bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stepwise oxygenation of the Paleozoic atmosphere
Authors: Krause Alexander J. , Mills Benjamin J. W. , Zhang Shuang , Planavsky Noah J. , Lenton Timothy M. , Poulton Simon W. 
Published: September 2018

AbstractOxygen is essential for animal life, and while geochemical proxies have been instrumental in determining the broad evolutionary history of oxygen on Earth, much of our insight into Phanerozoic oxygen comes from biogeochemical modelling. The GEOCARBSULF model utilizes carbon and sulphur isotope records to produce the most detailed history of Phanerozoic atmospheric O2 currently available. However, its predictions for the Paleozoic disagree with geochemical proxies, and with non-isotope modelling. Here we show that GEOCARBSULF oversimplifies the geochemistry of sulphur isotope fractionation, returning unrealistic values for the O2 sourced from pyrite burial when oxygen is low. We rebuild the model from first principles, utilizing an improved numerical scheme, the latest carbon isotope data, and we replace the sulphur cycle equations in line with forwards modelling approaches. Our new model, GEOCARBSULFOR, produces a revised, highly-detailed prediction for Phanerozoic O2 that is consistent with available proxy data, and independently supports a Paleozoic Oxygenation Event, which likely contributed to the observed radiation of complex, diverse fauna at this time.
Loss of pyruvate kinase M2 limits growth and triggers innate immune signaling in endothelial cells
Authors: Stone Oliver A. , El-Brolosy Mohamed , Wilhelm Kerstin , Liu Xiaojing , Romão Ana M. , Grillo Elisabetta , Lai Jason K. H. , Günther Stefan , Jeratsch Sylvia , Kuenne Carsten , Lee I-Ching , Braun Thomas , Santoro Massimo M. , Locasale Jason W. , Potente Michael , Stainier Didier Y. R. 
Published: September 2018

AbstractDespite their inherent proximity to circulating oxygen and nutrients, endothelial cells (ECs) oxidize only a minor fraction of glucose in mitochondria, a metabolic specialization that is poorly understood. Here we show that the glycolytic enzyme pyruvate kinase M2 (PKM2) limits glucose oxidation, and maintains the growth and epigenetic state of ECs. We find that loss of PKM2 alters mitochondrial substrate utilization and impairs EC proliferation and migration in vivo. Mechanistically, we show that the NF-κB transcription factor RELB is responsive to PKM2 loss, limiting EC growth through the regulation of P53. Furthermore, S-adenosylmethionine synthesis is impaired in the absence of PKM2, resulting in DNA hypomethylation, de-repression of endogenous retroviral elements (ERVs) and activation of antiviral innate immune signalling. This work reveals the metabolic and functional consequences of glucose oxidation in the endothelium, highlights the importance of PKM2 for endothelial growth and links metabolic dysfunction with autoimmune activation in ECs.
Prolonged bacterial lag time results in small colony variants that represent a sub-population of persisters
Authors: Vulin Clément , Leimer Nadja , Huemer Markus , Ackermann Martin , Zinkernagel Annelies S. 
Published: September 2018

AbstractPersisters are a subpopulation of bacteria that are not killed by antibiotics even though they lack genetic resistance. Here we provide evidence that persisters can manifest as small colony variants (SCVs) in clinical infections. We analyze growth kinetics of Staphylococcus aureus sampled from in vivo conditions and in vitro stress conditions that mimic growth in host compartments. We report that SCVs arise as a result of a long lag time, and that this phenotype emerges de novo during the growth phase in various stress conditions including abscesses and acidic media. We further observe that long lag time correlates with antibiotic usage. These observations suggest that treatment strategies should be carefully tailored to address bacterial persisters in clinics.
Genome-wide association study identifies two risk loci for tuberculosis in Han Chinese
Authors: Zheng Ruijuan , Li Zhiqiang , He Fusheng , Liu Haipeng , Chen Jianhua , Chen Jiayu , Xie Xuefeng , Zhou Juan , Chen Hao , Wu Xiangyang , Wu Juehui , Chen Boyu , Liu Yahui , Cui Haiyan , Fan Lin , Sha Wei , Liu Yin , Wang Jiqiang , Huang Xiaochen , Zhang Linfeng , Xu Feifan , Wang Jie , Feng Yonghong , Qin Lianhua , Yang Hua , Liu Zhonghua , Cui Zhenglin , Liu Feng , Chen Xinchun , Gao Shaorong , Sun Silong , Shi Yongyong , Ge Baoxue 
Published: September 2018

AbstractTuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), and remains a leading public health problem. Previous studies have identified host genetic factors that contribute to Mtb infection outcomes. However, much of the heritability in TB remains unaccounted for and additional susceptibility loci most likely exist. We perform a multistage genome-wide association study on 2949 pulmonary TB patients and 5090 healthy controls (833 cases and 1220 controls were genome-wide genotyped) from Han Chinese population. We discover two risk loci: 14q24.3 (rs12437118, Pcombined = 1.72 × 10−11, OR = 1.277, ESRRB) and 20p13 (rs6114027, Pcombined = 2.37 × 10−11, OR = 1.339, TGM6). Moreover, we determine that the rs6114027 risk allele is related to decreased TGM6 transcripts in PBMCs from pulmonary TB patients and severer pulmonary TB disease. Furthermore, we find that tgm6-deficient mice are more susceptible to Mtb infection. Our results provide new insights into the genetic etiology of TB.
Repurposing of promoters and enhancers during mammalian evolution
Authors: Carelli Francesco N. , Liechti Angélica , Halbert Jean , Warnefors Maria , Kaessmann Henrik 
Published: September 2018

AbstractPromoters and enhancers—key controllers of gene expression—have long been distinguished from each other based on their function. However, recent work suggested that common architectural and functional features might have facilitated the conversion of one type of element into the other during evolution. Here, based on cross-mammalian analyses of epigenome and transcriptome data, we provide support for this hypothesis by detecting 445 regulatory elements with signatures of activity turnover (termed P/E elements). Most events represent transformations of putative ancestral enhancers into promoters, leading to the emergence of species-specific transcribed loci or 5′ exons. Distinct GC sequence compositions and stabilizing 5′ splicing (U1) regulatory motif patterns may have predisposed P/E elements to regulatory repurposing, and changes in the U1 and polyadenylation signal densities and distributions likely drove the evolutionary activity switches. Our work suggests that regulatory repurposing facilitated regulatory innovation and the origination of new genes and exons during evolution.
Twist angle-dependent conductivities across MoS2/graphene heterojunctions
Authors: Liao Mengzhou , Wu Ze-Wen , Du Luojun , Zhang Tingting , Wei Zheng , Zhu Jianqi , Yu Hua , Tang Jian , Gu Lin , Xing Yanxia , Yang Rong , Shi Dongxia , Yao Yugui , Zhang Guangyu 
Published: September 2018

AbstractVan der Waals heterostructures stacked from different two-dimensional materials offer a unique platform for addressing many fundamental physics and construction of advanced devices. Twist angle between the two individual layers plays a crucial role in tuning the heterostructure properties. Here we report the experimental investigation of the twist angle-dependent conductivities in MoS2/graphene van der Waals heterojunctions. We found that the vertical conductivity of the heterojunction can be tuned by ∼5 times under different twist configurations, and the highest/lowest conductivity occurs at a twist angle of 0°/30°. Density functional theory simulations suggest that this conductivity change originates from the transmission coefficient difference in the heterojunctions with different twist angles. Our work provides a guidance in using the MoS2/graphene heterojunction for electronics, especially on reducing the contact resistance in MoS2 devices as well as other TMDCs devices contacted by graphene.
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls
Authors: Momozawa Yukihide , Iwasaki Yusuke , Parsons Michael T. , Kamatani Yoichiro , Takahashi Atsushi , Tamura Chieko , Katagiri Toyomasa , Yoshida Teruhiko , Nakamura Seigo , Sugano Kokichi , Miki Yoshio , Hirata Makoto , Matsuda Koichi , Spurdle Amanda B. , Kubo Michiaki 
Published: September 2018

AbstractPathogenic variants in highly penetrant genes are useful for the diagnosis, therapy, and surveillance for hereditary breast cancer. Large-scale studies are needed to inform future testing and variant classification processes in Japanese. We performed a case-control association study for variants in coding regions of 11 hereditary breast cancer genes in 7051 unselected breast cancer patients and 11,241 female controls of Japanese ancestry. Here, we identify 244 germline pathogenic variants. Pathogenic variants are found in 5.7% of patients, ranging from 15% in women diagnosed <40 years to 3.2% in patients ≥80 years, with BRCA1/2, explaining two-thirds of pathogenic variants identified at all ages. BRCA1/2, PALB2, and TP53 are significant causative genes. Patients with pathogenic variants in BRCA1/2 or PTEN have significantly younger age at diagnosis. In conclusion, BRCA1/2, PALB2, and TP53 are the major hereditary breast cancer genes, irrespective of age at diagnosis, in Japanese women.
A ballistic graphene superconducting microwave circuit
Authors: Schmidt Felix E. , Jenkins Mark D. , Watanabe Kenji , Taniguchi Takashi , Steele Gary A. 
Published: September 2018

AbstractJosephson junctions (JJ) are a fundamental component of microwave quantum circuits, such as tunable cavities, qubits, and parametric amplifiers. Recently developed encapsulated graphene JJs, with supercurrents extending over micron distance scales, have exciting potential applications as a new building block for quantum circuits. Despite this, the microwave performance of this technology has not been explored. Here, we demonstrate a microwave circuit based on a ballistic graphene JJ embedded in a superconducting cavity. We directly observe a gate-tunable Josephson inductance through the resonance frequency of the device and, using a detailed RF model, we extract this inductance quantitatively. We also observe the microwave losses of the device, and translate this into sub-gap resistances of the junction at μeV energy scales, not accessible in DC measurements. The microwave performance we observe here suggests that graphene Josephson junctions are a feasible platform for implementing coherent quantum circuits.
Improvement and extension of anti-EGFR targeting in breast cancer therapy by integration with the Avidin-Nucleic-Acid-Nano-Assemblies
Authors: Roncato Francesco , Rruga Fatlum , Porcù Elena , Casarin Elisabetta , Ronca Roberto , Maccarinelli Federica , Realdon Nicola , Basso Giuseppe , Alon Ronen , Viola Giampietro , Morpurgo Margherita 
Published: September 2018

AbstractNowadays, personalized cancer therapy relies on small molecules, monoclonal antibodies, or antibody–drug conjugates (ADC). Many nanoparticle (NP)-based drug delivery systems are also actively investigated, but their advantage over ADCs has not been demonstrated yet. Here, using the Avidin-Nucleic-Acid-Nano-Assemblies (ANANAS), a class of polyavidins multifuctionalizable with stoichiometric control, we compare quantitatively anti-EGFR antibody(cetuximab)-targeted NPs to the corresponding ADC. We show that ANANAS tethering of cetuximab promotes a more efficient EGFR-dependent vesicle-mediated internalization. Cetuximab-guided ANANAS carrying doxorubicin are more cytotoxic in vitro and much more potent in vivo than the corresponding ADC, leading to 43% tumor reduction at low drug dosage (0.56 mg/kg). Advantage of cetuximab-guided ANANAS with respect to the ADC goes beyond the increase in drug-to-antibody ratio. Even if further studies are needed, we propose that NP tethering could expand application of the anti-EGFR antibody to a wider number of cancer patients including the KRAS-mutated ones, currently suffering from poor prognosis.
Resolving the mechanisms of hygroscopic growth and cloud condensation nuclei activity for organic particulate matter
Authors: Liu Pengfei , Song Mijung , Zhao Tianning , Gunthe Sachin S. , Ham Suhan , He Yipeng , Qin Yi Ming , Gong Zhaoheng , Amorim Juliana C. , Bertram Allan K. , Martin Scot T. 
Published: September 2018

AbstractHygroscopic growth and cloud condensation nuclei activation are key processes for accurately modeling the climate impacts of organic particulate matter. Nevertheless, the microphysical mechanisms of these processes remain unresolved. Here we report complex thermodynamic behaviors, including humidity-dependent hygroscopicity, diameter-dependent cloud condensation nuclei activity, and liquid–liquid phase separation in the laboratory for biogenically derived secondary organic material representative of similar atmospheric organic particulate matter. These behaviors can be explained by the non-ideal mixing of water with hydrophobic and hydrophilic organic components. The non-ideality-driven liquid–liquid phase separation further enhances water uptake and induces lowered surface tension at high relative humidity, which result in a lower barrier to cloud condensation nuclei activation. By comparison, secondary organic material representing anthropogenic sources does not exhibit complex thermodynamic behavior. The combined results highlight the importance of detailed thermodynamic representations of the hygroscopicity and cloud condensation nuclei activity in models of the Earth’s climate system.
Ultra-low-field magneto-elastocaloric cooling in a multiferroic composite device
Authors: Hou Huilong , Finkel Peter , Staruch Margo , Cui Jun , Takeuchi Ichiro 
Published: September 2018

AbstractThe advent of caloric materials for magnetocaloric, electrocaloric, and elastocaloric cooling is changing the landscape of solid state cooling technologies with potentials for high-efficiency and environmentally friendly residential and commercial cooling and heat-pumping applications. Given that caloric materials are ferroic materials that undergo first (or second) order phase transitions near room temperature, they open up intriguing possibilities for multiferroic devices with hitherto unexplored functionalities coupling their thermal properties with different fields (magnetic, electric, and stress) through composite configurations. Here we demonstrate a magneto-elastocaloric effect with ultra-low magnetic field (0.16 T) in a compact geometry to generate a cooling temperature change as large as 4 K using a magnetostriction/superelastic alloy composite. Such composite systems can be used to circumvent shortcomings of existing technologies such as the need for high-stress actuation mechanism for elastocaloric materials and the high magnetic field requirement of magnetocaloric materials, while enabling new applications such as compact remote cooling devices.
Drivers of within-field spatial and temporal variability of crop yield across the US Midwest
Authors: Maestrini Bernardo , Basso Bruno 
Published: September 2018

AbstractNot all areas of a farmer’s field are equal; some always produce more relative to the rest of the field, others always less, while still other areas fluctuate in their production capacity from one year to the next, depending on the interaction between climate, soil, topography and management. Understanding why the yield in certain portions of a field has a high variability over time—we call these areas unstable—is of paramount importance both from an economic and an environmental point of view, as it is through the better management of these areas that we can improve yields or reduce input costs and environmental impact. In this research, we analyzed data from 338 fields cultivated with maize, soybean, wheat and cotton in the US Midwest to understand how topographic attributes and rain affect yield stability over time. In addition to this high resolution yield monitor dataset, we used publicly available data on topography, rain and soil information to test the hypothesis that within-field areas characterized by a low topographic wetness index (proxy for areas with probability of lower water content) always perform poorly (low and stable yield) compared to the rest of the field because they are drier, and that areas of a field characterized by a mid-high wetness index (high and stable yield) always perform well relative to rest of the field because they have greater water availability to plants. The relative performance of areas of a field with a very high wetness index (e.g. depressions) strongly depends on rain patterns because they may be waterlogged in wet years, yielding less than the rest of the field, or wetter during dry years, yielding more than the rest of the field. We present three different observations from this dataset to support our hypothesis. First, we show that the average topographic wetness index in the different stability zones is lower in low and stable yield areas, high in high and stable yield areas and even higher in unstable yield areas (p < 0.05). Second, we show that in dry years (low precipitation at plant emergence or in July), unstable zones perform relatively better compared to the rest of the field. Third, we show that temporal yield variability is positively correlated (p < 0.05) with the probability of observing gleying processes associated with waterlogging for part of the year. These findings shed light on mechanisms underlying temporal variability of yield and can help guide management solutions to increase profit and improve environmental quality.
Risk of Incident Cardiovascular Disease and Cardiovascular Risk Factors in First and Second-Generation Indians: The Singapore Indian Eye Study
Authors: Gupta Preeti , Gan Alfred Tau Liang , Man Ryan Eyn Kidd , Fenwick Eva K. , Tham Yih-Chung , Sabanayagam Charumathi , Wong Tien Yin , Cheng Ching-Yu , Lamoureux Ecosse L. 
Published: September 2018

AbstractPopulation-based data investigating generational differences in the risk of incident cardiovascular disease (CVD) and its risk determinants are rare. We examined the 6-year incidence of CVD and its risk factors in first- and second-generation ethnic Indians living in Singapore. 1749 participants (mean age [SD]: 55.5 [8.8] years; 47.5% male) from a population-based, longitudinal study of Indian adults were included for incident CVD outcome. Incident CVD was defined as self-reported myocardial infarction, angina pectoris or stroke which developed between baseline and follow-up. CVD-related risk factors included incident diabetes, hypertension, hyperlipidemia, obesity and chronic kidney disease (CKD). For incident CVD outcome, of the 1749 participants, 406 (23.2%) and 1343 (76.8%) were first and second-generation Indians, respectively. Of these, 73 (4.1%) reported incident CVD. In multivariable models, second-generation individuals had increased risk of developing CVD (RR = 2.04; 95% CI 1.04, 3.99; p = 0.038), hyperlipidemia (RR = 1.27; 95% CI 1.06, 1.53; p = 0.011), and CKD (RR = 1.92; 95% CI 1.22, 3.04; p = 0.005), compared to first-generation Indians. Second-generation Indians have increased risk of developing CVD and its associated risk factors such as hyperlipidemia and CKD compared to first-generation immigrants, independent of traditional CVD risk factors. More stratified and tailored CVD prevention strategies on second and subsequent generations of Indian immigrants in Singapore are warranted.
Analysis of the mechanisms regulating the expression of isoprenoid biosynthesis genes in hydroponically-grown Nicotiana benthamiana plants using virus-induced gene silencing
Authors: Atsumi Go , Kagaya Uiko , Tabayashi Noriko , Matsumura Takeshi 
Published: September 2018

AbstractSecondary metabolites in plants play important roles in defence against biotic and abiotic stresses. Although the biosynthesis pathways of secondary metabolites have been extensively studied, the regulatory mechanism of gene expression involved in these pathways remains poorly understood. In this study, we develop a virus-induced gene silencing (VIGS) system that enables a rapid analysis of the regulatory mechanism of genes involved in the biosynthesis of isoprenoids, one of the largest groups in secondary metabolites, using hydroponically-grown Nicotiana benthamiana. Using VIGS, we successfully reduced the transcript levels of 3-hydroxy-3-methylglutaryl-CoA reductase 1 (HMGR1), cycloartenol synthase 1 (CAS1), sterol side chain reductase 2 (SSR2) and S-adenosyl-L-Met-dependent C-24 sterol methyltransferase 1 (SMT1) in leaf, stem and root tissues in approximately 2 weeks. We identified novel feedback and feed-forward regulation of isoprenoid biosynthesis genes when CAS1, which encodes a key enzyme involved in the biosynthesis of sterols and steroidal glycoalkaloids, was down-regulated. Furthermore, the regulation of these genes differed among different tissues. These results demonstrate that our system can rapidly analyse the regulatory mechanisms involved in the biosynthesis of secondary metabolites.
Experimental Observation of the High Pressure Induced Substitutional Solid Solution and Phase Transformation in Sb2S3
Authors: Wang Yingying , Ma Yanmei , Liu Guangtao , Wang Jianyun , Li Yue , Li Quan , Zhang Jian , Ma Yanming , Zou Guangtian 
Published: September 2018

AbstractThe substitutional solid solutions composed of group VA-VIA nonmetallic elements has attracted considerable scientific interest since they provide a pressure-induced route to search for novel types of solid solutions with potential applications. Yet, the pressure-induced solid solution phase is unprecedented in the sulfide family. In this paper, the structural behavior of antimony trisulfide, Sb2S3, has been investigated in order to testify whether or not it can also be driven into the substitutional solid solution phase by high pressures. The experiments were carried out by using a diamond anvil cell and angle dispersive synchrotron X-ray diffraction up to 50.2 GPa at room temperature. The experimental results indicate that Sb2S3 undergoes a series of phase transitions at 5.0, 12.6, 16.9, 21.3, and 28.2 GPa, and develops ultimately into an Sb-S substitutional solid solution, which adopts a body-centered cubic disordered structure. In this structure, the Sb and S atoms are distributed randomly on the bcc lattice sites with space group Im-3m. The structural behavior of Sb2S3 is tentatively assigned by comparison within the A2B3 (A = Sb, Bi; B = Se, Te, S) series under high pressures.
Structural Analysis of Inhibitor Binding to CAMKK1 Identifies Features Necessary for Design of Specific Inhibitors
Authors: Santiago André da Silva , Couñago Rafael M. , Ramos Priscila Zonzini , Godoi Paulo H. C. , Massirer Katlin B. , Gileadi Opher , Elkins Jonathan M. 
Published: September 2018

AbstractThe calcium/calmodulin-dependent protein kinases (CAMKKs) are upstream activators of CAMK1 and CAMK4 signalling and have important functions in neural development, maintenance and signalling, as well as in other aspects of biology such as Ca2+ signalling in the cardiovascular system. To support the development of specific inhibitors of CAMKKs we have determined the crystal structure of CAMKK1 with two ATP-competitive inhibitors. The structures reveal small but exploitable differences between CAMKK1 and CAMKK2, despite the high sequence identity, which could be used in the generation of specific inhibitors. Screening of a kinase inhibitor library revealed molecules that bind potently to CAMKK1. Isothermal titration calorimetry revealed that the most potent inhibitors had binding energies largely dependent on favourable enthalpy. Together, the data provide a foundation for future inhibitor development activities.