bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of international organizations in equitable and just planned relocation
Authors: Nagle Alverio Gabriela , Hoagland Sara H. , Coughlan de Perez Erin , Mach Katharine J.
Published: May 2021

Since 2010, States party to the United Nations Framework Convention on Climate Change have recognized planned relocation as a viable adaptation to climate change. Planned relocation has been attempted in many communities globally and has raised serious issues of equity in some cases. Implementation driven by principles of equity is crucial in ensuring successful planned relocations that decrease loss and damage. In this Policy Analysis, we put forth a framework for equitable planned relocation rooted in theories of justice as a basis for implementation. The framework centers around three principles: comprehensive recognition of affected stakeholders in decision-making, consideration of socio-cultural risk factors relevant to relocation, and evaluation of multiple measures of well-being. There are many actors involved in planned relocation. Unique features and abilities of international organizations lend themselves to promoting equitable planned relocation in partnership with other stakeholders. Through the exploration of case studies, we identify best practices that international organizations have available to influence the design, implementation, and evaluation of planned relocation processes. These practices are relevant when striving for equity for all affected individuals and communities. Points of intervention include agenda-setting and advocacy, funding and implementation standards, and facilitation of international cooperation. International organizations also face barriers to supporting equitable planned relocation. Limitations include lack of enforcement mechanisms, limited resources, and fundamental dependence on existing governance structures and global collaboration. As the necessity of planned relocations grows, the need for leadership from international organizations in implementation is magnified, underscoring the importance of developing and evaluating approaches to just implementation.
Nation’s Business and the environment: the U.S. Chamber’s changing relationships with DDT, “ecologists,” regulations, and renewable energy
Authors: Orford Adam D.
Published: May 2021

Nation’s Businesswas a monthly business magazine published by the U.S. Chamber of Commerce, with a subscription list larger thanBusiness Week,Forbes, orFortune. This study explores how the magazine responded and adapted to the rise of environmentalism, and environmental regulation of business, by exploring its treatment of four topics: DDT, environmentalists, government regulation, and renewable energy. It is built on a full-text review of all issues ofNation’s Businesspublished between 1945 and 1981. It reveals the development of a variety of anti-environmental logics and discourses, including the delegitimization of environmentalism as emotional and irrational, the undermining of scientific conclusions as uncertain, the monetization of decision-making using cost-benefit analysis, and the problematization of government overregulation. The study thus traces the origins of the anti-environmental policies of the Reagan Administration to the business community of the preceding decade.
Terapia sostitutiva corticosteroidea alla luce delle nuove proposte farmacologiche (Plenadren®)
Authors: Cappiello Vincenzo , Giannelli Jacopo , Giordano Roberta
Published: May 2021

Sommario

La terapia sostitutiva corticosteroidea è indispensabile per la sopravvivenza dei pazienti con insufficienza surrenalica. Per oltre cinquant’anni sono stati impiegati steroidi a breve emivita e solo negli ultimi vent’anni sono state proposte nuove formulazioni derivate dall’idrocortisone, nate con l’obiettivo di migliorare gli effetti delle terapie convenzionali. In particolare, è stata prodotta una formulazione di idrocortisone a rilascio modificato in due fasi (DR-HC, Plenadren®). In questa rassegna si descriveranno le caratteristiche e gli effetti di tale formulazione.
fSDE: efficient evolutionary optimisation for many-objective aero-engine calibration
Authors: Liu Jialin , Zhang Qingquan , Pei Jiyuan , Tong Hao , Feng Xudong , Wu Feng
Published: May 2021

Engine calibration aims at simultaneously adjusting a set of parameters to ensure the performance of an engine under various working conditions using an engine simulator. Due to the large number of engine parameters to be calibrated, the performance measurements to be considered, and the working conditions to be tested, the calibration process is very time-consuming and relies on the human knowledge. In this paper, we consider non-convex constrained search space and model a real aero-engine calibration problem as a many-objective optimisation problem. A fast many-objective evolutionary optimisation algorithm with shift-based density estimation, called fSDE, is designed to search for parameters with an acceptable performance accuracy and improve the calibration efficiency. Our approach is compared to several state-of-the-art many- and multi-objective optimisation algorithms on the well-known many-objective optimisation benchmark test suite and a real aero-engine calibration problem, and achieves superior performance. To further validate our approach, the studied aero-engine calibration is also modelled as a single-objective optimisation problem and optimised by some classic and state-of-the-art evolutionary algorithms, compared to which fSDE not only provides more diverse solutions but also finds solutions of high-quality faster.
Performance test of a 5 kW solid oxide fuel cell system under high fuel utilization with industrial fuel gas feeding
Authors: Xu Ming , Wang Hanlin , Liu Mingxian , Zhao Jianning , Zhang Yuqiong , Li Pingping , Shi Mingliang , Gong Siqi , Zhang Zhaohuan , Li Chufu
Published: May 2021

As the demand for green energy with high efficiency and low carbon dioxide (CO2) emissions has increased, solid oxide fuel cells (SOFCs) have been intensively developed in recent years. Integrated gasification fuel cells (IGFCs) in particular show potential for large-scale power generation to further increase system efficiency. Thus, for commercial application of IGFCs, it is important to design reliable multi-stacks for large systems that show long-term stability and practical fuel gas for application to industrial equipment. In this work, a test rig (of a 5 kW SOFC system, with syngas from industrial gasifiers as fuel) was fabricated and subjected to long-term tests under high fuel utilization to investigate its performance. The maximum steady output power of the system was 5700 W using hydrogen and 5660 W using syngas and the maximum steady electrical efficiency was 61.24% while the fuel utilization efficiency was 89.25%. The test lasted for more than 500 h as the fuel utilization efficiency was larger than 83%. The performances of each stack tower were almost identical at both the initial stage and after long-term operation. After 500 h operation, the performances of the stack towers decreased only slightly under lower current and showed almost no change under high current. These results demonstrate the reliability of the multi-stack design and the prospect of this SOFC power-generation system for further enlarging its application in a MWth demonstration.
Nature kindergartens: a space for children’s participation
Authors: Alme Hilde , Reime Monika Alvestad
Published: May 2021

Children’s right to participate has become internationally recognised and the early years are a pivotal phase for realising children’s rights. Knowledge of how young children can enact their right to participation in different environmental and educational contexts is important for improving and facilitating pedagogical practices around the world. The use of the natural environment for educational purposes has become increasingly popular in the Nordic countries, the UK, Australia and in the United States. In this article, we explore how children and staff experience children’s participation through play and everyday life in kindergartens that organise most of the days outside. In Norway they are referred to as nature kindergartens. The primary data sources are focus group interviews with 30 children and 20 staff members from six nature kindergartens in Norway. The results show that the open and fluid character of nature creates a dynamic space for children’s play, stimulates creativity and social inclusion, promotes responsibility, and facilitates generational interdependency. Staff promote and participate in children’s initiatives but refrain from introducing and controlling activities. We conclude that the environmental and educational contexts in nature-kindergartens offer a range of participative situations while questioning whether all children have the capabilities for required active engagement.
Variations in Partitive Quotient Strategy Use by Children Who Have Been Taught the Part-Whole Fraction Sub-construct
Authors: George Lois , Voutsina Chronoula
Published: May 2021

This paper presents findings from a study that examined the strategies that children, who had only been taught the part-whole fraction sub-construct at school, used for finding the fraction associated with solving varied partitive quotient problems. A qualitative, microgenetic research design was used involving nine year 5 (aged 9–10) children engaged in eight individual task-based interviews over a 6-week period. The data analyzed showed that across the eight tasks, six of the nine children used more than one strategy for quantifying each person’s share but, by the third task, in general, each child had settled into a regular pattern of strategy use. The analyzed variations in children’s approaches to solving the partitive quotient problems revealed instances of when and how the part-whole fraction sub-construct interfered with children’s engagement with the partitive quotient problems. Considering that, internationally, the part-whole sub-construct is still the first fraction sub-construct that many children learn in schools, the findings are significant, since they provide new, in-depth insights into emerging approaches to solving partitive quotient tasks that are influenced by children’s existing part-whole knowledge. The findings provide new evidence for intra- and inter-individual variation in strategy use and strategy selection in tasks related to the partitive quotient meaning of fractions. The paper highlights for education, the need for teaching that introduces different fraction sub-constructs to learners early in their schooling so that one meaning of fractions does not become representative of all fraction knowledge.
Phytochemical mediated synthesis of silver nanoparticles and their antibacterial activity
Authors: Dogiparthi Lakshman Kumar , Sana Siva Sankar , Shaik Sumaya Zikreen , Kalvapalli Maneesha Reddy , Kurupati Gayathri , Kumar Godlaveeti Sreenivass , Gangadhar Lekshmi
Published: May 2021

In this present work, we described a bio-reduction method for the generation of silver nanoparticles (AgNPs) using aqueous leaf extract of Micrargeria wightii (M. wightii), which is a gifted alternative to other physicochemical routes. The prepared AgNPs were characterized by UV–visible spectroscopy (UV–vis), Fourier Transform Infrared Spectroscopy (FT-IR), X-ray diffraction (X-RD), Transmission Electron Microscopy (TEM) with EDX and Dynamic light scattering (DLS). UV–visible spectrum showed a characteristic absorption peak at 440 nm of synthesized AgNPs. FT-IR analysis confirmed the existence of plant metabolites, which are responsible for the reduction of Ag (I) ions into Ag (0) NPs. X-RD pattern studies confirm the presence of the pure face-centered cubiccrystalline nature of Ag. Energy-dispersive X-ray (E-DX) spectrum showed the elemental composition of synthesized nanoparticles. Furthermore, TEM images confirm the formation of spherical shaped nano-silver particles with sizes ranging from 30 to 70 nm and supported by particle size analyzer, Dynamic Light Scattering (DLS). Thus, the present investigation provides an easy, eco-friendly and straightforward route for the synthesis of the antibacterial agent against Bacillus subtilis subtilis and Pseudomonas aeruginosa, with 15 and 13 mm zone of inhibition (ZOI) respectively.
Constituency Effects and Legislative Dissent Under Closed-List Proportional Representation
Authors: Alemán Eduardo , Micozzi Juan Pablo , Pinto Pablo M. , Saiegh Sebastián
Published: May 2021

According to conventional wisdom, closed-list proportional representation (CLPR) electoral systems create incentives for legislators to favor the party line over their voters’ positions. However, electoral incentives may induce party leaders to tolerate “shirking” by some legislators, even under CLPR. This study argues that in considering whose deviations from the party line should be tolerated, party leaders exploit differences in voters’ relative electoral influence resulting from malapportionment. We expect defections in roll call votes to be more likely among legislators elected from overrepresented districts than among those from other districts. We empirically test this claim using data on Argentine legislators’ voting records and a unique dataset of estimates of voters’ and legislators’ placements in a common ideological space. Our findings suggest that even under electoral rules known for promoting unified parties, we should expect strategic defections to please voters, which can be advantageous for the party’s electoral fortunes.
Vapor Pressure Deficit and Sunlight Explain Seasonality of Leaf Phenology and Photosynthesis Across Amazonian Evergreen Broadleaved Forest
Authors: Chen Xiuzhi , Ciais Philippe , Maignan Fabienne , Zhang Yuan , Bastos Ana , Liu Liyang , Bacour Cédric , Fan Lei , Gentine Pierre , Goll Daniel , Green Julia , Kim Hyungjun , Li Laurent , Liu Yi , Peng Shushi , Tang Hao , Viovy Nicolas , Wigneron Jean‐Pierre , Wu Jin , Yuan Wenping , Zhang Haicheng
Published: May 2021

Amazonian evergreen forests show distinct canopy phenology and photosynthetic seasonality but the climatic triggers are not well understood. This imposes a challenge for modeling leaf phenology and photosynthesis seasonality in land surface models (LSMs) across Amazonian evergreen forest biome. On continental scale, we tested two climatic triggers suggested by site observations, vapor pressure deficit (VPD), and short‐wave incoming radiation (SW) for defining leaf shedding and incorporated VPD‐ and SW‐triggered new canopy phenology modules in the ORCHIDEE LSM (hereafter VPD‐AP and SW‐AP versions). Our results show that both VPD and SW are plausible precursors of large scale litterfall seasonality across the basin by comparing againstin situdata from 14 sites. Specially, both VPD‐AP and SW‐AP correctly capture the increases in litterfall during the early dry season, followed by a flush of new leaves with increasing photosynthetic rates during the later dry season. The VPD‐AP version performs better than the SW‐AP version in capturing a dry‐season increase of photosynthesis across the wet Amazonia areas where mean annual precipitation exceeds 2,000 mm yr−1, consistent with previous satellite data analysis. Both VPD‐AP and SW‐AP model versions perform well in northern, central and southern Amazon regions where the SW seasonality is unimodal, but miss the seasonality of satellite GPP proxies in the eastern region off the coast of Guyana shield where SW seasonality is bimodal. Our findings imply that atmospheric dryness and sunlight availability likely explain the seasonality of leaf shedding and leaf flush processes, respectively, and consequently control canopy photosynthesis in Amazonian evergreen forests.
Nanoscale Variations in Natural Amorphous and Nanocrystalline Weathering Products in Mafic to Intermediate Volcanic Terrains on Earth: Implications for Amorphous Detections on Mars
Authors: Smith R. J. , Horgan B. H. N.
Published: May 2021

Sedimentary amorphous and nanocrystalline materials are abundant on Mars, but their formation conditions are poorly understood due in part to instrument limitations and the lack of knowledge about terrestrial sedimentary amorphous and nanocrystalline material compositions and structures. Additionally, it is surprising that the Curiosity rover finds these metastable phases preserved in ancient (3–4 Gya) rocks in Gale crater. Here, we use X‐ray diffraction and high‐resolution transmission electron microscopy to investigate the X‐ray amorphous weathering products found in soils, sediments, and paleosols from Mars‐relevant mafic to intermediate volcanic terrains altered under different climates. The X‐ray amorphous components of our samples are often complex mixtures of amorphous and nanocrystalline materials with compositions that vary at the nanometer‐scale, but are dominated by iron‐oxide, Al2O3, and SiO2, the proportions of which reflect large‐scale weathering conditions, such that those formed in warm and wet climates are deficient in more mobile cations, and those formed under cooler climates reflect restricted cation leaching. We also find high abundances (∼40 wt.%) of X‐ray amorphous weathering products in lithified and diagenetically altered volcanic soils that have been preserved over time scales of ∼107 years. These results have wide‐reaching implications for soil property and paleoclimate investigations on Earth and Mars, and suggest that amorphous and nanocrystalline materials are important, but overlooked components of some sedimentary rocks on Earth. Future investigations are needed to better understand the kinetics behind the transformation from amorphous and nanocrystalline to crystalline materials and the factors that allow their preservation on Earth and Mars.
Inhibition of CCL7 derived from Mo-MDSCs prevents metastatic progression from latency in colorectal cancer
Authors: Ren Xiaoli , Xiao Jianbiao , Zhang Wanning , Wang Feifei , Yan Yongrong , Wu Xuehui , Zeng Zhicheng , He Yumei , Yang Wei , Liao Wangjun , Ding Yanqing , Liang Li
Published: May 2021

In colorectal cancer (CRC), overt metastases often appear after years of latency. But the signals that cause micro-metastatic cells to remain indolent, thereby enabling them to survive for extended periods of time, are unclear. Immunofluorescence and co-immunoprecipitation assays were used to explore the co-localization of CCL7 and CCR2. Immunohistochemical (IHC) assays were employed to detect the characters of metastatic HT29 cells in mice liver. Flow cytometry assays were performed to detect the immune cells. Bruberin vivo MS FX Pro Imager was used to observe the liver metastasis of CRC in mice. Quantitative real-time PCR (qRT-PCR) and western blot were employed to detect the expressions of related proteins. Trace RNA sequencing was employed to identify differentially expressed genes in MDSCs from liver micro-M and macro-M of CRC in mice. Here, we firstly constructed the vitro dormant cell models and metastatic dormant animal models of colorectal cancer. Then we found that myeloid-derived suppressor cells (MDSCs) were increased significantly from liver micro-metastases to macro-metastases of CRC in mice. Moreover, monocytic MDSCs (Mo-MDSC) significantly promoted the dormant activation of micro-metastatic cells compared to polymorphonuclear MDSCs (PMN-MDSC). Mechanistically, CCL7 secreted by Mo-MDSCs bound with membrane protein CCR2 of micro-metastatic cells and then stimulated the JAK/STAT3 pathway to activate the dormant cells. Low-dose administration of CCL7 and MDSCs inhibitors in vivo could significantly maintain the CRC metastatic cells dormant status for a long time to reduce metastasis or recurrence after radical operation. Clinically, the level of CCL7 in blood was positively related to the number of Mo-MDSCs in CCR patients, and highly linked with the short-time recurrence and distant metastasis. CCL7 secreted by Mo-MDSCs plays an important role in initiating the outgrowth of metastatic latent CRC cells. Inhibition of CCL7 might provide a potential therapeutic strategy for the prevention of metastasis recurrence.
Targeting epigenetic modulation of cholesterol synthesis as a therapeutic strategy for head and neck squamous cell carcinoma
Authors: Xu Xing , Chen Jun , Li Yan , Yang Xiaojie , Wang Qing , Wen Yanjun , Yan Ming , Zhang Jianjun , Xu Qin , Wei Yan , Chen Wantao , Wang Xu
Published: May 2021

The histone methyltransferase EZH2 silences gene expression via H3 lysine 27 trimethylation and has been recognized as an important antitumour therapeutic target. However, the clinical application of existing EZH2 inhibitors is not satisfactory for the treatment of solid tumours. To discover novel strategies against head and neck squamous cell carcinoma (HNSCC), we performed genomics, metabolomics and RNA omics studies in HNSCC cells treated with EZH2 inhibitors. It was found that EZH2 inhibitors strongly induced the expression of genes in cholesterol synthesis. Through extensive drug screening we found that inhibition of squalene epoxidase (a key enzyme of endogenous cholesterol synthesis) synergistically increased the squalene content and enhanced the sensitivity of HNSCC cells to EZH2 inhibitors. Our findings provide an experimental and theoretical basis for the development of new combinations of EZH2 inhibitors to treat HNSCC.
Disrupting tumour vasculature and recruitment of aPDL1-loaded platelets control tumour metastasis
Authors: Li Hongjun , Wang Zejun , Chen Zhaowei , Ci Tianyuan , Chen Guojun , Wen Di , Li Ruoxin , Wang Jinqiang , Meng Huan , Bryan Bell R. , Gu Zhifeng , Dotti Gianpietro , Gu Zhen
Published: May 2021

Although therapies of cancer are advancing, it remains challenging for therapeutics to reach the sites of metastasis, which accounts for majority of cancer associated death. In this study, we have developed a strategy that guides an anti-programmed cell death-ligand 1 (aPDL1) antibody to accumulate in metastatic lesions to promote anti-tumour immune responses. Briefly, we have developed a combination in which Vadimezan disrupts tumour blood vessels of tumour metastases and facilitates the recruitment and activation of adoptively transferred aPDL1-conjugated platelets. In situ activated platelets generate aPDL1-decorated platelet-derived microparticles (PMP) that diffuse within the tumour and elicit immune responses. The proposed combination increases 10-fold aPDL1 antibody accumulation in lung metastases as compared to the intravenous administration of the antibody and enhances the magnitude of immune responses leading to improved antitumour effects.
Cellular connectomes as arbiters of local circuit models in the cerebral cortex
Authors: Klinger Emmanuel , Motta Alessandro , Marr Carsten , Theis Fabian J. , Helmstaedter Moritz
Published: May 2021

With the availability of cellular-resolution connectivity maps, connectomes, from the mammalian nervous system, it is in question how informative such massive connectomic data can be for the distinction of local circuit models in the mammalian cerebral cortex. Here, we investigated whether cellular-resolution connectomic data can in principle allow model discrimination for local circuit modules in layer 4 of mouse primary somatosensory cortex. We used approximate Bayesian model selection based on a set of simple connectome statistics to compute the posterior probability over proposed models given a to-be-measured connectome. We find that the distinction of the investigated local cortical models is faithfully possible based on purely structural connectomic data with an accuracy of more than 90%, and that such distinction is stable against substantial errors in the connectome measurement. Furthermore, mapping a fraction of only 10% of the local connectome is sufficient for connectome-based model distinction under realistic experimental constraints. Together, these results show for a concrete local circuit example that connectomic data allows model selection in the cerebral cortex and define the experimental strategy for obtaining such connectomic data.
Tissue-specific activation of gene expression by the Synergistic Activation Mediator (SAM) CRISPRa system in mice
Authors: Hunt Charleen , Hartford Suzanne A. , White Derek , Pefanis Evangelos , Hanna Timothy , Herman Clarissa , Wiley Jarrell , Brown Heather , Su Qi , Xin Yurong , Voronin Dennis , Nguyen Hien , Altarejos Judith , Crosby Keith , Haines Jeffery , Cancelarich Sarah , Drummond Meghan , Moller-Tank Sven , Malpass Ryan , Buckley Jacqueline , del Pilar Molina-Portela Maria , Droguett Gustavo , Frendewey David , Chiao Eric , Zambrowicz Brian , Gong Guochun
Published: May 2021

CRISPR-based transcriptional activation is a powerful tool for functional gene interrogation; however, delivery difficulties have limited its applications in vivo. Here, we created a mouse model expressing all components of the CRISPR-Cas9 guide RNA-directed Synergistic Activation Mediator (SAM) from a single transcript that is capable of activating target genes in a tissue-specific manner. We optimized Lipid Nanoparticles and Adeno-Associated Virus guide RNA delivery approaches to achieve expression modulation of one or more genes in vivo. We utilized the SAM mouse model to generate a hypercholesteremia disease state that we could bidirectionally modulate with various guide RNAs. Additionally, we applied SAM to optimize gene expression in a humanized Transthyretin mouse model to recapitulate human expression levels. These results demonstrate that the SAM gene activation platform can facilitate in vivo research and drug discovery.
Towards single-chip radiofrequency signal processing via acoustoelectric electron–phonon interactions
Authors: Hackett Lisa , Miller Michael , Brimigion Felicia , Dominguez Daniel , Peake Greg , Tauke-Pedretti Anna , Arterburn Shawn , Friedmann Thomas A. , Eichenfield Matt
Published: May 2021

The addition of active, nonlinear, and nonreciprocal functionalities to passive piezoelectric acoustic wave technologies could enable all-acoustic and therefore ultra-compact radiofrequency signal processors. Toward this goal, we present a heterogeneously integrated acoustoelectric material platform consisting of a 50 nm indium gallium arsenide epitaxial semiconductor film in direct contact with a 41° YX lithium niobate piezoelectric substrate. We then demonstrate three of the main components of an all-acoustic radiofrequency signal processor: passive delay line filters, amplifiers, and circulators. Heterogeneous integration allows for simultaneous, independent optimization of the piezoelectric-acoustic and electronic properties, leading to the highest performing surface acoustic wave amplifiers ever developed in terms of gain per unit length and DC power dissipation, as well as the first-ever demonstrated acoustoelectric circulator with an isolation of 46 dB with a pulsed DC bias. Finally, we describe how the remaining components of an all-acoustic radiofrequency signal processor are an extension of this work.
A cytokine receptor-masked IL2 prodrug selectively activates tumor-infiltrating lymphocytes for potent antitumor therapy
Authors: Hsu Eric J. , Cao Xuezhi , Moon Benjamin , Bae Joonbeom , Sun Zhichen , Liu Zhida , Fu Yang-Xin
Published: May 2021

As a potent lymphocyte activator, interleukin-2 (IL-2) is an FDA-approved treatment for multiple metastatic cancers. However, its clinical use is limited by short half-life, low potency, and severe in vivo toxicity. Current IL-2 engineering strategies exhibit evidence of peripheral cytotoxicity. Here, we address these issues by engineering an IL-2 prodrug (ProIL2). We mask the activity of a CD8 T cell-preferential IL-2 mutein/Fc fusion protein with IL2 receptor beta linked to a tumor-associated protease substrate. ProIL2 restores activity after cleavage by tumor-associated enzymes, and preferentially activates inside tumors, where it expands antigen-specific CD8 T cells. This significantly reduces IL-2 toxicity and mortality without compromising antitumor efficacy. ProIL2 also overcomes resistance of cancers to immune checkpoint blockade. Lastly, neoadjuvant ProIL2 treatment can eliminate metastatic cancer through an abscopal effect. Taken together, our approach presents an effective tumor targeting therapy with reduced toxicity.
Contrasting epigenetic control of transgenes and endogenous genes promotes post-transcriptional transgene silencing in Arabidopsis
Authors: Butel Nicolas , Yu Agnès , Le Masson Ivan , Borges Filipe , Elmayan Taline , Taochy Christelle , Gursanscky Nial R. , Cao Jiangling , Bi Shengnan , Sawyer Anne , Carroll Bernard J. , Vaucheret Hervé
Published: May 2021

Transgenes that are stably expressed in plant genomes over many generations could be assumed to behave epigenetically the same as endogenous genes. Here, we report that whereas the histone H3K9me2 demethylase IBM1, but not the histone H3K4me3 demethylase JMJ14, counteracts DNA methylation of Arabidopsis endogenous genes, JMJ14, but not IBM1, counteracts DNA methylation of expressed transgenes. Additionally, JMJ14-mediated specific attenuation of transgene DNA methylation enhances the production of aberrant RNAs that readily induce systemic post-transcriptional transgene silencing (PTGS). Thus, the JMJ14 chromatin modifying complex maintains expressed transgenes in a probationary state of susceptibility to PTGS, suggesting that the host plant genome does not immediately accept expressed transgenes as being epigenetically the same as endogenous genes.
Combining density functional theory with macroscopic QED for quantum light-matter interactions in 2D materials
Authors: Svendsen Mark Kamper , Kurman Yaniv , Schmidt Peter , Koppens Frank , Kaminer Ido , Thygesen Kristian S.
Published: May 2021

A quantitative and predictive theory of quantum light-matter interactions in ultra thin materials involves several fundamental challenges. Any realistic model must simultaneously account for the ultra-confined plasmonic modes and their quantization in the presence of losses, while describing the electronic states from first principles. Herein we develop such a framework by combining density functional theory (DFT) with macroscopic quantum electrodynamics, which we use to show Purcell enhancements reaching 107 for intersubband transitions in few-layer transition metal dichalcogenides sandwiched between graphene and a perfect conductor. The general validity of our methodology allows us to put several common approximation paradigms to quantitative test, namely the dipole-approximation, the use of 1D quantum well model wave functions, and the Fermi’s Golden rule. The analysis shows that the choice of wave functions is of particular importance. Our work lays the foundation for practical ab initio-based quantum treatments of light-matter interactions in realistic nanostructured materials.
Plant DNA polymerases α and δ mediate replication of geminiviruses
Authors: Wu Mengshi , Wei Hua , Tan Huang , Pan Shaojun , Liu Qi , Bejarano Eduardo R. , Lozano-Durán Rosa
Published: May 2021

Geminiviruses are causal agents of devastating diseases in crops. Geminiviruses have circular single-stranded (ss) DNA genomes that are replicated in the nucleus of the infected plant cell through double-stranded (ds) DNA intermediates by the plant DNA replication machinery. Which host DNA polymerase mediates geminiviral multiplication, however, has so far remained elusive. Here, we show that subunits of the nuclear replicative DNA polymerases α and δ physically interact with the geminivirus-encoded replication enhancer protein, C3, and that these polymerases are required for viral replication. Our results suggest that, while DNA polymerase α is essential to generate the viral dsDNA intermediate, DNA polymerase δ mediates the synthesis of new copies of the geminiviral ssDNA genome, and that the virus-encoded C3 may act selectively, recruiting DNA polymerase δ over ε to favour productive replication.
A continuous metal-insulator transition driven by spin correlations
Authors: Feng Yejun , Wang Yishu , Silevitch D. M. , Cooper S. E. , Mandrus D. , Lee Patrick A. , Rosenbaum T. F.
Published: May 2021

While Mott insulators induced by Coulomb interactions are a well-recognized class of metal-insulator transitions, insulators purely driven by spin correlations are much less common, as the reduced energy scale often invites competition from other degrees of freedom. Here, we demonstrate a clean example of a spin-correlation-driven metal-insulator transition in the all-in-all-out pyrochlore antiferromagnet Cd2Os2O7, where the lattice symmetry is preserved by the antiferromagnetism. After the antisymmetric linear magnetoresistance from conductive, ferromagnetic domain walls is removed experimentally, the bulk Hall coefficient reveals four Fermi surfaces of both electron and hole types, sequentially departing the Fermi level with decreasing temperature below the Néel temperature, TN = 227 K. In Cd2Os2O7, the charge gap of a continuous metal-insulator transition opens only at T ~ 10 K << TN. The insulating mechanism parallels the Slater picture, but without a folded Brillouin zone, and contrasts sharply with Mott insulators and spin density waves, where the electronic gap opens above and at TN, respectively.
Alteration of circadian machinery in monocytes underlies chronic kidney disease-associated cardiac inflammation and fibrosis
Authors: Yoshida Yuya , Matsunaga Naoya , Nakao Takaharu , Hamamura Kengo , Kondo Hideaki , Ide Tomomi , Tsutsui Hiroyuki , Tsuruta Akito , Kurogi Masayuki , Nakaya Michio , Kurose Hitoshi , Koyanagi Satoru , Ohdo Shigehiro
Published: May 2021

Dysfunction of the circadian clock has been implicated in the pathogenesis of cardiovascular disease. The CLOCK protein is a core molecular component of the circadian oscillator, so that mice with a mutated Clock gene (Clk/Clk) exhibit abnormal rhythms in numerous physiological processes. However, here we report that chronic kidney disease (CKD)-induced cardiac inflammation and fibrosis are attenuated in Clk/Clk mice even though they have high blood pressure and increased serum angiotensin II levels. A search for the underlying cause of the attenuation of heart disorder in Clk/Clk mice with 5/6 nephrectomy (5/6Nx) led to identification of the monocytic expression of G protein-coupled receptor 68 (GPR68) as a risk factor of CKD-induced inflammation and fibrosis of heart. 5/6Nx induces the expression of GPR68 in circulating monocytes via altered CLOCK activation by increasing serum levels of retinol and its binding protein (RBP4). The high-GPR68-expressing monocytes have increased potential for producing inflammatory cytokines, and their cardiac infiltration under CKD conditions exacerbates inflammation and fibrosis of heart. Serum retinol and RBP4 levels in CKD patients are also sufficient to induce the expression of GPR68 in human monocytes. Our present study reveals an uncovered role of monocytic clock genes in CKD-induced heart failure.
The role of maternal preconception vitamin D status in human offspring sex ratio
Authors: Purdue-Smithe Alexandra C. , Kim Keewan , Nobles Carrie , Schisterman Enrique F. , Schliep Karen C. , Perkins Neil J. , Sjaarda Lindsey A. , Freeman Joshua R. , Robinson Sonia L. , Radoc Jeannie G. , Mills James L. , Silver Robert M. , Ye Aijun , Mumford Sunni L.
Published: May 2021

Evolutionary theory suggests that some animal species may experience shifts in their offspring sex ratio in response to maternal health and environmental conditions, and in some unfavorable conditions, females may be less likely to bear sons. Experimental data in both animals and humans indicate that maternal inflammation may disproportionately impact the viability of male conceptuses; however, it is unknown whether other factors associated with both pregnancy and inflammation, such as vitamin D status, are associated with the offspring sex ratio. Here, we show that among 1,228 women attempting pregnancy, preconception 25-hydroxyvitamin D concentrations are positively associated with the live birth of a male infant, with notably stronger associations among women with elevated high sensitivity C-reactive protein, a marker of systemic low-grade inflammation. Our findings suggest that vitamin D may mitigate maternal inflammation that would otherwise be detrimental to the implantation or survival of male conceptuses in utero.
Role of neutrophil extracellular traps in radiation resistance of invasive bladder cancer
Authors: Shinde-Jadhav Surashri , Mansure Jose Joao , Rayes Roni F. , Marcq Gautier , Ayoub Mina , Skowronski Rodrigo , Kool Ronald , Bourdeau France , Brimo Fadi , Spicer Jonathan , Kassouf Wassim
Published: May 2021

Radiation therapy (RT) is used in the management of several cancers; however, tumor radioresistance remains a challenge. Polymorphonuclear neutrophils (PMNs) are recruited to the tumor immune microenvironment (TIME) post-RT and can facilitate tumor progression by forming neutrophil extracellular traps (NETs). Here, we demonstrate a role for NETs as players in tumor radioresistance. Using a syngeneic bladder cancer model, increased NET deposition is observed in the TIME of mice treated with RT and inhibition of NETs improves overall radiation response. In vitro, the protein HMGB1 promotes NET formation through a TLR4-dependent manner and in vivo, inhibition of both HMGB1 and NETs significantly delays tumor growth. Finally, NETs are observed in bladder tumors of patients who did not respond to RT and had persistent disease post-RT, wherein a high tumoral PMN-to-CD8 ratio is associated with worse overall survival. Together, these findings identify NETs as a potential therapeutic target to increase radiation efficacy.
Characterization of an attenuated SARS-CoV-2 variant with a deletion at the S1/S2 junction of the spike protein
Authors: Wang Pui , Lau Siu-Ying , Deng Shaofeng , Chen Pin , Mok Bobo Wing-Yee , Zhang Anna Jinxia , Lee Andrew Chak-Yiu , Chan Kwok-Hung , Tam Rachel Chun-Yee , Xu Haoran , Zhou Runhong , Song Wenjun , Liu Li , To Kelvin Kai-Wang , Chan Jasper Fuk-Woo , Chen Zhiwei , Yuen Kwok-Yung , Chen Honglin
Published: May 2021

SARS-CoV-2 is of zoonotic origin and contains a PRRA polybasic cleavage motif which is considered critical for efficient infection and transmission in humans. We previously reported on a panel of attenuated SARS-CoV-2 variants with deletions at the S1/S2 junction of the spike protein. Here, we characterize pathogenicity, immunogenicity, and protective ability of a further cell-adapted SARS-CoV-2 variant, Ca-DelMut, in in vitro and in vivo systems. Ca-DelMut replicates more efficiently than wild type or parental virus in Vero E6 cells, but causes no apparent disease in hamsters, despite replicating in respiratory tissues. Unlike wild type virus, Ca-DelMut causes no obvious pathological changes and does not induce elevation of proinflammatory cytokines, but still triggers a strong neutralizing antibody and T cell response in hamsters and mice. Ca-DelMut immunized hamsters challenged with wild type SARS-CoV-2 are fully protected, with little sign of virus replication in the upper or lower respiratory tract, demonstrating sterilizing immunity.
Serum metabolic biomarkers for synucleinopathy conversion in isolated REM sleep behavior disorder
Authors: Laguna Ariadna , Xicoy Helena , Tolosa Eduardo , Serradell Mònica , Vilas Dolores , Gaig Carles , Fernández Manel , Yanes Oscar , Santamaria Joan , Amigó Núria , Iranzo Alex , Vila Miquel
Published: May 2021

Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is a prodromal stage of Lewy-type synucleinopathies (LTS), which can present either with an initial predominant parkinsonism (Parkinson’s disease (PD)) or dementia (dementia with Lewy bodies (DLB)). To provide insights into the underlying pathogenic mechanisms, the lipoprotein and protein glycosylation profile of 82 iRBD patients, collected before and/or after their conversion to an overt LTS, and 29 matched control serum samples were assessed by nuclear magnetic resonance (NMR) spectroscopy. Data were statistically analyzed to identify altered metabolites and construct predictive models. Univariant analysis detected no differences between iRBD patients with an LTS compared to controls. However, significant differences were found when the analysis distinguished between iRBD patients that manifested initially predominant parkinsonism (pre-PD) or dementia (pre-DLB). Significant differences were also found in the analysis of paired iRBD samples pre- and post-LTS diagnosis. Predictive models were built and distinguished between controls and pre-DLB patients, and between pre-DLB and pre-PD patients. This allowed a prediction of the possible future clinical outcome of iRBD patients. We provide evidence of altered lipoprotein and glycosylation profiles in subgroups of iRBD patients. Our results indicate that metabolic alterations and inflammation are involved in iRBD pathophysiology, and suggest biological differences underlying the progression of LTS in iRBD patients. Our data also indicate that profiling of serum samples by NMR may be a useful tool for identifying short-term high-risk iRBD patients for conversion to parkinsonism or dementia.
Ex vivo expansion of dysfunctional regulatory T lymphocytes restores suppressive function in Parkinson’s disease
Authors: Thome Aaron D. , Atassi Farah , Wang Jinghong , Faridar Alireza , Zhao Weihua , Thonhoff Jason R. , Beers David R. , Lai Eugene C. , Appel Stanley H.
Published: May 2021

Inflammation is a pathological hallmark of Parkinson’s disease (PD). Chronic pro-inflammatory responses contribute to the loss of neurons in the neurodegenerative process. The present study was undertaken to define the peripheral innate and adaptive immune contributions to inflammation in patients with PD. Immunophenotyping revealed a shift of peripheral myeloid and lymphoid cells towards a pro-inflammatory phenotype. Regulatory T cells (Tregs) were reduced in number, and their suppression of T responder proliferation decreased. The PD Tregs did not suppress activated pro-inflammatory myeloid cells. Ex vivo expansion of Tregs from patients with PD restored and enhanced their suppressive functions while expanded Tregs displayed increased expression of foxp3, il2ra (CD25), nt5e (CD73), il10, il13, ctla4, pdcd1 (PD1), and gzmb. Collectively, these findings documented a shift towards a pro-inflammatory peripheral immune response in patients with PD; the loss of Treg suppressive functions may contribute significantly to this response, supporting PD as a disorder with extensive systemic pro-inflammatory responses. The restoration and enhancement of Treg suppressive functions following ex vivo expansion may provide a potential cell therapeutic approach for patients with PD.
Volumetric and shape analysis of the hippocampus in temporal lobe epilepsy with GAD65 antibodies compared with non-immune epilepsy
Authors: Conde-Blanco Estefanía , Pascual-Diaz Saül , Carreño Mar , Muñoz-Moreno Emma , Pariente José Carlos , Boget Teresa , Manzanares Isabel , Donaire Antonio , Centeno María , Graus Francesc , Bargalló Nuria
Published: May 2021

Glutamic acid decarboxylase 65 antibodies (anti-GAD65) have been found in patients with late-onset chronic temporal lobe epilepsy (TLE). No prior neuroimaging studies have addressed how they affect hippocampal volume and shape and how they relate to cognitive abnormalities. We aimed to investigate both brain structure and function in patients with isolated TLE and high anti-GAD65 levels (RIA ≥ 2000 U/ml) compared to 8 non-immune mesial TLE (niTLE) and 8 healthy controls (HC). Hippocampal subfield volume properties were correlated with the duration of the disease and cognitive test scores. The affected hippocampus of GAD-TLE patients showed no volume changes to matched HC whereas niTLE volumes were significantly smaller. Epilepsy duration in GAD-TLE patients correlated negatively with volumes in the presubiculum, subiculum, CA1, CA2–3, CA4, molecular layer and granule cell-molecular layer of the dentate nucleus. We found differences by advanced vertex-wise shape analysis in the anterior hippocampus of the left GAD-TLE compared to HC whereas left niTLE showed bilateral posterior hippocampus deformation. Verbal deficits were similar in GAD-TLE and niTLE but did not correlate to volume changes. These data might suggest a distinct expression of hippocampal structural and functional abnormalities based on the immune response.
Cumulative incidence and risk factors for radiation induced leukoencephalopathy in high grade glioma long term survivors
Authors: Terziev Robert , Psimaras Dimitri , Marie Yannick , Feuvret Loic , Berzero Giulia , Jacob Julian , Dehais Caroline , Bompaire Flavie , Mueller Wolf , Kinnersley Ben , Delattre Jean-Yves , Idbaih Ahmed , Hoang-Xuan Khe , Sanson Marc , Ricard Damien
Published: May 2021

The incidence and risk factors associated with radiation-induced leukoencephalopathy (RIL) in long-term survivors of high-grade glioma (HGG) are still poorly investigated. We performed a retrospective research in our institutional database for patients with supratentorial HGG treated with focal radiotherapy, having a progression-free overall survival > 30 months and available germline DNA. We reviewed MRI scans for signs of leukoencephalopathy on T2/FLAIR sequences, and medical records for information on cerebrovascular risk factors and neurological symptoms. We investigated a panel of candidate single nucleotide polymorphisms (SNPs) to assess genetic risk. Eighty-one HGG patients (18 grade IV and 63 grade III, 50M/31F) were included in the study. The median age at the time of radiotherapy was 48 years old (range 18–69). The median follow-up after the completion of radiotherapy was 79 months. A total of 44 patients (44/81, 54.3%) developed RIL during follow-up. Twenty-nine of the 44 patients developed consistent symptoms such as subcortical dementia (n = 28), gait disturbances (n = 12), and urinary incontinence (n = 9). The cumulative incidence of RIL was 21% at 12 months, 42% at 36 months, and 48% at 60 months. Age > 60 years, smoking, and the germline SNP rs2120825 (PPARg locus) were associated with an increased risk of RIL. Our study identified potential risk factors for the development of RIL (age, smoking, and the germline SNP rs2120825) and established the rationale for testing PPARg agonists in the prevention and management of late-delayed radiation-induced neurotoxicity.
Total testosterone is not associated with lean mass or handgrip strength in pre-menopausal females
Authors: Alexander Sarah E. , Abbott Gavin , Aisbett Brad , Wadley Glenn D. , Hnatiuk Jill A. , Lamon Séverine
Published: May 2021

The aim of this study was to examine the relationship between endogenous testosterone concentrations and lean mass and handgrip strength in healthy, pre-menopausal females. Testosterone has been positively associated with lean mass and strength in young and older males. Whether this relationship exists in pre-menopausal females is unknown. Secondary data from the 2013–2014 National Health and Nutrition Examination Survey were used to test this relationship. Females were aged 18–40 (n = 716, age 30 ± 6 years, mean ± SD) and pre-menopausal. Multivariate linear regression models were used to examine associations between total testosterone, lean mass index (LMI) and handgrip strength. Mean ± SD testosterone concentration was 1.0 ± 0.6 nmol L−1 and mean free androgen index (FAI) was 0.02 ± 0.02. In pre-menopausal females, testosterone was not associated with LMI (β = 0.05; 95%CI − 0.04, 0.15; p = 0.237) or handgrip strength (β = 0.01; 95%CI − 0.11, 0.12; p = 0.926) in a statistically significant manner. Conversely, FAI was associated with LMI (β = − 0.03; 95%CI − 0.05, − 0.02; p = 0.000) in a quadratic manner, meaning LMI increases with increasing FAI levels. Handgrip strength was not associated with FAI (β = 0.06; 95%CI − 0.02, 0.15; p = 0.137). These findings indicate that FAI, but not total testosterone, is associated with LMI in pre-menopausal females. Neither FAI nor total testosterone are associated with handgrip strength in pre-menopausal females when testosterone concentrations are not altered pharmacologically.