bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel mRNA decay inhibitor abolishes pathophysiological cellular transition
Authors: Kami Daisuke , Ishizaki Toshimasa , Taya Toshihiko , Katoh Akira , Kouji Hiroyuki , Gojo Satoshi 
Published: June 2022

AbstractIn cells, mRNA synthesis and decay are influenced by each other, and their balance is altered by either external or internal cues, resulting in changes in cell dynamics. We previously reported that it is important that an array of mRNAs that shape a phenotype are degraded before cellular transitions, such as cellular reprogramming and differentiation. In adipogenesis, the interaction between DDX6 and 4E-T had a definitive impact on the pathway in the processing body (PB). We screened a library of α-helix analogs with an alkaloid-like backbone to identify compounds that inhibit the binding between DDX6 and 4E-T proteins, which occurs between the α-helix of structured and internally disordered proteins. IAMC-00192 was identified as a lead compound. This compound directly inhibited the interaction between DDX6 and 4E-T. IAMC-00192 inhibited the temporal increase in PB formation that occurs during adipogenesis and epithelial-mesenchymal transition (EMT) and significantly suppressed these cellular transitions. In the EMT model, the half-life of preexisting mRNAs in PBs was extended twofold by the compound. The novel inhibitor of RNA decay not only represents a potentially useful tool to analyze in detail the pathological conditions affected by RNA decay and how it regulates the pathological state. The identification of this inhibitor may lead to the discovery of a first-in-class RNA decay inhibitor drug.
Structural insights into human brain–gut peptide cholecystokinin receptors
Authors: Ding Yu , Zhang Huibing , Liao Yu-Ying , Chen Li-Nan , Ji Su-Yu , Qin Jiao , Mao Chunyou , Shen Dan-Dan , Lin Lin , Wang Hao , Zhang Yan , Li Xiao-Ming 
Published: June 2022

AbstractThe intestinal hormone and neuromodulator cholecystokinin (CCK) receptors CCK1R and CCK2R act as a signaling hub in brain–gut axis, mediating digestion, emotion, and memory regulation. CCK receptors exhibit distinct preferences for ligands in different posttranslational modification (PTM) states. CCK1R couples to Gs and Gq, whereas CCK2R primarily couples to Gq. Here we report the cryo-electron microscopy (cryo-EM) structures of CCK1R–Gs signaling complexes liganded either by sulfated cholecystokinin octapeptide (CCK-8) or a CCK1R-selective small-molecule SR146131, and CCK2R–Gq complexes stabilized by either sulfated CCK-8 or a CCK2R-selective ligand gastrin-17. Our structures reveal a location-conserved yet charge-distinct pocket discriminating the effects of ligand PTM states on receptor subtype preference, the unique pocket topology underlying selectivity of SR146131 and gastrin-17, the conformational changes in receptor activation, and key residues contributing to G protein subtype specificity, providing multiple structural templates for drug design targeting the brain–gut axis.
Dual chirped microcomb based parallel ranging at megapixel-line rates
Authors: Lukashchuk Anton , Riemensberger Johann , Karpov Maxim , Liu Junqiu , Kippenberg Tobias J. 
Published: June 2022

AbstractLaser-based ranging (LiDAR) - already ubiquitously used in industrial monitoring, atmospheric dynamics, or geodesy - is a key sensor technology. Coherent laser ranging, in contrast to time-of-flight approaches, is immune to ambient light, operates continuous-wave allowing higher average powers, and yields simultaneous velocity and distance information. State-of-the-art coherent single laser-detector architectures reach hundreds of kilopixel per second sampling rates, while emerging applications - autonomous driving, robotics, and augmented reality - mandate megapixel per second point sampling to support real-time video-rate imaging. Yet, such rates of coherent LiDAR have not been demonstrated. Recent advances in photonic chip-based microcombs provide a route to higher acquisition speeds via parallelization but require separation of individual channels at the detector side, increasing photonic integration complexity. Here we overcome the challenge and report a hardware-efficient swept dual-soliton microcomb technique that achieves coherent ranging and velocimetry at megapixel per second line scan measurement rates with up to 64 optical channels. Multiheterodyning two synchronously frequency-modulated microcombs yields distance and velocity information of all individual ranging channels on a single receiver alleviating the need for individual separation, detection, and digitization. The reported LiDAR implementation is compatible with photonic integration and demonstrates the significant advantages of acquisition speed afforded by the convergence of optical telecommunication and metrology technologies.
Cardiac fibroblasts regulate the development of heart failure via Htra3-TGF-β-IGFBP7 axis
Authors: Ko Toshiyuki , Nomura Seitaro , Yamada Shintaro , Fujita Kanna , Fujita Takanori , Satoh Masahiro , Oka Chio , Katoh Manami , Ito Masamichi , Katagiri Mikako , Sassa Tatsuro , Zhang Bo , Hatsuse Satoshi , Yamada Takanobu , Harada Mutsuo , Toko Haruhiro , Amiya Eisuke , Hatano Masaru , Kinoshita Osamu , Nawata Kan , Abe Hiroyuki , Ushiku Tetsuo , Ono Minoru , Ikeuchi Masashi , Morita Hiroyuki , Aburatani Hiroyuki , Komuro Issei 
Published: June 2022

AbstractTissue fibrosis and organ dysfunction are hallmarks of age-related diseases including heart failure, but it remains elusive whether there is a common pathway to induce both events. Through single-cell RNA-seq, spatial transcriptomics, and genetic perturbation, we elucidate that high-temperature requirement A serine peptidase 3 (Htra3) is a critical regulator of cardiac fibrosis and heart failure by maintaining the identity of quiescent cardiac fibroblasts through degrading transforming growth factor-β (TGF-β). Pressure overload downregulates expression of Htra3 in cardiac fibroblasts and activated TGF-β signaling, which induces not only cardiac fibrosis but also heart failure through DNA damage accumulation and secretory phenotype induction in failing cardiomyocytes. Overexpression of Htra3 in the heart inhibits TGF-β signaling and ameliorates cardiac dysfunction after pressure overload. Htra3-regulated induction of spatio-temporal cardiac fibrosis and cardiomyocyte secretory phenotype are observed specifically in infarct regions after myocardial infarction. Integrative analyses of single-cardiomyocyte transcriptome and plasma proteome in human reveal that IGFBP7, which is a cytokine downstream of TGF-β and secreted from failing cardiomyocytes, is the most predictable marker of advanced heart failure. These findings highlight the roles of cardiac fibroblasts in regulating cardiomyocyte homeostasis and cardiac fibrosis through the Htra3-TGF-β-IGFBP7 pathway, which would be a therapeutic target for heart failure.
Switching the NIR upconversion of nanoparticles for the orthogonal activation of photoacoustic imaging and phototherapy
Authors: Yang Yang , Huang Jinshu , Wei Wei , Zeng Qin , Li Xipeng , Xing Da , Zhou Bo , Zhang Tao 
Published: June 2022

AbstractPhototheranostics based on upconversion nanoparticles (UCNPs) offer the integration of imaging diagnostics and phototherapeutics. However, the programmable control of the photoactivation of imaging and therapy with minimum side effects is challenging due to the lack of ideal switchable UCNPs agents. Here we demonstrate a facile strategy to switch the near infrared emission at 800 nm from rationally designed UCNPs by modulating the irradiation laser into pulse output. We further synthesize a theranostic nanoagent by combining with a photosensitizer and a photoabsorbing agent assembled on the UCNPs. The orthogonal activation of in vivo photoacoustic imaging and photodynamic therapy can be achieved by altering the excitation modes from pulse to continuous-wave output upon a single 980 nm laser. No obvious harmful effects during photoexcitation was identified, suggesting their use for long-term imaging-guidance and phototherapy. This work provides an approach to the orthogonal activation of imaging diagnostics and photodynamic therapeutics.
Optical linewidth of soliton microcombs
Authors: Lei Fuchuan , Ye Zhichao , Helgason Óskar B. , Fülöp Attila , Girardi Marcello , Torres-Company Victor 
Published: June 2022

AbstractSoliton microcombs provide a versatile platform for realizing fundamental studies and technological applications. To be utilized as frequency rulers for precision metrology, soliton microcombs must display broadband phase coherence, a parameter characterized by the optical phase or frequency noise of the comb lines and their corresponding optical linewidths. Here, we analyse the optical phase-noise dynamics in soliton microcombs generated in silicon nitride high-Q microresonators and show that, because of the Raman self-frequency shift or dispersive-wave recoil, the Lorentzian linewidth of some of the comb lines can, surprisingly, be narrower than that of the pump laser. This work elucidates information about the physical limits in phase coherence of soliton microcombs and illustrates a new strategy for the generation of spectrally coherent light on chip.
Berry curvature-induced local spin polarisation in gated graphene/WTe2 heterostructures
Authors: Powalla Lukas , Kiemle Jonas , König Elio J. , Schnyder Andreas P. , Knolle Johannes , Kern Klaus , Holleitner Alexander , Kastl Christoph , Burghard Marko 
Published: June 2022

AbstractExperimental control of local spin-charge interconversion is of primary interest for spintronics. Van der Waals (vdW) heterostructures combining graphene with a strongly spin-orbit coupled two-dimensional (2D) material enable such functionality by design. Electric spin valve experiments have thus far provided global information on such devices, while leaving the local interplay between symmetry breaking, charge flow across the heterointerface and aspects of topology unexplored. Here, we probe the gate-tunable local spin polarisation in current-driven graphene/WTe2 heterostructures through magneto-optical Kerr microscopy. Even for a nominal in-plane transport, substantial out-of-plane spin accumulation is induced by a corresponding out-of-plane current flow. We present a theoretical model which fully explains the gate- and bias-dependent onset and spatial distribution of the intense Kerr signal as a result of a non-linear anomalous Hall effect in the heterostructure, which is enabled by its reduced point group symmetry. Our findings unravel the potential of 2D heterostructure engineering for harnessing topological phenomena for spintronics, and constitute an important step toward nanoscale, electrical spin control.
Re-programming mouse liver-resident invariant natural killer T cells for suppressing hepatic and diabetogenic autoimmunity
Authors: Umeshappa Channakeshava Sokke , Solé Patricia , Yamanouchi Jun , Mohapatra Saswat , Surewaard Bas G. J. , Garnica Josep , Singha Santiswarup , Mondal Debajyoti , Cortés-Vicente Elena , D’Mello Charlotte , Mason Andrew , Kubes Paul , Serra Pau , Yang Yang , Santamaria Pere 
Published: June 2022

AbstractInvariant NKT (iNKT) cells comprise a heterogeneous group of non-circulating, tissue-resident T lymphocytes that recognize glycolipids, including alpha-galactosylceramide (αGalCer), in the context of CD1d, but whether peripheral iNKT cell subsets are terminally differentiated remains unclear. Here we show that mouse and human liver-resident αGalCer/CD1d-binding iNKTs largely correspond to a novel Zbtb16+Tbx21+Gata3+MaflowRorc– subset that exhibits profound transcriptional, phenotypic and functional plasticity. Repetitive in vivo encounters of these liver iNKT (LiNKT) cells with intravenously delivered αGalCer/CD1d-coated nanoparticles (NP) trigger their differentiation into immunoregulatory, IL-10+IL-21-producing Zbtb16highMafhighTbx21+Gata3+Rorc– cells, termed LiNKTR1, expressing a T regulatory type 1 (TR1)-like transcriptional signature. This response is LiNKT-specific, since neither lung nor splenic tissue-resident iNKT cells from αGalCer/CD1d-NP-treated mice produce IL-10 or IL-21. Additionally, these LiNKTR1 cells suppress autoantigen presentation, and recognize CD1d expressed on conventional B cells to induce IL-10+IL-35-producing regulatory B (Breg) cells, leading to the suppression of liver and pancreas autoimmunity. Our results thus suggest that LiNKT cells are plastic for further functional diversification, with such plasticity potentially targetable for suppressing tissue-specific inflammatory phenomena.
Mafa-dependent GABAergic activity promotes mouse neonatal apneas
Authors: Lecoin Laure , Dempsey Bowen , Garancher Alexandra , Bourane Steeve , Ruffault Pierre-Louis , Morin-Surun Marie-Pierre , Rocques Nathalie , Goulding Martyn , Eychène Alain , Pouponnot Celio , Fortin Gilles , Champagnat Jean 
Published: June 2022

AbstractWhile apneas are associated with multiple pathological and fatal conditions, the underlying molecular mechanisms remain elusive. We report that a mutated form of the transcription factor Mafa (Mafa4A) that prevents phosphorylation of the Mafa protein leads to an abnormally high incidence of breath holding apneas and death in newbornMafa4A/4Amutant mice. This apneic breathing is phenocopied by restricting the mutation to central GABAergic inhibitory neurons and by activation of inhibitory Mafa neurons while reversed by inhibiting GABAergic transmission centrally. We find that Mafa activates theGad2promoter in vitro and that this activation is enhanced by the mutation that likely results in increased inhibitory drives onto target neurons. We also find that Mafa inhibitory neurons are absent from respiratory, sensory (primary and secondary) and pontine structures but are present in the vicinity of the hypoglossal motor nucleus including premotor neurons that innervate the geniohyoid muscle, to control upper airway patency. Altogether, our data reveal a role for Mafa phosphorylation in regulation of GABAergic drives and suggest a mechanism whereby reduced premotor drives to upper airway muscles may cause apneic breathing at birth.
Language models can learn complex molecular distributions
Authors: Flam-Shepherd Daniel , Zhu Kevin , Aspuru-Guzik Alán 
Published: June 2022

AbstractDeep generative models of molecules have grown immensely in popularity, trained on relevant datasets, these models are used to search through chemical space. The downstream utility of generative models for the inverse design of novel functional compounds, depends on their ability to learn a training distribution of molecules. The most simple example is a language model that takes the form of a recurrent neural network and generates molecules using a string representation. Since their initial use, subsequent work has shown that language models are very capable, in particular, recent research has demonstrated their utility in the low data regime. In this work, we investigate the capacity of simple language models to learn more complex distributions of molecules. For this purpose, we introduce several challenging generative modeling tasks by compiling larger, more complex distributions of molecules and we evaluate the ability of language models on each task. The results demonstrate that language models are powerful generative models, capable of adeptly learning complex molecular distributions. Language models can accurately generate: distributions of the highest scoring penalized LogP molecules in ZINC15, multi-modal molecular distributions as well as the largest molecules in PubChem. The results highlight the limitations of some of the most popular and recent graph generative models– many of which cannot scale to these molecular distributions.
Enyne diketones as substrate in asymmetric Nazarov cyclization for construction of chiral allene cyclopentenones
Authors: Tang Shengbiao , Zhang Peng , Shao Ying , Sun Jiangtao 
Published: June 2022

AbstractThe Nazarov cyclization is one of the most powerful tools for the stereoselective synthesis of various cyclopentenone scaffolds. Therefore, developing the new classes substrate of Nazarov reaction is an important endeavor in synthetic chemistry. Herein, we report enyne diketones, enables diastereo- and enantioselective construction of chiral allene cyclopentenones in moderate to good yields with good enantioselectivities (up to 97% ee). Importantly, it is a typical example for asymmetric synthesis of cyclopentanones with allene moiety using Nazarov cyclisation. Mechanistic studies indicate that this metal-organo relay catalysis protocol involves a rhodium-catalyzed tandem oxonium ylide formation/[2,3]-sigmatropic rearrangement/reverse benzylic acid rearrangement, followed by organo-catalyzed asymmetric Nazarov cyclization/alkyne-to-allene isomerization to give the final chiral allene cyclopentenones.
Multi-scale turbulence simulation suggesting improvement of electron heated plasma confinement
Authors: Maeyama Shinya , Watanabe Tomo-Hiko , Nakata Motoki , Nunami Masanori , Asahi Yuuichi , Ishizawa Akihiro 
Published: June 2022

AbstractTurbulent transport is a key physics process for confining magnetic fusion plasma. Recent theoretical and experimental studies of existing fusion experimental devices revealed the existence of cross-scale interactions between small (electron)-scale and large (ion)-scale turbulence. Since conventional turbulent transport modelling lacks cross-scale interactions, it should be clarified whether cross-scale interactions are needed to be considered in future experiments on burning plasma, whose high electron temperature is sustained with fusion-born alpha particle heating. Here, we present supercomputer simulations showing that electron-scale turbulence in high electron temperature plasma can affect the turbulent transport of not only electrons but also fuels and ash. Electron-scale turbulence disturbs the trajectories of resonant electrons responsible for ion-scale micro-instability and suppresses large-scale turbulent fluctuations. Simultaneously, ion-scale turbulent eddies also suppress electron-scale turbulence. These results indicate a mutually exclusive nature of turbulence with disparate scales. We demonstrate the possibility of reduced heat flux via cross-scale interactions.
Regulatory B cell repertoire defects predispose lung cancer patients to immune-related toxicity following checkpoint blockade
Authors: Patel Akshay J. , Willsmore Zena N. , Khan Naeem , Richter Alex , Naidu Babu , Drayson Mark T. , Papa Sophie , Cope Andrew , Karagiannis Sophia N. , Perucha Esperanza , Middleton Gary W. 
Published: June 2022

AbstractCheckpoint blockade with Pembrolizumab, has demonstrated durable clinical responses in advanced non-small cell lung cancer, however, treatment is offset by the development of high-grade immune related adverse events (irAEs) in some patients. Here, we show that in these patients a deficient Breg checkpoint fails to limit self-reactive T cell enhanced activity and auto-antibody formation enabled by PD-1/PD-L1 blockade, leading to severe auto-inflammatory sequelae. Principally a failure of IL-10 producing regulatory B cells as demonstrated through functional ex vivo assays and deep phenotyping mass cytometric analysis, is a major and significant finding in patients who develop high-grade irAEs when undergoing treatment with anti-PD1/PD-L1 checkpoint blockade. There is currently a lack of biomarkers to identify a priori those patients at greatest risk of developing severe auto-inflammatory syndrome. Pre-therapy B cell profiling could provide an important tool to identify lung cancer patients at high risk of developing severe irAEs on checkpoint blockade.
Serotonin and dopamine modulate aging in response to food odor and availability
Authors: Miller Hillary A. , Huang Shijiao , Dean Elizabeth S. , Schaller Megan L. , Tuckowski Angela M. , Munneke Allyson S. , Beydoun Safa , Pletcher Scott D. , Leiser Scott F. 
Published: June 2022

AbstractAn organism’s ability to perceive and respond to changes in its environment is crucial for its health and survival. Here we reveal how the most well-studied longevity intervention, dietary restriction, acts in-part through a cell non-autonomous signaling pathway that is inhibited by the presence of attractive smells. Using an intestinal reporter for a key gene induced by dietary restriction but suppressed by attractive smells, we identify three compounds that block food odor effects in C. elegans, thereby increasing longevity as dietary restriction mimetics. These compounds clearly implicate serotonin and dopamine in limiting lifespan in response to food odor. We further identify a chemosensory neuron that likely perceives food odor, an enteric neuron that signals through the serotonin receptor 5-HT1A/SER-4, and a dopaminergic neuron that signals through the dopamine receptor DRD2/DOP-3. Aspects of this pathway are conserved in D. melanogaster. Thus, blocking food odor signaling through antagonism of serotonin or dopamine receptors is a plausible approach to mimic the benefits of dietary restriction.
Enhanced BRAF engagement by NRAS mutants capable of promoting melanoma initiation
Authors: Murphy Brandon M. , Terrell Elizabeth M. , Chirasani Venkat R. , Weiss Tirzah J. , Lew Rachel E. , Holderbaum Andrea M. , Dhakal Aastha , Posada Valentina , Fort Marie , Bodnar Michael S. , Carey Leiah M. , Chen Min , Burd Craig J. , Coppola Vincenzo , Morrison Deborah K. , Campbell Sharon L. , Burd Christin E. 
Published: June 2022

AbstractA distinct profile of NRAS mutants is observed in each tumor type. It is unclear whether these profiles are determined by mutagenic events or functional differences between NRAS oncoproteins. Here, we establish functional hallmarks of NRAS mutants enriched in human melanoma. We generate eight conditional, knock-in mouse models and show that rare melanoma mutants (NRAS G12D, G13D, G13R, Q61H, and Q61P) are poor drivers of spontaneous melanoma formation, whereas common melanoma mutants (NRAS Q61R, Q61K, or Q61L) induce rapid tumor onset with high penetrance. Molecular dynamics simulations, combined with cell-based protein–protein interaction studies, reveal that melanomagenic NRAS mutants form intramolecular contacts that enhance BRAF binding affinity, BRAF-CRAF heterodimer formation, and MAPK > ERK signaling. Along with the allelic series of conditional mouse models we describe, these results establish a mechanistic basis for the enrichment of specific NRAS mutants in human melanoma.
Oxidation of Archean upper mantle caused by crustal recycling
Authors: Gao Lei , Liu Shuwen , Cawood Peter A. , Hu Fangyang , Wang Jintuan , Sun Guozheng , Hu Yalu 
Published: June 2022

AbstractThe redox evolution of Archean upper mantle impacted mantle melting and the nature of chemical equilibrium between mantle, ocean and atmosphere of the early Earth. Yet, the origin of these variations in redox remain controversial. Here we show that a global compilation of ∼3.8-2.5 Ga basalts can be subdivided into group B-1, showing modern mid-ocean ridge basalt-like features ((Nb/La)PM ≥ 0.75), and B-2, which are similar to contemporary island arc-related basalts ((Nb/La)PM < 0.75). Our V-Ti redox proxy indicates a more reducing upper mantle, and the results of both ambient and modified mantle obtained from B-1 and B-2 samples, respectively, exhibit a ∼1.0 log unit increase in their temporal evolution for most cratons. Increases in mantle oxygen fugacity are coincident with the changes in basalt Th/Nb ratios and Nd isotope ratios, indicating that crustal recycling played a crucial role, and this likely occurred either via plate subduction or lithospheric drips.