bluuebunny/crossref_metadata_2025_split huggingface dataset:
Omentin-1 prevents inflammation-induced osteoporosis by downregulating the pro-inflammatory cytokines
Authors: Rao Shan-Shan , Hu Yin , Xie Ping-Li , Cao Jia , Wang Zhen-Xing , Liu Jiang-Hua , Yin Hao , Huang Jie , Tan Yi-Juan , Luo Juan , Luo Ming-Jie , Tang Si-Yuan , Chen Tuan-Hui , Yuan Ling-Qing , Liao Er-Yuan , Xu Ran , Liu Zheng-Zhao , Chen Chun-Yuan , Xie Hui 
Published: April 2018

AbstractOsteoporosis is a frequent complication of chronic inflammatory diseases and increases in the pro-inflammatory cytokines make an important contribution to bone loss by promoting bone resorption and impairing bone formation. Omentin-1 is a newly identified adipocytokine that has anti-inflammatory effects, but little is known about the role of omentin-1 in inflammatory osteoporosis. Here we generated global omentin-1 knockout (omentin-1−/−) mice and demonstrated that depletion of omentin-1 induces inflammatory bone loss-like phenotypes in mice, as defined by abnormally elevated pro-inflammatory cytokines, increased osteoclast formation and bone tissue destruction, as well as impaired osteogenic activities. Using an inflammatory cell model induced by tumor necrosis factor-α (TNF-α), we determined that recombinant omentin-1 reduces the production of pro-inflammatory factors in the TNF-α-activated macrophages, and suppresses their anti-osteoblastic and pro-osteoclastic abilities. In the magnesium silicate-induced inflammatory osteoporosis mouse model, the systemic administration of adenoviral-delivered omentin-1 significantly protects from osteoporotic bone loss and inflammation. Our study suggests that omentin-1 can be used as a promising therapeutic agent for the prevention or treatment of inflammatory bone diseases by downregulating the pro-inflammatory cytokines.
Quantitative proteomic profiling of primary cancer-associated fibroblasts in oesophageal adenocarcinoma
Authors: Manousopoulou Antigoni , Hayden Annette , Mellone Massimiliano , Garay-Baquero Diana J. , White Cory H. , Noble Fergus , Lopez Monette , Thomas Gareth J. , Underwood Timothy J. , Garbis Spiros D. 
Published: April 2018

Abstract

Background
Cancer-associated fibroblasts (CAFs) form the major stromal component of the tumour microenvironment (TME). The present study aimed to examine the proteomic profiles of CAFs vs. normal fibroblasts (NOFs) from patients with oesophageal adenocarcinoma to gain insight into their pro-oncogenic phenotype.

Methods
CAFs/NOFs from four patients were sub-cultured and analysed using quantitative proteomics. Differentially expressed proteins (DEPs) were subjected to bioinformatics and compared with published proteomics and transcriptomics datasets.

Results
Principal component analysis of all profiled proteins showed that CAFs had high heterogeneity and clustered separately from NOFs. Bioinformatics interrogation of the DEPs demonstrated inhibition of adhesion of epithelial cells, adhesion of connective tissue cells and cell death of fibroblast cell lines in CAFs vs. NOFs (p < 0.0001). KEGG pathway analysis showed a significant enrichment of the insulin-signalling pathway (p = 0.03). Gene ontology terms related with myofibroblast phenotype, metabolism, cell adhesion/migration, hypoxia/oxidative stress, angiogenesis, immune/inflammatory response were enriched in CAFs vs. NOFs. Nestin, a stem-cell marker up-regulated in CAFs vs. NOFs, was confirmed to be expressed in the TME with immunohistochemistry.

Conclusions
The identified pathways and participating proteins may provide novel insight on the tumour-promoting properties of CAFs and unravel novel adjuvant therapeutic targets in the TME.
Use of the XRCC2 promoter for in vivo cancer diagnosis and therapy
Authors: Chen Yu , Li Zhen , Xu Zhu , Tang Huanyin , Guo Wenxuan , Sun Xiaoxiang , Zhang Wenjun , Zhang Jian , Wan Xiaoping , Jiang Ying , Mao Zhiyong 
Published: April 2018

AbstractThe homologous recombination (HR) pathway is a promising target for cancer therapy as it is frequently upregulated in tumors. One such strategy is to target tumors with cancer-specific, hyperactive promoters of HR genes including RAD51 and RAD51C. However, the promoter size and the delivery method have limited its potential clinical applications. Here we identified the ~2.1 kb promoter of XRCC2, similar to ~6.5 kb RAD51 promoter, as also hyperactivated in cancer cells. We found that XRCC2 expression is upregulated in nearly all types of cancers, to a degree comparable to RAD51 while much higher than RAD51C. Further study demonstrated that XRCC2 promoter is hyperactivated in cancer cell lines, and diphtheria toxin A (DTA) gene driven by XRCC2 promoter specifically eliminates cancer cells. Moreover, lentiviral vectors containing XRCC2 promoter driving firefly luciferase or DTA were created and applied to subcutaneous HeLa xenograft mice. We demonstrated that the pXRCC2-luciferase lentivirus is an effective tool for in vivo cancer visualization. Most importantly, pXRCC2-DTA lentivirus significantly inhibited the growth of HeLa xenografts in comparison to the control group. In summary, our results strongly indicate that virus-mediated delivery of constructs built upon the XRCC2 promoter holds great potential for tumor diagnosis and therapy.
β2 spectrin-mediated differentiation repressed the properties of liver cancer stem cells through β-catenin
Authors: Chen Yuhua , Meng Lingling , Shang Haitao , Dou Qian , Lu Zhiwen , Liu Liping , Wang Zhijun , He Xingxing , Song Yuhu 
Published: April 2018

AbstractβII-Spectrin (β2SP), a Smad3/4 adaptor protein during transforming growth factor (TGF) β/Smad signal pathway, plays a critical role in suppressing hepatocarcinogenesis. Dedifferentiation is a distinctive feature of cancer progression. Therefore, we investigated whether the disruption of β2SP contributed to tumorigenesis of hepatocellular carcinoma (HCC) through the dedifferentiation. Down-regulation of β2SP in hepatocytes was observed in cirrhotic liver and HCC. The level of β2SP expression was closely associated with the differentiation status of hepatocytes in rat model of hepatocarcinogenesis and clinical specimens. Transgenic expression of β2SP in HCC cells promoted the differentiation of HCC cells and suppressed the growth of HCC cells in vitro. Efficient transduction of β2SP into liver CSCs resulted in a reduction in colony formation ability, spheroid formation capacity, invasive activity, chemo-resistance properties, tumorigenicity in vivo. In addition, β2 spectrin exerted its effect through β catenin in liver CSCs. In conclusion, β2 spectrin repressed the properties of liver CSCs through inducing differentiation; thus, strategies to restore its levels and activities would be a novel strategy for HCC prevention and differentiation therapy
Endogenous c-Jun N-terminal kinase (JNK) activity marks the boundary between normal and malignant granulosa cells
Authors: Bildik Gamze , Akin Nazli , Senbabaoglu Filiz , Esmalian Yashar , Sahin Gizem Nur , Urman Defne , Karahuseyinoglu Sercin , Ince Umit , Palaoglu Erhan , Taskiran Cagatay , Arvas Macit , Guzel Yilmaz , Yakin Kayhan , Oktem Ozgur 
Published: April 2018

AbstractGranulosa cell tumor of the ovary (GCT) is a very rare tumor, accounting for only 2% of all ovarian tumors. It originates from sex cords in the ovary and can be divided into adult (95%) and juvenile (5%) types based on histologic findings. To date, no clear etiologic process has been identified other than a missense point mutation in the FOXL2 gene. Our previous works showed that c-Jun N-terminal kinase (JNK) pathway plays critical role in cell cycle progression and mitosis of normal and immortalized granulosa cells and follicle growth in rodent ovaries. These findings led us to investigate the role of JNK pathway in the granulosa cell tumor of the ovary. We used two different GCT cell lines (COV434 and KGN) and fresh GCT samples of adult and juvenile types obtained from the patients during surgery. We have discovered that endogenous kinase activity of JNK is markedly enhanced in the GCT samples and cell lines, whereas it was almost undetectable in mitotic non-malignant human granulosa cells. The inhibition of JNK pathway in GCT cell lines with two different pharmacologic inhibitors (SP600125 and AS601245) or siRNA resulted in a dose-dependent reduction in in vitro cell growth, increased apoptosis and diminished estradiol and AMH productions. JNK inhibition was also associated with a decrease in the number of cells positive for mitosis marker phospho-histone H3Ser 10 in the asynchronous cells; and diminished EdU uptake during S phase and cell cycle arrest at G2/M-phase transition in the synchronized cells. Ex vivo treatment of patient-derived GCT samples with JNK inhibitors for 24 h significantly decreased their in vitro growth and estradiol and AMH productions. Furthermore, in human GCT xenograft model, in vivo tumor growth was significantly reduced and plasma AMH levels were significantly decreased in SCID mice after administration of JNK inhibitors and siRNA. These findings suggest that targeting JNK pathway may provide therapeutic benefit in the treatment of granulosa cell tumors for which currently no curative therapy exists beyond surgery.
Bax retrotranslocation potentiates Bcl-xL’s antiapoptotic activity and is essential for switch-like transitions between MOMP competency and resistance
Authors: Hantusch Annika , Das Kushal K. , García-Sáez Ana J. , Brunner Thomas , Rehm Markus 
Published: April 2018

AbstractThe rapid, typically all-or-none process of mitochondrial outer membrane permeabilization (MOMP) constitutes a primary cell death decision that is controlled by the Bcl-2 family interactome. However, how strict all-or-none MOMP decisions are governed by and emanate from the dynamic interplay of pro- and antiapoptotic Bcl-2 family members remains incompletely understood. In particular, it is unclear to which extent the shuttling of Bcl-2 family species between lipid and aqueous phases contributes to regulating MOMP sensitivity. Here, we studied the interplay of tBid, Bax, and Bcl-xL, using a combined approach of deterministic mathematical modeling and retrospective as well as prospective experimental testing of model predictions. Systems modeling of the tBid–Bax interplay and their fluxes between cytosol and mitochondrial membranes reproduced experimental data on tBid-triggered Bax activation and oligomerization highly accurately. Extending these studies to analyze the cell-protective role of Bcl-xLstrikingly revealed that the activity of Bcl-xLto retrotranslocate activated Bax from membranes back into the cytosol is essential to reproduce or correctly predict experimental outcomes. These included the potency of Bcl-xLin suppressing Bax oligomerization, its role in limiting Bax membrane recruitment, the resistance threshold to low concentrations of MOMP triggers as well as a response potentiaton arising from combinations of tBid and sensitizer BH3-only peptides. Importantly, retrotranslocation activity of Bcl-xLis necessary to strictly separate conditions of MOMP competency and resistance. Our results therefore identify Bax retrotranslocation by Bcl-xLas an indispensable component of the molecular switch by which Bcl-2 family members govern cellular death decisions.
Klf4 glutamylation is required for cell reprogramming and early embryonic development in mice
Authors: Ye Buqing , Liu Benyu , Hao Lu , Zhu Xiaoxiao , Yang Liuliu , Wang Shuo , Xia Pengyan , Du Ying , Meng Shu , Huang Guanling , Qin Xiwen , Wang Yanying , Yan Xinlong , Li Chong , Hao Junfeng , Zhu Pingping , He Luyun , Tian Yong , Fan Zusen 
Published: April 2018

AbstractTemporal and spatial-specific regulation of pluripotency networks is largely dependent on the precise modifications of core transcription factors. Misregulation of glutamylation is implicated in severe physiological abnormalities. However, how glutamylation regulates cell reprogramming and pluripotency networks remains elusive. Here we show that cytosolic carboxypeptidases 1 (CCP1) or CCP6 deficiency substantially promotes induced pluripotent cell (iPSC) induction and pluripotency of embryonic stem cells (ESCs). Klf4 polyglutamylation at Glu381 by tubulin tyrosine ligase-like 4 (TTLL4) and TTLL1 during cell reprogramming impedes its lysine 48-linked ubiquitination and sustains Klf4 stability. Klf4-E381A knockin mice display impaired blastocyst development and embryonic lethality. Deletion of TTLL4 or TTLL1 abrogates cell reprogramming and early embryogenesis. Thus, Klf4 polyglutamylation plays a critical role in the regulation of cell reprogramming and pluripotency maintenance.
Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia
Authors: Vijayakrishnan Jayaram , Studd James , Broderick Peter , Kinnersley Ben , Holroyd Amy , Law Philip J. , Kumar Rajiv , Allan James M. , Harrison Christine J. , Moorman Anthony V. , Vora Ajay , Roman Eve , Rachakonda Sivaramakrishna , Kinsey Sally E. , Sheridan Eamonn , Thompson Pamela D. , Irving Julie A. , Koehler Rolf , Hoffmann Per , Nöthen Markus M. , Heilmann-Heimbach Stefanie , Jöckel Karl-Heinz , Easton Douglas F. , Pharaoh Paul D. P. , Dunning Alison M. , Peto Julian , Canzian Frederico , Swerdlow Anthony , Eeles Rosalind A. , Kote-Jarai ZSofia , Muir Kenneth , Pashayan Nora ,   The PRACTICAL Consortium, Henderson Brian E. , Haiman Christopher A. , Benlloch Sara , Schumacher Fredrick R. , Olama Ali Amin Al , Berndt Sonja I. , Conti David V. , Wiklund Fredrik , Chanock Stephen , Stevens Victoria L. , Tangen Catherine M. , Batra Jyotsna , Clements Judith , Gronberg Henrik , Schleutker Johanna , Albanes Demetrius , Weinstein Stephanie , Wolk Alicja , West Catharine , Mucci Lorelei , Cancel-Tassin Géraldine , Koutros Stella , Sorensen Karina Dalsgaard , Maehle Lovise , Neal David E. , Travis Ruth C. , Hamilton Robert J. , Ingles Sue Ann , Rosenstein Barry , Lu Yong-Jie , Giles Graham G. , Kibel Adam S. , Vega Ana , Kogevinas Manolis , Penney Kathryn L. , Park Jong Y. , Stanford Janet L. , Cybulski Cezary , Nordestgaard Børge G. , Brenner Hermann , Maier Christiane , Kim Jeri , John Esther M. , Teixeira Manuel R. , Neuhausen Susan L. , De Ruyck Kim , Razack Azad , Newcomb Lisa F. , Lessel Davor , Kaneva Radka , Usmani Nawaid , Claessens Frank , Townsend Paul A. , Gago-Dominguez Manuela , Roobol Monique J. , Menegaux Florence , Greaves Mel , Zimmerman Martin , Bartram Claus R. , Schrappe Martin , Stanulla Martin , Hemminki Kari , Houlston Richard S. 
Published: April 2018

AbstractGenome-wide association studies (GWAS) have advanced our understanding of susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL); however, much of the heritable risk remains unidentified. Here, we perform a GWAS and conduct a meta-analysis with two existing GWAS, totaling 2442 cases and 14,609 controls. We identify risk loci for BCP-ALL at 8q24.21 (rs28665337,P = 3.86 × 10−9, odds ratio (OR) = 1.34) and forETV6-RUNX1fusion-positive BCP-ALL at 2q22.3 (rs17481869,P = 3.20 × 10−8, OR = 2.14). Our findings provide further insights into genetic susceptibility to ALL and its biology.
The global distribution and spread of the mobilized colistin resistance gene mcr-1
Authors: Wang Ruobing , van Dorp Lucy , Shaw Liam P. , Bradley Phelim , Wang Qi , Wang Xiaojuan , Jin Longyang , Zhang Qing , Liu Yuqing , Rieux Adrien , Dorai-Schneiders Thamarai , Weinert Lucy Anne , Iqbal Zamin , Didelot Xavier , Wang Hui , Balloux Francois 
Published: April 2018

AbstractColistin represents one of the few available drugs for treating infections caused by carbapenem-resistant Enterobacteriaceae. As such, the recent plasmid-mediated spread of the colistin resistance gene mcr-1 poses a significant public health threat, requiring global monitoring and surveillance. Here, we characterize the global distribution of mcr-1 using a data set of 457 mcr-1-positive sequenced isolates. We find mcr-1 in various plasmid types but identify an immediate background common to all mcr-1 sequences. Our analyses establish that all mcr-1 elements in circulation descend from the same initial mobilization of mcr-1 by an ISApl1 transposon in the mid 2000s (2002–2008; 95% highest posterior density), followed by a marked demographic expansion, which led to its current global distribution. Our results provide the first systematic phylogenetic analysis of the origin and spread of mcr-1, and emphasize the importance of understanding the movement of antibiotic resistance genes across multiple levels of genomic organization.
A loop region of BAFF controls B cell survival and regulates recognition by different inhibitors
Authors: Vigolo Michele , Chambers Melissa G. , Willen Laure , Chevalley Dehlia , Maskos Klaus , Lammens Alfred , Tardivel Aubry , Das Dolon , Kowalczyk-Quintas Christine , Schuepbach-Mallepell Sonia , Smulski Cristian R. , Eslami Mahya , Rolink Antonius , Hummler Edith , Samy Eileen , Fomekong Nanfack Yves , Mackay Fabienne , Liao Maofu , Hess Henry , Jiang Xuliang , Schneider Pascal 
Published: April 2018

AbstractThe B cell survival factor (TNFSF13B/BAFF) is often elevated in autoimmune diseases and is targeted in the clinic for the treatment of systemic lupus erythematosus. BAFF contains a loop region designated the flap, which is dispensable for receptor binding. Here we show that the flap of BAFF has two functions. In addition to facilitating the formation of a highly active BAFF 60-mer as shown previously, it also converts binding of BAFF to TNFRSF13C (BAFFR) into a signaling event via oligomerization of individual BAFF-BAFFR complexes. Binding and activation of BAFFR can therefore be targeted independently to inhibit or activate the function of BAFF. Moreover, structural analyses suggest that the flap of BAFF 60-mer temporarily prevents binding of an anti-BAFF antibody (belimumab) but not of a decoy receptor (atacicept). The observed differences in profiles of BAFF inhibition may confer distinct biological and clinical efficacies to these therapeutically relevant inhibitors.
Surface tension-assisted additive manufacturing
Authors: Ragelle Héloïse , Tibbitt Mark W. , Wu Shang-Yun , Castillo Michael A. , Cheng George Z. , Gangadharan Sidharta P. , Anderson Daniel G. , Cima Michael J. , Langer Robert 
Published: April 2018

AbstractThe proliferation of computer-aided design and additive manufacturing enables on-demand fabrication of complex, three-dimensional structures. However, combining the versatility of cell-laden hydrogels within the 3D printing process remains a challenge. Herein, we describe a facile and versatile method that integrates polymer networks (including hydrogels) with 3D-printed mechanical supports to fabricate multicomponent (bio)materials. The approach exploits surface tension to coat fenestrated surfaces with suspended liquid films that can be transformed into solid films. The operating parameters for the process are determined using a physical model, and complex geometric structures are successfully fabricated. We engineer, by tailoring the window geometry, scaffolds with anisotropic mechanical properties that compress longitudinally (~30% strain) without damaging the hydrogel coating. Finally, the process is amenable to high cell density encapsulation and co-culture. Viability (>95%) was maintained 28 days after encapsulation. This general approach can generate biocompatible, macroscale devices with structural integrity and anisotropic mechanical properties.
Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults
Authors: Martens Christopher R. , Denman Blair A. , Mazzo Melissa R. , Armstrong Michael L. , Reisdorph Nichole , McQueen Matthew B. , Chonchol Michel , Seals Douglas R. 
Published: April 2018

AbstractNicotinamide adenine dinucleotide (NAD+) has emerged as a critical co-substrate for enzymes involved in the beneficial effects of regular calorie restriction on healthspan. As such, the use of NAD+ precursors to augment NAD+ bioavailability has been proposed as a strategy for improving cardiovascular and other physiological functions with aging in humans. Here we provide the evidence in a 2 × 6-week randomized, double-blind, placebo-controlled, crossover clinical trial that chronic supplementation with the NAD+ precursor vitamin, nicotinamide riboside (NR), is well tolerated and effectively stimulates NAD+ metabolism in healthy middle-aged and older adults. Our results also provide initial insight into the effects of chronic NR supplementation on physiological function in humans, and suggest that, in particular, future clinical trials should further assess the potential benefits of NR for reducing blood pressure and arterial stiffness in this group.
An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations
Authors: Liu Xiaonan , Salokas Kari , Tamene Fitsum , Jiu Yaming , Weldatsadik Rigbe G. , Öhman Tiina , Varjosalo Markku 
Published: April 2018

AbstractProtein-protein interactions govern almost all cellular functions. These complex networks of stable and transient associations can be mapped by affinity purification mass spectrometry (AP-MS) and complementary proximity-based labeling methods such as BioID. To exploit the advantages of both strategies, we here design and optimize an integrated approach combining AP-MS and BioID in a single construct, which we term MAC-tag. We systematically apply the MAC-tag approach to 18 subcellular and 3 sub-organelle localization markers, generating a molecular context database, which can be used to define a protein’s molecular location. In addition, we show that combining the AP-MS and BioID results makes it possible to obtain interaction distances within a protein complex. Taken together, our integrated strategy enables the comprehensive mapping of the physical and functional interactions of proteins, defining their molecular context and improving our understanding of the cellular interactome.
A comprehensive map coupling histone modifications with gene regulation in adult dopaminergic and serotonergic neurons
Authors: Södersten Erik , Toskas Konstantinos , Rraklli Vilma , Tiklova Katarina , Björklund Åsa K. , Ringnér Markus , Perlmann Thomas , Holmberg Johan 
Published: April 2018

AbstractThe brain is composed of hundreds of different neuronal subtypes, which largely retain their identity throughout the lifespan of the organism. The mechanisms governing this stability are not fully understood, partly due to the diversity and limited size of clinically relevant neuronal populations, which constitute a technical challenge for analysis. Here, using a strategy that allows for ChIP-seq combined with RNA-seq in small neuronal populations in vivo, we present a comparative analysis of permissive and repressive histone modifications in adult midbrain dopaminergic neurons, raphe nuclei serotonergic neurons, and embryonic neural progenitors. Furthermore, we utilize the map generated by our analysis to show that the transcriptional response of midbrain dopaminergic neurons following 6-OHDA or methamphetamine injection is characterized by increased expression of genes with promoters dually marked by H3K4me3/H3K27me3. Our study provides an in vivo genome-wide analysis of permissive/repressive histone modifications coupled to gene expression in these rare neuronal subtypes.