bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiplex gene regulation by CRISPR-ddCpf1
Authors: Zhang Xiaochun , Wang Jingman , Cheng Qiuxiang , Zheng Xuan , Zhao Guoping , Wang Jin 
Published: June 2017

AbstractThe clustered regularly interspaced short palindromic repeats (CRISPR)/dCas9 system has been widely applied in both transcriptional regulation and epigenetic studies. However, for multiple targets, independent expression of multiple single guide RNAs (sgRNAs) is needed, which is less convenient. To address the problem, we employed a DNase-dead Cpf1 mutant (ddCpf1) for multiplex gene regulation. We demonstrated that ddCpf1 alone could be employed for gene repression in Escherichia coli, and the repression was more effective with CRISPR RNAs (crRNAs) specifically targeting to the template strand of its target genes, which was different from that of dCas9. When targeting the promoter region, both strands showed effective repression by the ddCpf1/crRNA complex. The whole-transcriptome RNA-seq technique was further employed to demonstrate the high specificity of ddCpf1-mediated repression. Besides, we proved that the remaining RNase activity in ddCpf1 was capable of processing a precursor CRISPR array to simply generate multiple mature crRNAs in vivo, facilitating multiplex gene regulation. With the employment of this multiplex gene regulation strategy, we also showed how to quickly screen a library of candidate targets, that is, the two-component systems in E. coli. Therefore, based on our findings here, the CRISPR-ddCpf1 system may be further developed and widely applied in both biological research and clinical studies.
A molecular portrait of microsatellite instability across multiple cancers
Authors: Cortes-Ciriano Isidro , Lee Sejoon , Park Woong-Yang , Kim Tae-Min , Park Peter J. 
Published: June 2017

AbstractMicrosatellite instability (MSI) refers to the hypermutability of short repetitive sequences in the genome caused by impaired DNA mismatch repair. Although MSI has been studied for decades, large amounts of sequencing data now available allows us to examine the molecular fingerprints of MSI in greater detail. Here, we analyse ∼8,000 exomes and ∼1,000 whole genomes of cancer patients across 23 cancer types. Our analysis reveals that the frequency of MSI events is highly variable within and across tumour types. We also identify genes in DNA repair and oncogenic pathways recurrently subject to MSI and uncover non-coding loci that frequently display MSI. Finally, we propose a highly accurate exome-based predictive model for the MSI phenotype. These results advance our understanding of the genomic drivers and consequences of MSI, and our comprehensive catalogue of tumour-type-specific MSI loci will enable panel-based MSI testing to identify patients who are likely to benefit from immunotherapy.
Global metabolic interaction network of the human gut microbiota for context-specific community-scale analysis
Authors: Sung Jaeyun , Kim Seunghyeon , Cabatbat Josephine Jill T. , Jang Sungho , Jin Yong-Su , Jung Gyoo Yeol , Chia Nicholas , Kim Pan-Jun 
Published: June 2017

AbstractA system-level framework of complex microbe–microbe and host–microbe chemical cross-talk would help elucidate the role of our gut microbiota in health and disease. Here we report a literature-curated interspecies network of the human gut microbiota, called NJS16. This is an extensive data resource composed of ∼570 microbial species and 3 human cell types metabolically interacting through >4,400 small-molecule transport and macromolecule degradation events. Based on the contents of our network, we develop a mathematical approach to elucidate representative microbial and metabolic features of the gut microbial community in a given population, such as a disease cohort. Applying this strategy to microbiome data from type 2 diabetes patients reveals a context-specific infrastructure of the gut microbial ecosystem, core microbial entities with large metabolic influence, and frequently produced metabolic compounds that might indicate relevant community metabolic processes. Our network presents a foundation towards integrative investigations of community-scale microbial activities within the human gut.
Extreme temperatures in Southeast Asia caused by El Niño and worsened by global warming
Authors: Thirumalai Kaustubh , DiNezio Pedro N. , Okumura Yuko , Deser Clara 
Published: June 2017

AbstractIn April 2016, southeast Asia experienced surface air temperatures (SATs) that surpassed national records, exacerbated energy consumption, disrupted agriculture and caused severe human discomfort. Here we show using observations and an ensemble of global warming simulations the combined impact of the El Niño/Southern Oscillation (ENSO) phenomenon and long-term warming on regional SAT extremes. We find a robust relationship between ENSO and southeast Asian SATs wherein virtually all April extremes occur during El Niño years. We then quantify the relative contributions of long-term warming and the 2015–16 El Niño to the extreme April 2016 SATs. The results indicate that global warming increases the likelihood of record-breaking April extremes where we estimate that 29% of the 2016 anomaly was caused by warming and 49% by El Niño. These post-Niño Aprils can potentially be anticipated a few months in advance, and thus, help societies prepare for the projected continued increases in extremes.
Possible absence of critical thickness and size effect in ultrathin perovskite ferroelectric films
Authors: Gao Peng , Zhang Zhangyuan , Li Mingqiang , Ishikawa Ryo , Feng Bin , Liu Heng-Jui , Huang Yen-Lin , Shibata Naoya , Ma Xiumei , Chen Shulin , Zhang Jingmin , Liu Kaihui , Wang En-Ge , Yu Dapeng , Liao Lei , Chu Ying-Hao , Ikuhara Yuichi 
Published: June 2017

AbstractAlthough the size effect in ferroelectric thin films has been known for long time, the underlying mechanism is not yet fully understood and whether or not there is a critical thickness below which the ferroelectricity vanishes is still under debate. Here, we directly measure the thickness-dependent polarization in ultrathin PbZr0.2Ti0.8O3 films via quantitative annular bright field imaging. We find that the polarization is significantly suppressed for films <10-unit cells thick (∼4 nm). However, approximately the polarization never vanishes. The residual polarization is ∼16 μCcm−2 (∼17%) at 1.5-unit cells (∼0.6 nm) thick film on bare SrTiO3 and ∼22 μCcm−2 at 2-unit cells thick film on SrTiO3 with SrRuO3 electrode. The residual polarization in these ultrathin films is mainly attributed to the robust covalent Pb–O bond. Our atomic study provides new insights into mechanistic understanding of nanoscale ferroelectricity and the size effects.
Multimode entanglement in reconfigurable graph states using optical frequency combs
Authors: Cai Y. , Roslund J. , Ferrini G. , Arzani F. , Xu X. , Fabre C. , Treps N. 
Published: June 2017

AbstractMultimode entanglement is an essential resource for quantum information processing and quantum metrology. However, multimode entangled states are generally constructed by targeting a specific graph configuration. This yields to a fixed experimental setup that therefore exhibits reduced versatility and scalability. Here we demonstrate an optical on-demand, reconfigurable multimode entangled state, using an intrinsically multimode quantum resource and a homodyne detection apparatus. Without altering either the initial squeezing source or experimental architecture, we realize the construction of thirteen cluster states of various sizes and connectivities as well as the implementation of a secret sharing protocol. In particular, this system enables the interrogation of quantum correlations and fluctuations for any multimode Gaussian state. This initiates an avenue for implementing on-demand quantum information processing by only adapting the measurement process and not the experimental layout.
Sox5 regulates beta-cell phenotype and is reduced in type 2 diabetes
Authors: Axelsson A. S. , Mahdi T. , Nenonen H. A. , Singh T. , Hänzelmann S. , Wendt A. , Bagge A. , Reinbothe T. M. , Millstein J. , Yang X. , Zhang B. , Gusmao E. G. , Shu L. , Szabat M. , Tang Y. , Wang J. , Salö S. , Eliasson L. , Artner I. , Fex M. , Johnson J. D. , Wollheim C. B. , Derry J.M.J. , Mecham B. , Spégel P. , Mulder H. , Costa I.G. , Zhang E. , Rosengren A. H. 
Published: June 2017

AbstractType 2 diabetes (T2D) is characterized by insulin resistance and impaired insulin secretion, but the mechanisms underlying insulin secretion failure are not completely understood. Here, we show that a set of co-expressed genes, which is enriched for genes with islet-selective open chromatin, is associated with T2D. These genes are perturbed in T2D and have a similar expression pattern to that of dedifferentiated islets. We identify Sox5 as a regulator of the module. Sox5 knockdown induces gene expression changes similar to those observed in T2D and diabetic animals and has profound effects on insulin secretion, including reduced depolarization-evoked Ca2+-influx and β-cell exocytosis. SOX5 overexpression reverses the expression perturbations observed in a mouse model of T2D, increases the expression of key β-cell genes and improves glucose-stimulated insulin secretion in human islets from donors with T2D. We suggest that human islets in T2D display changes reminiscent of dedifferentiation and highlight SOX5 as a regulator of β-cell phenotype and function.
Split-BioID a conditional proteomics approach to monitor the composition of spatiotemporally defined protein complexes
Authors: Schopp Isabel Myriam , Amaya Ramirez Cinthia Claudia , Debeljak Jerneja , Kreibich Elisa , Skribbe Merle , Wild Klemens , Béthune Julien 
Published: June 2017

AbstractUnderstanding the function of the thousands of cellular proteins is a central question in molecular cell biology. As proteins are typically part of multiple dynamic and often overlapping macromolecular complexes exerting distinct functions, the identification of protein–protein interactions (PPI) and their assignment to specific complexes is a crucial but challenging task. We present a protein fragments complementation assay integrated with the proximity-dependent biotinylation technique BioID. Activated on the interaction of two proteins, split-BioID is a conditional proteomics approach that allows in a single and simple assay to both experimentally validate binary PPI and to unbiasedly identify additional interacting factors. Applying our method to the miRNA-mediated silencing pathway, we can probe the proteomes of two distinct functional complexes containing the Ago2 protein and uncover the protein GIGYF2 as a regulator of miRNA-mediated translation repression. Hence, we provide a novel tool to study dynamic spatiotemporally defined protein complexes in their native cellular environment.
Single-peptide DNA-dependent RNA polymerase homologous to multi-subunit RNA polymerase
Authors: Forrest David , James Katherine , Yuzenkova Yulia , Zenkin Nikolay 
Published: June 2017

AbstractTranscription in all living organisms is accomplished by multi-subunit RNA polymerases (msRNAPs). msRNAPs are highly conserved in evolution and invariably share a ∼400 kDa five-subunit catalytic core. Here we characterize a hypothetical ∼100 kDa single-chain protein, YonO, encoded by the SPβ prophage ofBacillus subtilis. YonO shares very distant homology with msRNAPs, but no homology with single-subunit polymerases. We show that despite homology to only a few amino acids of msRNAP, and the absence of most of the conserved domains, YonO is a highly processive DNA-dependent RNA polymerase. We demonstrate that YonO is abona fideRNAP of the SPβ bacteriophage that specifically transcribes its late genes, and thus represents a novel type of bacteriophage RNAPs. YonO and related proteins present in various bacteria and bacteriophages have diverged from msRNAPs before the Last Universal Common Ancestor, and, thus, may resemble the single-subunit ancestor of all msRNAPs.
IL-21-mediated reversal of NK cell exhaustion facilitates anti-tumour immunity in MHC class I-deficient tumours
Authors: Seo Hyungseok , Jeon Insu , Kim Byung-Seok , Park Myunghwan , Bae Eun-Ah , Song Boyeong , Koh Choong-Hyun , Shin Kwang-Soo , Kim Il-Kyu , Choi Kiyoung , Oh Taegwon , Min Jiyoun , Min Byung Soh , Han Yoon Dae , Kang Suk-Jo , Shin Sang Joon , Chung Yeonseok , Kang Chang-Yuil 
Published: June 2017

AbstractDuring cancer immunoediting, loss of major histocompatibility complex class I (MHC-I) in neoplasm contributes to the evasion of tumours from host immune system. Recent studies have demonstrated that most natural killer (NK) cells that are found in advanced cancers are defective, releasing the malignant MHC-I-deficient tumours from NK-cell-dependent immune control. Here, we show that a natural killer T (NKT)-cell-ligand-loaded tumour-antigen expressing antigen-presenting cell (APC)-based vaccine effectively eradicates these advanced tumours. During this process, we find that the co-expression of Tim-3 and PD-1 marks functionally exhausted NK cells in advanced tumours and that MHC-I downregulation in tumours is closely associated with the induction of NK-cell exhaustion in both tumour-bearing mice and cancer patients. Furthermore, the recovery of NK-cell function by IL-21 is critical for the anti-tumour effects of the vaccine against advanced tumours. These results reveal the process involved in the induction of NK-cell dysfunction in advanced cancers and provide a guidance for the development of strategies for cancer immunotherapy.
Improving the DNA specificity and applicability of base editing through protein engineering and protein delivery
Authors: Rees Holly A. , Komor Alexis C. , Yeh Wei-Hsi , Caetano-Lopes Joana , Warman Matthew , Edge Albert S. B. , Liu David R. 
Published: June 2017

AbstractWe recently developed base editing, a genome-editing approach that enables the programmable conversion of one base pair into another without double-stranded DNA cleavage, excess stochastic insertions and deletions, or dependence on homology-directed repair. The application of base editing is limited by off-target activity and reliance on intracellular DNA delivery. Here we describe two advances that address these limitations. First, we greatly reduce off-target base editing by installing mutations into our third-generation base editor (BE3) to generate a high-fidelity base editor (HF-BE3). Next, we purify and deliver BE3 and HF-BE3 as ribonucleoprotein (RNP) complexes into mammalian cells, establishing DNA-free base editing. RNP delivery of BE3 confers higher specificity even than plasmid transfection of HF-BE3, while maintaining comparable on-target editing levels. Finally, we apply these advances to deliver BE3 RNPs into both zebrafish embryos and the inner ear of live mice to achieve specific, DNA-free base editing in vivo.
Isolation, Detection, and Quantification of Cancer Biomarkers in HPV-Associated Malignancies
Authors: Inan Hakan , Wang Shuqi , Inci Fatih , Baday Murat , Zangar Richard , Kesiraju Sailaja , Anderson Karen S. , Cunningham Brian T. , Demirci Utkan 
Published: June 2017

AbstractHuman Papillomavirus (HPV) infection has been recognized as the main etiologic factor in the development of various cancers including penile, vulva, oropharyngeal and cervical cancers. In the development of cancer, persistent HPV infections induce E6 and E7 oncoproteins, which promote cell proliferation and carcinogenesis resulting elevated levels of host antibodies (e.g., anti-HPV16 E7 antibody). Currently, these cancers are clinically diagnosed using invasive biopsy-based tests, which are performed only in centralized labs by experienced clinical staff using time-consuming and expensive tools and technologies. Therefore, these obstacles constrain their utilization at primary care clinics and in remote settings, where resources are limited. Here, we present a rapid, inexpensive, reliable, easy-to-use, customized immunoassay platform following a microfluidic filter device to detect and quantify anti-HPV16 E7 antibodies from whole blood as a non-invasive assisting technology for diagnosis of HPV-associated malignancies, especially, at primary healthcare and remote settings. The platform can detect and quantify anti-HPV16 E7 antibody down to 2.87 ng/mL. We further validated our immunoassay in clinical patient samples and it provided significantly high responses as compared to control samples. Thus, it can be potentially implemented as a pretesting tool to identify high-risk groups for broad monitoring of HPV-associated cancers in resource-constrained settings.
Liraglutide improves liver microvascular dysfunction in cirrhosis: Evidence from translational studies
Authors: de Mesquita Fernanda Cristina , Guixé-Muntet Sergi , Fernández-Iglesias Anabel , Maeso-Díaz Raquel , Vila Sergi , Hide Diana , Ortega-Ribera Martí , Rosa José Luís , García-Pagán Juan Carlos , Bosch Jaime , de Oliveira Jarbas Rodrigues , Gracia-Sancho Jordi 
Published: June 2017

AbstractHepatic stellate cells (HSC) play a key role in the development of chronic liver disease (CLD). Liraglutide, well-established in type 2 diabetes, showed anti-inflammatory and anti-oxidant properties. We evaluated the effects of liraglutide on HSC phenotype and hepatic microvascular function using diverse pre-clinical models of CLD. Human and rat HSC were in vitro treated with liraglutide, or vehicle, and their phenotype, viability and proliferation were evaluated. In addition, liraglutide or vehicle was administered to rats with CLD. Liver microvascular function, fibrosis, HSC phenotype and sinusoidal endothelial phenotype were determined. Additionally, the effects of liraglutide on HSC phenotype were analysed in human precision-cut liver slices. Liraglutide markedly improved HSC phenotype and diminished cell proliferation. Cirrhotic rats receiving liraglutide exhibited significantly improved liver microvascular function, as evidenced by lower portal pressure, improved intrahepatic vascular resistance, and marked ameliorations in fibrosis, HSC phenotype and endothelial function. The anti-fibrotic effects of liraglutide were confirmed in human liver tissue and, although requiring further investigation, its underlying molecular mechanisms suggested a GLP1-R-independent and NF-κB-Sox9-dependent one. This study demonstrates for the first time that liraglutide improves the liver sinusoidal milieu in pre-clinical models of cirrhosis, encouraging its clinical evaluation in the treatment of chronic liver disease.
Comparisons of the biodistribution and toxicological examinations after repeated intravenous administration of silver and gold nanoparticles in mice
Authors: Yang Lin , Kuang Huijuan , Zhang Wanyi , Aguilar Zoraida P. , Wei Hua , Xu Hengyi 
Published: June 2017

AbstractNanoparticles (NPs) size, surface functionalization, and concentration were claimed to contribute to distribution and toxicity outcomes of NPs in vivo. However, intrinsic chemical compositions of NPs caused inconsistent biodistribution and toxic profiles which attracted little attention. In this study, silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs) were used to determine the biodistribution, toxickinetic, and genotoxicity variances in murine animals. The results demonstrated AgNPs and AuNPs were primarily deposited in the mononuclear phagocyte system (MPS) such as the liver and spleen. In particular, AuNPs seemed to be prominently stored in the liver, whereas AgNPs preferentially accumulated in more organs such as the heart, lung, kidney, etc. Also, the circulation in the blood and fecal excretions showed higher AgNPs contents in comparison with the AuNPs. Measurements of the mouse body and organ mass, hematology and biochemistry evaluation, and histopathological examinations indicated slight toxic difference between the AgNPs and AuNPs over a period of two months. RT-qPCR data revealed that AgNPs induced greater changes in gene expression with relevance to oxidative stress, apoptosis, and ion transport. Our observations proved that the NPs chemical composition played a critical role in their in vivo biodistribution and toxicity.
Combining Catalytic Microparticles with Droplets Formed by Phase Coexistence: Adsorption and Activity of Natural Clays at the Aqueous/Aqueous Interface
Authors: Pir Cakmak Fatma , Keating Christine D. 
Published: June 2017

AbstractNatural clay particles have been hypothesized as catalysts on the early Earth, potentially facilitating the formation of early organic (bio) molecules. Association of clay particles with droplets formed by liquid-liquid phase separation could provide a physical mechanism for compartmentalization of inorganic catalysts in primitive protocells. Here we explore the distribution of natural clay mineral particles in poly(ethylene glycol) (PEG)/dextran (Dx) aqueous two-phase systems (ATPS). We compared the three main types of natural clay: kaolinite, montmorillonite and illite, all of which are aluminosilicates of similar composition and surface charge. The three clay types differ in particle size, crystal structure, and their accumulation at the ATPS interface and ability to stabilize droplets against coalescence. Illite and kaolinite accumulated at the aqueous/aqueous interface, stabilizing droplets against coalescence but not preventing their eventual sedimentation due to the mass of adsorbed particles. The ability of each clay-containing ATPS to catalyze reaction of o-phenylenediamine with peroxide to form 2,3-diaminophenazone was evaluated. We observed modest rate increases for this reaction in the presence of clay-containing ATPS over clay in buffer alone, with illite outperforming the other clays. These findings are encouraging because they support the potential of combining catalytic mineral particles with aqueous microcompartments to form primitive microreactors.
On the phonon dissipation contribution to nanoscale friction by direct contact
Authors: de Mello S. R. Sales , da Costa M. E. H. Maia , Menezes C. M. , Boeira C. D. , Freire Jr F. L. , Alvarez F. , Figueroa C. A. 
Published: June 2017

AbstractThe friction phenomenon is a ubiquitous manifestation of nature. Models considering phononic, electronic, magnetic, and electrostatic interactions are invoked to explain the fundamental forces involved in the friction phenomenon. In order to establish the incidence of the phonon prompting at the nanoscale friction by direct contact, we study a diamond spherical dome sliding on carbon thin films containing different amount of deuterium and hydrogen. The friction coefficient decreases by substituting hydrogen by deuterium atoms. This result is consistent with an energy dissipation vibration local mechanism from a disordered distribution of bond terminators.