bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fragment optimization for GPCRs by molecular dynamics free energy calculations: Probing druggable subpockets of the A
2A
adenosine receptor binding site
Authors: Matricon Pierre , Ranganathan Anirudh , Warnick Eugene , Gao Zhan-Guo , Rudling Axel , Lambertucci Catia , Marucci Gabriella , Ezzati Aitakin , Jaiteh Mariama , Dal Ben Diego , Jacobson Kenneth A. , Carlsson Jens 
Published: July 2017

AbstractFragment-based lead discovery is becoming an increasingly popular strategy for drug discovery. Fragment screening identifies weakly binding compounds that require optimization to become high-affinity leads. As design of leads from fragments is challenging, reliable computational methods to guide optimization would be invaluable. We evaluated using molecular dynamics simulations and the free energy perturbation method (MD/FEP) in fragment optimization for the A2A adenosine receptor, a pharmaceutically relevant G protein-coupled receptor. Optimization of fragments exploring two binding site subpockets was probed by calculating relative binding affinities for 23 adenine derivatives, resulting in strong agreement with experimental data (R2 = 0.78). The predictive power of MD/FEP was significantly better than that of an empirical scoring function. We also demonstrated the potential of the MD/FEP to assess multiple binding modes and to tailor the thermodynamic profile of ligands during optimization. Finally, MD/FEP was applied prospectively to optimize three nonpurine fragments, and predictions for 12 compounds were evaluated experimentally. The direction of the change in binding affinity was correctly predicted in a majority of the cases, and agreement with experiment could be improved with rigorous parameter derivation. The results suggest that MD/FEP will become a powerful tool in structure-driven optimization of fragments to lead candidates.
High diversity of the Ganzhou Oviraptorid Fauna increased by a new “cassowary-like” crested species
Authors: Lü Junchang , Li Guoqing , Kundrát Martin , Lee Yuong-Nam , Sun Zhenyuan , Kobayashi Yoshitsugu , Shen Caizhi , Teng Fangfang , Liu Hanfeng 
Published: July 2017

AbstractA new oviraptorid dinosaur from the Late Cretaceous of Ganzhou, bringing oviraptrotid diversity of this region to seven taxa, is described. It is characterized by a distinct cassowary-like crest on the skull, no pleurocoels on the centra from the second through fourth cervical vertebrae, a neck twice as long as the dorsal vertebral column and slightly longer than the forelimb (including the manus). Phylogenetic analysis recovers the new oviraptorid taxon, Corythoraptor jacobsi, as closely related to Huanansaurus from Ganzhou. Osteochronology suggests that the type specimen of Corythoraptor had not reached stationary growth stage but died while decreasing growth rates. The histology implies that it would correspond to an immature individual approximately eight years old. We hypothesize, based on the inner structure compared to that in modern cassowaries, that the prominent casque of Corythoraptor was a multifunction-structure utilized in display, communication and probably expression of the fitness during mating seasons.
Match between soaring modes of black kites and the fine-scale distribution of updrafts
Authors: Santos Carlos D. , Hanssen Frank , Muñoz Antonio-Román , Onrubia Alejandro , Wikelski Martin , May Roel , Silva João P. 
Published: July 2017

AbstractUnderstanding how soaring birds use updrafts at small spatial scales is important to identify ecological constraints of movement, and may help to prevent conflicts between wind-energy development and the conservation of wildlife. We combined high-frequency GPS animal tracking and fine-spatial-scale uplift modelling to establish a link between flight behaviour of soaring birds and the distribution of updrafts. We caught 21 black kites (Milvus migrans) and GPS-tracked them while flying over the Tarifa region, on the Spanish side of the Strait of Gibraltar. This region has a diverse topography and land cover, favouring a heterogeneous updraft spatial distribution. Bird tracks were segmented and classified into flight modes from motion parameters. Thermal and orographic uplift velocities were modelled from publically available remote-sensing and meteorological data. We found that birds perform circular soaring in areas of higher predicted thermal uplift and linear soaring in areas of higher predicted orographic uplift velocity. We show that updraft maps produced from publically available data can be used to predict where soaring birds will concentrate their flight paths and how they will behave in flight. We recommend the use of this methodological approach to improve environmental impact assessments of new wind-energy installations.
Multimodal Fingerprints of Resting State Networks as assessed by Simultaneous Trimodal MR-PET-EEG Imaging
Authors: Shah N. J. , Arrubla J. , Rajkumar R. , Farrher E. , Mauler J. , Kops E. Rota , Tellmann L. , Scheins J. , Boers F. , Dammers J. , Sripad P. , Lerche C. , Langen K. J. , Herzog H. , Neuner I. 
Published: July 2017

AbstractSimultaneous MR-PET-EEG (magnetic resonance imaging - positron emission tomography – electroencephalography), a new tool for the investigation of neuronal networks in the human brain, is presented here for the first time. It enables the assessment of molecular metabolic information with high spatial and temporal resolution in a given brain simultaneously. Here, we characterize the brain’s default mode network (DMN) in healthy male subjects using multimodal fingerprinting by quantifying energy metabolism via 2- [18F]fluoro-2-desoxy-D-glucose PET (FDG-PET), the inhibition – excitation balance of neuronal activation via magnetic resonance spectroscopy (MRS), its functional connectivity via fMRI and its electrophysiological signature via EEG. The trimodal approach reveals a complementary fingerprint. Neuronal activation within the DMN as assessed with fMRI is positively correlated with the mean standard uptake value of FDG. Electrical source localization of EEG signals shows a significant difference between the dorsal DMN and sensorimotor network in the frequency range of δ, θ, α and β–1, but not with β–2 and β–3. In addition to basic neuroscience questions addressing neurovascular-metabolic coupling, this new methodology lays the foundation for individual physiological and pathological fingerprints for a wide research field addressing healthy aging, gender effects, plasticity and different psychiatric and neurological diseases.
Lactate oxidation facilitates growth of Mycobacterium tuberculosis in human macrophages
Authors: Billig Sandra , Schneefeld Marie , Huber Claudia , Grassl Guntram A. , Eisenreich Wolfgang , Bange Franz-Christoph 
Published: July 2017

AbstractMycobacterium tuberculosis (Mtb) uses alveolar macrophages as primary host cells during infection. In response to an infection, macrophages switch from pyruvate oxidation to reduction of pyruvate into lactate. Lactate might present an additional carbon substrate for Mtb. Here, we demonstrate that Mtb can utilize L-lactate as sole carbon source for in vitro growth. Lactate conversion is strictly dependent on one of two potential L-lactate dehydrogenases. A knock-out mutant lacking lldD2 (Rv1872c) was unable to utilize L-lactate. In contrast, the lldD1 (Rv0694) knock-out strain was not affected in growth on lactate and retained full enzymatic activity. On the basis of labelling experiments using [U-13C3]-L-lactate as a tracer the efficient uptake of lactate by Mtb and its conversion into pyruvate could be demonstrated. Moreover, carbon flux from lactate into the TCA cycle, and through gluconeogenesis was observed. Gluconeogenesis during lactate consumption depended on the phosphoenolpyruvate carboxykinase, a key enzyme for intracellular survival, showing that lactate utilization requires essential metabolic pathways. We observed that the ΔlldD2 mutant was impaired in replication in human macrophages, indicating a critical role for lactate oxidation during intracellular growth.
Eternal non-Markovianity: from random unitary to Markov chain realisations
Authors: Megier Nina , Chruściński Dariusz , Piilo Jyrki , Strunz Walter T. 
Published: July 2017

AbstractThe theoretical description of quantum dynamics in an intriguing way does not necessarily imply the underlying dynamics is indeed intriguing. Here we show how a known very interesting master equation with an always negative decay rate [eternal non-Markovianity (ENM)] arises from simple stochastic Schrödinger dynamics (random unitary dynamics). Equivalently, it may be seen as arising from a mixture of Markov (semi-group) open system dynamics. Both these approaches lead to a more general family of CPT maps, characterized by a point within a parameter triangle. Our results show how ENM quantum dynamics can be realised easily in the laboratory. Moreover, we find a quantum time-continuously measured (quantum trajectory) realisation of the dynamics of the ENM master equation based on unitary transformations and projective measurements in an extended Hilbert space, guided by a classical Markov process. Furthermore, a Gorini-Kossakowski-Sudarshan-Lindblad (GKSL) representation of the dynamics in an extended Hilbert space can be found, with a remarkable property: there is no dynamics in the ancilla state. Finally, analogous constructions for two qubits extend these results from non-CP-divisible to non-P-divisible dynamics.
Optical Band Gap Alteration of Graphene Oxide via Ozone Treatment
Authors: Hasan Md Tanvir , Senger Brian J. , Ryan Conor , Culp Marais , Gonzalez-Rodriguez Roberto , Coffer Jeffery L. , Naumov Anton V. 
Published: July 2017

AbstractGraphene oxide (GO) is a graphene derivative that emits fluorescence, which makes GO an attractive material for optoelectronics and biotechnology. In this work, we utilize ozone treatment to controllably tune the band gap of GO, which can significantly enhance its applications. Ozone treatment in aqueous GO suspensions yields the addition/rearrangement of oxygen-containing functional groups suggested by the increase in vibrational transitions of C-O and C=O moieties. Concomitantly it leads to an initial increase in GO fluorescence intensity and significant (100 nm) blue shifts in emission maxima. Based on the model of GO fluorescence originating from sp2 graphitic islands confined by oxygenated addends, we propose that ozone-induced functionalization decreases the size of graphitic islands affecting the GO band gap and emission energies. TEM analyses of GO flakes confirm the size decrease of ordered sp2 domains with ozone treatment, whereas semi-empirical PM3 calculations on model addend-confined graphitic clusters predict the inverse dependence of the band gap energies on sp2 cluster size. This mod﻿el explains ozone-induced increase in emission energies yielding fluorescence blue shifts and helps develop an understanding of the origins of GO fluorescence emission. Furthermore, ozone treatment provides a versatile approach to controllably alter GO band gap for optoelectronics and bio-sensing applications.
CREB Regulates Distinct Adaptive Transcriptional Programs in Astrocytes and Neurons
Authors: Pardo Luis , Valor Luis Miguel , Eraso-Pichot Abel , Barco Angel , Golbano Arantxa , Hardingham Giles E. , Masgrau Roser , Galea Elena 
Published: July 2017

AbstractThe cyclic AMP response element binding protein (CREB) is a primary hub of activity-driven genetic programs in neurons controlling plasticity, neurogenesis and survival. By contrast, the gene networks coordinated by CREB in astrocytes are unknown despite the fact that the astrocytic CREB is also activity-driven and neuroprotective. Herein we identified the transcriptional programs regulated by CREB in astrocytes as compared to neurons using, as study materials, transcriptome databases of astrocyte exposed to well-known activators of CREB-dependent transcription as well as publicly available transcriptomes of neuronal cultures. Functional CREB signatures were extracted from the transcriptomes using Gene Ontology, adult-brain gene lists generated by Translating Ribosome Affinity Purification (TRAP) and CREB-target gene repositories. We found minimal overlap between CREB signatures in astrocytes and neurons. In astrocytes, the top triad of functions regulated by CREB consists of ‘Gene expression’, ‘Mitochondria’, and ‘Signalling’, while in neurons it is ‘Neurotransmission’, ‘Signalling’ and ‘Gene expression’, the latter two being represented by different genes from those in astrocytes. The newly generated databases will provide a tool to explore novel means whereby CREB impinges on brain functions requiring adaptive, long-lasting changes by coordinating transcriptional cascades in astrocytes.
Modeling of an Inverted Drift Tube for Improved Mobility Analysis of Aerosol Particles
Authors: Nahin Minal , Oberreit Derek , Fukushima Nobuhiko , Larriba-Andaluz Carlos 
Published: July 2017

AbstractA new mobility particle analyzer, which has been termed Inverted Drift Tube, has been modeled analytically as well as numerically and proven to be a very capable instrument. The basis for the new design have been the shortcomings of the previous ion mobility spectrometers, in particular (a) diffusional broadening which leads to degradation of instrument resolution and (b) inadequate low and fixed resolution (not mobility dependent) for large sizes. To overcome the diffusional broadening and have a mobility based resolution, the IDT uses two varying controllable opposite forces, a flow of gas with velocity v
gas
, and a linearly increasing electric field that opposes the movement. A new parameter, the separation ratio Λ = v
drift
/v
gas
, is employed to determine the best possible separation for a given set of nanoparticles. Due to the system’s need to operate at room pressure, two methods of capturing the ions at the end of the drift tube have been developed, Intermittent Push Flow for a large range of mobilities, and Nearly-Stopping Potential Separation, with very high separation but limited only to a narrow mobility range. A chromatography existing concept of resolving power is used to differentiate between peak resolution in the IDT and acceptable separation between similar mobility sizes.
Transformation-induced changes in the DNA-nuclear matrix interface, revealed by high-throughput analysis of DNA halos
Authors: Wilson Rosemary H. C. , Coverley Dawn 
Published: July 2017

AbstractIn higher eukaryotic nuclei, DNA is periodically anchored to an extraction-resistant protein structure, via matrix attachment regions. We describe a refined and accessible method to non-subjectively, rapidly and reproducibly measure both size and stability of the intervening chromatin loops, and use it to demonstrate that malignant transformation compromises the DNA-nuclear matrix interface.
Toll-like Receptor 4 Deficiency Reduces Oxidative Stress and Macrophage Mediated Inflammation in Hypertensive Kidney
Authors: Pushpakumar Sathnur , Ren Lu , Kundu Sourav , Gamon Alejandra , Tyagi Suresh C. , Sen Utpal 
Published: July 2017

AbstractOxidative stress and inflammation are integral to hypertension-induced renal injury. A unifying feature for the two components is Toll-like receptors (TLR), which are key regulators of the innate immune system. Recent studies implicate TLR4 activation and oxidative stress in cardiovascular diseases and also as a link between inflammation and hypertension. However, its role in hypertension induced renal injury remains unexplored. In the present study, we investigated whether TLR-4 deficiency reduces Ang-II-induced renal injury and fibrosis by attenuating reactive oxygen species (ROS) production and inflammation. C3H/HeOuJ mice with normal TLR-4 and C3H/HeJLps-dwith dysfunctional TLR4 (TLR4 deficiency) were treated without or with Ang-II. In response to Ang-II, TLR4 deficient mice had reduced renal resistive index and increased renal cortical blood flow compared to mice with normal TLR4. Further, TLR4 deficiency reduced oxidative stress and increased antioxidant capacity (MnSOD, CuSOD and Catalase activity). TLR4 deficiency was also associated with reduced inflammation (MCP-1, MIP-2, TNF-α, IL-6 and CD68), decreased accumulation of bone marrow-derived fibroblasts and TGF-β expression. Our data suggests that in C3H/HeJLps-dmice, deficiency of functional TLR4 reduces oxidative stress and macrophage activation to decrease TGF-β-induced extracellular matrix protein deposition in the kidney in Ang-II induced hypertension.
Nano-plasmonic near field phase matching of attosecond pulses
Authors: Shaaran Tahir , Nicolas Rana , Iwan Bianca , Kovacev Milutin , Merdji Hamed 
Published: July 2017

AbstractNano-structures excited by light can enhance locally the electric field when tuned to plasmonic resonances. This phenomenon can be used to boost non-linear processes such as harmonic generation in crystals or in gases, Raman excitation, and four wave mixing. Here we present a theoretical investigation of the near-field phase matching of attosecond pulses emitted by high-order harmonic generation (HHG) of an atom immersed in a multi-cycle femtosecond infrared laser field and a spatially inhomogeneous plasmonic field. We demonstrate that the spatial inhomogeneity factor of the plasmonic field strongly affects the electron trajectory and recombination time which can be used to control the attosecond emission. For further insight into the plasmonic field effect, we monitor the phase of each quantum path as a function of the inhomogeneity strength. Moreover, we investigate the attosecond emission as a function of near-field phase matching effects. This is achieved by calculating the coherent field superposition of attosecond pulses emitted from various intensities or field inhomogeneities. Finally, far-field and near-field phase matching effects are combined to modulate the harmonic spectral phase towards the emission of a single attosecond pulse.
Origin of clay minerals in Early Eocene volcanic paleosols on King George Island, Maritime Antarctica
Authors: Spinola Diogo Noses , Pi-Puig Teresa , Solleiro-Rebolledo Elizabeth , Egli Markus , Sudo Masafumi , Sedov Sergey , Kühn Peter 
Published: July 2017

AbstractThe paleoclimate during the Early Eocene in Maritime Antarctica is characterized by cool conditions without a pronounced dry season. Soils formed on volcanic material under such climate conditions in modern analogue environments are usually Andosols rich in nanocrystalline minerals without pedogenic smectite. The paleosols formed on volcanic material on King Georges Island are covered by basalts, dated by 6 new 40Ar/39Ar datings to 51–48 Ma, and are rich in smectite. A pedogenic origin of the smectites would suggest a semi-arid rather than a wet non-seasonal humid paleoclimate. To investigate the origin of the smectites in these paleosols we used X-ray diffraction and microscopic techniques. Minor mineralogical changes between the volcanic parent material and the paleosols and a homogenous distribution of smectites throughout the paleosol horizons indicate that these smectites were mainly inherited from the pyroclastic parent material, which was altered prior to surficial weathering. Nevertheless, the mineralogical properties, such as degree of crystallinity and octahedral site occupancy, of these smectites were modified during the ancient soil formation. Our findings highlight that trioctahedral smectites were a product of deuteric alteration of pyroclastic rocks and were progressively transformed to dioctahedral smectites during weathering in a soil environment on King George Island.
ADME-Space: a new tool for medicinal chemists to explore ADME properties
Authors: Bocci Giovanni , Carosati Emanuele , Vayer Philippe , Arrault Alban , Lozano Sylvain , Cruciani Gabriele 
Published: July 2017

AbstractWe introduce a new chemical space for drugs and drug-like molecules, exclusively based on their in silico ADME behaviour. This ADME-Space is based on self-organizing map (SOM) applied to 26,000 molecules. Twenty accurate QSPR models, describing important ADME properties, were developed and, successively, used as new molecular descriptors not related to molecular structure. Applications include permeability, active transport, metabolism and bioavailability studies, but the method can be even used to discuss drug-drug interactions (DDIs) or it can be extended to additional ADME properties. Thus, the ADME-Space opens a new framework for the multi-parametric data analysis in drug discovery where all ADME behaviours of molecules are condensed in one map: it allows medicinal chemists to simultaneously monitor several ADME properties, to rapidly select optimal ADME profiles, retrieve warning on potential ADME problems and DDIs or select proper in vitro experiments.
Advantages of phylogenetic distance based constrained ordination analyses for the examination of microbial communities
Authors: Shankar V. , Agans R. , Paliy O. 
Published: July 2017

AbstractRecently developed high throughput molecular techniques such as massively parallel sequencing and phylogenetic microarrays generate vast datasets providing insights into microbial community structure and function. Because of the high dimensionality of these datasets, multivariate ordination analyses are often employed to examine such data. Here, we show how the use of phylogenetic distance based redundancy analysis provides ecological interpretation of microbial community differences. We also extend the previously developed method of principal response curves to incorporate phylogenetic distance measure, and we demonstrate the improved ability of this approach to provide ecologically relevant insights into temporal alterations of microbial communities.
Formulating formation mechanism of natural gas hydrates
Authors: Palodkar Avinash V. , Jana Amiya K. 
Published: July 2017

AbstractA large amount of energy, perhaps twice the total amount of all other hydrocarbon reserves combined, is trapped within gas hydrate deposits. Despite emerging as a potential energy source for the world over the next several hundred years and one of the key factors in causing future climate change, gas hydrate is poorly known in terms of its formation mechanism. To address this issue, a mathematical formulation is proposed in the form of a model to represent the physical insight into the process of hydrate growth that occurs on the surface and in the irregular nanometer-sized pores of the distributed porous particles. To evaluate the versatility of this rigorous model, the experimental data is used for methane (CH4) and carbon dioxide (CO2) hydrates grown in different porous media with a wide range of considerations.