bluuebunny/crossref_metadata_2025_split huggingface dataset:
The ancient CYP716 family is a major contributor to the diversification of eudicot triterpenoid biosynthesis
Authors: Miettinen Karel , Pollier Jacob , Buyst Dieter , Arendt Philipp , Csuk René , Sommerwerk Sven , Moses Tessa , Mertens Jan , Sonawane Prashant D , Pauwels Laurens , Aharoni Asaph , Martins José , Nelson David R. , Goossens Alain 
Published: February 2017

AbstractTriterpenoids are widespread bioactive plant defence compounds with potential use as pharmaceuticals, pesticides and other high-value products. Enzymes belonging to the cytochrome P450 family have an essential role in creating the immense structural diversity of triterpenoids across the plant kingdom. However, for many triterpenoid oxidation reactions, the corresponding enzyme remains unknown. Here we characterize CYP716 enzymes from different medicinal plant species by heterologous expression in engineered yeasts and report ten hitherto unreported triterpenoid oxidation activities, including a cyclization reaction, leading to a triterpenoid lactone. Kingdom-wide phylogenetic analysis of over 400 CYP716s from over 200 plant species reveals details of their evolution and suggests that in eudicots the CYP716s evolved specifically towards triterpenoid biosynthesis. Our findings underscore the great potential of CYP716s as a source for generating triterpenoid structural diversity and expand the toolbox available for synthetic biology programmes for sustainable production of bioactive plant triterpenoids.
Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia
Authors: Law Philip J. , Berndt Sonja I. , Speedy Helen E. , Camp Nicola J. , Sava Georgina P. , Skibola Christine F. , Holroyd Amy , Joseph Vijai , Sunter Nicola J. , Nieters Alexandra , Bea Silvia , Monnereau Alain , Martin-Garcia David , Goldin Lynn R. , Clot Guillem , Teras Lauren R. , Quintela Inés , Birmann Brenda M. , Jayne Sandrine , Cozen Wendy , Majid Aneela , Smedby Karin E. , Lan Qing , Dearden Claire , Brooks-Wilson Angela R. , Hall Andrew G. , Purdue Mark P. , Mainou-Fowler Tryfonia , Vajdic Claire M. , Jackson Graham H. , Cocco Pierluigi , Marr Helen , Zhang Yawei , Zheng Tongzhang , Giles Graham G. , Lawrence Charles , Call Timothy G. , Liebow Mark , Melbye Mads , Glimelius Bengt , Mansouri Larry , Glenn Martha , Curtin Karen , Diver W Ryan , Link Brian K. , Conde Lucia , Bracci Paige M. , Holly Elizabeth A. , Jackson Rebecca D. , Tinker Lesley F. , Benavente Yolanda , Boffetta Paolo , Brennan Paul , Maynadie Marc , McKay James , Albanes Demetrius , Weinstein Stephanie , Wang Zhaoming , Caporaso Neil E. , Morton Lindsay M. , Severson Richard K. , Riboli Elio , Vineis Paolo , Vermeulen Roel C. H. , Southey Melissa C. , Milne Roger L. , Clavel Jacqueline , Topka Sabine , Spinelli John J. , Kraft Peter , Ennas Maria Grazia , Summerfield Geoffrey , Ferri Giovanni M. , Harris Robert J. , Miligi Lucia , Pettitt Andrew R. , North Kari E. , Allsup David J. , Fraumeni Joseph F. , Bailey James R. , Offit Kenneth , Pratt Guy , Hjalgrim Henrik , Pepper Chris , Chanock Stephen J. , Fegan Chris , Rosenquist Richard , de Sanjose Silvia , Carracedo Angel , Dyer Martin J. S. , Catovsky Daniel , Campo Elias , Cerhan James R. , Allan James M. , Rothman Nathanial , Houlston Richard , Slager Susan 
Published: February 2017

AbstractSeveral chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223,P=5.04 × 10−13), 1q42.13 (rs41271473,P=1.06 × 10−10), 4q24 (rs71597109,P=1.37 × 10−10), 4q35.1 (rs57214277,P=3.69 × 10−8), 6p21.31 (rs3800461,P=1.97 × 10−8), 11q23.2 (rs61904987,P=2.64 × 10−11), 18q21.1 (rs1036935,P=3.27 × 10−8), 19p13.3 (rs7254272,P=4.67 × 10−8) and 22q13.33 (rs140522,P=2.70 × 10−9). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response.
DEK-targeting DNA aptamers as therapeutics for inflammatory arthritis
Authors: Mor-Vaknin Nirit , Saha Anjan , Legendre Maureen , Carmona-Rivera Carmelo , Amin M Asif , Rabquer Bradley J. , Gonzales-Hernandez Marta J. , Jorns Julie , Mohan Smriti , Yalavarthi Srilakshmi , Pai Dave A. , Angevine Kristine , Almburg Shelley J. , Knight Jason S. , Adams Barbara S. , Koch Alisa E. , Fox David A. , Engelke David R. , Kaplan Mariana J. , Markovitz David M. 
Published: February 2017

AbstractNovel therapeutics are required for improving the management of chronic inflammatory diseases. Aptamers are single-stranded RNA or DNA molecules that have recently shown utility in a clinical setting, as they can specifically neutralize biomedically relevant proteins, particularly cell surface and extracellular proteins. The nuclear chromatin protein DEK is a secreted chemoattractant that is abundant in the synovia of patients with juvenile idiopathic arthritis (JIA). Here, we show that DEK is crucial to the development of arthritis in mouse models, thus making it an appropriate target for aptamer-based therapy. Genetic depletion of DEK or treatment with DEK-targeted aptamers significantly reduces joint inflammation in vivo and greatly impairs the ability of neutrophils to form neutrophil extracellular traps (NETs). DEK is detected in spontaneously forming NETs from JIA patient synovial neutrophils, and DEK-targeted aptamers reduce NET formation. DEK is thus key to joint inflammation, and anti-DEK aptamers hold promise for the treatment of JIA and other types of arthritis.
mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases
Authors: Palmieri Michela , Pal Rituraj , Nelvagal Hemanth R. , Lotfi Parisa , Stinnett Gary R. , Seymour Michelle L. , Chaudhury Arindam , Bajaj Lakshya , Bondar Vitaliy V. , Bremner Laura , Saleem Usama , Tse Dennis Y. , Sanagasetti Deepthi , Wu Samuel M. , Neilson Joel R. , Pereira Fred A. , Pautler Robia G. , Rodney George G. , Cooper Jonathan D. , Sardiello Marco 
Published: February 2017

AbstractNeurodegenerative diseases characterized by aberrant accumulation of undigested cellular components represent unmet medical conditions for which the identification of actionable targets is urgently needed. Here we identify a pharmacologically actionable pathway that controls cellular clearance via Akt modulation of transcription factor EB (TFEB), a master regulator of lysosomal pathways. We show that Akt phosphorylates TFEB at Ser467 and represses TFEB nuclear translocation independently of mechanistic target of rapamycin complex 1 (mTORC1), a known TFEB inhibitor. The autophagy enhancer trehalose activates TFEB by diminishing Akt activity. Administration of trehalose to a mouse model of Batten disease, a prototypical neurodegenerative disease presenting with intralysosomal storage, enhances clearance of proteolipid aggregates, reduces neuropathology and prolongs survival of diseased mice. Pharmacological inhibition of Akt promotes cellular clearance in cells from patients with a variety of lysosomal diseases, thus suggesting broad applicability of this approach. These findings open new perspectives for the clinical translation of TFEB-mediated enhancement of cellular clearance in neurodegenerative storage diseases.
Axon degeneration induces glial responses through Draper-TRAF4-JNK signalling
Authors: Lu Tsai-Yi , MacDonald Jennifer M. , Neukomm Lukas J. , Sheehan Amy E. , Bradshaw Rachel , Logan Mary A. , Freeman Marc R. 
Published: February 2017

AbstractDraper/Ced-1/MEGF-10 is an engulfment receptor that promotes clearance of cellular debris in C. elegans, Drosophila and mammals. Draper signals through an evolutionarily conserved Src family kinase cascade to drive cytoskeletal rearrangements and target engulfment through Rac1. Glia also alter gene expression patterns in response to axonal injury but pathways mediating these responses are poorly defined. We show Draper is cell autonomously required for glial activation of transcriptional reporters after axonal injury. We identify TNF receptor associated factor 4 (TRAF4) as a novel Draper binding partner that is required for reporter activation and phagocytosis of axonal debris. TRAF4 and misshapen (MSN) act downstream of Draper to activate c-Jun N-terminal kinase (JNK) signalling in glia, resulting in changes in transcriptional reporters that are dependent on Drosophila AP-1 (dAP-1) and STAT92E. Our data argue injury signals received by Draper at the membrane are important regulators of downstream transcriptional responses in reactive glia.
Structure of the homodimeric androgen receptor ligand-binding domain
Authors: Nadal Marta , Prekovic Stefan , Gallastegui Nerea , Helsen Christine , Abella Montserrat , Zielinska Karolina , Gay Marina , Vilaseca Marta , Taulès Marta , Houtsmuller Adriaan B. , van Royen Martin E. , Claessens Frank , Fuentes-Prior Pablo , Estébanez-Perpiñá Eva 
Published: February 2017

AbstractThe androgen receptor (AR) plays a crucial role in normal physiology, development and metabolism as well as in the aetiology and treatment of diverse pathologies such as androgen insensitivity syndromes (AIS), male infertility and prostate cancer (PCa). Here we show that dimerization of AR ligand-binding domain (LBD) is induced by receptor agonists but not by antagonists. The 2.15-Å crystal structure of homodimeric, agonist- and coactivator peptide-bound AR-LBD unveils a 1,000-Å2 large dimerization surface, which harbours over 40 previously unexplained AIS- and PCa-associated point mutations. An AIS mutation in the self-association interface (P767A) disrupts dimer formation in vivo, and has a detrimental effect on the transactivating properties of full-length AR, despite retained hormone-binding capacity. The conservation of essential residues suggests that the unveiled dimerization mechanism might be shared by other nuclear receptors. Our work defines AR-LBD homodimerization as an essential step in the proper functioning of this important transcription factor.
Personality and Augmenting/Reducing (A/R) in auditory event-related potentials (ERPs) during emotional visual stimulation
Authors: De Pascalis Vilfredo , Fracasso Francesca , Corr Philip J. 
Published: February 2017

AbstractAn auditory augmenting/reducing ERP paradigm recorded for 5 intensity tones with emotional visual stimulation was used, for the first time, to test predictions derived from the revised Reinforcement Sensitivity Theory (rRST) of personality with respect to two major factors: behavioral inhibition system (BIS), fight/flight/freeze system (FFFS). Higher BIS and FFFS scores were negatively correlated with N1/P2 slopes at central sites (C3, Cz, C4). Conditional process analysis revealed that the BIS was a mediator of the association between the N1/P2 slope and the FFFS scores. An analysis of covariance showed that lower BIS scorers exhibited larger N1/P2 amplitudes across all tone intensities while watching negative, positive and neutral pictures. Additionally, lower FFFS scorers compared to higher FFFS scorers disclosed larger N1/P2 amplitudes to the highest tone intensities and these differences were even more pronounced while watching positive emotional pictures. Findings were explained assuming the operation of two different, but related processes: transmarginal inhibition for the BIS; the attention/emotional gating mechanism regulating cortical sensory input for the FFFS trait. These findings appear consistent with predictions derived from the rRST, which traced fear and anxiety to separate but interacting neurobehavioural systems.
Genome-wide indel/SSR scanning reveals significant loci associated with excellent agronomic traits of a cabbage (Brassica oleracea) elite parental line ‘01–20’
Authors: Lv Honghao , Wang Qingbiao , Han Fengqing , Liu Xing , Fang Zhiyuan , Yang Limei , Zhuang Mu , Liu Yumei , Li Zhansheng , Zhang Yangyong 
Published: February 2017

AbstractElite parental lines are of great significance to crop breeding. To discover unique genomic loci associated with excellent economic traits in the elite cabbage inbred-line ‘01–20’, we performed comparisons of phenotypes as well as whole-genome insertion-deletion/simple sequence repeat loci between ‘01–20’ and each of its five sister lines. ‘01–20’ has a range of excellent agronomic traits, including early-maturing, and improvements in plant type and leaf colour. Eight unique loci were discovered for ‘01–20’ and ‘01-07-258’, another elite line similar to ‘01–20’ at the whole-genome level. In addition, two excellent double-haploid lines derived from a cross of ‘01–20’ also inherited these loci. Based on the quantitative trait locus association results, five of these loci were found to be associated with important agronomic traits, which could explain why the elite parent ‘01–20’ possesses greener outer leaves, a more compact and upright plant-type, rounder head, shorter core length, and better taste. Additionally, some of these loci have clustering effects for quantitative trait loci associated with different traits; therefore, important genes in these regions were analysed. The obtained results should enable marker-assisted multi-trait selection at the whole-genome level in cabbage breeding and provide insights into significant genome loci and their breeding effects.
Generation of PDGFRα+ Cardioblasts from Pluripotent Stem Cells
Authors: Hong Seon Pyo , Song Sukhyun , Cho Sung Woo , Lee Seungjoo , Koh Bong Ihn , Bae Hosung , Kim Kyun Hoo , Park Jin-Sung , Do Hyo-Sang , Im Ilkyun , Heo Hye Jin , Ko Tae Hee , Park Jae-Hyeong , Youm Jae Boum , Kim Seong-Jin , Kim Injune , Han Jin , Han Yong-Mahn , Koh Gou Young 
Published: February 2017

AbstractIsolating actively proliferating cardioblasts is the first crucial step for cardiac regeneration through cell implantation. However, the origin and identity of putative cardioblasts are still unclear. Here, we uncover a novel class of cardiac lineage cells, PDGFRα+Flk1− cardioblasts (PCBs), from mouse and human pluripotent stem cells induced using CsAYTE, a combination of the small molecules Cyclosporin A, the rho-associated coiled-coil kinase inhibitor Y27632, the antioxidant Trolox, and the ALK5 inhibitor EW7197. This novel population of actively proliferating cells is cardiac lineage–committed but in a morphologically and functionally immature state compared to mature cardiomyocytes. Most important, most of CsAYTE-induced PCBs spontaneously differentiated into functional αMHC+ cardiomyocytes (M+CMs) and could be a potential cellular resource for cardiac regeneration.
Limb proportions show developmental plasticity in response to embryo movement
Authors: Pollard A. S. , Charlton B. G. , Hutchinson J. R. , Gustafsson T. , McGonnell I. M. , Timmons J. A. , Pitsillides A. A. 
Published: February 2017

AbstractAnimals have evolved limb proportions adapted to different environments, but it is not yet clear to what extent these proportions are directly influenced by the environment during prenatal development. The developing skeleton experiences mechanical loading resulting from embryo movement. We tested the hypothesis that environmentally-induced changes in prenatal movement influence embryonic limb growth to alter proportions. We show that incubation temperature influences motility and limb bone growth in West African Dwarf crocodiles, producing altered limb proportions which may, influence post-hatching performance. Pharmacological immobilisation of embryonic chickens revealed that altered motility, independent of temperature, may underpin this growth regulation. Use of the chick also allowed us to merge histological, immunochemical and cell proliferation labelling studies to evaluate changes in growth plate organisation, and unbiased array profiling to identify specific cellular and transcriptional targets of embryo movement. This disclosed that movement alters limb proportions and regulates chondrocyte proliferation in only specific growth plates. This selective targeting is related to intrinsic mTOR (mechanistic target of rapamycin) pathway activity in individual growth plates. Our findings provide new insights into how environmental factors can be integrated to influence cellular activity in growing bones and ultimately gross limb morphology, to generate phenotypic variation during prenatal development.
Novel Treatment of Chronic Graft-Versus-Host Disease in Mice Using the ER Stress Reducer 4-Phenylbutyric Acid
Authors: Mukai Shin , Ogawa Yoko , Urano Fumihiko , Kudo-Saito Chie , Kawakami Yutaka , Tsubota Kazuo 
Published: February 2017

AbstractChronic graft-versus-host disease (cGVHD) is a notorious complication of allogeneic hematopoietic stem cell transplantation and causes disabling systemic inflammation and fibrosis. In this novel study, we focused on a relationship between endoplasmic reticulum (ER) stress and cGVHD, and aimed to create effective treatment of cGVHD. A series of experiments were conducted using a mouse model of cGVHD. Our data suggested (1) that ER stress was elevated in organs affected by cGVHD and (2) that 4-phenylbutyric acid (PBA) could reduce cGVHD-induced ER stress and thereby alleviate systemic inflammation and fibrosis. Because fibroblasts are thought to be implicated in cGVHD-elicited fibrosis and because macrophages are reported to play a role in the development of cGVHD, we investigated cGVHD-triggered ER stress in fibroblasts and macrophages. Our investigation demonstrated (1) that indicators for ER stress and activation markers for fibroblasts were elevated in cGVHD-affected lacrimal gland fibroblasts and (2) that they could be reduced by PBA. Our work also indicated that splenic macrophages from PBA-dosed mice exhibited the lower levels of ER stress and M2 macrophage markers than those from cGVHD-affected mice. Collectively, this study suggests that the reduction of ER stress utilizing PBA can be a clinically translatable method to treat systemic cGVHD.
MicroRNA-130b targets PTEN to mediate drug resistance and proliferation of breast cancer cells via the PI3K/Akt signaling pathway
Authors: Miao Yuan , Zheng Wei , Li Nana , Su Zhen , Zhao Lifen , Zhou Huimin , Jia Li 
Published: February 2017

AbstractMultidrug resistance (MDR) correlates with treatment failure and poor prognosis among breast cancer patients. This study was aimed to investigate the possible mechanism by which microRNA-130b-3p (miR-130b) mediates the chemoresistance and proliferation of breast cancer. MiR-130b was found to be up-regulated in tumor tissues versus adjacent tissues of breast cancer, as well as in adriamycin (ADR) resistant breast cancer cell line (MCF-7/ADR) versus its parental line (MCF-7) and the non-malignant breast epithelial cell line (MCF-10A), demonstrating its crucial relevance for breast cancer biology. We identified that PTEN was a direct target of miR-130b and inversely correlated with miR-130b expression in breast cancer. Moreover, over-expression of miR-130b promoted drug resistance, proliferation and decreased apoptosis of MCF-7 cells, while suppression of miR-130b enhanced drug cytotoxicity and apoptosis, as well as reduced proliferation of MCF-7/ADR cells in vitro and in vivo. Particularly, miR-130b mediated the activity of phosphoinositide-3 kinase (PI3K)/Akt signaling pathway as well as the chemoresistance and proliferation of breast cancer cell lines, which was partially blocked following knockdown of PTEN. Altogether, miR-130b targets PTEN to induce MDR, proliferation, and apoptosis via PI3K/Akt signaling pathway. This provides a novel promising candidate for breast cancer therapy.
Structural analysis and evolution of specificity of the SUMO UFD E1-E2 interactions
Authors: Liu Bing , Lois L. Maria , Reverter David 
Published: February 2017

AbstractSUMO belongs to the ubiquitin-like family (UbL) of protein modifiers. SUMO is conserved among eukaryotes and is essential for the regulation of processes such as DNA damage repair, transcription, DNA replication and mitosis. UbL modification of proteins occurs via a specific enzymatic cascade formed by the crosstalk between the E1-activating enzyme, the E2-conjugating enzyme and the E3-ligase. An essential discrimination step in all UbL modifiers corresponds to the interaction between E1 and E2 enzymes, which is mediated by the recruitment of the E2 to the UFD domain (Ubiquitin-Fold Domain) of the E1 enzyme. To gain insights in the properties of this interface, we have compared the structures of the complexes between E1 UFD domain and E2 in human and yeast, revealing two alternative UFD platforms that interact with a conserved E2. Comparative sequence analysis of the E1 UFD domain indicates that the E2 binding region has been conserved across phylogenetic closely related species, in which higher sequence conservation can be found in the E2 binding region than in the entire UFD domain. These distinctive strategies for E1-E2 interactions through the UFD domain might be the consequence of a high selective pressure to ensure specificity of each modifier conjugation system.
A potent synthetic inorganic antibiotic with activity against drug-resistant pathogens
Authors: Hubick Shelby , Jayaraman Arumugam , McKeen Alexander , Reid Shelby , Alcorn Jane , Stavrinides John , Sterenberg Brian T. 
Published: February 2017

AbstractThe acronymously named “ESKAPE” pathogens represent a group of bacteria that continue to pose a serious threat to human health, not only due to their propensity for repeated emergence, but also due to their ability to “eskape” antibiotic treatment1,2. The evolution of multi-drug resistance in these pathogens alone has greatly outpaced the development of new therapeutics, necessitating an alternative strategy for antibiotic development that considers the evolutionary mechanisms driving antibiotic resistance. In this study, we synthesize a novel inorganic antibiotic, phosphopyricin, which has antibiotic activity against the Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE). We show that this potent antibiotic is bactericidal, and exhibits low toxicity in an acute dose assay in mice. As a synthetic compound that does not occur naturally, phosphopyricin would be evolutionarily foreign to microbes, thereby slowing the evolution of resistance. In addition, it loses antibiotic activity upon exposure to light, meaning that the active antibiotic will not accumulate in the general environment where strong selective pressures imposed by antibiotic residuals are known to accelerate resistance. Phosphopyricin represents an innovation in antimicrobials, having a synthetic core, and a photosensitive chemical architecture that would reduce accumulation in the environment.
Relevance of mortalin to cancer cell stemness and cancer therapy
Authors: Yun Chae-Ok , Bhargava Priyanshu , Na Youjin , Lee Jung-Sun , Ryu Jihoon , Kaul Sunil C. , Wadhwa Renu 
Published: February 2017

AbstractMortalin/mtHsp70 is a member of Hsp70 family of proteins. Enriched in a large variety of cancers, it has been shown to contribute to the process of carcinogenesis by multiple ways including inactivation of tumor suppressor p53 protein, deregulation of apoptosis and activation of EMT signaling. In this study, we report that upregulation of mortalin contributes to cancer cell stemness. Several cancer cell stemness markers, such as ABCG2, OCT-4, CD133, ALDH1, CD9, MRP1 and connexin were upregulated in mortalin-overexpressing cells that showed higher ability to form spheroids. These cells also showed higher migration, and were less responsive to a variety of cancer chemotherapeutic drugs. Of note, knockdown of mortalin by specific shRNA sensitized these cells to all the drugs used in this study. We report that low doses of anti-mortalin molecules, MKT-077 and CAPE, also caused similar sensitization of cancer cells to chemotherapeutic drugs and hence are potential candidates for effective cancer chemotherapy.