bluuebunny/crossref_metadata_2025_split huggingface dataset:
A quantum spin-probe molecular microscope
Authors: Perunicic V. S. , Hill C. D. , Hall L. T. , Hollenberg L.C.L. 
Published: October 2016

AbstractImaging the atomic structure of a single biomolecule is an important challenge in the physical biosciences. Whilst existing techniques all rely on averaging over large ensembles of molecules, the single-molecule realm remains unsolved. Here we present a protocol for 3D magnetic resonance imaging of a single molecule using a quantum spin probe acting simultaneously as the magnetic resonance sensor and source of magnetic field gradient. Signals corresponding to specific regions of the molecule’s nuclear spin density are encoded on the quantum state of the probe, which is used to produce a 3D image of the molecular structure. Quantum simulations of the protocol applied to the rapamycin molecule (C51H79NO13) show that the hydrogen and carbon substructure can be imaged at the angstrom level using current spin-probe technology. With prospects for scaling to large molecules and/or fast dynamic conformation mapping using spin labels, this method provides a realistic pathway for single-molecule microscopy.
Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors
Authors: Zuhl Andrea M. , Nolan Charles E. , Brodney Michael A. , Niessen Sherry , Atchison Kevin , Houle Christopher , Karanian David A. , Ambroise Claude , Brulet Jeffrey W. , Beck Elizabeth M. , Doran Shawn D. , O’Neill Brian T. , am Ende Christopher W. , Chang Cheng , Geoghegan Kieran F. , West Graham M. , Judkins Joshua C. , Hou Xinjun , Riddell David R. , Johnson Douglas S. 
Published: October 2016

AbstractInhibition of β-secretase BACE1 is considered one of the most promising approaches for treating Alzheimer’s disease. Several structurally distinct BACE1 inhibitors have been withdrawn from development after inducing ocular toxicity in animal models, but the target mediating this toxicity has not been identified. Here we use a clickable photoaffinity probe to identify cathepsin D (CatD) as a principal off-target of BACE1 inhibitors in human cells. We find that several BACE1 inhibitors blocked CatD activity in cells with much greater potency than that displayed in cell-free assays with purified protein. Through a series of exploratory toxicology studies, we show that quantifying CatD target engagement in cells with the probe is predictive of ocular toxicity in vivo. Taken together, our findings designate off-target inhibition of CatD as a principal driver of ocular toxicity for BACE1 inhibitors and more generally underscore the power of chemical proteomics for discerning mechanisms of drug action.
Circumpolar distribution and carbon storage of thermokarst landscapes
Authors: Olefeldt D. , Goswami S. , Grosse G. , Hayes D. , Hugelius G. , Kuhry P. , McGuire A. D. , Romanovsky V. E. , Sannel A.B.K. , Schuur E.A.G. , Turetsky M. R. 
Published: October 2016

AbstractThermokarst is the process whereby the thawing of ice-rich permafrost ground causes land subsidence, resulting in development of distinctive landforms. Accelerated thermokarst due to climate change will damage infrastructure, but also impact hydrology, ecology and biogeochemistry. Here, we present a circumpolar assessment of the distribution of thermokarst landscapes, defined as landscapes comprised of current thermokarst landforms and areas susceptible to future thermokarst development. At 3.6 × 106 km2, thermokarst landscapes are estimated to cover ∼20% of the northern permafrost region, with approximately equal contributions from three landscape types where characteristic wetland, lake and hillslope thermokarst landforms occur. We estimate that approximately half of the below-ground organic carbon within the study region is stored in thermokarst landscapes. Our results highlight the importance of explicitly considering thermokarst when assessing impacts of climate change, including future landscape greenhouse gas emissions, and provide a means for assessing such impacts at the circumpolar scale.
Tiam1/Rac1 complex controls Il17a transcription and autoimmunity
Authors: Kurdi Ahmed T. , Bassil Ribal , Olah Marta , Wu Chuan , Xiao Sheng , Taga Mariko , Frangieh Michael , Buttrick Thomas , Orent William , Bradshaw Elizabeth M. , Khoury Samia J. , Elyaman Wassim 
Published: October 2016

AbstractRORγt is a master transcription factor of Th17 cells and considered as a promising drug target for the treatment of autoimmune diseases. Here, we show the guanine nucleotide exchange factor, Tiam1, and its cognate Rho-family G protein, Rac1, regulate interleukin (IL)17A transcription and autoimmunity. Whereas Tiam1 genetic deficiency weakens IL-17A expression partially and inhibits the development of experimental autoimmune encephalomyelitis (EAE), deletion of Rac1 in T cells exhibits more robust effects on Th17 cells and EAE. We demonstrate Tiam1 and Rac1 form a complex with RORγt in the nuclear compartment of Th17 cells, and together bind and activate the Il17 promoter. The clinical relevance of these findings is emphasized by pharmacological targeting of Rac1 that suppresses both murine and human Th17 cells as well as EAE. Thus, our findings highlight a regulatory pathway of Tiam1/Rac1 in Th17 cells and suggest that it may be a therapeutic target in multiple sclerosis.
Giant piezoelectric voltage coefficient in grain-oriented modified PbTiO3 material
Authors: Yan Yongke , Zhou Jie E. , Maurya Deepam , Wang Yu U. , Priya Shashank 
Published: October 2016

AbstractA rapid surge in the research on piezoelectric sensors is occurring with the arrival of the Internet of Things. Single-phase oxide piezoelectric materials with giant piezoelectric voltage coefficient (g, induced voltage under applied stress) and high Curie temperature (Tc) are crucial towards providing desired performance for sensing, especially under harsh environmental conditions. Here, we report a grain-oriented (with 95% <001> texture) modified PbTiO3 ceramic that has a high Tc (364 °C) and an extremely large g33 (115 × 10−3 Vm N−1) in comparison with other known single-phase oxide materials. Our results reveal that self-polarization due to grain orientation along the spontaneous polarization direction plays an important role in achieving large piezoelectric response in a domain motion-confined material. The phase field simulations confirm that the large piezoelectric voltage coefficient g33 originates from maximized piezoelectric strain coefficient d33 and minimized dielectric permittivity ɛ33 in [001]-textured PbTiO3 ceramics where domain wall motions are absent.
Salicylic acid receptors activate jasmonic acid signalling through a non-canonical pathway to promote effector-triggered immunity
Authors: Liu Lijing , Sonbol Fathi-Mohamed , Huot Bethany , Gu Yangnan , Withers John , Mwimba Musoki , Yao Jian , He Sheng Yang , Dong Xinnian 
Published: October 2016

AbstractIt is an apparent conundrum how plants evolved effector-triggered immunity (ETI), involving programmed cell death (PCD), as a major defence mechanism against biotrophic pathogens, because ETI-associated PCD could leave them vulnerable to necrotrophic pathogens that thrive on dead host cells. Interestingly, during ETI, the normally antagonistic defence hormones, salicylic acid (SA) and jasmonic acid (JA) associated with defence against biotrophs and necrotrophs respectively, both accumulate to high levels. In this study, we made the surprising finding that JA is a positive regulator of RPS2-mediated ETI. Early induction of JA-responsive genes and de novo JA synthesis following SA accumulation is activated through the SA receptors NPR3 and NPR4, instead of the JA receptor COI1. We provide evidence that NPR3 and NPR4 may mediate this effect by promoting degradation of the JA transcriptional repressor JAZs. This unique interplay between SA and JA offers a possible explanation of how plants can mount defence against a biotrophic pathogen without becoming vulnerable to necrotrophic pathogens.
NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells
Authors: Ratajczak Joanna , Joffraud Magali , Trammell Samuel A. J. , Ras Rosa , Canela Núria , Boutant Marie , Kulkarni Sameer S. , Rodrigues Marcelo , Redpath Philip , Migaud Marie E. , Auwerx Johan , Yanes Oscar , Brenner Charles , Cantó Carles 
Published: October 2016

AbstractNAD+ is a vital redox cofactor and a substrate required for activity of various enzyme families, including sirtuins and poly(ADP-ribose) polymerases. Supplementation with NAD+ precursors, such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), protects against metabolic disease, neurodegenerative disorders and age-related physiological decline in mammals. Here we show that nicotinamide riboside kinase 1 (NRK1) is necessary and rate-limiting for the use of exogenous NR and NMN for NAD+ synthesis. Using genetic gain- and loss-of-function models, we further demonstrate that the role of NRK1 in driving NAD+ synthesis from other NAD+ precursors, such as nicotinamide or nicotinic acid, is dispensable. Using stable isotope-labelled compounds, we confirm NMN is metabolized extracellularly to NR that is then taken up by the cell and converted into NAD+. Our results indicate that mammalian cells require conversion of extracellular NMN to NR for cellular uptake and NAD+ synthesis, explaining the overlapping metabolic effects observed with the two compounds.
The solution structure of an anti-CRISPR protein
Authors: Maxwell Karen L. , Garcia Bianca , Bondy-Denomy Joseph , Bona Diane , Hidalgo-Reyes Yurima , Davidson Alan R. 
Published: October 2016

AbstractBacterial CRISPR–Cas adaptive immune systems use small guide RNAs to protect against phage infection and invasion by foreign genetic elements. We previously demonstrated that a group of Pseudomonas aeruginosa phages encode anti-CRISPR proteins that inactivate the type I-F and I-E CRISPR–Cas systems using distinct mechanisms. Here, we present the three-dimensional structure of an anti-CRISPR protein and map a functional surface that is critical for its potent inhibitory activity. The interaction of the anti-CRISPR protein with the CRISPR–Cas complex through this functional surface is proposed to prevent the binding of target DNA.
Land-use choices follow profitability at the expense of ecological functions in Indonesian smallholder landscapes
Authors: Clough Yann , Krishna Vijesh V. , Corre Marife D. , Darras Kevin , Denmead Lisa H. , Meijide Ana , Moser Stefan , Musshoff Oliver , Steinebach Stefanie , Veldkamp Edzo , Allen Kara , Barnes Andrew D. , Breidenbach Natalie , Brose Ulrich , Buchori Damayanti , Daniel Rolf , Finkeldey Reiner , Harahap Idham , Hertel Dietrich , Holtkamp A. Mareike , Hörandl Elvira , Irawan Bambang , Jaya I. Nengah Surati , Jochum Malte , Klarner Bernhard , Knohl Alexander , Kotowska Martyna M. , Krashevska Valentyna , Kreft Holger , Kurniawan Syahrul , Leuschner Christoph , Maraun Mark , Melati Dian Nuraini , Opfermann Nicole , Pérez-Cruzado César , Prabowo Walesa Edho , Rembold Katja , Rizali Akhmad , Rubiana Ratna , Schneider Dominik , Tjitrosoedirdjo Sri Sudarmiyati , Tjoa Aiyen , Tscharntke Teja , Scheu Stefan 
Published: October 2016

AbstractSmallholder-dominated agricultural mosaic landscapes are highlighted as model production systems that deliver both economic and ecological goods in tropical agricultural landscapes, but trade-offs underlying current land-use dynamics are poorly known. Here, using the most comprehensive quantification of land-use change and associated bundles of ecosystem functions, services and economic benefits to date, we show that Indonesian smallholders predominantly choose farm portfolios with high economic productivity but low ecological value. The more profitable oil palm and rubber monocultures replace forests and agroforests critical for maintaining above- and below-ground ecological functions and the diversity of most taxa. Between the monocultures, the higher economic performance of oil palm over rubber comes with the reliance on fertilizer inputs and with increased nutrient leaching losses. Strategies to achieve an ecological-economic balance and a sustainable management of tropical smallholder landscapes must be prioritized to avoid further environmental degradation.
Eukaryotic association module in phage WO genomes from Wolbachia
Authors: Bordenstein Sarah R. , Bordenstein Seth R. 
Published: October 2016

AbstractViruses are trifurcated into eukaryotic, archaeal and bacterial categories. This domain-specific ecology underscores why eukaryotic viruses typically co-opt eukaryotic genes and bacteriophages commonly harbour bacterial genes. However, the presence of bacteriophages in obligate intracellular bacteria of eukaryotes may promote DNA transfers between eukaryotes and bacteriophages. Here we report a metagenomic analysis of purified bacteriophage WO particles of Wolbachia and uncover a eukaryotic association module in the complete WO genome. It harbours predicted domains, such as the black widow latrotoxin C-terminal domain, that are uninterrupted in bacteriophage genomes, enriched with eukaryotic protease cleavage sites and combined with additional domains to forge one of the largest bacteriophage genes to date (14,256 bp). To the best of our knowledge, these eukaryotic-like domains have never before been reported in packaged bacteriophages and their phylogeny, distribution and sequence diversity imply lateral transfers between bacteriophage/prophage and animal genomes. Finally, the WO genome sequences and identification of attachment sites will potentially advance genetic manipulation of Wolbachia.
Effect of Mild Heating on Human Lens Epithelial Cells: A Possible Model of Lens Aging
Authors: Zhang Keke , Zhu Xiangjia , Lu Yi 
Published: October 2016

AbstractThis study aims to investigate the effect of mild heating on lens epithelial cells and to explore its possibility as an in vitro model for lens aging. Human lens epithelial cells (LECs) were heated at 50 °C for a cellular lens aging study. Analysis of the head group order of lens membranes was performed using Laurdan labeling. Immunofluorescence was performed to detect changes in α-crystallin expression and its cellular distribution. The chaperone-like activity of α-crystallin was also assessed. After mild heating, α-crystallin in LECs showed a tendency towards accumulation around the nucleus. The membrane head group environment of lens epithelial cells became more fluid with increasing time of exposure to mild heating, as indicated by increased water penetration. Furthermore, the chaperone activity of α-crystallin decreased, and suggests a relatively lower protective effect on other functional proteins in LECs. Thus, compared to the mild heating model based on lens tissue, this cellular model could provide a more convenient and accurate method for studying lens aging in vitro, including changes in membrane head group order in each cell, the real-time observation of crystallin distribution, and the monitoring of functional changes in the chaperone activity of crystallins as a result of aging.
Glycosylation site occupancy in health, congenital disorder of glycosylation and fatty liver disease
Authors: Hülsmeier Andreas J. , Tobler Micha , Burda Patricie , Hennet Thierry 
Published: October 2016

AbstractGlycosylation is an integral part in health and disease, as emphasized by the growing number of identified glycosylation defects. In humans, proteins are modified with a diverse range of glycoforms synthesized in complex biosynthetic pathways. Glycosylation disorders have been described in congenital disorders of glycosylation (CDG) as well as in acquired disease conditions such and non-alcoholic fatty liver disease (NAFLD). A hallmark in a subset of CDG cases is the reduced glycosylation site occupancy of asparagine-linked glycans. Using an optimized method protocol, we determined the glycosylation site occupancy from four proteins of hepatic and lymphatic origin from CDG and NAFLD patients. We found variable degrees of site occupancy, depending on the tissue of origin and the disease condition. In CDG glycosylation sites of IgG2 and IgA1 were occupied to normal levels. In NAFLD haptoglobin and transferrin glycosylation sites were hyper-glycosylated, a property qualifying for its use as a potential biomarker. Furthermore, we observed, that glycosylation sites of liver-originating transferrin and haptoglobin are differentially occupied under physiological conditions, a further instance not noticed in serum proteins to date. Our findings suggest the use of serum protein hyperglycosylation as a biomarker for early stages of NAFLD.
Cyr61 participates in the pathogenesis of acute lymphoblastic leukemia by enhancing cellular survival via the AKT/NF-κB signaling pathway
Authors: Zhu Xianjin , Song Yanfang , Wu Conglian , Pan Chuxi , Lu Pingxia , Wang Meihua , Zheng Peizheng , Huo Rongfen , Zhang Chenqing , Li Wanting , Lin Yulin , Cao Yingping , Li Ningli 
Published: October 2016

AbstractCyr61 (CCN1) is the product of a growth factor–inducible immediate early gene and is involved in cell adhesion, survival, proliferation and differentiation. Cyr61 is overexpressed in human tumors and is involved in the development of tumors. However, the role that Cyr61 plays in acute lymphoblastic leukemia (ALL) cells remains undetermined. The aim of this study was to identify the role of Cyr61 in regulating ALL cell survival. Here, we found that the level of Cyr61 was increased in the plasma and bone marrow (BM) from ALL patients compared with samples from normal control patients. Furthermore, we observed that Cyr61 could effectively stimulate Jurkat (T ALL cell lines), Nalm-6 (B ALL cell lines) and primary ALL cell survival. Mechanistically, we showed that Cyr61 stimulated ALL cell survival via the AKT/NF-κB signaling pathways and the consequent up-regulation of Bcl-2. Taken together, our study is the first to reveal that Cyr61 is elevated in ALL and promotes cell survival through the AKT/NF-κB pathway by up-regulating Bcl-2. Our findings suggest that Cyr61 plays an important role in the pathogenesis of ALL.
Combinatorial nanocarrier based drug delivery approach for amalgamation of anti-tumor agents in breast cancer cells: an improved nanomedicine strategy
Authors: Murugan Chandran , Rayappan Kathirvel , Thangam Ramar , Bhanumathi Ramasamy , Shanthi Krishnamurthy , Vivek Raju , Thirumurugan Ramasamy , Bhattacharyya Atanu , Sivasubramanian Srinivasan , Gunasekaran Palani , Kannan Soundarapandian 
Published: October 2016

AbstractCombination therapy of multiple drugs through a single system is exhibiting high therapeutic effects. We investigate nanocarrier mediated inhibitory effects of topotecan (TPT) and quercetin (QT) on triple negative breast cancer (TNBC) (MDA-MB-231) and multi drug resistant (MDR) type breast cancer cells (MCF-7) with respect to cellular uptake efficiency and therapeutic mechanisms asin vitroandin vivo. The synthesized mesoporous silica nanoparticle (MSN) pores used for loading TPT; the outer of the nanoparticles was decorated with poly (acrylic acid) (PAA)-Chitosan (CS) as anionic inner-cationic outer layer respectively and conjugated with QT. Subsequently, grafting of arginine-glycine-aspartic acid (cRGD) peptide on the surface of nanocarrier (CPMSN) thwarted the uptake by normal cells, but facilitated their uptake in cancer cells through integrin receptor mediated endocytosis and the dissociation of nanocarriers due to the ability to degrade CS and PAA in acidic pH, which enhance the intracellular release of drugs. Subsequently, the released drugs induce remarkable molecular activation as well as structural changes in tumor cell endoplasmic reticulum, nucleus and mitochondria that can trigger cell death. The valuable CPMSNs may open up new avenues in developing targeted therapeutic strategies to treat cancer through serving as an effective drug delivery podium.
Detection of aqueous VEGF concentrations before and after intravitreal injection of anti-VEGF antibody using low-volume sampling paper-based ELISA
Authors: Hsu Min-Yen , Hung Yu-Chien , Hwang De-Kuang , Lin Shang-Chi , Lin Keng-Hung , Wang Chun-Yuan , Choi Hin-Yeung , Wang Yu-Ping , Cheng Chao-Min 
Published: October 2016

AbstractIntraocular vascular endothelial growth factor (VEGF) levels play an important role in the pathogenesis of blindness-related diseases, such as age-related macular degeneration (AMD). Here, we aimed to develop a paper-based enzyme-linked immunosorbent assay (P-ELISA) to analyze the suppression of aqueous VEGF concentrations following intravitreal injection (IVI) of anti-VEGF antibody (bevacizumab or ranibizumab). A total of 25 eyes with wet AMD, one with myopic neovascularization, and one with polypoidal choroidal vasculopathy were enrolled in this study. The limit of detection using P-ELISA was 0.03 pg/mL. Forty-six consecutive samples of aqueous humor were acquired. From all samples, 66.67% (10/15) achieved complete VEGF suppression (below the detection limit) within 5 weeks of receiving IVI of anti-VEGF antibody. Only 13.33% of samples (2/15) achieved complete VEGF suppression 5 weeks after receiving treatment. In some patients, elevated VEGF was still detected 5 weeks after receipt of anti-VEGF antibody, and all samples (10/10) were found to have elevated VEGF levels 49 days after treatment. Thus, we suggest that monthly IVI of anti-VEGF antibody may be required to ensure durable VEGF inhibition. Ultrasensitive P-ELISA can detect elevated VEGF at an earlier time point and may facilitate decision-making regarding appropriate treatment strategies.
ADHD-associated risk taking is linked to exaggerated views of the benefits of positive outcomes
Authors: Shoham Rachel , Sonuga-Barke Edmund J. S. , Aloni Hamutal , Yaniv Ilan , Pollak Yehuda 
Published: October 2016

AbstractAttention deficit and hyperactivity disorder (ADHD) is often assumed to be associated with increased engagement in risk-taking behaviors. The current study sought to understand the mental processes underlying this association using a theory-driven behavioral economics perspective. Psychological risk-return models suggest that risk and benefit are inherently subjective, and risk taking is best understood as the interplay between cognitions and motivations regarding the benefits and risks of alternatives. A sample of 244 adults was assessed for ADHD symptoms. The likelihood of engagement in a range of risky behaviors (e.g., driving without wearing a seat belt), the magnitude of perceived benefit and risk ascribed to these behaviors, and benefit and risk attitudes of each participant were extracted from the Domain Specific Risk Taking (DOSPERT) scales. ADHD symptoms were correlated with more risky behaviors and perception of greater benefits from engaging in these behaviors, but were not correlated with risk perception. Mediation analysis revealed that the association between ADHD symptoms and engagement in risk taking was mediated by perceived benefits. These findings highlight the idea that people with high level ADHD symptoms tend to engage in risky behaviors because they find such behavior particularly appealing, rather than because they seek risk per se.