bluuebunny/crossref_metadata_2025_split huggingface dataset:
In situ microbeam surface X-ray scattering reveals alternating step kinetics during crystal growth
Authors: Ju Guangxu , Xu Dongwei , Thompson Carol , Highland Matthew J. , Eastman Jeffrey A. , Walkosz Weronika , Zapol Peter , Stephenson G. Brian 
Published: March 2021

AbstractThe stacking sequence of hexagonal close-packed and related crystals typically results in steps on vicinal {0001} surfaces that have alternating A and B structures with different growth kinetics. However, because it is difficult to experimentally identify which step has the A or B structure, it has not been possible to determine which has faster adatom attachment kinetics. Here we show that in situ microbeam surface X-ray scattering can determine whether A or B steps have faster kinetics under specific growth conditions. We demonstrate this for organo-metallic vapor phase epitaxy of (0001) GaN. X-ray measurements performed during growth find that the average width of terraces above A steps increases with growth rate, indicating that attachment rate constants are higher for A steps, in contrast to most predictions. Our results have direct implications for understanding the atomic-scale mechanisms of GaN growth and can be applied to a wide variety of related crystals.
Stabilisation of half MCM ring by Cdt1 during DNA insertion
Authors: Guerrero-Puigdevall Marina , Fernandez-Fuentes Narcis , Frigola Jordi 
Published: March 2021

AbstractOrigin licensing ensures precise once per cell cycle replication in eukaryotic cells. The Origin Recognition Complex, Cdc6 and Cdt1 load Mcm2-7 helicase (MCM) into a double hexamer, bound around duplex DNA. The complex formed by ORC-Cdc6 bound to duplex DNA (OC) recruits the MCM-Cdt1 complex into the replication origins. Through the stacking of both complexes, the duplex DNA is inserted inside the helicase by an unknown mechanism. In this paper we show that the DNA insertion comes with a topological problem in the stacking of OC with MCM-Cdt1. Unless an essential, conserved C terminal winged helix domain (C-WHD) of Cdt1 is present, the MCM splits into two halves. The binding of this domain with the essential C-WHD of Mcm6, allows the latching between the MCM-Cdt1 and OC, through a conserved Orc5 AAA-lid interaction. Our work provides new insights into how DNA is inserted into the eukaryotic replicative helicase, through a series of synchronized events.
A molecular photosensitizer achieves a Voc of 1.24 V enabling highly efficient and stable dye-sensitized solar cells with copper(II/I)-based electrolyte
Authors: Zhang Dan , Stojanovic Marko , Ren Yameng , Cao Yiming , Eickemeyer Felix T. , Socie Etienne , Vlachopoulos Nick , Moser Jacques-E. , Zakeeruddin Shaik M. , Hagfeldt Anders , Grätzel Michael 
Published: March 2021

AbstractTo develop photosensitizers with high open-circuit photovoltage (Voc) is a crucial strategy to enhance the power conversion efficiency (PCE) of co-sensitized solar cells. Here, we show a judiciously tailored organic photosensitizer, coded MS5, featuring the bulky donor N-(2’,4’-bis(dodecyloxy)-[1,1’-biphenyl]-4-yl)-2’,4’-bis(dodecyloxy)-N-phenyl-[1,1’-biphenyl]-4-amine and the electron acceptor 4-(benzo[c][1,2,5]thiadiazol-4-yl)benzoic acid. Employing MS5 with a copper (II/I) electrolyte enables a dye-sensitized solar cell (DSC) to achieve a strikingly high Voc of 1.24 V, with the Voc deficit as low as 130 mV and an ideality factor of merely 1.08. The co-sensitization of MS5 with the wider spectral-response dye XY1b produces a highly efficient and stable DSC with the PCE of 13.5% under standard AM1.5 G, 100 mW cm−2 solar radiation. Remarkably, the co-sensitized solar cell (active area of 2.8 cm2) presents a record PCE of 34.5% under ambient light, rendering it very attractive as an ambient light harvesting energy source for low power electronics.
Citrullination of pyruvate kinase M2 by PADI1 and PADI3 regulates glycolysis and cancer cell proliferation
Authors: Coassolo Sébastien , Davidson Guillaume , Negroni Luc , Gambi Giovanni , Daujat Sylvain , Romier Christophe , Davidson Irwin 
Published: March 2021

AbstractChromodomain helicase DNA binding protein 4 (CHD4) is an ATPase subunit of the Nucleosome Remodelling and Deacetylation (NuRD) complex that regulates gene expression. CHD4 is essential for growth of multiple patient derived melanoma xenografts and for breast cancer. Here we show that CHD4 regulates expression of PADI1 (Protein Arginine Deiminase 1) and PADI3 in multiple cancer cell types modulating citrullination of arginine residues of the allosterically-regulated glycolytic enzyme pyruvate kinase M2 (PKM2). Citrullination of PKM2 R106 reprogrammes cross-talk between PKM2 ligands lowering its sensitivity to the inhibitors Tryptophan, Alanine and Phenylalanine and promoting activation by Serine. Citrullination thus bypasses normal physiological regulation by low Serine levels to promote excessive glycolysis and reduced cell proliferation. We further show that PADI1 and PADI3 expression is up-regulated by hypoxia where PKM2 citrullination contributes to increased glycolysis. We provide insight as to how conversion of arginines to citrulline impacts key interactions within PKM2 that act in concert to reprogramme its activity as an additional mechanism regulating this important enzyme.
An endothelial activin A-bone morphogenetic protein receptor type 2 link is overdriven in pulmonary hypertension
Authors: Ryanto Gusty R. T. , Ikeda Koji , Miyagawa Kazuya , Tu Ly , Guignabert Christophe , Humbert Marc , Fujiyama Tomoyuki , Yanagisawa Masashi , Hirata Ken-ichi , Emoto Noriaki 
Published: March 2021

AbstractPulmonary arterial hypertension is a progressive fatal disease that is characterized by pathological pulmonary artery remodeling, in which endothelial cell dysfunction is critically involved. We herein describe a previously unknown role of endothelial angiocrine in pulmonary hypertension. By searching for genes highly expressed in lung microvascular endothelial cells, we identify inhibin-β-A as an angiocrine factor produced by pulmonary capillaries. We find that excess production of inhibin-β-A by endothelial cells impairs the endothelial function in an autocrine manner by functioning as activin-A. Mechanistically, activin-A induces bone morphogenetic protein receptor type 2 internalization and targeting to lysosomes for degradation, resulting in the signal deficiency in endothelial cells. Of note, endothelial cells isolated from the lung of patients with idiopathic pulmonary arterial hypertension show higher inhibin-β-A expression and produce more activin-A compared to endothelial cells isolated from the lung of normal control subjects. When endothelial activin-A-bone morphogenetic protein receptor type 2 link is overdriven in mice, hypoxia-induced pulmonary hypertension was exacerbated, whereas conditional knockout of inhibin-β-A in endothelial cells prevents the progression of pulmonary hypertension. These data collectively indicate a critical role for the dysregulated endothelial activin-A-bone morphogenetic protein receptor type 2 link in the progression of pulmonary hypertension, and thus endothelial inhibin-β-A/activin-A might be a potential pharmacotherapeutic target for the treatment of pulmonary arterial hypertension.
Top-down control of visual cortex by the frontal eye fields through oscillatory realignment
Authors: Veniero Domenica , Gross Joachim , Morand Stephanie , Duecker Felix , Sack Alexander T. , Thut Gregor 
Published: March 2021

AbstractVoluntary allocation of visual attention is controlled by top-down signals generated within the Frontal Eye Fields (FEFs) that can change the excitability of lower-level visual areas. However, the mechanism through which this control is achieved remains elusive. Here, we emulated the generation of an attentional signal using single-pulse transcranial magnetic stimulation to activate the FEFs and tracked its consequences over the visual cortex. First, we documented changes to brain oscillations using electroencephalography and found evidence for a phase reset over occipital sites at beta frequency. We then probed for perceptual consequences of this top-down triggered phase reset and assessed its anatomical specificity. We show that FEF activation leads to cyclic modulation of visual perception and extrastriate but not primary visual cortex excitability, again at beta frequency. We conclude that top-down signals originating in FEF causally shape visual cortex activity and perception through mechanisms of oscillatory realignment.
Removing leakage-induced correlated errors in superconducting quantum error correction
Authors: McEwen M. , Kafri D. , Chen Z. , Atalaya J. , Satzinger K. J. , Quintana C. , Klimov P. V. , Sank D. , Gidney C. , Fowler A. G. , Arute F. , Arya K. , Buckley B. , Burkett B. , Bushnell N. , Chiaro B. , Collins R. , Demura S. , Dunsworth A. , Erickson C. , Foxen B. , Giustina M. , Huang T. , Hong S. , Jeffrey E. , Kim S. , Kechedzhi K. , Kostritsa F. , Laptev P. , Megrant A. , Mi X. , Mutus J. , Naaman O. , Neeley M. , Neill C. , Niu M. , Paler A. , Redd N. , Roushan P. , White T. C. , Yao J. , Yeh P. , Zalcman A. , Chen Yu , Smelyanskiy V. N. , Martinis John M. , Neven H. , Kelly J. , Korotkov A. N. , Petukhov A. G. , Barends R. 
Published: March 2021

AbstractQuantum computing can become scalable through error correction, but logical error rates only decrease with system size when physical errors are sufficiently uncorrelated. During computation, unused high energy levels of the qubits can become excited, creating leakage states that are long-lived and mobile. Particularly for superconducting transmon qubits, this leakage opens a path to errors that are correlated in space and time. Here, we report a reset protocol that returns a qubit to the ground state from all relevant higher level states. We test its performance with the bit-flip stabilizer code, a simplified version of the surface code for quantum error correction. We investigate the accumulation and dynamics of leakage during error correction. Using this protocol, we find lower rates of logical errors and an improved scaling and stability of error suppression with increasing qubit number. This demonstration provides a key step on the path towards scalable quantum computing.
Structural and dynamic mechanisms of CBF3-guided centromeric nucleosome formation
Authors: Guan Ruifang , Lian Tengfei , Zhou Bing-Rui , He Emily , Wu Carl , Singleton Martin , Bai Yawen 
Published: March 2021

AbstractAccurate chromosome segregation relies on the specific centromeric nucleosome–kinetochore interface. In budding yeast, the centromere CBF3 complex guides the deposition of CENP-A, an H3 variant, to form the centromeric nucleosome in a DNA sequence-dependent manner. Here, we determine the structures of the centromeric nucleosome containing the native CEN3 DNA and the CBF3core bound to the canonical nucleosome containing an engineered CEN3 DNA. The centromeric nucleosome core structure contains 115 base pair DNA including a CCG motif. The CBF3core specifically recognizes the nucleosomal CCG motif through the Gal4 domain while allosterically altering the DNA conformation. Cryo-EM, modeling, and mutational studies reveal that the CBF3core forms dynamic interactions with core histones H2B and CENP-A in the CEN3 nucleosome. Our results provide insights into the structure of the budding yeast centromeric nucleosome and the mechanism of its assembly, which have implications for analogous processes of human centromeric nucleosome formation.
Local electronic structure rearrangements and strong anharmonicity in YH3 under pressures up to 180 GPa
Authors: Purans J. , Menushenkov A. P. , Besedin S. P. , Ivanov A. A. , Minkov V. S. , Pudza I. , Kuzmin A. , Klementiev K. V. , Pascarelli S. , Mathon O. , Rosa A. D. , Irifune T. , Eremets M. I. 
Published: March 2021

AbstractThe discovery of superconductivity above 250 K at high pressure in LaH10 and the prediction of overcoming the room temperature threshold for superconductivity in YH10 urge for a better understanding of hydrogen interaction mechanisms with the heavy atom sublattice in metal hydrides under high pressure at the atomic scale. Here we use locally sensitive X-ray absorption fine structure spectroscopy (XAFS) to get insight into the nature of phase transitions and the rearrangements of local electronic and crystal structure in archetypal metal hydride YH3 under pressure up to 180 GPa. The combination of the experimental methods allowed us to implement a multiscale length study of YH3: XAFS (short-range), Raman scattering (medium-range) and XRD (long-range). XANES data evidence a strong effect of hydrogen on the density of 4d yttrium states that increases with pressure and EXAFS data evidence a strong anharmonicity, manifested as yttrium atom vibrations in a double-well potential.
The essential role of PRAK in tumor metastasis and its therapeutic potential
Authors: Wang Yuqing , Wang Wei , Wu Haoming , Zhou Yu , Qin Xiaodan , Wang Yan , Wu Jia , Sun Xiu-Yuan , Yang Yan , Xu Hui , Qian Xiaoping , Pang Xuewen , Li Yan , Zhang Zhiqian , Han Jiahuai , Zhang Yu 
Published: March 2021

AbstractMetastasis is the leading cause of cancer-related death. Despite the recent advancements in cancer treatment, there is currently no approved therapy for metastasis. The present study reveals a potent and selective activity of PRAK in the regulation of tumor metastasis. While showing no apparent effect on the growth of primary breast cancers or subcutaneously inoculated tumor lines, Prak deficiency abrogates lung metastases in PyMT mice or mice receiving intravenous injection of tumor cells. Consistently, PRAK expression is closely associated with metastatic risk in human cancers. Further analysis indicates that loss of function of PRAK leads to a pronounced inhibition of HIF-1α protein synthesis, possibly due to reduced mTORC1 activities. Notably, pharmacological inactivation of PRAK with a clinically relevant inhibitor recapitulates the anti-metastatic effect of Prak depletion, highlighting the therapeutic potential of targeting PRAK in the control of metastasis.
Harnessing the central dogma for stringent multi-level control of gene expression
Authors: Greco F. Veronica , Pandi Amir , Erb Tobias J. , Grierson Claire S. , Gorochowski Thomas E. 
Published: March 2021

AbstractStrictly controlled inducible gene expression is crucial when engineering biological systems where even tiny amounts of a protein have a large impact on function or host cell viability. In these cases, leaky protein production must be avoided, but without affecting the achievable range of expression. Here, we demonstrate how the central dogma offers a simple solution to this challenge. By simultaneously regulating transcription and translation, we show how basal expression of an inducible system can be reduced, with little impact on the maximum expression rate. Using this approach, we create several stringent expression systems displaying >1000-fold change in their output after induction and show how multi-level regulation can suppress transcriptional noise and create digital-like switches between ‘on’ and ‘off’ states. These tools will aid those working with toxic genes or requiring precise regulation and propagation of cellular signals, plus illustrate the value of more diverse regulatory designs for synthetic biology.
Deep generative neural network for accurate drug response imputation
Authors: Jia Peilin , Hu Ruifeng , Pei Guangsheng , Dai Yulin , Wang Yin-Ying , Zhao Zhongming 
Published: March 2021

AbstractDrug response differs substantially in cancer patients due to inter- and intra-tumor heterogeneity. Particularly, transcriptome context, especially tumor microenvironment, has been shown playing a significant role in shaping the actual treatment outcome. In this study, we develop a deep variational autoencoder (VAE) model to compress thousands of genes into latent vectors in a low-dimensional space. We then demonstrate that these encoded vectors could accurately impute drug response, outperform standard signature-gene based approaches, and appropriately control the overfitting problem. We apply rigorous quality assessment and validation, including assessing the impact of cell line lineage, cross-validation, cross-panel evaluation, and application in independent clinical data sets, to warrant the accuracy of the imputed drug response in both cell lines and cancer samples. Specifically, the expression-regulated component (EReX) of the observed drug response achieves high correlation across panels. Using the well-trained models, we impute drug response of The Cancer Genome Atlas data and investigate the features and signatures associated with the imputed drug response, including cell line origins, somatic mutations and tumor mutation burdens, tumor microenvironment, and confounding factors. In summary, our deep learning method and the results are useful for the study of signatures and markers of drug response.
Dietary restriction transforms the mammalian protein persulfidome in a tissue-specific and cystathionine γ-lyase-dependent manner
Authors: Bithi Nazmin , Link Christopher , Henderson Yoko O. , Kim Suzie , Yang Jie , Li Ling , Wang Rui , Willard Belinda , Hine Christopher 
Published: March 2021

AbstractHydrogen sulfide (H2S) is a cytoprotective redox-active metabolite that signals through protein persulfidation (R-SSnH). Despite the known importance of persulfidation, tissue-specific persulfidome profiles and their associated functions are not well characterized, specifically under conditions and interventions known to modulate H2S production. We hypothesize that dietary restriction (DR), which increases lifespan and can boost H2S production, expands tissue-specific persulfidomes. Here, we find protein persulfidation enriched in liver, kidney, muscle, and brain but decreased in heart of young and aged male mice under two forms of DR, with DR promoting persulfidation in numerous metabolic and aging-related pathways. Mice lacking cystathionine γ-lyase (CGL) have overall decreased tissue protein persulfidation numbers and fail to functionally augment persulfidomes in response to DR, predominantly in kidney, muscle, and brain. Here, we define tissue- and CGL-dependent persulfidomes and how diet transforms their makeup, underscoring the breadth for DR and H2S to impact biological processes and organismal health.
Cerebellar Kv3.3 potassium channels activate TANK-binding kinase 1 to regulate trafficking of the cell survival protein Hax-1
Authors: Zhang Yalan , Varela Luis , Szigeti-Buck Klara , Williams Adam , Stoiljkovic Milan , Šestan-Peša Matija , Henao-Mejia Jorge , D’Acunzo Pasquale , Levy Efrat , Flavell Richard A. , Horvath Tamas L. , Kaczmarek Leonard K. 
Published: March 2021

AbstractMutations in KCNC3, which encodes the Kv3.3 potassium channel, cause degeneration of the cerebellum, but exactly how the activity of an ion channel is linked to the survival of cerebellar neurons is not understood. Here, we report that Kv3.3 channels bind and stimulate Tank Binding Kinase 1 (TBK1), an enzyme that controls trafficking of membrane proteins into multivesicular bodies, and that this stimulation is greatly increased by a disease-causing Kv3.3 mutation. TBK1 activity is required for the binding of Kv3.3 to its auxiliary subunit Hax-1, which prevents channel inactivation with depolarization. Hax-1 is also an anti-apoptotic protein required for survival of cerebellar neurons. Overactivation of TBK1 by the mutant channel leads to the loss of Hax-1 by its accumulation in multivesicular bodies and lysosomes, and also stimulates exosome release from neurons. This process is coupled to activation of caspases and increased cell death. Our studies indicate that Kv3.3 channels are directly coupled to TBK1-dependent biochemical pathways that determine the trafficking of cellular constituents and neuronal survival.
trans-Translation inhibitors bind to a novel site on the ribosome and clear Neisseria gonorrhoeae in vivo
Authors: Aron Zachary D. , Mehrani Atousa , Hoffer Eric D. , Connolly Kristie L. , Srinivas Pooja , Torhan Matthew C. , Alumasa John N. , Cabrera Mynthia , Hosangadi Divya , Barbor Jay S. , Cardinale Steven C. , Kwasny Steven M. , Morin Lucas R. , Butler Michelle M. , Opperman Timothy J. , Bowlin Terry L. , Jerse Ann , Stagg Scott M. , Dunham Christine M. , Keiler Kenneth C. 
Published: March 2021

AbstractBacterial ribosome rescue pathways that remove ribosomes stalled on mRNAs during translation have been proposed as novel antibiotic targets because they are essential in bacteria and are not conserved in humans. We previously reported the discovery of a family of acylaminooxadiazoles that selectively inhibit trans-translation, the main ribosome rescue pathway in bacteria. Here, we report optimization of the pharmacokinetic and antibiotic properties of the acylaminooxadiazoles, producing MBX-4132, which clears multiple-drug resistant Neisseria gonorrhoeae infection in mice after a single oral dose. Single particle cryogenic-EM studies of non-stop ribosomes show that acylaminooxadiazoles bind to a unique site near the peptidyl-transfer center and significantly alter the conformation of ribosomal protein bL27, suggesting a novel mechanism for specific inhibition of trans-translation by these molecules. These results show that trans-translation is a viable therapeutic target and reveal a new conformation within the bacterial ribosome that may be critical for ribosome rescue pathways.
A computational workflow for the expansion of heterologous biosynthetic pathways to natural product derivatives
Authors: Hafner Jasmin , Payne James , MohammadiPeyhani Homa , Hatzimanikatis Vassily , Smolke Christina 
Published: March 2021

AbstractPlant natural products (PNPs) and their derivatives are important but underexplored sources of pharmaceutical molecules. To access this untapped potential, the reconstitution of heterologous PNP biosynthesis pathways in engineered microbes provides a valuable starting point to explore and produce novel PNP derivatives. Here, we introduce a computational workflow to systematically screen the biochemical vicinity of a biosynthetic pathway for pharmaceutical compounds that could be produced by derivatizing pathway intermediates. We apply our workflow to the biosynthetic pathway of noscapine, a benzylisoquinoline alkaloid (BIA) with a long history of medicinal use. Our workflow identifies pathways and enzyme candidates for the production of (S)-tetrahydropalmatine, a known analgesic and anxiolytic, and three additional derivatives. We then construct pathways for these compounds in yeast, resulting in platforms for de novo biosynthesis of BIA derivatives and demonstrating the value of cheminformatic tools to predict reactions, pathways, and enzymes in synthetic biology and metabolic engineering.