bluuebunny/crossref_metadata_2025_split huggingface dataset:
CAMK2A supported tumor initiating cells of lung adenocarcinoma by upregulating SOX2 through EZH2 phosphorylation
Authors: Wang Si-Qi , Liu Jing , Qin Jing , Zhu Yun , Tin Vicky Pui-Chi , Yam Judy Wai Ping , Wong Maria Pik , Xiao Zhi-Jie 
Published: June 2020

AbstractTumor initiating cells (TIC) of lung cancer are mainly induced by stress-related plasticity. Calcium/Calmodulin dependent protein kinase II alpha (CAMK2A) is a key calcium signaling molecule activated by exogenous and endogenous stimuli with effects on multiple cell functions but little is known about its role on TIC. In human lung adenocarcinomas (AD), CAMK2A was aberrantly activated in a proportion of cases and was an independent risk factor predicting shorter survivals. Functionally, CAMK2A enhanced TIC phenotypes in vitro and in vivo. CAMK2A regulated SOX2 expression by reducing H3K27me3 and EZH2 occupancy at SOX2 regulatory regions, leading to its epigenetic de-repression with functional consequences. Further, CAMK2A caused kinase-dependent phosphorylation of EZH2 at T487 with suppression of EZH2 activity. Together, the data demonstrated the CAMK2A-EZH2-SOX2 axis on TIC regulation. This study provided phenotypic and mechanistic evidence for the TIC supportive role of CAMK2A, implicating a novel predictive and therapeutic target for lung cancer.
Small extracellular vesicles derived from human MSCs prevent allergic airway inflammation via immunomodulation on pulmonary macrophages
Authors: Fang Shu-Bin , Zhang Hong-Yu , Meng Xiang-Ci , Wang Cong , He Bi-Xin , Peng Ya-Qi , Xu Zhi-Bin , Fan Xing-Liang , Wu Zhang-Jin , Wu Zi-Cong , Zheng Song-Guo , Fu Qing-Ling 
Published: June 2020

AbstractAllergic airway inflammation is a major public health disease that affects up to 300 million people in the world. However, its management remains largely unsatisfactory. The dysfunction of pulmonary macrophages contributes greatly to the development of allergic airway inflammation. It has been reported that small extracellular vesicles derived from mesenchymal stromal cells (MSC-sEV) were able to display extensive therapeutic effects in some immune diseases. This study aimed to investigate the effects of MSC-sEV on allergic airway inflammation, and the role of macrophages involved in it. We successfully isolated MSC-sEV by using anion exchange chromatography, which were morphologically intact and positive for the specific EV markers. MSC-sEV significantly reduced infiltration of inflammatory cells and number of epithelial goblet cells in lung tissues of mice with allergic airway inflammation. Levels of inflammatory cells and cytokines in bronchoalveolar lavage fluid were also significantly decreased. Importantly, levels of monocytes-derived alveolar macrophages and M2 macrophages were significantly reduced by MSC-sEV. MSC-sEV were excreted through spleen and liver at 24 h post-administration in mice, and were able to be taken in by macrophages both in vivo and in vitro. In addition, proteomics analysis of MSC-sEV revealed that the indicated three types of MSC-sEV contained different quantities of proteins and shared 312 common proteins, which may be involved in the therapeutic effects of MSC-sEV. In total, our study demonstrated that MSC-sEV isolated by anion exchange chromatography were able to ameliorate Th2-dominant allergic airway inflammation through immunoregulation on pulmonary macrophages, suggesting that MSC-sEV were promising alternative therapy for allergic airway inflammation in the future.
Functional reconstruction of injured corpus cavernosa using 3D-printed hydrogel scaffolds seeded with HIF-1α-expressing stem cells
Authors: An Geng , Guo Feixiang , Liu Xuemin , Wang Zhifang , Zhu Ye , Fan Yong , Xuan Chengkai , Li Yan , Wu Hongkai , Shi Xuetao , Mao Chuanbin 
Published: June 2020

AbstractInjury of corpus cavernosa results in erectile dysfunction, but its treatment has been very difficult. Here we construct heparin-coated 3D-printed hydrogel scaffolds seeded with hypoxia inducible factor-1α (HIF-1α)-mutated muscle-derived stem cells (MDSCs) to develop bioengineered vascularized corpora. HIF-1α-mutated MDSCs significantly secrete various angiogenic factors in MDSCs regardless of hypoxia or normoxia. The biodegradable scaffolds, along with MDSCs, are implanted into corpus cavernosa defects in a rabbit model to show good histocompatibility with no immunological rejection, support vascularized tissue ingrowth, and promote neovascularisation to repair the defects. Evaluation of morphology, intracavernosal pressure, elasticity and shrinkage of repaired cavernous tissue prove that the bioengineered corpora scaffolds repair the defects and recover penile erectile and ejaculation function successfully. The function recovery restores the reproductive capability of the injured male rabbits. Our work demonstrates that the 3D-printed hydrogels with angiogenic cells hold great promise for penile reconstruction to restore reproductive capability of males.
Integrating whole-genome sequencing within the National Antimicrobial Resistance Surveillance Program in the Philippines
Authors: Argimón Silvia , Masim Melissa A. L. , Gayeta June M. , Lagrada Marietta L. , Macaranas Polle K. V. , Cohen Victoria , Limas Marilyn T. , Espiritu Holly O. , Palarca Janziel C. , Chilam Jeremiah , Jamoralin Manuel C. , Villamin Alfred S. , Borlasa Janice B. , Olorosa Agnettah M. , Hernandez Lara F. T. , Boehme Karis D. , Jeffrey Benjamin , Abudahab Khalil , Hufano Charmian M. , Sia Sonia B. , Stelling John , Holden Matthew T. G. , Aanensen David M. , Carlos Celia C. 
Published: June 2020

AbstractNational networks of laboratory-based surveillance of antimicrobial resistance (AMR) monitor resistance trends and disseminate these data to AMR stakeholders. Whole-genome sequencing (WGS) can support surveillance by pinpointing resistance mechanisms and uncovering transmission patterns. However, genomic surveillance is rare in low- and middle-income countries. Here, we implement WGS within the established Antimicrobial Resistance Surveillance Program of the Philippines via a binational collaboration. In parallel, we characterize bacterial populations of key bug-drug combinations via a retrospective sequencing survey. By linking the resistance phenotypes to genomic data, we reveal the interplay of genetic lineages (strains), AMR mechanisms, and AMR vehicles underlying the expansion of specific resistance phenotypes that coincide with the growing carbapenem resistance rates observed since 2010. Our results enhance our understanding of the drivers of carbapenem resistance in the Philippines, while also serving as the genetic background to contextualize ongoing local prospective surveillance.
Inactivation of Arid1a in the endometrium is associated with endometrioid tumorigenesis through transcriptional reprogramming
Authors: Suryo Rahmanto Yohan , Shen Wenjing , Shi Xu , Chen Xi , Yu Yu , Yu Zheng-Cheng , Miyamoto Tsutomu , Lee Meng-Horng , Singh Vivek , Asaka Ryoichi , Shimberg Geoffrey , Vitolo Michele I. , Martin Stuart S. , Wirtz Denis , Drapkin Ronny , Xuan Jianhua , Wang Tian-Li , Shih Ie-Ming 
Published: June 2020

AbstractSomatic inactivating mutations of ARID1A, a SWI/SNF chromatin remodeling gene, are prevalent in human endometrium-related malignancies. To elucidate the mechanisms underlying how ARID1A deleterious mutation contributes to tumorigenesis, we establish genetically engineered murine models with Arid1a and/or Pten conditional deletion in the endometrium. Transcriptomic analyses on endometrial cancers and precursors derived from these mouse models show a close resemblance to human uterine endometrioid carcinomas. We identify transcriptional networks that are controlled by Arid1a and have an impact on endometrial tumor development. To verify findings from the murine models, we analyze ARID1AWT and ARID1AKO human endometrial epithelial cells. Using a system biology approach and functional studies, we demonstrate that ARID1A-deficiency lead to loss of TGF-β tumor suppressive function and that inactivation of ARID1A/TGF-β axis promotes migration and invasion of PTEN-deleted endometrial tumor cells. These findings provide molecular insights into how ARID1A inactivation accelerates endometrial tumor progression and dissemination, the major causes of cancer mortality.
Designing antifilarial drug trials using clinical trial simulators
Authors: Walker Martin , Hamley Jonathan I. D. , Milton Philip , Monnot Frédéric , Pedrique Belén , Basáñez Maria-Gloria 
Published: June 2020

AbstractLymphatic filariasis and onchocerciasis are neglected tropical diseases (NTDs) targeted for elimination by mass (antifilarial) drug administration. These drugs are predominantly active against the microfilarial progeny of adult worms. New drugs or combinations are needed to improve patient therapy and to enhance the effectiveness of interventions in persistent hotspots of transmission. Several therapies and regimens are currently in (pre-)clinical testing. Clinical trial simulators (CTSs) project patient outcomes to inform the design of clinical trials but have not been widely applied to NTDs, where their resource-saving payoffs could be highly beneficial. We demonstrate the utility of CTSs using our individual-based onchocerciasis transmission model (EPIONCHO-IBM) that projects trial outcomes of a hypothetical macrofilaricidal drug. We identify key design decisions that influence the power of clinical trials, including participant eligibility criteria and post-treatment follow-up times for measuring infection indicators. We discuss how CTSs help to inform target product profiles.
An evolutionary path to altered cofactor specificity in a metalloenzyme
Authors: Barwinska-Sendra Anna , Garcia Yuritzi M. , Sendra Kacper M. , Baslé Arnaud , Mackenzie Eilidh S. , Tarrant Emma , Card Patrick , Tabares Leandro C. , Bicep Cédric , Un Sun , Kehl-Fie Thomas E. , Waldron Kevin J. 
Published: June 2020

AbstractAlmost half of all enzymes utilize a metal cofactor. However, the features that dictate the metal utilized by metalloenzymes are poorly understood, limiting our ability to manipulate these enzymes for industrial and health-associated applications. The ubiquitous iron/manganese superoxide dismutase (SOD) family exemplifies this deficit, as the specific metal used by any family member cannot be predicted. Biochemical, structural and paramagnetic analysis of two evolutionarily related SODs with different metal specificity produced by the pathogenic bacterium Staphylococcus aureus identifies two positions that control metal specificity. These residues make no direct contacts with the metal-coordinating ligands but control the metal’s redox properties, demonstrating that subtle architectural changes can dramatically alter metal utilization. Introducing these mutations into S. aureus alters the ability of the bacterium to resist superoxide stress when metal starved by the host, revealing that small changes in metal-dependent activity can drive the evolution of metalloenzymes with new cofactor specificity.
A genome-wide gain-of-function screen identifies CDKN2C as a HBV host factor
Authors: Eller Carla , Heydmann Laura , Colpitts Che C. , El Saghire Houssein , Piccioni Federica , Jühling Frank , Majzoub Karim , Pons Caroline , Bach Charlotte , Lucifora Julie , Lupberger Joachim , Nassal Michael , Cowley Glenn S. , Fujiwara Naoto , Hsieh Sen-Yung , Hoshida Yujin , Felli Emanuele , Pessaux Patrick , Sureau Camille , Schuster Catherine , Root David E. , Verrier Eloi R. , Baumert Thomas F. 
Published: June 2020

AbstractChronic HBV infection is a major cause of liver disease and cancer worldwide. Approaches for cure are lacking, and the knowledge of virus-host interactions is still limited. Here, we perform a genome-wide gain-of-function screen using a poorly permissive hepatoma cell line to uncover host factors enhancing HBV infection. Validation studies in primary human hepatocytes identified CDKN2C as an important host factor for HBV replication. CDKN2C is overexpressed in highly permissive cells and HBV-infected patients. Mechanistic studies show a role for CDKN2C in inducing cell cycle G1 arrest through inhibition of CDK4/6 associated with the upregulation of HBV transcription enhancers. A correlation between CDKN2C expression and disease progression in HBV-infected patients suggests a role in HBV-induced liver disease. Taken together, we identify a previously undiscovered clinically relevant HBV host factor, allowing the development of improved infectious model systems for drug discovery and the study of the HBV life cycle.
Site-selective electrooxidation of methylarenes to aromatic acetals
Authors: Xiong Peng , Zhao Huai-Bo , Fan Xue-Ting , Jie Liang-Hua , Long Hao , Xu Pin , Liu Zhan-Jiang , Wu Zheng-Jian , Cheng Jun , Xu Hai-Chao 
Published: June 2020

AbstractAldehyde is one of most synthetically versatile functional groups and can participate in numerous chemical transformations. While a variety of simple aromatic aldehydes are commercially available, those with a more complex substitution pattern are often difficult to obtain. Benzylic oxygenation of methylarenes is a highly attractive method for aldehyde synthesis as the starting materials are easy to obtain and handle. However, regioselective oxidation of functionalized methylarenes, especially those that contain heterocyclic moieties, to aromatic aldehydes remains a significant challenge. Here we show an efficient electrochemical method that achieves site-selective electrooxidation of methyl benzoheterocycles to aromatic acetals without using chemical oxidants or transition-metal catalysts. The acetals can be converted to the corresponding aldehydes through hydrolysis in one-pot or in a separate step. The synthetic utility of our method is highlighted by its application to the efficient preparation of the antihypertensive drug telmisartan.
Model-based analysis of sample index hopping reveals its widespread artifacts in multiplexed single-cell RNA-sequencing
Authors: Farouni Rick , Djambazian Haig , Ferri Lorenzo E. , Ragoussis Jiannis , Najafabadi Hamed S. 
Published: June 2020

AbstractIndex hopping is the main cause of incorrect sample assignment of sequencing reads in multiplexed pooled libraries. We introduce a statistical model for estimating the sample index-hopping rate in multiplexed droplet-based single-cell RNA-seq data and for probabilistic inference of the true sample of origin of hopped reads. We analyze several datasets and estimate the sample index hopping probability to range between 0.003–0.009, a small number that counter-intuitively gives rise to a large fraction of phantom molecules — the fraction of phantom molecules exceeds 8% in more than 25% of samples and reaches as high as 85% in low-complexity samples. Phantom molecules lead to widespread complications in downstream analyses, including transcriptome mixing across cells, emergence of phantom copies of cells from other samples, and misclassification of empty droplets as cells. We demonstrate that our approach can correct for these artifacts by accurately purging the majority of phantom molecules from the data.
Ultrastrong coupling between nanoparticle plasmons and cavity photons at ambient conditions
Authors: Baranov Denis G. , Munkhbat Battulga , Zhukova Elena , Bisht Ankit , Canales Adriana , Rousseaux Benjamin , Johansson Göran , Antosiewicz Tomasz J. , Shegai Timur 
Published: June 2020

AbstractUltrastrong coupling is a distinct regime of electromagnetic interaction that enables a rich variety of intriguing physical phenomena. Traditionally, this regime has been reached by coupling intersubband transitions of multiple quantum wells, superconducting artificial atoms, or two-dimensional electron gases to microcavity resonators. However, employing these platforms requires demanding experimental conditions such as cryogenic temperatures, strong magnetic fields, and high vacuum. Here, we use a plasmonic nanorod array positioned at the antinode of a resonant optical Fabry-Pérot microcavity to reach the ultrastrong coupling (USC) regime at ambient conditions and without the use of magnetic fields. From optical measurements we extract the value of the interaction strength over the transition energy as high as g/ω ~ 0.55, deep in the USC regime, while the nanorod array occupies only ∼4% of the cavity volume. Moreover, by comparing the resonant energies of the coupled and uncoupled systems, we indirectly observe up to ∼10% modification of the ground-state energy, which is a hallmark of USC. Our results suggest that plasmon-microcavity polaritons are a promising platform for room-temperature USC realizations in the optical and infrared ranges, and may lead to the long-sought direct visualization of the vacuum energy modification.
Glycan-dependent cell adhesion mechanism of Tc toxins
Authors: Roderer Daniel , Bröcker Felix , Sitsel Oleg , Kaplonek Paulina , Leidreiter Franziska , Seeberger Peter H. , Raunser Stefan 
Published: June 2020

AbstractToxin complex (Tc) toxins are virulence factors of pathogenic bacteria. Tcs are composed of three subunits: TcA, TcB and TcC. TcA facilitates receptor–toxin interaction and membrane permeation, TcB and TcC form a toxin-encapsulating cocoon. While the mechanisms of holotoxin assembly and pore formation have been described, little is known about receptor binding of TcAs. Here, we identify heparins/heparan sulfates and Lewis antigens as receptors for different TcAs from insect and human pathogens. Glycan array screening reveals that all tested TcAs bind negatively charged heparins. Cryo-EM structures ofMorganella morganiiTcdA4 andXenorhabdus nematophilaXptA1 reveal that heparins/heparan sulfates unexpectedly bind to different regions of the shell domain, including receptor-binding domains. In addition,Photorhabdus luminescensTcdA1 binds to Lewis antigens with micromolar affinity. Here, the glycan interacts with the receptor-binding domain D of the toxin. Our results suggest a glycan dependent association mechanism of Tc toxins on the host cell surface.
Skeletal muscle enhancer interactions identify genes controlling whole-body metabolism
Authors: Williams Kristine , Ingerslev Lars R. , Bork-Jensen Jette , Wohlwend Martin , Hansen Ann Normann , Small Lewin , Ribel-Madsen Rasmus , Astrup Arne , Pedersen Oluf , Auwerx Johan , Workman Christopher T. , Grarup Niels , Hansen Torben , Barrès Romain 
Published: June 2020

AbstractObesity and type 2 diabetes (T2D) are metabolic disorders influenced by lifestyle and genetic factors that are characterized by insulin resistance in skeletal muscle, a prominent site of glucose disposal. Numerous genetic variants have been associated with obesity and T2D, of which the majority are located in non-coding DNA regions. This suggests that most variants mediate their effect by altering the activity of gene-regulatory elements, including enhancers. Here, we map skeletal muscle genomic enhancer elements that are dynamically regulated after exposure to the free fatty acid palmitate or the inflammatory cytokine TNFα. By overlapping enhancer positions with the location of disease-associated genetic variants, and resolving long-range chromatin interactions between enhancers and gene promoters, we identify target genes involved in metabolic dysfunction in skeletal muscle. The majority of these genes also associate with altered whole-body metabolic phenotypes in the murine BXD genetic reference population. Thus, our combined genomic investigations identified genes that are involved in skeletal muscle metabolism.
Suppression of unwanted CRISPR-Cas9 editing by co-administration of catalytically inactivating truncated guide RNAs
Authors: Rose John C. , Popp Nicholas A. , Richardson Christopher D. , Stephany Jason J. , Mathieu Julie , Wei Cindy T. , Corn Jacob E. , Maly Dustin J. , Fowler Douglas M. 
Published: June 2020

AbstractCRISPR-Cas9 nucleases are powerful genome engineering tools, but unwanted cleavage at off-target and previously edited sites remains a major concern. Numerous strategies to reduce unwanted cleavage have been devised, but all are imperfect. Here, we report that off-target sites can be shielded from the active Cas9•single guide RNA (sgRNA) complex through the co-administration of dead-RNAs (dRNAs), truncated guide RNAs that direct Cas9 binding but not cleavage. dRNAs can effectively suppress a wide-range of off-targets with minimal optimization while preserving on-target editing, and they can be multiplexed to suppress several off-targets simultaneously. dRNAs can be combined with high-specificity Cas9 variants, which often do not eliminate all unwanted editing. Moreover, dRNAs can prevent cleavage of homology-directed repair (HDR)-corrected sites, facilitating scarless editing by eliminating the need for blocking mutations. Thus, we enable precise genome editing by establishing a flexible approach for suppressing unwanted editing of both off-targets and HDR-corrected sites.
Specific fibroblast subpopulations and neuronal structures provide local sources of Vegfc-processing components during zebrafish lymphangiogenesis
Authors: Wang Guangxia , Muhl Lars , Padberg Yvonne , Dupont Laura , Peterson-Maduro Josi , Stehling Martin , le Noble Ferdinand , Colige Alain , Betsholtz Christer , Schulte-Merker Stefan , van Impel Andreas 
Published: June 2020

AbstractProteolytical processing of the growth factor VEGFC through the concerted activity of CCBE1 and ADAMTS3 is required for lymphatic development to occur. How these factors act together in time and space, and which cell types produce these factors is not understood. Here we assess the function of Adamts3 and the related protease Adamts14 during zebrafish lymphangiogenesis and show both proteins to be able to process Vegfc. Only the simultaneous loss of both protein functions results in lymphatic defects identical tovegfcloss-of-function situations. Cell transplantation experiments demonstrate neuronal structures and/or fibroblasts to constitute cellular sources not only for both proteases but also for Ccbe1 and Vegfc. We further show that this locally restricted Vegfc maturation is needed to trigger normal lymphatic sprouting and directional migration. Our data provide a single-cell resolution model for establishing secretion and processing hubs for Vegfc during developmental lymphangiogenesis.
Tetrameric architecture of an active phenol-bound form of the AAA+ transcriptional regulator DmpR
Authors: Park Kwang-Hyun , Kim Sungchul , Lee Su-Jin , Cho Jee-Eun , Patil Vinod Vikas , Dumbrepatil Arti Baban , Song Hyung-Nam , Ahn Woo-Chan , Joo Chirlmin , Lee Seung-Goo , Shingler Victoria , Woo Eui-Jeon 
Published: June 2020

AbstractThe Pseudomonas putida phenol-responsive regulator DmpR is a bacterial enhancer binding protein (bEBP) from the AAA+ ATPase family. Even though it was discovered more than two decades ago and has been widely used for aromatic hydrocarbon sensing, the activation mechanism of DmpR has remained elusive. Here, we show that phenol-bound DmpR forms a tetramer composed of two head-to-head dimers in a head-to-tail arrangement. The DmpR-phenol complex exhibits altered conformations within the C-termini of the sensory domains and shows an asymmetric orientation and angle in its coiled-coil linkers. The structural changes within the phenol binding sites and the downstream ATPase domains suggest that the effector binding signal is propagated through the coiled-coil helixes. The tetrameric DmpR-phenol complex interacts with the σ54 subunit of RNA polymerase in presence of an ATP analogue, indicating that DmpR-like bEBPs tetramers utilize a mechanistic mode distinct from that of hexameric AAA+ ATPases to activate σ54-dependent transcription.