bluuebunny/crossref_metadata_2025 huggingface dataset:
Interplay between electrochemical reactions and mechanical responses in silicon–graphite anodes and its impact on degradation
Authors: Moon Junhyuk , Lee Heung Chan , Jung Heechul , Wakita Shinya , Cho Sungnim , Yoon Jaegu , Lee Joowook , Ueda Atsushi , Choi Bokkyu , Lee Sihyung , Ito Kimihiko , Kubo Yoshimi , Lim Alan Christian , Seo Jeong Gil , Yoo Jungho , Lee Seungyeon , Ham Yongnam , Baek Woonjoong , Ryu Young-Gyoon , Han In Taek
Published: May 2021

Durability of high-energy throughput batteries is a prerequisite for electric vehicles to penetrate the market. Despite remarkable progresses in silicon anodes with high energy densities, rapid capacity fading of full cells with silicon–graphite anodes limits their use. In this work, we unveil degradation mechanisms such as Li+ crosstalk between silicon and graphite, consequent Li+ accumulation in silicon, and capacity depression of graphite due to silicon expansion. The active material properties, i.e. silicon particle size and graphite hardness, are then modified based on these results to reduce Li+ accumulation in silicon and the subsequent degradation of the active materials in the anode. Finally, the cycling performance is tailored by designing electrodes to regulate Li+ crosstalk. The resultant full cell with an areal capacity of 6 mAh cm−2 has a cycle life of >750 cycles the volumetric energy density of 800 Wh L−1 in a commercial cell format.
The RNA landscape of the human placenta in health and disease
Authors: Gong Sungsam , Gaccioli Francesca , Dopierala Justyna , Sovio Ulla , Cook Emma , Volders Pieter-Jan , Martens Lennart , Kirk Paul D. W. , Richardson Sylvia , Smith Gordon C. S. , Charnock-Jones D. Stephen
Published: May 2021

The placenta is the interface between mother and fetus and inadequate function contributes to short and long-term ill-health. The placenta is absent from most large-scale RNA-Seq datasets. We therefore analyze long and small RNAs (~101 and 20 million reads per sample respectively) from 302 human placentas, including 94 cases of preeclampsia (PE) and 56 cases of fetal growth restriction (FGR). The placental transcriptome has the seventh lowest complexity of 50 human tissues: 271 genes account for 50% of all reads. We identify multiple circular RNAs and validate 6 of these by Sanger sequencing across the back-splice junction. Using large-scale mass spectrometry datasets, we find strong evidence of peptides produced by translation of two circular RNAs. We also identify novel piRNAs which are clustered on Chr1 and Chr14. PE and FGR are associated with multiple and overlapping differences in mRNA, lincRNA and circRNA but fewer consistent differences in small RNAs. Of the three protein coding genes differentially expressed in both PE and FGR, one encodes a secreted protein FSTL3 (follistatin-like 3). Elevated serum levels of FSTL3 in pregnant women are predictive of subsequent PE and FGR. To aid visualization of our placenta transcriptome data, we develop a web application (https://www.obgyn.cam.ac.uk/placentome/).
Global population structure and genotyping framework for genomic surveillance of the major dysentery pathogen, Shigella sonnei
Authors: Hawkey Jane , Paranagama Kalani , Baker Kate S. , Bengtsson Rebecca J. , Weill François-Xavier , Thomson Nicholas R. , Baker Stephen , Cerdeira Louise , Iqbal Zamin , Hunt Martin , Ingle Danielle J. , Dallman Timothy J. , Jenkins Claire , Williamson Deborah A. , Holt Kathryn E.
Published: May 2021

Shigella sonnei is the most common agent of shigellosis in high-income countries, and causes a significant disease burden in low- and middle-income countries. Antimicrobial resistance is increasingly common in all settings. Whole genome sequencing (WGS) is increasingly utilised for S. sonnei outbreak investigation and surveillance, but comparison of data between studies and labs is challenging. Here, we present a genomic framework and genotyping scheme for S. sonnei to efficiently identify genotype and resistance determinants from WGS data. The scheme is implemented in the software package Mykrobe and tested on thousands of genomes. Applying this approach to analyse >4,000 S. sonnei isolates sequenced in public health labs in three countries identified several common genotypes associated with increased rates of ciprofloxacin resistance and azithromycin resistance, confirming intercontinental spread of highly-resistant S. sonnei clones and demonstrating the genomic framework can facilitate monitoring the spread of resistant clones, including those that have recently emerged, at local and global scales.
Global land use changes are four times greater than previously estimated
Authors: Winkler Karina , Fuchs Richard , Rounsevell Mark , Herold Martin
Published: May 2021

Quantifying the dynamics of land use change is critical in tackling global societal challenges such as food security, climate change, and biodiversity loss. Here we analyse the dynamics of global land use change at an unprecedented spatial resolution by combining multiple open data streams (remote sensing, reconstructions and statistics) to create the HIstoric Land Dynamics Assessment + (HILDA +). We estimate that land use change has affected almost a third (32%) of the global land area in just six decades (1960-2019) and, thus, is around four times greater in extent than previously estimated from long-term land change assessments. We also identify geographically diverging land use change processes, with afforestation and cropland abandonment in the Global North and deforestation and agricultural expansion in the South. Here, we show that observed phases of accelerating (~1960–2005) and decelerating (2006–2019) land use change can be explained by the effects of global trade on agricultural production.
Dual vaccination against IL-4 and IL-13 protects against chronic allergic asthma in mice
Authors: Conde Eva , Bertrand Romain , Balbino Bianca , Bonnefoy Jonathan , Stackowicz Julien , Caillot Noémie , Colaone Fabien , Hamdi Samir , Houmadi Raïssa , Loste Alexia , Kamphuis Jasper B. J. , Huetz François , Guilleminault Laurent , Gaudenzio Nicolas , Mougel Aurélie , Hardy David , Snouwaert John N. , Koller Beverly H. , Serra Vincent , Bruhns Pierre , Grouard-Vogel Géraldine , Reber Laurent L.
Published: May 2021

Allergic asthma is characterized by elevated levels of IgE antibodies, type 2 cytokines such as interleukin-4 (IL-4) and IL-13, airway hyperresponsiveness (AHR), mucus hypersecretion and eosinophilia. Approved therapeutic monoclonal antibodies targeting IgE or IL-4/IL-13 reduce asthma symptoms but require costly lifelong administrations. Here, we develop conjugate vaccines against mouse IL-4 and IL-13, and demonstrate their prophylactic and therapeutic efficacy in reducing IgE levels, AHR, eosinophilia and mucus production in mouse models of asthma analyzed up to 15 weeks after initial vaccination. More importantly, we also test similar vaccines specific for human IL-4/IL-13 in mice expressing human IL-4/IL-13 and the related receptor, IL-4Rα, to find efficient neutralization of both cytokines and reduced IgE levels for at least 11 weeks post-vaccination. Our results imply that dual IL-4/IL-13 vaccination may represent a cost-effective, long-term therapeutic strategy for the treatment of allergic asthma as demonstrated in mouse models, although additional studies are warranted to assess its safety and feasibility.
Protecting local water quality has global benefits
Authors: Downing John A. , Polasky Stephen , Olmstead Sheila M. , Newbold Stephen C.
Published: May 2021

Surface water is among Earth’s most important resources. Yet, benefit–cost studies often report that the costs of water quality protection exceed its benefits. One possible reason for this seeming paradox is that often only a narrow range of local water quality benefits are considered. In particular, the climate damages from water pollution have rarely been quantified. Recent advances in global water science allow the computation of the global methane emission from lakes caused by human nutrient enrichment (eutrophication). Here, we estimate the present value of the global social cost of eutrophication-driven methane emissions from lakes between 2015 and 2050 to be $7.5–$81 trillion (2015 $US), and in a case-study for one well-studied lake (Lake Erie) we find the global value of avoiding eutrophication exceeds local values of either beach use or sport fishing by 10-fold.
Variability of plasmid fitness effects contributes to plasmid persistence in bacterial communities
Authors: Alonso-del Valle Aida , León-Sampedro Ricardo , Rodríguez-Beltrán Jerónimo , DelaFuente Javier , Hernández-García Marta , Ruiz-Garbajosa Patricia , Cantón Rafael , Peña-Miller Rafael , San Millán Alvaro
Published: May 2021

Plasmid persistence in bacterial populations is strongly influenced by the fitness effects associated with plasmid carriage. However, plasmid fitness effects in wild-type bacterial hosts remain largely unexplored. In this study, we determined the fitness effects of the major antibiotic resistance plasmid pOXA-48_K8 in wild-type, ecologically compatible enterobacterial isolates from the human gut microbiota. Our results show that although pOXA-48_K8 produced an overall reduction in bacterial fitness, it produced small effects in most bacterial hosts, and even beneficial effects in several isolates. Moreover, genomic results showed a link between pOXA-48_K8 fitness effects and bacterial phylogeny, helping to explain plasmid epidemiology. Incorporating our fitness results into a simple population dynamics model revealed a new set of conditions for plasmid stability in bacterial communities, with plasmid persistence increasing with bacterial diversity and becoming less dependent on conjugation. These results help to explain the high prevalence of plasmids in the greatly diverse natural microbial communities.
Single nucleus multi-omics regulatory landscape of the murine pituitary
Authors: Ruf-Zamojski Frederique , Zhang Zidong , Zamojski Michel , Smith Gregory R. , Mendelev Natalia , Liu Hanqing , Nudelman German , Moriwaki Mika , Pincas Hanna , Castanon Rosa Gomez , Nair Venugopalan D. , Seenarine Nitish , Amper Mary Anne S. , Zhou Xiang , Ongaro Luisina , Toufaily Chirine , Schang Gauthier , Nery Joseph R. , Bartlett Anna , Aldridge Andrew , Jain Nimisha , Childs Gwen V. , Troyanskaya Olga G. , Ecker Joseph R. , Turgeon Judith L. , Welt Corrine K. , Bernard Daniel J. , Sealfon Stuart C.
Published: May 2021

To provide a multi-omics resource and investigate transcriptional regulatory mechanisms, we profile the transcriptome, chromatin accessibility, and methylation status of over 70,000 single nuclei (sn) from adult mouse pituitaries. Paired snRNAseq and snATACseq datasets from individual animals highlight a continuum between developmental epigenetically-encoded cell types and transcriptionally-determined transient cell states. Co-accessibility analysis-based identification of a putative Fshb cis-regulatory domain that overlaps the fertility-linked rs11031006 human polymorphism, followed by experimental validation illustrate the use of this resource for hypothesis generation. We also identify transcriptional and chromatin accessibility programs distinguishing each major cell type. Regulons, which are co-regulated gene sets sharing binding sites for a common transcription factor driver, recapitulate cell type clustering. We identify both cell type-specific and sex-specific regulons that are highly correlated with promoter accessibility, but not with methylation state, supporting the centrality of chromatin accessibility in shaping cell-defining transcriptional programs. The sn multi-omics atlas is accessible at snpituitaryatlas.princeton.edu.
Helium in diamonds unravels over a billion years of craton metasomatism
Authors: Weiss Yaakov , Kiro Yael , Class Cornelia , Winckler Gisela , Harris Jeff W. , Goldstein Steven L.
Published: May 2021

Chemical events involving deep carbon- and water-rich fluids impact the continental lithosphere over its history. Diamonds are a by-product of such episodic fluid infiltrations, and entrapment of these fluids as microinclusions in lithospheric diamonds provide unique opportunities to investigate their nature. However, until now, direct constraints on the timing of such events have not been available. Here we report three alteration events in the southwest Kaapvaal lithosphere using U-Th-He geochronology of fluid-bearing diamonds, and constrain the upper limit of He diffusivity (to D ≈ 1.8 × 10−19 cm2 s−1), thus providing a means to directly place both upper and lower age limits on these alteration episodes. The youngest, during the Cretaceous, involved highly saline fluids, indicating a relationship with late-Mesozoic kimberlite eruptions. Remnants of two preceding events, by a Paleozoic silicic fluid and a Proterozoic carbonatitic fluid, are also encapsulated in Kaapvaal diamonds and are likely coeval with major surface tectonic events (e.g. the Damara and Namaqua–Natal orogenies).
The double-stranded DNA-binding proteins TEBP-1 and TEBP-2 form a telomeric complex with POT-1
Authors: Dietz Sabrina , Almeida Miguel Vasconcelos , Nischwitz Emily , Schreier Jan , Viceconte Nikenza , Fradera-Sola Albert , Renz Christian , Ceron-Noriega Alejandro , Ulrich Helle D. , Kappei Dennis , Ketting René F. , Butter Falk
Published: May 2021

Telomeres are bound by dedicated proteins, which protect them from DNA damage and regulate telomere length homeostasis. In the nematodeCaenorhabditis elegans, a comprehensive understanding of the proteins interacting with the telomere sequence is lacking. Here, we harnessed a quantitative proteomics approach to identify TEBP-1 and TEBP-2, two paralogs expressed in the germline and embryogenesis that associate to telomeres in vitro and in vivo.tebp-1andtebp-2mutants display strikingly distinct phenotypes:tebp-1mutants have longer telomeres than wild-type animals, whiletebp-2mutants display shorter telomeres and a Mortal Germline. Notably,tebp-1;tebp-2double mutant animals have synthetic sterility, with germlines showing signs of severe mitotic and meiotic arrest. Furthermore, we show that POT-1 forms a telomeric complex with TEBP-1 and TEBP-2, which bridges TEBP-1/-2 with POT-2/MRT-1. These results provide insights into the composition and organization of a telomeric protein complex inC. elegans.
Artificial intelligence-enabled fully automated detection of cardiac amyloidosis using electrocardiograms and echocardiograms
Authors: Goto Shinichi , Mahara Keitaro , Beussink-Nelson Lauren , Ikura Hidehiko , Katsumata Yoshinori , Endo Jin , Gaggin Hanna K. , Shah Sanjiv J. , Itabashi Yuji , MacRae Calum A. , Deo Rahul C.
Published: May 2021

Patients with rare conditions such as cardiac amyloidosis (CA) are difficult to identify, given the similarity of disease manifestations to more prevalent disorders. The deployment of approved therapies for CA has been limited by delayed diagnosis of this disease. Artificial intelligence (AI) could enable detection of rare diseases. Here we present a pipeline for CA detection using AI models with electrocardiograms (ECG) or echocardiograms as inputs. These models, trained and validated on 3 and 5 academic medical centers (AMC) respectively, detect CA with C-statistics of 0.85–0.91 for ECG and 0.89–1.00 for echocardiography. Simulating deployment on 2 AMCs indicated a positive predictive value (PPV) for the ECG model of 3–4% at 52–71% recall. Pre-screening with ECG enhance the echocardiography model performance at 67% recall from PPV of 33% to PPV of 74–77%. In conclusion, we developed an automated strategy to augment CA detection, which should be generalizable to other rare cardiac diseases.
Inositol triphosphate-triggered calcium release blocks lipid exchange at endoplasmic reticulum-Golgi contact sites
Authors: Malek Mouhannad , Wawrzyniak Anna M. , Koch Peter , Lüchtenborg Christian , Hessenberger Manuel , Sachsenheimer Timo , Jang Wonyul , Brügger Britta , Haucke Volker
Published: May 2021

Vesicular traffic and membrane contact sites between organelles enable the exchange of proteins, lipids, and metabolites. Recruitment of tethers to contact sites between the endoplasmic reticulum (ER) and the plasma membrane is often triggered by calcium. Here we reveal a function for calcium in the repression of cholesterol export at membrane contact sites between the ER and the Golgi complex. We show that calcium efflux from ER stores induced by inositol-triphosphate [IP3] accumulation upon loss of the inositol 5-phosphatase INPP5A or receptor signaling triggers depletion of cholesterol and associated Gb3 from the cell surface, resulting in a blockade of clathrin-independent endocytosis (CIE) of Shiga toxin. This phenotype is caused by the calcium-induced dissociation of oxysterol binding protein (OSBP) from the Golgi complex and from VAP-containing membrane contact sites. Our findings reveal a crucial function for INPP5A-mediated IP3 hydrolysis in the control of lipid exchange at membrane contact sites.
1.5 °C degrowth scenarios suggest the need for new mitigation pathways
Authors: Keyßer Lorenz T. , Lenzen Manfred
Published: May 2021

1.5  °C scenarios reported by the Intergovernmental Panel on Climate Change (IPCC) rely on combinations of controversial negative emissions and unprecedented technological change, while assuming continued growth in gross domestic product (GDP). Thus far, the integrated assessment modelling community and the IPCC have neglected to consider degrowth scenarios, where economic output declines due to stringent climate mitigation. Hence, their potential to avoid reliance on negative emissions and speculative rates of technological change remains unexplored. As a first step to address this gap, this paper compares 1.5  °C degrowth scenarios with IPCC archetype scenarios, using a simplified quantitative representation of the fuel-energy-emissions nexus. Here we find that the degrowth scenarios minimize many key risks for feasibility and sustainability compared to technology-driven pathways, such as the reliance on high energy-GDP decoupling, large-scale carbon dioxide removal and large-scale and high-speed renewable energy transformation. However, substantial challenges remain regarding political feasibility. Nevertheless, degrowth pathways should be thoroughly considered.
Elp2 mutations perturb the epitranscriptome and lead to a complex neurodevelopmental phenotype
Authors: Kojic Marija , Gawda Tomasz , Gaik Monika , Begg Alexander , Salerno-Kochan Anna , Kurniawan Nyoman D. , Jones Alun , Drożdżyk Katarzyna , Kościelniak Anna , Chramiec-Głąbik Andrzej , Hediyeh-Zadeh Soroor , Kasherman Maria , Shim Woo Jun , Sinniah Enakshi , Genovesi Laura A. , Abrahamsen Rannvá K. , Fenger Christina D. , Madsen Camilla G. , Cohen Julie S. , Fatemi Ali , Stark Zornitza , Lunke Sebastian , Lee Joy , Hansen Jonas K. , Boxill Martin F. , Keren Boris , Marey Isabelle , Saenz Margarita S. , Brown Kathleen , Alexander Suzanne A. , Mureev Sergey , Batzilla Alina , Davis Melissa J. , Piper Michael , Bodén Mikael , Burne Thomas H. J. , Palpant Nathan J. , Møller Rikke S. , Glatt Sebastian , Wainwright Brandon J.
Published: May 2021

Intellectual disability (ID) and autism spectrum disorder (ASD) are the most common neurodevelopmental disorders and are characterized by substantial impairment in intellectual and adaptive functioning, with their genetic and molecular basis remaining largely unknown. Here, we identify biallelic variants in the gene encoding one of the Elongator complex subunits, ELP2, in patients with ID and ASD. Modelling the variants in mice recapitulates the patient features, with brain imaging and tractography analysis revealing microcephaly, loss of white matter tract integrity and an aberrant functional connectome. We show that the Elp2 mutations negatively impact the activity of the complex and its function in translation via tRNA modification. Further, we elucidate that the mutations perturb protein homeostasis leading to impaired neurogenesis, myelin loss and neurodegeneration. Collectively, our data demonstrate an unexpected role for tRNA modification in the pathogenesis of monogenic ID and ASD and define Elp2 as a key regulator of brain development.
Immune evolution from preneoplasia to invasive lung adenocarcinomas and underlying molecular features
Authors: Dejima Hitoshi , Hu Xin , Chen Runzhe , Zhang Jiexin , Fujimoto Junya , Parra Edwin R. , Haymaker Cara , Hubert Shawna M. , Duose Dzifa , Solis Luisa M. , Su Dan , Fukuoka Junya , Tabata Kazuhiro , Pham Hoa H. N. , Mcgranahan Nicholas , Zhang Baili , Ye Jie , Ying Lisha , Little Latasha , Gumbs Curtis , Chow Chi-Wan , Estecio Marcos Roberto , Godoy Myrna C. B. , Antonoff Mara B. , Sepesi Boris , Pass Harvey I. , Behrens Carmen , Zhang Jianhua , Vaporciyan Ara A. , Heymach John V. , Scheet Paul , Lee J. Jack , Wu Jia , Futreal P. Andrew , Reuben Alexandre , Kadara Humam , Wistuba Ignacio I. , Zhang Jianjun
Published: May 2021

The mechanism by which anti-cancer immunity shapes early carcinogenesis of lung adenocarcinoma (ADC) is unknown. In this study, we characterize the immune contexture of invasive lung ADC and its precursors by transcriptomic immune profiling, T cell receptor (TCR) sequencing and multiplex immunofluorescence (mIF). Our results demonstrate that anti-tumor immunity evolved as a continuum from lung preneoplasia, to preinvasive ADC, minimally-invasive ADC and frankly invasive lung ADC with a gradually less effective and more intensively regulated immune response including down-regulation of immune-activation pathways, up-regulation of immunosuppressive pathways, lower infiltration of cytotoxic T cells (CTLs) and anti-tumor helper T cells (Th), higher infiltration of regulatory T cells (Tregs), decreased T cell clonality, and lower frequencies of top T cell clones in later-stages. Driver mutations, chromosomal copy number aberrations (CNAs) and aberrant DNA methylation may collectively impinge host immune responses and facilitate immune evasion, promoting the outgrowth of fit subclones in preneoplasia into dominant clones in invasive ADC.
Micron-scale phenomena observed in a turbulent laser-produced plasma
Authors: Rigon G. , Albertazzi B. , Pikuz T. , Mabey P. , Bouffetier V. , Ozaki N. , Vinci T. , Barbato F. , Falize E. , Inubushi Y. , Kamimura N. , Katagiri K. , Makarov S. , Manuel M. J.-E. , Miyanishi K. , Pikuz S. , Poujade O. , Sueda K. , Togashi T. , Umeda Y. , Yabashi M. , Yabuuchi T. , Gregori G. , Kodama R. , Casner A. , Koenig M.
Published: May 2021

Turbulence is ubiquitous in the universe and in fluid dynamics. It influences a wide range of high energy density systems, from inertial confinement fusion to astrophysical-object evolution. Understanding this phenomenon is crucial, however, due to limitations in experimental and numerical methods in plasma systems, a complete description of the turbulent spectrum is still lacking. Here, we present the measurement of a turbulent spectrum down to micron scale in a laser-plasma experiment. We use an experimental platform, which couples a high power optical laser, an x-ray free-electron laser and a lithium fluoride crystal, to study the dynamics of a plasma flow with micrometric resolution (~1μm) over a large field of view (>1 mm2). After the evolution of a Rayleigh–Taylor unstable system, we obtain spectra, which are overall consistent with existing turbulent theory, but present unexpected features. This work paves the way towards a better understanding of numerous systems, as it allows the direct comparison of experimental results, theory and numerical simulations.
Portable bioluminescent platform for in vivo monitoring of biological processes in non-transgenic animals
Authors: Yevtodiyenko Aleksey , Bazhin Arkadiy , Khodakivskyi Pavlo , Godinat Aurelien , Budin Ghyslain , Maric Tamara , Pietramaggiori Giorgio , Scherer Sandra S. , Kunchulia Marina , Eppeldauer George , Polyakov Sergey V. , Francis Kevin P. , Bryan Jeffrey N. , Goun Elena A.
Published: May 2021

Bioluminescent imaging (BLI) is one of the most powerful and widely used preclinical imaging modalities. However, the current technology relies on the use of transgenic luciferase-expressing cells and animals and therefore can only be applied to a limited number of existing animal models of human disease. Here, we report the development of a “portable bioluminescent” (PBL) technology that overcomes most of the major limitations of traditional BLI. We demonstrate that the PBL method is capable of noninvasive measuring the activity of both extracellular (e.g., dipeptidyl peptidase 4) and intracellular (e.g., cytochrome P450) enzymes in vivo in non-luciferase-expressing mice. Moreover, we successfully utilize PBL technology in dogs and human cadaver, paving the way for the translation of functional BLI to the noninvasive quantification of biological processes in large animals. The PBL methodology can be easily adapted for the noninvasive monitoring of a plethora of diseases across multiple species.
Engineered red blood cells as an off-the-shelf allogeneic anti-tumor therapeutic
Authors: Zhang Xuqing , Luo Mengyao , Dastagir Shamael R. , Nixon Mellissa , Khamhoung Annie , Schmidt Andrea , Lee Albert , Subbiah Naren , McLaughlin Douglas C. , Moore Christopher L. , Gribble Mary , Bayhi Nicholas , Amin Viral , Pepi Ryan , Pawar Sneha , Lyford Timothy J. , Soman Vikram , Mellen Jennifer , Carpenter Christopher L. , Turka Laurence A. , Wickham Thomas J. , Chen Tiffany F.
Published: May 2021

Checkpoint inhibitors and T-cell therapies have highlighted the critical role of T cells in anti-cancer immunity. However, limitations associated with these treatments drive the need for alternative approaches. Here, we engineer red blood cells into artificial antigen-presenting cells (aAPCs) presenting a peptide bound to the major histocompatibility complex I, the costimulatory ligand 4-1BBL, and interleukin (IL)-12. This leads to robust, antigen-specific T-cell expansion, memory formation, additional immune activation, tumor control, and antigen spreading in tumor models in vivo. The presence of 4-1BBL and IL-12 induces minimal toxicities due to restriction to the vasculature and spleen. The allogeneic aAPC, RTX-321, comprised of human leukocyte antigen-A*02:01 presenting the human papilloma virus (HPV) peptide HPV16 E711-19, 4-1BBL, and IL-12 on the surface, activates HPV-specific T cells and promotes effector function in vitro. Thus, RTX-321 is a potential ‘off-the-shelf’ in vivo cellular immunotherapy for treating HPV + cancers, including cervical and head/neck cancers.
Comprehensive cell type decomposition of circulating cell-free DNA with CelFiE
Authors: Caggiano Christa , Celona Barbara , Garton Fleur , Mefford Joel , Black Brian L. , Henderson Robert , Lomen-Hoerth Catherine , Dahl Andrew , Zaitlen Noah
Published: May 2021

Circulating cell-free DNA (cfDNA) in the bloodstream originates from dying cells and is a promising noninvasive biomarker for cell death. Here, we propose an algorithm, CelFiE, to accurately estimate the relative abundances of cell types and tissues contributing to cfDNA from epigenetic cfDNA sequencing. In contrast to previous work, CelFiE accommodates low coverage data, does not require CpG site curation, and estimates contributions from multiple unknown cell types that are not available in external reference data. In simulations, CelFiE accurately estimates known and unknown cell type proportions from low coverage and noisy cfDNA mixtures, including from cell types composing less than 1% of the total mixture. When used in two clinically-relevant situations, CelFiE correctly estimates a large placenta component in pregnant women, and an elevated skeletal muscle component in amyotrophic lateral sclerosis (ALS) patients, consistent with the occurrence of muscle wasting typical in these patients. Together, these results show how CelFiE could be a useful tool for biomarker discovery and monitoring the progression of degenerative disease.
Anomalous normal fluid response in a chiral superconductor UTe2
Authors: Bae Seokjin , Kim Hyunsoo , Eo Yun Suk , Ran Sheng , Liu I-lin , Fuhrman Wesley T. , Paglione Johnpierre , Butch Nicholas P. , Anlage Steven M.
Published: May 2021

Chiral superconductors have been proposed as one pathway to realize Majorana normal fluid at its boundary. However, the long-sought 2D and 3D chiral superconductors with edge and surface Majorana normal fluid are yet to be conclusively found. Here, we report evidence for a chiral spin-triplet pairing state of UTe2 with surface normal fluid response. The microwave surface impedance of the UTe2 crystal was measured and converted to complex conductivity, which is sensitive to both normal and superfluid responses. The anomalous residual normal fluid conductivity supports the presence of a significant normal fluid response. The superfluid conductivity follows the temperature behavior predicted for an axial spin-triplet state, which is further narrowed down to a chiral spin-triplet state with evidence of broken time-reversal symmetry. Further analysis excludes trivial origins for the observed normal fluid response. Our findings suggest that UTe2 can be a new platform to study exotic topological excitations in higher dimension.
Photon quantum entanglement in the MeV regime and its application in PET imaging
Authors: Watts D. P. , Bordes J. , Brown J. R. , Cherlin A. , Newton R. , Allison J. , Bashkanov M. , Efthimiou N. , Zachariou N. A.
Published: May 2021

Positron Emission Tomography (PET) is a widely-used imaging modality for medical research and clinical diagnosis. Imaging of the radiotracer is obtained from the detected hit positions of the two positron annihilation photons in a detector array. The image is degraded by backgrounds from random coincidences and in-patient scatter events which require correction. In addition to the geometric information, the two annihilation photons are predicted to be produced in a quantum-entangled state, resulting in enhanced correlations between their subsequent interaction processes. To explore this, the predicted entanglement in linear polarisation for the two photons was incorporated into a simulation and tested by comparison with experimental data from a cadmium zinc telluride (CZT) PET demonstrator apparatus. Adapted apparati also enabled correlation measurements where one of the photons had undergone a prior scatter process. We show that the entangled simulation describes the measured correlations and, through simulation of a larger preclinical PET scanner, illustrate a simple method to quantify and remove the unwanted backgrounds in PET using the quantum entanglement information alone.
Tanc2-mediated mTOR inhibition balances mTORC1/2 signaling in the developing mouse brain and human neurons
Authors: Kim Sun-Gyun , Lee Suho , Kim Yangsik , Park Jieun , Woo Doyeon , Kim Dayeon , Li Yan , Shin Wangyong , Kang Hyunjeong , Yook Chaehyun , Lee Minji , Kim Kyungdeok , Roh Junyeop Daniel , Ryu Jeseung , Jung Hwajin , Um Seung Min , Yang Esther , Kim Hyun , Han Jinju , Heo Won Do , Kim Eunjoon
Published: May 2021

mTOR signaling, involving mTORC1 and mTORC2 complexes, critically regulates neural development and is implicated in various brain disorders. However, we do not fully understand all of the upstream signaling components that can regulate mTOR signaling, especially in neurons. Here, we show a direct, regulated inhibition of mTOR by Tanc2, an adaptor/scaffolding protein with strong neurodevelopmental and psychiatric implications. While Tanc2-null mice show embryonic lethality, Tanc2-haploinsufficient mice survive but display mTORC1/2 hyperactivity accompanying synaptic and behavioral deficits reversed by mTOR-inhibiting rapamycin. Tanc2 interacts with and inhibits mTOR, which is suppressed by mTOR-activating serum or ketamine, a fast-acting antidepressant. Tanc2 and Deptor, also known to inhibit mTORC1/2 minimally affecting neurodevelopment, distinctly inhibit mTOR in early- and late-stage neurons. Lastly, Tanc2 inhibits mTORC1/2 in human neural progenitor cells and neurons. In summary, our findings show that Tanc2 is a mTORC1/2 inhibitor affecting neurodevelopment.
Posterior subthalamic nucleus (PSTh) mediates innate fear-associated hypothermia in mice
Authors: Liu Can , Lee Chia-Ying , Asher Greg , Cao Liqin , Terakoshi Yuka , Cao Peng , Kobayakawa Reiko , Kobayakawa Ko , Sakurai Katsuyasu , Liu Qinghua
Published: May 2021

The neural mechanisms of fear-associated thermoregulation remain unclear. Innate fear odor 2-methyl-2-thiazoline (2MT) elicits rapid hypothermia and elevated tail temperature, indicative of vasodilation-induced heat dissipation, in wild-type mice, but not in mice lacking Trpa1–the chemosensor for 2MT. Here we report that Trpa1−/− mice show diminished 2MT-evoked c-fos expression in the posterior subthalamic nucleus (PSTh), external lateral parabrachial subnucleus (PBel) and nucleus of the solitary tract (NTS). Whereas tetanus toxin light chain-mediated inactivation of NTS-projecting PSTh neurons suppress, optogenetic activation of direct PSTh-rostral NTS pathway induces hypothermia and tail vasodilation. Furthermore, selective opto-stimulation of 2MT-activated, PSTh-projecting PBel neurons by capturing activated neuronal ensembles (CANE) causes hypothermia. Conversely, chemogenetic suppression of vGlut2+ neurons in PBel or PSTh, or PSTh-projecting PBel neurons attenuates 2MT-evoked hypothermia and tail vasodilation. These studies identify PSTh as a major thermoregulatory hub that connects PBel to NTS to mediate 2MT-evoked innate fear-associated hypothermia and tail vasodilation.
A high-entropy manganite in an ordered nanocomposite for long-term application in solid oxide cells
Authors: Baiutti F. , Chiabrera F. , Acosta M. , Diercks D. , Parfitt D. , Santiso J. , Wang X. , Cavallaro A. , Morata A. , Wang H. , Chroneos A. , MacManus-Driscoll J. , Tarancon A.
Published: May 2021

The implementation of nano-engineered composite oxides opens up the way towards the development of a novel class of functional materials with enhanced electrochemical properties. Here we report on the realization of vertically aligned nanocomposites of lanthanum strontium manganite and doped ceria with straight applicability as functional layers in high-temperature energy conversion devices. By a detailed analysis using complementary state-of-the-art techniques, which include atom-probe tomography combined with oxygen isotopic exchange, we assess the local structural and electrochemical functionalities and we allow direct observation of local fast oxygen diffusion pathways. The resulting ordered mesostructure, which is characterized by a coherent, dense array of vertical interfaces, shows high electrochemically activity and suppressed dopant segregation. The latter is ascribed to spontaneous cationic intermixing enabling lattice stabilization, according to density functional theory calculations. This work highlights the relevance of local disorder and long-range arrangements for functional oxides nano-engineering and introduces an advanced method for the local analysis of mass transport phenomena.
Expression of FoxP2 in the basal ganglia regulates vocal motor sequences in the adult songbird
Authors: Xiao Lei , Merullo Devin P. , Koch Therese M. I. , Cao Mou , Co Marissa , Kulkarni Ashwinikumar , Konopka Genevieve , Roberts Todd F.
Published: May 2021

Disruption of the transcription factor FoxP2, which is enriched in the basal ganglia, impairs vocal development in humans and songbirds. The basal ganglia are important for the selection and sequencing of motor actions, but the circuit mechanisms governing accurate sequencing of learned vocalizations are unknown. Here, we show that expression of FoxP2 in the basal ganglia is vital for the fluent initiation and termination of birdsong, as well as the maintenance of song syllable sequencing in adulthood. Knockdown of FoxP2 imbalances dopamine receptor expression across striatal direct-like and indirect-like pathways, suggesting a role of dopaminergic signaling in regulating vocal motor sequencing. Confirming this prediction, we show that phasic dopamine activation, and not inhibition, during singing drives repetition of song syllables, thus also impairing fluent initiation and termination of birdsong. These findings demonstrate discrete circuit origins for the dysfluent repetition of vocal elements in songbirds, with implications for speech disorders.
Lying in wait: the resurgence of dengue virus after the Zika epidemic in Brazil
Authors: Brito Anderson Fernandes , Machado Lais Ceschini , Oidtman Rachel J. , Siconelli Márcio Junio Lima , Tran Quan Minh , Fauver Joseph R. , Carvalho Rodrigo Dias de Oliveira , Dezordi Filipe Zimmer , Pereira Mylena Ribeiro , de Castro-Jorge Luiza Antunes , Minto Elaine Cristina Manini , Passos Luzia Márcia Romanholi , Kalinich Chaney C. , Petrone Mary E. , Allen Emma , España Guido Camargo , Huang Angkana T. , Cummings Derek A. T. , Baele Guy , Franca Rafael Freitas Oliveira , da Fonseca Benedito Antônio Lopes , Perkins T. Alex , Wallau Gabriel Luz , Grubaugh Nathan D.
Published: May 2021

After the Zika virus (ZIKV) epidemic in the Americas in 2016, both Zika and dengue incidence declined to record lows in many countries in 2017–2018, but in 2019 dengue resurged in Brazil, causing ~2.1 million cases. In this study we use epidemiological, climatological and genomic data to investigate dengue dynamics in recent years in Brazil. First, we estimate dengue virus force of infection (FOI) and model mosquito-borne transmission suitability since the early 2000s. Our estimates reveal that DENV transmission was low in 2017–2018, despite conditions being suitable for viral spread. Our study also shows a marked decline in dengue susceptibility between 2002 and 2019, which could explain the synchronous decline of dengue in the country, partially as a result of protective immunity from prior ZIKV and/or DENV infections. Furthermore, we performed phylogeographic analyses using 69 newly sequenced genomes of dengue virus serotype 1 and 2 from Brazil, and found that the outbreaks in 2018–2019 were caused by local DENV lineages that persisted for 5–10 years, circulating cryptically before and after the Zika epidemic. We hypothesize that DENV lineages may circulate at low transmission levels for many years, until local conditions are suitable for higher transmission, when they cause major outbreaks.
A Stat1 bound enhancer promotes Nampt expression and function within tumor associated macrophages
Authors: Huffaker Thomas B. , Ekiz H. Atakan , Barba Cindy , Lee Soh-Hyun , Runtsch Marah C. , Nelson Morgan C. , Bauer Kaylyn M. , Tang William W. , Mosbruger Timothy L. , Cox James E. , Round June L. , Voth Warren P. , O’Connell Ryan M.
Published: May 2021

Tumor associated macrophage responses are regulated by distinct metabolic states that affect their function. However, the ability of specific signals in the local tumor microenvironment to program macrophage metabolism remains under investigation. Here, we identify NAMPT, the rate limiting enzyme in NAD salvage synthesis, as a target of STAT1 during cellular activation by interferon gamma, an important driver of macrophage polarization and antitumor responses. We demonstrate that STAT1 occupies a conserved element within the first intron of Nampt, termed Nampt-Regulatory Element-1 (NRE1). Through disruption of NRE1 or pharmacological inhibition, a subset of M1 genes is sensitive to NAMPT activity through its impact on glycolytic processes. scRNAseq is used to profile in vivo responses by NRE1-deficient, tumor-associated leukocytes in melanoma tumors through the creation of a unique mouse strain. Reduced Nampt and inflammatory gene expression are present in specific myeloid and APC populations; moreover, targeted ablation of NRE1 in macrophage lineages results in greater tumor burden. Finally, elevated NAMPT expression correlates with IFNγ responses and melanoma patient survival. This study identifies IFN and STAT1-inducible Nampt as an important factor that shapes the metabolic program and function of tumor associated macrophages.
Selective inhibition of cullin 3 neddylation through covalent targeting DCN1 protects mice from acetaminophen-induced liver toxicity
Authors: Zhou Haibin , Lu Jianfeng , Chinnaswamy Krishnapriya , Stuckey Jeanne A. , Liu Liu , McEachern Donna , Yang Chao-Yie , Bernard Denzil , Shen Hong , Rui Liangyou , Sun Yi , Wang Shaomeng
Published: May 2021

Cullin-RING E3 ligases (CRLs) regulate the turnover of approximately 20% of mammalian cellular proteins. Neddylation of individual cullin proteins is essential for the activation of each CRL. We report herein the discovery of DI-1548 and DI-1859 as two potent, selective and covalent DCN1 inhibitors. These inhibitors selectively inhibit neddylation of cullin 3 in cells at low nanomolar concentrations and are 2–3 orders of magnitude more potent than our previously reported reversible DCN1 inhibitor. Mass spectrometric analysis and co-crystal structures reveal that these compounds employ a unique mechanism of covalent bond formation with DCN1. DI-1859 induces a robust increase of NRF2 protein, a CRL3 substrate, in mouse liver and effectively protects mice from acetaminophen-induced liver damage. Taken together, this study demonstrates the therapeutic potential of selective inhibition of cullin neddylation.
A SARS-CoV-2 neutralizing antibody with extensive Spike binding coverage and modified for optimal therapeutic outcomes
Authors: Guo Yu , Huang Lisu , Zhang Guangshun , Yao Yanfeng , Zhou He , Shen Shu , Shen Bingqing , Li Bo , Li Xin , Zhang Qian , Chen Mingjie , Chen Da , Wu Jia , Fu Dan , Zeng Xinxin , Feng Mingfang , Pi Chunjiang , Wang Yuan , Zhou Xingdong , Lu Minmin , Li Yarong , Fang Yaohui , Lu Yun-Yueh , Hu Xue , Wang Shanshan , Zhang Wanju , Gao Ge , Adrian Francisco , Wang Qisheng , Yu Feng , Peng Yun , Gabibov Alexander G. , Min Juan , Wang Yuhui , Huang Heyu , Stepanov Alexey , Zhang Wei , Cai Yan , Liu Junwei , Yuan Zhiming , Zhang Chen , Lou Zhiyong , Deng Fei , Zhang Hongkai , Shan Chao , Schweizer Liang , Sun Kun , Rao Zihe
Published: May 2021

COVID-19 pandemic caused by SARS-CoV-2 constitutes a global public health crisis with enormous economic consequences. Monoclonal antibodies against SARS-CoV-2 can provide an important treatment option to fight COVID-19, especially for the most vulnerable populations. In this work, potent antibodies binding to SARS-CoV-2 Spike protein were identified from COVID-19 convalescent patients. Among them, P4A1 interacts directly with and covers majority of the Receptor Binding Motif of the Spike Receptor-Binding Domain, shown by high-resolution complex structure analysis. We further demonstrate the binding and neutralizing activities of P4A1 against wild type and mutant Spike proteins or pseudoviruses. P4A1 was subsequently engineered to reduce the potential risk for Antibody-Dependent Enhancement of infection and to extend its half-life. The engineered antibody exhibits an optimized pharmacokinetic and safety profile, and it results in complete viral clearance in a rhesus monkey model of COVID-19 following a single injection. These data suggest its potential against SARS-CoV-2 related diseases.
Critical role of interferons in gastrointestinal injury repair
Authors: McElrath Constance , Espinosa Vanessa , Lin Jian-Da , Peng Jianya , Sridhar Raghavendra , Dutta Orchi , Tseng Hsiang-Chi , Smirnov Sergey V. , Risman Heidi , Sandoval Marvin J. , Davra Viralkumar , Chang Yun-Juan , Pollack Brian P. , Birge Raymond B. , Galan Mark , Rivera Amariliz , Durbin Joan E. , Kotenko Sergei V.
Published: May 2021

The etiology of ulcerative colitis is poorly understood and is likely to involve perturbation of the complex interactions between the mucosal immune system and the commensal bacteria of the gut, with cytokines acting as important cross-regulators. Here we use IFN receptor-deficient mice in a dextran sulfate sodium (DSS) model of acute intestinal injury to study the contributions of type I and III interferons (IFN) to the initiation, progression and resolution of acute colitis. We find that mice lacking both types of IFN receptors exhibit enhanced barrier destruction, extensive loss of goblet cells and diminished proliferation of epithelial cells in the colon following DSS-induced damage. Impaired mucosal healing in double IFN receptor-deficient mice is driven by decreased amphiregulin expression, which IFN signaling can up-regulate in either the epithelial or hematopoietic compartment. Together, these data underscore the pleiotropic functions of IFNs and demonstrate that these critical antiviral cytokines also support epithelial regeneration following acute colonic injury.
Adjuvant oncolytic virotherapy for personalized anti-cancer vaccination
Authors: Roy D. G. , Geoffroy K. , Marguerie M. , Khan S. T. , Martin N. T. , Kmiecik J. , Bobbala D. , Aitken A. S. , de Souza C. T. , Stephenson K. B. , Lichty B. D. , Auer R. C. , Stojdl D. F. , Bell J. C. , Bourgeois-Daigneault M.-C.
Published: May 2021

By conferring systemic protection and durable benefits, cancer immunotherapies are emerging as long-term solutions for cancer treatment. One such approach that is currently undergoing clinical testing is a therapeutic anti-cancer vaccine that uses two different viruses expressing the same tumor antigen to prime and boost anti-tumor immunity. By providing the additional advantage of directly killing cancer cells, oncolytic viruses (OVs) constitute ideal platforms for such treatment strategy. However, given that the targeted tumor antigen is encoded into the viral genomes, its production requires robust infection and therefore, the vaccination efficiency partially depends on the unpredictable and highly variable intrinsic sensitivity of each tumor to OV infection. In this study, we demonstrate that anti-cancer vaccination using OVs (Adenovirus (Ad), Maraba virus (MRB), Vesicular stomatitis virus (VSV) and Vaccinia virus (VV)) co-administered with antigenic peptides is as efficient as antigen-engineered OVs and does not depend on viral replication. Our strategy is particularly attractive for personalized anti-cancer vaccines targeting patient-specific mutations. We suggest that the use of OVs as adjuvant platforms for therapeutic anti-cancer vaccination warrants testing for cancer treatment.
A coordinated progression of progenitor cell states initiates urinary tract development
Authors: Sanchez-Ferras Oraly , Pacis Alain , Sotiropoulou Maria , Zhang Yuhong , Wang Yu Chang , Bourgey Mathieu , Bourque Guillaume , Ragoussis Jiannis , Bouchard Maxime
Published: May 2021

The kidney and upper urinary tract develop through reciprocal interactions between the ureteric bud and the surrounding mesenchyme. Ureteric bud branching forms the arborized collecting duct system of the kidney, while ureteric tips promote nephron formation from dedicated progenitor cells. While nephron progenitor cells are relatively well characterized, the origin of ureteric bud progenitors has received little attention so far. It is well established that the ureteric bud is induced from the nephric duct, an epithelial duct derived from the intermediate mesoderm of the embryo. However, the cell state transitions underlying the progression from intermediate mesoderm to nephric duct and ureteric bud remain unknown. Here we show that nephric duct morphogenesis results from the coordinated organization of four major progenitor cell populations. Using single cell RNA-seq and Cluster RNA-seq, we show that these progenitors emerge in time and space according to a stereotypical pattern. We identify the transcription factors Tfap2a/b and Gata3 as critical coordinators of this progenitor cell progression. This study provides a better understanding of the cellular origin of the renal collecting duct system and associated urinary tract developmental diseases, which may inform guided differentiation of functional kidney tissue.