bluuebunny/crossref_metadata_2025_split huggingface dataset:
So What Is in an Earth System Model?
Authors: Jones C. D. 
Published: December 2019

AbstractUse of numerical models is at the heart of climate science. Models underpin process understanding; our ability to explain observed past changes and subsequently making predictions/projections of the coming decades to help guide climate policy. Roland Séférian and colleagues (2019, https://doi.org/10.1029/2019MS001791) have written an excellent paper documenting CNRM‐CERFACS's latest complex model, “CNRM‐ESM2‐1,” which will be used for CMIP6 simulations and will produce data to be analyzed by the research community for many years to come. Here I explain the importance of Seferian et al. and why it showcases a new degree of comprehensiveness needed for model documentation activity.
Evidence From High‐Resolution Topography for Multiple Earthquakes on High Slip‐to‐Length Fault Scarps: The Bilila‐Mtakataka Fault, Malawi
Authors: Hodge M. , Biggs J. , Fagereng Å. , Mdala H. , Wedmore L. N. J. , Williams J. N. 
Published: December 2019

AbstractGeomorphological features such as fault scarps and stream knickpoints are indicators of recent fault activity. Determining whether these features formed during a single earthquake or over multiple earthquakes cycles has important implications for the interpretation of the size and frequency of past events. Here, we focus on the Bilila‐Mtakataka fault, Malawi, where the 20 m high fault scarps exceed the height expected from a single earthquake rupture. We use a high‐resolution digital elevation model (1 m) to identify complexity in the fault scarp and knickpoints in river profiles. Of 39 selected scarp profiles, 20 showed evidence of either multiscarps or composite scarps, and of the seven selected river and stream profiles, five showed evidence for multiple knickpoints. A near‐uniform distribution of vertical offsets on the subscarps suggests they were formed by separate earthquakes. These independent methods agree that at least two earthquakes have occurred with an average vertical offset per event of 10 and 12 m. This contrasts earlier studies which proposed that this scarp formed during a single event and demonstrates the importance of high‐resolution topographic data for understanding tectonic geomorphology. We use a one‐dimensional diffusion model of scarp degradation to demonstrate how fault splays form multiscarps and estimate the diffusion ageof the Bilila‐Mtakataka fault scarp to be m, corresponding to years since formation. We calculate that a continuous rupture would equate to a Mearthquake, greater than the largest seismic event previously recorded in East Africa.
Integrated Drought Index (IDI) for Drought Monitoring and Assessment in India
Authors: Shah Deep , Mishra Vimal 
Published: December 2019

AbstractDrought monitoring and declaration in India are challenging due to the requirement of multiple drought indices representing meteorological, hydrological, and agricultural droughts that are often not available in near real‐time. In addition, the current drought monitoring efforts do not consider groundwater storage variability. To overcome this, we develop an Integrated Drought Index (IDI) that combines the response of meteorological, hydrological, and agricultural droughts and accounts for groundwater storage. We use the Gaussian copula to integrate the 12‐month Standardized Precipitation Index (SPI), 4‐month Standardized Runoff Index (SRI), 1‐month Standardized Soil moisture Index (SSI), and 1‐month Standardized Groundwater Index (SGI) to develop IDI. Hydrologic variables (total runoff, soil moisture, and groundwater) required in IDI were simulated using the Variable Infiltration Capacity (VIC) with SIMple Groundwater Model (VIC‐SIMGM). We evaluated IDI against the Drought Severity Index (DSI), terrestrial and groundwater storage anomalies from the Gravity Recovery and Climate Experiment (GRACE) satellites, groundwater well, and streamflow anomalies. Moreover, we identify the three major droughts with the highest severity (based on IDI) that occurred in 1965, 1987, and 2002 in the Sabarmati river basin. The three most severe droughts occurred in 1966, 1979, and 2010 in the Brahmani basin. Notwithstanding the large intermodel uncertainty, which arises primarily from precipitation projections, the drought frequency based on IDI is projected to decline in Sabarmati while it increases in Brahmani basin under the warming climate. Our results show that IDI can be effectively used for drought monitoring and assessment under retrospective and future climate in India.
Optical frequency synthesizer with an integrated erbium tunable laser
Authors: Xin Ming , Li Nanxi , Singh Neetesh , Ruocco Alfonso , Su Zhan , Magden Emir Salih , Notaros Jelena , Vermeulen Diedrik , Ippen Erich P. , Watts Michael R. , Kärtner Franz X. 
Published: December 2019

AbstractOptical frequency synthesizers have widespread applications in optical spectroscopy, frequency metrology, and many other fields. However, their applicability is currently limited by size, cost, and power consumption. Silicon photonics technology, which is compatible with complementary-metal-oxide-semiconductor fabrication processes, provides a low-cost, compact size, lightweight, and low-power-consumption solution. In this work, we demonstrate an optical frequency synthesizer using a fully integrated silicon-based tunable laser. The synthesizer can be self-calibrated by tuning the repetition rate of the internal mode-locked laser. A 20 nm tuning range from 1544 to 1564 nm is achieved with ~10−13 frequency instability at 10 s averaging time. Its flexibility and fast reconfigurability are also demonstrated by fine tuning the synthesizer and generating arbitrary specified patterns over time-frequency coordinates. This work promotes the frequency stability of silicon-based integrated tunable lasers and paves the way toward chip-scale low-cost optical frequency synthesizers.
Therapeutically targeting head and neck squamous cell carcinoma through synergistic inhibition of LSD1 and JMJD3 by TCP and GSK-J1
Authors: Zhang Wei , Cheng Jie , Diao Pengfei , Wang Dongmiao , Zhang Wei , Jiang Hongbing , Wang Yanling 
Published: December 2019

Abstract
Background
The histone demethylase LSD1 is a key mediator driving tumorigenesis, which holds potential as a promising therapeutic target. However, treatment with LSD1 inhibitors alone failed to result in complete cancer regression.

Methods
The synergistic effects of TCP (a LSD1 inhibitor) and GSK-J1 (a JMJD3 inhibitor) against HNSCC were determined in vitro and in preclinical animal models. Genes modulated by chemical agents or siRNAs in HNSCC cells were identified by RNA-seq and further functionally interrogated by bioinformatics approach. Integrative siRNA-mediated gene knockdown, rescue experiment and ChIP-qPCR assays were utilised to characterise the mediators underlying the therapeutic effects conferred by TCP and GSK-J1.

Results
Treatment with TCP and GSK-J1 impaired cell proliferation, induced apoptosis and senescence in vitro, which were largely recapitulated by simultaneous LSD1 and JMJD3 knockdown. Combinational treatment inhibited tumour growth and progression in vivo. Differentially expressed genes modulated by TCP and GSK-J1 were significantly enriched in cell proliferation, apoptosis and cancer-related pathways. SPP1 was identified as the mediator of synergy underlying the pro-apoptosis effects conferred by TCP and GSK-J1. Co-upregulation of LSD1 and JMJD3 associated with worse prognosis in patients with HNSCC.

Conclusions
Our findings revealed a novel therapeutic strategy of simultaneous LSD1 and JMJD3 inhibition against HNSCC.
Plasmacytoid dendritic cell deficiency in neonates enhances allergic airway inflammation via reduced production of IFN-α
Authors: Wu Min , Gao Liuchuang , He Miao , Liu Hangyu , Jiang Han , Shi Ketai , Shang Runshi , Liu Bing , Gao Shan , Chen Hebin , Gong Feili , Gelfand Erwin W. , Huang Yafei , Han Junyan 
Published: December 2019

Abstract
Allergic asthma, a chronic inflammatory airway disease associated with type 2 cytokines, often originates in early life. Immune responses at an early age exhibit a Th2 cell bias, but the precise mechanisms remain elusive. Plasmacytoid dendritic cells (pDCs), which play a regulatory role in allergic asthma, were shown to be deficient in neonatal mice. We report here that this pDC deficiency renders neonatal mice more susceptible to severe allergic airway inflammation than adult mice in an OVA-induced experimental asthma model. Adoptive transfer of pDCs or administration of IFN-α to neonatal mice prevented the development of allergic inflammation in wild type but not in IFNAR1−/− mice. Similarly, adult mice developed more severe allergic inflammation when pDCs were depleted. The protective effects of pDCs were mediated by the pDC-/IFN-α-mediated negative regulation of the secretion of epithelial cell-derived CCL20, GM-CSF, and IL-33, which in turn impaired the recruitment of cDC2 and ILC2 cells to the airway. In asthmatic patients, the percentage of pDCs and the level of IFN-α were lower in children than in adults. These results indicate that impairment of pDC-epithelial cell crosstalk in neonates is a susceptibility factor for the development of allergen-induced allergic airway inflammation.
The valley Nernst effect in WSe2
Authors: Dau Minh Tuan , Vergnaud Céline , Marty Alain , Beigné Cyrille , Gambarelli Serge , Maurel Vincent , Journot Timotée , Hyot Bérangère , Guillet Thomas , Grévin Benjamin , Okuno Hanako , Jamet Matthieu 
Published: December 2019

AbstractThe Hall effect can be extended by inducing a temperature gradient in lieu of electric field that is known as the Nernst (-Ettingshausen) effect. The recently discovered spin Nernst effect in heavy metals continues to enrich the picture of Nernst effect-related phenomena. However, the collection would not be complete without mentioning the valley degree of freedom benchmarked by the valley Hall effect. Here we show the experimental evidence of its missing counterpart, the valley Nernst effect. Using millimeter-sized WSe$${}_{2}$$2 mono-multi-layers and the ferromagnetic resonance-spin pumping technique, we are able to apply a temperature gradient by off-centering the sample in the radio frequency cavity and address a single valley through spin-valley coupling. The combination of a temperature gradient and the valley polarization leads to the valley Nernst effect in WSe$${}_{2}$$2 that we detect electrically at room temperature. The valley Nernst coefficient is in good agreement with the predicted value.
Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer
Authors: O’Connell James , Porter John , Kroeplien Boris , Norman Tim , Rapecki Stephen , Davis Rachel , McMillan David , Arakaki Tracy , Burgin Alex , Fox III David , Ceska Tom , Lecomte Fabien , Maloney Alison , Vugler Alex , Carrington Bruce , Cossins Benjamin P , Bourne Tim , Lawson Alastair 
Published: December 2019

AbstractTumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn’s disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein–protein interactions.
Multi-functional genome-wide CRISPR system for high throughput genotype–phenotype mapping
Authors: Lian Jiazhang , Schultz Carl , Cao Mingfeng , HamediRad Mohammad , Zhao Huimin 
Published: December 2019

AbstractGenome-scale engineering is an indispensable tool to understand genome functions due to our limited knowledge of cellular networks. Unfortunately, most existing methods for genome-wide genotype–phenotype mapping are limited to a single mode of genomic alteration, i.e. overexpression, repression, or deletion. Here we report a multi-functional genome-wide CRISPR (MAGIC) system to precisely control the expression level of defined genes to desired levels throughout the whole genome. By combining the tri-functional CRISPR system and array-synthesized oligo pools, MAGIC is used to create, to the best of our knowledge, one of the most comprehensive and diversified genomic libraries in yeast ever reported. The power of MAGIC is demonstrated by the identification of previously uncharacterized genetic determinants of complex phenotypes, particularly those having synergistic interactions when perturbed to different expression levels. MAGIC represents a powerful synthetic biology tool to investigate fundamental biological questions as well as engineer complex phenotypes for biotechnological applications.
Stress sensitization among severely neglected children and protection by social enrichment
Authors: Wade Mark , Zeanah Charles H. , Fox Nathan A. , Tibu Florin , Ciolan Laura E. , Nelson Charles A. 
Published: December 2019

AbstractChildhood adversity may sensitize certain individuals to later stress which triggers or amplifies psychopathology. The current study uses data from a longitudinal randomized controlled trial to examine whether severe early neglect among children reared in institutions increases vulnerability to the effects of later stressful life events on externalizing problems in adolescence, and whether social enrichment in the form of high-quality foster care buffers this risk. Children abandoned to Romanian institutions were randomly assigned to a foster care intervention or care-as-usual during early childhood. A sample of never-institutionalized children served as a comparison group. Here we report that, among those with prolonged institutional rearing, more stressful life events in preadolescence predicted higher externalizing problems in adolescence. This effect was not observed for never-institutionalized children or those in foster care, thus providing experimental evidence that positive caregiving experiences protect against the stress-sensitizing effects of childhood neglect on externalizing problems in adolescence.
Human muscle-derived CLEC14A-positive cells regenerate muscle independent of PAX7
Authors: Marg Andreas , Escobar Helena , Karaiskos Nikos , Grunwald Stefanie A. , Metzler Eric , Kieshauer Janine , Sauer Sascha , Pasemann Diana , Malfatti Edoardo , Mompoint Dominique , Quijano-Roy Susanna , Boltengagen Anastasiya , Schneider Joanna , Schülke Markus , Kunz Séverine , Carlier Robert , Birchmeier Carmen , Amthor Helge , Spuler Andreas , Kocks Christine , Rajewsky Nikolaus , Spuler Simone 
Published: December 2019

AbstractSkeletal muscle stem cells, called satellite cells and defined by the transcription factor PAX7, are responsible for postnatal muscle growth, homeostasis and regeneration. Attempts to utilize the regenerative potential of muscle stem cells for therapeutic purposes so far failed. We previously established the existence of human PAX7-positive cell colonies with high regenerative potential. We now identified PAX7-negative human muscle-derived cell colonies also positive for the myogenic markers desmin and MYF5. These include cells from a patient with a homozygous PAX7 c.86-1G > A mutation (PAX7null). Single cell and bulk transcriptome analysis show high intra- and inter-donor heterogeneity and reveal the endothelial cell marker CLEC14A to be highly expressed in PAX7null cells. All PAX7-negative cell populations, including PAX7null, form myofibers after transplantation into mice, and regenerate muscle after reinjury. Transplanted PAX7neg cells repopulate the satellite cell niche where they re-express PAX7, or, strikingly, CLEC14A. In conclusion, transplanted human cells do not depend on PAX7 for muscle regeneration.
Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations
Authors: Inoue Satoshi , Hirota Yasushi , Ueno Toshihide , Fukui Yamato , Yoshida Emiko , Hayashi Takuo , Kojima Shinya , Takeyama Reina , Hashimoto Taiki , Kiyono Tohru , Ikemura Masako , Taguchi Ayumi , Tanaka Tomoki , Tanaka Yosuke , Sakata Seiji , Takeuchi Kengo , Muraoka Ayako , Osuka Satoko , Saito Tsuyoshi , Oda Katsutoshi , Osuga Yutaka , Terao Yasuhisa , Kawazu Masahito , Mano Hiroyuki 
Published: December 2019

AbstractUterine adenomyosis is a benign disorder that often co-occurs with endometriosis and/or leiomyoma, and impairs quality of life. The genomic features of adenomyosis are unknown. Here we apply next-generation sequencing to adenomyosis (70 individuals and 192 multi-regional samples), as well as co-occurring leiomyoma and endometriosis, and find recurring KRAS mutations in 26/70 (37.1%) of adenomyosis cases. Multi-regional sequencing reveals oligoclonality in adenomyosis, with some mutations also detected in normal endometrium and/or co-occurring endometriosis. KRAS mutations are more frequent in cases of adenomyosis with co-occurring endometriosis, low progesterone receptor (PR) expression, or progestin (dienogest; DNG) pretreatment. DNG’s anti-proliferative effect is diminished via epigenetic silencing of PR in immortalized cells with mutant KRAS. Our genomic analyses suggest that adenomyotic lesions frequently contain KRAS mutations that may reduce DNG efficacy, and that adenomyosis and endometriosis may share molecular etiology, explaining their co-occurrence. These findings could lead to genetically guided therapy and/or relapse risk assessment after uterine-sparing surgery.
Requirement for p62 acetylation in the aggregation of ubiquitylated proteins under nutrient stress
Authors: You Zhiyuan , Jiang Wen-Xue , Qin Ling-Yun , Gong Zhou , Wan Wei , Li Jin , Wang Yusha , Zhang Hongtao , Peng Chao , Zhou Tianhua , Tang Chun , Liu Wei 
Published: December 2019

AbstractAutophagy receptor p62/SQSTM1 promotes the assembly and removal of ubiquitylated proteins by forming p62 bodies and mediating their encapsulation in autophagosomes. Here we show that under nutrient-deficient conditions, cellular p62 specifically undergoes acetylation, which is required for the formation and subsequent autophagic clearance of p62 bodies. We identify K420 and K435 in the UBA domain as the main acetylation sites, and TIP60 and HDAC6 as the acetyltransferase and deacetylase. Mechanically, acetylation at both K420 and K435 sites enhances p62 binding to ubiquitin by disrupting UBA dimerization, while K435 acetylation also directly increases the UBA-ubiquitin affinity. Furthermore, we show that acetylation of p62 facilitates polyubiquitin chain-induced p62 phase separation. Our results suggest an essential role of p62 acetylation in the selective degradation of ubiquitylated proteins in cells under nutrient stress, by specifically regulating the assembly of p62 bodies.
Machine learning for the detection of early immunological markers as predictors of multi-organ dysfunction
Authors: Bravo-Merodio Laura , Acharjee Animesh , Hazeldine Jon , Bentley Conor , Foster Mark , Gkoutos Georgios V. , Lord Janet M. 
Published: December 2019

AbstractThe immune response to major trauma has been analysed mainly within post-hospital admission settings where the inflammatory response is already underway and the early drivers of clinical outcome cannot be readily determined. Thus, there is a need to better understand the immediate immune response to injury and how this might influence important patient outcomes such as multi-organ dysfunction syndrome (MODS). In this study, we have assessed the immune response to trauma in 61 patients at three different post-injury time points (ultra-early (<=1 h), 4–12 h, 48–72 h) and analysed relationships with the development of MODS. We developed a pipeline using Absolute Shrinkage and Selection Operator and Elastic Net feature selection methods that were able to identify 3 physiological features (decrease in neutrophil CD62L and CD63 expression and monocyte CD63 expression and frequency) as possible biomarkers for MODS development. After univariate and multivariate analysis for each feature alongside a stability analysis, the addition of these 3 markers to standard clinical trauma injury severity scores yields a Generalized Liner Model (GLM) with an average Area Under the Curve value of 0.92 ± 0.06. This performance provides an 8% improvement over the Probability of Survival (PS14) outcome measure and a 13% improvement over the New Injury Severity Score (NISS) for identifying patients at risk of MODS.
Repeated Porphyromonas gingivalis W83 exposure leads to release pro-inflammatory cytokynes and angiotensin II in coronary artery endothelial cells
Authors: Viafara-García Sergio M. , Morantes Sandra Johanna , Chacon-Quintero Yersson , Castillo Diana Marcela , Lafaurie Gloria Inés , Buitrago Diana Marcela 
Published: December 2019

AbstractThe role of Porphyromonas gingivalis (P. gingivalis) or its virulence factors, including lipopolysaccharide (LPS) not only has been related with periodontitis but also with endothelial dysfunction, a key mechanism involved in the genesis of atherosclerosis and hypertension that involving systemic inflammatory markers as angiotensin II (Ang II) and cytokines. This study compares the effect of repeated and unique exposures of P. gingivalis W83 LPS and live bacteria on the production and expression of inflammatory mediators and vasoconstrictor molecules with Ang II. Human coronary artery endothelial cells (HCAEC) were stimulated with purified LPS of P. gingivalis (1.0, 3.5 or 7.0 μg/mL) or serial dilutions of live bacteria (MOI 1: 100 - 1:0,1) at a single or repeated exposure for a time of 24 h. mRNA expression levels of AGTR1, AGTR2, IL-8, IL-1β and MCP-1 were determined by RT-qPCR, and IL-6, MCP-1, IL-8, IL-1β and GM-CSF levels were measured by flow cytometry, ELISA determined Ang II levels. Live bacteria in a single dose increased mRNA levels of AGTR1, and repeated doses increased mRNA levels of IL-8 and IL-1β (p < 0.05). Repeated exposure of live-P. gingivalis induced significant production IL-6, MCP-1 and GM-CSF (p < 0.05). Moreover, these MCP-1, IL-6 and GM-CSF levels were greater than in cells treated with single exposure (p < 0.05), The expression of AGTR1 and production of Ang II induced by live-P. gingivalis W83 showed a vasomotor effect of whole bacteria in HCAEC more than LPS. In conclusion, the findings of this study suggest that repeated exposure of P. gingivalis in HCAEC induces the activation of proinflammatory and vasoconstrictor molecules that lead to endothelial dysfunction being a key mechanism of the onset and progression of arterial hypertension and atherosclerosis.