bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gadd45a opens up the promoter regions of miR-295 facilitating pluripotency induction
Authors: Li Linpeng , Chen Keshi , Wu Yi , Long Qi , Zhao Danyun , Ma Bochao , Pei Duanqing , Liu Xingguo 
Published: October 2017

AbstractMicroRNAs (miRNAs) play crucial roles in the establishment of pluripotent state by controlling pluripotent network. However, the molecular mechanisms controlling miRNAs during somatic cell reprogramming remain obscure. In this study, we show Gadd45a (growth arrest and DNA-damage-inducible protein 45a) enhances reprogramming by activating miR-295. Furthermore, we show that Gadd45a binds the promoter regions of miR-295. Nuclease accessibility assay indicates that Gadd45a opens the promoter regions of miR-295. Levels of H3K9Ac and H3K27Ac on the promoter regions of miR-295 were also increased. In conclusion, our results indicate that Gadd45a relaxes the promoter regions of miR-295 and promotes the expression of miR-295 during reprogramming, implying a concise mechanism of Gadd45a and miR-290 cluster cooperation in cell-fate determination.
RANKL-mediated harmonious dialogue between fetus and mother guarantees smooth gestation by inducing decidual M2 macrophage polarization
Authors: Meng Yu-Han , Zhou Wen-Jie , Jin Li-Ping , Liu Li-Bing , Chang Kai-Kai , Mei Jie , Li Hui , Wang Jian , Li Da-Jin , Li Ming-Qing 
Published: October 2017

AbstractDecidual macrophages (dMϕ) contribute to maternal–fetal tolerance. However, the mechanism of dMϕ differentiation during pregnancy is still largely unknown. Here, we report that receptor activator for nuclear factor-κ B ligand (RANKL), secreted by human embryonic trophoblasts and maternal decidual stromal cells (DSCs), polarizes dMϕ toward a M2 phenotype. This polarization is mediated through activation of Akt/signal transducer and activator of transcription 6 (STAT6) signaling, which is associated with the upregulation of histone H3 lysine-27 demethylase Jmjd3 and IRF4 in dMϕ. Such differentiated dMϕ can induce a Th2 bias that promotes maternal–fetal tolerance. Impaired expression of RANKL leads to dysfunction of dMϕ in vivo and increased rates of fetal loss in mice. Transfer of RANK+Mϕ reverses mouse fetal loss induced by Mϕ depletion. Compared with normal pregnancy, there are abnormally low levels of RANKL/RANK in villi and decidua from miscarriage patients. These results suggest that RANKL is a pivotal regulator of maternal–fetal tolerance by licensing dMϕ to ensure a successful pregnancy outcome. This observation provides a scientific basis on which a potential therapeutic strategy can be targeted to prevent pregnancy loss.
MBD2 upregulates miR-301a-5p to induce kidney cell apoptosis during vancomycin-induced AKI
Authors: Wang Juan , Li Huiling , Qiu Shuangfa , Dong Zheng , Xiang Xudong , Zhang Dongshan 
Published: October 2017

AbstractDespite DNA methylation occurred in acute kidney injury (AKI), how it influenced progression of AKI remains unclear. Methyl-CpG-binding domain protein 2 (MBD2), a protein readers of methylation, was used to analyze the impact of DNA methylation on vancomycin (VAN)-induced AKI. Here, in cultured human kidney tubular epithelial cells (HK-2), we show that knockdown of MBD2 by siRNA attenuated VAN-induced apoptosis, caspase activity, and the expression of BAX and cleaved caspase 3. Interestingly, knockdown of MBD2 by siRNA was associated with the suppression of miR-301a-5p. Mechanistic studies confirmed MBD2 binds to these methylated CpG elements of miR-301a-5p promoter, and then activates miR-301a-5p promoter by suppressing methylation. Furthermore, anti-miR-301a-5p significantly blocked VAN-induced apoptosis and caspase activity in HK-2 cells, which was accompanied by downregulation of p53, and upregulation of MITF, HDGF and MDM-4 together. The latter genes were further identified as target genes of miR-301a-5p, and silencing of MDM-4 promoted p53 accumulation. In vivo, mice with MBD2 knockout (MBD2-KO) were counteracted to VAN-induced AKI, indicated by the analysis of renal function, histology, apoptosis and inflammation. MBD2-KO also significantly suppressed the expression of miR-301a-5p, p53, BAX and cleaved caspase 3, and restored the expression of MDM-4, MITF and HDGF. Finally, in vivo inhibition of miR-301a-5p also ameliorated VAN-induced AKI. Together, these results show the novel MBD2/miR-301a-5p/MITF, HDGF and MDM-4/p53 pathway in VAN-induced AKI.
Impairment of PTX3 expression in osteoblasts: a key element for osteoporosis
Authors: Scimeca Manuel , Salustri Antonietta , Bonanno Elena , Nardozi Daniela , Rao Cecilia , Piccirilli Eleonora , Feola Maurizio , Tancredi Virginia , Rinaldi Annamaria , Iolascon Giovanni , Orlandi Augusto , Gasbarra Elena , Maffulli Nicola , Brandi Maria Luisa , Tarantino Umberto 
Published: October 2017

AbstractPentraxin 3 (PTX3) is a multifunctional glycoprotein regulating inflammatory response, cell proliferation and migration and deposition and remodelling of the extracellular matrix by a variety of cells. In this study, we investigated the possible role of PTX3 in bone homeostasis. To this end, we compared the expression and function of PTX3 in human osteoblasts of osteoporotic, osteoarthritic patients and young subjects not affected by bone diseases. Immunohistochemical analysis performed on bone head biopsies showed a close association between bone health and the number of osteoblasts expressing PTX3. Noteworthy, the proportion of PTX3-positive osteoblasts resulted to be significantly lower in osteoporotic patients compared with both young patients and osteoarthritic patients of the same age. Ex vivo culture of osteoblasts isolated from the three groups of patients confirmed in vivo observation. Specifically, we observed rare runt-related transcription factor 2 (RUNX2) immunopositive osteoblasts expressing PTX3 in cell cultures derived from osteoporotic patients and western blotting analysis showed 80% reduction of PTX3 in the corresponding culture extracts compared with young and osteoarthritic patients. The treatment of human osteoblast primary cultures derived from young patients with anti-PTX3 antibody dramatically affected osteoblast behaviour. Indeed, they lost the morphological and molecular features typical of mature osteoblasts, acquiring fibroblast-like shape and highly decreasing nuclear factor kappa-B ligand (RANKL) and RUNX2 expression. Also, the inhibition of PTX3 negatively affected osteoblast proliferation and their ability to form cell clusters and microhydroxyapatite crystals. Altogether, these results suggest a central role of PTX3 in bone homeostasis showing its involvement in osteoblast proliferation, differentiation and function.
p38α MAPK antagonizing JNK to control the hepatic fat accumulation in pediatric patients onset intestinal failure
Authors: Xiao Yongtao , Wang Jun , Yan Weihui , Zhou Kejun , Cao Yi , Cai Wei 
Published: October 2017

AbstractThe p38α mitogen-activated protein kinase (MAPK) has been related to gluconeogenesis and lipid metabolism. However, the roles and related mechanisms of p38α MAPK in intestinal failure (IF)-associated liver steatosis remained poor understood. Here, our experimental evidence suggested that p38α MAPK significantly suppressed the fat accumulation in livers of IF patients mainly through two mechanisms. On the one hand, p38α MAPK increased hepatic bile acid (BA) synthesis by upregulating the expression of the rate-limiting enzyme cholesterol 7-α-hydroxylase (CYP7A1) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), which in turn activated the transcription of the CYP7A1. On the other hand, p38α MAPK promoted fatty acid (FA) β-oxidation via upregulating peroxisome proliferator-activated receptor alpha (PPARα) and its transcriptional target genes carnitine palmitoyltransferase 1A (CPT1A) and peroxisomal acyl-coenzyme aoxidase 1 (ACOX1). Dual luciferase assays indicated that p38α MAPK increased the transcription of PPARα, PGC-1α and CYP7A1 by upregulating their promoters’ activities. In addition, in vitro and in vivo assays indicated p38α MAPK negatively regulates the hepatic steatosis by controlling JNK activation. In conculsion, our findings demonstrate that hepatic p38α MAPK functions as a negative regulator of liver steatosis in maintaining BA synthesis and FAO by antagonizing the c-Jun N-terminal kinase (JNK).
MYCN contributes to the malignant characteristics of erythroleukemia through EZH2-mediated epigenetic repression of p21
Authors: Liu Li , Xu Feng , Chang Chun-Kang , He Qi , Wu Ling-Yun , Zhang Zheng , Li Xiao 
Published: October 2017

AbstractMYC proto-oncogene family including c-myc and n-myc (MYCN) are critical for normal cell development and tumorigenesis. Overexpression of c-myc causes acute erythroleukemia in vivo. However, the role of MYCN in acute erythroleukemia remains poorly understood. In this study, we found that the patients with erythroleukemia showed higher expression of MYCN than normal controls. In vitro experiments, knockdown of MYCN resulted in decreased cell proliferation, elevated autonomously cell apoptosis and increased P21-mediated cell senescence. On the contrary, overexpression of MYCN obviously promoted cell proliferation, and induced erythroid differentiation block and apoptosis resistance to cytotoxic agent. Further gene microarray and functional analysis revealed that EZH2 is a target of MYCN. Knockdown of MYCN inhibited the expression of EZH2, and then activated p21 expression through removal of H3K27me3 at the p21 promoter. Overexpression of ezh2 could antagonize the p21 activation caused by MYCN knockdown. In addition, Aurora inhibitor MLN8237 inhibited the proliferation of erythroleukemia cells through repression of MYCN/EZH2 axis, whereas it minimally affected the normal hematopoietic cells. In conclusion, MYCN contributes to the malignant characteristics of erythroleukemia through EZH2-meidated epigenetic repression of p21. MYCN may serve as a therapy target for the patients with acute erythroleukemia.
Cross-tissue integration of genetic and epigenetic data offers insight into autism spectrum disorder
Authors: Andrews Shan V. , Ellis Shannon E. , Bakulski Kelly M. , Sheppard Brooke , Croen Lisa A. , Hertz-Picciotto Irva , Newschaffer Craig J. , Feinberg Andrew P. , Arking Dan E. , Ladd-Acosta Christine , Fallin M. Daniele 
Published: October 2017

AbstractIntegration of emerging epigenetic information with autism spectrum disorder (ASD) genetic results may elucidate functional insights not possible via either type of information in isolation. Here we use the genotype and DNA methylation (DNAm) data from cord blood and peripheral blood to identify SNPs associated with DNA methylation (meQTL lists). Additionally, we use publicly available fetal brain and lung meQTL lists to assess enrichment of ASD GWAS results for tissue-specific meQTLs. ASD-associated SNPs are enriched for fetal brain (OR = 3.55; P < 0.001) and peripheral blood meQTLs (OR = 1.58; P < 0.001). The CpG targets of ASD meQTLs across cord, blood, and brain tissues are enriched for immune-related pathways, consistent with other expression and DNAm results in ASD, and reveal pathways not implicated by genetic findings. This joint analysis of genotype and DNAm demonstrates the potential of both brain and blood-based DNAm for insights into ASD and psychiatric phenotypes more broadly.
A homologue of the Parkinson’s disease-associated protein LRRK2 undergoes a monomer-dimer transition during GTP turnover
Authors: Deyaert Egon , Wauters Lina , Guaitoli Giambattista , Konijnenberg Albert , Leemans Margaux , Terheyden Susanne , Petrovic Arsen , Gallardo Rodrigo , Nederveen-Schippers Laura M. , Athanasopoulos Panagiotis S. , Pots Henderikus , Van Haastert Peter J. M. , Sobott Frank , Gloeckner Christian Johannes , Efremov Rouslan , Kortholt Arjan , Versées Wim 
Published: October 2017

AbstractMutations in LRRK2 are a common cause of genetic Parkinson’s disease (PD). LRRK2 is a multi-domain Roco protein, harbouring kinase and GTPase activity. In analogy with a bacterial homologue, LRRK2 was proposed to act as a GTPase activated by dimerization (GAD), while recent reports suggest LRRK2 to exist under a monomeric and dimeric form in vivo. It is however unknown how LRRK2 oligomerization is regulated. Here, we show that oligomerization of a homologous bacterial Roco protein depends on the nucleotide load. The protein is mainly dimeric in the nucleotide-free and GDP-bound states, while it forms monomers upon GTP binding, leading to a monomer-dimer cycle during GTP hydrolysis. An analogue of a PD-associated mutation stabilizes the dimer and decreases the GTPase activity. This work thus provides insights into the conformational cycle of Roco proteins and suggests a link between oligomerization and disease-associated mutations in LRRK2.
Experimental realization of two-dimensional Dirac nodal line fermions in monolayer Cu2Si
Authors: Feng Baojie , Fu Botao , Kasamatsu Shusuke , Ito Suguru , Cheng Peng , Liu Cheng-Cheng , Feng Ya , Wu Shilong , Mahatha Sanjoy K. , Sheverdyaeva Polina , Moras Paolo , Arita Masashi , Sugino Osamu , Chiang Tai-Chang , Shimada Kenya , Miyamoto Koji , Okuda Taichi , Wu Kehui , Chen Lan , Yao Yugui , Matsuda Iwao 
Published: October 2017

AbstractTopological nodal line semimetals, a novel quantum state of materials, possess topologically nontrivial valence and conduction bands that touch at a line near the Fermi level. The exotic band structure can lead to various novel properties, such as long-range Coulomb interaction and flat Landau levels. Recently, topological nodal lines have been observed in several bulk materials, such as PtSn4, ZrSiS, TlTaSe2 and PbTaSe2. However, in two-dimensional materials, experimental research on nodal line fermions is still lacking. Here, we report the discovery of two-dimensional Dirac nodal line fermions in monolayer Cu2Si based on combined theoretical calculations and angle-resolved photoemission spectroscopy measurements. The Dirac nodal lines in Cu2Si form two concentric loops centred around the Γ point and are protected by mirror reflection symmetry. Our results establish Cu2Si as a platform to study the novel physical properties in two-dimensional Dirac materials and provide opportunities to realize high-speed low-dissipation devices.
Controlling the bioactivity of a peptide hormone in vivo by reversible self-assembly
Authors: Ouberai Myriam M. , Dos Santos Ana L. Gomes , Kinna Sonja , Madalli Shimona , Hornigold David C. , Baker David , Naylor Jacqueline , Sheldrake Laura , Corkill Dominic J. , Hood John , Vicini Paolo , Uddin Shahid , Bishop Steven , Varley Paul G. , Welland Mark E. 
Published: October 2017

AbstractThe use of peptides as therapeutic agents is undergoing a renaissance with the expectation of new drugs with enhanced levels of efficacy and safety. Their clinical potential will be only fully realised once their physicochemical and pharmacokinetic properties have been precisely controlled. Here we demonstrate a reversible peptide self-assembly strategy to control and prolong the bioactivity of a native peptide hormone in vivo. We show that oxyntomodulin, a peptide with potential to treat obesity and diabetes, self-assembles into a stable nanofibril formulation which subsequently dissociates to release active peptide and produces a pharmacological effect in vivo. The subcutaneous administration of the nanofibrils in rats results in greatly prolonged exposure, with a constant oxyntomodulin bioactivity detectable in serum for at least 5 days as compared to free oxyntomodulin which is undetectable after only 4 h. Such an approach is simple, cost-efficient and generic in addressing the limitations of peptide therapeutics.
Apical surface supracellular mechanical properties in polarized epithelium using noninvasive acoustic force spectroscopy
Authors: Cartagena-Rivera Alexander X. , Van Itallie Christina M. , Anderson James M. , Chadwick Richard S. 
Published: October 2017

Abstract
Maintenance of epithelial tissue integrity requires coordination between cell–cell adherens junctions, tight junctions (TJ), and the perijunctional actomyosin cytoskeleton. Here we addressed the hypothesis that alterations in TJ structure and remodeling of the actomyosin cytoskeleton modify epithelial mechanics. Current methods to measure supracellular mechanical properties disrupt intact monolayers, therefore, we developed a novel method using noncontact acoustic frequency-modulation atomic force microscopy (FM-AFM) and tested it on MDCK polarized monolayers. Our results show that double knockdown (dKD) of ZO-1/ZO-2 elevates the apical epithelial tension and effective viscosity. Interestingly, epithelial tension is more sensitive to inhibition of myosin II ATPase activity than to inhibition of ROCK activity, but viscosity is highly sensitive to both. Additionally, we showed epithelial intercellular pulling forces at tricellular junctions and adhesion forces in dKD cells are elevated with an increase in contractility. In conclusion, FM-AFM enables the physiological and quantitative investigation of mechanics in intact epithelium.
Younger Dryas ice margin retreat triggered by ocean surface warming in central-eastern Baffin Bay
Authors: Oksman Mimmi , Weckström Kaarina , Miettinen Arto , Juggins Stephen , Divine Dmitry V. , Jackson Rebecca , Telford Richard , Korsgaard Niels J. , Kucera Michal 
Published: October 2017

AbstractThe transition from the last ice age to the present-day interglacial was interrupted by the Younger Dryas (YD) cold period. While many studies exist on this climate event, only few include high-resolution marine records that span the YD. In order to better understand the interactions between ocean, atmosphere and ice sheet stability during the YD, more high-resolution proxy records from the Arctic, located proximal to ice sheet outlet glaciers, are required. Here we present the first diatom-based high-resolution quantitative reconstruction of sea surface conditions from central-eastern Baffin Bay, covering the period 14.0–10.2 kyr BP. Our record reveals warmer sea surface conditions and strong interactions between the ocean and the West Greenland ice margin during the YD. These warmer conditions were caused by increased Atlantic-sourced water inflow combined with amplified seasonality. Our results emphasize the importance of the ocean for ice sheet stability under the current changing climate.
Hyperconnected molecular glass network architectures with exceptional elastic properties
Authors: Burg Joseph A. , Oliver Mark S. , Frot Theo J. , Sherwood Mark , Lee Victor , Dubois Geraud , Dauskardt Reinhold H. 
Published: October 2017

AbstractHyperconnected network architectures can endow nanomaterials with remarkable mechanical properties that are fundamentally controlled by designing connectivity into the intrinsic molecular structure. For hybrid organic–inorganic nanomaterials, here we show that by using 1,3,5 silyl benzene precursors, the connectivity of a silicon atom within the network extends beyond its chemical coordination number, resulting in a hyperconnected network with exceptional elastic stiffness, higher than that of fully dense silica. The exceptional intrinsic stiffness of these hyperconnected glass networks is demonstrated with molecular dynamics models and these model predictions are calibrated through the synthesis and characterization of an intrinsically porous hybrid glass processed from 1,3,5(triethoxysilyl)benzene. The proposed molecular design strategy applies to any materials system wherein the mechanical properties are controlled by the underlying network connectivity.
APOBEC3H structure reveals an unusual mechanism of interaction with duplex RNA
Authors: Bohn Jennifer A. , Thummar Keyur , York Ashley , Raymond Alice , Brown W. Clay , Bieniasz Paul D. , Hatziioannou Theodora , Smith Janet L. 
Published: October 2017

AbstractThe APOBEC3 family of cytidine deaminases cause lethal hypermutation of retroviruses via deamination of newly reverse-transcribed viral DNA. Their ability to bind RNA is essential for virion infiltration and antiviral activity, yet the mechanisms of viral RNA recognition are unknown. By screening naturally occurring, polymorphic, non-human primate APOBEC3H variants for biological and crystallization properties, we obtained a 2.24-Å crystal structure of pig-tailed macaque APOBEC3H with bound RNA. Here, we report that APOBEC3H forms a dimer around a short RNA duplex and, despite the bound RNA, has potent cytidine deaminase activity. The structure reveals an unusual RNA-binding mode in which two APOBEC3H molecules at opposite ends of a seven-base-pair duplex interact extensively with both RNA strands, but form no protein–protein contacts. CLIP-seq analysis revealed that APOBEC3H preferentially binds to sequences in the viral genome predicted to contain duplexes, a property that may facilitate both virion incorporation and catalytic activity.
Collimated protons accelerated from an overdense gas jet irradiated by a 1 µm wavelength high-intensity short-pulse laser
Authors: Chen S. N. , Vranic M. , Gangolf T. , Boella E. , Antici P. , Bailly-Grandvaux M. , Loiseau P. , Pépin H. , Revet G. , Santos J. J. , Schroer A. M. , Starodubtsev Mikhail , Willi O. , Silva L. O. , d’Humières E. , Fuchs J. 
Published: October 2017

AbstractWe have investigated proton acceleration in the forward direction from a near-critical density hydrogen gas jet target irradiated by a high intensity (1018 W/cm2), short-pulse (5 ps) laser with wavelength of 1.054 μm. We observed the signature of the Collisionless Shock Acceleration mechanism, namely quasi-monoenergetic proton beams with small divergence in addition to the more commonly observed electron-sheath driven proton acceleration. The proton energies we obtained were modest (~MeV), but prospects for improvement are offered through further tailoring the gas jet density profile. Also, we observed that this mechanism is very robust in producing those beams and thus can be considered as a future candidate in laser-driven ion sources driven by the upcoming next generation of multi-PW near-infrared lasers.
Long-term passive acoustic recordings track the changing distribution of North Atlantic right whales (Eubalaena glacialis) from 2004 to 2014
Authors: Davis Genevieve E. , Baumgartner Mark F. , Bonnell Julianne M. , Bell Joel , Berchok Catherine , Bort Thornton Jacqueline , Brault Solange , Buchanan Gary , Charif Russell A. , Cholewiak Danielle , Clark Christopher W. , Corkeron Peter , Delarue Julien , Dudzinski Kathleen , Hatch Leila , Hildebrand John , Hodge Lynne , Klinck Holger , Kraus Scott , Martin Bruce , Mellinger David K. , Moors-Murphy Hilary , Nieukirk Sharon , Nowacek Douglas P. , Parks Susan , Read Andrew J. , Rice Aaron N. , Risch Denise , Širović Ana , Soldevilla Melissa , Stafford Kate , Stanistreet Joy E. , Summers Erin , Todd Sean , Warde Ann , Van Parijs Sofie M. 
Published: October 2017

AbstractGiven new distribution patterns of the endangered North Atlantic right whale (NARW;Eubalaena glacialis) population in recent years, an improved understanding of spatio-temporal movements are imperative for the conservation of this species. While so far visual data have provided most information on NARW movements, passive acoustic monitoring (PAM) was used in this study in order to better capture year-round NARW presence. This project used PAM data from 2004 to 2014 collected by 19 organizations throughout the western North Atlantic Ocean. Overall, data from 324 recorders (35,600 days) were processed and analyzed using a classification and detection system. Results highlight almost year-round habitat use of the western North Atlantic Ocean, with a decrease in detections in waters off Cape Hatteras, North Carolina in summer and fall. Data collected post 2010 showed an increased NARW presence in the mid-Atlantic region and a simultaneous decrease in the northern Gulf of Maine. In addition, NARWs were widely distributed across most regions throughout winter months. This study demonstrates that a large-scale analysis of PAM data provides significant value to understanding and tracking shifts in large whale movements over long time scales.