bluuebunny/crossref_metadata_2025 huggingface dataset:
Allies among Enemies: Political authority and party (dis)loyalty in Bangladesh
Authors: JACKMAN DAVID , MAÎTROT MATHILDE
Published: March 2021

The authority of political leaders in Bangladesh rests on diverse qualities, not least of which are the muscle and finance they can mobilize, and the relationships they can craft with senior party members. These are utilized to confront rivals both within and outside their own party. In some instances, the intensity of intra-party competition can be so severe that a further quality emerges: the capacity to find allies among enemies. Building local inter-party alliances can bolster the authority of politicians, yet be to the detriment of party coherence. This argument is developed through an analysis of mayoral and parliamentary elections held in the past decade in a small Bangladeshi city, where a ruling party member of parliament (MP) and opposition mayor appear to have developed such a relationship. This has thwarted the electoral ambitions of their fellow party members and has posed a serious challenge to party discipline. While political competition is often seen as being either inter- or intra-party, here it is focused around inter-party alliances. This portrayal suggests we need to give greater emphasis to the decentralized and local character that political authority can take in Bangladesh.
Industrial disability in the Japanese railways business: the activity of Testudō Kōsaikai, 1931–1955
Authors: Nagahiro Toshitaka
Published: March 2021

The industrialization process generated many disabilities. However, the historical study of industrial disability has not progressed. This study examines disability welfare in the Japanese railroad industry. In particular, Testudō Kōsaikai, an organization of the Japanese National Railways (JNR) established in 1931, was uniquely devoted to welfare activities by linking a profit-making business and the provision of welfare. To cover welfare costs, such as providing workshops for disabled people, Kōsaikai conducted profit-making businesses, such as sales at station stalls. However, the welfare of disabled people in the JNR, including the activities of Kōsaikai, has not been previously examined. This study clarified the structure of disability welfare in the Japanese railroad industry until the early postwar period. People with a lower degree of disability, such as one upper or lower member amputation, were employed by the JNR, while some of these people were employed by Kōsaikai as sellers or officers, or accepted job training in Kōsaikai workshops. On the contrary, although few people with higher degrees of disability were employed by the JNR and Kōsaikai, the latter employed their family members to compensate them for their living costs.
Dedicated to the Cause
Authors: Ferguson Neil , McAuley James W.
Published: March 2021

Abstract. The threat of terrorism and rise of extremist movements across the globe pose some of the greatest challenges the world currently faces. While there have been serious conceptual and methodological problems within the psychological study of terrorism, the nascent field has advanced and the evidence, theories, and models have developed in their sophistication. The current article explores the role of social or collective identity in instigating, propagating, and diminishing engagement in violent extremism. Specifically examining how when a fundamental need to belong is challenged through threats and uncertainty this can lead to the people joining entitative groups which can fuse personal and social identities. These identities can be further amplified through ingroup and outgroup processes leading to involvement in violent extremism. The paper also explores how identity can mediate the stress of this extremist lifestyle and sustain engagement in violence. In order to illustrate these processes the article draws on interviews with Northern Irish paramilitaries. Finally, the paper explores the role of identity in moderating violent extremism, and provides suggestions of approaches to promote desistence from violent extremism.
Preventing Violent Extremism – What Has Gender Got to Do With It?
Authors: True Jacqui , Eddyono Sri
Published: March 2021

Abstract. Violent extremism and acts of terrorism are a major threat to peace and security globally. To date though the gender dynamics of support for, participation in, and prevention of violent extremism have been largely neglected by psychology, sociology, and political science scholars. Drawing on field research in Indonesia where the threat of violent extremism is pervasive, this article asks how do gendered perceptions and ideologies fuel and spread extremism and violent extremism? It highlights how women resist, counter, and prevent fundamentalist and extremist ideologies and the gendered identities and ideologies associated with them in everyday life in order to bring a gendered perspective into an examination of the causes of violent extremism and efforts to prevent it.
Lower Crustal Earthquakes in the March 2018 Sequence Along the Western Margin of Afar
Authors: La Rosa Alessandro , Keir Derek , Doubre Cecile , Sani Federico , Corti Giacomo , Leroy Sylvie , Ayele Atalay , Pagli Carolina
Published: March 2021

During the evolution of continental rift systems, extension is thought to progressively focus in‐rift to the future breakup boundary while faults along the rift margins progressively deactivate. However, observational constraints on how strain is partitioned between rift axis and rift margins are still lacking. The Afar rift records the latest stages of rifting and incipient continental breakup. Here, we analyzed the recent MW 5.2 earthquake on the Western Afar Margin on March 24, 2018 and the associated seismic sequence of >500 earthquakes using 24 temporary seismic stations deployed during 2017–2018. We show seismicity occurring at lower crustal depths, from ∼15 to ∼30 km, with focal mechanisms and relocated earthquakes highlighting both west‐dipping and east‐dipping normal faults. We tested earthquake depth using InSAR by processing six independent interferograms using Sentinel‐1 data acquired from both ascending and descending tracks. None of them shows evidence of surface deformation. We tested possible ranges of depth by producing forward models for a fault located at progressively increasing depths. Models show that surface deformation is not significant for fault slip at depths greater than 15 km, in agreement with the hypocentral depth of 19 km derived from seismic data for the largest earthquake. Due to the localized nature of deep earthquakes near hot springs coupled with subsurface evidence for magmatism, we favor an interpretation of seismicity induced by migrating fluids such as magma or CO2. We suggest that deep fluid migration can occur at the rifted‐margin influencing seismicity during incipient continental rupture.
Deep Structure of the North Natal Valley (Mozambique) Using Combined Wide‐Angle and Reflection Seismic Data
Authors: Leprêtre A. , Schnürle P. , Evain M. , Verrier F. , Moorcroft D. , de Clarens P. , Corela C. , Afilhado A. , Loureiro A. , Leroy S. , d'Acremont E. , Thompson J. , Aslanian D. , Moulin M.
Published: March 2021

The North Natal Valley (NNV) and the Mozambique Coastal Plain (MCP) are key areas for the understanding of the SW Indian Ocean history since the Gondwana break‐up. Nevertheless, the deep structures and the nature of the NNV and MCP remain discussed in the absence of deep geophysical data. In 2016, the NNV, MCP and Limpopo margin (LM) have been investigated along seven wide‐angle and MCS profiles. The combined wide‐angle and reflection seismic interpretation along the N‐S MZ7 profile reveals an upper sedimentary sequence characterized by low velocities generally not exceeding 3 km/s, with thicknesses varying from 0.150 km in the central part to ∼2.8 km in the south. The underlying sequence is formed of a 2.53.0 km thick volcano‐sedimentary sequence which presents important lateral and with depth changes and presence of high velocity lenses, indicating inter‐bedded volcanic sills and recurrent magmatic episodes. The south of the NNV including the Naude Ridge (NR) presents a disturbed sedimentary cover with structural highs and southward‐dipping reflectors and sub‐basins. The crust, reaching 35–40 km onshore below the MCP, gently thins below the continental shelf to a regular thickness of ∼29 km below the NNV. Crustal velocities reveal low velocity gradients, with atypical high velocities. South the ND, the crust thins to 15 km. We interpret the velocity architecture combined with the evidences of volcanism at shallower depths as indicating an intensively intruded continental crust. Contrary to what is proposed in most geodynamic models, the Mozambique Coastal plain and the Natal Valley are both of continental nature, with an abrupt necking zone located south of NR. The Antarctica plate was therefore situated at the eastern limit of these two domains before the Gondwana breakup.
Köppen Climate Zones in China Over the Last 21,000 Years
Authors: Wu Beilei , Lang Xianmei , Jiang Dabang
Published: March 2021

This study investigates the spatiotemporal evolution of Köppen climate zones in China over the past 21,000 calendar years based on a set of transient simulations from TraCE‐21ka using version 3 of the Community Climate System Model (CCSM3). The model results reproduce the modern distribution of Köppen climate zones observed by the Climatic Research Unit (CRU) TS4.03 dataset reasonably well. More than half of the national land has experienced changes in climate types, which is characterized by the warmer and drier trend in major climate types from the last glacial maximum (LGM) to the present. This evolution mainly includes the emergence and northward extension of tropical climates in far south of China, slight expansion of arid climates toward surrounding regions, northward invasion of temperate climates at the expense of cold climates, and retreat of polar climates to the higher altitudes of the central Tibetan Plateau. Temperature and precipitation have played different roles in the transformations of various Köppen climate types. Temperature has been dominant throughout the entire period, and precipitation has become increasingly important since the late Holocene. The comparison between the reconstructed vegetation, as estimated from pollen records, and simulated vegetation inferred from Köppen climate types displays consistency in the aforementioned change trends over China.
Deriving Mercury Geodetic Parameters With Altimetric Crossovers From the Mercury Laser Altimeter (MLA)
Authors: Bertone S. , Mazarico E. , Barker M. K. , Goossens S. , Sabaka T. J. , Neumann G. A. , Smith D. E.
Published: March 2021

Based on the previous applications of laser altimetry to planetary geodesy at GSFC, we use the recently developed PyXover software package to analyze altimetric crossovers from the Mercury Laser Altimeter (MLA). Using PyXover, we place new constraints on Mercury's geodetic parameters via least squares minimization of crossover discrepancies. We simultaneously solve for orbital corrections for each MLA ground track, for the geodetic parameters of the International Astronomical Union‐recommended orientation model for Mercury (pole right‐ascension and declination coordinates, prime meridian rotation rate, and librations), and for the Mercury's Love number h2. We calibrate the formal errors of our solution based on closed‐loop simulations and on the level of robustness against a priori values, data selection, and parametrization. Our solution of the Mercury's rotational parameters is consistent with published values. In particular, our new estimate for the orientation of the pole places Mercury in a Cassini state, with an obliquity ϵ = 2.031 ± 0.03 arcmin compatible with previous “surface” related measurements. Moreover, we provide a first data‐based estimate of the Love number h2 = 1.55 ± 0.65. The latter is consistent with expectations from models of Mercury's interior, although its precision does not enable their refinement.
Stable Biological Production in the Eastern Equatorial Pacific Across the Plio‐Pleistocene Transition (∼3.35–2.0 Ma)
Authors: Jakob Kim A. , Ho S. Ling , Meckler A. Nele , Pross Jörg , Fiebig Jens , Keppler Frank , Friedrich Oliver
Published: March 2021

Upwelling within the Eastern Equatorial Pacific (EEP) Ocean is a key factor for the Earth's climate because it supports >10% of the present‐day biological production. The dynamics of upwelling in the EEP across the Plio‐Pleistocene transition—an interval particularly relevant for understanding near‐future warming due to Anthropocene‐like atmospheric carbon‐dioxide levels—have been intensively studied for the region east of the East Pacific Rise. In contrast, changes of the equatorial upwelling regime in the open Pacific Ocean west of this oceanographic barrier have received markedly less attention. We therefore provide new proxy records from Ocean Drilling Program Site 849 located within the EEP open‐ocean upwelling regime. Our target interval (∼3.35–2.0 Ma) covers the Plio‐Pleistocene transition characterized by the intensification of Northern Hemisphere Glaciation (iNHG). We use benthic δ18O values to generate a new, high‐resolution age model for Site 849, and sand‐accumulation rates together with benthic δ13C values to evaluate net export production. Although showing temporary substantial glacial‐interglacial variations, our records indicate stability in net export production on secular timescales across the iNHG. We suggest the following processes to have controlled the long‐term evolution of primary productivity at Site 849. First, nutrient export from the high latitudes to the EEP; second, a successive shoaling of the Pacific nutricline during the studied interval; and third, a simultaneous reduction in dust‐borne iron input.
The Margin‐Oblique Kumawa Strike‐Slip Fault in the Banda Forearc, East Indonesia: Structural Deformation, Tectonic Origin and Geohazard Implication
Authors: Yang Xiaodong , Singh Satish C. , Deighton Ian
Published: March 2021

The northeast Banda margin is affected by the arc‐continent collision between the Australian continental margin and the Banda arc. Unlike margin‐parallel strike‐slip faults in other subduction zones, the margin‐oblique Seram‐Kumawa Shear Zone (SKSZ) has greatly deformed the Banda forearc with 80 km displacement along plate boundary. It trends ∼ WNW‐ESE comprising the Kawa shear zone (KSZ, >200 km) on the Seram island and the Kumawa fault (KF, >200 km) offshore SE Seram. Using multibeam bathymetry, marine seismic reflection and earthquake data, we studied the active tectonics and driving mechanism of the SKSZ with focus on its offshore part (KF). Our results show: (1) the KF is a young (∼2 Ma), linear crustal structure with three segments from NW to SE: pull‐apart basin (dextral), diffuse shear zone (sinistral) and distinct fault trace (sinistral); (2) It propagates southeastward and cross‐cuts the entire upper plate with prominent seafloor expression, but without seismicity along it, similar to the Banda detachment caused by forearc extension; (3) By incorporating the oblique collision and regional tectonics with our results, we proposed that the KF is formed primarily by the upper plate extension induced by subduction rollback during the last 2 Ma, with minor contribution from oblique arc‐continent collision; (4) The slip rate of the KF has reduced from 40 mm/yr over 2 Ma to <14 mm/yr at present. These observations combined with the clear seafloor faulting, 80‐km displacement and occurrence of a Mw 5.2 earthquake on its horsetail fault suggest it is currently locked awaiting a large earthquake.
Function of γδ T cells in tumor immunology and their application to cancer therapy
Authors: Park Jang Hyun , Lee Heung Kyu
Published: March 2021

T cells of the γδ lineage are unconventional T cells with functions not restricted to MHC-mediated antigen presentation. Because of their broad antigen specificity and NK-like cytotoxicity, γδ T-cell importance in tumor immunology has been emphasized. However, some γδ T-cell subsets, especially those expressing IL-17, are immunosuppressive or tumor-promoting cells. Their cytokine profile and cytotoxicity are seemingly determined by cross-talk with microenvironment components, not by the γδTCR chain. Furthermore, much about the TCR antigen of γδ T cells remains unknown compared with the extreme diversity of their TCR chain pairs. Thus, the investigation and application of γδ T cells have been relatively difficult. Nevertheless, γδ T cells remain attractive targets for antitumor therapy because of their independence from MHC molecules. Because tumor cells have the ability to evade the immune system through MHC shedding, heterogeneous antigens, and low antigen spreading, MHC-independent γδ T cells represent good alternative targets for immunotherapy. Therefore, many approaches to using γδ T cells for antitumor therapy have been attempted, including induction of endogenous γδ T cell activation, adoptive transfer of expanded cells ex vivo, and utilization of chimeric antigen receptor (CAR)-T cells. Here, we discuss the function of γδ T cells in tumor immunology and their application to cancer therapy.
Resistance to BET inhibitors in lung adenocarcinoma is mediated by casein kinase phosphorylation of BRD4
Authors: Calder Jack , Nagelberg Amy , Luu Jennifer , Lu Daniel , Lockwood William W.
Published: March 2021

Targeting the epigenome to modulate gene expression programs driving cancer development has emerged as an exciting avenue for therapeutic intervention. Pharmacological inhibition of the bromodomain and extraterminal (BET) family of chromatin adapter proteins has proven effective in this regard, suppressing growth of diverse cancer types mainly through downregulation of the c-MYC oncogene, and its downstream transcriptional program. While initially effective, resistance to BET inhibitors (BETi) typically occurs through mechanisms that reactivate MYC expression. We have previously shown that lung adenocarcinoma (LAC) is inhibited by JQ1 through suppression of FOSL1, suggesting that the epigenetic landscape of tumor cells from different origins and differentiation states influences BETi response. Here, we assessed how these differences affect mechanisms of BETi resistance through the establishment of isogenic pairs of JQ1 sensitive and resistant LAC cell lines. We found that resistance to JQ1 in LAC occurs independent of FOSL1 while MYC levels remain unchanged between resistant cells and their JQ1-treated parental counterparts. Furthermore, while epithelial–mesenchymal transition (EMT) is observed upon resistance, TGF-β induced EMT did not confer resistance in JQ1 sensitive LAC lines, suggesting this is a consequence, rather than a driver of BETi resistance in our model systems. Importantly, siRNA knockdown demonstrated that JQ1 resistant cell lines are still dependent on BRD4 expression for survival and we found that phosphorylation of BRD4 is elevated in resistant LACs, identifying casein kinase 2 (CK2) as a candidate protein mediating this effect. Inhibition of CK2, as well as downstream transcriptional targets of phosphorylated BRD4—including AXL and activators of the PI3K pathway—synergize with JQ1 to inhibit BETi resistant LAC. Overall, this demonstrates that the mechanism of resistance to BETi varies depending on cancer type, with LAC cells developing JQ1 resistance independent of MYC regulation, and identifying CK2 phosphorylation of BRD4 as a potential target to overcome resistance in this cancer.
Correction: Small molecule induces mitochondrial fusion for neuroprotection via targeting CK2 without affecting its conventional kinase activity
Authors: Zeng Ke-Wu , Wang Jing-Kang , Wang Li-Chao , Guo Qiang , Liu Ting-Ting , Wang Fu-Jiang , Feng Na , Zhang Xiao-Wen , Liao Li-Xi , Zhao Mei-Mei , Liu Dan , Jiang Yong , Tu Pengfei
Published: March 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41392-021-00533-3
Erosion reduces soil microbial diversity, network complexity and multifunctionality
Authors: Qiu Liping , Zhang Qian , Zhu Hansong , Reich Peter B , Banerjee Samiran , van der Heijden Marcel G A , Sadowsky Michael J , Ishii Satoshi , Jia Xiaoxu , Shao Mingan , Liu Baoyuan , Jiao Huan , Li Haiqiang , Wei Xiaorong
Published: March 2021

While soil erosion drives land degradation, the impact of erosion on soil microbial communities and multiple soil functions remains unclear. This hinders our ability to assess the true impact of erosion on soil ecosystem services and our ability to restore eroded environments. Here we examined the effect of erosion on microbial communities at two sites with contrasting soil texture and climates. Eroded plots had lower microbial network complexity, fewer microbial taxa, and fewer associations among microbial taxa, relative to non-eroded plots. Soil erosion also shifted microbial community composition, with decreased relative abundances of dominant phyla such as Proteobacteria, Bacteroidetes, and Gemmatimonadetes. In contrast, erosion led to an increase in the relative abundances of some bacterial families involved in N cycling, such as Acetobacteraceae and Beijerinckiaceae. Changes in microbiota characteristics were strongly related with erosion-induced changes in soil multifunctionality. Together, these results demonstrate that soil erosion has a significant negative impact on soil microbial diversity and functionality.
Small phytoplankton contribute greatly to CO2-fixation after the diatom bloom in the Southern Ocean
Authors: Irion Solène , Christaki Urania , Berthelot Hugo , L’Helguen Stéphane , Jardillier Ludwig
Published: March 2021

Phytoplankton is composed of a broad-sized spectrum of phylogenetically diverse microorganisms. Assessing CO2-fixation intra- and inter-group variability is crucial in understanding how the carbon pump functions, as each group of phytoplankton may be characterized by diverse efficiencies in carbon fixation and export to the deep ocean. We measured the CO2-fixation of different groups of phytoplankton at the single-cell level around the naturally iron-fertilized Kerguelen plateau (Southern Ocean), known for intense diatoms blooms suspected to enhance CO2 sequestration. After the bloom, small cells (<20 µm) composed of phylogenetically distant taxa (prymnesiophytes, prasinophytes, and small diatoms) were growing faster (0.37 ± 0.13 and 0.22 ± 0.09 division d−1 on- and off-plateau, respectively) than larger diatoms (0.11 ± 0.14 and 0.09 ± 0.11 division d−1 on- and off-plateau, respectively), which showed heterogeneous growth and a large proportion of inactive cells (19 ± 13%). As a result, small phytoplankton contributed to a large proportion of the CO2 fixation (41–70%). The analysis of pigment vertical distribution indicated that grazing may be an important pathway of small phytoplankton export. Overall, this study highlights the need to further explore the role of small cells in CO2-fixation and export in the Southern Ocean.
Human-associated microbiota suppress invading bacteria even under disruption by antibiotics
Authors: Letten Andrew D , Baumgartner Michael , Pfrunder-Cardozo Katia R , Levine Jonathan M , Hall Alex R
Published: March 2021

In light of their adverse impacts on resident microbial communities, it is widely predicted that broad-spectrum antibiotics can promote the spread of resistance by releasing resistant strains from competition with other strains and species. We investigated the competitive suppression of a resistant strain of Escherichia coli inoculated into human-associated communities in the presence and absence of the broad and narrow spectrum antibiotics rifampicin and polymyxin B, respectively. We found strong evidence of community-level suppression of the resistant strain in the absence of antibiotics and, despite large changes in community composition and abundance following rifampicin exposure, suppression of the invading resistant strain was maintained in both antibiotic treatments. Instead, the strength of competitive suppression was more strongly associated with the source community (stool sample from individual human donor). This suggests microbiome composition strongly influences the competitive suppression of antibiotic-resistant strains, but at least some antibiotic-associated disruption can be tolerated before competitive release is observed. A deeper understanding of this association will aid the development of ecologically-aware strategies for managing antibiotic resistance.
EphA2 super-enhancer promotes tumor progression by recruiting FOSL2 and TCF7L2 to activate the target gene EphA2
Authors: Cui Shuang , Wu Qiong , Liu Ming , Su Mu , Liu ShiYou , Shao Lan , Han Xiao , He Hongjuan
Published: March 2021

Super-enhancers or stretch enhancers (SEs) consist of large clusters of active transcription enhancers which promote the expression of critical genes that define cell identity during development and disease. However, the role of many super-enhancers in tumor cells remains unclear. This study aims to explore the function and mechanism of a new super-enhancer in various tumor cells. A new super-enhancer that exists in a variety of tumors named EphA2-Super-enhancer (EphA2-SE) was found using multiple databases and further identified. CRISPR/Cas9-mediated deletion of EphA2-SE results in the significant downregulation of its target gene EphA2. Mechanistically, we revealed that the core active region of EphA2-SE comprises E1 component enhancer, which recruits TCF7L2 and FOSL2 transcription factors to drive the expression of EphA2, induce cell proliferation and metastasis. Bioinformatics analysis of RNA-seq data and functional experiments in vitro illustrated that EphA2-SE deletion inhibited cell growth and metastasis by blocking PI3K/AKT and Wnt/β-catenin pathway in HeLa, HCT-116 and MCF-7 cells. Overexpression of EphA2 in EphA2-SE−/− clones rescued the effect of EphA2-SE deletion on proliferation and metastasis. Subsequent xenograft animal model revealed that EphA2-SE deletion suppressed tumor proliferation and survival in vivo. Taken together, these findings demonstrate that EphA2-SE plays an oncogenic role and promotes tumor progression in various tumors by recruiting FOSL2 and TCF7L2 to drive the expression of oncogene EphA2.
Overexpression of Annexin A2 promotes proliferation by forming a Glypican 1/c-Myc positive feedback loop: prognostic significance in human glioma
Authors: Li Xin , Nie Shengdan , Lv Ziyang , Ma Lingran , Song Yuxi , Hu Zhongxu , Hu Xin , Liu Zhiqiang , Zhou Gaoya , Dai Zhijie , Song Tao , Liu Jiajia , Wang Shan
Published: March 2021

In order to set up a reliable prediction system for the tumor grade and prognosis in glioma patients, we clarify the complicated crosstalk of Annexin A2 (ANXA2) with Glypican 1 (GPC1) and demonstrate whether combined indexes of ANXA2 and GPC1 could improve the prognostic evaluation for glioma patients. We found that ANXA2-induced glioma cell proliferation in a c-Myc-dependent manner. ANXA2 increased the expression of GPC1 via c-Myc and the upregulated GPC1 further promoted the c-Myc level, forming a positive feedback loop, which eventually led to enhanced proliferation of glioma cells. Both mRNA and protein levels of ANXA2 were upregulated in glioma tissues and coincided with the overexpression of GPC1. Besides, we utilized tissue microarrays (TMAs) and immunohistochemistry to demonstrate that glioma patients with both high expression of ANXA2 and GPC1 tended to have higher rate of tumor recurrence and shorter overall survival (OS). In conclusion, the overexpression of ANXA2 promotes proliferation of glioma cells by forming a GPC1/c-Myc positive feedback loop, and ANXA2 together with its downstream target GPC1 could be a potential “combination biomarker” for predicting prognosis of glioma patients.
Transcriptional profiling reveals the transcription factor networks regulating the survival of striatal neurons
Authors: Yang Lin , Su Zihao , Wang Ziwu , Li Zhenmeiyu , Shang Zicong , Du Heng , Liu Guoping , Qi Dashi , Yang Zhengang , Xu Zhejun , Zhang Zhuangzhi
Published: March 2021

The striatum is structurally highly diverse, and its organ functionality critically depends on normal embryonic development. Although several studies have been conducted on the gene functional changes that occur during striatal development, a system-wide analysis of the underlying molecular changes is lacking. Here, we present a comprehensive transcriptome profile that allows us to explore the trajectory of striatal development and identify the correlation between the striatal development and Huntington’s disease (HD). Furthermore, we applied an integrative transcriptomic profiling approach based on machine learning to systematically map a global landscape of 277 transcription factor (TF) networks. Most of these TF networks are linked to biological processes, and some unannotated genes provide information about the corresponding mechanisms. For example, we found that the Meis2 and Six3 were crucial for the survival of striatal neurons, which were verified using conditional knockout (CKO) mice. Finally, we used RNA-Seq to speculate their downstream targets.
Gut-Ex-Vivo system as a model to study gluten response in celiac disease
Authors: Gagliardi Mara , Clemente Nausicaa , Monzani Romina , Fusaro Luca , Ferrari Eleonora , Saverio Valentina , Grieco Giovanna , Pańczyszyn Elżbieta , Carton Flavia , Santoro Claudio , Del Mare-Roumani Sara , Amidror Sivan , Yissachar Nissan , Boccafoschi Francesca , Zucchelli Silvia , Corazzari Marco
Published: March 2021

Celiac disease (CD) is a complex immune-mediated chronic disease characterized by a consistent inflammation of the gastrointestinal tract induced by gluten intake in genetically predisposed individuals. Although initiated by the interaction between digestion-derived gliadin, a gluten component, peptides, and the intestinal epithelium, the disorder is highly complex and involving other components of the intestine, such as the immune system. Therefore, conventional model systems, mainly based on two- or three-dimension cell cultures and co-cultures, cannot fully recapitulate such a complex disease. The development of mouse models has facilitated the study of different interacting cell types involved in the disorder, together with the impact of environmental factors. However, such in vivo models are often expensive and time consuming. Here we propose an organ ex vivo culture (gut-ex-vivo system) based on small intestines from gluten-sensitive mice cultivated in a dynamic condition, able to fully recapitulate the biochemical and morphological features of the mouse model exposed to gliadin (4 weeks), in 16 h. Indeed, upon gliadin exposure, we observed: i) a down-regulation of cystic fibrosis transmembrane regulator (CFTR) and an up-regulation of transglutaminase 2 (TG2) at both mRNA and protein levels; ii) increased intestinal permeability associated with deregulated tight junction protein expression; iii) induction and production of pro-inflammatory cytokines such as interleukin (IL)-15, IL-17 and interferon gamma (IFNγ); and iv) consistent alteration of intestinal epithelium/villi morphology. Altogether, these data indicate that the proposed model can be efficiently used to study the pathogenesis of CD, test new or repurposed molecules to accelerate the search for new treatments, and to study the impact of the microbiome and derived metabolites, in a time- and cost- effective manner.
Hyperbolic enhancement of photocurrent patterns in minimally twisted bilayer graphene
Authors: Sunku S. S. , Halbertal D. , Stauber T. , Chen S. , McLeod A. S. , Rikhter A. , Berkowitz M. E. , Lo C. F. B. , Gonzalez-Acevedo D. E. , Hone J. C. , Dean C. R. , Fogler M. M. , Basov D. N.
Published: March 2021

Quasi-periodic moiré patterns and their effect on electronic properties of twisted bilayer graphene have been intensely studied. At small twist angle θ, due to atomic reconstruction, the moiré superlattice morphs into a network of narrow domain walls separating micron-scale AB and BA stacking regions. We use scanning probe photocurrent imaging to resolve nanoscale variations of the Seebeck coefficient occurring at these domain walls. The observed features become enhanced in a range of mid-infrared frequencies where the hexagonal boron nitride substrate is optically hyperbolic. Our results illustrate the capabilities of the nano-photocurrent technique for probing nanoscale electronic inhomogeneities in two-dimensional materials.
A computer-guided design tool to increase the efficiency of cellular conversions
Authors: Jung Sascha , Appleton Evan , Ali Muhammad , Church George M. , del Sol Antonio
Published: March 2021

Human cell conversion technology has become an important tool for devising new cell transplantation therapies, generating disease models and testing gene therapies. However, while transcription factor over-expression-based methods have shown great promise in generating cell types in vitro, they often endure low conversion efficiency. In this context, great effort has been devoted to increasing the efficiency of current protocols and the development of computational approaches can be of great help in this endeavor. Here we introduce a computer-guided design tool that combines a computational framework for prioritizing more efficient combinations of instructive factors (IFs) of cellular conversions, called IRENE, with a transposon-based genomic integration system for efficient delivery. Particularly, IRENE relies on a stochastic gene regulatory network model that systematically prioritizes more efficient IFs by maximizing the agreement of the transcriptional and epigenetic landscapes between the converted and target cells. Our predictions substantially increased the efficiency of two established iPSC-differentiation protocols (natural killer cells and melanocytes) and established the first protocol for iPSC-derived mammary epithelial cells with high efficiency.
Moiré excitons in MoSe2-WSe2 heterobilayers and heterotrilayers
Authors: Förg Michael , Baimuratov Anvar S. , Kruchinin Stanislav Yu. , Vovk Ilia A. , Scherzer Johannes , Förste Jonathan , Funk Victor , Watanabe Kenji , Taniguchi Takashi , Högele Alexander
Published: March 2021

Layered two-dimensional materials exhibit rich transport and optical phenomena in twisted or lattice-incommensurate heterostructures with spatial variations of interlayer hybridization arising from moiré interference effects. Here, we report experimental and theoretical studies of excitons in twisted heterobilayers and heterotrilayers of transition metal dichalcogenides. Using MoSe2-WSe2 stacks as representative realizations of twisted van der Waals bilayer and trilayer heterostructures, we observe contrasting optical signatures and interpret them in the theoretical framework of interlayer moiré excitons in different spin and valley configurations. We conclude that the photoluminescence of MoSe2-WSe2 heterobilayer is consistent with joint contributions from radiatively decaying valley-direct interlayer excitons and phonon-assisted emission from momentum-indirect reservoirs that reside in spatially distinct regions of moiré supercells, whereas the heterotrilayer emission is entirely due to momentum-dark interlayer excitons of hybrid-layer valleys. Our results highlight the profound role of interlayer hybridization for transition metal dichalcogenide heterostacks and other realizations of multi-layered semiconductor van der Waals heterostructures.
Integration of Alzheimer’s disease genetics and myeloid genomics identifies disease risk regulatory elements and genes
Authors: Novikova Gloriia , Kapoor Manav , TCW Julia , Abud Edsel M. , Efthymiou Anastasia G. , Chen Steven X. , Cheng Haoxiang , Fullard John F. , Bendl Jaroslav , Liu Yiyuan , Roussos Panos , Björkegren Johan LM , Liu Yunlong , Poon Wayne W. , Hao Ke , Marcora Edoardo , Goate Alison M.
Published: March 2021

Genome-wide association studies (GWAS) have identified more than 40 loci associated with Alzheimer’s disease (AD), but the causal variants, regulatory elements, genes and pathways remain largely unknown, impeding a mechanistic understanding of AD pathogenesis. Previously, we showed that AD risk alleles are enriched in myeloid-specific epigenomic annotations. Here, we show that they are specifically enriched in active enhancers of monocytes, macrophages and microglia. We integrated AD GWAS with myeloid epigenomic and transcriptomic datasets using analytical approaches to link myeloid enhancer activity to target gene expression regulation and AD risk modification. We identify AD risk enhancers and nominate candidate causal genes among their likely targets (includingAP4E1, AP4M1, APBB3, BIN1, MS4A4A, MS4A6A, PILRA, RABEP1, SPI1, TP53INP1, andZYX) in twenty loci. Fine-mapping of these enhancers nominates candidate functional variants that likely modify AD risk by regulating gene expression in myeloid cells. In the MS4A locus we identified a single candidate functional variant and validated it in human induced pluripotent stem cell (hiPSC)-derived microglia and brain. Taken together, this study integrates AD GWAS with multiple myeloid genomic datasets to investigate the mechanisms of AD risk alleles and nominates candidate functional variants, regulatory elements and genes that likely modulate disease susceptibility.
An ARF GTPase module promoting invasion and metastasis through regulating phosphoinositide metabolism
Authors: Nacke Marisa , Sandilands Emma , Nikolatou Konstantina , Román-Fernández Álvaro , Mason Susan , Patel Rachana , Lilla Sergio , Yelland Tamas , Galbraith Laura C. A. , Freckmann Eva C. , McGarry Lynn , Morton Jennifer P. , Shanks Emma , Leung Hing Y. , Markert Elke , Ismail Shehab , Zanivan Sara , Blyth Karen , Bryant David M.
Published: March 2021

The signalling pathways underpinning cell growth and invasion use overlapping components, yet how mutually exclusive cellular responses occur is unclear. Here, we report development of 3-Dimensional culture analyses to separately quantify growth and invasion. We identify that alternate variants of IQSEC1, an ARF GTPase Exchange Factor, act as switches to promote invasion over growth by controlling phosphoinositide metabolism. All IQSEC1 variants activate ARF5- and ARF6-dependent PIP5-kinase to promote PI(3,4,5)P3-AKT signalling and growth. In contrast, select pro-invasive IQSEC1 variants promote PI(3,4,5)P3 production to form invasion-driving protrusions. Inhibition of IQSEC1 attenuates invasion in vitro and metastasis in vivo. Induction of pro-invasive IQSEC1 variants and elevated IQSEC1 expression occurs in a number of tumour types and is associated with higher-grade metastatic cancer, activation of PI(3,4,5)P3 signalling, and predicts long-term poor outcome across multiple cancers. IQSEC1-regulated phosphoinositide metabolism therefore is a switch to induce invasion over growth in response to the same external signal. Targeting IQSEC1 as the central regulator of this switch may represent a therapeutic vulnerability to stop metastasis.
Schwann cell plasticity regulates neuroblastic tumor cell differentiation via epidermal growth factor-like protein 8
Authors: Weiss Tamara , Taschner-Mandl Sabine , Janker Lukas , Bileck Andrea , Rifatbegovic Fikret , Kromp Florian , Sorger Helena , Kauer Maximilian O. , Frech Christian , Windhager Reinhard , Gerner Christopher , Ambros Peter F. , Ambros Inge M.
Published: March 2021

Adult Schwann cells (SCs) possess an inherent plastic potential. This plasticity allows SCs to acquire repair-specific functions essential for peripheral nerve regeneration. Here, we investigate whether stromal SCs in benign-behaving peripheral neuroblastic tumors adopt a similar cellular state. We profile ganglioneuromas and neuroblastomas, rich and poor in SC stroma, respectively, and peripheral nerves after injury, rich in repair SCs. Indeed, stromal SCs in ganglioneuromas and repair SCs share the expression of nerve repair-associated genes. Neuroblastoma cells, derived from aggressive tumors, respond to primary repair-related SCs and their secretome with increased neuronal differentiation and reduced proliferation. Within the pool of secreted stromal and repair SC factors, we identify EGFL8, a matricellular protein with so far undescribed function, to act as neuritogen and to rewire cellular signaling by activating kinases involved in neurogenesis. In summary, we report that human SCs undergo a similar adaptive response in two patho-physiologically distinct situations, peripheral nerve injury and tumor development.
Nano-imaging photoresponse in a moiré unit cell of minimally twisted bilayer graphene
Authors: Hesp Niels C. H. , Torre Iacopo , Barcons-Ruiz David , Herzig Sheinfux Hanan , Watanabe Kenji , Taniguchi Takashi , Krishna Kumar Roshan , Koppens Frank H. L.
Published: March 2021

Graphene-based moiré superlattices have recently emerged as a unique class of tuneable solid-state systems that exhibit significant optoelectronic activity. Local probing at length scales of the superlattice should provide deeper insight into the microscopic mechanisms of photoresponse and the exact role of the moiré lattice. Here, we employ a nanoscale probe to study photoresponse within a single moiré unit cell of minimally twisted bilayer graphene. Our measurements reveal a spatially rich photoresponse, whose sign and magnitude are governed by the fine structure of the moiré lattice and its orientation with respect to measurement contacts. This results in a strong directional effect and a striking spatial dependence of the gate-voltage response within the moiré domains. The spatial profile and carrier-density dependence of the measured photocurrent point towards a photo-thermoelectric induced response that is further corroborated by good agreement with numerical simulations. Our work shows sub-diffraction photocurrent spectroscopy is an exceptional tool for uncovering the optoelectronic properties of moiré superlattices.
Dynamic relocalization of cytosolic type III secretion system components prevents premature protein secretion at low external pH
Authors: Wimmi Stephan , Balinovic Alexander , Jeckel Hannah , Selinger Lisa , Lampaki Dimitrios , Eisemann Emma , Meuskens Ina , Linke Dirk , Drescher Knut , Endesfelder Ulrike , Diepold Andreas
Published: March 2021

Many bacterial pathogens use a type III secretion system (T3SS) to manipulate host cells. Protein secretion by the T3SS injectisome is activated upon contact to any host cell, and it has been unclear how premature secretion is prevented during infection. Here we report that in the gastrointestinal pathogens Yersinia enterocolitica and Shigella flexneri, cytosolic injectisome components are temporarily released from the proximal interface of the injectisome at low external pH, preventing protein secretion in acidic environments, such as the stomach. We show that in Yersinia enterocolitica, low external pH is detected in the periplasm and leads to a partial dissociation of the inner membrane injectisome component SctD, which in turn causes the dissociation of the cytosolic T3SS components. This effect is reversed upon restoration of neutral pH, allowing a fast activation of the T3SS at the native target regions within the host. These findings indicate that the cytosolic components form an adaptive regulatory interface, which regulates T3SS activity in response to environmental conditions.
Protein context shapes the specificity of SH3 domain-mediated interactions in vivo
Authors: Dionne Ugo , Bourgault Émilie , Dubé Alexandre K. , Bradley David , Chartier François J. M. , Dandage Rohan , Dibyachintan Soham , Després Philippe C. , Gish Gerald D. , Pham N. T. Hang , Létourneau Myriam , Lambert Jean-Philippe , Doucet Nicolas , Bisson Nicolas , Landry Christian R.
Published: March 2021

Protein–protein interactions (PPIs) between modular binding domains and their target peptide motifs are thought to largely depend on the intrinsic binding specificities of the domains. The large family of SRC Homology 3 (SH3) domains contribute to cellular processes via their ability to support such PPIs. While the intrinsic binding specificities of SH3 domains have been studied in vitro, whether each domain is necessary and sufficient to define PPI specificity in vivo is largely unknown. Here, by combining deletion, mutation, swapping and shuffling of SH3 domains and measurements of their impact on protein interactions in yeast, we find that most SH3s do not dictate PPI specificity independently from their host protein in vivo. We show that the identity of the host protein and the position of the SH3 domains within their host are critical for PPI specificity, for cellular functions and for key biophysical processes such as phase separation. Our work demonstrates the importance of the interplay between a modular PPI domain such as SH3 and its host protein in establishing specificity to wire PPI networks. These findings will aid understanding how protein networks are rewired during evolution and in the context of mutation-driven diseases such as cancer.
The amyloid structure of mouse RIPK3 (receptor interacting protein kinase 3) in cell necroptosis
Authors: Wu Xia-lian , Hu Hong , Dong Xing-qi , Zhang Jing , Wang Jian , Schwieters Charles D. , Liu Jing , Wu Guo-xiang , Li Bing , Lin Jing-yu , Wang Hua-yi , Lu Jun-xia
Published: March 2021

RIPK3 amyloid complex plays crucial roles during TNF-induced necroptosis and in response to immune defense in both human and mouse. Here, we have structurally characterized mouse RIPK3 homogeneous self-assembly using solid-state NMR, revealing a well-ordered N-shaped amyloid core structure featured with 3 parallel in-register β-sheets. This structure differs from previously published human RIPK1/RIPK3 hetero-amyloid complex structure, which adopted a serpentine fold. Functional studies indicate both RIPK1-RIPK3 binding and RIPK3 amyloid formation are essential but not sufficient for TNF-induced necroptosis. The structural integrity of RIPK3 fibril with three β-strands is necessary for signaling. Molecular dynamics simulations with a mouse RIPK1/RIPK3 model indicate that the hetero-amyloid is less stable when adopting the RIPK3 fibril conformation, suggesting a structural transformation of RIPK3 from RIPK1-RIPK3 binding to RIPK3 amyloid formation. This structural transformation would provide the missing link connecting RIPK1-RIPK3 binding to RIPK3 homo-oligomer formation in the signal transduction.
Aptardi predicts polyadenylation sites in sample-specific transcriptomes using high-throughput RNA sequencing and DNA sequence
Authors: Lusk Ryan , Stene Evan , Banaei-Kashani Farnoush , Tabakoff Boris , Kechris Katerina , Saba Laura M.
Published: March 2021

Annotation of polyadenylation sites from short-read RNA sequencing alone is a challenging computational task. Other algorithms rooted in DNA sequence predict potential polyadenylation sites; however, in vivo expression of a particular site varies based on a myriad of conditions. Here, we introduce aptardi (alternative polyadenylation transcriptome analysis from RNA-Seq data and DNA sequence information), which leverages both DNA sequence and RNA sequencing in a machine learning paradigm to predict expressed polyadenylation sites. Specifically, as input aptardi takes DNA nucleotide sequence, genome-aligned RNA-Seq data, and an initial transcriptome. The program evaluates these initial transcripts to identify expressed polyadenylation sites in the biological sample and refines transcript 3′-ends accordingly. The average precision of the aptardi model is twice that of a standard transcriptome assembler. In particular, the recall of the aptardi model (the proportion of true polyadenylation sites detected by the algorithm) is improved by over three-fold. Also, the model—trained using the Human Brain Reference RNA commercial standard—performs well when applied to RNA-sequencing samples from different tissues and different mammalian species. Finally, aptardi’s input is simple to compile and its output is easily amenable to downstream analyses such as quantitation and differential expression.