bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantifying E2F1 protein dynamics in single cells
Authors: Mathey‐Prevot Bernard , Parker Bao‐Tran , Im Carolyn , Hong Cierra , Dong Peng , Yao Guang , You Lingchong
Published: March 2020

Background

E2F1 protein, a major effector of the Rb/E2F pathway plays a central role in regulating cell‐fate decisions involved in proliferation, apoptosis, and differentiation. Its expression is highly dynamic and tightly modulated through a combination of transcriptional, translational and posttranslational controls. However, the mechanisms by which its expression and activity can promote different cellular outcomes remain to be fully elucidated. To better document E2F1 expression in live cells, we have engineered a series of fluorescent E2F1 protein reporters that quantitatively capture E2F1 protein dynamics.

Methods

Reporter constructs, under the control of the mouse or human E2F1 proximal promoter, were designed to express an E2F1‐Venus fusion protein incapable of binding DNA. In addition, constructs either included or excluded the 3′ untranslated region (3′UTR) of the E2F1 gene. These constructs were introduced into fibroblasts and epithelial cells, and expression of the fusion reporter protein was validated and quantified in single cells using live imaging.

Results

In all cases, expression of the reporter protein effectively recapitulated the behavior of E2F1 under various conditions, including cell cycle progression and genotoxic stress. No or little fluorescent signal of the reporter was detected in G0, but as the cycle progressed, expression of the reporter protein steadily increased in the nucleus, peaking a few hours before cell division, but declining to baseline 2–3 h prior to the onset of mitosis. The absence of the E2F1 3′UTR in the constructs led to considerably higher steady‐state levels of the fusion protein, which although normally regulated, exhibited a slightly less complex dynamic profile during the cell cycle or genotoxic stress. Lastly, the presence or absence of Rb failed to impact the overall detection and levels of the reporter proteins.

Conclusions

Our validated E2F1 protein reporters complement nicely other reporters of the Rb/E2F pathway and provide a unique tool to follow the complex dynamics of E2F1 expression in real time in single cells.
Construction of a CRISPR‐based paired‐sgRNA library for chromosomal deletion of long non‐coding RNAs
Authors: Tao Minzhen , Mu Qiaochu , Zhang Yurui , Xie Zhen
Published: March 2020

Background

Derived from an adaptive bacterial immune system, the clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR‐associated 9 (Cas9) system has shown great potential in high‐throughput functional genomic screening, especially for protein‐coding genes. However, it is still challenging to apply the similar strategy to study non‐coding genomic elements such as long non‐coding RNAs (lncRNAs) or clusters of microRNAs, because short insertions or deletions may not be sufficient to generate loss‐of‐function phenotypes.

Methods

Here, we presented a systematic strategy for designing a CRISPR‐based paired‐sgRNA library for high‐throughput screening in non‐coding regions. Due to the abundance of lncRNAs and their diverse regulatory roles in vivo, we repurposed microarray datasets to select 600 highly expressed lncRNAs in non‐small‐cell lung cancer and designed two schemes for lncRNA deletion with ~20 paired‐sgRNAs for each lncRNA. Through Golden‐Gate assembly, we generated a pooled CRISPR‐based library with a total of 12,878 sgRNA pairs.

Results

Over 80% of paired‐sgRNAs were recovered from final pooled library with a relatively even distribution. Cleavage efficiency of sgRNA pairs was validated through experiments of transient transfection and viral infection. Moreover, randomly selected paired‐sgRNAs showed that efficient deletion of genomic DNA could be achieved with a deletion size within the range of 500 to 3000 bp.

Conclusions

In summary, we have demonstrated a strategy to design and construct a pooled paired‐sgRNA library to generate genomic deletion in the lncRNA regions, validated their deletion efficiency and explored the relationship of deletion efficiency with respect to deletion size. This method would be also suitable for investigation of other uncharacterized non‐coding genomic regions in mammalian cells in an efficient and cost‐effective manner.
ZokorDB: tissue specific regulatory network annotation for non‐coding elements of plateau zokor
Authors: Xin Jingxue , Hao Junjun , Chen Lang , Zhang Tao , Li Lei , Chen Luonan , Zhao Wenmin , Lu Xuemei , Shi Peng , Wang Yong
Published: March 2020

Background

Plateau zokor inhabits in sealed burrows from 2,000 to 4,200 meters at Qinghai‐Tibet Plateau. This extreme living environment makes it a great model to study animal adaptation to hypoxia, low temperature, and high carbon dioxide concentration.

Methods

We provide an integrated resource, ZokorDB, for tissue specific regulatory network annotation for zokor. ZokorDB is based on a high‐quality draft genome of a plateau zokor at 3,300 m and its transcriptional profiles in brain, heart, liver, kidney, and lung. The conserved non‐coding elements of zokor are annotated by their nearest genes and upstream transcriptional factor motif binding sites.

Results

ZokorDB provides a general draft gene regulatory network (GRN), i.e., potential transcription factor (TF) binds to non‐coding regulatory elements and regulates the expression of target genes (TG). Furthermore, we refined the GRN by incorporating matched RNA‐seq and DNase‐seq data from mouse ENCODE project and reconstructed five tissue‐specific regulatory networks.

Conclusions

A web‐based, open‐access database is developed for easily searching, visualizing, and downloading the annotation and data. The pipeline of non‐coding region annotation for zokor will be useful for other non‐model species. ZokorDB is free available at the website (bigd.big.ac.cn/zokordb/).
A general approach to compensation for losses incurred due to public health interventions in the infectious disease context
Authors: Holm Søren
Published: March 2020

This paper develops a general approach to how society should compensate for losses that individuals incur due to public health interventions aimed at controlling the spread of infectious diseases. The paper falls in three parts. The first part provides an initial introduction to the issues and briefly outlines five different kinds of public health interventions that will be used as test cases. They are all directed at individuals and aimed at controlling the spread of infectious diseases (1) isolation, (2) quarantine, (3) recommended voluntary social distancing, (4) changes in health care provision for asymptomatic carriers of multi-resistant microorganisms, and (5) vaccination. The interventions will be briefly described including the various risks, burdens and harms individuals who are subject to these interventions may incur. The second part briefly surveys current compensation mechanisms as far as any exist and argue that even where they exist they are clearly insufficient and do not provide adequate compensation. The third part will then develop a general framework for compensation for losses incurred due to public health interventions in the infectious disease context. This is the major analytical and constructive part of the paper. It first analyses pragmatic and ethical arguments supporting the existence of an obligation on the part of the state to compensate for such losses, and then considers whether this obligation can be defeated by (1) resource considerations, or (2) issues relating to personal responsibility.
Correction to: Refinements and higher-order beliefs: a unified survey
Authors: Kajii Atsushi , Morris Stephen
Published: March 2020

The article "Refinements and higher-order beliefs: a unified survey", written by Atsushi Kajii and Stephen Morris.
Modeling higher order adaptivity of a network by multilevel network reification
Authors: Treur Jan
Published: March 2020

In network models for real-world domains, often network adaptation has to be addressed by incorporating certain network adaptation principles. In some cases, also higher order adaptation occurs: the adaptation principles themselves also change over time. To model such multilevel adaptation processes, it is useful to have some generic architecture. Such an architecture should describe and distinguish the dynamics within the network (base level), but also the dynamics of the network itself by certain adaptation principles (first-order adaptation level), and also the adaptation of these adaptation principles (second-order adaptation level), and may be still more levels of higher order adaptation. This paper introduces a multilevel network architecture for this, based on the notion network reification. Reification of a network occurs when a base network is extended by adding explicit states representing the characteristics of the structure of the base network. It will be shown how this construction can be used to explicitly represent network adaptation principles within a network. When the reified network is itself also reified, also second-order adaptation principles can be explicitly represented. The multilevel network reification construction introduced here is illustrated for an adaptive adaptation principle from social science for bonding based on homophily and one for metaplasticity in Cognitive Neuroscience.
Cosmology with Phase 1 of the Square Kilometre Array Red Book 2018: Technical specifications and performance forecasts
Authors:   Square Kilometre Array Cosmology Science Working Group:, Bacon David J. , Battye Richard A. , Bull Philip , Camera Stefano , Ferreira Pedro G. , Harrison Ian , Parkinson David , Pourtsidou Alkistis , Santos Mário G. , Wolz Laura , Abdalla Filipe , Akrami Yashar , Alonso David , Andrianomena Sambatra , Ballardini Mario , Bernal José Luis , Bertacca Daniele , Bengaly Carlos A. P. , Bonaldi Anna , Bonvin Camille , Brown Michael L. , Chapman Emma , Chen Song , Chen Xuelei , Cunnington Steven , Davis Tamara M. , Dickinson Clive , Fonseca José , Grainge Keith , Harper Stuart , Jarvis Matt J. , Maartens Roy , Maddox Natasha , Padmanabhan Hamsa , Pritchard Jonathan R. , Raccanelli Alvise , Rivi Marzia , Roychowdhury Sambit , Sahlén Martin , Schwarz Dominik J. , Siewert Thilo M. , Viel Matteo , Villaescusa-Navarro Francisco , Xu Yidong , Yamauchi Daisuke , Zuntz Joe
Published: March 2020

We present a detailed overview of the cosmological surveys that we aim to carry out with Phase 1 of the Square Kilometre Array (SKA1) and the science that they will enable. We highlight three main surveys: a medium-deep continuum weak lensing and low-redshift spectroscopic HI galaxy survey over 5 000 deg2; a wide and deep continuum galaxy and HI intensity mapping (IM) survey over 20 000 deg2 from

$z = 0.35$

to 3; and a deep, high-redshift HI IM survey over 100 deg2 from

$z = 3$

to 6. Taken together, these surveys will achieve an array of important scientific goals: measuring the equation of state of dark energy out to

$z \sim 3$

with percent-level precision measurements of the cosmic expansion rate; constraining possible deviations from General Relativity on cosmological scales by measuring the growth rate of structure through multiple independent methods; mapping the structure of the Universe on the largest accessible scales, thus constraining fundamental properties such as isotropy, homogeneity, and non-Gaussianity; and measuring the HI density and bias out to

$z = 6$

. These surveys will also provide highly complementary clustering and weak lensing measurements that have independent systematic uncertainties to those of optical and near-infrared (NIR) surveys like Euclid, LSST, and WFIRST leading to a multitude of synergies that can improve constraints significantly beyond what optical or radio surveys can achieve on their own. This document, the 2018 Red Book, provides reference technical specifications, cosmological parameter forecasts, and an overview of relevant systematic effects for the three key surveys and will be regularly updated by the Cosmology Science Working Group in the run up to start of operations and the Key Science Programme of SKA1.
Modulation of the intestinal microbiota and the metabolites produced by the administration of ice cream and a dietary supplement containing the same probiotics
Authors: Rodrigues Vivian Cristina da Cruz , Duque Ana Luiza Rocha Faria , Fino Luciana de Carvalho , Simabuco Fernando Moreira , Sartoratto Adilson , Cabral Lucélia , Noronha Melline Fontes , Sivieri Katia , Antunes Adriane Elisabete Costa
Published: March 2020

The aim of the present work was to compare the capacity to modulate the intestinal microbiota and the production of metabolites after 14 d administration of a commercial dietary supplement and a manufactured ice cream, both containing the same quantity of inulin and the same viable counts of Lactobacillus acidophilus LA-5 and Bifidobacterium animalis BB-12, using the Simulator of the Human Intestinal Microbial Ecosystem (SHIME®) model. Samples of the colonic contents were evaluated microbiologically by real-time quantitative PCR (qRT-PCR) and next-generation sequencing and chemically by the production of SCFA (acetate, propionate and butyrate) and ammonium ions ($\text{NH}_4^ + $). Statistical analyses were carried out for all the variables using the two-way ANOVA followed by the Tukey multiple comparisons test (P < 0·05) for metabolite production, qRT-PCR and the bioinformatics analysis for microbiota diversity. Dietary supplement and ice cream were able to deliver the probiotic L. acidophilus and B. animalis to the simulated colon and modulate the microbiota, increasing beneficial micro-organisms such as Bifidobacterium spp., Bacteroides spp. and Faecalibacterium spp. for dietary supplement administration, and Lactobacillus spp. for ice cream supplementation. However, the ice cream matrix was probably more favourable for the maintenance of the metabolic activity of the probiotics in the SHIME® model, due to the larger amounts of acetate, propionate, butyrate and ammonium ions obtained after 14 d of supplementation. In conclusion, both ways of probiotic supplementation could be efficient, each with its own particularities.
The Psychology of Repression and Polarization
Authors: Nugent Elizabeth R.
Published: March 2020

How does political polarization occur under repressive conditions? Drawing on psychological theories of social identity, the author posits that the nature of repression drives polarization. Repression alters group identities, changing the perceived distance between groups and ultimately shaping the level of affective and preference polarization between them through differentiation processes. The author tests the proposed causal relationship using mixed-method data and analysis.The results of a laboratory experiment reveal that exposure to a targeted repression prime results in greater in-group identification and polarization between groups, whereas exposure to a widespread prime results in decreased levels of these same measurements. The effect of the primes appears to be mediated through group identification. Case-study evidence of polarization between political opposition groups that were differently repressed in Egypt and Tunisia reinforces these results. The findings have implications for understanding how polarization, as conditioned by repression, may alter the likelihood of the cooperative behavior among opposition actors necessary for the success of democratic politics.
Toll-based reinforcement learning for efficient equilibria in route choice
Authors: Ramos Gabriel de O. , Da Silva Bruno C. , Rădulescu Roxana , Bazzan Ana L. C. , Nowé Ann
Published: March 2020

The problem of traffic congestion incurs numerous social and economical repercussions and has thus become a central issue in every major city in the world. For this work we look at the transportation domain from a multiagent system perspective, where every driver can be seen as an autonomous decision-making agent. We explore how learning approaches can help achieve an efficient outcome, even when agents interact in a competitive environment for sharing common resources. To this end, we consider the route choice problem, where self-interested drivers need to independently learn which routes minimise their expected travel costs. Such a selfish behaviour results in the so-called user equilibrium, which is inefficient from the system’s perspective. In order to mitigate the impact of selfishness, we present Toll-based Q-learning (TQ-learning, for short). TQ-learning employs the idea of marginal-cost tolling (MCT), where each driver is charged according to the cost it imposes on others. The use of MCT leads agents to behave in a socially desirable way such that the is attainable. In contrast to previous works, however, our tolling scheme is distributed (i.e., each agent can compute its own toll), is charged a posteriori (i.e., at the end of each trip), and is fairer (i.e., agents pay exactly their marginal costs). Additionally, we provide a general formulation of the toll values for univariate, homogeneous polynomial cost functions. We present a theoretical analysis of TQ-learning, proving that it converges to a system-efficient equilibrium (i.e., an equilibrium aligned to the system optimum) in the limit. Furthermore, we perform an extensive empirical evaluation on realistic road networks to support our theoretical findings, showing that TQ-learning indeed converges to the optimum, which translates into a reduction of the congestion levels by 9.1%, on average.
Characteristics of Disaster-Related Suicide in Fukushima Prefecture After the Nuclear Accident
Authors: Takebayashi Yoshitake , Hoshino Hiroshi , Kunii Yasuto , Niwa Shin-Ichi , Maeda Masaharu
Published: March 2020

Abstract. Background: Suicide is a major concern after the 2011 earthquake and nuclear accident in Fukushima. Aims: This study delineates characteristics of the disaster-related suicides in Fukushima. Method: Data provided by the Fukushima Prefectural Police and data published by the Fukushima or Japanese Government were analyzed. Numbers of disaster-related suicides and evacuees were compared among the three prefectures affected. Age, sex, occupation, and means for disaster-related suicides in Fukushima were compared with overall suicides in Fukushima or Japan. History of medical treatment, changes in job and family structure after the disaster, and signs of contemplation were examined within the disaster-related suicides of Fukushima. Results: While other prefectures have experienced a drop in disaster-related suicides, Fukushima has not. Age-standardized disaster-related suicide rates were remarkably higher in men than in women. Moreover, disaster-related suicide rates in Fukushima were higher in women in their 50s and 80s as compared with overall suicide rates in Fukushima or Japan. Limitations: No detailed comparisons were made between disaster-related and non-disaster-related suicides. Conclusion: Disaster-related suicide rates were higher in men than in women. Also, it was found that the disaster-related suicide rates of elderly women were higher compared with overall suicide rates in Japan and Fukushima. In addition, many who died by suicide showed signs of contemplation before the attempt and had started psychiatric treatment. Improvement of suicide risk assessment skills for mental health professionals and gatekeeper training among residents will be essential to prevent disaster-related suicides.
Mesozoic‐Cenozoic Regional Stress Field Evolution in Svalbard
Authors: Maher Harmon , Senger Kim , Braathen Alvar , Mulrooney Mark Joseph , Smyrak‐Sikora Aleksandra , Osmundsen Per Terje , Ogata Kei
Published: March 2020

Cooling fracture orientations in diabase sills associated with the Cretaceous High Arctic Large Igneous Province and syn‐sedimentary Triassic faults help constrain a model for Svalbard's (NE Barents Shelf) Mesozoic stress field evolution. Fracture data from Edgeøya and adjacent islands in SE Svalbard, from S Spitsbergen, and from literature were used to model preferred orientations and temporal relationships. Orthogonal, roughly E‐W and N‐S, joints and veins in sills from SE Svalbard are interpreted as cooling fractures influenced by the ambient stress field. Aligned preferred orientations within the Triassic host strata are associated with a regional Cretaceous jointing episode driven by sill emplacement and/or erosional unloading. The regional maximum horizontal stress (likely σ1) is inferred to have been parallel to a dominant ≈E‐W set. Spitsbergen's more complex joint patterns are associated with proximity to the Cenozoic West Spitsbergen Fold‐and‐Thrust Belt, but ≈E‐W and ≈N‐S orientations occur and are typically the earlier set. Syn‐sedimentary, ≈NW‐SE striking, Triassic normal faults in SE Svalbard aligned with the maximum horizontal stress indicate a Triassic to Cretaceous counterclockwise stress field shift, with additional counterclockwise shifting during Cenozoic dextral transpression between Svalbard and Greenland. Localized joint preferred orientations consistent with both decoupled and coupled transpression occur. Changes in the regional maximum horizontal stress and deformation regime may reflect timing of which plate margin was crucial in influencing Svalbard's plate interior stress field, starting with Triassic Uralian activity to the E, then Cretaceous Amerasian Basin development to the NW, culminating with Cenozoic dextral transpression and transtension to the SW.
Linking Agricultural GHG Emissions to Global Trade Network
Authors: Zhao Xueli , Wu Xiaofang , Guan ChengHe , Ma Rong , Nielsen Chris P. , Zhang Bo
Published: March 2020

As part of the climate policy to meet the 2 °C target, actions in all economic sectors, including agriculture, are required to mitigate global greenhouse gas emissions. While there has been an ever‐increasing focus on agricultural greenhouse gas (AGHG) emissions, limited attention has been paid to their economic drivers in the globalized world economy and related mitigation potentials. This paper makes a first attempt to trace AGHG emissions via global trade networks using a multiregional input‐output model and a complex network model. Over one third of global AGHG emissions in 2012 can be linked with products traded internationally, of which intermediate trade and final trade contribute 64.2% and 35.8%, respectively. Japan, the United States, Germany, the United Kingdom, and Hong Kong are the world's five largest net importers of embodied emissions, while Ethiopia, Australia, Pakistan, India, and Argentina are the five largest net exporters. Some hunger‐afflicted developing countries in Asia and Africa are important embodied emission exporters, due to their large‐scale exports of agricultural products. Trade‐related virtual AGHG emission transfers shape a highly heterogenous network, due to the coexistence of numerous peripheral economies and a few highly connected hub economies. The network clustering structure is revealed by the regional integration of several trading communities, while hub economies are collectors and distributors in the global trade network, with important implications for emission mitigation. Achieving AGHG emission reduction calls for a combination of supply‐ and demand‐side policies covering the global trade network.
Glacier Outflow Dissolved Organic Matter as a Window Into Seasonally Changing Carbon Sources: Leverett Glacier, Greenland
Authors: Kellerman A. M. , Hawkings J. R. , Wadham J. L. , Kohler T. J. , Stibal M. , Grater E. , Marshall M. , Hatton J. E. , Beaton A. , Spencer R. G. M.
Published: March 2020

The Greenland Ice Sheet is losing mass at a remarkable rate as a result of climatic warming. This mass loss coincides with the export of dissolved organic matter (DOM) in glacial meltwaters. However, little is known about how the source and composition of exported DOM changes over the melt season, which is key for understanding its fate in downstream ecosystems. Over the 2015 ablation season, we sampled the outflow of Leverett Glacier, a large land‐terminating glacier of the Greenland Ice Sheet. Dissolved organic carbon (DOC) concentrations and DOM fluorescence were analyzed to assess the evolution of DOM sources over the course of the melt season. DOC concentrations and red‐shifted fluorescence were highly associated (R2 > 0.95) and suggest terrestrial inputs from overridden soils dominated DOM early season inputs before progressive dilution with increasing discharge. During the outburst period, supraglacial drainage events disrupted the subglacial drainage system and introduced dominant protein‐like fluorescence signatures not observed in basal flow. These results suggest that subglacial hydrology and changing water sources influence exported DOC concentration and DOM composition, and these sources were differentiated using fluorescence characteristics. Red‐shifted fluorescence components were robust proxies for DOC concentration. Finally, the majority of DOM flux, which occurs during the outburst and postoutburst periods, was characterized by protein‐like fluorescence from supraglacial and potentially subglacial microbial sources. As protein‐like fluorescence is linked to the bioavailability of DOM, the observed changes likely reflect seasonal variations in the impact of glacial inputs on secondary production in downstream ecosystems due to shifting hydrologic regimes.
Robust and replicable measurement for prepulse inhibition of the acoustic startle response
Authors: Miller Eric A. , Kastner David B. , Grzybowski Michael N. , Dwinell Melinda R. , Geurts Aron M. , Frank Loren M.
Published: March 2020

Measuring animal behavior in the context of experimental manipulation is critical for modeling, and understanding neuropsychiatric disease. Prepulse inhibition of the acoustic startle response (PPI) is a behavioral phenomenon studied extensively for this purpose, but the results of PPI studies are often inconsistent. As a result, the utility of this phenomenon remains uncertain. Here, we deconstruct the phenomenon of PPI and confirm several limitations of the methodology traditionally utilized to describe PPI, including that the underlying startle response has a non-Gaussian distribution, and that the traditional PPI metric changes with different stimuli. We then develop a novel model that reveals PPI to be a combination of the previously appreciated scaling of the startle response, as well as a scaling of sound processing. Using our model, we find no evidence for differences in PPI in a rat model of Fragile-X Syndrome (FXS) compared with wild-type controls. These results in the rat provide a reliable methodology that could be used to clarify inconsistent PPI results in mice and humans. In contrast, we find robust differences between wild-type male and female rats. Our model allows us to understand the nature of these differences, and we find that both the startle-scaling and sound-scaling components of PPI are a function of the baseline startle response. Males and females differ specifically in the startle-scaling, but not the sound-scaling, component of PPI. These findings establish a robust experimental and analytical approach that has the potential to provide a consistent biomarker of brain function.
Long non-coding RNA HOTAIR knockdown enhances radiosensitivity through regulating microRNA-93/ATG12 axis in colorectal cancer
Authors: Liu Yingqiang , Chen Xijuan , Chen Xiling , Liu Junqi , Gu Hao , Fan Ruitai , Ge Hong
Published: March 2020

Colorectal cancer (CRC) is a global healthcare problem. Radioresistance is a huge setback for CRC radiotherapy. In this text, the roles and molecular mechanisms of long non-coding RNA HOTAIR in CRC tumorigenesis and radioresistance were further investigated. ATG12 mRNA, HOTAIR, and microRNA-93 (miR-93) levels were measured by quantitative reverse transcription polymerase chain reaction (RT-qPCR) assay. Protein levels of LC3 I, LC3 II, p62, ATG12, cleaved caspase 3, Bax, and Bcl-2 were detected by western blotting assay in cells and were examined by immunohistochemistry (IHC) assay in tissues. Cell survival fractions, viability, and apoptotic rates were determined by clonogenic survival assay, CCK-8 assay, and flow cytometry analysis, respectively. The relationships of HOTAIR, miR-93, and ATG12 were tested by bioinformatics analysis and luciferase reporter assay. Mouse xenograft tumor models were established to investigate the influence of HOTAIR knockdown on CRC radioresistance in vivo. We found that HOTAIR expression was markedly upregulated in plasma from CRC patients after radiotherapy and CRC cells after irradiation. HOTAIR knockdown, miR-93 overexpression, or ATG12 silencing weakened cell viability, induced cell apoptosis, inhibited cell autophagy, and enhanced cell radiosensitivity in CRC. HOTAIR exerted its functions by downregulating miR-93. Moreover, HOTAIR functioned as a molecular sponge of miR-93 to regulate ATG12 expression. ATG12 protein expression was markedly upregulated and associated with miR-93 and HOTAIR expression in CRC tissues. Furthermore, HOTAIR knockdown enhanced radiosensitivity of CRC xenograft tumors by regulating miR-93/ATG12 axis. In conclusion, HOTAIR knockdown potentiated radiosensitivity through regulating miR-93/ATG12 axis in CRC, further elucidating the roles and molecular basis of HOTAIR in CRC radioresistance.
Metformin inhibits IL-1β secretion via impairment of NLRP3 inflammasome in keratinocytes: implications for preventing the development of psoriasis
Authors: Tsuji Gaku , Hashimoto-Hachiya Akiko , Yen Vu Hai , Takemura Masaki , Yumine Ayako , Furue Kazuhisa , Furue Masutaka , Nakahara Takeshi
Published: March 2020

Psoriasis is a systemic inflammatory disease significantly associated with comorbidities including type 2 diabetes mellitus (T2DM). Metformin is utilized as a first-line agent for treating T2DM. Although metformin reportedly inhibits mature IL-1β secretion via NLRP3 inflammasome in macrophages of T2DM patients, it remains unclear whether it affects skin inflammation in psoriasis. To test this, we analysed normal human epidermal keratinocytes (NHEKs), a major skin component, stimulated with the key mediators of psoriasis development, TNF-α and IL-17A. This stimulation induced the upregulation of pro-IL-1β mRNA and protein levels, and subsequently mature IL-1β secretion, which was inhibited by metformin treatment. To further reveal the mechanism involved, we examined how metformin treatment affected NLRP3 inflammasome activated by TNF-α and IL-17A stimulation. We found that this treatment downregulated caspase-1 expression, a key mediator of NLRP3 inflammasome. Furthermore, inhibitors of AMPK and SIRT1 abrogated the downregulation of caspase-1 induced by metformin treatment, indicating that AMPK and SIRT1 are essential for the inhibitory effect on NLRP3 inflammasome in NHEKs. As IL-1β stimulation induced upregulation of IL-36γ, CXCL1, CXCL2, CCL20, S100A7, S100A8 and S100A9 mRNA and protein levels in NHEKs, we examined whether metformin treatment affects such gene expression. Metformin treatment inhibited upregulation of IL-36γ, CXCL1, CXCL2, CCL20, S100A7, S100A8 and S100A9 mRNA and protein levels induced by TNF-α and IL-17A stimulation. Finally, we examined whether metformin administration affected psoriasis development in an imiquimod-induced mouse psoriasis model. Oral metformin treatment significantly decreased ear thickness, epidermal hyperplasia and inflammatory cell infiltration. A cytokine profile in the epidermis under metformin treatment showed that IL-1β, Cxcl1, Cxcl2, S100a7, S100a8 and S100A9 mRNA levels were downregulated compared with control levels. These results indicate that metformin administration prevented psoriasis development in vivo. Collectively, our findings suggest that metformin-mediated anti-psoriatic effects on the skin have the potential for treating psoriasis in T2DM patients.
Targeting immunometabolism as an anti-inflammatory strategy
Authors: Pålsson-McDermott Eva M. , O’Neill Luke A. J.
Published: March 2020

The growing field of immunometabolism has taught us how metabolic cellular reactions and processes not only provide a means to generate ATP and biosynthetic precursors, but are also a way of controlling immunity and inflammation. Metabolic reprogramming of immune cells is essential for both inflammatory as well as anti-inflammatory responses. Four anti-inflammatory therapies, DMF, Metformin, Methotrexate and Rapamycin all work by affecting metabolism and/or regulating or mimicking endogenous metabolites with anti-inflammatory effects. Evidence is emerging for the targeting of specific metabolic events as a strategy to limit inflammation in different contexts. Here we discuss these recent developments and speculate on the prospect of targeting immunometabolism in the effort to develop novel anti-inflammatory therapeutics. As accumulating evidence for roles of an intricate and elaborate network of metabolic processes, including lipid, amino acid and nucleotide metabolism provides key focal points for developing new therapies, we here turn our attention to glycolysis and the TCA cycle to provide examples of how metabolic intermediates and enzymes can provide potential novel therapeutic targets.
The discovery of dynamic chiral anomaly in a Weyl semimetal NbAs
Authors: Yuan Xiang , Zhang Cheng , Zhang Yi , Yan Zhongbo , Lyu Tairu , Zhang Mengyao , Li Zhilin , Song Chaoyu , Zhao Minhao , Leng Pengliang , Ozerov Mykhaylo , Chen Xiaolong , Wang Nanlin , Shi Yi , Yan Hugen , Xiu Faxian
Published: March 2020

The experimental discovery of Weyl semimetals offers unprecedented opportunities to study Weyl physics in condensed matters. Unique electromagnetic response of Weyl semimetals such as chiral magnetic effect has been observed and presented by the axial θ E · B term in electromagnetic Lagrangian (E and B are the electric and magnetic field, respectively). But till now, the experimental progress in this direction in Weyl semimetals is restricted to the DC regime. Here we report experimental access to the dynamic regime in Weyl semimetal NbAs by combining the internal deformation potential of coupled phonons with applied static magnetic field. While the dynamic E · B field is realized, it produces an anomalous phonon activity with a characteristic angle-dependence. Our results provide an effective approach to achieve the dynamic regime beyond the widely-investigated DC limit which enables the coupling between the Weyl fermions and the electromagnetic wave for further study of novel light-matter interactions in Weyl semimetals.
Resolving dynamics and function of transient states in single enzyme molecules
Authors: Sanabria Hugo , Rodnin Dmitro , Hemmen Katherina , Peulen Thomas-Otavio , Felekyan Suren , Fleissner Mark R. , Dimura Mykola , Koberling Felix , Kühnemuth Ralf , Hubbell Wayne , Gohlke Holger , Seidel Claus A. M.
Published: March 2020

We use a hybrid fluorescence spectroscopic toolkit to monitor T4 Lysozyme (T4L) in action by unraveling the kinetic and dynamic interplay of the conformational states. In particular, by combining single-molecule and ensemble multiparameter fluorescence detection, EPR spectroscopy, mutagenesis, and FRET-positioning and screening, and other biochemical and biophysical tools, we characterize three short-lived conformational states over the ns-ms timescale. The use of 33 FRET-derived distance sets, to screen available T4L structures, reveal that T4L in solution mainly adopts the known open and closed states in exchange at 4 µs. A newly found minor state, undisclosed by, at present, more than 500 crystal structures of T4L and sampled at 230 µs, may be actively involved in the product release step in catalysis. The presented fluorescence spectroscopic toolkit will likely accelerate the development of dynamic structural biology by identifying transient conformational states that are highly abundant in biology and critical in enzymatic reactions.
Structural evolution at the oxidative and reductive limits in the first electrochemical cycle of Li1.2Ni0.13Mn0.54Co0.13O2
Authors: Yin Wei , Grimaud Alexis , Rousse Gwenaelle , Abakumov Artem M. , Senyshyn Anatoliy , Zhang Leiting , Trabesinger Sigita , Iadecola Antonella , Foix Dominique , Giaume Domitille , Tarascon Jean-Marie
Published: March 2020

High-energy-density lithium-rich materials are of significant interest for advanced lithium-ion batteries, provided that several roadblocks, such as voltage fade and poor energy efficiency are removed. However, this remains challenging as their functioning mechanisms during first cycle are not fully understood. Here we enlarge the cycling potential window for Li1.2Ni0.13Mn0.54Co0.13O2 electrode, identifying novel structural evolution mechanism involving a structurally-densified single-phase A’ formed under harsh oxidizing conditions throughout the crystallites and not only at the surface, in contrast to previous beliefs. We also recover a majority of first-cycle capacity loss by applying a constant-voltage step on discharge. Using highly reducing conditions we obtain additional capacity via a new low-potential P” phase, which is involved into triggering oxygen redox on charge. Altogether, these results provide deeper insights into the structural-composition evolution of Li1.2Ni0.13Mn0.54Co0.13O2 and will help to find measures to cure voltage fade and improve energy efficiency in this class of material.
Transposon age and non-CG methylation
Authors: Wang Zhengming , Baulcombe David C.
Published: March 2020

Silencing of transposable elements (TEs) is established by small RNA-directed DNA methylation (RdDM). Maintenance of silencing is then based on a combination of RdDM and RNA-independent mechanisms involving DNA methyltransferase MET1 and chromodomain DNA methyltransferases (CMTs). Involvement of RdDM, according to this model should decrease with TE age but here we show a different pattern in tomato and Arabidopsis. In these species the CMTs silence long terminal repeat (LTR) transposons in the distal chromatin that are younger than those affected by RdDM. To account for these findings we propose that, after establishment of primary RdDM as in the original model, there is an RNA-independent maintenance phase involving CMTs followed by secondary RdDM. This progression of epigenetic silencing in the gene-rich distal chromatin is likely to influence the transcriptome either in cis or in trans depending on whether the mechanisms are RNA-dependent or -independent.
Two distinct modes of DNMT1 recruitment ensure stable maintenance DNA methylation
Authors: Nishiyama Atsuya , Mulholland Christopher B. , Bultmann Sebastian , Kori Satomi , Endo Akinori , Saeki Yasushi , Qin Weihua , Trummer Carina , Chiba Yoshie , Yokoyama Haruka , Kumamoto Soichiro , Kawakami Toru , Hojo Hironobu , Nagae Genta , Aburatani Hiroyuki , Tanaka Keiji , Arita Kyohei , Leonhardt Heinrich , Nakanishi Makoto
Published: March 2020

Stable inheritance of DNA methylation is critical for maintaining differentiated phenotypes in multicellular organisms. We have recently identified dual mono-ubiquitylation of histone H3 (H3Ub2) by UHRF1 as an essential mechanism to recruit DNMT1 to chromatin. Here, we show that PCNA-associated factor 15 (PAF15) undergoes UHRF1-dependent dual mono-ubiquitylation (PAF15Ub2) on chromatin in a DNA replication-coupled manner. This event will, in turn, recruit DNMT1. During early S-phase, UHRF1 preferentially ubiquitylates PAF15, whereas H3Ub2 predominates during late S-phase. H3Ub2 is enhanced under PAF15 compromised conditions, suggesting that H3Ub2 serves as a backup for PAF15Ub2. In mouse ES cells, loss of PAF15Ub2 results in DNA hypomethylation at early replicating domains. Together, our results suggest that there are two distinct mechanisms underlying replication timing-dependent recruitment of DNMT1 through PAF15Ub2 and H3Ub2, both of which are prerequisite for high fidelity DNA methylation inheritance.
Oxide-ion conduction in the Dion–Jacobson phase CsBi2Ti2NbO10−δ
Authors: Zhang Wenrui , Fujii Kotaro , Niwa Eiki , Hagihala Masato , Kamiyama Takashi , Yashima Masatomo
Published: March 2020

Oxide-ion conductors have found applications in various electrochemical devices, such as solid-oxide fuel cells, gas sensors, and separation membranes. Dion–Jacobson phases are known for their rich magnetic and electrical properties; however, there have been no reports on oxide-ion conduction in this family of materials. Here, for the first time to the best of our knowledge, we show the observation of fast oxygen anionic conducting behavior in CsBi2Ti2NbO10−δ. The bulk ionic conductivity of this Dion–Jacobson phase is 8.9 × 10−2 S cm−1 at 1073 K, a level that is higher than that of the conventional yttria-stabilized zirconia. The oxygen ion transport is attributable to the large anisotropic thermal motions of oxygen atoms, the presence of oxygen vacancies, and the formation of oxide-ion conducting layers in the crystal structure. The present finding of high oxide-ion conductivity in rare-earth-free CsBi2Ti2NbO10−δ suggests the potential of Dion–Jacobson phases as a platform to identify superior oxide-ion conductors.
A fluoroxalate cathode material for potassium-ion batteries with ultra-long cyclability
Authors: Ji Bifa , Yao Wenjiao , Zheng Yongping , Kidkhunthod Pinit , Zhou Xiaolong , Tunmee Sarayut , Sattayaporn Suchinda , Cheng Hui-Ming , He Haiyan , Tang Yongbing
Published: March 2020

Potassium-ion batteries are a compelling technology for large scale energy storage due to their low-cost and good rate performance. However, the development of potassium-ion batteries remains in its infancy, mainly hindered by the lack of suitable cathode materials. Here we show that a previously known frustrated magnet, KFeC2O4F, could serve as a stable cathode for potassium ion storage, delivering a discharge capacity of ~112 mAh g−1 at 0.2 A g−1 and 94% capacity retention after 2000 cycles. The unprecedented cycling stability is attributed to the rigid framework and the presence of three channels that allow for minimized volume fluctuation when Fe2+/Fe3+ redox reaction occurs. Further, pairing this KFeC2O4F cathode with a soft carbon anode yields a potassium-ion full cell with an energy density of ~235 Wh kg−1, impressive rate performance and negligible capacity decay within 200 cycles. This work sheds light on the development of low-cost and high-performance K-based energy storage devices.
Electron transport chain activity is a predictor and target for venetoclax sensitivity in multiple myeloma
Authors: Bajpai Richa , Sharma Aditi , Achreja Abhinav , Edgar Claudia L. , Wei Changyong , Siddiqa Arusha A. , Gupta Vikas A. , Matulis Shannon M. , McBrayer Samuel K. , Mittal Anjali , Rupji Manali , Barwick Benjamin G. , Lonial Sagar , Nooka Ajay K. , Boise Lawrence H. , Nagrath Deepak , Shanmugam Mala
Published: March 2020

The BCL-2 antagonist venetoclax is highly effective in multiple myeloma (MM) patients exhibiting the 11;14 translocation, the mechanistic basis of which is unknown. In evaluating cellular energetics and metabolism of t(11;14) and non-t(11;14) MM, we determine that venetoclax-sensitive myeloma has reduced mitochondrial respiration. Consistent with this, low electron transport chain (ETC) Complex I and Complex II activities correlate with venetoclax sensitivity. Inhibition of Complex I, using IACS-010759, an orally bioavailable Complex I inhibitor in clinical trials, as well as succinate ubiquinone reductase (SQR) activity of Complex II, using thenoyltrifluoroacetone (TTFA) or introduction of SDHC R72C mutant, independently sensitize resistant MM to venetoclax. We demonstrate that ETC inhibition increases BCL-2 dependence and the ‘primed’ state via the ATF4-BIM/NOXA axis. Further, SQR activity correlates with venetoclax sensitivity in patient samples irrespective of t(11;14) status. Use of SQR activity in a functional-biomarker informed manner may better select for MM patients responsive to venetoclax therapy.
Climate adaptation by crop migration
Authors: Sloat Lindsey L. , Davis Steven J. , Gerber James S. , Moore Frances C. , Ray Deepak K. , West Paul C. , Mueller Nathaniel D.
Published: March 2020

Many studies have estimated the adverse effects of climate change on crop yields, however, this literature almost universally assumes a constant geographic distribution of crops in the future. Movement of growing areas to limit exposure to adverse climate conditions has been discussed as a theoretical adaptive response but has not previously been quantified or demonstrated at a global scale. Here, we assess how changes in rainfed crop area have already mediated growing season temperature trends for rainfed maize, wheat, rice, and soybean using spatially-explicit climate and crop area data from 1973 to 2012. Our results suggest that the most damaging impacts of warming on rainfed maize, wheat, and rice have been substantially moderated by the migration of these crops over time and the expansion of irrigation. However, continued migration may incur substantial environmental costs and will depend on socio-economic and political factors in addition to land suitability and climate.
Ultra-high open-circuit voltage of tin perovskite solar cells via an electron transporting layer design
Authors: Jiang Xianyuan , Wang Fei , Wei Qi , Li Hansheng , Shang Yuequn , Zhou Wenjia , Wang Cheng , Cheng Peihong , Chen Qi , Chen Liwei , Ning Zhijun
Published: March 2020

Tin perovskite is rising as a promising candidate to address the toxicity and theoretical efficiency limitation of lead perovskite. However, the voltage and efficiency of tin perovskite solar cells are much lower than lead counterparts. Herein, indene-C60 bisadduct with higher energy level is utilized as an electron transporting material for tin perovskite solar cells. It suppresses carrier concentration increase caused by remote doping, which significantly reduces interface carriers recombination. Moreover, indene-C60 bisadduct increases the maximum attainable photovoltage of the device. As a result, the use of indene-C60 bisadduct brings unprecedentedly high voltage of 0.94 V, which is over 50% higher than that of 0.6 V for device based on [6,6]-phenyl-C61-butyric acid methyl ester. The device shows a record power conversion efficiency of 12.4% reproduced in an accredited independent photovoltaic testing lab.
DJ-1 suppresses ferroptosis through preserving the activity of S-adenosyl homocysteine hydrolase
Authors: Cao Ji , Chen Xiaobing , Jiang Li , Lu Bin , Yuan Meng , Zhu Difeng , Zhu Hong , He Qiaojun , Yang Bo , Ying Meidan
Published: March 2020

Ferroptosis is a newly characterized form of regulated cell death mediated by iron-dependent accumulation of lipid reactive oxygen species and holds great potential for cancer therapy. However, the molecular mechanisms underlying ferroptosis remain largely elusive. In this study, we define an integrative role of DJ-1 in ferroptosis. Inhibition of DJ-1 potently enhances the sensitivity of tumor cells to ferroptosis inducers both in vitro and in vivo. Metabolic analysis and metabolite rescue assay reveal that DJ-1 depletion inhibits the transsulfuration pathway by disrupting the formation of the S-adenosyl homocysteine hydrolase tetramer and impairing its activity. Consequently, more ferroptosis is induced when homocysteine generation is decreased, which might be the only source of glutathione biosynthesis when cystine uptake is blocked. Thus, our findings show that DJ-1 determines the response of cancer cells to ferroptosis, and highlight a candidate therapeutic target to potentially improve the effect of ferroptosis-based antitumor therapy.