bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modelling proteins’ hidden conformations to predict antibiotic resistance
Authors: Hart Kathryn M. , Ho Chris M. W. , Dutta Supratik , Gross Michael L. , Bowman Gregory R. 
Published: October 2016

AbstractTEM β-lactamase confers bacteria with resistance to many antibiotics and rapidly evolves activity against new drugs. However, functional changes are not easily explained by differences in crystal structures. We employ Markov state models to identify hidden conformations and explore their role in determining TEM’s specificity. We integrate these models with existing drug-design tools to create a new technique, called Boltzmann docking, which better predicts TEM specificity by accounting for conformational heterogeneity. Using our MSMs, we identify hidden states whose populations correlate with activity against cefotaxime. To experimentally detect our predicted hidden states, we use rapid mass spectrometric footprinting and confirm our models’ prediction that increased cefotaxime activity correlates with reduced Ω-loop flexibility. Finally, we design novel variants to stabilize the hidden cefotaximase states, and find their populations predict activity against cefotaxime in vitro and in vivo. Therefore, we expect this framework to have numerous applications in drug and protein design.
Competitive solvent-molecule interactions govern primary processes of diphenylcarbene in solvent mixtures
Authors: Knorr Johannes , Sokkar Pandian , Schott Sebastian , Costa Paolo , Thiel Walter , Sander Wolfram , Sanchez-Garcia Elsa , Nuernberger Patrick 
Published: October 2016

AbstractPhotochemical reactions in solution often proceed via competing reaction pathways comprising intermediates that capture a solvent molecule. A disclosure of the underlying reaction mechanisms is challenging due to the rapid nature of these processes and the intricate identification of how many solvent molecules are involved. Here combining broadband femtosecond transient absorption and quantum mechanics/molecular mechanics simulations, we show for one of the most reactive species, diphenylcarbene, that the decision-maker is not the nearest solvent molecule but its neighbour. The hydrogen bonding dynamics determine which reaction channels are accessible in binary solvent mixtures at room temperature. In-depth analysis of the amount of nascent intermediates corroborates the importance of a hydrogen-bonded complex with a protic solvent molecule, in striking analogy to complexes found at cryogenic temperatures. Our results show that adjacent solvent molecules take the role of key abettors rather than bystanders for the fate of the reactive intermediate.
Differential hepatic distribution of insulin receptor substrates causes selective insulin resistance in diabetes and obesity
Authors: Kubota Naoto , Kubota Tetsuya , Kajiwara Eiji , Iwamura Tomokatsu , Kumagai Hiroki , Watanabe Taku , Inoue Mariko , Takamoto Iseki , Sasako Takayoshi , Kumagai Katsuyoshi , Kohjima Motoyuki , Nakamuta Makoto , Moroi Masao , Sugi Kaoru , Noda Tetsuo , Terauchi Yasuo , Ueki Kohjiro , Kadowaki Takashi 
Published: October 2016

AbstractHepatic insulin signalling involves insulin receptor substrates (Irs) 1/2, and is normally associated with the inhibition of gluconeogenesis and activation of lipogenesis. In diabetes and obesity, insulin no longer suppresses hepatic gluconeogenesis, while continuing to activate lipogenesis, a state referred to as ‘selective insulin resistance’. Here, we show that ‘selective insulin resistance’ is caused by the differential expression of Irs1 and Irs2 in different zones of the liver. We demonstrate that hepatic Irs2-knockout mice develop ‘selective insulin resistance’, whereas mice lacking in Irs1, or both Irs1 and Irs2, develop ‘total insulin resistance’. In obese diabetic mice, Irs1/2-mediated insulin signalling is impaired in the periportal zone, which is the primary site of gluconeogenesis, but enhanced in the perivenous zone, which is the primary site of lipogenesis. While hyperinsulinaemia reduces Irs2 expression in both the periportal and perivenous zones, Irs1 expression, which is predominantly in the perivenous zone, remains mostly unaffected. These data suggest that ‘selective insulin resistance’ is induced by the differential distribution, and alterations of hepatic Irs1 and Irs2 expression.
A high-quality human reference panel reveals the complexity and distribution of genomic structural variants
Authors: Hehir-Kwa Jayne Y. , Marschall Tobias , Kloosterman Wigard P. , Francioli Laurent C. , Baaijens Jasmijn A. , Dijkstra Louis J. , Abdellaoui Abdel , Koval Vyacheslav , Thung Djie Tjwan , Wardenaar René , Renkens Ivo , Coe Bradley P. , Deelen Patrick , de Ligt Joep , Lameijer Eric-Wubbo , van Dijk Freerk , Hormozdiari Fereydoun ,   The Genome of the Netherlands Consortium, Bovenberg Jasper A. , de Craen Anton J. M. , Beekman Marian , Hofman Albert , Willemsen Gonneke , Wolffenbuttel Bruce , Platteel Mathieu , Du Yuanping , Chen Ruoyan , Cao Hongzhi , Cao Rui , Sun Yushen , Cao Jeremy Sujie , Neerincx Pieter B. T. , Dijkstra Martijn , Byelas George , Kanterakis Alexandros , Bot Jan , Vermaat Martijn , Laros Jeroen F. J. , den Dunnen Johan T. , de Knijff Peter , Karssen Lennart C. , van Leeuwen Elisa M. , Amin Najaf , Rivadeneira Fernando , Estrada Karol , Hottenga Jouke-Jan , Kattenberg V. Mathijs , van Enckevort David , Mei Hailiang , Santcroos Mark , van Schaik Barbera D. C. , Handsaker Robert E. , McCarroll Steven A. , Ko Arthur , Sudmant Peter , Nijman Isaac J. , Uitterlinden André G. , van Duijn Cornelia M. , Eichler Evan E. , de Bakker Paul I. W. , Swertz Morris A. , Wijmenga Cisca , van Ommen Gert-Jan B. , Slagboom P. Eline , Boomsma Dorret I. , Schönhuth Alexander , Ye Kai , Guryev Victor 
Published: October 2016

AbstractStructural variation (SV) represents a major source of differences between individual human genomes and has been linked to disease phenotypes. However, the majority of studies provide neither a global view of the full spectrum of these variants nor integrate them into reference panels of genetic variation. Here, we analyse whole genome sequencing data of 769 individuals from 250 Dutch families, and provide a haplotype-resolved map of 1.9 million genome variants across 9 different variant classes, including novel forms of complex indels, and retrotransposition-mediated insertions of mobile elements and processed RNAs. A large proportion are previously under reported variants sized between 21 and 100 bp. We detect 4 megabases of novel sequence, encoding 11 new transcripts. Finally, we show 191 known, trait-associated SNPs to be in strong linkage disequilibrium with SVs and demonstrate that our panel facilitates accurate imputation of SVs in unrelated individuals.
Genome sequence of the basal haplorrhine primate Tarsius syrichta reveals unusual insertions
Authors: Schmitz Jürgen , Noll Angela , Raabe Carsten A. , Churakov Gennady , Voss Reinhard , Kiefmann Martin , Rozhdestvensky Timofey , Brosius Jürgen , Baertsch Robert , Clawson Hiram , Roos Christian , Zimin Aleksey , Minx Patrick , Montague Michael J. , Wilson Richard K. , Warren Wesley C. 
Published: October 2016

AbstractTarsiers are phylogenetically located between the most basal strepsirrhines and the most derived anthropoid primates. While they share morphological features with both groups, they also possess uncommon primate characteristics, rendering their evolutionary history somewhat obscure. To investigate the molecular basis of such attributes, we present here a new genome assembly of the Philippine tarsier (Tarsius syrichta), and provide extended analyses of the genome and detailed history of transposable element insertion events. We describe the silencing ofAlumonomers on the lineage leading to anthropoids, and recognize an unexpected abundance of long terminal repeat-derived and LINE1-mobilized transposed elements (Tarsiusinterspersed elements; TINEs). For the first time in mammals, we identify a complete mitochondrial genome insertion within the nuclear genome, then reveal tarsier-specific, positive gene selection and posit population size changes over time. The genomic resources and analyses presented here will aid efforts to more fully understand the ancient characteristics of primate genomes.
Tuning the catalytic CO hydrogenation to straight- and long-chain aldehydes/alcohols and olefins/paraffins
Authors: Xiang Yizhi , Kruse Norbert 
Published: October 2016

AbstractThe catalytic CO hydrogenation is one of the most versatile large-scale chemical syntheses leading to variable chemical feedstock. While traditionally mainly methanol and long-chain hydrocarbons are produced by CO hydrogenation, here we show that the same reaction can be tuned to produce long-chain n-aldehydes, 1-alcohols and olefins, as well as n-paraffins over potassium-promoted CoMn catalysts. The sum selectivity of aldehydes and alcohols is usually >50 wt% whereof up to ∼97% can be n-aldehydes. While the product slate contains ∼60% n-aldehydes at "Equation missing"/pCO=0.5, a 65/35% slate of paraffins/alcohols is obtained at a ratio of 9. A linear Anderson–Schulz–Flory behaviour, independent of the "Equation missing"/pCO ratio, is found for the sum of C4+ products. We advocate a synergistic interaction between a Mn5O8 oxide and a bulk Co2C phase, promoted by the presence of potassium, to be responsible for the unique product spectra in our studies.
Spatiotemporal control of cell–cell reversible interactions using molecular engineering
Authors: Shi Peng , Ju Enguo , Yan Zhengqing , Gao Nan , Wang Jiasi , Hou Jianwen , Zhang Yan , Ren Jinsong , Qu Xiaogang 
Published: October 2016

AbstractManipulation of cell–cell interactions has potential applications in basic research and cell-based therapy. Herein, using a combination of metabolic glycan labelling and bio-orthogonal click reaction, we engineer cell membranes with β-cyclodextrin and subsequently manipulate cell behaviours via photo-responsive host-guest recognition. With this methodology, we demonstrate reversible manipulation of cell assembly and disassembly. The method enables light-controllable reversible assembly of cell–cell adhesion, in contrast with previously reported irreversible effects, in which altered structure could not be reused. We also illustrate the utility of the method by designing a cell-based therapy. Peripheral blood mononuclear cells modified with aptamer are effectively redirected towards target cells, resulting in enhanced cell apoptosis. Our approach allows precise control of reversible cell–cell interactions and we expect that it will promote further developments of cell-based therapy.
The scaffold protein Tks4 is required for the differentiation of mesenchymal stromal cells (MSCs) into adipogenic and osteogenic lineages
Authors: Dülk Metta , Kudlik Gyöngyi , Fekete Anna , Ernszt Dávid , Kvell Krisztián , Pongrácz Judit E. , Merő Balázs L. , Szeder Bálint , Radnai László , Geiszt Miklós , Csécsy Dalma E. , Kovács Tamás , Uher Ferenc , Lányi Árpád , Vas Virag , Buday László 
Published: October 2016

AbstractThe commitment steps of mesenchymal stromal cells (MSCs) to adipogenic and other lineages have been widely studied but not fully understood. Therefore, it is critical to understand which molecules contribute to the conversion of stem cells into differentiated cells. The scaffold protein Tks4 plays a role in podosome formation, EGFR signaling and ROS production. Dysfunction of Tks4 causes a hereditary disease called Frank-ter Haar syndrome with a variety of defects concerning certain mesenchymal tissues (bone, fat and cartilage) throughout embryogenic and postnatal development. In this study, we aimed to analyze how the mutation of Tks4 affects the differentiation potential of multipotent bone marrow MSCs (BM-MSCs). We generated a Tks4 knock-out mouse strain on C57Bl/6 background and characterized BM-MSCs isolated from wild type and Tks4−/− mice to evaluate their differentiation. Tks4−/− BM-MSCs had reduced ability to differentiate into osteogenic and adipogenic lineages compared to wild type. Studying the expression profile of a panel of lipid-regulated genes during adipogenic induction revealed that the expression of adipogenic transcription factors, genes responsible for lipid droplet formation, sterol and fatty acid metabolism was delayed or reduced in Tks4−/− BM-MSCs. Taken together, these results establish a novel function for Tks4 in the regulation of MSC differentiation.
Improved Cryopreservation of Human Umbilical Vein Endothelial Cells: A Systematic Approach
Authors: Sultani A. Billal , Marquez-Curtis Leah A. , Elliott Janet A. W. , McGann Locksley E. 
Published: October 2016

AbstractCryopreservation of human umbilical vein endothelial cells (HUVECs) facilitated their commercial availability for use in vascular biology, tissue engineering and drug delivery research; however, the key variables in HUVEC cryopreservation have not been comprehensively studied. HUVECs are typically cryopreserved by cooling at 1 °C/min in the presence of 10% dimethyl sulfoxide (DMSO). We applied interrupted slow cooling (graded freezing) and interrupted rapid cooling with a hold time (two-step freezing) to identify where in the cooling process cryoinjury to HUVECs occurs. We found that linear cooling at 1 °C/min resulted in higher membrane integrities than linear cooling at 0.2 °C/min or nonlinear two-step freezing. DMSO addition procedures and compositions were also investigated. By combining hydroxyethyl starch with DMSO, HUVEC viability after cryopreservation was improved compared to measured viabilities of commercially available cryopreserved HUVECs and viabilities for HUVEC cryopreservation studies reported in the literature. Furthermore, HUVECs cryopreserved using our improved procedure showed high tube forming capability in a post-thaw angiogenesis assay, a standard indicator of endothelial cell function. As well as presenting superior cryopreservation procedures for HUVECs, the methods developed here can serve as a model to optimize the cryopreservation of other cells.
Characterization of maize roothairless6 which encodes a D-type cellulose synthase and controls the switch from bulge formation to tip growth
Authors: Li Li , Hey Stefan , Liu Sanzhen , Liu Qiang , McNinch Colton , Hu Heng-Cheng , Wen Tsui-Jung , Marcon Caroline , Paschold Anja , Bruce Wesley , Schnable Patrick S. , Hochholdinger Frank 
Published: October 2016

AbstractRoot hairs are tubular extensions of the epidermis. Root hairs of the monogenic recessive maize mutant roothairless 6 (rth6) are arrested after bulge formation during the transition to tip growth and display a rough cell surface. BSR-Seq in combination with Seq-walking and subsequent analyses of four independently generated mutant alleles established that rth6 encodes CSLD5 a plasma membrane localized 129 kD D-type cellulose synthase with eight transmembrane domains. Cellulose synthases are required for the biosynthesis of cellulose, the most abundant biopolymer of plant cell walls. Phylogenetic analyses revealed that RTH6 is part of a monocot specific clade of D-type cellulose synthases. D-type cellulose synthases are highly conserved in the plant kingdom with five gene family members in maize and homologs even among early land plants such as the moss Physcomitrella patens or the clubmoss Selaginella moellendorffii. Expression profiling demonstrated that rth6 transcripts are highly enriched in root hairs as compared to all other root tissues. Moreover, in addition to the strong knock down of rth6 expression in young primary roots of the mutant rth6, the gene is also significantly down-regulated in rth3 and rth5 mutants, while it is up-regulated in rth2 mutants, suggesting that these genes interact in cell wall biosynthesis.
Mechanism and comparison of needle-type non-thermal direct and indirect atmospheric pressure plasma jets on the degradation of dyes
Authors: Attri Pankaj , Yusupov Maksudbek , Park Ji Hoon , Lingamdinne Lakshmi Prasanna , Koduru Janardhan Reddy , Shiratani Masaharu , Choi Eun Ha , Bogaerts Annemie 
Published: October 2016

AbstractPurified water supply for human use, agriculture and industry is the major global priority nowadays. The advanced oxidation process based on atmospheric pressure non-thermal plasma (NTP) has been used for purification of wastewater, although the underlying mechanisms of degradation of organic pollutants are still unknown. In this study we employ two needle-type atmospheric pressure non-thermal plasma jets, i.e., indirect (ID-APPJ) and direct (D-APPJ) jets operating at Ar feed gas, for the treatment of methylene blue, methyl orange and congo red dyes, for two different times (i.e., 20 min and 30 min). Specifically, we study the decolorization/degradation of all three dyes using the above mentioned plasma sources, by means of UV-Vis spectroscopy, HPLC and a density meter. We also employ mass spectroscopy to verify whether only decolorization or also degradation takes place after treatment of the dyes by the NTP jets. Additionally, we analyze the interaction of OH radicals with all three dyes using reactive molecular dynamics simulations, based on the density functional-tight binding method. This investigation represents the first report on the degradation of these three different dyes by two types of NTP setups, analyzed by various methods, and based on both experimental and computational studies.
Nonlinear backbone torsional pair correlations in proteins
Authors: Long Shiyang , Tian Pu 
Published: October 2016

AbstractProtein allostery requires dynamical structural correlations. Physical origin of which, however, remain elusive despite intensive studies during last two and half decades. Based on analysis of molecular dynamics (MD) simulation trajectories for ten proteins with different sizes and folds, we found that nonlinear backbone torsional pair (BTP) correlations, which are mainly spatially long-ranged and are dominantly executed by loop residues, exist extensively in most analyzed proteins. Examination of torsional motion for correlated BTPs suggested that such nonlinear correlations are mainly associated aharmonic torsional state transitions and in some cases strongly anisotropic local torsional motion of participating torsions and occur on widely different and relatively longer time scales. In contrast, correlations between backbone torsions in stable α helices and β strands are mainly linear and spatially short-ranged and are more likely to associate with harmonic local torsional motion. Further analysis revealed that the direct cause of nonlinear contributions are heterogeneous linear correlations. These findings implicate a general search strategy for novel allosteric modulation sites of protein activities.
Characterization of the DNA dependent activation of human ARTD2/PARP2
Authors: Obaji Ezeogo , Haikarainen Teemu , Lehtiö Lari 
Published: October 2016

AbstractHuman ADP-ribosyltransferase 2 (ARTD2/PARP2) is an enzyme catalyzing a post-translational modification, ADP-ribosylation. It is one of the three DNA dependent ARTDs in the 17 member enzyme family. ADP-ribosylation catalyzed by ARTD2 is involved in the regulation of multiple cellular processes such as control of chromatin remodeling, transcription and DNA repair. Here we used a combination of biochemical and biophysical methods to elucidate the structure and function of ARTD2. The solution structures revealed the binding mode of the ARTD2 monomer and dimer to oligonucleotides that mimic damaged DNA. In the complex, DNA binds between the WGR domain and the catalytic fragment. The binding mode is supported by biophysical data that indicate all domains contribute to DNA binding. Also, our study showed that ARTD2 is preferentially activated by short 5′-phosphorylated DNA oligonucleotides. We demonstrate that the N-terminus functions as a high-affinity DNA-binding module, while the WGR domain contributes to DNA binding specificity and subsequent catalytic activation. Our data further suggest that ARTD2 would function in double strand break repair as a dimeric module, while in single strand break repair it would function as a monomer.
Splice variants of the CaV1.3 L-type calcium channel regulate dendritic spine morphology
Authors: Stanika Ruslan , Campiglio Marta , Pinggera Alexandra , Lee Amy , Striessnig Jörg , Flucher Bernhard E. , Obermair Gerald J. 
Published: October 2016

AbstractDendritic spines are the postsynaptic compartments of glutamatergic synapses in the brain. Their number and shape are subject to change in synaptic plasticity and neurological disorders including autism spectrum disorders and Parkinson’s disease. The L-type calcium channel CaV1.3 constitutes an important calcium entry pathway implicated in the regulation of spine morphology. Here we investigated the importance of full-length CaV1.3L and two C-terminally truncated splice variants (CaV1.342A and CaV1.343S) and their modulation by densin-180 and shank1b for the morphology of dendritic spines of cultured hippocampal neurons. Live-cell immunofluorescence and super-resolution microscopy of epitope-tagged CaV1.3L revealed its localization at the base-, neck- and head-region of dendritic spines. Expression of the short splice variants or deletion of the C-terminal PDZ-binding motif in CaV1.3L induced aberrant dendritic spine elongation. Similar morphological alterations were induced by co-expression of densin-180 or shank1b with CaV1.3L and correlated with increased CaV1.3 currents and dendritic calcium signals in transfected neurons. Together, our findings suggest a key role of CaV1.3 in regulating dendritic spine structure. Under physiological conditions it may contribute to the structural plasticity of glutamatergic synapses. Conversely, altered regulation of CaV1.3 channels may provide an important mechanism in the development of postsynaptic aberrations associated with neurodegenerative disorders.
Biodiversity loss and turnover in alternative states in the Mediterranean Sea: a case study on meiofauna
Authors: Bianchelli Silvia , Buschi Emanuela , Danovaro Roberto , Pusceddu Antonio 
Published: October 2016

AbstractIn the Mediterranean Sea hard-bottom macroalgal meadows may switch to alternative and less-productive barrens grounds, as a result of sea urchins overgrazing. Meiofauna (and especially nematodes) represent key components of benthic ecosystems, are highly-diversified, sensitive to environmental change and anthropogenic impacts, but, so-far, have been neglected in studies on regime shifts. We report here that sedimentary organic matter contents, meiofaunal taxa richness and community composition, nematode α- and β-biodiversity vary significantly between alternative macroalgal and barren states. The observed differences are consistent in six areas spread across the Mediterranean Sea, irrespective of barren extent. Our results suggest also that the low biodiversity levels in barren states are the result of habitat loss/fragmentation, which is associated also with a lower availability of trophic resources. Furthermore, differences in meiofaunal and nematode abundance, biomass and diversity between macroalgal meadow and barren states persist when the latter is not fully formed, or consists of patches interspersed in macroalgal meadows. Since barren grounds are expanding rapidly along the Mediterranean Sea and meiofauna are a key trophic component in marine ecosystems, we suggest that the extension and persistence of barrens at the expenses of macroalgal meadows could also affect resilience of higher trophic level.