bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of the supergravity on the formation and cycle life of non-aqueous lithium metal batteries
Authors: Gao Yuliang , Qiao Fahong , You Jingyuan , Ren Zengying , Li Nan , Zhang Kun , Shen Chao , Jin Ting , Xie Keyu
Published: January 2022

Extra-terrestrial explorations require electrochemical energy storage devices able to operate in gravity conditions different from those of planet earth. In this context, lithium (Li)-based batteries have not been fully investigated, especially cell formation and cycling performances under supergravity (i.e., gravity > 9.8 m s−2) conditions. To shed some light on these aspects, here, we investigate the behavior of non-aqueous Li metal cells under supergravity conditions. The physicochemical and electrochemical characterizations reveal that, distinctly from earth gravity conditions, smooth and dense Li metal depositions are obtained under supergravity during Li metal deposition on a Cu substrate. Moreover, supergravity allows the formation of an inorganic-rich solid electrolyte interphase (SEI) due to the strong interactions between Li+ and salt anions, which promote significant decomposition of the anions on the negative electrode surface. Tests in full Li metal pouch cell configuration (using LiNi0.8Co0.1Mn0.1O2-based positive electrode and LiFSI-based electrolyte solution) also demonstrate the favorable effect of the supergravity in terms of deposition morphology and SEI composition and ability to carry out 200 cycles at 2 C (400 mA g−1) rate with a capacity retention of 96%.
Mechanism for inverted-repeat recombination induced by a replication fork barrier
Authors: Marie Léa , Symington Lorraine S.
Published: January 2022

Replication stress and abundant repetitive sequences have emerged as primary conditions underlying genomic instability in eukaryotes. To gain insight into the mechanism of recombination between repeated sequences in the context of replication stress, we used a prokaryotic Tus/Ter barrier designed to induce transient replication fork stalling near inverted repeats in the budding yeast genome. Our study reveals that the replication fork block stimulates a unique recombination pathway dependent on Rad51 strand invasion and Rad52-Rad59 strand annealing activities, Mph1/Rad5 fork remodelers, Mre11/Exo1/Dna2 resection machineries, Rad1-Rad10 nuclease and DNA polymerase δ. Furthermore, we show recombination at stalled replication forks is limited by the Srs2 helicase and Mus81-Mms4/Yen1 nucleases. Physical analysis of the replication-associated recombinants revealed that half are associated with an inversion of sequence between the repeats. Based on our extensive genetic characterization, we propose a model for recombination of closely linked repeats that can robustly generate chromosome rearrangements.
Computation-guided asymmetric total syntheses of resveratrol dimers
Authors: Nakajima Masaya , Adachi Yusuke , Nemoto Tetsuhiro
Published: January 2022

Although computational simulation-based natural product syntheses are in their initial stages of development, this concept can potentially become an indispensable resource in the field of organic synthesis. Herein we report the asymmetric total syntheses of several resveratrol dimers based on a comprehensive computational simulation of their biosynthetic pathways. Density functional theory (DFT) calculations suggested inconsistencies in the biosynthesis of vaticahainol A and B that predicted the requirement of structural corrections of these natural products. According to the computational predictions, total syntheses were examined and the correct structures of vaticahainol A and B were confirmed. The established synthetic route was applied to the asymmetric total synthesis of (−)-malibatol A, (−)-vaticahainol B, (+)-vaticahainol A, (+)-vaticahainol C, and (−)-albiraminol B, which provided new insight into the biosynthetic pathway of resveratrol dimers. This study demonstrated that computation-guided organic synthesis can be a powerful strategy to advance the chemical research of natural products.
Facile construction of fully sp2-carbon conjugated two-dimensional covalent organic frameworks containing benzobisthiazole units
Authors: Wang Yuancheng , Hao Wenbo , Liu Hui , Chen Renzeng , Pan Qingyan , Li Zhibo , Zhao Yingjie
Published: January 2022

Developing a facile strategy for the construction of vinylene-linked fully π-conjugated covalent organic frameworks (COFs) remains a huge challenge. Here, a versatile condition of Knoevenagel polycondensation for constructing vinylene-linked 2D COFs was explored. Three new examples of vinylene-linked 2D COFs (BTH-1, 2, 3) containing benzobisthiazoles units as functional groups were successfully prepared under this versatile and mild condition. The electron-deficient benzobisthiazole units and cyano-vinylene linkages were both integrated into the π conjugated COFs skeleton and acted as acceptor moieties. Interestingly, we found the construction of a highly ordered and conjugated D-A system is favorable for photocatalytic activity. BTH-3 with benzotrithiophene as the donor with a strong D-A effect exhibited an attractive photocatalytic HER of 15.1 mmol h−1g−1 under visible light irradiation.
Visualization and validation of twin nucleation and early-stage growth in magnesium
Authors: Jiang Lin , Gong Mingyu , Wang Jian , Pan Zhiliang , Wang Xin , Zhang Dalong , Wang Y. Morris , Ciston Jim , Minor Andrew M. , Xu Mingjie , Pan Xiaoqing , Rupert Timothy J. , Mahajan Subhash , Lavernia Enrique J. , Beyerlein Irene J. , Schoenung Julie M.
Published: January 2022

The abrupt occurrence of twinning when Mg is deformed leads to a highly anisotropic response, making it too unreliable for structural use and too unpredictable for observation. Here, we describe an in-situ transmission electron microscopy experiment on Mg crystals with strategically designed geometries for visualization of a long-proposed but unverified twinning mechanism. Combining with atomistic simulations and topological analysis, we conclude that twin nucleation occurs through a pure-shuffle mechanism that requires prismatic-basal transformations. Also, we verified a crystal geometry dependent twin growth mechanism, that is the early-stage growth associated with instability of plasticity flow, which can be dominated either by slower movement of prismatic-basal boundary steps, or by faster glide-shuffle along the twinning plane. The fundamental understanding of twinning provides a pathway to understand deformation from a scientific standpoint and the microstructure design principles to engineer metals with enhanced behavior from a technological standpoint.
Robust and durable serological response following pediatric SARS-CoV-2 infection
Authors: Renk Hanna , Dulovic Alex , Seidel Alina , Becker Matthias , Fabricius Dorit , Zernickel Maria , Junker Daniel , Groß Rüdiger , Müller Janis , Hilger Alexander , Bode Sebastian F. N. , Fritsch Linus , Frieh Pauline , Haddad Anneke , Görne Tessa , Remppis Jonathan , Ganzemueller Tina , Dietz Andrea , Huzly Daniela , Hengel Hartmut , Kaier Klaus , Weber Susanne , Jacobsen Eva-Maria , Kaiser Philipp D. , Traenkle Bjoern , Rothbauer Ulrich , Stich Maximilian , Tönshoff Burkhard , Hoffmann Georg F. , Müller Barbara , Ludwig Carolin , Jahrsdörfer Bernd , Schrezenmeier Hubert , Peter Andreas , Hörber Sebastian , Iftner Thomas , Münch Jan , Stamminger Thomas , Groß Hans-Jürgen , Wolkewitz Martin , Engel Corinna , Liu Weimin , Rizzi Marta , Hahn Beatrice H. , Henneke Philipp , Franz Axel R. , Debatin Klaus-Michael , Schneiderhan-Marra Nicole , Janda Ales , Elling Roland
Published: January 2022

The quality and persistence of children’s humoral immune response following SARS-CoV-2 infection remains largely unknown but will be crucial to guide pediatric SARS-CoV-2 vaccination programs. Here, we examine 548 children and 717 adults within 328 households with at least one member with a previous laboratory-confirmed SARS-CoV-2 infection. We assess serological response at 3–4 months and 11–12 months after infection using a bead-based multiplex immunoassay for 23 human coronavirus antigens including SARS-CoV-2 and its Variants of Concern (VOC) and endemic human coronaviruses (HCoVs), and additionally by three commercial SARS-CoV-2 antibody assays. Neutralization against wild type SARS-CoV-2 and the Delta VOC are analysed in a pseudotyped virus assay. Children, compared to adults, are five times more likely to be asymptomatic, and have higher specific antibody levels which persist longer (96.2% versus 82.9% still seropositive 11–12 months post infection). Of note, symptomatic and asymptomatic infections induce similar humoral responses in all age groups. SARS-CoV-2 infection occurs independent of HCoV serostatus. Neutralization responses of children and adults are similar, although neutralization is reduced for both against the Delta VOC. Overall, the long-term humoral immune response to SARS-CoV-2 infection in children is of longer duration than in adults even after asymptomatic infection.
Systematic analysis of drug-associated myocarditis reported in the World Health Organization pharmacovigilance database
Authors: Nguyen Lee S. , Cooper Leslie T. , Kerneis Mathieu , Funck-Brentano Christian , Silvain Johanne , Brechot Nicolas , Hekimian Guillaume , Ammirati Enrico , Ben M’Barek Badr , Redheuil Alban , Gandjbakhch Estelle , Bihan Kevin , Lebrun-Vignes Bénédicte , Ederhy Stephane , Dolladille Charles , Moslehi Javid J. , Salem Joe-Elie
Published: January 2022

While multiple pharmacological drugs have been associated with myocarditis, temporal trends and overall mortality have not been reported. Here we report the spectrum and main features of 5108 reports of drug-induced myocarditis, in a worldwide pharmacovigilance analysis, comprising more than 21 million individual-case-safety reports from 1967 to 2020. Significant association between myocarditis and a suspected drug is assessed using disproportionality analyses, which use Bayesian information component estimates. Overall, we identify 62 drugs associated with myocarditis, 41 of which are categorized into 5 main pharmacological classes: antipsychotics (n = 3108 reports), salicylates (n = 340), antineoplastic-cytotoxics (n = 190), antineoplastic-immunotherapies (n = 538), and vaccines (n = 790). Thirty-eight (61.3%) drugs were not previously reported associated with myocarditis. Antipsychotic was the first (1979) and most reported class (n = 3018). In 2019, the two most reported classes were antipsychotics (54.7%) and immunotherapies (29.5%). Time-to-onset between treatment start and myocarditis is 15 [interquartile range: 10; 23] days. Subsequent mortality is 10.3% and differs between drug classes with immunotherapies the highest, 32.5% and salicylates the lowest, 2.6%. These elements highlight the diversity of presentations of myocarditis depending on drug class, and show the emerging role of antineoplastic drugs in the field of drug-induced myocarditis.
Linking post-translational modifications and protein turnover by site-resolved protein turnover profiling
Authors: Zecha Jana , Gabriel Wassim , Spallek Ria , Chang Yun-Chien , Mergner Julia , Wilhelm Mathias , Bassermann Florian , Kuster Bernhard
Published: January 2022

Proteome-wide measurements of protein turnover have largely ignored the impact of post-translational modifications (PTMs). To address this gap, we employ stable isotope labeling and mass spectrometry to measure the turnover of >120,000 peptidoforms including >33,000 phosphorylated, acetylated, and ubiquitinated peptides for >9,000 native proteins. This site-resolved protein turnover (SPOT) profiling discloses global and site-specific differences in turnover associated with the presence or absence of PTMs. While causal relationships may not always be immediately apparent, we speculate that PTMs with diverging turnover may distinguish states of differential protein stability, structure, localization, enzymatic activity, or protein-protein interactions. We show examples of how the turnover data may give insights into unknown functions of PTMs and provide a freely accessible online tool that allows interrogation and visualisation of all turnover data. The SPOT methodology is applicable to many cell types and modifications, offering the potential to prioritize PTMs for future functional investigations.
Sea-ice retreat suggests re-organization of water mass transformation in the Nordic and Barents Seas
Authors: Moore G. W. K. , Våge K. , Renfrew I. A. , Pickart R. S.
Published: January 2022

Water mass transformation in the Nordic and Barents Seas, triggered by air-sea heat fluxes, is an integral component of the Atlantic Meridional Overturning Circulation (AMOC). These regions are undergoing rapid warming, associated with a retreat in ice cover. Here we present an analysis covering 1950−2020 of the spatiotemporal variability of the air-sea heat fluxes along the region’s boundary currents, where water mass transformation impacts are large. We find there is an increase in the air-sea heat fluxes along these currents that is a function of the currents’ orientation relative to the axis of sea-ice change suggesting enhanced water mass transformation is occurring. Previous work has shown a reduction in heat fluxes in the interior of the Nordic Seas. As a result, a reorganization seems to be underway in where water mass transformation occurs, that needs to be considered when ascertaining how the AMOC will respond to a warming climate.
An application-specific image processing array based on WSe2 transistors with electrically switchable logic functions
Authors: Zeng Senfeng , Liu Chunsen , Huang Xiaohe , Tang Zhaowu , Liu Liwei , Zhou Peng
Published: January 2022

With the rapid development of artificial intelligence, parallel image processing is becoming an increasingly important ability of computing hardware. To meet the requirements of various image processing tasks, the basic pixel processing unit contains multiple functional logic gates and a multiplexer, which leads to notable circuit redundancy. The pixel processing unit retains a large optimizing space to solve the area redundancy issues in parallel computing. Here, we demonstrate a pixel processing unit based on a single WSe2 transistor that has multiple logic functions (AND and XNOR) that are electrically switchable. We further integrate these pixel processing units into a low transistor-consumption image processing array, where both image intersection and image comparison tasks can be performed. Owing to the same image processing power, the consumption of transistors in our image processing unit is less than 16% of traditional circuits.
Options for reforming agricultural subsidies from health, climate, and economic perspectives
Authors: Springmann M. , Freund F.
Published: January 2022

Agricultural subsidies are an important factor for influencing food production and therefore part of a food system that is seen as neither healthy nor sustainable. Here we analyse options for reforming agricultural subsidies in line with health and climate-change objectives on one side, and economic objectives on the other. Using an integrated modelling framework including economic, environmental, and health assessments, we find that on a global scale several reform options could lead to reductions in greenhouse gas emissions and improvements in population health without reductions in economic welfare. Those include a repurposing of up to half of agricultural subsidies to support the production of foods with beneficial health and environmental characteristics, including fruits, vegetables, and other horticultural products, and combining such repurposing with a more equal distribution of subsidy payments globally. The findings suggest that reforming agricultural subsidy schemes based on health and climate-change objectives can be economically feasible and contribute to transitions towards healthy and sustainable food systems.
Dynamics of spike-and nucleocapsid specific immunity during long-term follow-up and vaccination of SARS-CoV-2 convalescents
Authors: Koerber Nina , Priller Alina , Yazici Sarah , Bauer Tanja , Cheng Cho-Chin , Mijočević Hrvoje , Wintersteller Hannah , Jeske Samuel , Vogel Emanuel , Feuerherd Martin , Tinnefeld Kathrin , Winter Christof , Ruland Jürgen , Gerhard Markus , Haller Bernhard , Christa Catharina , Zelger Otto , Roggendorf Hedwig , Halle Martin , Erber Johanna , Lingor Paul , Keppler Oliver , Zehn Dietmar , Protzer Ulrike , Knolle Percy A.
Published: January 2022

Anti-viral immunity continuously declines over time after SARS-CoV-2 infection. Here, we characterize the dynamics of anti-viral immunity during long-term follow-up and after BNT162b2 mRNA-vaccination in convalescents after asymptomatic or mild SARS-CoV-2 infection. Virus-specific and virus-neutralizing antibody titers rapidly declined in convalescents over 9 months after infection, whereas virus-specific cytokine-producing polyfunctional T cells persisted, among which IL-2-producing T cells correlated with virus-neutralizing antibody titers. Among convalescents, 5% of individuals failed to mount long-lasting immunity after infection and showed a delayed response to vaccination compared to 1% of naïve vaccinees, but successfully responded to prime/boost vaccination. During the follow-up period, 8% of convalescents showed a selective increase in virus-neutralizing antibody titers without accompanying increased frequencies of circulating SARS-CoV-2-specific T cells. The same convalescents, however, responded to vaccination with simultaneous increase in antibody and T cell immunity revealing the strength of mRNA-vaccination to increase virus-specific immunity in convalescents.
Helical structure motifs made searchable for functional peptide design
Authors: Tsai Cheng-Yu , Salawu Emmanuel Oluwatobi , Li Hongchun , Lin Guan-Yu , Kuo Ting-Yu , Voon Liyin , Sharma Adarsh , Hu Kai-Di , Cheng Yi-Yun , Sahoo Sobha , Stuart Lutimba , Chen Chih-Wei , Chang Yuan-Yu , Lu Yu-Lin , Ke Simai , Ortiz Christopher Llynard D. , Fang Bai-Shan , Wu Chen-Chi , Lan Chung-Yu , Fu Hua-Wen , Yang Lee-Wei
Published: January 2022

The systematic design of functional peptides has technological and therapeutic applications. However, there is a need for pattern-based search engines that help locate desired functional motifs in primary sequences regardless of their evolutionary conservation. Existing databases such as The Protein Secondary Structure database (PSS) no longer serves the community, while the Dictionary of Protein Secondary Structure (DSSP) annotates the secondary structures when tertiary structures of proteins are provided. Here, we extract 1.7 million helices from the PDB and compile them into a database (Therapeutic Peptide Design database; TP-DB) that allows queries of compounded patterns to facilitate the identification of sequence motifs of helical structures. We show how TP-DB helps us identify a known purification-tag-specific antibody that can be repurposed into a diagnostic kit for Helicobacter pylori. We also show how the database can be used to design a new antimicrobial peptide that shows better Candida albicans clearance and lower hemolysis than its template homologs. Finally, we demonstrate how TP-DB can suggest point mutations in helical peptide blockers to prevent a targeted tumorigenic protein-protein interaction. TP-DB is made available at http://dyn.life.nthu.edu.tw/design/.
GPR182 limits antitumor immunity via chemokine scavenging in mouse melanoma models
Authors: Torphy Robert J. , Sun Yi , Lin Ronggui , Caffrey-Carr Alayna , Fujiwara Yuki , Ho Felix , Miller Emily N. , McCarter Martin D. , Lyons Traci R. , Schulick Richard D. , Kedl Ross M. , Zhu Yuwen
Published: January 2022

For many solid tumors, immune checkpoint blockade therapy has become first line treatment, yet a large proportion of patients with immunologically cold tumors do not benefit due to the paucity of tumor infiltrating lymphocytes. Here we show that the orphan G Protein-Coupled Receptor 182 (GPR182) contributes to immunotherapy resistance in cancer via scavenging chemokines that are important for lymphocyte recruitment to tumors. GPR182 is primarily upregulated in melanoma-associated lymphatic endothelial cells (LECs) during tumorigenesis, and this atypical chemokine receptor endocytoses chemokines promiscuously. In GPR182-deficient mice, T cell infiltration into transplanted melanomas increases, leading to enhanced effector T cell function and improved antitumor immunity. Ablation of GPR182 leads to increased intratumoral concentrations of multiple chemokines and thereby sensitizes poorly immunogenic tumors to immune checkpoint blockade and adoptive cellular therapies. CXCR3 blockade reverses the improved antitumor immunity and T cell infiltration characteristic of GPR182-deficient mice. Our study thus identifies GPR182 as an upstream regulator of the CXCL9/CXCL10/CXCR3 axis that limits antitumor immunity and as a potential therapeutic target in immunologically cold tumors.
Single-cell chromatin accessibility landscape in kidney identifies additional cell-of-origin in heterogenous papillary renal cell carcinoma
Authors: Wang Qi , Zhang Yang , Zhang Bolei , Fu Yao , Zhao Xiaozhi , Zhang Jing , Zuo Ke , Xing Yuexian , Jiang Song , Qin Zhaohui , Li Erguang , Guo Hongqian , Liu Zhihong , Yang Jingping
Published: January 2022

Papillary renal cell carcinoma (pRCC) is the most heterogenous renal cell carcinoma. Patient survival varies and no effective therapies for advanced pRCC exist. Histological and molecular characterization studies have highlighted the heterogeneity of pRCC tumours. Recent studies identified the proximal tubule (PT) cell as a cell-of-origin for pRCC. However, it remains elusive whether other pRCC subtypes have different cell-of-origin. Here, by obtaining genome-wide chromatin accessibility profiles of normal human kidney cells using single-cell transposase-accessible chromatin-sequencing and comparing the profiles with pRCC samples, we discover that besides PT cells, pRCC can also originate from kidney collecting duct principal cells. We show pRCCs with different cell-of-origin exhibit different molecular characteristics and clinical behaviors. Further, metabolic reprogramming appears to mediate the progression of pRCC to the advanced state. Here, our results suggest that determining cell-of-origin and monitoring origin-dependent metabolism could potentially be useful for early diagnosis and treatment of pRCC.
Regulation of the luminescence mechanism of two-dimensional tin halide perovskites
Authors: Zhang Tianju , Zhou Chaocheng , Feng Xuezhen , Dong Ningning , Chen Hong , Chen Xianfeng , Zhang Long , Lin Jia , Wang Jun
Published: January 2022

Two-dimensional (2D) Sn-based perovskites are a kind of non-toxic environment-friendly luminescent material. However, the research on the luminescence mechanism of this type of perovskite is still very controversial, which greatly limits the further improvement and application of the luminescence performance. At present, the focus of controversy is defects and phonon scattering rates. In this work, we combine the organic cation control engineering with temperature-dependent transient absorption spectroscopy to systematically study the interband exciton relaxation pathways in layered A2SnI4 (A = PEA+, BA+, HA+, and OA+) structures. It is revealed that exciton-phonon scattering and exciton-defect scattering have different effects on exciton relaxation. Our study further confirms that the deformation potential scattering by charged defects, not by the non-polar optical phonons, dominates the excitons interband relaxation, which is largely different from the Pb-based perovskites. These results enhance the understanding of the origin of the non-radiative pathway in Sn-based perovskite materials.
Functional dissection of inherited non-coding variation influencing multiple myeloma risk
Authors: Ajore Ram , Niroula Abhishek , Pertesi Maroulio , Cafaro Caterina , Thodberg Malte , Went Molly , Bao Erik L. , Duran-Lozano Laura , Lopez de Lapuente Portilla Aitzkoa , Olafsdottir Thorunn , Ugidos-Damboriena Nerea , Magnusson Olafur , Samur Mehmet , Lareau Caleb A. , Halldorsson Gisli H. , Thorleifsson Gudmar , Norddahl Gudmundur L. , Gunnarsdottir Kristbjorg , Försti Asta , Goldschmidt Hartmut , Hemminki Kari , van Rhee Frits , Kimber Scott , Sperling Adam S. , Kaiser Martin , Anderson Kenneth , Jonsdottir Ingileif , Munshi Nikhil , Rafnar Thorunn , Waage Anders , Weinhold Niels , Thorsteinsdottir Unnur , Sankaran Vijay G. , Stefansson Kari , Houlston Richard , Nilsson Björn
Published: January 2022

Thousands of non-coding variants have been associated with increased risk of human diseases, yet the causal variants and their mechanisms-of-action remain obscure. In an integrative study combining massively parallel reporter assays (MPRA), expression analyses (eQTL, meQTL, PCHiC) and chromatin accessibility analyses in primary cells (caQTL), we investigate 1,039 variants associated with multiple myeloma (MM). We demonstrate that MM susceptibility is mediated by gene-regulatory changes in plasma cells and B-cells, and identify putative causal variants at six risk loci (SMARCD3, WAC, ELL2, CDCA7L, CEP120, and PREX1). Notably, three of these variants co-localize with significant plasma cell caQTLs, signaling the presence of causal activity at these precise genomic positions in an endogenous chromosomal context in vivo. Our results provide a systematic functional dissection of risk loci for a hematologic malignancy.
Gain-of-function genetic screening identifies the antiviral function of TMEM120A via STING activation
Authors: Li Shuo , Qian Nianchao , Jiang Chao , Zu Wenhong , Liang Anthony , Li Mamie , Elledge Stephen J. , Tan Xu
Published: January 2022

Zika virus (ZIKV) infection can be associated with neurological pathologies, such as microcephaly in newborns and Guillain-Barre syndrome in adults. Effective therapeutics are currently not available. As such, a comprehensive understanding of virus-host interactions may guide the development of medications for ZIKV. Here we report a human genome-wide overexpression screen to identify host factors that regulate ZIKV infection and find TMEM120A as a ZIKV restriction factor. TMEM120A overexpression significantly inhibits ZIKV replication, while TMEM120A knockdown increases ZIKV infection in cell lines. Moreover, Tmem120a knockout in mice facilitates ZIKV infection in primary mouse embryonic fibroblasts (MEF) cells. Mechanistically, the antiviral activity of TMEM120A is dependent on STING, as TMEM120A interacts with STING, promotes the translocation of STING from the endoplasmic reticulum (ER) to ER-Golgi intermediate compartment (ERGIC) and enhances the phosphorylation of downstream TBK1 and IRF3, resulting in the expression of multiple antiviral cytokines and interferon-stimulated genes. In summary, our gain-of-function screening identifies TMEM120A as a key activator of the antiviral signaling of STING.
A combined experimental and theoretical study on the reactivity of nitrenes and nitrene radical anions
Authors: Guo Yujing , Pei Chao , Koenigs Rene M.
Published: January 2022

Nitrene transfer reactions represent one of the key reactions to rapidly construct new carbon-nitrogen bonds and typically require transition metal catalysts to control the reactivity of the pivotal nitrene intermediate. Herein, we report on the application of iminoiodinanes in amination reactions under visible light photochemical conditions. While a triplet nitrene can be accessed under catalyst-free conditions, the use of a suitable photosensitizer allows the access of a nitrene radical anion. Computational and mechanistic studies rationalize the access and reactivity of triplet nitrene and nitrene radical anion and allow the direct comparison of both amination reagents. We conclude with applications of both reagents in organic synthesis and showcase their reactivity in the reaction with olefins, which underline their markedly distinct reactivity. Both reagents can be accessed under mild reaction conditions at room temperature without the necessity to exclude moisture or air, which renders these metal-free, photochemical amination reactions highly practical.
Gasdermin D pores are dynamically regulated by local phosphoinositide circuitry
Authors: Santa Cruz Garcia Ana Beatriz , Schnur Kevin P. , Malik Asrar B. , Mo Gary C. H.
Published: January 2022

Gasdermin D forms large, ~21 nm diameter pores in the plasma membrane to drive the cell death program pyroptosis. These pores are thought to be permanently open, and the resultant osmotic imbalance is thought to be highly damaging. Yet some cells mitigate and survive pore formation, suggesting an undiscovered layer of regulation over the function of these pores. However, no methods exist to directly reveal these mechanistic details. Here, we combine optogenetic tools, live cell fluorescence biosensing, and electrophysiology to demonstrate that gasdermin pores display phosphoinositide-dependent dynamics. We quantify repeated and fast opening-closing of these pores on the tens of seconds timescale, visualize the dynamic pore geometry, and identify the signaling that controls dynamic pore activity. The identification of this circuit allows pharmacological tuning of pyroptosis and control of inflammatory cytokine release by living cells.
Forward-looking insights in laser-generated ultra-intense γ-ray and neutron sources for nuclear application and science
Authors: Günther M. M. , Rosmej O. N. , Tavana P. , Gyrdymov M. , Skobliakov A. , Kantsyrev A. , Zähter S. , Borisenko N. G. , Pukhov A. , Andreev N. E.
Published: January 2022

Ultra-intense MeV photon and neutron beams are indispensable tools in many research fields such as nuclear, atomic and material science as well as in medical and biophysical applications. For applications in laboratory nuclear astrophysics, neutron fluxes in excess of 1021 n/(cm2 s) are required. Such ultra-high fluxes are unattainable with existing conventional reactor- and accelerator-based facilities. Currently discussed concepts for generating high-flux neutron beams are based on ultra-high power multi-petawatt lasers operating around 1023 W/cm2 intensities. Here, we present an efficient concept for generating γ and neutron beams based on enhanced production of direct laser-accelerated electrons in relativistic laser interactions with a long-scale near critical density plasma at 1019 W/cm2 intensity. Experimental insights in the laser-driven generation of ultra-intense, well-directed multi-MeV beams of photons more than 1012 ph/sr and an ultra-high intense neutron source with greater than 6 × 1010 neutrons per shot are presented. More than 1.4% laser-to-gamma conversion efficiency above 10 MeV and 0.05% laser-to-neutron conversion efficiency were recorded, already at moderate relativistic laser intensities and ps pulse duration. This approach promises a strong boost of the diagnostic potential of existing kJ PW laser systems used for Inertial Confinement Fusion (ICF) research.
Genome-wide meta-analysis of phytosterols reveals five novel loci and a detrimental effect on coronary atherosclerosis
Authors: Scholz Markus , Horn Katrin , Pott Janne , Gross Arnd , Kleber Marcus E. , Delgado Graciela E. , Mishra Pashupati Prasad , Kirsten Holger , Gieger Christian , Müller-Nurasyid Martina , Tönjes Anke , Kovacs Peter , Lehtimäki Terho , Raitakari Olli , Kähönen Mika , Gylling Helena , Baber Ronny , Isermann Berend , Stumvoll Michael , Loeffler Markus , März Winfried , Meitinger Thomas , Peters Annette , Thiery Joachim , Teupser Daniel , Ceglarek Uta
Published: January 2022

Phytosterol serum concentrations are under tight genetic control. The relationship between phytosterols and coronary artery disease (CAD) is controversially discussed. We perform a genome-wide meta-analysis of 32 phytosterol traits reflecting resorption, cholesterol synthesis and esterification in six studies with up to 9758 subjects and detect ten independent genome-wide significant SNPs at seven genomic loci. We confirm previously established associations at ABCG5/8 and ABO and demonstrate an extended locus heterogeneity at ABCG5/8 with different functional mechanisms. New loci comprise HMGCR, NPC1L1, PNLIPRP2, SCARB1 and APOE. Based on these results, we perform Mendelian Randomization analyses (MR) revealing a risk-increasing causal relationship of sitosterol serum concentrations and CAD, which is partly mediated by cholesterol. Here we report that phytosterols are polygenic traits. MR add evidence of both, direct and indirect causal effects of sitosterol on CAD.
The role of methanotrophy in the microbial carbon metabolism of temperate lakes
Authors: Reis Paula C. J. , Thottathil Shoji D. , Prairie Yves T.
Published: January 2022

Previous stable isotope and biomarker evidence has indicated that methanotrophy is an important pathway in the microbial loop of freshwater ecosystems, despite the low cell abundance of methane-oxidizing bacteria (MOB) and the low methane concentrations relative to the more abundant dissolved organic carbon (DOC). However, quantitative estimations of the relative contribution of methanotrophy to the microbial carbon metabolism of lakes are scarce, and the mechanism allowing methanotrophy to be of comparable importance to DOC-consuming heterotrophy remained elusive. Using incubation experiments, microscopy, and multiple water column profiles in six temperate lakes, we show that MOB play a much larger role than their abundances alone suggest because of their larger cell size and higher specific activity. MOB activity is tightly constrained by the local methane:oxygen ratio, with DOC-rich lakes with large hypolimnetic volume fraction showing a higher carbon consumption through methanotrophy than heterotrophy at the whole water column level. Our findings suggest that methanotrophy could be a critical microbial carbon consumption pathway in many temperate lakes, challenging the prevailing view of a DOC-centric microbial metabolism in these ecosystems.
G-quadruplex DNA structures in human stem cells and differentiation
Authors: Zyner Katherine G. , Simeone Angela , Flynn Sean M. , Doyle Colm , Marsico Giovanni , Adhikari Santosh , Portella Guillem , Tannahill David , Balasubramanian Shankar
Published: January 2022

The establishment of cell identity during embryonic development involves the activation of specific gene expression programmes and is underpinned by epigenetic factors including DNA methylation and histone post-translational modifications. G-quadruplexes are four-stranded DNA secondary structures (G4s) that have been implicated in transcriptional regulation and cancer. Here, we show that G4s are key genomic structural features linked to cellular differentiation. We find that G4s are highly abundant in human embryonic stem cells and are lost during lineage specification. G4s are prevalent in enhancers and promoters. G4s that are found in common between embryonic and downstream lineages are tightly linked to transcriptional stabilisation of genes involved in essential cellular functions as well as transitions in the histone post-translational modification landscape. Furthermore, the application of small molecules that stabilise G4s causes a delay in stem cell differentiation, keeping cells in a more pluripotent-like state. Collectively, our data highlight G4s as important epigenetic features that are coupled to stem cell pluripotency and differentiation.
Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps
Authors: Plé Coline , Tam Heng-Keat , Vieira Da Cruz Anais , Compagne Nina , Jiménez-Castellanos Juan-Carlos , Müller Reinke T. , Pradel Elizabeth , Foong Wuen Ee , Malloci Giuliano , Ballée Alexia , Kirchner Moritz A. , Moshfegh Parisa , Herledan Adrien , Herrmann Andrea , Deprez Benoit , Willand Nicolas , Vargiu Attilio Vittorio , Pos Klaas M. , Flipo Marion , Hartkoorn Ruben C.
Published: January 2022

Efflux transporters of the RND family confer resistance to multiple antibiotics in Gram-negative bacteria. Here, we identify and chemically optimize pyridylpiperazine-based compounds that potentiate antibiotic activity in E. coli through inhibition of its primary RND transporter, AcrAB-TolC. Characterisation of resistant E. coli mutants and structural biology analyses indicate that the compounds bind to a unique site on the transmembrane domain of the AcrB L protomer, lined by key catalytic residues involved in proton relay. Molecular dynamics simulations suggest that the inhibitors access this binding pocket from the cytoplasm via a channel exclusively present in the AcrB L protomer. Thus, our work unveils a class of allosteric efflux-pump inhibitors that likely act by preventing the functional catalytic cycle of the RND pump.
Grainyhead 1 acts as a drug-inducible conserved transcriptional regulator linked to insulin signaling and lifespan
Authors: Grigolon Giovanna , Araldi Elisa , Erni Reto , Wu Jia Yee , Thomas Carolin , La Fortezza Marco , Laube Beate , Pöhlmann Doris , Stoffel Markus , Zarse Kim , Carreira Erick M. , Ristow Michael , Fischer Fabian
Published: January 2022

Aging is impacted by interventions across species, often converging on metabolic pathways. Transcription factors regulate longevity yet approaches for their pharmacological modulation to exert geroprotection remain sparse. We show that increased expression of the transcription factor Grainyhead 1 (GRH-1) promotes lifespan and pathogen resistance in Caenorhabditis elegans. A compound screen identifies FDA-approved drugs able to activate human GRHL1 and promote nematodal GRH-1-dependent longevity. GRHL1 activity is regulated by post-translational lysine methylation and the phosphoinositide (PI) 3-kinase C2A. Consistently, nematodal longevity following impairment of the PI 3-kinase or insulin/IGF-1 receptor requires grh-1. In BXD mice, Grhl1 expression is positively correlated with lifespan and insulin sensitivity. In humans, GRHL1 expression positively correlates with insulin receptor signaling and also with lifespan. Fasting blood glucose levels, including in individuals with type 2 diabetes, are negatively correlated with GRHL1 expression. Thereby, GRH-1/GRHL1 is identified as a pharmacologically malleable transcription factor impacting insulin signaling and lifespan.
Smart facemask for wireless CO2 monitoring
Authors: Escobedo P. , Fernández-Ramos M. D. , López-Ruiz N. , Moyano-Rodríguez O. , Martínez-Olmos A. , Pérez de Vargas-Sansalvador I. M. , Carvajal M. A. , Capitán-Vallvey L. F. , Palma A. J.
Published: January 2022

The use of facemasks by the general population is recommended worldwide to prevent the spread of SARS-CoV-2. Despite the evidence in favour of facemasks to reduce community transmission, there is also agreement on the potential adverse effects of their prolonged usage, mainly caused by CO2 rebreathing. Herein we report the development of a sensing platform for gaseous CO2 real-time determination inside FFP2 facemasks. The system consists of an opto-chemical sensor combined with a flexible, battery-less, near-field-enabled tag with resolution and limit of detection of 103 and 140 ppm respectively, and sensor lifetime of 8 h, which is comparable with recommended FFP2 facemask usage times. We include a custom smartphone application for wireless powering, data processing, alert management, results displaying and sharing. Through performance tests during daily activity and exercise monitoring, we demonstrate its utility for non-invasive, wearable health assessment and its potential applicability for preclinical research and diagnostics.
Engineering shape memory and morphing protein hydrogels based on protein unfolding and folding
Authors: Bian Qingyuan , Fu Linglan , Li Hongbin
Published: January 2022

Engineering shape memory/morphing materials have achieved considerable progress in polymer-based systems with broad potential applications. However, engineering protein-based shape memory/morphing materials remains challenging and under-explored. Here we report the design of a bilayer protein-based shape memory/morphing hydrogel based on protein folding-unfolding mechanism. We fabricate the protein-bilayer structure using two tandem modular elastomeric proteins (GB1)8and (FL)8. Both protein layers display distinct denaturant-dependent swelling profiles and Young’s moduli. Due to such protein unfolding-folding induced changes in swelling, the bilayer hydrogels display highly tunable and reversible bidirectional bending deformation depending upon the denaturant concentration and layer geometry. Based on these programmable and reversible bending behaviors, we further utilize the protein-bilayer structure as hinge to realize one-dimensional to two-dimensional and two-dimensional to three-dimensional folding transformations of patterned hydrogels. The present work will offer new inspirations for the design and fabrication of novel shape morphing materials.
Solid-state cooling by elastocaloric polymer with uniform chain-lengths
Authors: Zhang Shixian , Yang Quanling , Li Chenjian , Fu Yuheng , Zhang Huaqing , Ye Zhiwei , Zhou Xingnan , Li Qi , Wang Tao , Wang Shan , Zhang Wenqing , Xiong Chuanxi , Wang Qing
Published: January 2022

Although the elastocaloric effect was found in natural rubber as early as 160 years ago, commercial elastocaloric refrigeration based on polymer elastomers has stagnated owing to their deficient elastocaloric effects and large extension ratios. Herein, we demonstrate that polymer elastomers with uniform molecular chain-lengths exhibit enormous elastocaloric effects through reversible conformational changes. An adiabatic temperature change of −15.3 K and an isothermal entropy change of 145 J kg−1 K−1, obtained from poly(styrene-b-ethylene-co-butylene-b-styrene) near room temperature, exceed those of previously reported elastocaloric polymers. A rotary-motion cooling device is tailored to high-strains characteristics of rubbers, which effectively discharges the cooling energy of polymer elastomers. Our work provides a strategy for the enhancement of elastocaloric effects and could promote the commercialization of solid-state cooling devices based on polymer elastomers.
Connected function of PRAF/RLD and GNOM in membrane trafficking controls intrinsic cell polarity in plants
Authors: Wang Lu , Li Dongmeng , Yang Kezhen , Guo Xiaoyu , Bian Chao , Nishimura Takeshi , Le Jie , Morita Miyo Terao , Bergmann Dominique C. , Dong Juan
Published: January 2022

Cell polarity is a fundamental feature underlying cell morphogenesis and organismal development. In the Arabidopsis stomatal lineage, the polarity protein BASL controls stomatal asymmetric cell division. However, the cellular machinery by which this intrinsic polarity site is established remains unknown. Here, we identify the PRAF/RLD proteins as BASL physical partners and mutating four PRAF members leads to defects in BASL polarization. Members of PRAF proteins are polarized in stomatal lineage cells in a BASL-dependent manner. Developmental defects of the praf mutants phenocopy those of the gnom mutants. GNOM is an activator of the conserved Arf GTPases and plays important roles in membrane trafficking. We further find PRAF physically interacts with GNOM in vitro and in vivo. Thus, we propose that the positive feedback of BASL and PRAF at the plasma membrane and the connected function of PRAF and GNOM in endosomal trafficking establish intrinsic cell polarity in the Arabidopsis stomatal lineage.
Dynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation
Authors: Deganutti Giuseppe , Liang Yi-Lynn , Zhang Xin , Khoshouei Maryam , Clydesdale Lachlan , Belousoff Matthew J. , Venugopal Hari , Truong Tin T. , Glukhova Alisa , Keller Andrew N. , Gregory Karen J. , Leach Katie , Christopoulos Arthur , Danev Radostin , Reynolds Christopher A. , Zhao Peishen , Sexton Patrick M. , Wootten Denise
Published: January 2022

The glucagon-like peptide-1 receptor (GLP-1R) has broad physiological roles and is a validated target for treatment of metabolic disorders. Despite recent advances in GLP-1R structure elucidation, detailed mechanistic understanding of how different peptides generate profound differences in G protein-mediated signalling is still lacking. Here we combine cryo-electron microscopy, molecular dynamics simulations, receptor mutagenesis and pharmacological assays, to interrogate the mechanism and consequences of GLP-1R binding to four peptide agonists; glucagon-like peptide-1, oxyntomodulin, exendin-4 and exendin-P5. These data reveal that distinctions in peptide N-terminal interactions and dynamics with the GLP-1R transmembrane domain are reciprocally associated with differences in the allosteric coupling to G proteins. In particular, transient interactions with residues at the base of the binding cavity correlate with enhanced kinetics for G protein activation, providing a rationale for differences in G protein-mediated signalling efficacy from distinct agonists.
Population homogeneity for the antibody response to COVID-19 BNT162b2/Comirnaty vaccine is only reached after the second dose across all adult age ranges
Authors: Faro-Viana João , Bergman Marie-Louise , Gonçalves Lígia A. , Duarte Nádia , Coutinho Teresa P. , Borges Patrícia C. , Diwo Christian , Castro Rute , Matoso Paula , Malheiro Vanessa , Brennand Ana , Kosack Lindsay , Akpogheneta Onome , Figueira João M. , Cardoso Conceição , Casaca Ana M. , Alves Paula M. , Nunes Telmo , Penha-Gonçalves Carlos , Demengeot Jocelyne
Published: January 2022

While mRNA vaccines are administrated worldwide in an effort to contain the COVID-19 pandemic, the heterogeneity of the humoral immune response they induce at the population scale remains unclear. Here, in a prospective, longitudinal, cohort-study, including 1245 hospital care workers and 146 nursing home residents scheduled for BNT162b2 vaccination, together covering adult ages from 19 to 99 years, we analyse seroconversion to SARS-CoV-2 spike protein and amount of spike-specific IgG, IgM and IgA before vaccination, and 3-5 weeks after each dose. We show that immunogenicity after a single vaccine dose is biased to IgG, heterogeneous and reduced with increasing age. The second vaccine dose normalizes IgG seroconversion in all age strata. These findings indicate two dose mRNA vaccines is required to reach population scale humoral immunity. The results advocate for the interval between the two doses not to be extended, and for serological monitoring of elderly and immunosuppressed vaccinees.
Oxylipin metabolism is controlled by mitochondrial β-oxidation during bacterial inflammation
Authors: Misheva Mariya , Kotzamanis Konstantinos , Davies Luke C. , Tyrrell Victoria J. , Rodrigues Patricia R. S. , Benavides Gloria A. , Hinz Christine , Murphy Robert C. , Kennedy Paul , Taylor Philip R. , Rosas Marcela , Jones Simon A. , McLaren James E. , Deshpande Sumukh , Andrews Robert , Schebb Nils Helge , Czubala Magdalena A. , Gurney Mark , Aldrovandi Maceler , Meckelmann Sven W. , Ghazal Peter , Darley-Usmar Victor , White Daniel A. , O’Donnell Valerie B.
Published: January 2022

Oxylipins are potent biological mediators requiring strict control, but how they are removed en masse during infection and inflammation is unknown. Here we show that lipopolysaccharide (LPS) dynamically enhances oxylipin removal via mitochondrial β-oxidation. Specifically, genetic or pharmacological targeting of carnitine palmitoyl transferase 1 (CPT1), a mitochondrial importer of fatty acids, reveal that many oxylipins are removed by this protein during inflammation in vitro and in vivo. Using stable isotope-tracing lipidomics, we find secretion-reuptake recycling for 12-HETE and its intermediate metabolites. Meanwhile, oxylipin β-oxidation is uncoupled from oxidative phosphorylation, thus not contributing to energy generation. Testing for genetic control checkpoints, transcriptional interrogation of human neonatal sepsis finds upregulation of many genes involved in mitochondrial removal of long-chain fatty acyls, such as ACSL1,3,4, ACADVL, CPT1B, CPT2 and HADHB. Also, ACSL1/Acsl1 upregulation is consistently observed following the treatment of human/murine macrophages with LPS and IFN-γ. Last, dampening oxylipin levels by β-oxidation is suggested to impact on their regulation of leukocyte functions. In summary, we propose mitochondrial β-oxidation as a regulatory metabolic checkpoint for oxylipins during inflammation.