bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proximity-enabled covalent binding of IL-2 to IL-2Rα selectively activates regulatory T cells and suppresses autoimmunity
Authors: Zhang Bo , Sun Jiaqi , Yuan Yeshuang , Ji Dezhong , Sun Yeting , Liu Yudong , Li Shengjie , Zhu Xingxing , Wu Xunyao , Hu Jin , Xie Qiu , Wu Ling , Liu Lulu , Cheng Boyang , Zhang Yuanjie , Jiang Lingjuan , Zhao Lidan , Yu Fei , Song Wei , Wang Min , Xu Yue , Ma Shiliang , Fei Yunyun , Zhang Lihe , Zhou Demin , Zhang Xuan 
Published: January 2023

AbstractInterleukin-2 (IL-2) is a pleiotropic cytokine that orchestrates bidirectional immune responses via regulatory T cells (Tregs) and effector cells, leading to paradoxical consequences. Here, we report a strategy that exploited genetic code expansion-guided incorporation of the latent bioreactive artificial amino acid fluorosulfate-L-tyrosine (FSY) into IL-2 for proximity-enabled covalent binding to IL-2Rα to selectively promote Treg activation. We found that FSY-bearing IL-2 variants, such as L72-FSY, covalently bound to IL-2Rα via sulfur-fluoride exchange when in proximity, resulting in persistent recycling of IL-2 and selectively promoting the expansion of Tregs but not effector cells. Further assessment of L72-FSY-expanded Tregs demonstrated that L72-FSY maintained Tregs in a central memory phenotype without driving terminal differentiation, as demonstrated by simultaneously attenuated expression of lymphocyte activation gene-3 (LAG-3) and enhanced expression of programmed cell death protein-1 (PD-1). Subcutaneous administration of L72-FSY in murine models of pristane-induced lupus and graft-versus-host disease (GvHD) resulted in enhanced and sustained therapeutic efficacy compared with wild-type IL-2 treatment. The efficacy of L72-FSY was further improved by N-terminal PEGylation, which increased its circulatory retention for preferential and sustained effects. This proximity-enabled covalent binding strategy may accelerate the development of pleiotropic cytokines as a new class of immunomodulatory therapies.
Interferon-γ secreted by recruited Th1 cells in peritoneal cavity inhibits the formation of malignant ascites
Authors: Liu Chang , Xiao Zhuanglong , Du Li , Zhu Shenghua , Xiang Hongyu , Wang Zehui , Liu Fang , Song Yuhu 
Published: January 2023

Abstract
Type 1 T helper (Th1) cells generate an efficient antitumor immune response in multiple malignancies. The functions of Th1 cells in malignant ascites (MA) have not been elucidated. The distribution of helper T cells in peritoneal fluid and peripheral blood was determined in patients and animal models with malignant ascites. The effects of Th1-derived interferon-γ (IFN-γ) on the formation of malignant ascites were investigated. The mechanism underlying the recruitment of Th1 cells into peritoneal cavity was explored. In patients with malignant ascites and animal models of malignant ascites, the percentage of Th1 cells increased in peritoneal fluid compared with peripheral blood. Next, our experiment demonstrated that Th1 cells inhibited the growth of tumor cells by secreting IFN-γ in vitro. In murine models of malignant ascites, increased peritoneal fluid and shorter survival time were observed in IFN-γ−/− mice compared with wild-type (WT) mice. Then, the levels of C-X-C motif chemokine ligand (CXCL) 9/10 and the ratio of CXCR3+ Th1 cells indicated the involvement of CXCL9, 10/CXCR3 axis in the recruitment of Th1 cells into peritoneal cavity. As expected, in murine models of malignant ascites, the gradient between ascitic Th1 ratio and blood Th1 ratio decreased in CXCR3−/− mice compared with WT mice. IFN-γ secreted by recruited Th1 cells in peritoneal cavity inhibits the formation of malignant ascites. Hence, manipulation of Th1 cells or IFN-γ will provide a therapeutic candidate against malignant ascites.
Role of Rho GTPases in inflammatory bowel disease
Authors: Li Xiaoling , Zhang Mudan , Zhou Gaoshi , Xie Zhuo , Wang Ying , Han Jing , Li Li , Wu Qirui , Zhang Shenghong 
Published: January 2023

AbstractRat sarcoma virus homolog (Rho) guanosine triphosphatases (GTPases) function as “molecular switch” in cellular signaling regulation processes and are associated with the pathogenesis of inflammatory bowel disease (IBD). This chronic intestinal tract inflammation primarily encompasses two diseases: Crohn’s disease and ulcerative colitis. The pathogenesis of IBD is complex and considered to include four main factors and their interactions: genetics, intestinal microbiota, immune system, and environment. Recently, several novel pathogenic components have been identified. In addition, potential therapies for IBD targeting Rho GTPases have emerged and proven to be clinically effective. This review mainly focuses on Rho GTPases and their possible mechanisms in IBD pathogenesis. The therapeutic possibility of Rho GTPases is also discussed.
Lyophilized mRNA-lipid nanoparticle vaccines with long-term stability and high antigenicity against SARS-CoV-2
Authors: Ai Liangxia , Li Yafei , Zhou Li , Yao Wenrong , Zhang Hao , Hu Zhaoyu , Han Jinyu , Wang Weijie , Wu Junmiao , Xu Pan , Wang Ruiyue , Li Zhangyi , Li Zhouwang , Wei Chengliang , Liang Jianqun , Chen Haobo , Yang Zhimiao , Guo Ming , Huang Zhixiang , Wang Xin , Zhang Zhen , Xiang Wenjie , Sun Dazheng , Xu Lianqiang , Huang Meiyan , Lv Bin , Peng Peiqi , Zhang Shangfeng , Ji Xuhao , Luo Huiyi , Chen Nanping , Chen Jianping , Lan Ke , Hu Yong 
Published: January 2023

AbstractAdvanced mRNA vaccines play vital roles against SARS-CoV-2. However, most current mRNA delivery platforms need to be stored at −20 °C or −70 °C due to their poor stability, which severely restricts their availability. Herein, we develop a lyophilization technique to prepare SARS-CoV-2 mRNA-lipid nanoparticle vaccines with long-term thermostability. The physiochemical properties and bioactivities of lyophilized vaccines showed no change at 25 °C over 6 months, and the lyophilized SARS-CoV-2 mRNA vaccines could elicit potent humoral and cellular immunity whether in mice, rabbits, or rhesus macaques. Furthermore, in the human trial, administration of lyophilized Omicron mRNA vaccine as a booster shot also engendered strong immunity without severe adverse events, where the titers of neutralizing antibodies against Omicron BA.1/BA.2/BA.4 were increased by at least 253-fold after a booster shot following two doses of the commercial inactivated vaccine, CoronaVac. This lyophilization platform overcomes the instability of mRNA vaccines without affecting their bioactivity and significantly improves their accessibility, particularly in remote regions.
Structural and dynamic insights into supra-physiological activation and allosteric modulation of a muscarinic acetylcholine receptor
Authors: Xu Jun , Wang Qinggong , Hübner Harald , Hu Yunfei , Niu Xiaogang , Wang Haoqing , Maeda Shoji , Inoue Asuka , Tao Yuyong , Gmeiner Peter , Du Yang , Jin Changwen , Kobilka Brian K. 
Published: January 2023

AbstractThe M2 muscarinic receptor (M2R) is a prototypical G-protein-coupled receptor (GPCR) that serves as a model system for understanding GPCR regulation by both orthosteric and allosteric ligands. Here, we investigate the mechanisms governing M2R signaling versatility using cryo-electron microscopy (cryo-EM) and NMR spectroscopy, focusing on the physiological agonist acetylcholine and a supra-physiological agonist iperoxo, as well as a positive allosteric modulator LY2119620. These studies reveal that acetylcholine stabilizes a more heterogeneous M2R-G-protein complex than iperoxo, where two conformers with distinctive G-protein orientations were determined. We find that LY2119620 increases the affinity for both agonists, but differentially modulates agonists efficacy in G-protein and β-arrestin pathways. Structural and spectroscopic analysis suggest that LY211620 stabilizes distinct intracellular conformational ensembles from agonist-bound M2R, which may enhance β-arrestin recruitment while impairing G-protein activation. These results highlight the role of conformational dynamics in the complex signaling behavior of GPCRs, and could facilitate design of better drugs.
Magmatic plumbing and dynamic evolution of the 2021 La Palma eruption
Authors: del Fresno Carmen , Cesca Simone , Klügel Andreas , Domínguez Cerdeña Itahiza , Díaz-Suárez Eduardo A. , Dahm Torsten , García-Cañada Laura , Meletlidis Stavros , Milkereit Claus , Valenzuela-Malebrán Carla , López-Díaz Rubén , López Carmen 
Published: January 2023

AbstractThe 2021 volcanic eruption at La Palma, Canary Islands, was the island’s most voluminous historical eruption. Little is known about this volcano’s feeding system. During the eruption, seismicity was distributed in two clusters at ~10-14 km and ~33-39 km depth, separated by an aseismic zone. This gap coincides with the location of weak seismic swarms in 2017-2021 and where petrological data have implied pre-eruptive magma storage. Here we use seismological methods to understand the seismic response to magma transfer, with 8,488 hypocentral relocations resolving small-scale seismogenic structures, and 156 moment tensors identifying stress heterogeneities and principal axes flips. Results suggest a long-lasting preparatory stage with the progressive destabilisation of an intermediate, mushy reservoir, and a co-eruptive stage with seismicity controlled by the drainage and interplay of two localised reservoirs. Our study provides new insights into the plumbing system that will improve the monitoring of future eruptions in the island.
Cross-species transcriptomic atlas of dorsal root ganglia reveals species-specific programs for sensory function
Authors: Jung Min , Dourado Michelle , Maksymetz James , Jacobson Amanda , Laufer Benjamin I. , Baca Miriam , Foreman Oded , Hackos David H. , Riol-Blanco Lorena , Kaminker Joshua S. 
Published: January 2023

AbstractSensory neurons of the dorsal root ganglion (DRG) are critical for maintaining tissue homeostasis by sensing and initiating responses to stimuli. While most preclinical studies of DRGs are conducted in rodents, much less is known about the mechanisms of sensory perception in primates. We generated a transcriptome atlas of mouse, guinea pig, cynomolgus monkey, and human DRGs by implementing a common laboratory workflow and multiple data-integration approaches to generate high-resolution cross-species mappings of sensory neuron subtypes. Using our atlas, we identified conserved core modules highlighting subtype-specific biological processes related to inflammatory response. We also identified divergent expression of key genes involved in DRG function, suggesting species-specific adaptations specifically in nociceptors that likely point to divergent function of nociceptors. Among these, we validated that TAFA4, a member of the druggable genome, was expressed in distinct populations of DRG neurons across species, highlighting species-specific programs that are critical for therapeutic development.
Sb2S3-templated synthesis of sulfur-doped Sb-N-C with hierarchical architecture and high metal loading for H2O2 electrosynthesis
Authors: Yan Minmin , Wei Zengxi , Gong Zhichao , Johannessen Bernt , Ye Gonglan , He Guanchao , Liu Jingjing , Zhao Shuangliang , Cui Chunyu , Fei Huilong 
Published: January 2023

AbstractSelective two-electron (2e−) oxygen reduction reaction (ORR) offers great opportunities for hydrogen peroxide (H2O2) electrosynthesis and its widespread employment depends on identifying cost-effective catalysts with high activity and selectivity. Main-group metal and nitrogen coordinated carbons (M-N-Cs) are promising but remain largely underexplored due to the low metal-atom density and the lack of understanding in the structure-property correlation. Here, we report using a nanoarchitectured Sb2S3 template to synthesize high-density (10.32 wt%) antimony (Sb) single atoms on nitrogen- and sulfur-codoped carbon nanofibers (Sb-NSCF), which exhibits both high selectivity (97.2%) and mass activity (114.9 A g−1 at 0.65 V) toward the 2e− ORR in alkaline electrolyte. Further, when evaluated with a practical flow cell, Sb-NSCF shows a high production rate of 7.46 mol gcatalyst−1 h−1 with negligible loss in activity and selectivity in a 75-h continuous electrolysis. Density functional theory calculations demonstrate that the coordination configuration and the S dopants synergistically contribute to the enhanced 2e− ORR activity and selectivity of the Sb-N4 moieties.
CD8+ lymphocytes do not impact SIV reservoir establishment under ART
Authors: Statzu Maura , Jin Wang , Fray Emily J. , Wong Andrew Kam Ho , Kumar Mithra R. , Ferrer Elizabeth , Docken Steffen S. , Pinkevych Mykola , McBrien Julia B. , Fennessey Christine M. , Keele Brandon F. , Liang Shan , Harper Justin L. , Mutascio Simona , Franchitti Lavinia , Wang Hong , Cicetti Davide , Bosinger Steven E. , Carnathan Diane G. , Vanderford Thomas H. , Margolis David M. , Garcia-Martinez J. Victor , Chahroudi Ann , Paiardini Mirko , Siliciano Janet , Davenport Miles P. , Kulpa Deanna A. , Siliciano Robert S. , Silvestri Guido 
Published: January 2023

AbstractPersistence of the human immunodeficiency virus type-1 (HIV-1) latent reservoir in infected individuals remains a problem despite fully suppressive antiretroviral therapy (ART). While reservoir formation begins during acute infection, the mechanisms responsible for its establishment remain unclear. CD8+ T cells are important during the initial control of viral replication. Here we examined the effect of CD8+ T cells on formation of the latent reservoir in simian immunodeficiency virus (SIV)-infected macaques by performing experimental CD8+ depletion either before infection or before early (that is, day 14 post-infection) ART initiation. We found that CD8+ depletion resulted in slower decline of viremia, indicating that CD8+ lymphocytes reduce the average lifespan of productively infected cells during acute infection and early ART, presumably through SIV-specific cytotoxic T lymphocyte (CTL) activity. However, CD8+ depletion did not change the frequency of infected CD4+ T cells in the blood or lymph node as measured by the total cell-associated viral DNA or intact provirus DNA assay. In addition, the size of the persistent reservoir remained the same when measuring the kinetics of virus rebound after ART interruption. These data indicate that during early SIV infection, the viral reservoir that persists under ART is established largely independent of CTL control.
Screening cell–cell communication in spatial transcriptomics via collective optimal transport
Authors: Cang Zixuan , Zhao Yanxiang , Almet Axel A. , Stabell Adam , Ramos Raul , Plikus Maksim V. , Atwood Scott X. , Nie Qing 
Published: January 2023

AbstractSpatial transcriptomic technologies and spatially annotated single-cell RNA sequencing datasets provide unprecedented opportunities to dissect cell–cell communication (CCC). However, incorporation of the spatial information and complex biochemical processes required in the reconstruction of CCC remains a major challenge. Here, we present COMMOT (COMMunication analysis by Optimal Transport) to infer CCC in spatial transcriptomics, which accounts for the competition between different ligand and receptor species as well as spatial distances between cells. A collective optimal transport method is developed to handle complex molecular interactions and spatial constraints. Furthermore, we introduce downstream analysis tools to infer spatial signaling directionality and genes regulated by signaling using machine learning models. We apply COMMOT to simulation data and eight spatial datasets acquired with five different technologies to show its effectiveness and robustness in identifying spatial CCC in data with varying spatial resolutions and gene coverages. Finally, COMMOT identifies new CCCs during skin morphogenesis in a case study of human epidermal development.
Convolutional networks for supervised mining of molecular patterns within cellular context
Authors: de Teresa-Trueba Irene , Goetz Sara K. , Mattausch Alexander , Stojanovska Frosina , Zimmerli Christian E. , Toro-Nahuelpan Mauricio , Cheng Dorothy W. C. , Tollervey Fergus , Pape Constantin , Beck Martin , Diz-Muñoz Alba , Kreshuk Anna , Mahamid Julia , Zaugg Judith B. 
Published: January 2023

AbstractCryo-electron tomograms capture a wealth of structural information on the molecular constituents of cells and tissues. We present DeePiCt (deep picker in context), an open-source deep-learning framework for supervised segmentation and macromolecular complex localization in cryo-electron tomography. To train and benchmark DeePiCt on experimental data, we comprehensively annotated 20 tomograms of Schizosaccharomyces pombe for ribosomes, fatty acid synthases, membranes, nuclear pore complexes, organelles, and cytosol. By comparing DeePiCt to state-of-the-art approaches on this dataset, we show its unique ability to identify low-abundance and low-density complexes. We use DeePiCt to study compositionally distinct subpopulations of cellular ribosomes, with emphasis on their contextual association with mitochondria and the endoplasmic reticulum. Finally, applying pre-trained networks to a HeLa cell tomogram demonstrates that DeePiCt achieves high-quality predictions in unseen datasets from different biological species in a matter of minutes. The comprehensively annotated experimental data and pre-trained networks are provided for immediate use by the community.
No evidence of a positive effect of learning Chinese language as an L2 on spatial ability
Authors: Likhanov Maxim , Bogdanova Olga , Alenina Evgenia , Kolienko Tatiana , Kovas Yulia 
Published: January 2023

AbstractSpatial ability (SA) was shown to be a robust predictor of success in various educational contexts, including STEM. Thus, ways to improve SA are of interest to educational psychology. There is some evidence that SA might be improved via learning character-based language, e.g. Chinese as a second language (CSL), however, the existing research is quite limited. The study aims to investigate an effect of CSL learning on SA in schoolchildren from Year 2 to Year 7. Current study employs a sample of Russian schoolchildren (N = 283), who learnt: English only, English and Spanish; or English and Chinese. Participants completed Raven’s progressive matrices and Mental rotation task at the age of 8 and again at the age of 14. Our data showed negligible group differences in the initial SA level at Year 2 (before learning second language). Similar negligible differences were found at Year 7. Regression analysis showed that SA was predicted by intelligence (Raven’s) and gender but not language learnt at both ages. This pattern of results indicates that learning a Chinese as a second language is unlikely to affect SA. Further research is needed to investigate whether other factors, such as length, intensity and context of learning, moderate this link.
Limited water stress modulates expression of circadian clock genes in Brachypodium distachyon roots
Authors: Gombos Magdolna , Hapek Nóra , Kozma-Bognár László , Grezal Gábor , Zombori Zoltán , Kiss Edina , Györgyey János 
Published: January 2023

AbstractOrganisms have evolved a circadian clock for the precise timing of their biological processes. Studies primarily on model dicots have shown the complexity of the inner timekeeper responsible for maintaining circadian oscillation in plants and have highlighted that circadian regulation is more than relevant to a wide range of biological processes, especially organ development and timing of flowering. Contribution of the circadian clock to overall plant fitness and yield has also long been known. Nevertheless, the organ- and species-specific functions of the circadian clock and its relation to stress adaptation have only recently been identified. Here we report transcriptional changes of core clock genes of the model monocot Brachypodium distachyon under three different light regimes (18:6 light:dark, 24:0 light and 0:24 dark) in response to mild drought stress in roots and green plant parts. Comparative monitoring of core clock gene expression in roots and green plant parts has shown that both phase and amplitude of expression in the roots of Brachypodium plants differ markedly from those in the green plant parts, even under well-watered conditions. Moreover, circadian clock genes responded to water depletion differently in root and shoot. These results suggest an organ-specific form and functions of the circadian clock in Brachypodium roots.
Metabolic rewiring in MYC-driven medulloblastoma by BET-bromodomain inhibition
Authors: Graziani Vittoria , Garcia Aida Rodriguez , Alcolado Lourdes Sainero , Le Guennec Adrien , Henriksson Marie Arsenian , Conte Maria R. 
Published: January 2023

AbstractMedulloblastoma (MB) is the most common malignant brain tumour in children. High-risk MB patients harbouring MYC amplification or overexpression exhibit a very poor prognosis. Aberrant activation of MYC markedly reprograms cell metabolism to sustain tumorigenesis, yet how metabolism is dysregulated in MYC-driven MB is not well understood. Growing evidence unveiled the potential of BET-bromodomain inhibitors (BETis) as next generation agents for treating MYC-driven MB, but whether and how BETis may affect tumour cell metabolism to exert their anticancer activities remains unknown. In this study, we explore the metabolic features characterising MYC-driven MB and examine how these are altered by BET-bromodomain inhibition. To this end, we employed an NMR-based metabolomics approach applied to the MYC-driven MB D283 and D458 cell lines before and after the treatment with the BETi OTX-015. We found that OTX-015 triggers a metabolic shift in both cell lines resulting in increased levels of myo-inositol, glycerophosphocholine, UDP-N-acetylglucosamine, glycine, serine, pantothenate and phosphocholine. Moreover, we show that OTX-015 alters ascorbate and aldarate metabolism, inositol phosphate metabolism, phosphatidylinositol signalling system, glycerophospholipid metabolism, ether lipid metabolism, aminoacyl-tRNA biosynthesis, and glycine, serine and threonine metabolism pathways in both cell lines. These insights provide a metabolic characterisation of MYC-driven childhood MB cell lines, which could pave the way for the discovery of novel druggable pathways. Importantly, these findings will also contribute to understand the downstream effects of BETis on MYC-driven MB, potentially aiding the development of new therapeutic strategies to combat medulloblastoma.
Poverty from fetal life onward and child brain morphology
Authors: Koyama Yuna , Hidalgo Andrea P. Cortes , Lacey Rebecca E. , White Tonya , Jansen Pauline W. , Fujiwara Takeo , Tiemeier Henning 
Published: January 2023

AbstractPoverty is a risk factor for impaired child development, an association possibly mediated by brain morphology. Previous studies lacked prospective poverty assessments during pregnancy and did not stratify by majority/minority status. We investigated the association of household poverty from fetal life forward with brain morphological differences at age 10 years, in 2166 mother–child dyads. Overall, the results showed no associations between any poverty exposure early in life and brain volumes. However, there was the evidence of timing effects: children exposed to poverty in utero had smaller amygdala volumes (B =  − 0.18, 95%CI − 0.30; − 0.07,pFDR-adjusted = 0.009). There were also differences in associations by majority/minority status (cerebral white matter: p for interaction = 0.04). Dutch children exposed to childhood poverty showed smaller cerebral white matter volumes than their control (B =  − 0.26, 95%CI − 0.45; − 0.06,pFDR-adjusted = 0.035). This association was not observed in the minority population (B =  − 0.05, 95%CI − 0.23; 0.12,pFDR-adjusted = 0.542). The smaller cerebral white matter volume mediated the association between childhood poverty and poorer school performance in Dutch children. Our findings point to the importance of poverty exposure in the fetal period and suggest different mechanisms and vulnerabilities across majority/minority groups.