bluuebunny/crossref_metadata_2025_split huggingface dataset:
The autism/neuroprotection-linked ADNP/NAP regulate the excitatory glutamatergic synapse
Authors: Sragovich Shlomo , Malishkevich Anna , Piontkewitz Yael , Giladi Eliezer , Touloumi Olga , Lagoudaki Roza , Grigoriadis Nikolaos , Gozes Illana 
Published: January 2019

AbstractActivity-dependent neuroprotective protein (ADNP), essential for brain formation, was discovered as a leading de novo mutated gene causing the autism-like ADNP syndrome. This syndrome is phenotypically characterized by global developmental delays, intellectual disabilities, speech impediments, and motor dysfunctions. The Adnp haploinsufficient mouse mimics the human ADNP syndrome in terms of synapse density and gene expression patterns, as well as in developmental, motor, and cognitive abilities. Peripheral ADNP was also discovered as a biomarker for Alzheimer’s disease and schizophrenia, with nasal administration of the ADNP snippet peptide NAP (enhancing endogenous ADNP activity) leading to partial cognitive and functional protection at the cellular, animal and clinical settings. Here, a novel formulation for effective delivery of NAP is provided with superior brain penetration capabilities. Also provided are methods for treating pertinent clinical implications such as autism, cognitive impairments, olfactory deficits, and muscle strength using the formulation in the Adnp haploinsufficient mouse. Results showed a dramatically specific increase in brain/body bioavailability with the new formulation, without breaching the blood brain barrier. Additional findings included improvements using daily intranasal treatments with NAP, at the behavioral and brain structural levels, diffusion tensor imaging (DTI), translatable to clinical practice. Significant effects on hippocampal and cerebral cortical expression of the presynaptic Slc17a7 gene encoding vesicular excitatory glutamate transporter 1 (VGLUT1) were observed at the RNA and immunohistochemical levels, explaining the DTI results. These findings tie for the first time a reduction in presynaptic glutamatergic synapses with the autism/Alzheimer’s/schizophrenia-linked ADNP deficiency coupled with amelioration by NAP (CP201).
Abnormal ER quality control of neural GPI-anchored proteins via dysfunction in ER export processing in the frontal cortex of elderly subjects with schizophrenia
Authors: Kim Pitna , Scott Madeline R. , Meador-Woodruff James H. 
Published: January 2019

AbstractAbnormalities of posttranslational protein modifications (PTMs) have recently been implicated in the pathophysiology of schizophrenia. Glycosylphosphatidylinositols (GPIs) are a class of complex glycolipids, which anchor surface proteins and glycoproteins to the cell membrane. GPI attachment to proteins represents one of the most common PTMs and GPI-associated proteins (GPI-APs) facilitate many cell surface processes, including synapse development and maintenance. Mutations in the GPI processing pathway are associated with intellectual disability, emphasizing the potential role of GPI-APs in cognition and schizophrenia-associated cognitive dysfunction. As initial endoplasmic reticulum (ER)-associated protein processing is essential for GPI-AP function, we measured protein expression of molecules involved in attachment (GPAA1), modification (PGAP1), and ER export (Tmp21) of GPI-APs, in homogenates and in an ER enriched fraction derived from dorsolateral prefrontal cortex (DLPFC) of 15 matched pairs of schizophrenia and comparison subjects. In total homogenate we found a significant decrease in transmembrane protein 21 (Tmp21) and in the ER-enriched fraction we found reduced expression of post-GPI attachment protein (PGAP1). PGAP1 modifies GPI-anchors through inositol deacylation, allowing it to be recognized by Tmp21. Tmp21 is a component of the p24 complex that recognizes GPI-anchored proteins, senses the status of the GPI-anchor, and regulates incorporation into COPII vesicles for export to the Golgi apparatus. Together, these proteins are the molecular mechanisms underlying GPI-AP quality control and ER export. To investigate the potential consequences of a deficit in export and/or quality control, we measured cell membrane-associated expression of known GPI-APs that have been previously implicated in schizophrenia, including GPC1, NCAM, MDGA2, and EPHA1, using Triton X-114 phase separation. Additionally, we tested the sensitivity of those candidate proteins to phosphatidylinositol-specific phospholipase C (PI-PLC), an enzyme that cleaves GPI from GPI-APs. While we did not observe a difference in the amount of these GPI-APs in Triton X-114 phase separated membrane fractions, we found decreased NCAM and GPC1 within the PI-PLC sensitive fraction. These findings suggest dysregulation of ER-associated GPI-AP protein processing, with impacts on post-translational modifications of proteins previously implicated in schizophrenia such as NCAM and GPC1. These findings provide evidence for a deficit in ER protein processing pathways in this illness.
Enhancer hijacking activates oncogenic transcription factor NR4A3 in acinic cell carcinomas of the salivary glands
Authors: Haller Florian , Bieg Matthias , Will Rainer , Körner Cindy , Weichenhan Dieter , Bott Alexander , Ishaque Naveed , Lutsik Pavlo , Moskalev Evgeny A. , Mueller Sarina K. , Bähr Marion , Woerner Angelika , Kaiser Birgit , Scherl Claudia , Haderlein Marlen , Kleinheinz Kortine , Fietkau Rainer , Iro Heinrich , Eils Roland , Hartmann Arndt , Plass Christoph , Wiemann Stefan , Agaimy Abbas 
Published: January 2019

AbstractThe molecular pathogenesis of salivary gland acinic cell carcinoma (AciCC) is poorly understood. The secretory Ca-binding phosphoprotein (SCPP) gene cluster at 4q13 encodes structurally related phosphoproteins of which some are specifically expressed at high levels in the salivary glands and constitute major components of saliva. Here we report on recurrent rearrangements [t(4;9)(q13;q31)] in AciCC that translocate active enhancer regions from the SCPP gene cluster to the region upstream of Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3) at 9q31. We show that NR4A3 is specifically upregulated in AciCCs, and that active chromatin regions and gene expression signatures in AciCCs are highly correlated with the NR4A3 transcription factor binding motif. Overexpression of NR4A3 in mouse salivary gland cells increases expression of known NR4A3 target genes and has a stimulatory functional effect on cell proliferation. We conclude that NR4A3 is upregulated through enhancer hijacking and has important oncogenic functions in AciCC.
Cross-species genomic landscape comparison of human mucosal melanoma with canine oral and equine melanoma
Authors: Wong Kim , van der Weyden Louise , Schott Courtney R. , Foote Alastair , Constantino-Casas Fernando , Smith Sionagh , Dobson Jane M. , Murchison Elizabeth P. , Wu Hong , Yeh Iwei , Fullen Douglas R. , Joseph Nancy , Bastian Boris C. , Patel Rajiv M. , Martincorena Inigo , Robles-Espinoza Carla Daniela , Iyer Vivek , Kuijjer Marieke L. , Arends Mark J. , Brenn Thomas , Harms Paul W. , Wood Geoffrey A. , Adams David J. 
Published: January 2019

AbstractMucosal melanoma is a rare and poorly characterized subtype of human melanoma. Here we perform a cross-species analysis by sequencing tumor-germline pairs from 46 primary human muscosal, 65 primary canine oral and 28 primary equine melanoma cases from mucosal sites. Analysis of these data reveals recurrently mutated driver genes shared between species such asNRAS,FAT4, PTPRJ, TP53andPTEN, and pathogenic germline alleles ofBRCA1, BRCA2andTP53. We identify a UV mutation signature in a small number of samples, including human cases from the lip and nasal mucosa. A cross-species comparative analysis of recurrent copy number alterations identifies several candidate drivers includingMDM2,B2M,KNSTRNandBUB1B. Comparison of somatic mutations in recurrences and metastases to those in the primary tumor suggests pervasive intra-tumor heterogeneity. Collectively, these studies suggest a convergence of some genetic changes in mucosal melanomas between species but also distinctly different paths to tumorigenesis.
Author Correction: Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia
Authors: Vijayakrishnan Jayaram , Studd James , Broderick Peter , Kinnersley Ben , Holroyd Amy , Law Philip J. , Kumar Rajiv , Allan James M. , Harrison Christine J. , Moorman Anthony V. , Vora Ajay , Roman Eve , Rachakonda Sivaramakrishna , Kinsey Sally E. , Sheridan Eamonn , Thompson Pamela D. , Irving Julie A. , Koehler Rolf , Hoffmann Per , Nöthen Markus M. , Heilmann-Heimbach Stefanie , Jöckel Karl-Heinz , Easton Douglas F. , Pharaoh Paul D. P. , Dunning Alison M. , Peto Julian , Canzian Frederico , Swerdlow Anthony , Eeles Rosalind A. , Kote-Jarai Zsofia , Muir Kenneth , Pashayan Nora ,   The PRACTICAL consortium, Henderson Brian E. , Haiman Christopher A. , Benlloch Sara , Schumacher Fredrick R. , Olama Ali Amin Al , Berndt Sonja I. , Conti David V. , Wiklund Fredrik , Chanock Stephen , Stevens Victoria L. , Tangen Catherine M. , Batra Jyotsna , Clements Judith , Gronberg Henrik , Schleutker Johanna , Albanes Demetrius , Weinstein Stephanie , Wolk Alicja , West Catharine , Mucci Lorelei , Cancel-Tassin Géraldine , Koutros Stella , Sorensen Karina Dalsgaard , Maehle Lovise , Neal David E. , Travis Ruth C. , Hamilton Robert J. , Ingles Sue Ann , Rosenstein Barry , Lu Yong-Jie , Giles Graham G. , Kibel Adam S. , Vega Ana , Kogevinas Manolis , Penney Kathryn L. , Park Jong Y. , Stanford Janet L. , Cybulski Cezary , Nordestgaard Børge G. , Brenner Hermann , Maier Christiane , Kim Jeri , John Esther M. , Teixeira Manuel R. , Neuhausen Susan L. , De Ruyck Kim , Razack Azad , Newcomb Lisa F. , Lessel Davor , Kaneva Radka , Usmani Nawaid , Claessens Frank , Townsend Paul A. , Gago-Dominguez Manuela , Roobol Monique J. , Menegaux Florence , Greaves Mel , Zimmerman Martin , Bartram Claus R. , Schrappe Martin , Stanulla Martin , Hemminki Kari , Houlston Richard S. 
Published: January 2019

The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.
Over 56.55% Faradaic efficiency of ambient ammonia synthesis enabled by positively shifting the reaction potential
Authors: Wang Mengfan , Liu Sisi , Qian Tao , Liu Jie , Zhou Jinqiu , Ji Haoqing , Xiong Jie , Zhong Jun , Yan Chenglin 
Published: January 2019

AbstractAmbient electrochemical N2 reduction is emerging as a highly promising alternative to the Haber–Bosch process but is typically hampered by a high reaction barrier and competing hydrogen evolution, leading to an extremely low Faradaic efficiency. Here, we demonstrate that under ambient conditions, a single-atom catalyst, iron on nitrogen-doped carbon, could positively shift the ammonia synthesis process to an onset potential of 0.193 V, enabling a dramatically enhanced Faradaic efficiency of 56.55%. The only doublet coupling representing 15NH4+ in an isotopic labeling experiment confirms reliable NH3 production data. Molecular dynamics simulations suggest efficient N2 access to the single-atom iron with only a small energy barrier, which benefits preferential N2 adsorption instead of H adsorption via a strong exothermic process, as further confirmed by first-principle calculations. The released energy helps promote the following process and the reaction bottleneck, which is widely considered to be the first hydrogenation step, is successfully overcome.
A GWAS in Latin Americans highlights the convergent evolution of lighter skin pigmentation in Eurasia
Authors: Adhikari Kaustubh , Mendoza-Revilla Javier , Sohail Anood , Fuentes-Guajardo Macarena , Lampert Jodie , Chacón-Duque Juan Camilo , Hurtado Malena , Villegas Valeria , Granja Vanessa , Acuña-Alonzo Victor , Jaramillo Claudia , Arias William , Lozano Rodrigo Barquera , Everardo Paola , Gómez-Valdés Jorge , Villamil-Ramírez Hugo , Silva de Cerqueira Caio C. , Hunemeier Tábita , Ramallo Virginia , Schuler-Faccini Lavinia , Salzano Francisco M. , Gonzalez-José Rolando , Bortolini Maria-Cátira , Canizales-Quinteros Samuel , Gallo Carla , Poletti Giovanni , Bedoya Gabriel , Rothhammer Francisco , Tobin Desmond J. , Fumagalli Matteo , Balding David , Ruiz-Linares Andrés 
Published: January 2019

AbstractWe report a genome-wide association scan in >6,000 Latin Americans for pigmentation of skin and eyes. We found eighteen signals of association at twelve genomic regions. These include one novel locus for skin pigmentation (in 10q26) and three novel loci for eye pigmentation (in 1q32, 20q13 and 22q12). We demonstrate the presence of multiple independent signals of association in the 11q14 and 15q13 regions (comprising the GRM5/TYR and HERC2/OCA2 genes, respectively) and several epistatic interactions among independently associated alleles. Strongest association with skin pigmentation at 19p13 was observed for an Y182H missense variant (common only in East Asians and Native Americans) in MFSD12, a gene recently associated with skin pigmentation in Africans. We show that the frequency of the derived allele at Y182H is significantly correlated with lower solar radiation intensity in East Asia and infer that MFSD12 was under selection in East Asians, probably after their split from Europeans.
Strong-correlation induced high-mobility electrons in Dirac semimetal of perovskite oxide
Authors: Fujioka J. , Yamada R. , Kawamura M. , Sakai S. , Hirayama M. , Arita R. , Okawa T. , Hashizume D. , Hoshino M. , Tokura Y. 
Published: January 2019

AbstractElectrons in conventional metals become less mobile under the influence of electron correlation. Contrary to this empirical knowledge, we report here that electrons with the highest mobility ever found in known bulk oxide semiconductors emerge in the strong-correlation regime of the Dirac semimetal of perovskite CaIrO3. The transport measurements reveal that the high mobility exceeding 60,000 cm2V−1s−1 originates from the proximity of the Fermi energy to the Dirac node (ΔE < 10 meV). The calculation based on the density functional theory and the dynamical mean field theory reveals that the energy difference becomes smaller as the system approaches the Mott transition, highlighting a crucial role of correlation effects cooperating with the spin-orbit coupling. The correlation-induced self-tuning of Dirac node enables the quantum limit at a modest magnetic field with a giant magnetoresistance, thus providing an ideal platform to study the novel phenomena of correlated Dirac electron.
Phosphorylation-deficient G-protein-biased μ-opioid receptors improve analgesia and diminish tolerance but worsen opioid side effects
Authors: Kliewer A. , Schmiedel F. , Sianati S. , Bailey A. , Bateman J. T. , Levitt E. S. , Williams J. T. , Christie M. J. , Schulz S. 
Published: January 2019

AbstractOpioid analgesics are powerful pain relievers; however, over time, pain control diminishes as analgesic tolerance develops. The molecular mechanisms initiating tolerance have remained unresolved to date. We have previously shown that desensitization of the μ-opioid receptor and interaction with β-arrestins is controlled by carboxyl-terminal phosphorylation. Here we created knockin mice with a series of serine- and threonine-to-alanine mutations that render the receptor increasingly unable to recruit β-arrestins. Desensitization is inhibited in locus coeruleus neurons of mutant mice. Opioid-induced analgesia is strongly enhanced and analgesic tolerance is greatly diminished. Surprisingly, respiratory depression, constipation, and opioid withdrawal signs are unchanged or exacerbated, indicating that β-arrestin recruitment does not contribute to the severity of opioid side effects and, hence, predicting that G-protein-biased µ-agonists are still likely to elicit severe adverse effects. In conclusion, our findings identify carboxyl-terminal multisite phosphorylation as key step that drives acute μ-opioid receptor desensitization and long-term tolerance.
A highly efficient and faithful MDS patient-derived xenotransplantation model for pre-clinical studies
Authors: Song Yuanbin , Rongvaux Anthony , Taylor Ashley , Jiang Tingting , Tebaldi Toma , Balasubramanian Kunthavai , Bagale Arun , Terzi Yunus Kasim , Gbyli Rana , Wang Xiaman , Fu Xiaoying , Gao Yimeng , Zhao Jun , Podoltsev Nikolai , Xu Mina , Neparidze Natalia , Wong Ellice , Torres Richard , Bruscia Emanuela M. , Kluger Yuval , Manz Markus G. , Flavell Richard A. , Halene Stephanie 
Published: January 2019

AbstractComprehensive preclinical studies of Myelodysplastic Syndromes (MDS) have been elusive due to limited ability of MDS stem cells to engraft current immunodeficient murine hosts. Here we report a MDS patient-derived xenotransplantation model in cytokine-humanized immunodeficient “MISTRG” mice that provides efficient and faithful disease representation across all MDS subtypes. MISTRG MDS patient-derived xenografts (PDX) reproduce patients’ dysplastic morphology with multi-lineage representation, including erythro- and megakaryopoiesis. MISTRG MDS-PDX replicate the original sample’s genetic complexity and can be propagated via serial transplantation. MISTRG MDS-PDX demonstrate the cytotoxic and differentiation potential of targeted therapeutics providing superior readouts of drug mechanism of action and therapeutic efficacy. Physiologic humanization of the hematopoietic stem cell niche proves critical to MDS stem cell propagation and function in vivo. The MISTRG MDS-PDX model opens novel avenues of research and long-awaited opportunities in MDS research.
Penaeid shrimp genome provides insights into benthic adaptation and frequent molting
Authors: Zhang Xiaojun , Yuan Jianbo , Sun Yamin , Li Shihao , Gao Yi , Yu Yang , Liu Chengzhang , Wang Quanchao , Lv Xinjia , Zhang Xiaoxi , Ma Ka Yan , Wang Xiaobo , Lin Wenchao , Wang Long , Zhu Xueli , Zhang Chengsong , Zhang Jiquan , Jin Songjun , Yu Kuijie , Kong Jie , Xu Peng , Chen Jack , Zhang Hongbin , Sorgeloos Patrick , Sagi Amir , Alcivar-Warren Acacia , Liu Zhanjiang , Wang Lei , Ruan Jue , Chu Ka Hou , Liu Bin , Li Fuhua , Xiang Jianhai 
Published: January 2019

AbstractCrustacea, the subphylum of Arthropoda which dominates the aquatic environment, is of major importance in ecology and fisheries. Here we report the genome sequence of the Pacific white shrimp Litopenaeus vannamei, covering ~1.66 Gb (scaffold N50 605.56 Kb) with 25,596 protein-coding genes and a high proportion of simple sequence repeats (>23.93%). The expansion of genes related to vision and locomotion is probably central to its benthic adaptation. Frequent molting of the shrimp may be explained by an intensified ecdysone signal pathway through gene expansion and positive selection. As an important aquaculture organism, L. vannamei has been subjected to high selection pressure during the past 30 years of breeding, and this has had a considerable impact on its genome. Decoding the L. vannamei genome not only provides an insight into the genetic underpinnings of specific biological processes, but also provides valuable information for enhancing crustacean aquaculture.
Label-free spatio-temporal monitoring of cytosolic mass, osmolarity, and volume in living cells
Authors: Midtvedt Daniel , Olsén Erik , Höök Fredrik , Jeffries Gavin D. M. 
Published: January 2019

AbstractMicroorganisms adapt their biophysical properties in response to changes in their local environment. However, quantifying these changes at the single-cell level has only recently become possible, largely relying on fluorescent labeling strategies. In this work, we utilize yeast (Saccharomyces cerevisiae) to demonstrate label-free quantification of changes in both intracellular osmolarity and macromolecular concentration in response to changes in the local environment. By combining a digital holographic microscope with a millifluidic chip, the temporal response of cellular water flux was successfully isolated from the rate of production of higher molecular weight compounds, in addition to identifying the produced compounds in terms of the product of their refractive index increment $$\left( {\frac{{{{{\mathrm{d}}n}}}}{{{{{\mathrm{d}}c}}}}} \right)$$

d
n

d
c

and molar mass. The ability to identify, quantify and temporally resolve multiple biophysical processes in living cells at the single cell level offers a crucial complement to label-based strategies, suggesting broad applicability in studies of a wide-range of cellular processes.
Quantized angular momentum in topological optical systems
Authors: Silveirinha Mário G. 
Published: January 2019

AbstractThe Chern index characterizes the topological phases of nonreciprocal photonic systems. Unlike in electronics, the photonic Chern number has no clear physical meaning, except that it determines the number of unidirectional edge states supported by an interface with a trivial mirror. Here, we fill in this gap by demonstrating that the photonic Chern number can be understood as the quantum of the light-angular momentum in a photonic insulator cavity. It is proven that for a large cavity, the thermal fluctuation-induced angular momentum is precisely quantized in the band-gaps of the bulk states. The nontrivial expectation of the light angular momentum is due to a circulation of thermal energy in closed orbits. Remarkably, this result can be extended to systems without a topological classification, and in such a case the “quantum” of the angular momentum density is determined by the net number of unidirectional edge states supported by the cavity walls.
Lignin-polysaccharide interactions in plant secondary cell walls revealed by solid-state NMR
Authors: Kang Xue , Kirui Alex , Dickwella Widanage Malitha C. , Mentink-Vigier Frederic , Cosgrove Daniel J. , Wang Tuo 
Published: January 2019

AbstractLignin is a complex aromatic biopolymer that strengthens and waterproofs plant secondary cell walls, enabling mechanical stability in trees and long-distance water transport in xylem. Lignin removal is a key step in paper production and biomass conversion to biofuels, motivating efforts to re-engineer lignin biosynthesis. However, the physical nature of lignin’s interactions with wall polysaccharides is not well understood. Here we show that lignin self-aggregates to form highly hydrophobic and dynamically unique nanodomains, with extensive surface contacts to xylan. Solid-state NMR spectroscopy of intact maize stems, supported by dynamic nuclear polarization, reveals that lignin has abundant electrostatic interactions with the polar motifs of xylan. Lignin preferentially binds xylans with 3-fold or distorted 2-fold helical screw conformations, indicative of xylans not closely associated with cellulose. These findings advance our knowledge of the molecular-level organization of lignocellulosic biomass, providing the structural foundation for optimization of post-harvest processing for biofuels and biomaterials.