bluuebunny/crossref_metadata_2025 huggingface dataset:
A Novel Hybrid Finite Element‐Spectral Boundary Integral Scheme for Modeling Earthquake Cycles: Application to Rate and State Faults With Low‐Velocity Zones
Authors: Abdelmeguid Mohamed , Ma Xiao , Elbanna Ahmed
Published: October 2019

We present a novel hybrid finite element‐spectral boundary integral (SBI) scheme that enables efficient simulation of earthquake cycles. This combined finite element‐SBI approach captures the benefits of finite elements in modeling problems with nonlinearities, as well as the computational superiority of SBI. The domain truncation enabled by this scheme allows us to utilize high‐resolution finite elements discretization to capture inhomogeneities or complexities that may exist in a narrow region surrounding the fault. Combined with an adaptive time stepping algorithm, this framework opens new opportunities for modeling earthquake cycles with high‐resolution fault zone physics. In this initial study, we consider a two‐dimensional antiplane model with a vertical strike‐slip fault governed by rate and state friction in the quasi‐dynamic limit under the radiation damping approximation. The proposed approach is first verified using the benchmark problem BP‐1 from the Southern California Earthquake Center sequence of earthquake and aseismic slip community verification effort. The computational framework is then utilized to model the earthquake sequence and aseismic slip of a fault embedded within a low‐velocity fault zone (LVFZ) with different widths and compliance levels. Our results indicate that sufficiently compliant LVFZs contribute to the emergence of subsurface events that fail to penetrate to the free surface and may experience earthquake clusters with nonuniform interseismic time. Furthermore, the LVFZ leads to slip rate amplification relative to the homogeneous elastic case. We discuss the implications of our results for understanding earthquake complexity as an interplay of fault friction and bulk heterogeneities.
Modeling Sediment Flocculation in Langmuir Turbulence
Authors: Liu Jinliang , Liang Jun‐Hong , Xu Kehui , Chen Qin , Ozdemir Celalettin Emre
Published: October 2019

Cohesive sediments exist as flocs of different sizes, which are built and destroyed through flocculation processes including both aggregation and breakup. This study investigates sediment flocculation processes in wave‐driven Langmuir turbulence that is commonly observed in coastal ocean through embedding a size‐resolving flocculation model into a turbulence‐resolving hydrodynamic model. The specific research questions are how Langmuir turbulence affects flocculation processes and how flocculation processes impact the spatial and size distributions of suspended cohesive sediment. The results show that Langmuir turbulence suspends flocs in the water column and organizes flocs of different sizes. By modulating the encounter of flocs and redistributing flocs in the turbulence field, Langmuir turbulence enhances the aggregation and breakup rates of flocs that are located in similar regions with high turbulent dissipation rates and suppresses those of others. As an outcome of modulated flocculation processes, floc size distribution changes with depth and floc mass concentration profiles change with floc size. The addition of wave breaking increases the shear rate near the surface and reduces the median floc size and averaged settling velocity, leading to increase in total floc mass concentration in the whole water column. Wave breaking also increases cross‐shelf sediment transport by more than 15% under the simulated conditions, which is comparable to that due to Langmuir turbulence compared to shear turbulence. Both floc size distribution and floc concentration vary with wind and wave conditions.
Ural Blocking Driving Extreme Arctic Sea Ice Loss, Cold Eurasia, and Stratospheric Vortex Weakening in Autumn and Early Winter 2016–2017
Authors: Tyrlis Evangelos , Manzini Elisa , Bader Jürgen , Ukita Jinro , Nakamura Hisashi , Matei Daniela
Published: October 2019

This study investigates the dynamics that led to the repeated cold surges over midlatitude Eurasia, exceptionally warm conditions and sea ice loss over the Arctic, and the unseasonable weakening of the stratospheric polar vortex in autumn and early winter 2016–2017. We use ERA‐Interim reanalysis data and COBE sea ice and sea surface temperature observational data to trace the dynamical pathways that caused these extreme phenomena. Following abnormally low sea ice conditions in early autumn over the Pacific sector of the Arctic basin, blocking anticyclones became dominant over Eurasia throughout autumn. Ural blocking (UB) activity was four times above climatological levels and organized in several successive events. UB episodes played a key role in the unprecedented sea ice loss observed in late autumn 2016 over the Barents‐Kara Seas and the weakening of the stratospheric vortex. Each blocking induced circulation anomalies that resulted in cold air advection to its south and warm advection to its north. The near‐surface warming anomalies over the Arctic and cooling anomalies over midlatitude Eurasia varied in phase with the life cycles of UB episodes. The sea ice cover minimum over the Barents‐Kara Seas in 2016 was not observed in late summer but rather in mid‐November and December shortly after the two strongest UB episodes. Each UB episode drove intense upward flux of wave activity that resulted in unseasonable weakening of the stratospheric vortex in November. The surface impact of this weakening can be linked to the migration of blocking activity and cold spells toward Europe in early winter 2017.
Wetter Global Arid Regions Driven by Volcanic Eruptions
Authors: Zuo Meng , Zhou Tianjun , Man Wenmin
Published: October 2019

Arid regions are among the most sensitive areas to climate change; a better understanding of the impact of volcanic eruptions on the hydroclimate over global arid regions is helpful for adaptation but is not well studied. Here we show evidences that arid regions exhibit a wetter condition after volcanic eruptions based on reconstructions and observations, especially for volcanoes located in the Northern hemisphere and tropics. Such “dry gets wetter” response is further supported by climate model simulations driven by volcanic aerosol forcing. The dynamic processes related to changes in atmospheric circulation are found to play a dominant role in precipitation responses. The wetter condition over northern hemispheric (southern hemispheric) (NH (SH)) arid regions after southern (northern) hemispheric volcanic eruptions is caused by enhanced cross‐equator flow, while the increased precipitation over global arid regions and NH (SH) arid regions following tropical volcanic eruptions and northern (southern) eruptions, respectively, are mainly controlled by the monsoon‐desert coupling mechanism. The response of the extreme precipitation is consistent with that of the mean precipitation but more sensitive on a regional scale. The results indicate that volcanic eruptions at different latitudes should be considered in the design of near‐term decadal climate prediction experiments and the implementation of geoengineering activities.
UKESM1: Description and Evaluation of the U.K. Earth System Model
Authors: Sellar Alistair A. , Jones Colin G. , Mulcahy Jane P. , Tang Yongming , Yool Andrew , Wiltshire Andy , O'Connor Fiona M. , Stringer Marc , Hill Richard , Palmieri Julien , Woodward Stephanie , de Mora Lee , Kuhlbrodt Till , Rumbold Steven T. , Kelley Douglas I. , Ellis Rich , Johnson Colin E. , Walton Jeremy , Abraham Nathan Luke , Andrews Martin B. , Andrews Timothy , Archibald Alex T. , Berthou Ségolène , Burke Eleanor , Blockley Ed , Carslaw Ken , Dalvi Mohit , Edwards John , Folberth Gerd A. , Gedney Nicola , Griffiths Paul T. , Harper Anna B. , Hendry Maggie A. , Hewitt Alan J. , Johnson Ben , Jones Andy , Jones Chris D. , Keeble James , Liddicoat Spencer , Morgenstern Olaf , Parker Robert J. , Predoi Valeriu , Robertson Eddy , Siahaan Antony , Smith Robin S. , Swaminathan Ranjini , Woodhouse Matthew T. , Zeng Guang , Zerroukat Mohamed
Published: October 2019

We document the development of the first version of the U.K. Earth System Model UKESM1. The model represents a major advance on its predecessor HadGEM2‐ES, with enhancements to all component models and new feedback mechanisms. These include a new core physical model with a well‐resolved stratosphere; terrestrial biogeochemistry with coupled carbon and nitrogen cycles and enhanced land management; tropospheric‐stratospheric chemistry allowing the holistic simulation of radiative forcing from ozone, methane, and nitrous oxide; two‐moment, five‐species, modal aerosol; and ocean biogeochemistry with two‐way coupling to the carbon cycle and atmospheric aerosols. The complexity of coupling between the ocean, land, and atmosphere physical climate and biogeochemical cycles in UKESM1 is unprecedented for an Earth system model. We describe in detail the process by which the coupled model was developed and tuned to achieve acceptable performance in key physical and Earth system quantities and discuss the challenges involved in mitigating biases in a model with complex connections between its components. Overall, the model performs well, with a stable pre‐industrial state and good agreement with observations in the latter period of its historical simulations. However, global mean surface temperature exhibits stronger‐than‐observed cooling from 1950 to 1970, followed by rapid warming from 1980 to 2014. Metrics from idealized simulations show a high climate sensitivity relative to previous generations of models: Equilibrium climate sensitivity is 5.4 K, transient climate response ranges from 2.68 to 2.85 K, and transient climate response to cumulative emissions is 2.49 to 2.66 K TtC−1.
Characterizing Evaporation Ducts Within the Marine Atmospheric Boundary Layer Using Artificial Neural Networks
Authors: Sit Hilarie , Earls Christopher J.
Published: October 2019

We apply a multilayer perceptron machine learning (ML) regression approach to infer electromagnetic (EM) duct heights within the marine atmospheric boundary layer (MABL) using sparsely sampled EM propagation data obtained within a bistatic context. This paper explains the rationale behind the selection of the ML network architecture, along with other model hyperparameters, in an effort to demystify the process of arriving at a useful ML model. The resulting speed of our ML predictions of EM duct heights, using sparse data measurements within MABL, indicates the suitability of the proposed method for real‐time applications.
Patient-derived organoids as a potential model to predict response to PD-1/PD-L1 checkpoint inhibitors
Authors: Scognamiglio Giosue , De Chiara Annarosaria , Parafioriti Antonina , Armiraglio Elisabetta , Fazioli Flavio , Gallo Michele , Aversa Laura , Camerlingo Rosa , Cacciatore Francesco , Colella Gianluca , Pili Roberto , de Nigris Filomena
Published: October 2019

Selection of cancer patients for treatment with immune checkpoint inhibitors remains a challenge due to tumour heterogeneity and variable biomarker detection. PD-L1 expression in 24 surgical chordoma specimen was determined immunohistochemically with antibodies 28-8 and E1L3N. The ability of patient-derived organoids to detect treatment effects of nivolumab was explored by quantitative and qualitative immunofluorescence and FACS analysis. The more sensitive antibody, E1L3N (ROC = 0.896, p = 0.001), was associated with greater tumour diameters (p = 0.014) and detected both tumour cells and infiltrating lymphocytes in 54% of patients, but only 1–15% of their cells. Organoids generated from PD-L1-positive patients contained both tumour cells and PD-1/CD8-positive lymphocytes and responded to nivolumab treatment with marked dose-dependent diameter reductions of up to 50% and increased cell death in both PD-L1-positive and negative organoids. Patient-derived organoids may be valuable to predict individual responses to immunotherapy even in patients with low or no immunohistochemical PD-L1 expression.
Single cell analysis to dissect molecular heterogeneity and disease evolution in metastatic melanoma
Authors: Fattore Luigi , Ruggiero Ciro Francesco , Liguoro Domenico , Mancini Rita , Ciliberto Gennaro
Published: October 2019

Originally described as interpatient variability, tumour heterogeneity has now been demonstrated to occur intrapatiently, within the same lesion, or in different lesions of the same patient. Tumour heterogeneity involves both genetic and epigenetic changes. Intrapatient heterogeneity is responsible for generating subpopulations of cancer cells which undergo clonal evolution with time. Tumour heterogeneity develops also as a consequence of the selective pressure imposed by the immune system. It has been demonstrated that tumour heterogeneity and different spatiotemporal interactions between all the cellular compontents within the tumour microenvironment lead to cancer adaptation and to therapeutic pressure. In this context, the recent advent of single cell analysis approaches which are able to better study tumour heterogeneity from the genomic, transcriptomic and proteomic standpoint represent a major technological breakthrough. In this review, using metastatic melanoma as a prototypical example, we will focus on applying single cell analyses to the study of clonal trajectories which guide the evolution of drug resistance to targeted therapy.
CXCR7 regulates epileptic seizures by controlling the synaptic activity of hippocampal granule cells
Authors: Xu Tao , Yu Xinyuan , Deng Jing , Ou Shu , Liu Xi , Wang Teng , Liu Ying , Yang Juan , Tan Changhong , Yuan Jinxian , Chen Yangmei
Published: October 2019

C–X–C motif chemokine receptor 7 (CXCR7), which mediates the immune response in the brain, was recently reported to regulate neurological functions. However, the role of CXCR7 in epilepsy remains unclear. Here, we found that CXCR7 was upregulated in the hippocampal dentate gyrus (DG) of mice subjected to kainic acid (KA)-induced epilepsy and in the brain tissues of patients with temporal lobe epilepsy. Silencing CXCR7 in the hippocampal DG region exerted an antiepileptic effect on the KA-induced mouse model of epilepsy, whereas CXCR7 overexpression produced a seizure-aggravating effect. Mechanistically, CXCR7 selectively regulated N-methyl-d-aspartate receptor (NMDAR)-mediated synaptic neurotransmission in hippocampal dentate granule cells by modulating the cell membrane expression of the NMDAR subunit2A, which requires the activation of extracellular signal-regulated kinase 1/2 (ERK1/2). Thus, CXCR7 may regulate epileptic seizures and represents a novel target for antiepileptic treatments.
Correction: MAG induces apoptosis in cerebellar granule neurons through p75NTR demarcating granule layer/white matter boundary
Authors: Fernández-Suárez Diana , Krapacher Favio A. , Andersson Annika , Ibáñez Carlos F. , Kisiswa Lilian
Published: October 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Symmetry group factorization reveals the structure-function relation in the neural connectome of Caenorhabditis elegans
Authors: Morone Flaviano , Makse Hernán A.
Published: October 2019

The neural connectome of the nematode Caenorhabditis elegans has been completely mapped, yet in spite of being one of the smallest connectomes (302 neurons), the design principles that explain how the connectome structure determines its function remain unknown. Here, we find symmetries in the locomotion neural circuit of C. elegans, each characterized by its own symmetry group which can be factorized into the direct product of normal subgroups. The action of these normal subgroups partitions the connectome into sectors of neurons that match broad functional categories. Furthermore, symmetry principles predict the existence of novel finer structures inside these normal subgroups forming feedforward and recurrent networks made of blocks of imprimitivity. These blocks constitute structures made of circulant matrices nested in a hierarchy of block-circulant matrices, whose functionality is understood in terms of neural processing filters responsible for fast processing of information.
Dynamic modulation of modal coupling in microelectromechanical gyroscopic ring resonators
Authors: Zhou Xin , Zhao Chun , Xiao Dingbang , Sun Jiangkun , Sobreviela Guillermo , Gerrard Dustin D. , Chen Yunhan , Flader Ian , Kenny Thomas W. , Wu Xuezhong , Seshia Ashwin A.
Published: October 2019

Understanding and controlling modal coupling in micro/nanomechanical devices is integral to the design of high-accuracy timing references and inertial sensors. However, insight into specific physical mechanisms underlying modal coupling, and the ability to tune such interactions is limited. Here, we demonstrate that tuneable mode coupling can be achieved in capacitive microelectromechanical devices with dynamic electrostatic fields enabling strong coupling between otherwise uncoupled modes. A vacuum-sealed microelectromechanical silicon ring resonator is employed in this work, with relevance to the gyroscopic lateral modes of vibration. It is shown that a parametric pumping scheme can be implemented through capacitive electrodes surrounding the device that allows for the mode coupling strength to be dynamically tuned, as well as allowing greater flexibility in the control of the coupling stiffness. Electrostatic pump based sideband coupling is demonstrated, and compared to conventional strain-mediated sideband operations. Electrostatic coupling is shown to be very efficient, enabling strong, tunable dynamical coupling.
Split selectable markers
Authors: Jillette Nathaniel , Du Menghan , Zhu Jacqueline Jufen , Cardoz Peter , Cheng Albert Wu
Published: October 2019

Selectable markers are widely used in transgenesis and genome editing for selecting engineered cells with a desired genotype but the variety of markers is limited. Here we present split selectable markers that each allow for selection of multiple “unlinked” transgenes in the context of lentivirus-mediated transgenesis as well as CRISPR-Cas-mediated knock-ins. Split marker gene segments fused to protein splicing elements called “inteins” can be separately co-segregated with different transgenic vectors, and rejoin via protein trans-splicing to reconstitute a full-length marker protein in host cells receiving all intended vectors. Using a lentiviral system, we create and validate 2-split Hygromycin, Puromycin, Neomycin and Blasticidin resistance genes as well as mScarlet fluorescent proteins. By combining split points, we create 3- and 6-split Hygromycin resistance genes, demonstrating that higher-degree split markers can be generated by a “chaining” design. We adapt the split marker system for selecting biallelically engineered cells after CRISPR gene editing. Future engineering of split markers may allow selection of a higher number of genetic modifications in target cells.
Theabrownin from Pu-erh tea attenuates hypercholesterolemia via modulation of gut microbiota and bile acid metabolism
Authors: Huang Fengjie , Zheng Xiaojiao , Ma Xiaohui , Jiang Runqiu , Zhou Wangyi , Zhou Shuiping , Zhang Yunjing , Lei Sha , Wang Shouli , Kuang Junliang , Han Xiaolong , Wei Meilin , You Yijun , Li Mengci , Li Yitao , Liang Dandan , Liu Jiajian , Chen Tianlu , Yan Chao , Wei Runmin , Rajani Cynthia , Shen Chengxing , Xie Guoxiang , Bian Zhaoxiang , Li Houkai , Zhao Aihua , Jia Wei
Published: October 2019

Pu-erh tea displays cholesterol-lowering properties, but the underlying mechanism has not been elucidated. Theabrownin is one of the most active and abundant pigments in Pu-erh tea. Here, we show that theabrownin alters the gut microbiota in mice and humans, predominantly suppressing microbes associated with bile-salt hydrolase (BSH) activity. Theabrownin increases the levels of ileal conjugated bile acids (BAs) which, in turn, inhibit the intestinal FXR-FGF15 signaling pathway, resulting in increased hepatic production and fecal excretion of BAs, reduced hepatic cholesterol, and decreased lipogenesis. The inhibition of intestinal FXR-FGF15 signaling is accompanied by increased gene expression of enzymes in the alternative BA synthetic pathway, production of hepatic chenodeoxycholic acid, activation of hepatic FXR, and hepatic lipolysis. Our results shed light into the mechanisms behind the cholesterol- and lipid-lowering effects of Pu-erh tea, and suggest that decreased intestinal BSH microbes and/or decreased FXR-FGF15 signaling may be potential anti-hypercholesterolemia and anti-hyperlipidemia therapies.
Split intein-mediated selection of cells containing two plasmids using a single antibiotic
Authors: Palanisamy Navaneethan , Degen Anna , Morath Anna , Ballestin Ballestin Jara , Juraske Claudia , Öztürk Mehmet Ali , Sprenger Georg A. , Youn Jung-Won , Schamel Wolfgang W. , Di Ventura Barbara
Published: October 2019

To build or dissect complex pathways in bacteria and mammalian cells, it is often necessary to recur to at least two plasmids, for instance harboring orthogonal inducible promoters. Here we present SiMPl, a method based on rationally designed split enzymes and intein-mediated protein trans-splicing, allowing the selection of cells carrying two plasmids with a single antibiotic. We show that, compared to the traditional method based on two antibiotics, SiMPl increases the production of the antimicrobial non-ribosomal peptide indigoidine and the non-proteinogenic aromatic amino acid para-amino-L-phenylalanine from bacteria. Using a human T cell line, we employ SiMPl to obtain a highly pure population of cells double positive for the two chains of the T cell receptor, TCRα and TCRβ, using a single antibiotic. SiMPl has profound implications for metabolic engineering and for constructing complex synthetic circuits in bacteria and mammalian cells.
Procr-expressing progenitor cells are responsible for murine ovulatory rupture repair of ovarian surface epithelium
Authors: Wang Jingqiang , Wang Daisong , Chu Kun , Li Wen , Zeng Yi Arial
Published: October 2019

Ovarian surface epithelium (OSE) undergoes recurring ovulatory rupture and repair. The OSE replenishing mechanism post ovulation remains unclear. Here we report that the expression of Protein C Receptor (Procr) marks a progenitor population in adult mice that is responsible for OSE repair post ovulation. Procr+  cells are the major cell source for OSE repair. The mechanism facilitating the rapid re-epithelialization is through the immediate expansion of Procr+  cells upon OSE rupture. Targeted ablation of Procr+  cells impedes the repairing process. Moreover, Procr+  cells displayed robust colony-formation capacity in culture, which we harnessed and established a long-term culture and expansion system of OSE cells. Finally, we show that Procr+  cells and previously reported Lgr5+ cells have distinct lineage tracing behavior in OSE homeostasis. Our study suggests that Procr marks progenitor cells that are critical for OSE ovulatory rupture and homeostasis, providing insight into how adult stem cells respond upon injury.
Soil net nitrogen mineralisation across global grasslands
Authors: Risch A. C. , Zimmermann S. , Ochoa-Hueso R. , Schütz M. , Frey B. , Firn J. L. , Fay P. A. , Hagedorn F. , Borer E. T. , Seabloom E. W. , Harpole W. S. , Knops J. M. H. , McCulley R. L. , Broadbent A. A. D. , Stevens C. J. , Silveira M. L. , Adler P. B. , Báez S. , Biederman L. A. , Blair J. M. , Brown C. S. , Caldeira M. C. , Collins S. L. , Daleo P. , di Virgilio A. , Ebeling A. , Eisenhauer N. , Esch E. , Eskelinen A. , Hagenah N. , Hautier Y. , Kirkman K. P. , MacDougall A. S. , Moore J. L. , Power S. A. , Prober S. M. , Roscher C. , Sankaran M. , Siebert J. , Speziale K. L. , Tognetti P. M. , Virtanen R. , Yahdjian L. , Moser B.
Published: October 2019

Soil nitrogen mineralisation (Nmin), the conversion of organic into inorganic N, is important for productivity and nutrient cycling. The balance between mineralisation and immobilisation (net Nmin) varies with soil properties and climate. However, because most global-scale assessments of net Nminare laboratory-based, its regulation under field-conditions and implications for real-world soil functioning remain uncertain. Here, we explore the drivers of realised (field) and potential (laboratory) soil net Nminacross 30 grasslands worldwide. We find that realised Nminis largely explained by temperature of the wettest quarter, microbial biomass, clay content and bulk density. Potential Nminonly weakly correlates with realised Nmin, but contributes to explain realised net Nminwhen combined with soil and climatic variables. We provide novel insights of global realised soil net Nminand show that potential soil net Nmindata available in the literature could be parameterised with soil and climate data to better predict realised Nmin.
Plasticity of the Mycobacterium tuberculosis respiratory chain and its impact on tuberculosis drug development
Authors: Beites Tiago , O’Brien Kathryn , Tiwari Divya , Engelhart Curtis A. , Walters Shaun , Andrews Jenna , Yang Hee-Jeong , Sutphen Michelle L. , Weiner Danielle M. , Dayao Emmanuel K. , Zimmerman Matthew , Prideaux Brendan , Desai Prashant V. , Masquelin Thierry , Via Laura E. , Dartois Véronique , Boshoff Helena I. , Barry Clifton E. , Ehrt Sabine , Schnappinger Dirk
Published: October 2019

The viability of Mycobacterium tuberculosis (Mtb) depends on energy generated by its respiratory chain. Cytochrome bc1-aa3 oxidase and type-2 NADH dehydrogenase (NDH-2) are respiratory chain components predicted to be essential, and are currently targeted for drug development. Here we demonstrate that an Mtb cytochrome bc1-aa3 oxidase deletion mutant is viable and only partially attenuated in mice. Moreover, treatment of Mtb-infected marmosets with a cytochrome bc1-aa3 oxidase inhibitor controls disease progression and reduces lesion-associated inflammation, but most lesions become cavitary. Deletion of both NDH-2 encoding genes (Δndh-2 mutant) reveals that the essentiality of NDH-2 as shown in standard growth media is due to the presence of fatty acids. The Δndh-2 mutant is only mildly attenuated in mice and not differently susceptible to clofazimine, a drug in clinical use proposed to engage NDH-2. These results demonstrate the intrinsic plasticity of Mtb’s respiratory chain, and highlight the challenges associated with targeting the pathogen’s respiratory enzymes for tuberculosis drug development.
Rewiring carbon metabolism in yeast for high level production of aromatic chemicals
Authors: Liu Quanli , Yu Tao , Li Xiaowei , Chen Yu , Campbell Kate , Nielsen Jens , Chen Yun
Published: October 2019

The production of bioactive plant compounds using microbial hosts is considered a safe, cost-competitive and scalable approach to their production. However, microbial production of some compounds like aromatic amino acid (AAA)-derived chemicals, remains an outstanding metabolic engineering challenge. Here we present the construction of aSaccharomyces cerevisiaeplatform strain able to produce high levels ofp-coumaric acid, an AAA-derived precursor for many commercially valuable chemicals. This is achieved through engineering the AAA biosynthesis pathway, introducing a phosphoketalose-based pathway to divert glycolytic flux towards erythrose 4-phosphate formation, and optimizing carbon distribution between glycolysis and the AAA biosynthesis pathway by replacing the promoters of several important genes at key nodes between these two pathways. This results in a maximump-coumaric acid titer of 12.5 g L−1and a maximum yield on glucose of 154.9 mg g−1.
Using slow frame rate imaging to extract fast receptive fields
Authors: Mano Omer , Creamer Matthew S. , Matulis Catherine A. , Salazar-Gatzimas Emilio , Chen Juyue , Zavatone-Veth Jacob A. , Clark Damon A.
Published: October 2019

In functional imaging, large numbers of neurons are measured during sensory stimulation or behavior. This data can be used to map receptive fields that describe neural associations with stimuli or with behavior. The temporal resolution of these receptive fields has traditionally been limited by image acquisition rates. However, even when acquisitions scan slowly across a population of neurons, individual neurons may be measured at precisely known times. Here, we apply a method that leverages the timing of neural measurements to find receptive fields with temporal resolutions higher than the image acquisition rate. We use this temporal super-resolution method to resolve fast voltage and glutamate responses in visual neurons in Drosophila and to extract calcium receptive fields from cortical neurons in mammals. We provide code to easily apply this method to existing datasets. This method requires no specialized hardware and can be used with any optical indicator of neural activity.
Clinically relevant molecular subtypes and genomic alteration-independent differentiation in gynecologic carcinosarcoma
Authors: Gotoh Osamu , Sugiyama Yuko , Takazawa Yutaka , Kato Kazuyoshi , Tanaka Norio , Omatsu Kohei , Takeshima Nobuhiro , Nomura Hidetaka , Hasegawa Kosei , Fujiwara Keiichi , Taki Mana , Matsumura Noriomi , Noda Tetsuo , Mori Seiichi
Published: October 2019

Carcinosarcoma (CS) of the uterus or ovary is a rare, aggressive and biphasic neoplasm composed of carcinoma and sarcoma elements. Previous genomic studies have identified the driver genes and genomic properties associated with CS. However, there is still no molecular subtyping scheme with clinical relevance for this disease. Here, we sequence 109 CS samples, focusing on 596 genes. We identify four molecular subtypes that resemble those observed in endometrial carcinoma:POLE-mutated, microsatellite instability, copy number high, and copy number low subtypes. These molecular subtypes are linked with DNA repair deficiencies, potential therapeutic strategies, and multiple clinicopathological features, including patient outcomes. Multi-regional comparative sequencing reveals genomic alteration-independent CS cell differentiation. Transcriptome and DNA methylome analyses confirm epithelial-mesenchymal transition as a mechanism of sarcoma differentiation. The current study thus provides therapeutic possibilities for CS as well as clues to understanding the molecular histogenic mechanism of its development.
Altered structural brain asymmetry in autism spectrum disorder in a study of 54 datasets
Authors: Postema Merel C. , van Rooij Daan , Anagnostou Evdokia , Arango Celso , Auzias Guillaume , Behrmann Marlene , Filho Geraldo Busatto , Calderoni Sara , Calvo Rosa , Daly Eileen , Deruelle Christine , Di Martino Adriana , Dinstein Ilan , Duran Fabio Luis S. , Durston Sarah , Ecker Christine , Ehrlich Stefan , Fair Damien , Fedor Jennifer , Feng Xin , Fitzgerald Jackie , Floris Dorothea L. , Freitag Christine M. , Gallagher Louise , Glahn David C. , Gori Ilaria , Haar Shlomi , Hoekstra Liesbeth , Jahanshad Neda , Jalbrzikowski Maria , Janssen Joost , King Joseph A. , Kong Xiang Zhen , Lazaro Luisa , Lerch Jason P. , Luna Beatriz , Martinho Mauricio M. , McGrath Jane , Medland Sarah E. , Muratori Filippo , Murphy Clodagh M. , Murphy Declan G. M. , O’Hearn Kirsten , Oranje Bob , Parellada Mara , Puig Olga , Retico Alessandra , Rosa Pedro , Rubia Katya , Shook Devon , Taylor Margot J. , Tosetti Michela , Wallace Gregory L. , Zhou Fengfeng , Thompson Paul M. , Fisher Simon E. , Buitelaar Jan K. , Francks Clyde
Published: October 2019

Altered structural brain asymmetry in autism spectrum disorder (ASD) has been reported. However, findings have been inconsistent, likely due to limited sample sizes. Here we investigated 1,774 individuals with ASD and 1,809 controls, from 54 independent data sets of the ENIGMA consortium. ASD was significantly associated with alterations of cortical thickness asymmetry in mostly medial frontal, orbitofrontal, cingulate and inferior temporal areas, and also with asymmetry of orbitofrontal surface area. These differences generally involved reduced asymmetry in individuals with ASD compared to controls. Furthermore, putamen volume asymmetry was significantly increased in ASD. The largest case-control effect size was Cohen’sd = −0.13, for asymmetry of superior frontal cortical thickness. Most effects did not depend on age, sex, IQ, severity or medication use. Altered lateralized neurodevelopment may therefore be a feature of ASD, affecting widespread brain regions with diverse functions. Large-scale analysis was necessary to quantify subtle alterations of brain structural asymmetry in ASD.
Practical and stereoselective electrocatalytic 1,2-diamination of alkenes
Authors: Cai Chen-Yan , Shu Xiao-Min , Xu Hai-Chao
Published: October 2019

The 1,2-diamine motif is widely present in natural products, pharmaceutical compounds, and catalysts used in asymmetric synthesis. The simultaneous introduction of two amino groups across an alkene feedstock is an appealing yet challenging approach for the synthesis of 1,2-diamines, primarily due to the inhibitory effect of the diamine products to transition metal catalysts and the difficulty in controlling reaction diastereoselectivity and regioselectivity. Herein we report a scalable electrocatalytic 1,2-diamination reaction that can be used to convert stable, easily available aryl alkenes and sulfamides to 1,2-diamines with excellent diastereoselectivity. Monosubstituted sulfamides react in a regioselective manner to afford 1,2-diamines bearing different substituents on the two amino groups. The combination of an organic redox catalyst and electricity not only obviates the use of any transition metal catalyst and oxidizing reagent, but also ensures broad reaction compatibility with a variety of electronically and sterically diverse substrates.
A multi-omics digital research object for the genetics of sleep regulation
Authors: Jan Maxime , Gobet Nastassia , Diessler Shanaz , Franken Paul , Xenarios Ioannis
Published: October 2019

With the aim to uncover the molecular pathways underlying the regulation of sleep, we recently assembled an extensive and comprehensive systems genetics dataset interrogating a genetic reference population of mice at the levels of the genome, the brain and liver transcriptomes, the plasma metabolome, and the sleep-wake phenome. To facilitate a meaningful and efficient re-use of this public resource by others we designed, describe in detail, and made available a Digital Research Object (DRO), embedding data, documentation, and analytics. We present and discuss both the advantages and limitations of our multi-modal resource and analytic pipeline. The reproducibility of the results was tested by a bioinformatician not implicated in the original project and the robustness of results was assessed by re-annotating genetic and transcriptome data from the mm9 to the mm10 mouse genome assembly.
A multi-modal data resource for investigating topographic heterogeneity in patient-derived xenograft tumors
Authors: Rajaram Satwik , Roth Maike A. , Malato Julia , VandenBerg Scott , Hann Byron , Atreya Chloe E. , Altschuler Steven J. , Wu Lani F.
Published: October 2019

Patient-derived xenografts (PDXs) are an essential pre-clinical resource for investigating tumor biology. However, cellular heterogeneity within and across PDX tumors can strongly impact the interpretation of PDX studies. Here, we generated a multi-modal, large-scale dataset to investigate PDX heterogeneity in metastatic colorectal cancer (CRC) across tumor models, spatial scales and genomic, transcriptomic, proteomic and imaging assay modalities. To showcase this dataset, we present analysis to assess sources of PDX variation, including anatomical orientation within the implanted tumor, mouse contribution, and differences between replicate PDX tumors. A unique aspect of our dataset is deep characterization of intra-tumor heterogeneity via immunofluorescence imaging, which enables investigation of variation across multiple spatial scales, from subcellular to whole tumor levels. Our study provides a benchmark data resource to investigate PDX models of metastatic CRC and serves as a template for future, quantitative investigations of spatial heterogeneity within and across PDX tumor models.
A spatio-temporal continuous soil moisture dataset over the Tibet Plateau from 2002 to 2015
Authors: Cui Yaokui , Zeng Chao , Zhou Jie , Xie Hongjie , Wan Wei , Hu Ling , Xiong Wentao , Chen Xi , Fan Wenjie , Hong Yang
Published: October 2019

Surface soil moisture is a key variable in the exchange of water and energy between the land surface and the atmosphere, and critical to meteorology, hydrology, and ecology. The Tibetan Plateau (TP), known as “The third pole of the world” and “Asia’s water towers”, exerts huge influences on and sensitive to global climates. In this situation, longer time series of soil moisture can provide sufficient information to understand the role of the TP. This paper presents the first comprehensive dataset (2002–2015) of spatio-temporal continuous soil moisture at 0.25° resolution, based on satellite-based optical (i.e. MODIS) and microwave (ECV) products using a machine learning method named general regression neural network (GRNN). The dataset itself reveals significant information on the soil moisture and its changes over the TP, and can aid to understand the potential driven mechanisms for climate change over the TP.
Deep-diving pilot whales make cheap, but powerful, echolocation clicks with 50 µL of air
Authors: Foskolos Ilias , Aguilar de Soto Natacha , Madsen Peter Teglberg , Johnson Mark
Published: October 2019

Echolocating toothed whales produce powerful clicks pneumatically to detect prey in the deep sea where this long-range sensory channel makes them formidable top predators. However, air supplies for sound production compress with depth following Boyle’s law suggesting that deep-diving whales must use very small air volumes per echolocation click to facilitate continuous sensory flow in foraging dives. Here we test this hypothesis by analysing click-induced acoustic resonances in the nasal air sacs, recorded by biologging tags. Using 27000 clicks from 102 dives of 23 tagged pilot whales (Globicephala macrorhynchus), we show that click production requires only 50 µL of air/click at 500 m depth increasing gradually to 100 µL at 1000 m. With such small air volumes, the metabolic cost of sound production is on the order of 40 J per dive which is a negligible fraction of the field metabolic rate. Nonetheless, whales must make frequent pauses in echolocation to recycle air between nasal sacs. Thus, frugal use of air and periodic recycling of very limited air volumes enable pilot whales, and likely other toothed whales, to echolocate cheaply and almost continuously throughout foraging dives, providing them with a strong sensory advantage in diverse aquatic habitats.
Supercritical water anomalies in the vicinity of the Widom line
Authors: Karalis Konstantinos , Ludwig Christian , Niceno Bojan
Published: October 2019

Supercritical water is used in a variety of chemical and industrial applications. As a consequence, a detailed knowledge of the structure-properties correlations is of uttermost importance. Although supercritical water was considered as a homogeneous fluid, recent studies revealed an anomalous behaviour due to nanoscale density fluctuations (inhomogeneity). The inhomogeneity is clearly demarked through the Widom line (maxima in response factions) and drastically affect the properties. In the current study the physical properties of supercritical water have been determined by classical molecular dynamics simulations using a variety of polarized and polarizable interatomic potentials. Their validity which was not available at supercritical conditions has been assessed based on the ability to reproduce experimental data. Overall, the polarized TIP4P/2005 model accurately predicted the properties of water in both liquid-like and gas-like regions. All interatomic potentials captured the anomalous behaviour providing a direct evidence of molecular-scale inhomogeneity.
Assessment of Nano-Indentation Method in Mechanical Characterization of Heterogeneous Nanocomposite Materials Using Experimental and Computational Approaches
Authors: Karimzadeh A. , R. Koloor S. S. , Ayatollahi M. R. , Bushroa A. R. , Yahya M. Y.
Published: October 2019

This study investigates the capacity of the nano-indentation method in the mechanical characterization of a heterogeneous dental restorative nanocomposite using experimental and computational approaches. In this respect, Filtek Z350 XT was selected as a nano-particle reinforced polymer nanocomposite with a specific range of the particle size (50 nm to 4 µm), within the range of indenter contact area of the nano-indentation experiment. A Sufficient number of nano-indentation tests were performed in various locations of the nanocomposite to extract the hardness and elastic modulus properties. A hybrid computational-experimental approach was developed to examine the extracted properties by linking the internal behaviour and the global response of the nanocomposite. In the computational part, several representative models of the nanocomposite were created in a finite element environment to simulate the mechanism of elastic-plastic deformation of the nanocomposite under Berkovich indenter. Dispersed values of hardness and elastic modulus were obtained through the experiment with 26.8 and 48.5 percent average errors, respectively, in comparison to the nanocomposite properties, respectively. A disordered shape was predicted for plastic deformation of the equilateral indentation mark, representing the interaction of the particles and matrix, which caused the experiment results reflect the local behaviour of the nanocomposite instead of the real material properties.
Ionic transport through a protein nanopore: a Coarse-Grained Molecular Dynamics Study
Authors: Basdevant Nathalie , Dessaux Delphine , Ramirez Rosa
Published: October 2019

The MARTINI coarse-grained (CG) force field is used to test the ability of CG models to simulate ionic transport through protein nanopores. The ionic conductivity of CG ions in solution was computed and compared with experimental results. Next, we studied the electrostatic behavior of a solvated CG lipid bilayer in salt solution under an external electric field. We showed this approach correctly describes the experimental conditions under a potential bias. Finally, we performed CG molecular dynamics simulations of the ionic transport through a protein nanopore (α-hemolysin) inserted in a lipid bilayer, under different electric fields, for 2–3 microseconds. The resulting I − V curve is qualitatively consistent with experiments, although the computed current is one order of magnitude smaller. Current saturation was observed for potential biases over ±350 mV. We also discuss the time to reach a stationary regime and the role of the protein flexibility in our CG simulations.
A comparative assessment of conventional and molecular methods, including MinION nanopore sequencing, for surveying water quality
Authors: Acharya Kishor , Khanal Santosh , Pantha Kalyan , Amatya Niroj , Davenport Russell J. , Werner David
Published: October 2019

Nucleic acid based techniques, such as quantitative PCR (qPCR) and next generation sequencing (NGS), provide new insights into microbial water quality, but considerable uncertainty remains around their correct interpretation. We demonstrate, for different water sources in informal settlements in the Kathmandu Valley, Nepal, significant Spearman rank correlations between conventional and molecular microbiology methods that indicate faecal contamination. At family and genera level, 16S rRNA amplicon sequencing results obtained with the low-cost, portable next generation sequencer MinION from Oxford Nanopore Technologies had significant Spearman rank correlations with Illumina MiSeq sequencing results. However, method validation by amplicon sequencing of a MOCK microbial community revealed the need to ascertain MinION sequencing results for putative pathogens at species level with complementary qPCR assays. Vibrio cholerae hazards were poorly associated with plate count faecal coliforms, but flagged up by the MinION screening method, and confirmed by a qPCR assay. Plate counting methods remain important to assess viability of faecal coliforms in disinfected water sources. We outline a systematic approach for data collection and interpretation of such complementary results. In the Kathmandu Valley, there is high variability of water quality from different sources, including for treated water samples, illustrating the importance of disinfection at the point of use.
A topological transition by confinement of a phase separating system with radial quenching
Authors: Tsukada Tsuyoshi , Kurita Rei
Published: October 2019

Physicochemical systems are strongly modified by spatial confinement; the effect is more pronounced the stronger the confinement is, making its influence particularly important nanotechnology applications. For example, a critical point of a phase transition is shifted by a finite size effect; structure can be changed through wetting to a container wall. Recently, it has been shown that pattern formation during a phase separation is changed when a system is heterogeneously quenched instead of homogeneously. Flux becomes anisotropic due to a heterogeneous temperature field; this suggests that the mechanism behind heterogeneous quenching is different from that of homogeneous quenching. Here, we numerically study the confinement effect for heterogeneously quenched systems. We find that the pattern formed by the phase separation undergoes a topological change with stronger confinement i.e. when the height of a simulation box is varied, transforming from a one-dimensional layered pattern to a two-dimensional pattern. We show that the transition is induced by suppression of the heterogeneous flux by spatial confinement. Systems with heterogeneous flux are ubiquitous; the effect is expected to be relevant to a wide variety of non-equilibrium processes under the action of spatial confinement.
Firing activities of a fractional-order FitzHugh-Rinzel bursting neuron model and its coupled dynamics
Authors: Mondal Argha , Sharma Sanjeev Kumar , Upadhyay Ranjit Kumar , Mondal Arnab
Published: October 2019

Fractional-order dynamics of excitable systems can be physically described as a memory dependent phenomenon. It can produce diverse and fascinating oscillatory patterns for certain types of neuron models. To address these characteristics, we consider a nonlinear fast-slow FitzHugh-Rinzel (FH-R) model that exhibits elliptic bursting at a fixed set of parameters with a constant input current. The generalization of this classical order model provides a wide range of neuronal responses (regular spiking, fast-spiking, bursting, mixed-mode oscillations, etc.) in understanding the single neuron dynamics. So far, it is not completely understood to what extent the fractional-order dynamics may redesign the firing properties of excitable systems. We investigate how the classical order system changes its complex dynamics and how the bursting changes to different oscillations with stability and bifurcation analysis depending on the fractional exponent (0 < α ≤ 1). This occurs due to the memory trace of the fractional-order dynamics. The firing frequency of the fractional-order FH-R model is less than the classical order model, although the first spike latency exists there. Further, we investigate the responses of coupled FH-R neurons with small coupling strengths that synchronize at specific fractional-orders. The interesting dynamical characteristics suggest various neurocomputational features that can be induced in this fractional-order system which enriches the functional neuronal mechanisms.