bluuebunny/crossref_metadata_2025_split huggingface dataset:
NF-κB-driven improvement of EHD1 contributes to erlotinib resistance in EGFR-mutant lung cancers
Authors: Wang Xiaoyuan , Yin Hang , Zhang Hongxia , Hu Jing , Lu Hailing , Li Chunhong , Cao Mengru , Yan Shi , Cai Li 
Published: April 2018

AbstractAcquired resistance to epidermal growth factor receptor-tyrosine-kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, is a critical obstacle in the treatment of EGFR mutant-positive non-small cell lung cancer (NSCLC). EHD1, a protein of the C-terminal Eps15 homology domain-containing (EHD) family, plays a role in regulating endocytic recycling, but the mechanistic details involved in EGFR-TKI resistance and cancer stemness remain largely unclear. Here, we found that a lower EHD1 expression improved both EGFR-TKIs sensitivity, which is consistent with a lower CD133 expression, and progression-free survival in NSCLC patients. The overexpression of EHD1 markedly increased erlotinib resistance and lung cancer cell stemness in vitro and in vivo. Moreover, we demonstrated that miR-590 targeted the 3′-UTR of EHD1 and was regulated by NK-κB, resulting in downregulated EHD1 expression, increased erlotinib sensitivity and repressed NSCLC cancer stem-like properties in vitro and in vivo. We found that EHD1 was an important factor in EGFR-TKI resistance and the cancer stem-like cell phenotype of lung cancer, and these results suggest that targeting the NF-κB/miR-590/EHD1 pathway has potential therapeutic promise in EGFR-mutant NSCLC patients with acquired EGFR-TKI resistance.
Cancer-associated fibroblasts induce PDL1+ neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma
Authors: Cheng Yusheng , Li Hui , Deng Yinan , Tai Yan , Zeng Kaining , Zhang Yingcai , Liu Wei , Zhang Qi , Yang Yang 
Published: April 2018

AbstractEmerging evidence indicate that cancer-associated fibroblasts (CAFs) affect tumor progression by reshaping the tumor microenvironment. Neutrophils are prominent components of solid tumors and important in cancer progression. Whether the phenotype and function of neutrophils in hepatocellular carcinoma (HCC) are influenced by CAFs is not well understood. Herein, we investigated the effect of HCC-derived CAFs (HCC-CAFs) on the neutrophils and explored the biological role of this effect. We found that HCC-CAFs induced chemotaxis of neutrophils and protected them from spontaneous apoptosis. Neutrophils were activated by the conditioned medium from HCC-CAFs with increased expression of CD66b, PDL1, IL8, TNFa, and CCL2, and with decreased expression of CD62L. HCC-CAF-primed neutrophils impaired T-cell function through the PD1/PDL1 signaling pathway. We revealed that HCC-CAFs induced the activation of STAT3 pathways in neutrophils, which are essential for the survival and function of activated neutrophils. In addition, we demonstrated that HCC-CAF-derived IL6 was responsible for the STAT3 activation of neutrophils. Collectively, our results suggest that HCC-CAFs regulate the survival, activation, and function of neutrophils within HCC through an IL6–STAT3–PDL1 signaling cascade, which presents a novel mechanism for the role of CAFs in remodeling the cancer niche and provides a potential target for HCC therapy.
Tumor-associated macrophages-derived exosomes promote the migration of gastric cancer cells by transfer of functional Apolipoprotein E
Authors: Zheng Peiming , Luo Qin , Wang Weiwei , Li Junhua , Wang Tingting , Wang Ping , Chen Lei , Zhang Peng , Chen Hui , Liu Yi , Dong Ping , Xie Guohua , Ma Yanhui , Jiang Li , Yuan Xiangliang , Shen Lisong 
Published: April 2018

AbstractTumor-associated macrophages (TAMs) are a major component of the tumor microenvironment and have been shown to contribute to tumor aggressiveness. However, the detailed mechanisms underlying the pro-metastatic effect of TAMs on gastric cancer are not clearly defined. Here, we show that TAMs are enriched in gastric cancer. TAMs are characterized by M2-polarized phenotype and promote migration of gastric cancer cells in vitro and in vivo. Furthermore, we find that M2-derived exosomes determine the TAMs-mediated pro-migratory activity. Using mass spectrometry, we identify that apolipoprotein E (ApoE) is highly specific and effective protein in M2 macrophages-derived exosomes. Moreover, TAMs are uniquely immune cells population expressed ApoE in gastric cancer microenvironment. However, exosomes derived from M2 macrophages of Apoe
−/−
mice have no significant effect on the migration of gastric cancer cells in vitro and in vivo. Mechanistically, M2 macrophage-derived exosomes mediate an intercellular transfer of ApoE-activating PI3K-Akt signaling pathway in recipient gastric cancer cells to remodel the cytoskeleton-supporting migration. Collectively, our findings signify that the exosome-mediated transfer of functional ApoE protein from TAMs to the tumor cells promotes the migration of gastric cancer cells.
Two-thirds of global cropland area impacted by climate oscillations
Authors: Heino Matias , Puma Michael J. , Ward Philip J. , Gerten Dieter , Heck Vera , Siebert Stefan , Kummu Matti 
Published: April 2018

AbstractThe El Niño Southern Oscillation (ENSO) peaked strongly during the boreal winter 2015–2016, leading to food insecurity in many parts of Africa, Asia and Latin America. Besides ENSO, the Indian Ocean Dipole (IOD) and the North Atlantic Oscillation (NAO) are known to impact crop yields worldwide. Here we assess for the first time in a unified framework the relationships between ENSO, IOD and NAO and simulated crop productivity at the sub-country scale. Our findings reveal that during 1961–2010, crop productivity is significantly influenced by at least one large-scale climate oscillation in two-thirds of global cropland area. Besides observing new possible links, especially for NAO in Africa and the Middle East, our analyses confirm several known relationships between crop productivity and these oscillations. Our results improve the understanding of climatological crop productivity drivers, which is essential for enhancing food security in many of the most vulnerable places on the planet.
Placenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum
Authors: Fejzo Marlena S. , Sazonova Olga V. , Sathirapongsasuti J. Fah , Hallgrímsdóttir Ingileif B. , Vacic Vladimir , MacGibbon Kimber W. , Schoenberg Frederic P. , Mancuso Nicholas , Slamon Dennis J. , Mullin Patrick M. ,   23andMe Research Team, Agee Michelle , Alipanahi Babak , Auton Adam , Bell Robert K. , Bryc Katarzyna , Elson Sarah L. , Fontanillas Pierre , Furlotte Nicholas A. , Hinds David A. , Hromatka Bethann S. , Huber Karen E. , Kleinman Aaron , Litterman Nadia K. , McIntyre Matthew H. , Mountain Joanna L. , Noblin Elizabeth S. , Northover Carrie A. M. , Pitts Steven J. , Shelton Janie F. , Shringarpure Suyash , Tian Chao , Tung Joyce Y. , Wilson Catherine H. 
Published: April 2018

AbstractHyperemesis gravidarum (HG), severe nausea and vomiting of pregnancy, occurs in 0.3–2% of pregnancies and is associated with maternal and fetal morbidity. The cause of HG remains unknown, but familial aggregation and results of twin studies suggest that understanding the genetic contribution is essential for comprehending the disease etiology. Here, we conduct a genome-wide association study (GWAS) for binary (HG) and ordinal (severity of nausea and vomiting) phenotypes of pregnancy complications. Two loci, chr19p13.11 and chr4q12, are genome-wide significant (p < 5 × 10−8) in both association scans and are replicated in an independent cohort. The genes implicated at these two loci are GDF15 and IGFBP7 respectively, both known to be involved in placentation, appetite, and cachexia. While proving the casual roles of GDF15 and IGFBP7 in nausea and vomiting of pregnancy requires further study, this GWAS provides insights into the genetic risk factors contributing to the disease.
Drought drives rapid shifts in tropical rainforest soil biogeochemistry and greenhouse gas emissions
Authors: O’Connell Christine S. , Ruan Leilei , Silver Whendee L. 
Published: April 2018

AbstractClimate change models predict more frequent and severe droughts in the humid tropics. How drought will impact tropical forest carbon and greenhouse gas dynamics is poorly understood. Here we report the effects of the severe 2015 Caribbean drought on soil moisture, oxygen, phosphorus (P), and greenhouse gas emissions in a humid tropical forest in Puerto Rico. Drought significantly decreases inorganic P concentrations, an element commonly limiting to net primary productivity in tropical forests, and significantly increases organic P. High-frequency greenhouse gas measurements show varied impacts across topography. Soil carbon dioxide emissions increase by 60% on slopes and 163% in valleys. Methane (CH4) consumption increases significantly during drought, but high CH4 fluxes post-drought offset this sink after 7 weeks. The rapid response and slow recovery to drought suggest tropical forest biogeochemistry is more sensitive to climate change than previously believed, with potentially large direct and indirect consequences for regional and global carbon cycles.
TRIM11 activates the proteasome and promotes overall protein degradation by regulating USP14
Authors: Chen Liang , Zhu Guixin , Johns Eleanor M. , Yang Xiaolu 
Published: April 2018

AbstractThe proteasome is a complex protease critical for protein quality control and cell regulation, and its dysfunction is associated with cancer and other diseases. However, the mechanisms that control proteasome activity in normal and malignant cells remain unclear. Here we report that TRIM11 enhances degradation of aberrant and normal regulatory proteins, and augments overall rate of proteolysis. Mechanistically, TRIM11 binds to both the proteasome and USP14, a deubiquitinase that prematurely removes ubiquitins from proteasome-bound substrates and also noncatalytically inhibits the proteasome, and precludes their association, thereby increasing proteasome activity. TRIM11 promotes cell survival and is upregulated upon heat shock. Moreover, TRIM11 is required for tumor growth, and increased expression of TRIM11 correlates with poor clinical survival. These findings identify TRIM11 as an important activator of the proteasome, define a pathway that adjusts proteasome activity, and reveal a mechanism by which tumor cells acquire higher degradative power to support oncogenic growth.
A tiny Triassic saurian from Connecticut and the early evolution of the diapsid feeding apparatus
Authors: Pritchard Adam C. , Gauthier Jacques A. , Hanson Michael , Bever Gabriel S. , Bhullar Bhart-Anjan S. 
Published: April 2018

AbstractFollowing the Permo–Triassic Extinction, large-bodied diapsid reptiles—with a body length >1 m—rapidly expanded their ecological roles. This diversification is reflected in enormous disparity in the development of the rostrum and adductor chamber. However, it is unclear how marked the diversity of the feeding apparatus was in contemporary small-bodied diapsids. Here we describe the remarkably small skull (2.5 cm long) of a saurian reptile, Colobops noviportensis, gen. et sp. nov., from the Triassic New Haven Arkose of Connecticut, USA. The taxon possesses an exceptionally reinforced snout and strikingly expanded supratemporal fossae for adductor musculature relative to any known Mesozoic or Recent diapsid of similar size. Our phylogenetic analyses support C. noviportensis as an early diverging pan-archosaur. Colobops noviportensis reveals extraordinary disparity of the feeding apparatus in small-bodied early Mesozoic diapsids, and a suite of morphologies, functionally related to a powerful bite, unknown in any small-bodied diapsid.
PHA-4/FoxA senses nucleolar stress to regulate lipid accumulation in Caenorhabditis elegans
Authors: Wu Jieyu , Jiang Xue , Li Yamei , Zhu Tingting , Zhang Jingjing , Zhang Zhiguo , Zhang Linqiang , Zhang Yuru , Wang Yanli , Zou Xiaoju , Liang Bin 
Published: April 2018

AbstractThe primary function of the nucleolus is ribosome biogenesis, which is an extremely energetically expensive process. Failures in ribosome biogenesis cause nucleolar stress with an altered energy status. However, little is known about the underlying mechanism linking nucleolar stress to energy metabolism. Here we show that nucleolar stress is triggered by inactivation of RSKS-1 (ribosomal protein S6 kinase), RRP-8 (ribosomal RNA processing 8), and PRO-2/3 (proximal proliferation), all of which are involved in ribosomal RNA processing or inhibition of rDNA transcription by actinomycin D (AD), leading to excessive lipid accumulation in Caenorhabditiselegans. The transcription factor PHA-4/FoxA acts as a sensor of nucleolar stress to bind to and transactivate the expression of the lipogenic genes pod-2 (acetyl-CoA carboxylase), fasn-1 (fatty acid synthase), and dgat-2 (diacylglycerol O-acyltransferase 2), consequently promoting lipid accumulation. Importantly, inactivation of pha-4 or dgat-2 is sufficient to abolish nucleolar stress-induced lipid accumulation and prolonged starvation survival. The results revealed a distinct PHA-4-mediated lipogenesis pathway that senses nucleolar stress and shifts excessive energy for storage as fat.
Aftershock sequences and seismic-like organization of acoustic events produced by a single propagating crack
Authors: Barés Jonathan , Dubois Alizée , Hattali Lamine , Dalmas Davy , Bonamy Daniel 
Published: April 2018

AbstractBrittle fractures of inhomogeneous materials like rocks, concrete, or ceramics are of two types: Nominally brittle and driven by the propagation of a single dominant crack or quasi-brittle and resulting from the accumulation of many microcracks. The latter goes along with acoustic noise, whose analysis has revealed that events form aftershock sequences obeying characteristic laws reminiscent of those in seismology. Yet, their origin lacks explanation. Here we show that such a statistical organization is not only specific to the multi-cracking situations of quasi-brittle failure and seismology, but also rules the acoustic events produced by a propagating crack. This simpler situation has permitted us to relate these laws to the overall scale-free distribution of inter-event time and energy and to uncover their selection by the crack speed. These results provide a comprehensive picture of how acoustic events are organized upon material failure in the most fundamental of fracture states: single propagating cracks.
A lever-like transduction pathway for long-distance chemical- and mechano-gating of the mechanosensitive Piezo1 channel
Authors: Wang Yanfeng , Chi Shaopeng , Guo Huifang , Li Guang , Wang Li , Zhao Qiancheng , Rao Yu , Zu Liansuo , He Wei , Xiao Bailong 
Published: April 2018

AbstractPiezo1 represents a prototype of eukaryotic mechanotransduction channels. The full-length 2547-residue mouse Piezo1 possesses a unique 38-transmembrane-helix (TM) topology and is organized into a three-bladed, propeller-shaped architecture, comprising a central ion-conducting pore, three peripheral blade-like structures, and three 90-Å-long intracellular beam-resembling structures that bridge the blades to the pore. However, how mechanical force and chemicals activate the gigantic Piezo1 machinery remains elusive. Here we identify a novel set of Piezo1 chemical activators, termed Jedi, which activates Piezo1 through the extracellular side of the blade instead of the C-terminal extracellular domain of the pore, indicating long-range allosteric gating. Remarkably, Jedi-induced activation of Piezo1 requires the key mechanotransduction components, including the two extracellular loops in the distal blade and the two leucine residues in the proximal end of the beam. Thus, Piezo1 employs the peripheral blade-beam-constituted lever-like apparatus as a designated transduction pathway for long-distance mechano- and chemical-gating of the pore.
Degradation of blue-phosphorescent organic light-emitting devices involves exciton-induced generation of polaron pair within emitting layers
Authors: Kim Sinheui , Bae Hye Jin , Park Sangho , Kim Wook , Kim Joonghyuk , Kim Jong Soo , Jung Yongsik , Sul Soohwan , Ihn Soo-Ghang , Noh Changho , Kim Sunghan , You Youngmin 
Published: April 2018

AbstractDegradation of organic materials is responsible for the short operation lifetimes of organic light-emitting devices, but the mechanism by which such degradation is initiated has yet to be fully established. Here we report a new mechanism for degradation of emitting layers in blue-phosphorescent devices. We investigate binary mixtures of a wide bandgap host and a series of novel Ir(III) complex dopants having N-heterocyclocarbenic ligands. Our mechanistic study reveals the charge-neutral generation of polaron pairs (radical ion pairs) by electron transfer from the dopant to host excitons. Annihilation of the radical ion pair occurs by charge recombination, with such annihilation competing with bond scission. Device lifetime correlates linearly with the rate constant for the annihilation of the radical ion pair. Our findings demonstrate the importance of controlling exciton-induced electron transfer, and provide novel strategies to design materials for long-lifetime blue electrophosphorescence devices.
Lymphotoxin α fine-tunes T cell clonal deletion by regulating thymic entry of antigen-presenting cells
Authors: Lopes Noëlla , Charaix Jonathan , Cédile Oriane , Sergé Arnauld , Irla Magali 
Published: April 2018

AbstractMedullary thymic epithelial cells (mTEC) purge the T cell repertoire of autoreactive thymocytes. Although dendritic cells (DC) reinforce this process by transporting innocuous peripheral self-antigens, the mechanisms that control their thymic entry remain unclear. Here we show that mTEC-CD4+thymocyte crosstalk regulates the thymus homing of SHPS-1+conventional DCs (cDC), plasmacytoid DCs (pDC) and macrophages. This homing process is controlled by lymphotoxin α (LTα), which negatively regulates CCL2, CCL8 and CCL12 chemokines in mTECs. Consequently,Ltα-deficient mice have increased expression of these chemokines that correlates with augmented classical NF-κB subunits and increased thymic recruitment of cDCs, pDCs and macrophages. This enhanced migration depends mainly on the chemokine receptor CCR2, and increases thymic clonal deletion. Altogether, this study identifies a fine-tuning mechanism of T cell repertoire selection and paves the way for therapeutic interventions to treat autoimmune disorders.
BAFF-neutralizing interaction of belimumab related to its therapeutic efficacy for treating systemic lupus erythematosus
Authors: Shin Woori , Lee Hyun Tae , Lim Heejin , Lee Sang Hyung , Son Ji Young , Lee Jee Un , Yoo Ki-Young , Ryu Seong Eon , Rhie Jaejun , Lee Ju Yeon , Heo Yong-Seok 
Published: April 2018

AbstractBAFF, a member of the TNF superfamily, has been recognized as a good target for autoimmune diseases. Belimumab, an anti-BAFF monoclonal antibody, was approved by the FDA for use in treating systemic lupus erythematosus. However, the molecular basis of BAFF neutralization by belimumab remains unclear. Here our crystal structure of the BAFF–belimumab Fab complex shows the precise epitope and the BAFF-neutralizing mechanism of belimumab, and demonstrates that the therapeutic activity of belimumab involves not only antagonizing the BAFF–receptor interaction, but also disrupting the formation of the more active BAFF 60-mer to favor the induction of the less active BAFF trimer through interaction with the flap region of BAFF. In addition, the belimumab HCDR3 loop mimics the DxL(V/L) motif of BAFF receptors, thereby binding to BAFF in a similar manner as endogenous BAFF receptors. Our data thus provides insights for the design of new drugs targeting BAFF for the treatment of autoimmune diseases.
Poly-ligand profiling differentiates trastuzumab-treated breast cancer patients according to their outcomes
Authors: Domenyuk Valeriy , Gatalica Zoran , Santhanam Radhika , Wei Xixi , Stark Adam , Kennedy Patrick , Toussaint Brandon , Levenberg Symon , Wang Jie , Xiao Nianqing , Greil Richard , Rinnerthaler Gabriel , Gampenrieder Simon P. , Heimberger Amy B. , Berry Donald A. , Barker Anna , Quackenbush John , Marshall John L. , Poste George , Vacirca Jeffrey L. , Vidal Gregory A. , Schwartzberg Lee S. , Halbert David D. , Voss Andreas , Magee Daniel , Miglarese Mark R. , Famulok Michael , Mayer Günter , Spetzler David 
Published: April 2018

AbstractAssessing the phenotypic diversity underlying tumour progression requires the identification of variations in the respective molecular interaction networks. Here we report proof-of-concept for a platform called poly-ligand profiling (PLP) that surveys these system states and distinguishes breast cancer patients who did or did not derive benefit from trastuzumab. We perform tissue-SELEX on breast cancer specimens to enrich single-stranded DNA (ssDNA) libraries that preferentially interact with molecular components associated with the two clinical phenotypes. Testing of independent sample sets verifies the ability of PLP to classify trastuzumab-treated patients according to their clinical outcomes with ROC-AUC of 0.78. Standard HER2 testing of the same patients gives a ROC-AUC of 0.47. Kaplan–Meier analysis reveals a median increase in benefit from trastuzumab-containing treatments of 300 days for PLP-positive compared to PLP-negative patients. If prospectively validated, PLP may increase success rates in precision oncology and clinical trials, thus improving both patient care and drug development.
Structural characterization of a highly-potent V3-glycan broadly neutralizing antibody bound to natively-glycosylated HIV-1 envelope
Authors: Barnes Christopher O. , Gristick Harry B. , Freund Natalia T. , Escolano Amelia , Lyubimov Artem Y. , Hartweger Harald , West Anthony P. , Cohen Aina E. , Nussenzweig Michel C. , Bjorkman Pamela J. 
Published: April 2018

AbstractBroadly neutralizing antibodies (bNAbs) isolated from HIV-1-infected individuals inform HIV-1 vaccine design efforts. Developing bNAbs with increased efficacy requires understanding how antibodies interact with the native oligomannose and complex-type N-glycan shield that hides most protein epitopes on HIV-1 envelope (Env). Here we present crystal structures, including a 3.8-Å X-ray free electron laser dataset, of natively glycosylated Env trimers complexed with BG18, the most potent V3/N332gp120 glycan-targeting bNAb reported to date. Our structures show conserved contacts mediated by common D gene-encoded residues with the N332gp120 glycan and the gp120 GDIR peptide motif, but a distinct Env-binding orientation relative to PGT121/10-1074 bNAbs. BG18’s binding orientation provides additional contacts with N392gp120 and N386gp120 glycans near the V3-loop base and engages protein components of the V1-loop. The BG18-natively-glycosylated Env structures facilitate understanding of bNAb–glycan interactions critical for using V3/N332gp120 bNAbs therapeutically and targeting their epitope for immunogen design.