bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractNitrene 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

AbstractGasdermin 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

AbstractUltra-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

AbstractPhytosterol 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

AbstractPrevious 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

AbstractThe 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

AbstractEfflux 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

AbstractAging 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

AbstractThe 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

AbstractEngineering 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

AbstractAlthough 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

AbstractCell 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

AbstractThe 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

AbstractWhile 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

AbstractOxylipins 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.
Phylogenetically and functionally diverse microorganisms reside under the Ross Ice Shelf
Authors: Martínez-Pérez Clara , Greening Chris , Bay Sean K. , Lappan Rachael J. , Zhao Zihao , De Corte Daniele , Hulbe Christina , Ohneiser Christian , Stevens Craig , Thomson Blair , Stepanauskas Ramunas , González José M. , Logares Ramiro , Herndl Gerhard J. , Morales Sergio E. , Baltar Federico 
Published: January 2022

AbstractThroughout coastal Antarctica, ice shelves separate oceanic waters from sunlight by hundreds of meters of ice. Historical studies have detected activity of nitrifying microorganisms in oceanic cavities below permanent ice shelves. However, little is known about the microbial composition and pathways that mediate these activities. In this study, we profiled the microbial communities beneath the Ross Ice Shelf using a multi-omics approach. Overall, beneath-shelf microorganisms are of comparable abundance and diversity, though distinct composition, relative to those in the open meso- and bathypelagic ocean. Production of new organic carbon is likely driven by aerobic lithoautotrophic archaea and bacteria that can use ammonium, nitrite, and sulfur compounds as electron donors. Also enriched were aerobic organoheterotrophic bacteria capable of degrading complex organic carbon substrates, likely derived from in situ fixed carbon and potentially refractory organic matter laterally advected by the below-shelf waters. Altogether, these findings uncover a taxonomically distinct microbial community potentially adapted to a highly oligotrophic marine environment and suggest that ocean cavity waters are primarily chemosynthetically-driven systems.