bluuebunny/crossref_metadata_2025_split huggingface dataset:
TLR4 signaling drives mesenchymal stromal cells commitment to promote tumor microenvironment transformation in multiple myeloma
Authors: Giallongo Cesarina , Tibullo Daniele , Camiolo Giuseppina , Parrinello Nunziatina L. , Romano Alessandra , Puglisi Fabrizio , Barbato Alessandro , Conticello Concetta , Lupo Gabriella , Anfuso Carmelina Daniela , Lazzarino Giacomo , Li Volti Giovanni , Palumbo Giuseppe Alberto , Di Raimondo Francesco 
Published: September 2019

AbstractInflammation represents a key feature and hallmark of tumor microenvironment playing a major role in the interaction with mesenchymal stromal cells (MSC) in cancer progression. The aim of the present study was to investigate the crosstalk between MSCs and myeloma cells (MM) in the pro-inflammatory microenvironment promoting immune evasion and tumor growth. MSC were collected from patients with diagnosis of MGUS (n = 10), smoldering myeloma (n = 7), multiple myeloma at diagnosis (n = 16), relapse (n = 5) or refractory (n = 3), and from age-matched healthy controls (HC, n = 10) and cultured with peripheral blood mononucleated cells (PBMC) from healthy volunteer donors. Similarly to MM, we showed that MSC from smoldering multiple myeloma (SMM) patients activated neutrophils and conferred an immunosuppressive and pro-angiogenic phenotype. Furthermore, co-cultures of plasma cells (PC) and HC-MSC suggested that such activation is driven by MM cells through the switching into a pro-inflammatory phenotype mediated by toll-like receptor 4 (TLR4). These results were further confirmed using a zebrafish as an immunocompetent in vivo model, showing the role of MM–MSC in supporting PCs engraftment and Th2 response. Such effect was abolished following inhibition of TLR4 signaling in MM–MSC before co-injection with PC. Moreover, the addition of a TLR4 inhibitor in the co-culture of HC-MSC with MM cells prevented the activation of the pro-tumor activity in PC-educated MSC. In conclusion, our study provides evidence that TLR4 signaling plays a key role in MSC transformation by inducing a pro-tumor phenotype associated with a permissive microenvironment allowing immune escape and tumor growth.
Mesophilic microorganisms build terrestrial mats analogous to Precambrian microbial jungles
Authors: Finke N. , Simister R. L. , O’Neil A. H. , Nomosatryo S. , Henny C. , MacLean L. C. , Canfield D. E. , Konhauser K. , Lalonde S. V. , Fowle D. A. , Crowe S. A. 
Published: September 2019

AbstractDevelopment of Archean paleosols and patterns of Precambrian rock weathering suggest colonization of continents by subaerial microbial mats long before evolution of land plants in the Phanerozoic Eon. Modern analogues for such mats, however, have not been reported, and possible biogeochemical roles of these mats in the past remain largely conceptual. We show that photosynthetic, subaerial microbial mats from Indonesia grow on mafic bedrocks at ambient temperatures and form distinct layers with features similar to Precambrian mats and paleosols. Such subaerial mats could have supported a substantial aerobic biosphere, including nitrification and methanotrophy, and promoted methane emissions and oxidative weathering under ostensibly anoxic Precambrian atmospheres. High C-turnover rates and cell abundances would have made these mats prime locations for early microbial diversification. Growth of landmass in the late Archean to early Proterozoic Eons could have reorganized biogeochemical cycles between land and sea impacting atmospheric chemistry and climate.
Circular RNA CircFndc3b modulates cardiac repair after myocardial infarction via FUS/VEGF-A axis
Authors: Garikipati Venkata Naga Srikanth , Verma Suresh Kumar , Cheng Zhongjian , Liang Dongming , Truongcao May M. , Cimini Maria , Yue Yujia , Huang Grace , Wang Chunlin , Benedict Cindy , Tang Yan , Mallaredy Vandana , Ibetti Jessica , Grisanti Laurel , Schumacher Sarah M. , Gao Erhe , Rajan Sudarsan , Wilusz Jeremy E. , Goukassian David , Houser Steven R. , Koch Walter J. , Kishore Raj 
Published: September 2019

AbstractCircular RNAs are generated from many protein-coding genes, but their role in cardiovascular health and disease states remains unknown. Here we report identification of circRNA transcripts that are differentially expressed in post myocardial infarction (MI) mouse hearts including circFndc3b which is significantly down-regulated in the post-MI hearts. Notably, the human circFndc3b ortholog is also significantly down-regulated in cardiac tissues of ischemic cardiomyopathy patients. Overexpression of circFndc3b in cardiac endothelial cells increases vascular endothelial growth factor-A expression and enhances their angiogenic activity and reduces cardiomyocytes and endothelial cell apoptosis. Adeno-associated virus 9 -mediated cardiac overexpression of circFndc3b in post-MI hearts reduces cardiomyocyte apoptosis, enhances neovascularization and improves left ventricular functions. Mechanistically, circFndc3b interacts with the RNA binding protein Fused in Sarcoma to regulate VEGF expression and signaling. These findings highlight a physiological role for circRNAs in cardiac repair and indicate that modulation of circFndc3b expression may represent a potential strategy to promote cardiac function and remodeling after MI.
Ultra-long-acting tunable biodegradable and removable controlled release implants for drug delivery
Authors: Benhabbour S. Rahima , Kovarova Martina , Jones Clinton , Copeland Daijha J. , Shrivastava Roopali , Swanson Michael D. , Sykes Craig , Ho Phong T. , Cottrell Mackenzie L. , Sridharan Anush , Fix Samantha M. , Thayer Orrin , Long Julie M. , Hazuda Daria J. , Dayton Paul A. , Mumper Russell J. , Kashuba Angela D. M. , Victor Garcia J. 
Published: September 2019

AbstractHere we report an ultra-long-acting tunable, biodegradable, and removable polymer-based delivery system that offers sustained drug delivery for up to one year for HIV treatment or prophylaxis. This robust formulation offers the ability to integrate multiple drugs in a single injection, which is particularly important to address the potential for drug resistance with monotherapy. Six antiretroviral drugs were selected based on their solubility inN-methyl-2-pyrrolidone and relevance as a combination therapy for HIV treatment or prevention. All drugs released with concentrations above their protein-adjusted inhibitory concentration and retained their physical and chemical properties within the formulation and upon release. The versatility of this formulation to integrate multiple drugs and provide sustained plasma concentrations from several weeks to up to one year, combined with its ability to be removed to terminate the treatment if necessary, makes it attractive as a drug delivery platform technology for a wide range of applications.
Linked-read sequencing of gametes allows efficient genome-wide analysis of meiotic recombination
Authors: Sun Hequan , Rowan Beth A. , Flood Pádraic J. , Brandt Ronny , Fuss Janina , Hancock Angela M. , Michelmore Richard W. , Huettel Bruno , Schneeberger Korbinian 
Published: September 2019

AbstractMeiotic crossovers (COs) ensure proper chromosome segregation and redistribute the genetic variation that is transmitted to the next generation. Large populations and the demand for genome-wide, fine-scale resolution challenge existing methods for CO identification. Taking advantage of linked-read sequencing, we develop a highly efficient method for genome-wide identification of COs at kilobase resolution in pooled recombinants. We first test this method using a pool of Arabidopsis F2 recombinants, and recapitulate results obtained from the same plants using individual whole-genome sequencing. By applying this method to a pool of pollen DNA from an F1 plant, we establish a highly accurate CO landscape without generating or sequencing a single recombinant plant. The simplicity of this approach enables the simultaneous generation and analysis of multiple CO landscapes, accelerating the pace at which mechanisms for the regulation of recombination can be elucidated through efficient comparisons of genotypic and environmental effects on recombination.
A fungal pathogen deploys a small silencing RNA that attenuates mosquito immunity and facilitates infection
Authors: Cui Chunlai , Wang Yan , Liu Jingnan , Zhao Jing , Sun Peilu , Wang Sibao 
Published: September 2019

AbstractInsecticidal fungi represent a promising alternative to chemical pesticides for disease vector control. Here, we show that the pathogenic fungus Beauveria bassiana exports a microRNA-like RNA (bba-milR1) that hijacks the host RNA-interference machinery in mosquito cells by binding to Argonaute 1 (AGO1). bba-milR1 is highly expressed during fungal penetration of the mosquito integument, and suppresses host immunity by silencing expression of the mosquito Toll receptor ligand Spätzle 4 (Spz4). Later, upon entering the hemocoel, bba-milR1 expression is decreased, which avoids induction of the host proteinase CLIPB9 that activates the melanization response. Thus, our results indicate that the pathogen deploys a cross-kingdom small-RNA effector that attenuates host immunity and facilitates infection.
Enhanced CRISPR-based DNA demethylation by Casilio-ME-mediated RNA-guided coupling of methylcytosine oxidation and DNA repair pathways
Authors: Taghbalout Aziz , Du Menghan , Jillette Nathaniel , Rosikiewicz Wojciech , Rath Abhijit , Heinen Christopher D. , Li Sheng , Cheng Albert W. 
Published: September 2019

AbstractHere we develop a methylation editing toolbox, Casilio-ME, that enables not only RNA-guided methylcytosine editing by targeting TET1 to genomic sites, but also by co-delivering TET1 and protein factors that couple methylcytosine oxidation to DNA repair activities, and/or promote TET1 to achieve enhanced activation of methylation-silenced genes. Delivery of TET1 activity by Casilio-ME1 robustly alters the CpG methylation landscape of promoter regions and activates methylation-silenced genes. We augment Casilio-ME1 to simultaneously deliver the TET1-catalytic domain and GADD45A (Casilio-ME2) or NEIL2 (Casilio-ME3) to streamline removal of oxidized cytosine intermediates to enhance activation of targeted genes. Using two-in-one effectors or modular effectors, Casilio-ME2 and Casilio-ME3 remarkably boost gene activation and methylcytosine demethylation of targeted loci. We expand the toolbox to enable a stable and expression-inducible system for broader application of the Casilio-ME platforms. This work establishes a platform for editing DNA methylation to enable research investigations interrogating DNA methylomes.
Inactivation of NF-κB2 (p52) restrains hepatic glucagon response via preserving PDE4B induction
Authors: Zhang Wen-Song , Pan An , Zhang Xu , Ying Ang , Ma Gaoxiang , Liu Bao-Lin , Qi Lian-Wen , Liu Qun , Li Ping 
Published: September 2019

AbstractGlucagon promotes hepatic gluconeogenesis and maintains whole-body glucose levels during fasting. The regulatory factors that are involved in fasting glucagon response are not well understood. Here we report a role of p52, a key activator of the noncanonical nuclear factor-kappaB signaling, in hepatic glucagon response. We show that p52 is activated in livers of HFD-fed and glucagon-challenged mice. Knockdown of p52 lowers glucagon-stimulated hyperglycemia, while p52 overexpression augments glucagon response. Mechanistically, p52 binds to phosphodiesterase 4B promoter to inhibit its transcription and promotes cAMP accumulation, thus augmenting the glucagon response through cAMP/PKA signaling. The anti-diabetic drug metformin and ginsenoside Rb1 lower blood glucose at least in part by inhibiting p52 activation. Our findings reveal that p52 mediates glucagon-triggered hepatic gluconeogenesis and suggests that pharmacological intervention to prevent p52 processing is a potential therapeutic strategy for diabetes.
Mechanistic Insights into β-Lactamase-Catalysed Carbapenem Degradation Through Product Characterisation
Authors: Lohans Christopher T. , Freeman Emily I. , Groesen Emma van , Tooke Catherine L. , Hinchliffe Philip , Spencer James , Brem Jürgen , Schofield Christopher J. 
Published: September 2019

Abstractβ-Lactamases are a major threat to the clinical use of carbapenems, which are often antibiotics of last resort. Despite this, the reaction outcomes and mechanisms by which β-lactamases degrade carbapenems are still not fully understood. The carbapenem bicyclic core consists of a β-lactam ring fused to a pyrroline ring. Following β-lactamase-mediated opening of the β-lactam, the pyrroline may interconvert between an enamine (2-pyrroline) form and two epimeric imine (1-pyrroline) forms; previous crystallographic and spectroscopic studies have reported all three of these forms in the contexts of hydrolysis by different β-lactamases. As we show by NMR spectroscopy, the serine β-lactamases (KPC-2, SFC-1, CMY-10, OXA-23, and OXA-48) and metallo-β-lactamases (NDM-1, VIM-1, BcII, CphA, and L1) tested all degrade carbapenems to preferentially give the Δ2 (enamine) and/or (R)-Δ1 (imine) products. Rapid non-enzymatic tautomerisation of the Δ2 product to the (R)-Δ1 product prevents assignment of the nascent enzymatic product by NMR. The observed stereoselectivity implies that carbapenemases control the form of their pyrroline ring intermediate(s)/product(s), thereby preventing pyrroline tautomerisation from inhibiting catalysis.
Subtractive inhibition assay for the detection of Campylobacter jejuni in chicken samples using surface plasmon resonance
Authors: Masdor Noor Azlina , Altintas Zeynep , Shukor Mohd. Yunus , Tothill Ibtisam E. 
Published: September 2019

AbstractIn this work, a subtractive inhibition assay (SIA) based on surface plasmon resonance (SPR) for the rapid detection of Campylobacter jejuni was developed. For this, rabbit polyclonal antibody with specificity to C. jejuni was first mixed with C. jejuni cells and unbound antibody was subsequently separated using a sequential process of centrifugation and then detected using an immobilized goat anti-rabbit IgG polyclonal antibody on the SPR sensor chip. This SIA-SPR method showed excellent sensitivity for C. jejuni with a limit of detection (LOD) of 131 ± 4 CFU mL−1 and a 95% confidence interval from 122 to 140 CFU mL−1. The method has also high specificity. The developed method showed low cross-reactivity to bacterial pathogens such as Salmonellaenterica serovar Typhimurium (7.8%), Listeria monocytogenes (3.88%) and Escherichia coli (1.56%). The SIA-SPR method together with the culturing (plating) method was able to detect C. jejuni in the real chicken sample at less than 500 CFU mL−1, the minimum infectious dose for C. jejuni while a commercial ELISA kit was unable to detect the bacterium. Since the currently available detection tools rely on culturing methods, which take more than 48 hours to detect the bacterium, the developed method in this work has the potential to be a rapid and sensitive detection method for C. jejuni.
High-performance flat-type InGaN-based light-emitting diodes with local breakdown conductive channel
Authors: Baek Seung-Hye , Lee Hyun-Jin , Lee Sung-Nam 
Published: September 2019

AbstractFlat-type InGaN-based light-emitting diodes (LEDs) without an n-type contact electrode were developed by using a local breakdown conductive channel (LBCC), and the effect of the In content of the InGaN quantum wells (QWs) on the local breakdown phenomenon was investigated. Electroluminescence and X-ray analyses demonstrated that the homogeneity and crystallinity of the InGaN QWs deteriorated as the In content of the InGaN QWs increased, thereby increasing the reverse leakage current and decreasing the breakdown voltage. After reverse breakdown with a reverse current of several mA, an LBCC was formed on the GaN-based LEDs. The surface size and anisotropic shape of the LBCC increased as the indium content of the InGaN QWs in the LEDs increased. Moreover, a flat-type InGaN LED without an n-type electrode was developed by using the LBCC. Notably, the resistance of the LBCC decreased with increasing indium content in the InGaN QWs, leading to lower resistance and higher light emission of the flat-type InGaN-based LEDs without an n-type contact electrode.
L-arginine supplementation and thromboxane synthase inhibition increases cerebral blood flow in experimental cerebral malaria
Authors: Moreira Aline S. , Estato Vanessa , Malvar David C. , Sanches Guilherme S. , Gomes Fabiana , Tibirica Eduardo , Daniel-Ribeiro Cláudio Tadeu , Carvalho Leonardo J. M. 
Published: September 2019

AbstractCerebral malaria pathogenesis involves vascular dysfunction with low nitric oxide (NO) bioavailability, vasoconstriction and impaired vasodilation, leading to ischemia, tissue hypoxia and ultimately death. Cerebral blood flow (CBF) involves NO and other pathways, including arachidonic acid (AA)-derived metabolites. Here we show that mice with experimental cerebral malaria (ECM) by P. berghei ANKA showed marked decreases in CBF (as assessed by laser speckle contrast imaging - LSCI) and that administration of L-arginine supplementation (50 mg/kg) and/or of the thromboxane synthase inhibitor Ozagrel (100 mg/kg) induced immediate increases in CBF. L-arginine in combination with artesunate (32 mg/kg) induced immediate reversal of brain ischemia in the short-term (1 hour), but the effect subsided after 3 and 6 hours. Neither L-arginine nor Ozagrel reversed blood brain barrier breakdown. Mice with ECM showed brain levels of selected AA-derived metabolites with a vasoconstrictor profile, with increased levels of 8-isoprostanes, 20-HETE and 14,15-DHET, whereas mice infected with a non-ECM-inducing strain of P. berghei (NK65) showed a vasodilator profile, with normal levels of 20-HETE and 14,15-DHET and increased levels of PGE2. L-arginine is capable of partially reversing cerebral ischemia and AA metabolites may play a role in the cerebrovascular dysfunction in ECM.
Emerging recombination of the C2 sub-genotype of HFMD-associated CV-A4 is persistently and extensively circulating in China
Authors: Ji Tianjiao , Guo Yue , Lv Likun , Wang Jianxing , Shi Yong , Yu Qiuli , Zhang Fan , Tong Wenbin , Ma Jiangtao , Zeng Hanri , Zhao Hua , Zhang Yong , Han Taoli , Song Yang , Yan Dongmei , Yang Qian , Zhu Shuangli , Zhang Yan , Xu Wenbo 
Published: September 2019

AbstractSporadic outbreaks caused by coxsackievirus A4 (CV-A4) have been reported worldwide. To further elucidate the detailed genetic characteristics and evolutionary recombination events of CV-A4, virus samples from nationwide hand, foot and mouth disease (HFMD) surveillance, encompassing 27 out of the 31 provinces in China, were investigated. Comprehensive and systematic phylogenetic analyses were performed by using 29 complete genomes, 142 complete CV-A4 VP1 sequences. Four genotypes (A, B, C and D) and five sub-genotypes (C1-C5) were re-identified based on the complete VP1 sequences. C2 is the predominant sub-genotype of CV-A4 associated with HFMD and has evolved into 3 clusters. Cluster 1 is a major cluster that has been persistently and extensively circulating in China since 2006 and has been associated with all severe cases. All the sequences showed high homology with the CV-A4 prototype in the P1 region, while higher identities with CV-A5, CV-14 and CV-16 in the P2 and P3 regions. Recombination analysis revealed that C2 had two specific genetic recombination patterns with other EV-A prototypes in the 5′-UTR and 3D region compared with C5. These recombination patterns might be associated with the increased transmissibility of C2 viruses, which were obtained due to their persistent and extensive circulation in populations.
A mass spectrometry-based assay using metabolic labeling to rapidly monitor chromatin accessibility of modified histone proteins
Authors: Sidoli Simone , Lopes Mariana , Lund Peder J. , Goldman Naomi , Fasolino Maria , Coradin Mariel , Kulej Katarzyna , Bhanu Natarajan V. , Vahedi Golnaz , Garcia Benjamin A. 
Published: September 2019

AbstractHistone post-translational modifications (PTMs) contribute to chromatin accessibility due to their chemical properties and their ability to recruit enzymes responsible for DNA readout and chromatin remodeling. To date, more than 400 different histone PTMs and thousands of combinations of PTMs have been identified, the vast majority with still unknown biological function. Identification and quantification of histone PTMs has become routine in mass spectrometry (MS) but, since raising antibodies for each PTM in a study can be prohibitive, lots of potential is lost from MS datasets when uncharacterized PTMs are found to be significantly regulated. We developed an assay that uses metabolic labeling and MS to associate chromatin accessibility with histone PTMs and their combinations. The labeling is achieved by spiking in the cell media a 5x concentration of stable isotope labeled arginine and allow cells to grow for at least one cell cycle. We quantified the labeling incorporation of about 200 histone peptides with a proteomics workflow, and we confirmed that peptides carrying PTMs with extensively characterized roles in active transcription or gene silencing were in highly or poorly labeled forms, respectively. Data were further validated using next-generation sequencing to assess the transcription rate of chromatin regions modified with five selected PTMs. Furthermore, we quantified the labeling rate of peptides carrying co-existing PTMs, proving that this method is suitable for combinatorial PTMs. We focus on the abundant bivalent mark H3K27me3K36me2, showing that H3K27me3 dominantly represses histone swapping rate even in the presence of the more permissive PTM H3K36me2. Together, we envision this method will help to generate hypotheses regarding histone PTM functions and, potentially, elucidate the role of combinatorial histone codes.
Formation of Pseudomonas aeruginosa Biofilms in Full-thickness Scald Burn Wounds in Rats
Authors: Brandenburg Kenneth S. , Weaver Alan J. , Karna S. L. Rajasekhar , You Tao , Chen Ping , Stryk Shaina Van , Qian Liwu , Pineda Uzziel , Abercrombie Johnathan J. , Leung Kai P. 
Published: September 2019

AbstractUsing Sprague-Dawley rats (350–450 g; n = 61) and the recently updated Walker-Mason rat scald burn model, we demonstrated that Pseudomonas aeruginosa readily formed biofilms within full-thickness burn wounds. Following the burn, wounds were surface-inoculated with P. aeruginosa in phosphate-buffered saline (PBS), while sterile PBS was used for controls. On post-burn days 1, 3, 7, and 11, animals were euthanized and samples collected for quantitative bacteriology, bacterial gene expression, complete blood cell counts, histology, and myeloperoxidase activity. Robust biofilm infections developed in the full-thickness burn wounds inoculated with 1 × 104 CFU of P. aeruginosa. Both histology and scanning electron microscopy showed the pathogen throughout the histologic cross-sections of burned skin. Quantigene analysis revealed significant upregulation of alginate and pellicle biofilm matrix genes of P. aeruginosa within the burn eschar. Additionally, expression of P. aeruginosa proteases and siderophores increased significantly in the burn wound environment. Interestingly, the host’s neutrophil response to the pathogen was not elevated in either the eschar or circulating blood when compared to the control burn. This new full-thickness burn biofilm infection model will be used to test new anti-biofilm therapies that may be deployed with soldiers in combat for immediate use at the site of burn injury on the battlefield.