bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of the safety and immunomodulatory effects of sargramostim in a randomized, double-blind phase 1 clinical Parkinson’s disease trial
Authors: Gendelman Howard E. , Zhang Yuning , Santamaria Pamela , Olson Katherine E. , Schutt Charles R. , Bhatti Danish , Shetty Bhagya Laxmi Dyavar , Lu Yaman , Estes Katherine A. , Standaert David G. , Heinrichs-Graham Elizabeth , Larson LuAnn , Meza Jane L. , Follett Matthew , Forsberg Erica , Siuzdak Gary , Wilson Tony W. , Peterson Carolyn , Mosley R. Lee 
Published: March 2017

AbstractA potential therapeutic role for immune transformation in Parkinson’s disease evolves from more than a decade of animal investigations demonstrating regulatory T cell (Treg) nigrostriatal neuroprotection. To bridge these results to human disease, we conducted a randomized, placebo-controlled double-blind phase 1 trial with a well-studied immune modulator, sargramostim (granulocyte-macrophage colony-stimulating factor). We enrolled 17 age-matched non-Parkinsonian subjects as non-treated controls and 20 Parkinson’s disease patients. Both Parkinson’s disease patients and controls were monitored for 2 months for baseline profiling. Parkinson’s disease patients were then randomized into two equal groups to self-administer placebo (saline) or sargramostim subcutaneously at 6 μg/kg/day for 56 days. Adverse events for the sargramostim and placebo groups were 100% (10/10) and 80% (8/10), respectively. These included injection site reactions, increased total white cell counts, and upper extremity bone pain. One urticarial and one vasculitis reaction were found to be drug and benzyl alcohol related, respectively. An additional patient with a history of cerebrovascular disease suffered a stroke on study. Unified Parkinson’s disease rating scale, Part III scores in the sargramostim group showed modest improvement after 6 and 8 weeks of treatment when compared with placebo. This paralleled improved magnetoencephalography-recorded cortical motor activities and Treg numbers and function compared with pretreated Parkinson’s disease patients and non-Parkinsonian controls. Peripheral Treg transformation was linked to serum tryptophan metabolites, including L-kynurenine, quinolinic acid, and serotonin. These data offer a potential paradigm shift in modulating immune responses for potential therapeutic gain for Parkinson’s disease. Confirmation of these early study results requires larger numbers of enrolled patients and further clinical investigation.
Seven LncRNA-mRNA based risk score predicts the survival of head and neck squamous cell carcinoma
Authors: Zhang Zhi-Li , Zhao Li-jing , Chai Liang , Zhou Shui-Hong , Wang Feng , Wei Yan , Xu Ya-Ping , Zhao Peng 
Published: March 2017

AbstractDysregulation of mRNAs and long non-coding RNAs (lncRNAs) is one of the most important features of carcinogenesis and cancer development. However, studies integrating the expression of mRNAs and lncRNAs to predict the survival of head and neck squamous cell carcinoma (HNSC) are still limited, hitherto. In current work, we identified survival related mRNAs and lncRNAs in three datasets (TCGA dataset, E-TABM-302, GSE41613). By random forest, seven gene signatures (six mRNAs and lncRNA) were further selected to develop the risk score model. The risk score was significantly associated with survival in both training and testing datasets (E-TABM-302, GSE41613, and E-MTAB-1324). Furthermore, correlation analyses showed that the risk score is independent from clinicopathological features. According to Cox multivariable hazard model and nomogram, the risk score contributes the most to survival than the other clinical information, including gender, age, histologic grade, and alcohol taking. The Gene Set Enrichment Analysis (GSEA) indicates that the risk score is associated with cancer related pathways. In summary, the lncRNA-mRNA based risk score model we developed successfully predicts the survival of 755 HNSC samples in five datasets and two platforms. It is independent from clinical information and performs better than clinical information for prognosis.
Cross-beta nanostructures based on dinaphthylalanine Gd-conjugates loaded with doxorubicin
Authors: Diaferia Carlo , Gianolio Eliana , Sibillano Teresa , Mercurio Flavia Anna , Leone Marilisa , Giannini Cinzia , Balasco Nicole , Vitagliano Luigi , Morelli Giancarlo , Accardo Antonella 
Published: March 2017

AbstractVery recently we proposed novel di- and tetra-phenylalanine peptides derivatized with gadolinium complexes as potentials supramolecular diagnostic agents for applications in MRI (Magnetic Resonance Imaging). It was observed that in very short FF dipeptide building blocks, the propensity to aggregate decreases significantly after modification with bulky moiety such as Gd-complexes, thus limiting their potential as CAs. We hypothesized that the replacement of the Phe side chain with more extended aromatic groups could improve the self-assembling. Here we describe the synthesis, structural and relaxometric behavior of a novel water soluble self-assembled peptide CA based on 2-naphthylalanine (2Nal). The peptide conjugate Gd-DOTA-L6-(2Nal)2 is able to self-assemble in long fibrillary nanostructures in water solution (up to 1.0 mg/mL). CD and FTIR spectroscopies indicate a β sheet secondary structure with an antiparallel orientation of single strands. All data are in good agreement with WAXS and SAXS characterizations that show the typical “cross-β pattern” for fibrils at the solid state. Molecular modeling indicates the three-dimensional structure of the peptide spine of aggregates is essentially constituted by extended β-sheet motifs stabilized by hydrogen bonds and hydrophobic interactions. The high relaxivity of nanoaggregates (12.3 mM−1 s−1 at 20 MHz) and their capability to encapsulate doxorubicin suggest their potential application as supramolecular theranostic agents.
The role of axonal Kv1 channels in CA3 pyramidal cell excitability
Authors: Rama Sylvain , Zbili Mickael , Fékété Aurélie , Tapia Mónica , Benitez Maria José , Boumedine Norah , Garrido Juan José , Debanne Dominique 
Published: March 2017

AbstractAxonal ion channels control spike initiation and propagation along the axon and determine action potential waveform. We show here that functional suppression of axonal Kv1 channels with local puff of dendrotoxin (DTx), laser or mechanical axotomy significantly increased excitability measured in the cell body. Importantly, the functional effect of DTx puffing or axotomy was not limited to the axon initial segment but was also seen on axon collaterals. In contrast, no effects were observed when DTx was puffed on single apical dendrites or after single dendrotomy. A simple model with Kv1 located in the axon reproduced the experimental observations and showed that the distance at which the effects of axon collateral cuts are seen depends on the axon space constant. In conclusion, Kv1 channels located in the axon proper greatly participate in intrinsic excitability of CA3 pyramidal neurons. This finding stresses the importance of the axonal compartment in the regulation of intrinsic neuronal excitability.
Evaluation of reference genes at different developmental stages for quantitative real-time PCR in Aedes aegypti
Authors: Dzaki Najat , Ramli Karima N. , Azlan Azali , Ishak Intan H. , Azzam Ghows 
Published: March 2017

AbstractThe mosquitoAedes aegypti (Ae. aegypti) is the most notorious vector of illness-causing viruses such as Dengue, Chikugunya, and Zika. Although numerous genetic expression studies utilizing quantitative real-time PCR (qPCR) have been conducted with regards toAe. aegypti, a panel of genes to be used suitably as references for the purpose of expression-level normalization within this epidemiologically important insect is presently lacking. Here, the usability of seven widely-utilized reference genes i.e. actin (ACT), eukaryotic elongation factor 1 alpha (eEF1α), alpha tubulin (α-tubulin), ribosomal proteins L8, L32 and S17 (RPL8, RPL32andRPS17), and glyceraldeyde 3-phosphate dehydrogenase (GAPDH) were investigated. Expression patterns of the reference genes were observed in sixteen pre-determined developmental stages and in cell culture. Gene stability was inferred from qPCR data through three freely available algorithms i.e. BestKeeper, geNorm, and NormFinder. The consensus rankings generated from stability values provided by these programs suggest a combination of at least two genes for normalization.ACTandRPS17are the most dependably expressed reference genes and therefore, we propose anACT/RPS17combination for normalization in allAe. aegyptiderived samples.GAPDHperformed least desirably, and is thus not a recommended reference gene. This study emphasizes the importance of validating reference genes inAe. aegyptifor qPCR based research.
Late assembly of the Vibrio cholerae cell division machinery postpones septation to the last 10% of the cell cycle
Authors: Galli Elisa , Paly Evelyne , Barre François-Xavier 
Published: March 2017

AbstractBacterial cell division is a highly regulated process, which involves the formation of a complex apparatus, the divisome, by over a dozen proteins. In the few model bacteria in which the division process was detailed, divisome assembly occurs in two distinct steps: a few proteins, including the FtsZ tubulin-like protein, form a membrane associated contractile ring, the Z-ring, at ~30% of the cell cycle. The Z-ring serves as a scaffold for the recruitment of a second series of proteins, including integral membrane and periplasmic cell wall remodelling enzymes, at ~50% of the cell cycle. Actual septation occupies most of the remaining half of the cell cycle. In contrast, we present evidence suggesting that early pre-divisional Z-rings form between 40 and 50% of the cell cycle and mature into fully assembled divisome at about 80% of the cell cycle in Vibrio cholerae. Thus, actual septation is restricted to a very short amount of time. Our results further suggest that late assembly of the divisome probably helps maintain the asymmetric polar organisation of V. cholerae cells by limiting the accumulation of a cell pole marker, HubP, at the nascent cell poles.
Estimating the abundance of airborne pollen and fungal spores at variable elevations using an aircraft: how high can they fly?
Authors: Damialis Athanasios , Kaimakamis Evangelos , Konoglou Maria , Akritidis Ioannis , Traidl-Hoffmann Claudia , Gioulekas Dimitrios 
Published: March 2017

AbstractAirborne pollen and fungal spores are monitored mainly in highly populated, urban environments, for allergy prevention purposes. However, their sources can frequently be located outside cities’ fringes with more vegetation. So as to shed light to this paradox, we investigated the diversity and abundance of airborne pollen and fungal spores at various environmental regimes. We monitored pollen and spores using an aircraft and a car, at elevations from sea level to 2,000 m above ground, in the region of Thesssaloniki, Greece. We found a total of 24 pollen types and more than 15 spore types. Pollen and spores were detected throughout the elevational transect. Lower elevations exhibited higher pollen concentrations in only half of plant taxa and higher fungal spore concentrations in onlyUstilago. Pinaceae andQuercuspollen were the most abundant recorded by airplane (>54% of the total). Poaceae pollen were the most abundant via car measurements (>77% of the total).CladosporiumandAlternariaspores were the most abundant in all cases (aircraft: >69% and >17%, car: >45% and >27%, respectively). We conclude that pollen and fungal spores can be diverse and abundant even outside the main source area, evidently because of long-distance transport incidents.
A single residue controls electron transfer gating in photosynthetic reaction centers
Authors: Shlyk Oksana , Samish Ilan , Matěnová Martina , Dulebo Alexander , Poláková Helena , Kaftan David , Scherz Avigdor 
Published: March 2017

AbstractInterquinone QA− → QB electron-transfer (ET) in isolated photosystem II reaction centers (PSII-RC) is protein-gated. The temperature-dependent gating frequency “k” is described by the Eyring equation till levelling off at T ≥ 240 °K. Although central to photosynthesis, the gating mechanism has not been resolved and due to experimental limitations, could not be explored in vivo. Here we mimic the temperature dependency of “k” by enlarging VD1-208, the volume of a single residue at the crossing point of the D1 and D2 PSII-RC subunits in Synechocystis 6803 whole cells. By controlling the interactions of the D1/D2 subunits, VD1-208 (or 1/T) determines the frequency of attaining an ET-active conformation. Decelerated ET, impaired photosynthesis, D1 repair rate and overall cell physiology upon increasing VD1-208 to above 130 Å3, rationalize the >99% conservation of small residues at D1-208 and its homologous motif in non-oxygenic bacteria. The experimental means and resolved mechanism are relevant for numerous transmembrane protein-gated reactions.
Exonuclease processivity of archaeal replicative DNA polymerase in association with PCNA is expedited by mismatches in DNA
Authors: Yoda Takuya , Tanabe Maiko , Tsuji Toshiyuki , Yoda Takao , Ishino Sonoko , Shirai Tsuyoshi , Ishino Yoshizumi , Takeyama Haruko , Nishida Hirokazu 
Published: March 2017

AbstractFamily B DNA polymerases comprise polymerase and 3′ −>5′ exonuclease domains, and detect a mismatch in a newly synthesized strand to remove it in cooperation with Proliferating cell nuclear antigen (PCNA), which encircles the DNA to provide a molecular platform for efficient protein–protein and protein–DNA interactions during DNA replication and repair. Once the repair is completed, the enzyme must stop the exonucleolytic process and switch to the polymerase mode. However, the cue to stop the degradation is unclear. We constructed several PCNA mutants and found that the exonuclease reaction was enhanced in the mutants lacking the conserved basic patch, located on the inside surface of PCNA. These mutants may mimic the Pol/PCNA complex processing the mismatched DNA, in which PCNA cannot interact rigidly with the irregularly distributed phosphate groups outside the dsDNA. Indeed, the exonuclease reaction with the wild type PCNA was facilitated by mismatched DNA substrates. PCNA may suppress the exonuclease reaction after the removal of the mismatched nucleotide. PCNA seems to act as a “brake” that stops the exonuclease mode of the DNA polymerase after the removal of a mismatched nucleotide from the substrate DNA, for the prompt switch to the DNA polymerase mode.
FOXO transcription factors protect against the diet-induced fatty liver disease
Authors: Pan Xiaoyan , Zhang Yang , Kim Hyeong-Geug , Liangpunsakul Suthat , Dong X. Charlie 
Published: March 2017

AbstractForkhead O transcription factors (FOXOs) have been implicated in glucose and lipid homeostasis; however, the role of FOXOs in the development of nonalcoholic fatty liver disease (NAFLD) is not well understood. In this study, we designed experiments to examine the effects of two different diets—very high fat diet (HFD) and moderately high fat plus cholesterol diet (HFC)—on wildtype (WT) and liver-specific Foxo1/3/4 triple knockout mice (LTKO). Both diets induced severe hepatic steatosis in the LTKO mice as compared to WT controls. However, the HFC diet led to more severe liver injury and fibrosis compared to the HFD diet. At the molecular levels, hepatic Foxo1/3/4 deficiency triggered a significant increase in the expression of inflammatory and fibrotic genes including Emr1, Ccl2, Col1a1, Tgfb, Pdgfrb, and Timp1. Thus, our data suggest that FOXO transcription factors play a salutary role in the protection against the diet-induced fatty liver disease.
Effect of modulation of PPAR-γ activity on Kupffer cells M1/M2 polarization in the development of non-alcoholic fatty liver disease
Authors: Luo Wenjing , Xu Qinyu , Wang Qi , Wu Huimin , Hua Jing 
Published: March 2017

AbstractAbnormal lipid-mediated hepatic inflammatory-immune dysfunction and chronic low grade inflammation play an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Macrophage polarization is an important mechanism for the regulation of inflammatory response. Since PPAR-γ has emerged as a master regulator of macrophage polarization, we aimed to investigate the lipid-induced macrophage/Kupffer cell polarization in vivo and in vitro, and explore the association between PPAR-γ activity and macrophages M1/M2 polarization shifting. Here we showed that long-term high-fat diet increased Kupffer cells content with M1-predominant phenotype and increasing production of pro-inflammatory cytokines. Saturated fatty acids polarized Kupffer cells/macrophages to an M1-predominant phenotype while n-3 PUFA polarized Kupffer cells/macrophages to an M2 phenotype, which was associated with activation of NF-κB signal pathway and PPAR-γ respectively. Furthermore, up-regulation of PPAR-γ shifted lipid-induced macrophages polarization from M1-predominant phenotype to M2 phenotype. Macrophages polarization switch was associated with the interaction between PPAR-γ and NF-κBp65 signal pathway. Rosiglitazone restored high-fat diet-induced imblance of Kupffer cells M1/M2 polarization and alleviated hepatic steatosis as well as local pro-inflammatory response. These findings suggest that manipulation of PPAR-γ activity has the potential to balance lipid-induced M1/M2 macrophage/Kupffer cell polarization, and leading to prevent the development of NAFLD.
Effects of Gliadin consumption on the Intestinal Microbiota and Metabolic Homeostasis in Mice Fed a High-fat Diet
Authors: Zhang Li , Andersen Daniel , Roager Henrik Munch , Bahl Martin Iain , Hansen Camilla Hartmann Friis , Danneskiold-Samsøe Niels Banhos , Kristiansen Karsten , Radulescu Ilinca Daria , Sina Christian , Frandsen Henrik Lauritz , Hansen Axel Kornerup , Brix Susanne , Hellgren Lars I. , Licht Tine Rask 
Published: March 2017

AbstractDietary gluten causes severe disorders like celiac disease in gluten-intolerant humans. However, currently understanding of its impact in tolerant individuals is limited. Our objective was to test whether gliadin, one of the detrimental parts of gluten, would impact the metabolic effects of an obesogenic diet. Mice were fed either a defined high-fat diet (HFD) containing 4% gliadin (n = 20), or a gliadin-free, isocaloric HFD (n = 20) for 23 weeks. Combined analysis of several parameters including insulin resistance, histology of liver and adipose tissue, intestinal microbiota in three gut compartments, gut barrier function, gene expression, urinary metabolites and immune profiles in intestinal, lymphoid, liver and adipose tissues was performed. Mice fed the gliadin-containing HFD displayed higher glycated hemoglobin and higher insulin resistance as evaluated by the homeostasis model assessment, more hepatic lipid accumulation and smaller adipocytes than mice fed the gliadin-free HFD. This was accompanied by alterations in the composition and activity of the gut microbiota, gut barrier function, urine metabolome, and immune phenotypes within liver and adipose tissue. Our results reveal that gliadin disturbs the intestinal environment and affects metabolic homeostasis in obese mice, suggesting a detrimental effect of gluten intake in gluten-tolerant subjects consuming a high-fat diet.
Somatic genome editing with CRISPR/Cas9 generates and corrects a metabolic disease
Authors: Jarrett Kelsey E. , Lee Ciaran M. , Yeh Yi-Hsien , Hsu Rachel H. , Gupta Rajat , Zhang Min , Rodriguez Perla J. , Lee Chang Seok , Gillard Baiba K. , Bissig Karl-Dimiter , Pownall Henry J. , Martin James F. , Bao Gang , Lagor William R. 
Published: March 2017

AbstractGermline manipulation using CRISPR/Cas9 genome editing has dramatically accelerated the generation of new mouse models. Nonetheless, many metabolic disease models still depend upon laborious germline targeting, and are further complicated by the need to avoid developmental phenotypes. We sought to address these experimental limitations by generating somatic mutations in the adult liver using CRISPR/Cas9, as a new strategy to model metabolic disorders. As proof-of-principle, we targeted the low-density lipoprotein receptor (Ldlr), which when deleted, leads to severe hypercholesterolemia and atherosclerosis. Here we show that hepatic disruption of Ldlr with AAV-CRISPR results in severe hypercholesterolemia and atherosclerosis. We further demonstrate that co-disruption of Apob, whose germline loss is embryonically lethal, completely prevented disease through compensatory inhibition of hepatic LDL production. This new concept of metabolic disease modeling by somatic genome editing could be applied to many other systemic as well as liver-restricted disorders which are difficult to study by germline manipulation.
Nanoscale zero-valent iron/persulfate enhanced upflow anaerobic sludge blanket reactor for dye removal: Insight into microbial metabolism and microbial community
Authors: Pan Fei , Zhong Xiaohan , Xia Dongsheng , Yin Xianze , Li Fan , Zhao Dongye , Ji Haodong , Liu Wen 
Published: March 2017

AbstractThis study investigated the efficiency of nanoscale zero-valent iron combined with persulfate (NZVI/PS) for enhanced degradation of brilliant red X-3B in an upflow anaerobic sludge blanket (UASB) reactor, and examined the effects of NZVI/PS on anaerobic microbial communities during the treatment process. The addition of NZVI (0.5 g/L) greatly enhanced the decolourization rate of X-3B from 63.8% to 98.4%. The Biolog EcoPlateTM technique was utilized to examine microbial metabolism in the reactor, and the Illumina MiSeq high-throughput sequencing revealed 22 phyla and 88 genera of the bacteria. The largest genera (Lactococcus) decreased from 33.03% to 7.94%, while the Akkermansia genera increased from 1.69% to 20.23% according to the abundance in the presence of 0.2 g/L NZVI during the biological treatment process. Meanwhile, three strains were isolated from the sludge in the UASB reactors and identified by 16 S rRNA analysis. The distribution of three strains was consistent with the results from the Illumina MiSeq high throughput sequencing. The X-ray photoelectron spectroscopy results indicated that Fe(0) was transformed into Fe(II)/Fe(III) during the treatment process, which are beneficial for the microorganism growth, and thus promoting their metabolic processes and microbial community.
Double-flow focused liquid injector for efficient serial femtosecond crystallography
Authors: Oberthuer Dominik , Knoška Juraj , Wiedorn Max O. , Beyerlein Kenneth R. , Bushnell David A. , Kovaleva Elena G. , Heymann Michael , Gumprecht Lars , Kirian Richard A. , Barty Anton , Mariani Valerio , Tolstikova Aleksandra , Adriano Luigi , Awel Salah , Barthelmess Miriam , Dörner Katerina , Xavier P. Lourdu , Yefanov Oleksandr , James Daniel R. , Nelson Garrett , Wang Dingjie , Calvey George , Chen Yujie , Schmidt Andrea , Szczepek Michael , Frielingsdorf Stefan , Lenz Oliver , Snell Edward , Robinson Philip J. , Šarler Božidar , Belšak Grega , Maček Marjan , Wilde Fabian , Aquila Andrew , Boutet Sébastien , Liang Mengning , Hunter Mark S. , Scheerer Patrick , Lipscomb John D. , Weierstall Uwe , Kornberg Roger D. , Spence John C. H. , Pollack Lois , Chapman Henry N. , Bajt Saša 
Published: March 2017

AbstractSerial femtosecond crystallography requires reliable and efficient delivery of fresh crystals across the beam of an X-ray free-electron laser over the course of an experiment. We introduce a double-flow focusing nozzle to meet this challenge, with significantly reduced sample consumption, while improving jet stability over previous generations of nozzles. We demonstrate its use to determine the first room-temperature structure of RNA polymerase II at high resolution, revealing new structural details. Moreover, the double flow-focusing nozzles were successfully tested with three other protein samples and the first room temperature structure of an extradiol ring-cleaving dioxygenase was solved by utilizing the improved operation and characteristics of these devices.