoperative mandibular models were segmented for comparison against the surgical plan. A precision comparison was carried out among the three groups. Correlations between obtained rami and plates discrepancies and between planned rami displacements and obtained rami discrepancies were calculated. Intraoperatively, all PSIs were successfully applied. The procedure was found to be accurate in planned mandibular anatomy reproduction. Different guide designs did not differ in mandibular outcome precision. Plate positional discrepancies influenced the corresponding ramus position, mainly in roll angle and vertical translation. Ramus planned displacement was found to be a further potential source of inaccuracy, possibly due to osteosynthesis surface interference.
Utilitarianism in minimal-group decision making is less common than equality-based morality, mostly harm-oriented, and rarely impartial
Authors: Roets Arne , Bostyn Dries H. , De keersmaecker Jonas , Haesevoets Tessa , Van Assche Jasper , Van Hiel Alain 
Published: August 2020

AbstractIn the study of utilitarian morality, the sacrificial dilemma paradigm has been the dominant approach for years. However, to address some of the most pressing issues in the current research literature, the present studies adopt an alternative approach by using a minimal group paradigm in which participants have to make decisions about the allocation of resources. This approach allows not only to pit utilitarianism against equality-based morality, but also to study these modes of morality for both harm and benefit, and to directly address the role of group identity affecting the (im)partial nature of ‘utilitarian’ (i.e., outcome maximizing) decisions. In our experiments, across four different samples (total N = 946), we demonstrate that although participants generally prefer equality-based allocations over maximizing distributions, outcome maximizing choices become more prevalent when they served to minimize harm compared to maximizing benefit. Furthermore, reducing the objective value of the equal distribution outcomes further prompts participants to adopt a more utilitarian approach in situations involving harm, but has little effect in situations where benefits have to be distributed. Finally, the introduction of (minimal) group identity consistently demonstrates that decisions that maximize the overall outcome are more likely if they also serve the ingroup compared to when they rather serve the outgroup. We discuss how these findings have meaningful implications that may be especially relevant for recent movements that advocate a utilitarian approach to charity, and for our understanding of (im)partiality in lay people’s ‘utilitarian’ decision making.
Lipid membrane templated misfolding and self-assembly of intrinsically disordered tau protein
Authors: Majewski Jaroslaw , Jones Emmalee M. , Vander Zanden Crystal M. , Biernat Jacek , Mandelkow Eckhard , Chi Eva Y. 
Published: August 2020

AbstractThe aggregation of the intrinsically disordered tau protein into highly ordered β-sheet-rich fibrils is implicated in the pathogenesis of a range of neurodegenerative disorders. The mechanism of tau fibrillogenesis remains unresolved, particularly early events that trigger the misfolding and assembly of the otherwise soluble and stable tau. We investigated the role the lipid membrane plays in modulating the aggregation of three tau variants, the largest isoform hTau40, the truncated construct K18, and a hyperphosphorylation-mimicking mutant hTau40/3Epi. Despite being charged and soluble, the tau proteins were also highly surface active and favorably interacted with anionic lipid monolayers at the air/water interface. Membrane binding of tau also led to the formation of a macroscopic, gelatinous layer at the air/water interface, possibly related to tau phase separation. At the molecular level, tau assembled into oligomers composed of ~ 40 proteins misfolded in a β-sheet conformation at the membrane surface, as detected by in situ synchrotron grazing-incidence X-ray diffraction. Concomitantly, membrane morphology and lipid packing became disrupted. Our findings support a general tau aggregation mechanism wherein tau’s inherent surface activity and favorable interactions with anionic lipids drive tau-membrane association, inducing misfolding and self-assembly of the disordered tau into β-sheet-rich oligomers that subsequently seed fibrillation and deposition into diseased tissues.
Heteromeric Kv7.2 current changes caused by loss-of-function of KCNQ2 mutations are correlated with long-term neurodevelopmental outcomes
Authors: Lee Inn-Chi , Yang Jiann-Jou , Wong Swee-Hee , Liou Ying-Ming , Li Shuan-Yow 
Published: August 2020

AbstractPediatric epilepsy caused by KCNQ2 mutations can manifest benign familial neonatal convulsions (BFNC) to neonatal-onset epileptic encephalopathy (EE). Patients might manifest mild to profound neurodevelopmental disabilities. We analysed c.853C > A (P285T) and three mutations that cause KCNQ2 protein changes in the 247 position: c.740C > T (S247L), c.740C > A (S247X), and c.740C > G (S247W). S247L, S247W, and P285T cause neonatal-onset EE and poor neurodevelopmental outcomes; S247X cause BFNC and normal outcome. We investigated the phenotypes correlated with human embryonic kidney 293 (HEK293) cell functional current changes. More cell-current changes and a worse conductance curve were present in the homomeric transfected S247X than in S247L, S247W, and P285T. But in the heteromeric channel, S247L, S247W and P285T had more current impairments than did S247X. The protein expressions of S247X were nonfunctional. The outcomes were most severe in S247L and S247W, and severity was correlated with heteromeric current. Current changes were more significant in cells with homomeric S247X, but currents were “rescued” after heteromeric transfection of KCNQ2 and KCNQ3. This was not the case in cells with S247L, S247W. Our findings support that homomeric current changes are common in KCNQ2 neonatal-onset EE and KCNQ2 BFNC; however, heteromeric functional current changes are correlated with long-term neurodevelopmental outcomes.
Precise 3D modulation of electro-optical parameters during neurotransmitter uncaging experiments with neurons in vitro
Authors: Cozzolino Marco , Bazzurro Virginia , Gatta Elena , Bianchini Paolo , Angeli Elena , Robello Mauro , Diaspro Alberto 
Published: August 2020

AbstractRuthenium–bipyridinetriphenylphosphine–GABA (RuBi–GABA) is a caged compound that allows studying the neuronal transmission in a specific region of a neuron. The inhibitory neurotransmitter γ-aminobutyric acid (GABA) is bound to a caged group that blocks the interaction of the neurotransmitter with its receptor site. Following linear—one-photon (1P)—and non-linear—multi-photon—absorption of light, the covalent bond of the caged molecule is broken, and GABA is released. Such a controlled release in time and space allows investigating the interaction with its receptor in four dimensions (X,Y,Z,t). Taking advantage of this strategy, we succeeded in addressing the modulation of GABAA in rat cerebellar neurons by coupling the photoactivation process, by confocal or two-photon excitation microscopy, with the electrophysiological technique of the patch-clamp in the whole-cell configuration. Key parameters have been comprehensively investigated and correlated in a temporally and spatially confined way, namely: photoactivation laser power, time of exposure, and distance of the uncaging point from the cell of interest along the X, Y, Z spatial coordinates. The goal of studying specific biological events as a function of controlled physical parameters has been achieved.