bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of KRAS-dependent lung cancer cell growth by deltarasin: blockage of autophagy increases its cytotoxicity
Authors: Leung Elaine Lai Han , Luo Lian Xiang , Liu Zhong Qiu , Wong Vincent Kam Wai , Lu Lin Lin , Xie Ying , Zhang Ni , Qu Yuan Qing , Fan Xing Xing , Li Ying , Huang Min , Xiao Dai Kai , Huang Jun , Zhou Yan Ling , He Jian Xing , Ding Jian , Yao Xiao Jun , Ward David C. , Liu Liang 
Published: February 2018

AbstractDeltarasin is a recently identified small molecule that can inhibit KRAS–PDEδ interactions by binding to a hydrophobic pocket on PDEδ, resulting in the impairment of cell growth, KRAS activity, and RAS/RAF signaling in human pancreatic ductal adenocarcinoma cell lines. Since KRAS mutations are the most common oncogene mutations in lung adenocarcinomas, implicated in over 30% of all lung cancer cases, we examined the ability of deltarasin to inhibit KRAS-dependent lung cancer cell growth. Here, for the first time, we document that deltarasin produces both apoptosis and autophagy in KRAS-dependent lung cancer cells in vitro and inhibits lung tumor growth in vivo. Deltarasin induces apoptosis by inhibiting the interaction of with PDEδ and its downstream signaling pathways, while it induces autophagy through the AMPK-mTOR signaling pathway. Importantly, the autophagy inhibitor, 3-methyl adenine (3-MA) markedly enhances deltarasin-induced apoptosis via elevation of reactive oxygen species (ROS). In contrast, inhibition of ROS by N-acetylcysteine (NAC) significantly attenuated deltarasin-induced cell death. Collectively, these observations suggest that the anti-cancer cell activity of deltarasin can be enhanced by simultaneously blocking “tumor protective” autophagy, but inhibited if combined with an anti-oxidant.
KRAS induces lung tumorigenesis through microRNAs modulation
Authors: Shi Lei , Middleton Justin , Jeon Young-Jun , Magee Peter , Veneziano Dario , Laganà Alessandro , Leong Hui-Sun , Sahoo Sudhakar , Fassan Matteo , Booton Richard , Shah Rajesh , Crosbie Philip A. J. , Garofalo Michela 
Published: February 2018

AbstractOncogenic KRAS induces tumor onset and development by modulating gene expression via different molecular mechanisms. MicroRNAs (miRNAs) are small non-coding RNAs that have been established as main players in tumorigenesis. By overexpressing wild type or mutant KRAS (KRASG12D) and using inducible human and mouse cell lines, we analyzed KRAS-regulated microRNAs in non-small-cell lung cancer (NSCLC). We show that miR-30c and miR-21 are significantly upregulated by both KRAS isoforms and induce drug resistance and enhance cell migration/invasion via inhibiting crucial tumor suppressor genes, such as NF1, RASA1, BID, and RASSF8. MiR-30c and miR-21 levels were significantly elevated in tumors from patients that underwent surgical resection of early stages NSCLC compared to normal lung and in plasma from the same patients. Systemic delivery of LNA-anti-miR-21 in combination with cisplatin in vivo completely suppressed the development of lung tumors in a mouse model of lung cancer. Mechanistically, we demonstrated that ELK1 is responsible for miR-30c and miR-21 transcriptional activation by direct binding to the miRNA proximal promoter regions. In summary, our study defines that miR-30c and miR-21 may be valid biomarkers for early NSCLC detection and their silencing could be beneficial for therapeutic applications.
Generalized leaky integrate-and-fire models classify multiple neuron types
Authors: Teeter Corinne , Iyer Ramakrishnan , Menon Vilas , Gouwens Nathan , Feng David , Berg Jim , Szafer Aaron , Cain Nicholas , Zeng Hongkui , Hawrylycz Michael , Koch Christof , Mihalas Stefan 
Published: February 2018

AbstractThere is a high diversity of neuronal types in the mammalian neocortex. To facilitate construction of system models with multiple cell types, we generate a database of point models associated with the Allen Cell Types Database. We construct a set of generalized leaky integrate-and-fire (GLIF) models of increasing complexity to reproduce the spiking behaviors of 645 recorded neurons from 16 transgenic lines. The more complex models have an increased capacity to predict spiking behavior of hold-out stimuli. We use unsupervised methods to classify cell types, and find that high level GLIF model parameters are able to differentiate transgenic lines comparable to electrophysiological features. The more complex model parameters also have an increased ability to differentiate between transgenic lines. Thus, creating simple models is an effective dimensionality reduction technique that enables the differentiation of cell types from electrophysiological responses without the need for a priori-defined features. This database will provide a set of simplified models of multiple cell types for the community to use in network models.
Formalising recall by genotype as an efficient approach to detailed phenotyping and causal inference
Authors: Corbin Laura J. , Tan Vanessa Y. , Hughes David A. , Wade Kaitlin H. , Paul Dirk S. , Tansey Katherine E. , Butcher Frances , Dudbridge Frank , Howson Joanna M. , Jallow Momodou W. , John Catherine , Kingston Nathalie , Lindgren Cecilia M. , O’Donavan Michael , O’Rahilly Stephen , Owen Michael J. , Palmer Colin N. A. , Pearson Ewan R. , Scott Robert A. , van Heel David A. , Whittaker John , Frayling Tim , Tobin Martin D. , Wain Louise V. , Smith George Davey , Evans David M. , Karpe Fredrik , McCarthy Mark I. , Danesh John , Franks Paul W. , Timpson Nicholas J. 
Published: February 2018

AbstractDetailed phenotyping is required to deepen our understanding of the biological mechanisms behind genetic associations. In addition, the impact of potentially modifiable risk factors on disease requires analytical frameworks that allow causal inference. Here, we discuss the characteristics of Recall-by-Genotype (RbG) as a study design aimed at addressing both these needs. We describe two broad scenarios for the application of RbG: studies using single variants and those using multiple variants. We consider the efficacy and practicality of the RbG approach, provide a catalogue of UK-based resources for such studies and present an online RbG study planner.
Can civil lawsuits stem the tide of direct-to-consumer marketing of unproven stem cell interventions
Authors: Horner Claire , Tenenbaum Evelyn , Sipp Douglas , Master Zubin 
Published: February 2018

AbstractThe sale of unproven stem cell interventions (SCIs) by commercial entities has proliferated in highly developed countries, most notably in the USA. Yet, there have been few criminal prosecutions and regulatory enforcement actions against providers who have violated laws and best practice standards due to the lack of resources and legal ambiguity. While the stem cell research community has invested much in protecting patients and preventing the growth of this industry, some patients are seeking remedies under civil law to hold stem cell clinics responsible for fraudulent practices. Several patients have filed lawsuits against providers demanding compensation for physical injuries caused by unproven treatments and financial losses due to fraud and false advertising. Lawsuits can be used as a tool not only to compensate plaintiffs but also to achieve positive public health and policy outcomes. In this paper, we explore the value of a public health litigation strategy as a countermeasure against the exploitative practices of the unproven SCI industry by analyzing stem cell lawsuits and comparing them with other major public health litigation efforts. We argue that stem cell lawsuits complement other approaches to reining in unsafe practices. In particular, stem cell lawsuits could intensify publicity and raise awareness of the harms of unproven treatments, set legal precedent, reshape the media narrative from one focused on the right to try or practice to one highlighting the need for adequate safety and efficacy standards, and encourage authorities to turn their attention to policy reform and enforcement.
New insights into the cellular responses to iron nanoparticles in Capsicum annuum
Authors: Yuan Junxia , Chen Yu , Li Huasheng , Lu Jinying , Zhao Hui , Liu Min , Nechitaylo Galina S. , Glushchenko Natalia N. 
Published: February 2018

AbstractIn this study, the anatomical and ultrastructural responses of Capsicum annuum to iron nanoparticles (Fe NPs) were determined. The results showed that the bio-effects of Fe NPs on plants could be positive or negative, depending on the additive concentrations. Low concentrations of Fe NPs were found to promote plant growth. Light and electron microscope analyses showed that the Fe NPs promoted plant growth by altering the leaf organization, and increasing the chloroplast number and grana stacking, as well as regulating the development of vascular bundles. Meanwhile, it was found that the Fe NPs could be absorbed in the roots, and then transported to the central cylinder in bio-available forms, where they were translocated and utilized by the leaves and stems. In contrast, high concentrations of Fe NPs appeared to be harmful to the plants, and the majority of Fe NPs were aggregated into cell walls and transported via the apoplastic pathway in the roots, which may potentially block the transfer of iron nutrients. Taken together, the aforementioned data showed that the rational use of Fe NPs could alleviate iron deficiency, and Fe NPs could be an ideal supply for Fe2+ ions fertilizers in agriculture.
Global Peak in Atmospheric Radiocarbon Provides a Potential Definition for the Onset of the Anthropocene Epoch in 1965
Authors: Turney Chris S. M. , Palmer Jonathan , Maslin Mark A. , Hogg Alan , Fogwill Christopher J. , Southon John , Fenwick Pavla , Helle Gerhard , Wilmshurst Janet M. , McGlone Matt , Bronk Ramsey Christopher , Thomas Zoë , Lipson Mathew , Beaven Brent , Jones Richard T. , Andrews Oliver , Hua Quan 
Published: February 2018

AbstractAnthropogenic activity is now recognised as having profoundly and permanently altered the Earth system, suggesting we have entered a human-dominated geological epoch, the ‘Anthropocene’. To formally define the onset of the Anthropocene, a synchronous global signature within geological-forming materials is required. Here we report a series of precisely-dated tree-ring records from Campbell Island (Southern Ocean) that capture peak atmospheric radiocarbon (14C) resulting from Northern Hemisphere-dominated thermonuclear bomb tests during the 1950s and 1960s. The only alien tree on the island, a Sitka spruce (Picea sitchensis), allows us to seasonally-resolve Southern Hemisphere atmospheric 14C, demonstrating the ‘bomb peak’ in this remote and pristine location occurred in the last-quarter of 1965 (October-December), coincident with the broader changes associated with the post-World War II ‘Great Acceleration’ in industrial capacity and consumption. Our findings provide a precisely-resolved potential Global Stratotype Section and Point (GSSP) or ‘golden spike’, marking the onset of the Anthropocene Epoch.
Joint Effect of Non-invasive Central Systolic Blood Pressure and Peripheral Systolic Blood Pressure on Incident Hypertension in a Chinese Community-based Population
Authors: Wang Shixuan , Zhou Zechen , Fan Fangfang , Qi Litong , Jia Jia , Sun Pengfei , Jiang Yimeng , Kou Minghao , Chen Dafang , Zhang Yan , Huo Yong 
Published: February 2018

AbstractCentral blood pressure level is not always consistent with peripheral blood pressure level, and especially their joint effect on incident hypertension is not well established. A total of 1607 non-hypertensive subjects from an atherosclerosis cohort in Beijing, China were included. Central systolic blood pressure (cSBP) was obtained using Omron HEM-9000AI machine and peripheral systolic blood pressure (pSBP) was measured using Omron HEM-7117 electronic sphygmomanometer, separately. Hypertension was defined as BP ≥ 140/90 mmHg or self-reported hypertension or taking any antihypertension drugs at the follow-up survey. After a median follow-up of 2.3 years, incident hypertension was 13.1%. Every 1 standard deviation increase of cSBP and pSBP was associated with 1.98 (95%CI: 1.69–2.33) and 2.84 (95%CI: 2.30–3.52) times of incident hypertension after adjustment for confounders. Moreover, hypertension risk in single pSBP ≥ 120 mmHg group, single cSBP ≥ 120 mmHg group, and both pSBP and cSBP ≥ 120 mmHg group was 2.83 (95%CI: 0.98–8.16), 3.28 (95%CI: 1.24–8.70), and 11.47 (95%CI: 4.97–26.46) times higher than both pSBP and cSBP < 120 mmHg group, respectively. The joint effect of cSBP and pSBP is superior to either cSBP or pSBP to predict incident hypertension in a Chinese community-based population. Screening of central blood pressure should be considered in non-hypertensive population for the purpose of primary intervention, especially for subjects with pSBP ≥ 120 mmHg.
Isoniazid resistance levels of Mycobacterium tuberculosis can largely be predicted by high-confidence resistance-conferring mutations
Authors: Lempens Pauline , Meehan Conor J. , Vandelannoote Koen , Fissette Kristina , de Rijk Pim , Van Deun Armand , Rigouts Leen , de Jong Bouke C. 
Published: February 2018

AbstractThe majority of Mycobacterium tuberculosis isolates resistant to isoniazid harbour a mutation in katG. Since these mutations cause a wide range of minimum inhibitory concentrations (MICs), largely below the serum level reached with higher dosing (15 mg/L upon 15–20 mg/kg), the drug might still remain partly active in presence of a katG mutation. We therefore investigated which genetic mutations predict the level of phenotypic isoniazid resistance in clinical M. tuberculosis isolates. To this end, the association between known and unknown isoniazid resistance-conferring mutations in whole genome sequences, and the isoniazid MICs of 176 isolates was examined. We found mostly moderate-level resistance characterized by a mode of 6.4 mg/L for the very common katG Ser315Thr mutation, and always very high MICs (≥19.2 mg/L) for the combination of katG Ser315Thr and inhA c-15t. Contrary to common belief, isolates harbouring inhA c-15t alone, partly also showed moderate-level resistance, particularly when combined with inhA Ser94Ala. No overt association between low-confidence or unknown mutations, except in katG, and isoniazid resistance (level) was found. Except for the rare katG deletion, line probe assay is thus not sufficiently accurate to predict the level of isoniazid resistance for a single mutation in katG or inhA.
Simultaneous Strength-Ductility Enhancement of a Nano-Lamellar AlCoCrFeNi2.1 Eutectic High Entropy Alloy by Cryo-Rolling and Annealing
Authors: Bhattacharjee T. , Wani I. S. , Sheikh S. , Clark I. T. , Okawa T. , Guo S. , Bhattacharjee P. P. , Tsuji N. 
Published: February 2018

AbstractNano-lamellar (L12 + B2) AlCoCrFeNi2.1 eutectic high entropy alloy (EHEA) was processed by cryo-rolling and annealing. The EHEA developed a novel hierarchical microstructure featured by fine lamellar regions consisting of FCC lamellae filled with ultrafine FCC grains (average size ~200–250 nm) and B2 lamellae, and coarse non-lamellar regions consisting of ultrafine FCC (average size ~200–250 nm), few coarse recrystallized FCC grains and rather coarse unrecrystallized B2 phase (~2.5 µm). This complex and hierarchical microstructure originated from differences in strain-partitioning amongst the constituent phases, affecting the driving force for recrystallization. The hierarchical microstructure of the cryo-rolled and annealed material resulted in simultaneous enhancement in strength (Yield Strength/YS: 1437 ± 26 MPa, Ultimate Tensile Strength/UTS: 1562 ± 33 MPa) and ductility (elongation to failure/ef ~ 14 ± 1%) as compared to the as-cast as well as cold-rolled and annealed materials. The present study for the first time demonstrated that cryo-deformation and annealing could be a novel microstructural design strategy for overcoming strength-ductility trade off in multiphase high entropy alloys.
Ceramic Microbial Fuel Cells Stack: power generation in standard and supercapacitive mode
Authors: Santoro Carlo , Flores-Cadengo Cristina , Soavi Francesca , Kodali Mounika , Merino-Jimenez Irene , Gajda Iwona , Greenman John , Ieropoulos Ioannis , Atanassov Plamen 
Published: February 2018

AbstractIn this work, a microbial fuel cell (MFC) stack containing 28 ceramic MFCs was tested in both standard and supercapacitive modes. The MFCs consisted of carbon veil anodes wrapped around the ceramic separator and air-breathing cathodes based on activated carbon catalyst pressed on a stainless steel mesh. The anodes and cathodes were connected in parallel. The electrolytes utilized had different solution conductivities ranging from 2.0 mScm−1 to 40.1 mScm−1, simulating diverse wastewaters. Polarization curves of MFCs showed a general enhancement in performance with the increase of the electrolyte solution conductivity. The maximum stationary power density was 3.2 mW (3.2 Wm−3) at 2.0 mScm−1 that increased to 10.6 mW (10.6 Wm−3) at the highest solution conductivity (40.1 mScm−1). For the first time, MFCs stack with 1 L operating volume was also tested in supercapacitive mode, where full galvanostatic discharges are presented. Also in the latter case, performance once again improved with the increase in solution conductivity. Particularly, the increase in solution conductivity decreased dramatically the ohmic resistance and therefore the time for complete discharge was elongated, with a resultant increase in power. Maximum power achieved varied between 7.6 mW (7.6 Wm−3) at 2.0 mScm−1 and 27.4 mW (27.4 Wm−3) at 40.1 mScm−1.
Consequences of SPAK inactivation on Hyperkalemic Hypertension caused by WNK1 mutations: evidence for differential roles of WNK1 and WNK4
Authors: Rafael Chloé , Soukaseum Christelle , Baudrie Véronique , Frère Perrine , Hadchouel Juliette 
Published: February 2018

AbstractMutations of the gene encoding WNK1 [With No lysine (K) kinase 1] or WNK4 cause Familial Hyperkalemic Hypertension (FHHt). Previous studies have shown that the activation of SPAK (Ste20-related Proline/Alanine-rich Kinase) plays a dominant role in the development of FHHt caused by WNK4 mutations. The implication of SPAK in FHHt caused by WNK1 mutation has never been investigated. To clarify this issue, we crossed WNK1+/FHHt mice with SPAK knock-in mice in which the T-loop Thr243 residue was mutated to alanine to prevent activation by WNK kinases. We show that WNK1+/FHHT:SPAK
243A/243A
mice display an intermediate phenotype, between that of control and SPAK
243A/243A
mice, with normal blood pressure but hypochloremic metabolic alkalosis. NCC abundance and phosphorylation levels also decrease below the wild-type level in the double-mutant mice but remain higher than in SPAK
243A/243A
mice. This is different from what was observed in WNK4-FHHt mice in which SPAK inactivation completely restored the phenotype and NCC expression to wild-type levels. Although these results confirm that FHHt caused by WNK1 mutations is dependent on the activation of SPAK, they suggest that WNK1 and WNK4 play different roles in the distal nephron.
Specific Recognition of Arginine Methylated Histone Tails by JMJD5 and JMJD7
Authors: Liu Haolin , Wang Chao , Lee Schuyler , Ning Fangkun , Wang Yang , Zhang Qianqian , Chen Zhongzhou , Zang Jianye , Nix Jay , Dai Shaodong , Marrack Philippa , Hagman James , Kappler John , Zhang Gongyi 
Published: February 2018

AbstractWe have reported that JMJD5 and JMJD7 (JMJD5/7) are responsible for the clipping of arginine methylated histone tails to generate “tailless nucleosomes”, which could release the pausing RNA polymerase II (Pol II) into productive transcription elongation. JMJD5/7 function as endopeptidases that cleave histone tails specifically adjacent to methylated arginine residues and continue to degrade N-terminal residues of histones via their aminopeptidase activity. Here, we report structural and biochemical studies on JMJD5/7 to understand the basis of substrate recognition and catalysis mechanism by this JmjC subfamily. Recognition between these enzymes and histone substrates is specific, which is reflected by the binding data between enzymes and substrates. High structural similarity between JMJD5 and JMJD7 is reflected by the shared common substrates and high binding affinity. However, JMJD5 does not bind to arginine methylated histone tails with additional lysine acetylation while JMJD7 does not bind to arginine methylated histone tails with additional lysine methylation. Furthermore, the complex structures of JMJD5 and arginine derivatives revealed a Tudor domain-like binding pocket to accommodate the methylated sidechain of arginine, but not lysine. There also exists a glutamine close to the catalytic center, which may suggest a unique imidic acid mediated catalytic mechanism for proteolysis by JMJD5/7.
Isolation of uracil auxotroph mutants of coral symbiont alga for symbiosis studies
Authors: Ishii Yuu , Maruyama Shinichiro , Fujimura-Kamada Konomi , Kutsuna Natsumaro , Takahashi Shunichi , Kawata Masakado , Minagawa Jun 
Published: February 2018

AbstractCoral reef ecosystems rely on stable symbiotic relationship between the dinoflagellate Symbiodinium spp. and host cnidarian animals. The collapse of such symbiosis could cause coral ‘bleaching’ and subsequent host death. Despite huge interest on Symbiodinium, lack of mutant strains and readily available genetic tools have hampered molecular research. A major issue was the tolerance to marker antibiotics. Here, we isolated Symbiodinium mutants requiring uracil for growth, and hence, useful in transformation screening. We cultured Symbiodinium spp. cells in the presence of 5-fluoroorotic acid (5FOA), which inhibits the growth of cells expressing URA3 encoding orotidine-5′-monophosphate decarboxylase, and isolated cells that require uracil for growth. Sequence analyses and genetic complementation tests using yeast demonstrated that one of the mutant cell lines had a point mutation in URA3, resulting in a splicing error at an unusual exon–intron junction, and consequently, loss of enzyme activity. This mutant could maintain a symbiotic relationship with the model sea anemone Exaiptasia pallida only in sea water containing uracil. Results show that the URA3 mutant will be a useful tool for screening Symbiodinium transformants, both ex and in hospite, as survival in the absence of uracil is possible only upon successful introduction of URA3.
A dual-mode mobile phone microscope using the onboard camera flash and ambient light
Authors: Orth A. , Wilson E. R. , Thompson J. G. , Gibson B. C. 
Published: February 2018

AbstractMobile phone microscopes are a natural platform for point-of-care imaging, but current solutions require an externally powered illumination source, thereby adding bulk and cost. We present a mobile phone microscope that uses the internal flash or sunlight as the illumination source, thereby reducing complexity whilst maintaining functionality and performance. The microscope is capable of both brightfield and darkfield imaging modes, enabling microscopic visualisation of samples ranging from plant to mammalian cells. We describe the microscope design principles, assembly process, and demonstrate its imaging capabilities through the visualisation of unlabelled cell nuclei to observing the motility of cattle sperm and zooplankton.