bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sequential targeting of PI3Kδ and LAG3 as an effective anti-cancer approach
Authors: Lauder Sarah N. , Vanhaesebroeck Bart , Gallimore Awen 
Published: April 2021

SummaryEmerging studies have demonstrated the potential of PI3Kδ blockade as an immunotherapy for solid tumours. In pre-clinical models, we recently demonstrated that anti-LAG3 immune checkpoint blockade vastly potentiated PI3Kδ-based immunotherapy, enabling successful tumour control in all treated mice.
MLL5 improves ATRA driven differentiation and promotes xenotransplant engraftment in acute promyelocytic leukemia model
Authors: Pereira-Martins Diego A. , Weinhäuser Isabel , Coelho-Silva Juan Luiz , França-Neto Pedro L. , Almeida Luciana Y. , Bianco Thiago M. , Silva Cleide L. , França Rafael F. , Traina Fabiola , Rego Eduardo M. , Schuringa Jan Jacob , Lucena-Araujo Antonio R. 
Published: April 2021

AbstractAlthough the mixed lineage leukemia 5 (MLL5) gene has prognostic implications in acute promyelocyte leukemia (APL), the underlying mechanism remains to be elucidated. Here, we demonstrate the critical role exerted by MLL5 in APL regarding cell proliferation and resistance to drug-induced apoptosis, through mtROS regulation. Additionally, MLL5 overexpression increased the responsiveness of APL leukemic cells to all-trans retinoic acid (ATRA)-induced differentiation, via regulation of the epigenetic modifiers SETD7 and LSD1. In silico analysis indicated that APL blasts with MLL5high transcript levels were associated with retinoic acid binding and downstream signaling, while MLL5low blasts displayed decreased expression of epigenetic modifiers (such as KMT2C, PHF8 and ARID4A). Finally, APL xenograft transplants demonstrated improved engraftment of MLL5-expressing cells and increased myeloid differentiation over time. Concordantly, evaluation of engrafted blasts revealed increased responsiveness of MLL5-expressing cells to ATRA-induced granulocytic differentiation. Together, we describe the epigenetic changes triggered by the interaction of MLL5 and ATRA resulting in enhanced granulocytic differentiation.
Membrane lymphotoxin-α2β is a novel tumor necrosis factor (TNF) receptor 2 (TNFR2) agonist
Authors: Kucka Kirstin , Lang Isabell , Zhang Tengyu , Siegmund Daniela , Medler Juliane , Wajant Harald 
Published: April 2021

AbstractIn the early 1990s, it has been described that LTα and LTβ form LTα2β and LTαβ2heterotrimers, which bind to TNFR1 and LTβR, respectively. Afterwards, the LTαβ2–LTβR system has been intensively studied while the LTα2β–TNFR1 interaction has been ignored to date, presumably due to the fact that at the time of identification of the LTα2β–TNFR1 interaction one knew already two ligands for TNFR1, namely TNF and LTα. Here, we show that LTα2β interacts not only with TNFR1 but also with TNFR2. We furthermore demonstrate that membrane-bound LTα2β (memLTα2β), despite its asymmetric structure, stimulates TNFR1 and TNFR2 signaling. Not surprising in view of its ability to interact with TNFR2, LTα2β is inhibited by Etanercept, which is approved for the treatment of rheumatoid arthritis and also inhibits TNF and LTα.
Single loss of a Trp53 allele triggers an increased oxidative, DNA damage and cytokine inflammatory responses through deregulation of IκBα expression
Authors: Marruecos Laura , Manils Joan , Moreta Cristina , Gómez Diana , Filgaira Ingrid , Serafin Anna , Cañas Xavier , Espinosa Lluís , Soler Concepció 
Published: April 2021

AbstractDose of Trp53, the main keeper of genome stability, influences tumorigenesis; however, the causes underlying and driving tumorigenesis over time by the loss of a single p53 allele are still poorly characterized. Here, we found that single p53 allele loss specifically impacted the oxidative, DNA damage and inflammatory status of hematopoietic lineages. In particular, single Trp53 allele loss in mice triggered oxidative stress in peripheral blood granulocytes and spleenocytes, whereas lack of two Trp53 alleles produced enhanced oxidative stress in thymus cells, resulting in a higher incidence of lymphomas in the Trp53 knockout (KO) mice compared with hemizygous (HEM). In addition, single or complete loss of Trp53 alleles, as well as p53 downregulation, led to a differential increase in basal, LPS- and UVB-induced expression of a plethora of pro-inflammatory cytokine, such as interleukin-12 (Il-12a), TNFα (Tnfa) and interleukin (Il-23a) in bone marrow-derived macrophage cells (BMDMs) compared to WT cells. Interestingly, p53-dependent increased inflammatory gene expression correlated with deregulated expression of the NF-κB pathway inhibitor IκBα. Chromatin immunoprecipitation data revealed decreased p65 binding to Nfkbia in the absence of p53 and p53 binding to Nfkbia promoter, uncovering a novel crosstalk mechanism between p53 and NF-κB transcription factors. Overall, our data suggest that single Trp53 allele loss can drive a sustained inflammatory, DNA damage and oxidative stress response that, over time, facilitate and support carcinogenesis.
LncRNA MALAT1 promotes gastric cancer progression via inhibiting autophagic flux and inducing fibroblast activation
Authors: Wang Zhenqiang , Wang Xinjing , Zhang Tianqi , Su Liping , Liu Bingya , Zhu Zhenggang , Li Chen 
Published: April 2021

AbstractAutophagy defection contributes to inflammation dysregulation, which plays an important role in gastric cancer (GC) progression. Various studies have demonstrated that long noncoding RNA could function as novel regulators of autophagy. Previously, long noncoding RNA MALAT1 was reported upregulated in GC cells and could positively regulate autophagy in various cancers. Here, we for the first time found that MALAT1 could promote interleukin-6 (IL-6) secretion in GC cells by blocking autophagic flux. Moreover, IL-6 induced by MALAT1 could activate normal to cancer-associated fibroblast conversion. The interaction between GC cells and cancer-associated fibroblasts in the tumour microenvironment could facilitate cancer progression. Mechanistically, MALAT1 overexpression destabilized the PTEN mRNA in GC cells by competitively interacting with the RNA-binding protein ELAVL1 to activate the AKT/mTOR pathway for impairing autophagic flux. As a consequence of autophagy inhibition, SQSTM1 accumulation promotes NF-κB translocation to elevate IL-6 expression. Overall, these results demonstrated that intercellular interaction between GC cells and fibroblasts was mediated by autophagy inhibition caused by increased MALAT1 that promotes GC progression, providing novel prevention and therapeutic strategies for GC.
Maheshvara regulates JAK/STAT signaling by interacting and stabilizing hopscotch transcripts which leads to apoptosis in Drosophila melanogaster
Authors: Maurya Bhawana , Surabhi Satya , Das Rituparna , Pandey Pranjali , Mukherjee Ashim , Mutsuddi Mousumi 
Published: April 2021

AbstractMaheshvara (mahe), an RNA helicase that is widely conserved across taxa, regulates Notch signaling and neuronal development in Drosophila. In order to identify novel components regulated by mahe, transcriptome profiling of ectopic mahe was carried out and this revealed striking upregulation of JAK/STAT pathway components like upd1, upd2, upd3, and socs36E. Further, significant downregulation of the pathway components in mahe loss-of-function mutant as well as upon lowering the level of mahe by RNAi, supported and strengthened our transcriptome data. Parallelly, we observed that mahe, induced caspase-dependent apoptosis in photoreceptor neurons, and this phenotype was significantly modulated by JAK/STAT pathway components. RNA immunoprecipitation unveiled the presence of JAK/STAT tyrosine kinase hopscotch (hop) transcripts in the complex immunoprecipitated with Mahe, which ultimately resulted in stabilization and elevation of hop transcripts. Additionally, we also observed the surge in activity of downstream transcription factor Stat92E, which is indicative of activation of the JAK/STAT signaling, and this in turn led to apoptosis via upregulation of hid. Taken together, our data provide a novel regulation of JAK/STAT pathway by RNA helicase Maheshvara, which ultimately promotes apoptosis.
Functional comparison of SARS-CoV-2 with closely related pangolin and bat coronaviruses
Authors: Nie Jianhui , Li Qianqian , Zhang Li , Cao Yang , Zhang Yue , Li Tao , Wu Jiajing , Liu Shuo , Zhang Mengyi , Zhao Chenyan , Liu Huan , Nie Lingling , Qin Haiyang , Wang Meng , Lu Qiong , Li Xiaoyu , Liu Junkai , Liang Haoyu , Jiang Taijiao , Duan Kai , Yang Xiaoming , Shen Yuelei , Huang Weijin , Wang Youchun 
Published: April 2021

AbstractThe origin and intermediate host for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is yet to be determined. Coronaviruses found to be closely related to SARS-CoV-2 include RaTG13 derived from bat and two clusters (PCoV-GD and PCoV-GX) of coronaviruses identified in pangolin. Here, we studied the infectivity and antigenicity patterns of SARS-CoV-2 and the three related coronaviruses. Compared with the other three viruses, RaTG13 showed almost no infectivity to a variety of cell lines. The two pangolin coronaviruses and SARS-CoV-2 showed similar infectious activity. However, in SARS-CoV-2-susceptible cell lines, the pangolin coronaviruses presented even higher infectivity. The striking difference between the SARS-CoV-2 and pangolin coronaviruses is that the latter can infect porcine cells, which could be partially attributed to an amino acid difference at the position of 498 of the spike protein. The infection by SARS-CoV-2 was mainly mediated by Furin and TMPRSS2, while PCoV-GD and PCoV-GX mainly depend on Cathepsin L. Extensive cross-neutralization was found between SARS-CoV-2 and PCoV-GD. However, almost no cross-neutralization was observed between PCoV-GX and SARS-CoV-2 or PCoV-GD. More attention should be paid to pangolin coronaviruses and to investigate the possibility of these coronaviruses spreading across species to become zoonoses among pigs or humans.
T cell assays differentiate clinical and subclinical SARS-CoV-2 infections from cross-reactive antiviral responses
Authors: Ogbe Ane , Kronsteiner Barbara , Skelly Donal T. , Pace Matthew , Brown Anthony , Adland Emily , Adair Kareena , Akhter Hossain Delowar , Ali Mohammad , Ali Serat-E , Angyal Adrienn , Ansari M. Azim , Arancibia-Cárcamo Carolina V. , Brown Helen , Chinnakannan Senthil , Conlon Christopher , de Lara Catherine , de Silva Thushan , Dold Christina , Dong Tao , Donnison Timothy , Eyre David , Flaxman Amy , Fletcher Helen , Gardner Joshua , Grist James T. , Hackstein Carl-Philipp , Jaruthamsophon Kanoot , Jeffery Katie , Lambe Teresa , Lee Lian , Li Wenqin , Lim Nicholas , Matthews Philippa C. , Mentzer Alexander J. , Moore Shona C. , Naisbitt Dean J. , Ogese Monday , Ogg Graham , Openshaw Peter , Pirmohamed Munir , Pollard Andrew J. , Ramamurthy Narayan , Rongkard Patpong , Rowland-Jones Sarah , Sampson Oliver , Screaton Gavin , Sette Alessandro , Stafford Lizzie , Thompson Craig , Thomson Paul J. , Thwaites Ryan , Vieira Vinicius , Weiskopf Daniela , Zacharopoulou Panagiota ,   Oxford Immunology Network Covid-19 Response T Cell Consortium, Chalk Jeremy , Kerr Georgina , Phalora Prabhjeet , Csala Anna , Jones Mathew , Robinson Nicola , Brown Rachael , Hutchings Claire , Provine Nicholas , Ratcliff Jeremy , Amini Ali ,   Oxford Protective T Cell Immunology for COVID-19 (OPTIC) Clinical Team, Borak Martyna , Dimitriadis Stavros , Fordwoh Thomas , Horsington Bryn , Johnson Sile , Morrow Jordan , Warren Yolanda , Wells Charlie , Turtle Lance , Klenerman Paul , Goulder Philip , Frater John , Barnes Eleanor , Dunachie Susanna 
Published: April 2021

AbstractIdentification of protective T cell responses against SARS-CoV-2 requires distinguishing people infected with SARS-CoV-2 from those with cross-reactive immunity to other coronaviruses. Here we show a range of T cell assays that differentially capture immune function to characterise SARS-CoV-2 responses. Strong ex vivo ELISpot and proliferation responses to multiple antigens (including M, NP and ORF3) are found in 168 PCR-confirmed SARS-CoV-2 infected volunteers, but are rare in 119 uninfected volunteers. Highly exposed seronegative healthcare workers with recent COVID-19-compatible illness show T cell response patterns characteristic of infection. By contrast, >90% of convalescent or unexposed people show proliferation and cellular lactate responses to spike subunits S1/S2, indicating pre-existing cross-reactive T cell populations. The detection of T cell responses to SARS-CoV-2 is therefore critically dependent on assay and antigen selection. Memory responses to specific non-spike proteins provide a method to distinguish recent infection from pre-existing immunity in exposed populations.
Variable number tandem repeats mediate the expression of proximal genes
Authors: Bakhtiari Mehrdad , Park Jonghun , Ding Yuan-Chun , Shleizer-Burko Sharona , Neuhausen Susan L. , Halldórsson Bjarni V. , Stefánsson Kári , Gymrek Melissa , Bafna Vineet 
Published: April 2021

AbstractVariable number tandem repeats (VNTRs) account for significant genetic variation in many organisms. In humans, VNTRs have been implicated in both Mendelian and complex disorders, but are largely ignored by genomic pipelines due to the complexity of genotyping and the computational expense. We describe adVNTR-NN, a method that uses shallow neural networks to genotype a VNTR in 18 seconds on 55X whole genome data, while maintaining high accuracy. We use adVNTR-NN to genotype 10,264 VNTRs in 652 GTEx individuals. Associating VNTR length with gene expression in 46 tissues, we identify 163 “eVNTRs”. Of the 22 eVNTRs in blood where independent data is available, 21 (95%) are replicated in terms of significance and direction of association. 49% of the eVNTR loci show a strong and likely causal impact on the expression of genes and 80% have maximum effect size at least 0.3. The impacted genes are involved in diseases including Alzheimer’s, obesity and familial cancers, highlighting the importance of VNTRs for understanding the genetic basis of complex diseases.
Multi-phase seismic source imprint of tropical cyclones
Authors: Retailleau Lise , Gualtieri Lucia 
Published: April 2021

AbstractThe coupling between the ocean activity driven by winds and the solid Earth generates seismic signals recorded by seismometers worldwide. The 2–10 s period band, known as secondary microseism, represents the largest background seismic wavefield. While moving over the ocean, tropical cyclones generate particularly strong and localized sources of secondary microseisms that are detected remotely by seismic arrays. We assess and compare the seismic sources of P, SV, and SH waves associated with typhoon Ioke (2006) during its extra-tropical transition. To understand their generation mechanisms, we compare the observed multi-phase sources with theoretical sources computed with a numerical ocean wave model, and we assess the influence of the ocean resonance (or ocean site effect) and coastal reflection of ocean waves. We show how the location and lateral extent of the associated seismic source is period- and phase-dependent. This information is crucial for the use of body waves for ambient noise imaging and gives insights about the sea state, complementary to satellite data.
Policy assessments for the carbon emission flows and sustainability of Bitcoin blockchain operation in China
Authors: Jiang Shangrong , Li Yuze , Lu Quanying , Hong Yongmiao , Guan Dabo , Xiong Yu , Wang Shouyang 
Published: April 2021

AbstractThe growing energy consumption and associated carbon emission of Bitcoin mining could potentially undermine global sustainable efforts. By investigating carbon emission flows of Bitcoin blockchain operation in China with a simulation-based Bitcoin blockchain carbon emission model, we find that without any policy interventions, the annual energy consumption of the Bitcoin blockchain in China is expected to peak in 2024 at 296.59 Twh and generate 130.50 million metric tons of carbon emission correspondingly. Internationally, this emission output would exceed the total annualized greenhouse gas emission output of the Czech Republic and Qatar. Domestically, it ranks in the top 10 among 182 cities and 42 industrial sectors in China. In this work, we show that moving away from the current punitive carbon tax policy to a site regulation policy which induces changes in the energy consumption structure of the mining activities is more effective in limiting carbon emission of Bitcoin blockchain operation.
Deficiency of TMEM53 causes a previously unknown sclerosing bone disorder by dysregulation of BMP-SMAD signaling
Authors: Guo Long , Iida Aritoshi , Bhavani Gandham SriLakshmi , Gowrishankar Kalpana , Wang Zheng , Xue Jing-yi , Wang Juan , Miyake Noriko , Matsumoto Naomichi , Hasegawa Takanori , Iizuka Yusuke , Matsuda Masashi , Nakashima Tomoki , Takechi Masaki , Iseki Sachiko , Yambe Shinsei , Nishimura Gen , Koseki Haruhiko , Shukunami Chisa , Girisha Katta M. , Ikegawa Shiro 
Published: April 2021

AbstractBone formation represents a heritable trait regulated by many signals and complex mechanisms. Its abnormalities manifest themselves in various diseases, including sclerosing bone disorder (SBD). Exploration of genes that cause SBD has significantly improved our understanding of the mechanisms that regulate bone formation. Here, we discover a previously unknown type of SBD in four independent families caused by bi-allelic loss-of-function pathogenic variants in TMEM53, which encodes a nuclear envelope transmembrane protein. Tmem53-/- mice recapitulate the human skeletal phenotypes. Analyses of the molecular pathophysiology using the primary cells from the Tmem53-/- mice and the TMEM53 knock-out cell lines indicates that TMEM53 inhibits BMP signaling in osteoblast lineage cells by blocking cytoplasm-nucleus translocation of BMP2-activated Smad proteins. Pathogenic variants in the patients impair the TMEM53-mediated blocking effect, thus leading to overactivated BMP signaling that promotes bone formation and contributes to the SBD phenotype. Our results establish a previously unreported SBD entity (craniotubular dysplasia, Ikegawa type) and contribute to a better understanding of the regulation of BMP signaling and bone formation.
Creating polar antivortex in PbTiO3/SrTiO3 superlattice
Authors: Abid Adeel Y. , Sun Yuanwei , Hou Xu , Tan Congbing , Zhong Xiangli , Zhu Ruixue , Chen Haoyun , Qu Ke , Li Yuehui , Wu Mei , Zhang Jingmin , Wang Jinbin , Liu Kaihui , Bai Xuedong , Yu Dapeng , Ouyang Xiaoping , Wang Jie , Li Jiangyu , Gao Peng 
Published: April 2021

AbstractNontrivial topological structures offer a rich playground in condensed matters and promise alternative device configurations for post-Moore electronics. While recently a number of polar topologies have been discovered in confined ferroelectric PbTiO3 within artificially engineered PbTiO3/SrTiO3 superlattices, little attention was paid to possible topological polar structures in SrTiO3. Here we successfully create previously unrealized polar antivortices within the SrTiO3 of PbTiO3/SrTiO3 superlattices, accomplished by carefully engineering their thicknesses guided by phase-field simulation. Field- and thermal-induced Kosterlitz–Thouless-like topological phase transitions have also been demonstrated, and it was discovered that the driving force for antivortex formation is electrostatic instead of elastic. This work completes an important missing link in polar topologies, expands the reaches of topological structures, and offers insight into searching and manipulating polar textures.
Spin photogalvanic effect in two-dimensional collinear antiferromagnets
Authors: Xiao Rui-Chun , Shao Ding-Fu , Li Yu-Hang , Jiang Hua 
Published: April 2021

AbstractRecent discovered two-dimensional (2D) antiferromagnetic (AFM) van der Waals quantum materials have attracted increasing interest due to the emergent exotic physical phenomena. The spintronic properties utilizing the intrinsic AFM state in 2D antiferromagnets, however, have been rarely found. Here we show that the spin photogalvanic effect (SPGE), which has been predicted in three-dimensional (3D) antiferromagnets, can intrinsically emerge in 2D antiferromagnets for promising spintronic applications. Based on the symmetry analysis of possible AFM orders in the honeycomb lattice, we conclude suitable 2D AFM candidate materials for realizing the SPGE. We choose two experimentally synthesized 2D collinear AFM materials, monolayer MnPS3, and bilayer CrCl3, as representative materials to perform first-principles calculations, and find that they support sizable SPGE. The SPGE in collinear 2D AFM materials can be utilized to generate pure spin current in a contactless and ultra-fast way.
WLTC and real-driving emissions for an autochthonous biofuel from wine-industry waste
Authors: Lapuerta Magín , Rodríguez-Fernández José , Ramos Ángel , Donoso David , Canoira Laureano 
Published: April 2021

AbstractResidues from the wine industry constitute an abundant feedstock for biodiesel production in wine-producing countries. The use of grapeseed oil, together with bioethanol obtained from distillation of wine surplus or grape skins and stalks and wine lees, as reagents in the transesterification reaction, results in a mixture of fatty acid ethyl esters (FAEE), which is a fully renewable, autochthonous, and waste-derived biofuel. In this work, a blend of FAEE produced from grape seed oil with diesel fuel was selected based on a study of fuel properties, and the optimal blend, with 30% v/v of FAEE, was tested in a Euro 6 engine following the Worldwide harmonized Light-duty Test Cycle (WLTC) and a Real Driving Emissions Cycle (RDE), as required in the new certification procedures. Engine performance and emissions from this blend and a commercial diesel fuel were compared. The FAEE blend showed a significant potential to reduce particle emissions, both in mass and number (from 23% in number to 46.5% in mass for WLTC, and from 56% in number to 61% in mass for RDE), and CO (25.5% for WLTC and 39% for RDE) but penalized NOx (32% higher in WLTC and 26.4% higher in RDE).
Identification of PDGFRα-positive interstitial cells in the distal segment of the murine vas deferens
Authors: Hiroshige Tasuku , Uemura Kei-Ichiro , Hirashima Shingo , Hino Kiyosato , Togo Akinobu , Ohta Keisuke , Igawa Tsukasa , Nakamura Kei-Ichiro 
Published: April 2021

AbstractPlatelet-derived growth factor receptor-α (PDGFRα)-positive interstitial cells (ICs) are widely distributed in various organs and may be involved in the motility of various tubular organs. We, for the first time, aimed to investigate the distribution, immunohistochemical characteristics, and ultrastructure of PDGFRα-positive ICs in murine vas deferens, using confocal laser scanning microscopy, transmission electron microscopy (TEM), and immuno-electron microscopy (immuno-EM). For immunofluorescence, we used antibodies against PDGFRα and other markers of ICs. PDGFRα-positive ICs were distributed widely in the lamina propria, smooth muscles, and serosal layers. Although most PDGFRα-positive ICs labeled CD34, they did not label CD34 in the subepithelial layers. Additionally, PDGFRα-positive ICs were in close proximity to each other, as also to the surrounding cells. TEM and immuno-EM findings revealed that PDGFRα-positive ICs established close physical interactions with adjacent ICs. Extracellular vesicles were also detected around the PDGFRα-positive ICs. Our morphological findings suggest that PDGFRα-positive ICs may have several subpopulations, which can play an important role in intercellular signaling via direct contact with the IC network and the extracellular vesicles in the murine vas deferens. Further investigation on PDGFRα-positive ICs in the vas deferens may lead to understanding the vas deferens mortility.