bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cooling and Vertical Motions of Crustal Wedges Prior to, During, and After Lateral Extrusion in the Eastern Alps: New Field Kinematic and Fission Track Data from the Mur‐Mürz Fault System
Authors: van Gelder I. E. , Willingshofer E. , Andriessen P. A. M. , Schuster R. , Sokoutis D. 
Published: February 2020

AbstractNew structural and thermochronological (zircon and apatite fission track) data from the eastern most Alps highlight distinct deformation phases affecting the Austroalpine unit along a major sinistral strike‐slip fault system, the Mur‐Mürz fault (MMF). The data link deformation to vertical motions prior to, during, and after the main phase of lateral extrusion of the orogen. Zircon fission track ages document rapid (ca. 15 °C/Myr) and diachronous (eastward younging) cooling and rock exhumation during the latest Cretaceous to Paleocene. Subsequent regional Eocene to early Miocene cooling below the closure temperature of the apatite fission track system occurred at slow rates (ca. 2 °C/Myr), suggesting that the region was not subject to major surface uplift and erosion during that period. Fault kinematic analysis along the MMF document pre‐extrusion NNW‐SSE contraction, middle Miocene syn‐extrusion NE‐SW to NNE‐SSW directed shortening, and Late Miocene E‐W contraction. All phases are characterized by strike‐slip fault regimes. Formation of the complex MMF zone triggered the exhumation of small, fault‐bound crustal blocks within the fault zone as documented by middle Miocene apatite fission track ages. Overall, ages are similar on both sides of the fault suggesting that lateral extrusion along the MMF was not associated with significant differential vertical motions. Local Pliocene rock cooling and exhumation was probably related to the buttressing effect of the underthrust Bohemian basement spur. Whereas large‐scale, post‐extrusion surface uplift of the extruding crustal wedges, such as the “Styrian block,” must have been related to long‐wavelength deformation processes affecting the easternmost Alps.
Experimental Estimates of Optical Backscattering Associated With Submicron Particles in Clear Oceanic Waters
Authors: Zhang Xiaodong , Hu Lianbo , Xiong Yuanheng , Huot Yannick , Gray Deric 
Published: February 2020

AbstractThe volume scattering functions for bulk and two submicron size fractions (passing through 0.7 μm GF/F and 0.2 μm membrane filters) were measured in the North Pacific Ocean using a LISST‐VSF to assess the contributions by submicron particles to the overall particle scattering. The contribution by submicron particles increased generally with scattering angle and peaked around 110°. The total backscattering by both submicron fractions did not vary, but that by larger particles increased, with the trophic level. Consequently, the fractional backscattering contribution by submicron particles decreased from approximately 50% to 30% as the chlorophyll‐a concentration increased from <0.1 to 0.3 mg m−3. Despite the experiment covering a limited range of trophic levels, our results confirm that backscattering by submicron particles in clear ocean waters is significant and seems to form a background independent of the backscattering by larger particles.
PERK-mediated expression of peptidylglycine α-amidating monooxygenase supports angiogenesis in glioblastoma
Authors: Soni Himanshu , Bode Julia , Nguyen Chi D. L. , Puccio Laura , Neßling Michelle , Piro Rosario M. , Bub Jonas , Phillips Emma , Ahrends Robert , Eipper Betty A. , Tews Björn , Goidts Violaine 
Published: February 2020

AbstractPKR-like kinase (PERK) plays a significant role in inducing angiogenesis in various cancer types including glioblastoma. By proteomics analysis of the conditioned medium from a glioblastoma cell line treated with a PERK inhibitor, we showed that peptidylglycine α-amidating monooxygenase (PAM) expression is regulated by PERK under hypoxic conditions. Moreover, PERK activation via CCT020312 (a PERK selective activator) increased the cleavage and thus the generation of PAM cleaved cytosolic domain (PAM sfCD) that acts as a signaling molecule from the cytoplasm to the nuclei. PERK was also found to interact with PAM, suggesting a possible involvement in the generation of PAM sfCD. Knockdown of PERK or PAM reduced the formation of tubes by HUVECs in vitro. Furthermore, in vivo data highlighted the importance of PAM in the growth of glioblastoma with reduction of PAM expression in engrafted tumor significantly increasing the survival in mice. In summary, our data revealed PAM as a potential target for antiangiogenic therapy in glioblastoma.
Developments in continuous therapy and maintenance treatment approaches for patients with newly diagnosed multiple myeloma
Authors: Dimopoulos Meletios A. , Jakubowiak Andrzej J. , McCarthy Philip L. , Orlowski Robert Z. , Attal Michel , Bladé Joan , Goldschmidt Hartmut , Weisel Katja C. , Ramasamy Karthik , Zweegman Sonja , Spencer Andrew , Huang Jeffrey S. Y. , Lu Jin , Sunami Kazutaka , Iida Shinsuke , Chng Wee-Joo , Holstein Sarah A. , Rocci Alberto , Skacel Tomas , Labotka Richard , Palumbo Antonio , Anderson Kenneth C. 
Published: February 2020

AbstractThe evolving paradigm of continuous therapy and maintenance treatment approaches in multiple myeloma (MM) offers prolonged disease control and improved outcomes compared to traditional fixed-duration approaches. Potential benefits of long-term strategies include sustained control of disease symptoms, as well as continued cytoreduction and clonal control, leading to unmeasurable residual disease and the possibility of transforming MM into a chronic or functionally curable condition. “Continuous therapy” commonly refers to administering a doublet or triplet regimen until disease progression, whereas maintenance approaches typically involve single-agent or doublet treatment following more intensive prior therapy with autologous stem cell transplant (ASCT) or doublet, triplet, or even quadruplet induction therapy. However, the requirements for agents and regimens within these contexts are similar: treatments must be tolerable for a prolonged period of time, should not be associated with cumulative or chronic toxicity, should not adversely affect patients’ quality of life, should ideally be convenient with a minimal treatment burden for patients, and should not impact the feasibility or efficacy of subsequent treatment at relapse. Multiple agents have been and are being investigated as long-term options in the treatment of newly diagnosed MM (NDMM), including the immunomodulatory drugs lenalidomide and thalidomide, the proteasome inhibitors bortezomib, carfilzomib, and ixazomib, and the monoclonal antibodies daratumumab, elotuzumab, and isatuximab. Here we review the latest results with long-term therapy approaches in three different settings in NDMM: (1) maintenance treatment post ASCT; (2) continuous frontline therapy in nontransplant patients; (3) maintenance treatment post-frontline therapy in the nontransplant setting. We also discuss evidence from key phase 3 trials. Our review demonstrates how the paradigm of long-term treatment is increasingly well-established across NDMM treatment settings, potentially resulting in further improvements in patient outcomes, and highlights key clinical issues that will need to be addressed in order to provide optimal benefit.
Epigenetic specifications of host chromosome docking sites for latent Epstein-Barr virus
Authors: Kim Kyoung-Dong , Tanizawa Hideki , De Leo Alessandra , Vladimirova Olga , Kossenkov Andrew , Lu Fang , Showe Louise C. , Noma Ken-ichi , Lieberman Paul M. 
Published: February 2020

AbstractEpstein-Barr virus (EBV) genomes persist in latently infected cells as extrachromosomal episomes that attach to host chromosomes through the tethering functions of EBNA1, a viral encoded sequence-specific DNA binding protein. Here we employ circular chromosome conformation capture (4C) analysis to identify genome-wide associations between EBV episomes and host chromosomes. We find that EBV episomes in Burkitt’s lymphoma cells preferentially associate with cellular genomic sites containing EBNA1 binding sites enriched with B-cell factors EBF1 and RBP-jK, the repressive histone mark H3K9me3, and AT-rich flanking sequence. These attachment sites correspond to transcriptionally silenced genes with GO enrichment for neuronal function and protein kinase A pathways. Depletion of EBNA1 leads to a transcriptional de-repression of silenced genes and reduction in H3K9me3. EBV attachment sites in lymphoblastoid cells with different latency type show different correlations, suggesting that host chromosome attachment sites are functionally linked to latency type gene expression programs.
FMN reduces Amyloid-β toxicity in yeast by regulating redox status and cellular metabolism
Authors: Chen Xin , Ji Boyang , Hao Xinxin , Li Xiaowei , Eisele Frederik , Nyström Thomas , Petranovic Dina 
Published: February 2020

AbstractAlzheimer’s disease (AD) is defined by progressive neurodegeneration, with oligomerization and aggregation of amyloid-β peptides (Aβ) playing a pivotal role in its pathogenesis. In recent years, the yeast Saccharomyces cerevisiae has been successfully used to clarify the roles of different human proteins involved in neurodegeneration. Here, we report a genome-wide synthetic genetic interaction array to identify toxicity modifiers of Aβ42, using yeast as the model organism. We find that FMN1, the gene encoding riboflavin kinase, and its metabolic product flavin mononucleotide (FMN) reduce Aβ42 toxicity. Classic experimental analyses combined with RNAseq show the effects of FMN supplementation to include reducing misfolded protein load, altering cellular metabolism, increasing NADH/(NADH + NAD+) and NADPH/(NADPH + NADP+) ratios and increasing resistance to oxidative stress. Additionally, FMN supplementation modifies Htt103QP toxicity and α-synuclein toxicity in the humanized yeast. Our findings offer insights for reducing cytotoxicity of Aβ42, and potentially other misfolded proteins, via FMN-dependent cellular pathways.
A living biobank of ovarian cancer ex vivo models reveals profound mitotic heterogeneity
Authors: Nelson Louisa , Tighe Anthony , Golder Anya , Littler Samantha , Bakker Bjorn , Moralli Daniela , Murtuza Baker Syed , Donaldson Ian J. , Spierings Diana C. J. , Wardenaar René , Neale Bethanie , Burghel George J. , Winter-Roach Brett , Edmondson Richard , Clamp Andrew R. , Jayson Gordon C. , Desai Sudha , Green Catherine M. , Hayes Andy , Foijer Floris , Morgan Robert D. , Taylor Stephen S. 
Published: February 2020

AbstractHigh-grade serous ovarian carcinoma is characterised by TP53 mutation and extensive chromosome instability (CIN). Because our understanding of CIN mechanisms is based largely on analysing established cell lines, we developed a workflow for generating ex vivo cultures from patient biopsies to provide models that support interrogation of CIN mechanisms in cells not extensively cultured in vitro. Here, we describe a “living biobank” of ovarian cancer models with extensive replicative capacity, derived from both ascites and solid biopsies. Fifteen models are characterised by p53 profiling, exome sequencing and transcriptomics, and karyotyped using single-cell whole-genome sequencing. Time-lapse microscopy reveals catastrophic and highly heterogeneous mitoses, suggesting that analysis of established cell lines probably underestimates mitotic dysfunction in advanced human cancers. Drug profiling reveals cisplatin sensitivities consistent with patient responses, demonstrating that this workflow has potential to generate personalized avatars with advantages over current pre-clinical models and the potential to guide clinical decision making.
A conserved strategy of chalcone isomerase-like protein to rectify promiscuous chalcone synthase specificity
Authors: Waki Toshiyuki , Mameda Ryo , Nakano Takuya , Yamada Sayumi , Terashita Miho , Ito Keisuke , Tenma Natsuki , Li Yanbing , Fujino Naoto , Uno Kaichi , Yamashita Satoshi , Aoki Yuichi , Denessiouk Konstantin , Kawai Yosuke , Sugawara Satoko , Saito Kazuki , Yonekura-Sakakibara Keiko , Morita Yasumasa , Hoshino Atsushi , Takahashi Seiji , Nakayama Toru 
Published: February 2020

AbstractLand plants produce diverse flavonoids for growth, survival, and reproduction. Chalcone synthase is the first committed enzyme of the flavonoid biosynthetic pathway and catalyzes the production of 2′,4,4′,6′-tetrahydroxychalcone (THC). However, it also produces other polyketides, including p-coumaroyltriacetic acid lactone (CTAL), because of the derailment of the chalcone-producing pathway. This promiscuity of CHS catalysis adversely affects the efficiency of flavonoid biosynthesis, although it is also believed to have led to the evolution of stilbene synthase and p-coumaroyltriacetic acid synthase. In this study, we establish that chalcone isomerase-like proteins (CHILs), which are encoded by genes that are ubiquitous in land plant genomes, bind to CHS to enhance THC production and decrease CTAL formation, thereby rectifying the promiscuous CHS catalysis. This CHIL function has been confirmed in diverse land plant species, and represents a conserved strategy facilitating the efficient influx of substrates from the phenylpropanoid pathway to the flavonoid pathway.
Improved betulinic acid biosynthesis using synthetic yeast chromosome recombination and semi-automated rapid LC-MS screening
Authors: Gowers G.-O. F. , Chee S. M. , Bell D. , Suckling L. , Kern M. , Tew D. , McClymont D. W. , Ellis T. 
Published: February 2020

AbstractSynthetic biology, genome engineering and directed evolution offer innumerable tools to expedite engineering of strains for optimising biosynthetic pathways. One of the most radical is SCRaMbLE, a system of inducible in vivo deletion and rearrangement of synthetic yeast chromosomes, diversifying the genotype of millions of Saccharomyces cerevisiae cells in hours. SCRaMbLE can yield strains with improved biosynthetic phenotypes but is limited by screening capabilities. To address this bottleneck, we combine automated sample preparation, an ultra-fast 84-second LC-MS method, and barcoded nanopore sequencing to rapidly isolate and characterise the best performing strains. Here, we use SCRaMbLE to optimise yeast strains engineered to produce the triterpenoid betulinic acid. Our semi-automated workflow screens 1,000 colonies, identifying and sequencing 12 strains with between 2- to 7-fold improvement in betulinic acid titre. The broad applicability of this workflow to rapidly isolate improved strains from a variant library makes this a valuable tool for biotechnology.
Glucose, Cyc8p and Tup1p regulate biofilm formation and dispersal in wild Saccharomyces cerevisiae
Authors: Van Nguyen Phu , Plocek Vítězslav , Váchová Libuše , Palková Zdena 
Published: February 2020

AbstractSaccharomyces cerevisiae is a mainly beneficial yeast, widely used in the food industry. However, there is growing evidence of its potential pathogenicity, leading to fungemia and invasive infections. The medical impact of yeast pathogens depends on formation of biofilms: multicellular structures, protected from the environment. Cell adhesion is a prerequisite of biofilm formation. We investigated the adherence of wild and genetically modified S. cerevisiae strains, formation of solid–liquid interface biofilms and associated regulation. Planktonic and static cells of wild strain BRF adhered and formed biofilms in glucose-free medium. Tup1p and Cyc8p were key positive and negative regulators, respectively. Glucose caused increased Cyc8p levels and blocked cell adhesion. Even low glucose levels, comparable with levels in the blood, allowed biofilm dispersal and release of planktonic cells. Cyc8p could thus modulate cell adhesion in different niches, dependently on environmental glucose level, e.g., high-glucose blood versus low-glucose tissues in host organisms.
Allele-specific miRNA-binding analysis identifies candidate target genes for breast cancer risk
Authors: Jacinta-Fernandes Ana , Xavier Joana M. , Magno Ramiro , Lage Joel G. , Maia Ana-Teresa 
Published: February 2020

AbstractMost breast cancer (BC) risk-associated single-nucleotide polymorphisms (raSNPs) identified in genome-wide association studies (GWAS) are believed tocis-regulate the expression of genes. We hypothesise thatcis-regulatory variants contributing to disease risk may be affecting microRNA (miRNA) genes and/or miRNA binding. To test this, we adapted two miRNA-binding prediction algorithms—TargetScan and miRanda—to perform allele-specific queries, and integrated differential allelic expression (DAE) and expression quantitative trait loci (eQTL) data, to query 150 genome-wide significant ($$P\le 5\times {10}^{-8}$$P≤5×10−8) raSNPs, plus proxies. We found that no raSNP mapped to a miRNA gene, suggesting that altered miRNA targeting is an unlikely mechanism involved in BC risk. Also, 11.5% (6 out of 52) raSNPs located in 3′-untranslated regions of putative miRNA target genes were predicted to alter miRNA::mRNA (messenger RNA) pair binding stability in five candidate target genes. Of these, we proposeRNF115, at locus 1q21.1, as a strong novel target gene associated with BC risk, and reinforce the role of miRNA-mediatedcis-regulation at locus 19p13.11. We believe that integrating allele-specific querying in miRNA-binding prediction, and data supportingcis-regulation of expression, improves the identification of candidate target genes in BC risk, as well as in other common cancers and complex diseases.
The Dopamine D5 receptor contributes to activation of cholinergic interneurons during L-DOPA induced dyskinesia
Authors: Castello Julia , Cortés Marisol , Malave Lauren , Kottmann Andreas , Sibley David R. , Friedman Eitan , Rebholz Heike 
Published: February 2020

AbstractThe dopamine D5 receptor (D5R) is a Gαs-coupled dopamine receptor belonging to the dopamine D1-like receptor family. Together with the dopamine D2 receptor it is highly expressed in striatal cholinergic interneurons and therefore is poised to be a positive regulator of cholinergic activity in response to L-DOPA in the dopamine-depleted parkinsonian brain. Tonically active cholinergic interneurons become dysregulated during chronic L-DOPA administration and participate in the expression of L-DOPA induced dyskinesia. The molecular mechanisms involved in this process have not been elucidated, however a correlation between dyskinesia severity and pERK expression in cholinergic cells has been described. To better understand the function of the D5 receptor and how it affects cholinergic interneurons in L-DOPA induced dyskinesia, we used D5R knockout mice that were rendered parkinsonian by unilateral 6-OHDA injection. In the KO mice, expression of pERK was strongly reduced indicating that activation of these cells is at least in part driven by the D5 receptor. Similarly, pS6, another marker for the activity status of cholinergic interneurons was also reduced. However, mice lacking D5R exhibited slightly worsened locomotor performance in response to L-DOPA and enhanced LID scores. Our findings suggest that D5R can modulate L-DOPA induced dyskinesia and is a critical activator of CINs via pERK and pS6.
Quantifying residue-specific conformational dynamics of a highly reactive 29-mer peptide
Authors: Lindemann William R. , Evans Ethan D. , Mijalis Alexander J. , Saouaf Olivia M. , Pentelute Bradley L. , Ortony Julia H. 
Published: February 2020

AbstractUnderstanding structural transitions within macromolecules remains an important challenge in biochemistry, with important implications for drug development and medicine. Insight into molecular behavior often requires residue-specific dynamics measurement at micromolar concentrations. We studied MP01-Gen4, a library peptide selected to rapidly undergo bioconjugation, by using electron paramagnetic resonance (EPR) to measure conformational dynamics. We mapped the dynamics of MP01-Gen4 with residue-specificity and identified the regions involved in a structural transformation related to the conjugation reaction. Upon reaction, the conformational dynamics of residues near the termini slow significantly more than central residues, indicating that the reaction induces a structural transition far from the reaction site. Arrhenius analysis demonstrates a nearly threefold decrease in the activation energy of conformational diffusion upon reaction (8.0 kBT to 3.4 kBT), which occurs across the entire peptide, independently of residue position. This novel approach to EPR spectral analysis provides insight into the positional extent of disorder and the nature of the energy landscape of a highly reactive, intrinsically disordered library peptide before and after conjugation.
Waterfowl occurrence and residence time as indicators of H5 and H7 avian influenza in North American Poultry
Authors: Humphreys John M. , Ramey Andrew M. , Douglas David C. , Mullinax Jennifer M. , Soos Catherine , Link Paul , Walther Patrick , Prosser Diann J. 
Published: February 2020

AbstractAvian influenza (AI) affects wild aquatic birds and poses hazards to human health, food security, and wildlife conservation globally. Accordingly, there is a recognized need for new methods and tools to help quantify the dynamic interaction between wild bird hosts and commercial poultry. Using satellite-marked waterfowl, we applied Bayesian joint hierarchical modeling to concurrently model species distributions, residency times, migration timing, and disease occurrence probability under an integrated animal movement and disease distribution modeling framework. Our results indicate that migratory waterfowl are positively related to AI occurrence over North America such that as waterfowl occurrence probability or residence time increase at a given location, so too does the chance of a commercial poultry AI outbreak. Analyses also suggest that AI occurrence probability is greatest during our observed waterfowl northward migration, and less during the southward migration. Methodologically, we found that when modeling disparate facets of disease systems at the wildlife-agriculture interface, it is essential that multiscale spatial patterns be addressed to avoid mistakenly inferring a disease process or disease-environment relationship from a pattern evaluated at the improper spatial scale. The study offers important insights into migratory waterfowl ecology and AI disease dynamics that aid in better preparing for future outbreaks.
An efficient and targeted synthetic approach towards new highly substituted 6-amino-pyrazolo[1,5-a]pyrimidines with α-glucosidase inhibitory activity
Authors: Peytam Fariba , Adib Mehdi , Shourgeshty Reihaneh , Firoozpour Loghman , Rahmanian-Jazi Mahmoud , Jahani Mehdi , Moghimi Setareh , Divsalar Kouros , Faramarzi Mohammad Ali , Mojtabavi Somayeh , Safari Fatemeh , Mahdavi Mohammad , Foroumadi Alireza 
Published: February 2020

AbstractIn an attempt to find novel α-glucosidase inhibitors, an efficient, straightforward reaction to synthesize a library of fully substituted 6-amino-pyrazolo[1,5-a]pyrimidines 3 has been investigated. Heating a mixture of α-azidochalcones 1 and 3-aminopyrazoles 2 under the mild condition afforded desired compounds with a large substrate scope in good to excellent yields. All obtained products were evaluated as α-glucosidase inhibitors and exhibited excellent potency with IC50 values ranging from 15.2 ± 0.4 µM to 201.3 ± 4.2 µM. Among them, compound 3d was around 50-fold more potent than acarbose (IC50 = 750.0 ± 1.5 µM) as standard inhibitor. Regarding product structures, kinetic study and molecular docking were carried out for two of the most potent ones.