bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protein–ligand binding with the coarse-grained Martini model
Authors: Souza Paulo C. T. , Thallmair Sebastian , Conflitti Paolo , Ramírez-Palacios Carlos , Alessandri Riccardo , Raniolo Stefano , Limongelli Vittorio , Marrink Siewert J. 
Published: July 2020

AbstractThe detailed understanding of the binding of small molecules to proteins is the key for the development of novel drugs or to increase the acceptance of substrates by enzymes. Nowadays, computer-aided design of protein–ligand binding is an important tool to accomplish this task. Current approaches typically rely on high-throughput docking essays or computationally expensive atomistic molecular dynamics simulations. Here, we present an approach to use the recently re-parametrized coarse-grained Martini model to perform unbiased millisecond sampling of protein–ligand interactions of small drug-like molecules. Remarkably, we achieve high accuracy without the need of any a priori knowledge of binding pockets or pathways. Our approach is applied to a range of systems from the well-characterized T4 lysozyme over members of the GPCR family and nuclear receptors to a variety of enzymes. The presented results open the way to high-throughput screening of ligand libraries or protein mutations using the coarse-grained Martini model.
Structural analysis of the SARS-CoV-2 methyltransferase complex involved in RNA cap creation bound to sinefungin
Authors: Krafcikova Petra , Silhan Jan , Nencka Radim , Boura Evzen 
Published: July 2020

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic. 2′-O-RNA methyltransferase (MTase) is one of the enzymes of this virus that is a potential target for antiviral therapy as it is crucial for RNA cap formation; an essential process for viral RNA stability. This MTase function is associated with the nsp16 protein, which requires a cofactor, nsp10, for its proper activity. Here we show the crystal structure of the nsp10-nsp16 complex bound to the pan-MTase inhibitor sinefungin in the active site. Our structural comparisons reveal low conservation of the MTase catalytic site between Zika and SARS-CoV-2 viruses, but high conservation of the MTase active site between SARS-CoV-2 and SARS-CoV viruses; these data suggest that the preparation of MTase inhibitors targeting several coronaviruses - but not flaviviruses - should be feasible. Together, our data add to important information for structure-based drug discovery.
Genome assembly of wild tea tree DASZ reveals pedigree and selection history of tea varieties
Authors: Zhang Weiyi , Zhang Youjun , Qiu Haiji , Guo Yafei , Wan Haoliang , Zhang Xiaoliang , Scossa Federico , Alseekh Saleh , Zhang Qinghua , Wang Pu , Xu Li , Schmidt Maximilian H-W , Jia Xinxin , Li Daili , Zhu Anting , Guo Fei , Chen Wei , Ni Dejiang , Usadel Björn , Fernie Alisdair R. , Wen Weiwei 
Published: July 2020

AbstractWild teas are valuable genetic resources for studying domestication and breeding. Here we report the assembly of a high-quality chromosome-scale reference genome for an ancient tea tree. The further RNA sequencing of 217 diverse tea accessions clarifies the pedigree of tea cultivars and reveals key contributors in the breeding of Chinese tea. Candidate genes associated with flavonoid biosynthesis are identified by genome-wide association study. Specifically, diverse allelic function of CsANR, CsF3’5’H and CsMYB5 is verified by transient overexpression and enzymatic assays, providing comprehensive insights into the biosynthesis of catechins, the most important bioactive compounds in tea plants. The inconspicuous differentiation between ancient trees and cultivars at both genetic and metabolic levels implies that tea may not have undergone long-term artificial directional selection in terms of flavor-related metabolites. These genomic resources provide evolutionary insight into tea plants and lay the foundation for better understanding the biosynthesis of beneficial natural compounds.
Mycobacterium tuberculosis FasR senses long fatty acyl-CoA through a tunnel and a hydrophobic transmission spine
Authors: Lara Julia , Diacovich Lautaro , Trajtenberg Felipe , Larrieux Nicole , Malchiodi Emilio L. , Fernández Marisa M. , Gago Gabriela , Gramajo Hugo , Buschiazzo Alejandro 
Published: July 2020

AbstractMycobacterium tuberculosis is a pathogen with a unique cell envelope including very long fatty acids, implicated in bacterial resistance and host immune modulation. FasR is a TetR-like transcriptional activator that plays a central role in sensing mycobacterial long-chain fatty acids and regulating lipid biosynthesis. Here we disclose crystal structures of M. tuberculosis FasR in complex with acyl effector ligands and with DNA, uncovering its molecular sensory and switching mechanisms. A long tunnel traverses the entire effector-binding domain, enabling long fatty acyl effectors to bind. Only when the tunnel is entirely occupied, the protein dimer adopts a rigid configuration with its DNA-binding domains in an open state, leading to DNA dissociation. The protein-folding hydrophobic core connects the two domains, and is completed into a continuous spine when the effector binds. Such a transmission spine is conserved in a large number of TetR-like regulators, offering insight into effector-triggered allosteric functional control.
Therapeutic paradigm of dual targeting VEGF and PDGF for effectively treating FGF-2 off-target tumors
Authors: Hosaka Kayoko , Yang Yunlong , Seki Takahiro , Du Qiqiao , Jing Xu , He Xingkang , Wu Jieyu , Zhang Yin , Morikawa Hiromasa , Nakamura Masaki , Scherzer Martin , Sun Xiaoting , Xu Yuanfu , Cheng Tao , Li Xuri , Liu Xialin , Li Qi , Liu Yizhi , Hong An , Chen Yuguo , Cao Yihai 
Published: July 2020

AbstractFGF-2 displays multifarious functions in regulation of angiogenesis and vascular remodeling. However, effective drugs for treating FGF-2+ tumors are unavailable. Here we show that FGF-2 modulates tumor vessels by recruiting NG2+ pricytes onto tumor microvessels through a PDGFRβ-dependent mechanism. FGF-2+ tumors are intrinsically resistant to clinically available drugs targeting VEGF and PDGF. Surprisingly, dual targeting the VEGF and PDGF signaling produces a superior antitumor effect in FGF-2+ breast cancer and fibrosarcoma models. Mechanistically, inhibition of PDGFRβ ablates FGF-2-recruited perivascular coverage, exposing anti-VEGF agents to inhibit vascular sprouting. These findings show that the off-target FGF-2 is a resistant biomarker for anti-VEGF and anti-PDGF monotherapy, but a highly beneficial marker for combination therapy. Our data shed light on mechanistic interactions between various angiogenic and remodeling factors in tumor neovascularization. Optimization of antiangiogenic drugs with different principles could produce therapeutic benefits for treating their resistant off-target cancers.
DNA sequence-dependent activity and base flipping mechanisms of DNMT1 regulate genome-wide DNA methylation
Authors: Adam Sabrina , Anteneh Hiwot , Hornisch Maximilian , Wagner Vincent , Lu Jiuwei , Radde Nicole E. , Bashtrykov Pavel , Song Jikui , Jeltsch Albert 
Published: July 2020

AbstractDNA methylation maintenance by DNMT1 is an essential process in mammals but molecular mechanisms connecting DNA methylation patterns and enzyme activity remain elusive. Here, we systematically analyzed the specificity of DNMT1, revealing a pronounced influence of the DNA sequences flanking the target CpG site on DNMT1 activity. We determined DNMT1 structures in complex with preferred DNA substrates revealing that DNMT1 employs flanking sequence-dependent base flipping mechanisms, with large structural rearrangements of the DNA correlating with low catalytic activity. Moreover, flanking sequences influence the conformational dynamics of the active site and cofactor binding pocket. Importantly, we show that the flanking sequence preferences of DNMT1 highly correlate with genomic methylation in human and mouse cells, and 5-azacytidine triggered DNA demethylation is more pronounced at CpG sites with flanks disfavored by DNMT1. Overall, our findings uncover the intricate interplay between CpG-flanking sequence, DNMT1-mediated base flipping and the dynamic landscape of DNA methylation.
Understanding coordination reaction for producing stable electrode with various low work functions
Authors: Fukagawa Hirohiko , Suzuki Kazuma , Ito Hirokazu , Inagaki Kaito , Sasaki Tsubasa , Oono Taku , Hasegawa Munehiro , Morii Katsuyuki , Shimizu Takahisa 
Published: July 2020

AbstractThe realisation of a cathode with various work functions (WFs) is required to maximise the potential of organic semiconductors that have various electron affinities. However, the barrier-free contact for electrons could only be achieved by using reactive materials, which significantly reduce the environmental stability of organic devices. We show that a stable electrode with various WFs can be produced by utilising the coordination reaction between several phenanthroline derivatives and the electrode. Although the low WF of the electrode realised by using reactive materials is specific to the material, the WF of the phenanthroline-modified electrode is tunable depending on the amount of electron transfer associated with the coordination reaction. A phenanthroline-modified electrode that has a higher electron injection efficiency than lithium fluoride has been demonstrated. The observation of various WFs induced by the coordination reaction affords strategic perspectives on the development of stable cathodes unique to organic electronics.
Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer
Authors: Aubert Léo , Nandagopal Neethi , Steinhart Zachary , Lavoie Geneviève , Nourreddine Sami , Berman Jacob , Saba-El-Leil Marc K. , Papadopoli David , Lin Sichun , Hart Traver , Macleod Graham , Topisirovic Ivan , Gaboury Louis , Fahrni Christoph J. , Schramek Daniel , Meloche Sylvain , Angers Stephane , Roux Philippe P. 
Published: July 2020

AbstractDespite its importance in human cancers, including colorectal cancers (CRC), oncogenic KRAS has been extremely challenging to target therapeutically. To identify potential vulnerabilities in KRAS-mutated CRC, we characterize the impact of oncogenic KRAS on the cell surface of intestinal epithelial cells. Here we show that oncogenic KRAS alters the expression of a myriad of cell-surface proteins implicated in diverse biological functions, and identify many potential surface-accessible therapeutic targets. Cell surface-based loss-of-function screens reveal that ATP7A, a copper-exporter upregulated by mutant KRAS, is essential for neoplastic growth. ATP7A is upregulated at the surface of KRAS-mutated CRC, and protects cells from excess copper-ion toxicity. We find that KRAS-mutated cells acquire copper via a non-canonical mechanism involving macropinocytosis, which appears to be required to support their growth. Together, these results indicate that copper bioavailability is a KRAS-selective vulnerability that could be exploited for the treatment of KRAS-mutated neoplasms.
Achieving asymmetry and trapping in diffusion with spatiotemporal metamaterials
Authors: Camacho Miguel , Edwards Brian , Engheta Nader 
Published: July 2020

AbstractThe process of diffusion is central to the ever increasing entropic state of the universe and is fundamental in many branches of science and engineering. Although non-reciprocal metamaterials are well developed for wave systems, the studies of diffusive metamaterials have been limited by their characteristic spatial inversion symmetry and time inversion antisymmetry. Here, we achieve large spatial asymmetric diffusion characteristics inside a metamaterial whose material parameters are space- and time-modulated. Inside such a spatiotemporal metamaterial, diffusion occurs as if the material had an intrinsic flow velocity, whose direction is dictated by the relative phase between the modulations of the conductivity and capacity. This creates dramatic out-of-equilibrium concentrations and depletions, which we demonstrate experimentally for the diffusion of electric charges in a one-dimensional electrical system composed of an array of space-time-modulated variable capacitors and switches. These results may offer exciting possibilities in various fields, including electronics, thermal management, chemical mixing, etc.
The unified myofibrillar matrix for force generation in muscle
Authors: Willingham T. Bradley , Kim Yuho , Lindberg Eric , Bleck Christopher K. E. , Glancy Brian 
Published: July 2020

AbstractHuman movement occurs through contraction of the basic unit of the muscle cell, the sarcomere. Sarcomeres have long been considered to be arranged end-to-end in series along the length of the muscle into tube-like myofibrils with many individual, parallel myofibrils comprising the bulk of the muscle cell volume. Here, we demonstrate that striated muscle cells form a continuous myofibrillar matrix linked together by frequently branching sarcomeres. We find that all muscle cells contain highly connected myofibrillar networks though the frequency of sarcomere branching goes down from early to late postnatal development and is higher in slow-twitch than fast-twitch mature muscles. Moreover, we show that the myofibrillar matrix is united across the entire width of the muscle cell both at birth and in mature muscle. We propose that striated muscle force is generated by a singular, mesh-like myofibrillar network rather than many individual, parallel myofibrils.
Divergent effects of climate change on future groundwater availability in key mid-latitude aquifers
Authors: Wu Wen-Ying , Lo Min-Hui , Wada Yoshihide , Famiglietti James S. , Reager John T. , Yeh Pat J.-F. , Ducharne Agnès , Yang Zong-Liang 
Published: July 2020

AbstractGroundwater provides critical freshwater supply, particularly in dry regions where surface water availability is limited. Climate change impacts on GWS (groundwater storage) could affect the sustainability of freshwater resources. Here, we used a fully-coupled climate model to investigate GWS changes over seven critical aquifers identified as significantly distressed by satellite observations. We assessed the potential climate-driven impacts on GWS changes throughout the 21st century under the business-as-usual scenario (RCP8.5). Results show that the climate-driven impacts on GWS changes do not necessarily reflect the long-term trend in precipitation; instead, the trend may result from enhancement of evapotranspiration, and reduction in snowmelt, which collectively lead to divergent responses of GWS changes across different aquifers. Finally, we compare the climate-driven and anthropogenic pumping impacts. The reduction in GWS is mainly due to the combined impacts of over-pumping and climate effects; however, the contribution of pumping could easily far exceed the natural replenishment.
A New Phylogenomic Approach For Quantifying Horizontal Gene Transfer Trends in Prokaryotes
Authors: Avni Eliran , Snir Sagi 
Published: July 2020

AbstractIt is well established nowadays that among prokaryotes, various families of orthologous genes exhibit conflicting evolutionary history. A prime factor for this conflict is horizontal gene transfer (HGT) - the transfer of genetic material not via vertical descent. Thus, the prevalence of HGT is challenging the meaningfulness of the classical Tree of Life concept. Here we present a comprehensive study of HGT representing the entire prokaryotic world. We mainly rely on a novel analytic approach for analyzing an aggregate of gene histories, by means of the quartet plurality distribution (QPD) that we develop. Through the analysis of real and simulated data, QPD is used to reveal evidence of a barrier against HGT, separating the archaea from the bacteria and making HGT between the two domains, in general, quite rare. In contrast, bacteria’s confined HGT is substantially more frequent than archaea’s. Our approach also reveals that despite intensive HGT, a strong tree-like signal can be extracted, corroborating several previous works. Thus, QPD, which enables one to analytically combine information from an aggregate of gene trees, can be used for understanding patterns and rates of HGT in prokaryotes, as well as for validating or refuting models of horizontal genetic transfers and evolution in general.
Microstructural controls of anticrack nucleation in highly porous brittle solids
Authors: Ritter Jonas , Löwe Henning , Gaume Johan 
Published: July 2020

AbstractPorous brittle solids have the ability to collapse and fail even under compressive stresses. In fracture mechanics, this singular behavior, often referred to as anticrack, demands for appropriate continuum models to predict the catastrophic failure. To identify universal controls of anticracks, we link the microstructure of a porous solid with its yield surface at the onset of plastic flow. We utilize an assembly method for porous structures, which allows to independently vary microstructural properties (density and coordination number) and perform discrete element simulations under mixed-mode (shear-compression) loading. In rescaled stress coordinates, the concurrent influence of the microstructural properties can be cast into a universal, ellipsoidal form of the yield surface that reveals an associative plastic flow rule, as a common feature of these materials. Our results constitute a constructive approach for continuum modeling of anticrack nucleation and propagation in highly porous brittle, engineering and geo-materials.
Fungus-growing insects host a distinctive microbiota apparently adapted to the fungiculture environment
Authors: Barcoto Mariana O. , Carlos-Shanley Camila , Fan Huan , Ferro Milene , Nagamoto Nilson S. , Bacci Mauricio , Currie Cameron R. , Rodrigues Andre 
Published: July 2020

AbstractSome lineages of ants, termites, and beetles independently evolved a symbiotic association with lignocellulolytic fungi cultivated for food, in a lifestyle known as fungiculture. Fungus-growing insects’ symbiosis also hosts a bacterial community thought to integrate their physiology. Similarities in taxonomic composition support the microbiota of fungus-growing insects as convergent, despite differences in fungus-rearing by these insects. Here, by comparing fungus-growing insects to several hosts ranging diverse dietary patterns, we investigate whether the microbiota taxonomic and functional profiles are characteristic of the fungiculture environment. Compared to other hosts, the microbiota associated with fungus-growing insects presents a distinctive taxonomic profile, dominated by Gammaproteobacteria at class level and by Pseudomonas at genera level. Even with a functional profile presenting similarities with the gut microbiota of herbivorous and omnivorous hosts, some differentially abundant features codified by the microbiota of fungus-growing insects suggest these communities occupying microhabitats that are characteristic of fungiculture. These features include metabolic pathways involved in lignocellulose breakdown, detoxification of plant secondary metabolites, metabolism of simple sugars, fungal cell wall deconstruction, biofilm formation, antimicrobials biosynthesis, and metabolism of diverse nutrients. Our results suggest that the microbiota could be functionally adapted to the fungiculture environment, codifying metabolic pathways potentially relevant to the fungus-growing insects’ ecosystems functioning.
The effect of NMDA-R antagonist, MK-801, on neuronal mismatch along the rat auditory thalamocortical pathway
Authors: Parras Gloria G. , Valdés-Baizabal Catalina , Harms Lauren , Michie Patricia T. , Malmierca Manuel S. 
Published: July 2020

AbstractEfficient sensory processing requires that the brain maximize its response to unexpected stimuli, while suppressing responsivity to expected events. Mismatch negativity (MMN) is an auditory event-related potential that occurs when a regular pattern is interrupted by an event that violates the expected properties of the pattern. According to the predictive coding framework there are two mechanisms underlying the MMN: repetition suppression and prediction error. MMN has been found to be reduced in individuals with schizophrenia, an effect believed to be underpinned by glutamate N-methyl-d-aspartate receptor (NMDA-R) dysfunction. In the current study, we aimed to test how the NMDA-R antagonist, MK-801 in the anaesthetized rat, affected repetition suppression and prediction error processes along the auditory thalamocortical pathway. We found that low-dose systemic administration of MK-801 differentially affect thalamocortical responses, namely, increasing thalamic repetition suppression and cortical prediction error. Results demonstrate an enhancement of neuronal mismatch, also confirmed by large scale-responses. Furthermore, MK-801 produces faster and stronger dynamics of adaptation along the thalamocortical hierarchy. Clearly more research is required to understand how NMDA-R antagonism and dosage affects processes contributing to MMN. Nonetheless, because a low dose of an NMDA-R antagonist increased neuronal mismatch, the outcome has implications for schizophrenia treatment.
Listening to pulses of radiation: design of a submersible thermoacoustic sensor
Authors: Barmak Rafael , Cernicchiaro Geraldo 
Published: July 2020

AbstractNowadays, various collaborations are creating immense machines to try to track and understand the origin of high-energy cosmic particles (e.g., IceCube, ANTARES, Baikal-GVD, P-ONE). The detection mechanism of these sophisticated experiments relies mainly on an optical signal generated by the passage of charged particles on a dielectric medium (Čerenkov radiation). Unfortunately, the dim light produced by passing particles cannot travel too far until it fades away, creating the necessity to instrument large areas with short spacing between sensors. The range limitation of the optical technique has created a fertile ground for experimenting on the detection of acoustic signals generated by radiation—thermoacoustics. Despite the increased use of the thermoacoustic technique, the instrumentation to capture the faint acoustic signals is still scarce. Therefore, this work has the objective to contribute with information on the critical stages of an affordable submersible thermoacoustic sensor: namely the piezoelectric transducer and the amplifying electronics. We tested the sensor in a $$170\,{\textit{l}}$$170l non-anechoic tank using an infrared ($$\lambda =1064\,\hbox {nm}$$λ=1064nm) Q-switched Nd:YAG laser as a pulsed energy source to create the characteristic signals of the thermoacoustic phenomena. In accordance with the thermoacoustic model, a polarity inversion of the pressure signal was observed when transiting from temperatures below the point of maximum density of water to temperatures above it. Also, the amplitude of the acoustic signal displayed a linear relationship with pulse energies up to $$(51.1 \pm 1.7)\,\hbox {mJ}$$(51.1±1.7)mJ ($$R^2 \sim 0.98$$R2∼0.98). Despite the use of cost-effective parts and simple construction methods, the proposed sensor design is a viable instrument for experimental thermoacoustic investigations on high-energy particles.