bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overaccumulation of p53-mediated autophagy protects against betulinic acid-induced apoptotic cell death in colorectal cancer cells
Authors: Wang Sen , Wang Kexin , Zhang Chundong , Zhang Wanfeng , Xu Qian , Wang Yitao , Zhang Yulin , Li Yi , Zhang Ying , Zhu Huifang , Song Fangzhou , Lei Yunlong , Bu Youquan 
Published: October 2017

AbstractBetulinic acid (BA) exhibits cytotoxic activity against some cancer cells. However, the molecular mechanism of BA against CRC cells was little reported. Here, we proved that BA elicited CRC cells' growth inhibition and apoptosis in a dose-dependent manner. In addition, BA treatment induced autophagy via inhibiting the AKT-MTOR signaling pathway. Inhibition of autophagy by either administration of autophagic inhibitor chloroquine or siRNA-mediated knockdown of ATG5 could augment BA-induced apoptotic cell death as well as inhibition of cell proliferation. Moreover, we found that p53 was firstly activated by short exposure to BA and then was rapidly degraded via the ubiquitin-mediated degradation pathway in both wtp53 and mutp53 CRC cells. Notably, more preferential cytotoxicity of BA was obtained in mutp53 cells (IC50 values: HT29, 125 μM; SW480, 58 μM) rather than wtp53 cells (IC50 values: HCT116, 178 μM). Further experiments demonstrated that siRNA-mediated p53 knockdown attenuated BA-induced autophagy, and forced overexpression of p53 augmented BA-induced autophagy, indicating that p53-enhanced BA-induced autophagy. Moreover, BA enhanced the sensitivity of mutp53 cells to chemotherapy drugs such as 5-FU and ADR by degradation of mutp53. Overall, our study proved that BA could induce CRC cell death by inducing apoptosis and reduce the overaccumulation of BA-induced protective autophagy by degrading wtp53 and mutp53 dependent on the ubiquitin-mediated degradation pathway to achieve killer effect, suggesting that BA might serve as a novel desirable drug for mutp53 cancer therapy.
Bypassing the Kohn-Sham equations with machine learning
Authors: Brockherde Felix , Vogt Leslie , Li Li , Tuckerman Mark E. , Burke Kieron , Müller Klaus-Robert 
Published: October 2017

AbstractLast year, at least 30,000 scientific papers used the Kohn–Sham scheme of density functional theory to solve electronic structure problems in a wide variety of scientific fields. Machine learning holds the promise of learning the energy functional via examples, bypassing the need to solve the Kohn–Sham equations. This should yield substantial savings in computer time, allowing larger systems and/or longer time-scales to be tackled, but attempts to machine-learn this functional have been limited by the need to find its derivative. The present work overcomes this difficulty by directly learning the density-potential and energy-density maps for test systems and various molecules. We perform the first molecular dynamics simulation with a machine-learned density functional on malonaldehyde and are able to capture the intramolecular proton transfer process. Learning density models now allows the construction of accurate density functionals for realistic molecular systems.
Non-canonical reader modules of BAZ1A promote recovery from DNA damage
Authors: Oppikofer Mariano , Sagolla Meredith , Haley Benjamin , Zhang Hui-Min , Kummerfeld Sarah K. , Sudhamsu Jawahar , Flynn E. Megan , Bai Tianyi , Zhang Jennifer , Ciferri Claudio , Cochran Andrea G. 
Published: October 2017

AbstractMembers of the ISWI family of chromatin remodelers mobilize nucleosomes to control DNA accessibility and, in some cases, are required for recovery from DNA damage. However, it remains poorly understood how the non-catalytic ISWI subunits BAZ1A and BAZ1B might contact chromatin to direct the ATPase SMARCA5. Here, we find that the plant homeodomain of BAZ1A, but not that of BAZ1B, has the unusual function of binding DNA. Furthermore, the BAZ1A bromodomain has a non-canonical gatekeeper residue and binds relatively weakly to acetylated histone peptides. Using CRISPR-Cas9-mediated genome editing we find that BAZ1A and BAZ1B each recruit SMARCA5 to sites of damaged chromatin and promote survival. Genetic engineering of structure-designed bromodomain and plant homeodomain mutants reveals that reader modules of BAZ1A and BAZ1B, even when non-standard, are critical for DNA damage recovery in part by regulating ISWI factors loading at DNA lesions and supporting transcriptional programs required for survival.
High-fidelity DNA replication in Mycobacterium tuberculosis relies on a trinuclear zinc center
Authors: Baños-Mateos Soledad , van Roon Anne-Marie M. , Lang Ulla F. , Maslen Sarah L. , Skehel J. Mark , Lamers Meindert H. 
Published: October 2017

AbstractHigh-fidelity DNA replication depends on a proofreading 3′–5′ exonuclease that is associated with the replicative DNA polymerase. The replicative DNA polymerase DnaE1 from the major pathogen Mycobacterium tuberculosis (Mtb) uses its intrinsic PHP-exonuclease that is distinct from the canonical DEDD exonucleases found in the Escherichia coli and eukaryotic replisomes. The mechanism of the PHP-exonuclease is not known. Here, we present the crystal structure of the Mtb DnaE1 polymerase. The PHP-exonuclease has a trinuclear zinc center, coordinated by nine conserved residues. Cryo-EM analysis reveals the entry path of the primer strand in the PHP-exonuclease active site. Furthermore, the PHP-exonuclease shows a striking similarity to E. coli endonuclease IV, which provides clues regarding the mechanism of action. Altogether, this work provides important insights into the PHP-exonuclease and reveals unique properties that make it an attractive target for novel anti-mycobacterial drugs.
The metabolic enzyme fructose-1,6-bisphosphate aldolase acts as a transcriptional regulator in pathogenic Francisella
Authors: Ziveri Jason , Tros Fabiola , Guerrera Ida Chiara , Chhuon Cerina , Audry Mathilde , Dupuis Marion , Barel Monique , Korniotis Sarantis , Fillatreau Simon , Gales Lara , Cahoreau Edern , Charbit Alain 
Published: October 2017

AbstractThe enzyme fructose-bisphosphate aldolase occupies a central position in glycolysis and gluconeogenesis pathways. Beyond its housekeeping role in metabolism, fructose-bisphosphate aldolase has been involved in additional functions and is considered as a potential target for drug development against pathogenic bacteria. Here, we address the role of fructose-bisphosphate aldolase in the bacterial pathogen Francisella novicida. We demonstrate that fructose-bisphosphate aldolase is important for bacterial multiplication in macrophages in the presence of gluconeogenic substrates. In addition, we unravel a direct role of this metabolic enzyme in transcription regulation of genes katG and rpoA, encoding catalase and an RNA polymerase subunit, respectively. We propose a model in which fructose-bisphosphate aldolase participates in the control of host redox homeostasis and the inflammatory immune response.
Quorum sensing integrates environmental cues, cell density and cell history to control bacterial competence
Authors: Moreno-Gámez Stefany , Sorg Robin A. , Domenech Arnau , Kjos Morten , Weissing Franz J. , van Doorn G. Sander , Veening Jan-Willem 
Published: October 2017

AbstractStreptococcus pneumoniae becomes competent for genetic transformation when exposed to an autoinducer peptide known as competence-stimulating peptide (CSP). This peptide was originally described as a quorum-sensing signal, enabling individual cells to regulate competence in response to population density. However, recent studies suggest that CSP may instead serve as a probe for sensing environmental cues, such as antibiotic stress or environmental diffusion. Here, we show that competence induction can be simultaneously influenced by cell density, external pH, antibiotic-induced stress, and cell history. Our experimental data is explained by a mathematical model where the environment and cell history modify the rate at which cells produce or sense CSP. Taken together, model and experiments indicate that autoinducer concentration can function as an indicator of cell density across environmental conditions, while also incorporating information on environmental factors or cell history, allowing cells to integrate cues such as antibiotic stress into their quorum-sensing response. This unifying perspective may apply to other debated quorum-sensing systems.
Molecular identification of the wheat male fertility gene Ms1 and its prospects for hybrid breeding
Authors: Tucker Elise J. , Baumann Ute , Kouidri Allan , Suchecki Radoslaw , Baes Mathieu , Garcia Melissa , Okada Takashi , Dong Chongmei , Wu Yongzhong , Sandhu Ajay , Singh Manjit , Langridge Peter , Wolters Petra , Albertsen Marc C. , Cigan A. Mark , Whitford Ryan 
Published: October 2017

AbstractThe current rate of yield gain in crops is insufficient to meet the predicted demands. Capturing the yield boost from heterosis is one of the few technologies that offers rapid gain. Hybrids are widely used for cereals, maize and rice, but it has been a challenge to develop a viable hybrid system for bread wheat due to the wheat genome complexity, which is both large and hexaploid. Wheat is our most widely grown crop providing 20% of the calories for humans. Here, we describe the identification of Ms1, a gene proposed for use in large-scale, low-cost production of male-sterile (ms) female lines necessary for hybrid wheat seed production. We show that Ms1 completely restores fertility to ms1d, and encodes a glycosylphosphatidylinositol-anchored lipid transfer protein, necessary for pollen exine development. This represents a key step towards developing a robust hybridization platform in wheat.
An NF-κB-microRNA regulatory network tunes macrophage inflammatory responses
Authors: Mann Mati , Mehta Arnav , Zhao Jimmy L. , Lee Kevin , Marinov Georgi K. , Garcia-Flores Yvette , Lu Li-Fan , Rudensky Alexander Y. , Baltimore David 
Published: October 2017

AbstractThe innate inflammatory response must be tightly regulated to ensure effective immune protection. NF-κB is a key mediator of the inflammatory response, and its dysregulation has been associated with immune-related malignancies. Here, we describe a miRNA-based regulatory network that enables precise NF-κB activity in mouse macrophages. Elevated miR-155 expression potentiates NF-κB activity in miR-146a-deficient mice, leading to both an overactive acute inflammatory response and chronic inflammation. Enforced miR-155 expression overrides miR-146a-mediated repression of NF-κB activation, thus emphasizing the dominant function of miR-155 in promoting inflammation. Moreover, miR-155-deficient macrophages exhibit a suboptimal inflammatory response when exposed to low levels of inflammatory stimuli. Importantly, we demonstrate a temporal asymmetry between miR-155 and miR-146a expression during macrophage activation, which creates a combined positive and negative feedback network controlling NF-κB activity. This miRNA-based regulatory network enables a robust yet time-limited inflammatory response essential for functional immunity.
Electrical magnetochiral effect induced by chiral spin fluctuations
Authors: Yokouchi T. , Kanazawa N. , Kikkawa A. , Morikawa D. , Shibata K. , Arima T. , Taguchi Y. , Kagawa F. , Tokura Y. 
Published: October 2017

AbstractChirality of matter can produce unique responses in optics, electricity and magnetism. In particular, magnetic crystals transmit their handedness to the magnetism via antisymmetric exchange interaction of relativistic origin, producing helical spin orders as well as their fluctuations. Here we report for a chiral magnet MnSi that chiral spin fluctuations manifest themselves in the electrical magnetochiral effect, i.e. the nonreciprocal and nonlinear response characterized by the electrical resistance depending on inner product of current and magnetic field. Prominent electrical magnetochiral signals emerge at specific temperature-magnetic field-pressure regions: in the paramagnetic phase just above the helical ordering temperature and in the partially-ordered topological spin state at low temperatures and high pressures, where thermal and quantum spin fluctuations are conspicuous in proximity of classical and quantum phase transitions, respectively. The finding of the asymmetric electron scattering by chiral spin fluctuations may explore new electromagnetic functionality in chiral magnets.
Replication fork reversal triggers fork degradation in BRCA2-defective cells
Authors: Mijic Sofija , Zellweger Ralph , Chappidi Nagaraja , Berti Matteo , Jacobs Kurt , Mutreja Karun , Ursich Sebastian , Ray Chaudhuri Arnab , Nussenzweig Andre , Janscak Pavel , Lopes Massimo 
Published: October 2017

AbstractBesides its role in homologous recombination, the tumor suppressor BRCA2 protects stalled replication forks from nucleolytic degradation. Defective fork stability contributes to chemotherapeutic sensitivity of BRCA2-defective tumors by yet-elusive mechanisms. Using DNA fiber spreading and direct visualization of replication intermediates, we report that reversed replication forks are entry points for fork degradation in BRCA2-defective cells. Besides MRE11 and PTIP, we show that RAD52 promotes stalled fork degradation and chromosomal breakage in BRCA2-defective cells. Inactivation of these factors restores reversed fork frequency and chromosome integrity in BRCA2-defective cells. Conversely, impairing fork reversal prevents fork degradation, but increases chromosomal breakage, uncoupling fork protection, and chromosome stability. We propose that BRCA2 is dispensable for RAD51-mediated fork reversal, but assembles stable RAD51 nucleofilaments on regressed arms, to protect them from degradation. Our data uncover the physiopathological relevance of fork reversal and illuminate a complex interplay of homologous recombination factors in fork remodeling and stability.
The recording and characteristics of pulmonary rehabilitation in patients with COPD using The Health Information Network (THIN) primary care database
Authors: Hakamy Ali , McKeever Tricia M. , Gibson Jack E. , Bolton Charlotte E. 
Published: October 2017

AbstractPulmonary rehabilitation is recommended for patients with COPD to improve physical function, breathlessness and quality of life. Using The Health Information Network (THIN) primary care database in UK, we compared the demographic and clinical parameters of patients with COPD in relation to coding of pulmonary rehabilitation, and to investigate whether there is a survival benefit from pulmonary rehabilitation. We identified patients with COPD, diagnosed from 2004 and extracted information on demographics, pulmonary rehabilitation and clinical parameters using the relevant Read codes. Thirty six thousand one hundred and eighty nine patients diagnosed with COPD were included with a mean (SD) age of 67 (11) years, 53% were male and only 9.8% had a code related to either being assessed, referred, or completing pulmonary rehabilitation ever. Younger age at diagnosis, better socioeconomic status, worse dyspnoea score, current smoking, and higher comorbidities level are more likely to have a record of pulmonary rehabilitation. Of those with a recorded MRC of 3 or worse, only 2057 (21%) had a code of pulmonary rehabilitation. Survival analysis revealed that patients with coding for pulmonary rehabilitation were 22% (95% CI 0.69–0.88) less likely to die than those who had no coding. In UK THIN records, a substantial proportion of eligible patients with COPD have not had a coded pulmonary rehabilitation record. Survival was improved in those with PR record but coding for other COPD treatments were also better in this group. GP practices need to improve the coding for PR to highlight any unmet need locally.
Photonic Sorting of Aligned, Crystalline Carbon Nanotube Textiles
Authors: Bulmer John S. , Gspann Thurid S. , Orozco Francisco , Sparkes Martin , Koerner Hilmar , Di Bernardo A. , Niemiec Arkadiusz , Robinson J. W. A. , Koziol Krzysztof K. , Elliott James A. , O’Neill William 
Published: October 2017

AbstractFloating catalyst chemical vapor deposition uniquely generates aligned carbon nanotube (CNT) textiles with individual CNT lengths magnitudes longer than competing processes, though hindered by impurities and intrinsic/extrinsic defects. We present a photonic-based post-process, particularly suited for these textiles, that selectively removes defective CNTs and other carbons not forming a threshold thermal pathway. In this method, a large diameter laser beam rasters across the surface of a partly aligned CNT textile in air, suspended from its ends. This results in brilliant, localized oxidation, where remaining material is an optically transparent film comprised of few-walled CNTs with profound and unique improvement in microstructure alignment and crystallinity. Raman spectroscopy shows substantial D peak suppression while preserving radial breathing modes. This increases the undoped, specific electrical conductivity at least an order of magnitude to beyond that of single-crystal graphite. Cryogenic conductivity measurements indicate intrinsic transport enhancement, opposed to simply removing nonconductive carbons/residual catalyst.
Digital nonlinearity compensation in high-capacity optical communication systems considering signal spectral broadening effect
Authors: Xu Tianhua , Karanov Boris , Shevchenko Nikita A. , Lavery Domaniç , Liga Gabriele , Killey Robert I. , Bayvel Polina 
Published: October 2017

AbstractNyquist-spaced transmission and digital signal processing have proved effective in maximising the spectral efficiency and reach of optical communication systems. In these systems, Kerr nonlinearity determines the performance limits, and leads to spectral broadening of the signals propagating in the fibre. Although digital nonlinearity compensation was validated to be promising for mitigating Kerr nonlinearities, the impact of spectral broadening on nonlinearity compensation has never been quantified. In this paper, the performance of multi-channel digital back-propagation (MC-DBP) for compensating fibre nonlinearities in Nyquist-spaced optical communication systems is investigated, when the effect of signal spectral broadening is considered. It is found that accounting for the spectral broadening effect is crucial for achieving the best performance of DBP in both single-channel and multi-channel communication systems, independent of modulation formats used. For multi-channel systems, the degradation of DBP performance due to neglecting the spectral broadening effect in the compensation is more significant for outer channels. Our work also quantified the minimum bandwidths of optical receivers and signal processing devices to ensure the optimal compensation of deterministic nonlinear distortions.
Linked magnolol dimer as a selective PPARγ agonist – Structure-based rational design, synthesis, and bioactivity evaluation
Authors: Dreier Dominik , Latkolik Simone , Rycek Lukas , Schnürch Michael , Dymáková Andrea , Atanasov Atanas G. , Ladurner Angela , Heiss Elke H. , Stuppner Hermann , Schuster Daniela , Mihovilovic Marko D. , Dirsch Verena M. 
Published: October 2017

AbstractThe nuclear receptors peroxisome proliferator-activated receptor γ (PPARγ) and its hetero-dimerization partner retinoid X receptor α (RXRα) are considered as drug targets in the treatment of diseases like the metabolic syndrome and diabetes mellitus type 2. Effort has been made to develop new agonists for PPARγ to obtain ligands with more favorable properties than currently used drugs. Magnolol was previously described as dual agonist of PPARγ and RXRα. Here we show the structure-based rational design of a linked magnolol dimer within the ligand binding domain of PPARγ and its synthesis. Furthermore, we evaluated its binding properties and functionality as a PPARγ agonist in vitro with the purified PPARγ ligand binding domain (LBD) and in a cell-based nuclear receptor transactivation model in HEK293 cells. We determined the synthesized magnolol dimer to bind with much higher affinity to the purified PPARγ ligand binding domain than magnolol (Ki values of 5.03 and 64.42 nM, respectively). Regarding their potency to transactivate a PPARγ-dependent luciferase gene both compounds were equally effective. This is likely due to the PPARγ specificity of the newly designed magnolol dimer and lack of RXRα-driven transactivation activity by this dimeric compound.
Glomalin contributed more to carbon, nutrients in deeper soils, and differently associated with climates and soil properties in vertical profiles
Authors: Wang Wenjie , Zhong Zhaoliang , Wang Qiong , Wang Humei , Fu Yujie , He Xingyuan 
Published: October 2017

AbstractDespite vital importance in soil conditioning and a proxy for arbuscular mycorrhizal (AMF), glomalin-related soil protein (GRSP) contribution to soil carbon and nutrients at vertical soil profiles and underlying mechanism were not well-defined yet. Thus, 360 soil samples were collected from 72 farmland 1-m soil profiles in northeastern China, and soil physiochemical properties, nutrients, glomalin characteristics, local climates were determined. Linear decreases of glomalin amounts were observed from the top to deep soils, and glomalin/SOC (glomalin ratio to total SOC) in the 80–100 cm soil (EEG, easily-extracted GRSP, 2.2%; TG, total GRSP, 19%) was 1.34–1.5-fold higher than did in the 0–20 cm soil. Different statistical analyses crosschecked that the lower pH and higher SOC usually accompanied with the higher EEG and TG, while EEG was more sensitive to climates; Moreover, glomalin was more physiochemical-regulated in the deep soils, but more nutrient-regulation was found in the surface soils. Structure Equation Model showed that soil depths and climates indirectly affected TG and EEG features through soil properties, except significant direct effects on EEG. In future, glomalin assessment should fully consider these for identifying the AMF importance in the whole 1-m profile, and our findings also favor degrade soil improvement from glomalin rehabilitation.
The thiazide sensitive sodium chloride co-transporter NCC is modulated by site-specific ubiquitylation
Authors: Rosenbaek Lena L. , Rizzo Federica , Wu Qi , Rojas-Vega Lorena , Gamba Gerardo , MacAulay Nanna , Staub Olivier , Fenton Robert A. 
Published: October 2017

AbstractThe renal sodium chloride cotransporter, NCC, in the distal convoluted tubule is important for maintaining body Na+ and K+ homeostasis. Endogenous NCC is highly ubiquitylated, but the role of individual ubiquitylation sites is not established. Here, we assessed the role of 10 ubiquitylation sites for NCC function. Transient transfections of HEK293 cells with human wildtype (WT) NCC or various K to R mutants identified greater membrane abundance for K706R, K828R and K909R mutants. Relative to WT-NCC, stable tetracycline inducible MDCKI cell lines expressing K706R, K828R and K909R mutants had significantly higher total and phosphorylated NCC levels at the apical plasma membrane under basal conditions. Low chloride stimulation increased membrane abundance of all mutants to similar or greater levels than WT-NCC. Under basal conditions K828R and K909R mutants had less ubiquitylated NCC in the plasma membrane, and all mutants displayed reduced NCC ubiquitylation following low chloride stimulation. Thiazide-sensitive sodium-22 uptakes were elevated in the mutants and internalization from the plasma membrane was significantly less than WT-NCC. K909R had increased half-life, whereas chloroquine or MG132 treatment indicated that K706 and K909 play roles in lysosomal and proteasomal NCC degradation, respectively. In conclusion, site-specific ubiquitylation of NCC plays alternative roles for NCC function.