bluuebunny/crossref_metadata_2025 huggingface dataset:
Implications of Simulating Global Digital Elevation Models for Flood Inundation Studies
Authors: Hawker Laurence , Rougier Jonathan , Neal Jeffrey , Bates Paul , Archer Leanne , Yamazaki Dai
Published: September 2018

The Shuttle Radar Topography Mission has long been used as a source topographic information for flood hazard models, especially in data‐sparse areas. Error corrected versions have been produced, culminating in the latest global error reduced digital elevation model (DEM)—the Multi‐Error‐Removed‐Improved‐Terrain (MERIT) DEM. This study investigates the spatial error structure of MERIT and Shuttle Radar Topography Mission, before simulating plausible versions of the DEMs using fitted semivariograms. By simulating multiple DEMs, we allow modelers to explore the impact of topographic uncertainty on hazard assessment even in data‐sparse locations where typically only one DEM is currently used. We demonstrate this for a flood model in the Mekong Delta and a catchment in Fiji using deterministic DEMs and DEM ensembles simulated using our approach. By running an ensemble of simulated DEMs we avoid the spurious precision of using a single DEM in a deterministic simulation. We conclude that using an ensemble of the MERIT DEM simulated using semivariograms by land cover class gives inundation estimates closer to a light detection and ranging‐based benchmark. This study is the first to analyze the spatial error structure of the MERIT DEM and the first to simulate DEMs and apply these to flood models at this scale. The research workflow is available via an R package called DEMsimulation.
Spatially Distributed Conceptual Hydrological Model Building: A Generic Top‐Down Approach Starting From Lumped Models
Authors: Tran Quoc Quan , De Niel J. , Willems P.
Published: September 2018

Changing environmental conditions might have severe impacts on future flood frequencies and water availability. In order to develop mitigation strategies by carrying out impact studies, lumped hydrological models might not suffice anymore and the need for flexibility in spatial resolution arises. Recent developments already allow to change the grid size of hydrological models depending on the needs and to use different spatial resolutions in parallel for different applications. These developments, however, still face some challenges such as the following: how to avoid strong or sudden changes in simulation results when level of spatial details is changed and how to limit the problem of overparameterization/equifinality while increasing the spatial resolution. We developed a methodology to partially meet these challenges by building parsimonious distributed conceptual hydrological models with a flexible spatial resolution. The methodology starts with calibrated lumped conceptual models. Parameters are then spatially disaggregated based on spatially variable catchment properties, introducing only few additional calibration parameters. The approach is demonstrated for three different conceptual rainfall‐runoff models for two medium‐sized Belgian catchments. The resulting spatial models are found to be accurate with respect to the observations and consistent with the lumped conceptual model results, when evaluated for peak, low, and cumulative total runoff and subflows at downstream and internal gauging stations. A climate change impact analysis further shows consistency of lumped and spatial model results for changing conditions.
Phosphoglycerate dehydrogenase inhibition induces p-mTOR-independent autophagy and promotes multilineage differentiation in embryonal carcinoma stem-like cells
Authors: Sharif Tanveer , Martell Emma , Dai Cathleen , Ghassemi-Rad Mohammad Saleh , Lee Kristen , Singh Sheila K. , Weaver Ian C. G. , Gujar Shashi
Published: September 2018

Cancer cells with a less differentiated stem-like phenotype are more resistant to therapeutic manipulations than their differentiated counterparts, and are considered as one of the main causes of cancer persistence and relapse. As such, induction of differentiation in cancer stem-like cells (CSLCs) has emerged as an alternative strategy to enhance the efficacy of anticancer therapies. CSLCs are metabolically distinct from differentiated cells, and any aberration from the intrinsic metabolic state can induce differentiation of CSLCs. Therefore, metabolism-related molecular targets, with a capacity to promote differentiation within CSLCs, are of therapeutic importance. Here, we demonstrate that phosphoglycerate dehydrogenase (PHGDH), an essential enzyme catalyzing the synthesis of amino acid serine, is important for maintaining the poorly differentiated, stem-like state of CSLCs. Our data shows that PHGDH deficiency impairs the tumorsphere formation capacity in embryonal carcinoma stem-like cells (ECSLCs), breast cancer stem-like cells (BCSLCs) and patient-derived brain tumor-initiating cells (BTICs), which is accompanied by the reduced expression of characteristic stemness-promoting factors, such as Oct4, Nanog, Sox-2, and Bmi-1. Mechanistically, PHGDH deficiency in ECSLCs promotes differentiation to various lineages via degradation of Oct4 and by increasing the stability of differentiation marker β3-tubulin. Furthermore, PHGDH inhibition promotes p-mTOR independent but Beclin-1-dependent autophagy, independent of apoptosis. When studied in combination, the inhibition of both PHGDH and p-mTOR in ECSLCs causes further augmentation of autophagy, and additionally promotes apoptosis, demonstrating the clinical applicability of PHGDH-based manipulations in cancer therapies. Recapitulating these in vitro findings in CSLC models, the intratumoral PHGDH expression in patient-derived tumors is positively correlated with the mRNA levels of stemness factors, especially Oct4, and cancer patients co-expressing high levels of PHGDH and Oct4 display significantly lower survival than those with low PHGDH/Oct4 co-expression. Altogether, this study identifies a clinically-relevant role for PHGDH in the regulation of stemness-differentiation axis within CSLCs.
VDAC2 interacts with PFKP to regulate glucose metabolism and phenotypic reprogramming of glioma stem cells
Authors: Zhou Kai , Yao Yue-Liang , He Zhi-Cheng , Chen Cong , Zhang Xiao-Ning , Yang Kai-Di , Liu Yu-Qi , Liu Qing , Fu Wen-Juan , Chen Ya-Ping , Niu Qin , Ma Qing-Hua , Zhou Rong , Yao Xiao-Hong , Zhang Xia , Cui You-Hong , Bian Xiu-Wu , Shi Yu , Ping Yi-Fang
Published: September 2018

Plastic phenotype convention between glioma stem cells (GSCs) and non-stem tumor cells (NSTCs) significantly fuels glioblastoma heterogeneity that causes therapeutic failure. Recent progressions indicate that glucose metabolic reprogramming could drive cell fates. However, the metabolic pattern of GSCs and NSTCs and its association with tumor cell phenotypes remain largely unknown. Here we found that GSCs were more glycolytic than NSTCs, and voltage-dependent anion channel 2 (VDAC2), a mitochondrial membrane protein, was critical for metabolic switching between GSCs and NSTCs to affect their phenotypes. VDAC2 was highly expressed in NSTCs relative to GSCs and coupled a glycolytic rate-limiting enzyme platelet-type of phosphofructokinase (PFKP) on mitochondrion to inhibit PFKP-mediated glycolysis required for GSC maintenance. Disruption of VDAC2 induced dedifferentiation of NSTCs to acquire GSC features, including the enhanced self-renewal, preferential expression of GSC markers, and increased tumorigenicity. Inversely, enforced expression ofVDAC2 impaired the self-renewal and highly tumorigenic properties of GSCs. PFK inhibitor clotrimazole compromised the effect of VDAC2 disruption on glycolytic reprogramming and GSC phenotypic transition. Clinically, VDAC2 expression inversely correlated with glioma grades (Immunohistochemical staining scores of VDAC2 were 4.7 ± 2.8, 3.2 ± 1.9, and 1.9 ± 1.9 for grade II, grade III, and IV, respectively, p < 0.05 for all) and the patients with high expression of VDAC2 had longer overall survival than those with low expression of VDAC2 (p = 0.0008). In conclusion, we demonstrate that VDAC2 is a new glycolytic regulator controlling the phenotype transition between glioma stem cells and non-stem cells and may serves as a new prognostic indicator and a potential therapeutic target for glioma patients.
Caspase-11-mediated tubular epithelial pyroptosis underlies contrast-induced acute kidney injury
Authors: Zhang Zhen , Shao Xinghua , Jiang Na , Mou Shan , Gu Leyi , Li Shu , Lin Qisheng , He Yipei , Zhang Minfang , Zhou Wenyan , Ni Zhaohui
Published: September 2018

Contrast-induced acute kidney injury (CI-AKI) is a serious complication in patients after administration of iodinated contrast media and is associated with a significant high risk for severe renal failure and death due to the wholesale necrosis of the tubules and interstitial inflammation. Pyroptosis is a form of programmed lytic cell death that is triggered by inflammatory caspases, but little is known about its role in tubular epithelial cell (TEC) death and contrast-induced acute kidney injury. Here we show that systemic exposure to contrast media causes severe tubular epithelial pyroptosis that is mediated by the inflammatory caspases, caspases 4/5 in human TECs, or the murine homolog caspase-11 in mice in vivo and in mouse TECs in vitro. Knockdown of caspase-4/5 preserved human TECs from cell death and reduced the release of mature IL-1β, and in caspase-11-deficient mice, contrast-induced acute kidney injury was abrogated, indicating a central role for caspase-11 in acute kidney injury. In addition, deletion of caspase-11 in TECs reduced Gsdmd cleavage, which is the key process for execution of pyroptosis. These results establish the requisite role of epithelial pyroptosis in contrast-induced acute kidney injury and suggest that epithelial inflammatory caspases are an important therapeutic target for acute kidney injury.
MARVELD1 depletion leads to dysfunction of motor and cognition via regulating glia-dependent neuronal migration during brain development
Authors: Liu Weizhe , Han Fang , Qu Shuai , Yao Yuanfei , Zhao Jianxiang , Akhtar Muhammad Luqman , Ci Yanpeng , Zhang Hao , Li Hongfei , Zhao Yufang , Yue Lei , Zhang Yao , Wang Changlin , Li Yu
Published: September 2018

The establishment of functional neuronal connectivity is dependent on the neuronal migration and the accurate positioning of neurons in the developing brain. Abnormal neuronal migration can trigger neuronal maturation defects and apoptosis. However, many genetic bases remain unclear in neuronal migration disorders during brain development. In this study, we reported that MARVELD1-defected mice displayed motor and cognitive dysfunction resulting from aberrant neuronal migration during brain development. The laminar organization of the cerebral cortex and cerebellum in MARVELD1 knockout (KO) mice is disrupted, indicating impaired radial neuronal migration. Furthermore, we used the cerebellum as a model to explore the radial neuronal migration processes, and the results demonstrated that the proper neuronal migration depended on MARVELD1 expression in glial cells of the developing brain. MARVELD1 suppressed the expression of ITGB1 and FAK Tyr397 phosphorylation in glia-dependent manner. The inhibition of the MARVELD1/ITGB1/FAK signalling pathway in MARVELD1 KO mice could reverse the defects in neuronal migration in vitro. Our findings revealed that MARVELD1 regulated neuronal migration by mediating the formation of glial fibres and ITGB1/FAK signalling pathway. The depletion of MARVELD1 during mouse brain development led to the abnormity of motor and cognition functions.
Silencing long non-coding RNA Kcnq1ot1 alleviates pyroptosis and fibrosis in diabetic cardiomyopathy
Authors: Yang Fan , Qin Ying , Lv Jie , Wang Yueqiu , Che Hui , Chen Xi , Jiang Yanan , Li Anqi , Sun Xi , Yue Er , Ren Long , Li Yang , Bai Yunlong , Wang Lihong
Published: September 2018

Diabetes cardiomyopathy (DCM) is a critical complication of long-term chronic diabetes mellitus and is characterized by myocardial fibrosis and myocardial hypertrophy. It has been suggested that DCM is related to pyroptosis, a programmed cell death associated with inflammation. The long non-coding RNA Kcnq1ot1 is involved in different pathophysiological mechanisms of multiple diseases, including acute myocardial damage and arrhythmia. Our previous study found that Kcnq1ot1 was elevated in left ventricular tissue of diabetic mice. However, whether Kcnq1ot1 is capable of regulating pyroptosis and fibrosis in high glucose-treated cardiac fibroblasts remains unknown. The aim of the study was to investigate the mechanisms of Kcnq1ot1 in DCM. Our study revealed that silencing Kcnq1ot1 by a lentivirus-shRNA improved cardiac function and fibrosis, ameliorated pyroptosis, and inhibited TGF-β1/smads pathway in C57BL/6 mice. In vitro, experiments revealed that Kcnq1ot1 and pyroptosis were activated in cardiac fibroblasts treated with 30 mmol/l glucose. Furthermore, Kcnq1ot1 knockdown by a small interfering RNA decreased caspase-1 expression. Bioinformatic prediction and luciferase assays showed that Kcnq1ot1 functioned as a competing endogenous RNA to regulate the expression of caspase-1 by sponging miR-214-3p. In addition, silencing Kcnq1ot1 promoted gasdermin D cleavage and the secretion of IL-1β, thus repressing the TGF-β1/smads pathway in high glucose-treated cardiac fibroblasts through miR-214-3p and caspase-1. Therefore, Kcnq1ot1/miR-214-3p/caspase-1/TGF-β1 signal pathway presents a new mechanism of DCM progression and could potentially be a novel therapeutic target.
Enah overexpression is correlated with poor survival and aggressive phenotype in gastric cancer
Authors: Chen Di , Xu Li , Li Xiaowei , Chu Yi , Jiang Mingzuo , Xu Bing , Zhao Min , Wang Weijie , Wang Hua , Kang Huijie , Wang Kai , Wu Kaichun , Liang Jie , Ren Gui
Published: September 2018

Enabled homolog (Enah), which is a member of the Ena/VASP family that also includes VASP (vasodilator-stimulated phosphoprotein) and Ena/VASP like, is a mammalian ortholog of Drosophila Enabled (Ena). An increasing number of studies demonstrated Enah overexpression is involved in human colorectal carcinomas, breast cancers and hepatocellular carcinoma. However, the significance of Enah expression in gastric cancer (GC) is poorly elucidated. Here, we demonstrate that Enah is upregulated in GC and associated with AJCC stage, depth of invasion and poor overall survival (OS). Knockdown of Enah inhibited GC cell proliferation and metastasis and vice versa. Further experiments suggested that p-Erk1/2, p-AKT, p-p65, Vimentin and Fibronectin were downregulated and E-cadherin was upregulated after Enah silencing, implicating altered functions in GC proliferation and metastasis. Thus, our study suggests that Enah is a harmful factor for GC and a novel target for GC treatment.
USP24 induces IL-6 in tumor-associated microenvironment by stabilizing p300 and β-TrCP and promotes cancer malignancy
Authors: Wang Yi-Chang , Wu Yu-Syuan , Hung Chia-Yang , Wang Shao-An , Young Ming-Jer , Hsu Tsung-I , Hung Jan-Jong
Published: September 2018

We have previously demonstrated that USP24 is involved in cancer progression. Here, we found that USP24 expression is upregulated in M2 macrophages and lung cancer cells. Conditioned medium from USP24-knockdown M2 macrophages decreases the migratory and chemotactic activity of lung cancer cells and the angiogenic properties of human microvascular endothelial cell 1 (HMEC-1). IL-6 expression is significantly decreased in USP24-knockdown M2 macrophages and lung cancer cells, and IL-6-replenished conditioned medium restores the migratory, chemotactic and angiogenetic properties of the cells. USP24 stabilizes p300 and β-TrCP to increase the levels of histone-3 acetylation and NF-κB, and decreases the levels of DNMT1 and IκB, thereby increasing IL-6 transcription in M2 macrophages and lung cancer cells, results in cancer malignancy finally. IL-6 has previously been a target for cancer drug development. Here, we provide direct evidence to support that USP24 promotes IL-6 expression, which might be beneficial for cancer therapy.
A unique intracellular tyrosine in neuroligin-1 regulates AMPA receptor recruitment during synapse differentiation and potentiation
Authors: Letellier Mathieu , Szíber Zsófia , Chamma Ingrid , Saphy Camille , Papasideri Ioanna , Tessier Béatrice , Sainlos Matthieu , Czöndör Katalin , Thoumine Olivier
Published: September 2018

To better understand the molecular mechanisms by which early neuronal connections mature into synapses, we examined the impact of neuroligin-1 (Nlg1) phosphorylation on synapse differentiation, focusing on a unique intracellular tyrosine (Y782), which differentially regulates Nlg1 binding to PSD-95 and gephyrin. By expressing Nlg1 point mutants (Y782A/F) in hippocampal neurons, we show using imaging and electrophysiology that Y782 modulates the recruitment of functional AMPA receptors (AMPARs). Nlg1-Y782F impaired both dendritic spine formation and AMPAR diffusional trapping, but not NMDA receptor recruitment, revealing the assembly of silent synapses. Furthermore, replacing endogenous Nlg1 with either Nlg1-Y782A or -Y782F in CA1 hippocampal neurons impaired long-term potentiation (LTP), demonstrating a critical role of AMPAR synaptic retention. Screening of tyrosine kinases combined with pharmacological inhibitors point to Trk family members as major regulators of endogenous Nlg1 phosphorylation and synaptogenic function. Thus, Nlg1 tyrosine phosphorylation signaling is a critical event in excitatory synapse differentiation and LTP.
Insights into a dual function amide oxidase/macrocyclase from lankacidin biosynthesis
Authors: Dorival Jonathan , Risser Fanny , Jacob Christophe , Collin Sabrina , Dräger Gerald , Paris Cédric , Chagot Benjamin , Kirschning Andreas , Gruez Arnaud , Weissman Kira J.
Published: September 2018

Acquisition of new catalytic activity is a relatively rare evolutionary event. A striking example appears in the pathway to the antibiotic lankacidin, as a monoamine oxidase (MAO) family member, LkcE, catalyzes both an unusual amide oxidation, and a subsequent intramolecular Mannich reaction to form the polyketide macrocycle. We report evidence here for the molecular basis for this dual activity. The reaction sequence involves several essential active site residues and a conformational change likely comprising an interdomain hinge movement. These features, which have not previously been described in the MAO family, both depend on a unique dimerization mode relative to all structurally characterized members. Taken together, these data add weight to the idea that designing new multifunctional enzymes may require changes in both architecture and catalytic machinery. Encouragingly, however, our data also show LkcE to bind alternative substrates, supporting its potential utility as a general cyclization catalyst in synthetic biology.
Clonal dynamics in osteosarcoma defined by RGB marking
Authors: Gambera Stefano , Abarrategi Ander , González-Camacho Fernando , Morales-Molina Álvaro , Roma Josep , Alfranca Arantzazu , García-Castro Javier
Published: September 2018

Osteosarcoma is a type of bone tumour characterized by considerable levels of phenotypic heterogeneity, aneuploidy, and a high mutational rate. The life expectancy of osteosarcoma patients has not changed during the last three decades and thus much remains to be learned about the disease biology. Here, we employ a RGB-based single-cell tracking system to study the clonal dynamics occurring in a de novo-induced murine osteosarcoma model. We show that osteosarcoma cells present initial polyclonal dynamics, followed by clonal dominance associated with adaptation to the microenvironment. Interestingly, the dominant clones are composed of subclones with a similar tumour generation potential when they are re-implanted in mice. Moreover, individual spontaneous metastases are clonal or oligoclonal, but they have a different cellular origin than the dominant clones present in primary tumours. In summary, we present evidence that osteosarcomagenesis can follow a neutral evolution model, in which different cancer clones coexist and propagate simultaneously.
Superplasticity in an organic crystal
Authors: Takamizawa Satoshi , Takasaki Yuichi , Sasaki Toshiyuki , Ozaki Noriaki
Published: September 2018

Superplasticity, which enables processing on hard-to-work solids, has been recognized only in metallic solids. While metallic materials and plastics (polymer solids) essentially possess high plastic workability, functional crystalline solids present difficulties in molding. Organic crystals especially are fragile, in the common view, and they are far from the stage of materials development. From the viewpoint of practical application; however, organic crystals are especially attractive because they are composed of ubiquitous elements and often exhibit higher performance than metallic materials. Thus, finding superplastic deformation of organic crystals, especially in a single-crystal-to-single-crystal manner, will pave the way for their material applications. This study confirmed superplasticity in a crystal of a simple organic compound: N,N-dimethyl-4-nitroaniline. The crystal exhibits single-crystal-to-single-crystal superplastic deformation without heating. This finding of “organosuperplasticity” will contribute to the future design of functional solids that do not lose their crystalline quality in molding.
Publisher Correction: Hypermethylation of gene body CpG islands predicts high dosage of functional oncogenes in liver cancer
Authors: Arechederra Maria , Daian Fabrice , Yim Annie , Bazai Sehrish K. , Richelme Sylvie , Dono Rosanna , Saurin Andrew J. , Habermann Bianca H. , Maina Flavio
Published: September 2018

In the original version of this Article, the sixth sentence of the abstract incorrectly read ‘Most of the genes upregulated and with hypermethylated CGIs in the Alb-R26Met HCC model undergo the same change.’, and should have read ‘Most of the genes upregulated and with hypermethylated CGIs in the Alb-R26Met HCC model undergo the same change in a large proportion of HCC patients.’. This has been corrected in both the PDF and HTML versions of the Article.
Curvotaxis directs cell migration through cell-scale curvature landscapes
Authors: Pieuchot Laurent , Marteau Julie , Guignandon Alain , Dos Santos Thomas , Brigaud Isabelle , Chauvy Pierre-François , Cloatre Thomas , Ponche Arnaud , Petithory Tatiana , Rougerie Pablo , Vassaux Maxime , Milan Jean-Louis , Tusamda Wakhloo Nayana , Spangenberg Arnaud , Bigerelle Maxence , Anselme Karine
Published: September 2018

Cells have evolved multiple mechanisms to apprehend and adapt finely to their environment. Here we report a new cellular ability, which we term “curvotaxis” that enables the cells to respond to cell-scale curvature variations, a ubiquitous trait of cellular biotopes. We develop ultra-smooth sinusoidal surfaces presenting modulations of curvature in all directions, and monitor cell behavior on these topographic landscapes. We show that adherent cells avoid convex regions during their migration and position themselves in concave valleys. Live imaging combined with functional analysis shows that curvotaxis relies on a dynamic interplay between the nucleus and the cytoskeleton—the nucleus acting as a mechanical sensor that leads the migrating cell toward concave curvatures. Further analyses show that substratum curvature affects focal adhesions organization and dynamics, nuclear shape, and gene expression. Altogether, this work identifies curvotaxis as a new cellular guiding mechanism and promotes cell-scale curvature as an essential physical cue.
Robust quantum valley Hall effect for vortices in an interacting bosonic quantum fluid
Authors: Bleu O. , Malpuech G. , Solnyshkov D. D.
Published: September 2018

Topologically protected pseudospin transport, analogous to the quantum spin Hall effect, cannot be strictly implemented for photons and in general bosons because of the lack of symmetry-protected pseudospins. Here we show that the required protection can be provided by the real-space topological excitation of an interacting quantum fluid: a quantum vortex. We consider a Bose-Einstein condensate at the Γ point of the Brillouin zone of a quantum valley Hall system based on two staggered honeycomb lattices. We demonstrate the existence of a coupling between the vortex winding and the valley of the bulk Bloch band. This leads to chiral vortex propagation on each side of the zigzag interface between two regions of inverted staggering. The topological protection provided by the vortex winding prevents valley pseudospin mixing and resonant backscattering, allowing a truly topologically protected valley pseudospin transport.
Atomically precise graphene etch stops for three dimensional integrated systems from two dimensional material heterostructures
Authors: Son Jangyup , Kwon Junyoung , Kim SunPhil , Lv Yinchuan , Yu Jaehyung , Lee Jong-Young , Ryu Huije , Watanabe Kenji , Taniguchi Takashi , Garrido-Menacho Rita , Mason Nadya , Ertekin Elif , Huang Pinshane Y. , Lee Gwan-Hyoung , M. van der Zande Arend
Published: September 2018

Atomically precise fabrication methods are critical for the development of next-generation technologies. For example, in nanoelectronics based on van der Waals heterostructures, where two-dimensional materials are stacked to form devices with nanometer thicknesses, a major challenge is patterning with atomic precision and individually addressing each molecular layer. Here we demonstrate an atomically thin graphene etch stop for patterning van der Waals heterostructures through the selective etch of two-dimensional materials with xenon difluoride gas. Graphene etch stops enable one-step patterning of sophisticated devices from heterostructures by accessing buried layers and forming one-dimensional contacts. Graphene transistors with fluorinated graphene contacts show a room temperature mobility of 40,000 cm2 V−1 s−1 at carrier density of 4 × 1012 cm−2 and contact resistivity of 80 Ω·μm. We demonstrate the versatility of graphene etch stops with three-dimensionally integrated nanoelectronics with multiple active layers and nanoelectromechanical devices with performance comparable to the state-of-the-art.
Intracellular nucleosomes constrain a DNA linking number difference of −1.26 that reconciles the Lk paradox
Authors: Segura Joana , Joshi Ricky S. , Díaz-Ingelmo Ofelia , Valdés Antonio , Dyson Silvia , Martínez-García Belén , Roca Joaquim
Published: September 2018

The interplay between chromatin structure and DNA topology is a fundamental, yet elusive, regulator of genome activities. A paradigmatic case is the “linking number paradox” of nucleosomal DNA, which refers to the incongruence between the near two left-handed superhelical turns of DNA around the histone octamer and the DNA linking number difference (∆Lk) stabilized by individual nucleosomes, which has been experimentally estimated to be about −1.0. Here, we analyze the DNA topology of a library of mononucleosomes inserted into small circular minichromosomes to determine the average ∆Lkrestrained by individual nucleosomes in vivo. Our results indicate that most nucleosomes stabilize about −1.26 units of ∆Lk. This value balances the twist (∆Tw ≈ + 0.2) and writhe (∆Wr ≈ −1.5) deformations of nucleosomal DNA in terms of the equation ∆Lk = ∆Tw + ∆Wr. Our finding reconciles the existing discrepancy between theoretical and observed measurement of the ΔLkconstrained by nucleosomes.
Predicting wave overtopping thresholds on coral reef-island shorelines with future sea-level rise
Authors: Beetham E. , Kench P. S.
Published: September 2018

Wave-driven flooding is a serious hazard on coral reef-fringed coastlines that will be exacerbated by global sea-level rise. Despite the global awareness of atoll island vulnerability, little is known about the physical processes that control wave induced flooding on reef environments. To resolve the primary controls on wave-driven flooding at present and future sea levels, we present a globally applicable method for calculating wave overtopping thresholds on reef coastlines. A unique dataset of 60,000 fully nonlinear wave transformation simulations representing a wide range of wave energy, morphology and sea levels conditions was analysed to develop a tool for exploring the future trajectory of atoll island vulnerability to sea-level rise. The proposed reef-island overtopping threshold (RIOT) provides a widely applicable first-order assessment of reef-coast vulnerability to wave hazards with sea-level. Future overtopping thresholds identified for different atoll islands reveal marked spatial variability and highlight distinct morphological characteristics that enhance coastal resilience.
Malaria vaccine candidate based on Duffy-binding protein elicits strain transcending functional antibodies in a Phase I trial
Authors: Singh Kavita , Mukherjee Paushali , Shakri Ahmad Rushdi , Singh Ankita , Pandey Gaurav , Bakshi Meenakshi , Uppal Geetanjali , Jena Rajender , Rawat Ankita , Kumar Purnima , Bhardwaj Rukmini , Yazdani Syed Shams , Hans Dhiraj , Mehta Shantanu , Srinivasan Ajay , Anil K. , Madhusudhan R. L. , Patel Jaya , Singh Amit , Rao Rajeshwar , Gangireddy Santosh , Patil Rudrappa , Kaviraj Swarnendu , Singh Sanjay , Carter Darrick , Reed Steve , Kaslow David C. , Birkett Ashley , Chauhan Virander S. , Chitnis Chetan E.
Published: September 2018

Reticulocyte invasion by Plasmodium vivax requires interaction of the Duffy-binding protein (PvDBP) with host Duffy antigen receptor for chemokines (DARCs). The binding domain of PvDBP maps to a cysteine-rich region referred to as region II (PvDBPII). Blocking this interaction offers a potential path to prevent P. vivax blood-stage growth and P. vivax malaria. This forms the rationale for development of a vaccine based on PvDBPII. Here we report results of a Phase I randomized trial to evaluate the safety and immunogenicity of recombinant PvDBPII formulated with glucopyranosyl lipid adjuvant-stable emulsion (GLA-SE). Thirty-six malaria-naive, healthy Indian male subjects aged 18–45 years were assigned into three cohorts corresponding to doses of 10, 25 and 50 µg of PvDBPII formulated with 5 µg of GLA-SE. Each cohort included nine PvDBPII/GLA-SE vaccinees and three hepatitis B control vaccine recipients. Each subject received the assigned vaccine intramuscularly on days 0, 28 and 56, and was followed up till day 180. No serious AE was reported and PvDBPII/GLA-SE was well-tolerated and safe. Analysis by ELISA showed that all three doses of PvDBPII elicited antigen-specific binding-inhibitory antibodies. The 50 µg dose elicited antibodies against PvDBPII that had the highest binding-inhibitory titres and were most persistent. Importantly, the antibody responses were strain transcending and blocked receptor binding of diverse PvDBP alleles. These results support further clinical development of PvDBPII/GLA-SE to evaluate efficacy against sporozoite or blood-stage challenge in controlled human malaria infection (CHMI) models and against natural P. vivax challenge in malaria endemic areas.
Prevention of atherothrombotic events in patients with diabetes mellitus: from antithrombotic therapies to new-generation glucose-lowering drugs
Authors: Patti Giuseppe , Cavallari Ilaria , Andreotti Felicita , Calabrò Paolo , Cirillo Plinio , Denas Gentian , Galli Mattia , Golia Enrica , Maddaloni Ernesto , Marcucci Rossella , Parato Vito Maurizio , Pengo Vittorio , Prisco Domenico , Ricottini Elisabetta , Renda Giulia , Santilli Francesca , Simeone Paola , De Caterina Raffaele ,   on behalf of the Working Group on Thrombosis of the Italian Society of Cardiology
Published: September 2018

Diabetes mellitus is an important risk factor for a first cardiovascular event and for worse outcomes after a cardiovascular event has occurred. This situation might be caused, at least in part, by the prothrombotic status observed in patients with diabetes. Therefore, contemporary antithrombotic strategies, including more potent agents or drug combinations, might provide greater clinical benefit in patients with diabetes than in those without diabetes. In this Consensus Statement, our Working Group explores the mechanisms of platelet and coagulation activity, the current debate on antiplatelet therapy in primary cardiovascular disease prevention, and the benefit of various antithrombotic approaches in secondary prevention of cardiovascular disease in patients with diabetes. While acknowledging that current data are often derived from underpowered, observational studies or subgroup analyses of larger trials, we propose antithrombotic strategies for patients with diabetes in various cardiovascular settings (primary prevention, stable coronary artery disease, acute coronary syndromes, ischaemic stroke and transient ischaemic attack, peripheral artery disease, atrial fibrillation, and venous thromboembolism). Finally, we summarize the improvements in cardiovascular outcomes observed with the latest glucose-lowering drugs, and on the basis of the available evidence, we expand and integrate current guideline recommendations on antithrombotic strategies in patients with diabetes for both primary and secondary prevention of cardiovascular disease.
Differentiation enhances Zika virus infection of neuronal brain cells
Authors: Sánchez-San Martín Claudia , Li Tony , Bouquet Jerome , Streithorst Jessica , Yu Guixia , Paranjpe Aditi , Chiu Charles Y.
Published: September 2018

Zika virus (ZIKV) is an emerging, mosquito-borne pathogen associated with a widespread 2015–2016 epidemic in the Western Hemisphere and a proven cause of microcephaly and other fetal brain defects in infants born to infected mothers. ZIKV infections have been also linked to other neurological illnesses in infected adults and children, including Guillain-Barré syndrome (GBS), acute flaccid paralysis (AFP) and meningoencephalitis, but the viral pathophysiology behind those conditions remains poorly understood. Here we investigated ZIKV infectivity in neuroblastoma SH-SY5Y cells, both undifferentiated and following differentiation with retinoic acid. We found that multiple ZIKV strains, representing both the prototype African and contemporary Asian epidemic lineages, were able to replicate in SH-SY5Y cells. Differentiation with resultant expression of mature neuron markers increased infectivity in these cells, and the extent of infectivity correlated with degree of differentiation. New viral particles in infected cells were visualized by electron microscopy and found to be primarily situated inside vesicles; overt damage to the Golgi apparatus was also observed. Enhanced ZIKV infectivity in a neural cell line following differentiation may contribute to viral neuropathogenesis in the developing or mature central nervous system.
Yes-associated protein promotes the abnormal proliferation of psoriatic keratinocytes via an amphiregulin dependent pathway
Authors: Jia Jinjing , Li Changji , Yang Jiao , Wang Xin , Li Ruilian , Luo Suju , Li Zhengxiao , Liu Jiankang , Liu Zhi , Zheng Yan
Published: September 2018

Psoriasis is a chronic inflammatory skin disease with high morbidity, poor treatment methods and high rates of relapse. Keratinocyte hyperproliferation and shortened cell cycles are important pathophysiological features of psoriasis. As a known oncogene, Yes-associated protein (YAP) plays a role in promoting cell proliferation and inhibiting cell apoptosis; however, whether YAP is involved in the pathogenesis of psoriasis remains to be determined. Amphiregulin (AREG), a transcriptional target of YAP, was found to be upregulated in psoriasis, and overexpression of AREG promoted keratinocyte proliferation. In the present study, immunohistochemistry showed that YAP expression was elevated in the skin of psoriasis patients and in the Imiquimod (IMQ) mouse model of psoriasis. Knockdown of YAP in HaCaT cells inhibited cell proliferation, caused cell cycle arrest in G0/G1 phase and promoted apoptosis. These changes in YAP-knockdown HaCaT cells were related to changes in AREG expression. We concluded that YAP may play an important role in the regulation of abnormal keratinocyte proliferation via an AREG-dependent pathway and that YAP could be a new target in the treatment of psoriasis.
The Vapour-Vapour Interface Observation and Appraisement of a Gas-Condensate/Supercritical CO2 System
Authors: Jia Ying , Shi Yunqing , Huang Lei , Yan Jin , Zheng Rongchen , Sun Lei
Published: September 2018

Injecting supercritical CO2 into gas reservoir is a novel trial to improve condensate gas recovery and decrease the hydrocarbon liquid dropout. A good understanding of the effect of supercritical CO2 on the phase behavior properties of these hydrocarbons is essential for accurately forecasting the displacing performance and storing process of the reservoirs with numerical simulators. This paper presents novel phase behavior experimental procedures and phase equilibrium evaluation methodology for gas-condensate phase system mixed with supercritical CO2 over a wide range of temperatures and pressures. A unique phase behavior phenomena was also reported. The mass transfer between two vapour phases was also measured. In order to interpret and identify the interface property between condensate gas and supercritical CO2, a multiphase thermodynamic VLV equilibrium model was established. Finally, taken YKL condensate gas in Northwest China as an example, the region where the conditions in terms of pressure, temperature and CO2 concentration can yield VLV equilibrium was found. The calculation results of multiphase thermodynamic model for condensate-CO2 system in this paper are close to the experimental data and can truthfully reflect the phase behavior of interface between CO2 and condensate gas. The research results indicate that it is the existence of the interface between CO2 and condensate gas that makes CO2 possible be an attractive option to successfully displace condensate gas and decrease CO2 emissions.
The influence of acoustic startle probes on fear learning in humans
Authors: de Haan Michelle I. C. , van Well Sonja , Visser Renée M. , Scholte H. Steven , van Wingen Guido A. , Kindt Merel
Published: September 2018

Even though human fear-conditioning involves affective learning as well as expectancy learning, most studies assess only one of the two distinct processes. Commonly used read-outs of associative fear learning are the fear-potentiated startle reflex (FPS), pupil dilation and US-expectancy ratings. FPS is thought to reflect the affective aspect of fear learning, while pupil dilation reflects a general arousal response. However, in order to measure FPS, aversively loud acoustic probes are presented during conditioning, which might in itself exert an effect on fear learning. Here we tested the effect of startle probes on fear learning by comparing brain activation (fMRI), pupil dilation and US-expectancy ratings with and without acoustic startle probes within subjects. Regardless of startle probes, fear conditioning resulted in enhanced dACC, insula and ventral striatum activation. Interaction analyses showed that startle probes diminished differential pupil dilation between CS+ and CS− due to increased pupil responses to CS−. A trend significant interaction effect was observed for US-expectancy and amygdala activation. Startle probes affect differential fear learning by impeding safety learning, as measured with pupil dilation, a read-out of the cognitive component of fear learning. However, we observed no significant effect of acoustic startle probes on other measures of fear learning.
New Experimental Equipment Recreating Geo-Reservoir Conditions in Large, Fractured, Porous Samples to Investigate Coupled Thermal, Hydraulic and Polyaxial Stress Processes
Authors: McDermott C. I. , Fraser-Harris A. , Sauter M. , Couples G. D. , Edlmann K. , Kolditz O. , Lightbody A. , Somerville J. , Wang W.
Published: September 2018

Use of the subsurface for energy resources (enhanced geothermal systems, conventional and unconventional hydrocarbons), or for storage of waste (CO2, radioactive), requires the prediction of how fluids and the fractured porous rock mass interact. The GREAT cell (Geo-Reservoir Experimental Analogue Technology) is designed to recreate subsurface conditions in the laboratory to a depth of 3.5 km on 200 mm diameter rock samples containing fracture networks, thereby enabling these predictions to be validated. The cell represents an important new development in experimental technology, uniquely creating a truly polyaxial rotatable stress field, facilitating fluid flow through samples, and employing state of the art fibre optic strain sensing, capable of thousands of detailed measurements per hour. The cell’s mechanical and hydraulic operation is demonstrated by applying multiple continuous orientations of principal stress to a homogeneous benchmark sample, and to a fractured sample with a dipole borehole fluid fracture flow experiment, with backpressure. Sample strain for multiple stress orientations is compared to numerical simulations validating the operation of the cell. Fracture permeability as a function of the direction and magnitude of the stress field is presented. Such experiments were not possible to date using current state of the art geotechnical equipment.
IFITM proteins inhibit HIV-1 protein synthesis
Authors: Lee Wing-Yiu Jason , Fu Rebecca Menhua , Liang Chen , Sloan Richard D.
Published: September 2018

Interferon induced transmembrane proteins (IFITMs) inhibit the cellular entry of a broad range of viruses, but it has been suspected that for HIV-1 IFITMs may also inhibit a post-integration replicative step. We show that IFITM expression reduces HIV-1 viral protein synthesis by preferentially excluding viral mRNA transcripts from translation and thereby restricts viral production. Codon-optimization of proviral DNA rescues viral translation, implying that IFITM-mediated restriction requires recognition of viral RNA elements. In addition, we find that expression of the viral accessory protein Nef can help overcome the IFITM-mediated inhibition of virus production. Our studies identify a novel role for IFITMs in inhibiting HIV replication at the level of translation, but show that the effects can be overcome by the lentiviral protein Nef.
The lipid mediator lysophosphatidic acid induces folding of disordered peptides with basic amphipathic character into rare conformations
Authors: Juhász Tünde , Mihály Judith , Kohut Gergely , Németh Csaba , Liliom Károly , Beke-Somfai Tamás
Published: September 2018

Membrane-active, basic amphipathic peptides represent a class of biomolecules with diverse functions. Sequentially close protein segments also show similar behaviour in several ways. Here we investigated the effect of the lipid mediator lysophosphatidic acid (LPA) on the conformation of structurally disordered peptides including extracellular antimicrobial peptides (AMPs), and calmodulin-binding motifs derived from cytosolic and membrane target proteins. The interaction with associated LPA resulted in gain of ordered secondary structure elements, which for most cases were previously uncharacteristic of the particular peptide. Results revealed mechanism of the LPA-peptide interactions with regulation of the lipid on peptide conformation and oligomerization in a concentration-dependent manner involving (1) relocation of tryptophan residues into the lipid cluster, (2) multiple contacts between the binding partners dictated by complex driving forces, (3) multiple peptide binding to LPA associates with an affinity in the low micromolar range, and (4) selectivity for LPA compared with structurally related lipids. In line with recent findings showing endogenous molecules inducing structural changes in AMPs, we propose that accumulation of LPA in signalling or pathological processes might modulate host-defense activity or trigger certain processes by direct interaction with cationic amphipathic peptide sequences.
Sensitivity to CT-optimal, Affective Touch Depends on Adult Attachment Style
Authors: Krahé Charlotte , von Mohr Mariana , Gentsch Antje , Guy Lisette , Vari Chiara , Nolte Tobias , Fotopoulou Aikaterini
Published: September 2018

Affective touch supports affiliative bonds and social cognition. In particular, gentle, stroking touch, which has recently been associated with the C Tactile (CT) system, is typically perceived as pleasant and prosocial. However, it remains unknown whether pre-existing models of social relating influence the perception of CT-optimal touch. In this study (N = 44 adults), we examined how individual differences in attachment styles relate to the perception of CT-optimal touch, as well as to a different modality of interoception, namely heartbeat perception. Using the gold-standard assessment of attachment (Adult Attachment Interview), we found that insecure attachment was associated with reduced pleasantness discrimination between CT-optimal vs. non-CT optimal touch. Acknowledging the different traditions in measuring attachment, we also used a well-validated self-report questionnaire that pertains to explicit representations of current close relationships. Using this measure, we found that higher scores in attachment anxiety (but not attachment avoidance) were associated with reduced pleasantness discrimination between CT-optimal vs. non-CT optimal touch. Attachment patterns (in both measures) were not related to cardiac perception accuracy. These results corroborate and extend previous literature on CT-optimal touch and its relation with affiliative bonds and social cognition. Given that attachment was not related to perceived cardiac accuracy, these findings point to the specificity of the relationship between CT-optimal touch and attachment.
Three-Dimensional Retinal Organoids Facilitate the Investigation of Retinal Ganglion Cell Development, Organization and Neurite Outgrowth from Human Pluripotent Stem Cells
Authors: Fligor Clarisse M. , Langer Kirstin B. , Sridhar Akshayalakshmi , Ren Yuan , Shields Priya K. , Edler Michael C. , Ohlemacher Sarah K. , Sluch Valentin M. , Zack Donald J. , Zhang Chi , Suter Daniel M. , Meyer Jason S.
Published: September 2018

Retinal organoids are three-dimensional structures derived from human pluripotent stem cells (hPSCs) which recapitulate the spatial and temporal differentiation of the retina, serving as effective in vitro models of retinal development. However, a lack of emphasis has been placed upon the development and organization of retinal ganglion cells (RGCs) within retinal organoids. Thus, initial efforts were made to characterize RGC differentiation throughout early stages of organoid development, with a clearly defined RGC layer developing in a temporally-appropriate manner expressing a complement of RGC-associated markers. Beyond studies of RGC development, retinal organoids may also prove useful for cellular replacement in which extensive axonal outgrowth is necessary to reach post-synaptic targets. Organoid-derived RGCs could help to elucidate factors promoting axonal outgrowth, thereby identifying approaches to circumvent a formidable obstacle to RGC replacement. As such, additional efforts demonstrated significant enhancement of neurite outgrowth through modulation of both substrate composition and growth factor signaling. Additionally, organoid-derived RGCs exhibited diverse phenotypes, extending elaborate growth cones and expressing numerous guidance receptors. Collectively, these results establish retinal organoids as a valuable tool for studies of RGC development, and demonstrate the utility of organoid-derived RGCs as an effective platform to study factors influencing neurite outgrowth from organoid-derived RGCs.