bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunometabolism in cancer: basic mechanisms and new targeting strategy
Authors: Su Ranran , Shao Yingying , Huang Manru , Liu Donghui , Yu Haiyang , Qiu Yuling 
Published: May 2024

AbstractMaturing immunometabolic research empowers immune regulation novel approaches. Progressive metabolic adaptation of tumor cells permits a thriving tumor microenvironment (TME) in which immune cells always lose the initial killing capacity, which remains an unsolved dilemma even with the development of immune checkpoint therapies. In recent years, many studies on tumor immunometabolism have been reported. The development of immunometabolism may facilitate anti-tumor immunotherapy from the recurrent crosstalk between metabolism and immunity. Here, we discuss clinical studies of the core signaling pathways of immunometabolism and their inhibitors or agonists, as well as the specific functions of these pathways in regulating immunity and metabolism, and discuss some of the identified immunometabolic checkpoints. Understanding the comprehensive advances in immunometabolism helps to revise the status quo of cancer treatment.
Task-oriented machine learning surrogates for tipping points of agent-based models
Authors: Fabiani Gianluca , Evangelou Nikolaos , Cui Tianqi , Bello-Rivas Juan M. , Martin-Linares Cristina P. , Siettos Constantinos , Kevrekidis Ioannis G. 
Published: May 2024

AbstractWe present a machine learning framework bridging manifold learning, neural networks, Gaussian processes, and Equation-Free multiscale approach, for the construction of different types of effective reduced order models from detailed agent-based simulators and the systematic multiscale numerical analysis of their emergent dynamics. The specific tasks of interest here include the detection of tipping points, and the uncertainty quantification of rare events near them. Our illustrative examples are an event-driven, stochastic financial market model describing the mimetic behavior of traders, and a compartmental stochastic epidemic model on an Erdös-Rényi network. We contrast the pros and cons of the different types of surrogate models and the effort involved in learning them. Importantly, the proposed framework reveals that, around the tipping points, the emergent dynamics of both benchmark examples can be effectively described by a one-dimensional stochastic differential equation, thus revealing the intrinsic dimensionality of the normal form of the specific type of the tipping point. This allows a significant reduction in the computational cost of the tasks of interest.
MAPP unravels frequent co-regulation of splicing and polyadenylation by RNA-binding proteins and their dysregulation in cancer
Authors: Bak Maciej , van Nimwegen Erik , Kouzel Ian U. , Gur Tamer , Schmidt Ralf , Zavolan Mihaela , Gruber Andreas J. 
Published: May 2024

AbstractMaturation of eukaryotic pre-mRNAs via splicing and polyadenylation is modulated across cell types and conditions by a variety of RNA-binding proteins (RBPs). Although there exist over 1,500 RBPs in human cells, their binding motifs and functions still remain to be elucidated, especially in the complex environment of tissues and in the context of diseases. To overcome the lack of methods for the systematic and automated detection of sequence motif-guided pre-mRNA processing regulation from RNA sequencing (RNA-Seq) data we have developed MAPP (Motif Activity on Pre-mRNA Processing). Applying MAPP to RBP knock-down experiments reveals that many RBPs regulate both splicing and polyadenylation of nascent transcripts by acting on similar sequence motifs. MAPP not only infers these sequence motifs, but also unravels the position-dependent impact of the RBPs on pre-mRNA processing. Interestingly, all investigated RBPs that act on both splicing and 3’ end processing exhibit a consistently repressive or activating effect on both processes, providing a first glimpse on the underlying mechanism. Applying MAPP to normal and malignant brain tissue samples unveils that the motifs bound by the PTBP1 and RBFOX RBPs coordinately drive the oncogenic splicing program active in glioblastomas demonstrating that MAPP paves the way for characterizing pre-mRNA processing regulators under physiological and pathological conditions.
Ser/Leu-swapped cell-free translation system constructed with natural/in vitro transcribed-hybrid tRNA set
Authors: Fujino Tomoshige , Sonoda Ryogo , Higashinagata Taito , Mishiro-Sato Emi , Kano Keiko , Murakami Hiroshi 
Published: May 2024

AbstractThe Ser/Leu-swapped genetic code can act as a genetic firewall, mitigating biohazard risks arising from horizontal gene transfer in genetically modified organisms. Our prior work demonstrated the orthogonality of this swapped code to the standard genetic code using a cell-free translation system comprised of 21 in vitro transcribed tRNAs. In this study, to advance this system for protein engineering, we introduce a natural/in vitro transcribed-hybrid tRNA set. This set combines natural tRNAs from Escherichia coli (excluding Ser, Leu, and Tyr) and in vitro transcribed tRNAs, encompassing anticodon-swapped tRNASerGAG and tRNALeuGGA. This approach reduces the number of in vitro transcribed tRNAs required from 21 to only 4. In this optimized system, the production of a model protein, superfolder green fluorescent protein, increases to 3.5-fold. With this hybrid tRNA set, the Ser/Leu-swapped cell-free translation system will stand as a potent tool for protein production with reduced biohazard concerns in future biological endeavors.
Molecular fingerprinting of biological nanoparticles with a label-free optofluidic platform
Authors: Stollmann Alexia , Garcia-Guirado Jose , Hong Jae-Sang , Rüedi Pascal , Im Hyungsoon , Lee Hakho , Ortega Arroyo Jaime , Quidant Romain 
Published: May 2024

AbstractLabel-free detection of multiple analytes in a high-throughput fashion has been one of the long-sought goals in biosensing applications. Yet, for all-optical approaches, interfacing state-of-the-art label-free techniques with microfluidics tools that can process small volumes of sample with high throughput, and with surface chemistry that grants analyte specificity, poses a critical challenge to date. Here, we introduce an optofluidic platform that brings together state-of-the-art digital holography with PDMS microfluidics by using supported lipid bilayers as a surface chemistry building block to integrate both technologies. Specifically, this platform fingerprints heterogeneous biological nanoparticle populations via a multiplexed label-free immunoaffinity assay with single particle sensitivity. First, we characterise the robustness and performance of the platform, and then apply it to profile four distinct ovarian cell-derived extracellular vesicle populations over a panel of surface protein biomarkers, thus developing a unique biomarker fingerprint for each cell line. We foresee that our approach will find many applications where routine and multiplexed characterisation of biological nanoparticles are required.
Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis
Authors: Zhang Zhenlei , Wu Yufan , Fu Jinrong , Yu Xiujie , Su Yang , Jia Shikai , Cheng Huili , Shen Yan , He Xianghui , Ren Kai , Zheng Xiangqian , Guan Haixia , Rao Feng , Zhao Li 
Published: May 2024

AbstractMAPK pathway-driven tumorigenesis, often induced by BRAFV600E, relies on epithelial dedifferentiation. However, how lineage differentiation events are reprogrammed remains unexplored. Here, we demonstrate that proteostatic reactivation of developmental factor, TBX3, accounts for BRAF/MAPK-mediated dedifferentiation and tumorigenesis. During embryonic development, BRAF/MAPK upregulates USP15 to stabilize TBX3, which orchestrates organogenesis by restraining differentiation. The USP15-TBX3 axis is reactivated during tumorigenesis, and Usp15 knockout prohibits BRAFV600E-driven tumor development in a Tbx3-dependent manner. Deleting Tbx3 or Usp15 leads to tumor redifferentiation, which parallels their overdifferentiation tendency during development, exemplified by disrupted thyroid folliculogenesis and elevated differentiation factors such as Tpo, Nis, Tg. The clinical relevance is highlighted in that both USP15 and TBX3 highly correlates with BRAFV600E signature and poor tumor prognosis. Thus, USP15 stabilized TBX3 represents a critical proteostatic mechanism downstream of BRAF/MAPK-directed developmental homeostasis and pathological transformation, supporting that tumorigenesis largely relies on epithelial dedifferentiation achieved via embryonic regulatory program reinitiation.
Geologically younger ecosystems are more dependent on soil biodiversity for supporting function
Authors: Feng Jiao , Liu Yu-Rong , Eldridge David , Huang Qiaoyun , Tan Wenfeng , Delgado-Baquerizo Manuel 
Published: May 2024

AbstractSoil biodiversity contains the metabolic toolbox supporting organic matter decomposition and nutrient cycling in the soil. However, as soil develops over millions of years, the buildup of plant cover, soil carbon and microbial biomass may relax the dependence of soil functions on soil biodiversity. To test this hypothesis, we evaluate the within-site soil biodiversity and function relationships across 87 globally distributed ecosystems ranging in soil age from centuries to millennia. We found that within-site soil biodiversity and function relationship is negatively correlated with soil age, suggesting a stronger dependence of ecosystem functioning on soil biodiversity in geologically younger than older ecosystems. We further show that increases in plant cover, soil carbon and microbial biomass as ecosystems develop, particularly in wetter conditions, lessen the critical need of soil biodiversity to sustain function. Our work highlights the importance of soil biodiversity for supporting function in drier and geologically younger ecosystems with low microbial biomass.
Interplay between Mg2+ and Ca2+ at multiple sites of the ryanodine receptor
Authors: Nayak Ashok R. , Rangubpit Warin , Will Alex H. , Hu Yifan , Castro-Hartmann Pablo , Lobo Joshua J. , Dryden Kelly , Lamb Graham D. , Sompornpisut Pornthep , Samsó Montserrat 
Published: May 2024

AbstractRyR1 is an intracellular Ca2+ channel important in excitable cells such as neurons and muscle fibers. Ca2+ activates it at low concentrations and inhibits it at high concentrations. Mg2+ is the main physiological RyR1 inhibitor, an effect that is overridden upon activation. Despite the significance of Mg2+-mediated inhibition, the molecular-level mechanisms remain unclear. In this work we determined two cryo-EM structures of RyR1 with Mg2+ up to 2.8 Å resolution, identifying multiple Mg2+ binding sites. Mg2+ inhibits at the known Ca2+ activating site and we propose that the EF hand domain is an inhibitory divalent cation sensor. Both divalent cations bind to ATP within a crevice, contributing to the precise transmission of allosteric changes within the enormous channel protein. Notably, Mg2+ inhibits RyR1 by interacting with the gating helices as validated by molecular dynamics. This structural insight enhances our understanding of how Mg2+ inhibition is overcome during excitation.
The nucleic acid binding protein SFPQ represses EBV lytic reactivation by promoting histone H1 expression
Authors: Murray-Nerger Laura A. , Lozano Clarisel , Burton Eric M. , Liao Yifei , Ungerleider Nathan A. , Guo Rui , Gewurz Benjamin E. 
Published: May 2024

AbstractEpstein-Barr virus (EBV) uses a biphasic lifecycle of latency and lytic reactivation to infect >95% of adults worldwide. Despite its central role in EBV persistence and oncogenesis, much remains unknown about how EBV latency is maintained. We used a human genome-wide CRISPR/Cas9 screen to identify that the nuclear protein SFPQ was critical for latency. SFPQ supported expression of linker histone H1, which stabilizes nucleosomes and regulates nuclear architecture, but has not been previously implicated in EBV gene regulation. H1 occupied latent EBV genomes, including the immediate early gene BZLF1 promoter. Upon reactivation, SFPQ was sequestered into sub-nuclear puncta, and EBV genomic H1 occupancy diminished. Enforced H1 expression blocked EBV reactivation upon SFPQ knockout, confirming it as necessary downstream of SFPQ. SFPQ knockout triggered reactivation of EBV in B and epithelial cells, as well as of Kaposi’s sarcoma-associated herpesvirus in B cells, suggesting a conserved gamma-herpesvirus role. These findings highlight SFPQ as a major regulator of H1 expression and EBV latency.
Endocardial HDAC3 is required for myocardial trabeculation
Authors: Jang Jihyun , Bentsen Mette , Kim Ye Jun , Kim Erick , Garg Vidu , Cai Chen-Leng , Looso Mario , Li Deqiang 
Published: May 2024

AbstractFailure of proper ventricular trabeculation is often associated with congenital heart disease. Support from endocardial cells, including the secretion of extracellular matrix and growth factors is critical for trabeculation. However, it is poorly understood how the secretion of extracellular matrix and growth factors is initiated and regulated by endocardial cells. We find that genetic knockout of histone deacetylase 3 in the endocardium in mice results in early embryo lethality and ventricular hypotrabeculation. Single cell RNA sequencing identifies significant downregulation of extracellular matrix components in histone deacetylase 3 knockout endocardial cells. Secretome from cultured histone deacetylase 3 knockout mouse cardiac endothelial cells lacks transforming growth factor ß3 and shows significantly reduced capacity in stimulating cultured cardiomyocyte proliferation, which is remarkably rescued by transforming growth factor ß3 supplementation. Mechanistically, we identify that histone deacetylase 3 knockout induces transforming growth factor ß3 expression through repressing microRNA-129-5p. Our findings provide insights into the pathogenesis of congenital heart disease and conceptual strategies to promote myocardial regeneration.
Accelerating reliable multiscale quantum refinement of protein–drug systems enabled by machine learning
Authors: Yan Zeyin , Wei Dacong , Li Xin , Chung Lung Wa 
Published: May 2024

AbstractBiomacromolecule structures are essential for drug development and biocatalysis. Quantum refinement (QR) methods, which employ reliable quantum mechanics (QM) methods in crystallographic refinement, showed promise in improving the structural quality or even correcting the structure of biomacromolecules. However, vast computational costs and complex quantum mechanics/molecular mechanics (QM/MM) setups limit QR applications. Here we incorporate robust machine learning potentials (MLPs) in multiscale ONIOM(QM:MM) schemes to describe the core parts (e.g., drugs/inhibitors), replacing the expensive QM method. Additionally, two levels of MLPs are combined for the first time to overcome MLP limitations. Our unique MLPs+ONIOM-based QR methods achieve QM-level accuracy with significantly higher efficiency. Furthermore, our refinements provide computational evidence for the existence of bonded and nonbonded forms of the Food and Drug Administration (FDA)-approved drug nirmatrelvir in one SARS-CoV-2 main protease structure. This study highlights that powerful MLPs accelerate QRs for reliable protein–drug complexes, promote broader QR applications and provide more atomistic insights into drug development.
Structures of H5N1 influenza polymerase with ANP32B reveal mechanisms of genome replication and host adaptation
Authors: Staller Ecco , Carrique Loïc , Swann Olivia C. , Fan Haitian , Keown Jeremy R. , Sheppard Carol M. , Barclay Wendy S. , Grimes Jonathan M. , Fodor Ervin 
Published: May 2024

AbstractAvian influenza A viruses (IAVs) pose a public health threat, as they are capable of triggering pandemics by crossing species barriers. Replication of avian IAVs in mammalian cells is hindered by species-specific variation in acidic nuclear phosphoprotein 32 (ANP32) proteins, which are essential for viral RNA genome replication. Adaptive mutations enable the IAV RNA polymerase (FluPolA) to surmount this barrier. Here, we present cryo-electron microscopy structures of monomeric and dimeric avian H5N1 FluPolA with human ANP32B. ANP32B interacts with the PA subunit of FluPolA in the monomeric form, at the site used for its docking onto the C-terminal domain of host RNA polymerase II during viral transcription. ANP32B acts as a chaperone, guiding FluPolA towards a ribonucleoprotein-associated FluPolA to form an asymmetric dimer—the replication platform for the viral genome. These findings offer insights into the molecular mechanisms governing IAV genome replication, while enhancing our understanding of the molecular processes underpinning mammalian adaptations in avian-origin FluPolA.
A non-canonical visual cortical-entorhinal pathway contributes to spatial navigation
Authors: Shao Qiming , Chen Ligu , Li Xiaowan , Li Miao , Cui Hui , Li Xiaoyue , Zhao Xinran , Shi Yuying , Sun Qiang , Yan Kaiyue , Wang Guangfu 
Published: May 2024

AbstractVisual information is important for accurate spatial coding and memory-guided navigation. As a crucial area for spatial cognition, the medial entorhinal cortex (MEC) harbors diverse spatially tuned cells and functions as the major gateway relaying sensory inputs to the hippocampus containing place cells. However, how visual information enters the MEC has not been fully understood. Here, we identify a pathway originating in the secondary visual cortex (V2) and directly targeting MEC layer 5a (L5a). L5a neurons served as a network hub for visual processing in the MEC by routing visual inputs from multiple V2 areas to other local neurons and hippocampal CA1. Interrupting this pathway severely impaired visual stimulus-evoked neural activity in the MEC and performance of mice in navigation tasks. These observations reveal a visual cortical-entorhinal pathway highlighting the role of MEC L5a in sensory information transmission, a function typically attributed to MEC superficial layers before.
Public engagement for inclusive and sustainable governance of climate interventions
Authors: Fritz Livia , Baum Chad M. , Low Sean , Sovacool Benjamin K. 
Published: May 2024

AbstractThe need for public engagement is increasingly evident as discussions intensify around emerging methods for carbon dioxide removal and controversial proposals around solar geoengineering. Based on 44 focus groups in 22 countries across the Global North and Global South (N = 323 participants), this article traces public preferences for a variety of bottom-up and top-down engagement practices ranging from information recipient to broad decision authority. Here, we show that engagement practices need to be responsive to local political cultures and socio-technical environments, while attending to the global dimensions and interconnectedness of the issues at stake. Establishing public engagement as a cornerstone of inclusive and sustainable governance of climate-intervention technologies requires (i) recognizing the diversity of forms and intensities of engaging, (ii) considering national contexts and modes of engagement, (iii) tailoring to technological idiosyncrasies, (iv) adopting power-sensitive practices, (v) accounting for publics’ prior experience, (vi) establishing trust and procedural legitimacy and (vii) engaging with tensions and value disagreements.
Remote epitaxy of single-crystal rhombohedral WS2 bilayers
Authors: Chang Chao , Zhang Xiaowen , Li Weixuan , Guo Quanlin , Feng Zuo , Huang Chen , Ren Yunlong , Cai Yingying , Zhou Xu , Wang Jinhuan , Tang Zhilie , Ding Feng , Wei Wenya , Liu Kaihui , Xu Xiaozhi 
Published: May 2024

AbstractCompared to transition metal dichalcogenide (TMD) monolayers, rhombohedral-stacked (R-stacked) TMD bilayers exhibit remarkable electrical performance, enhanced nonlinear optical response, giant piezo-photovoltaic effect and intrinsic interfacial ferroelectricity. However, from a thermodynamics perspective, the formation energies of R-stacked and hexagonal-stacked (H-stacked) TMD bilayers are nearly identical, leading to mixed stacking of both H- and R-stacked bilayers in epitaxial films. Here, we report the remote epitaxy of centimetre-scale single-crystal R-stacked WS2 bilayer films on sapphire substrates. The bilayer growth is realized by a high flux feeding of the tungsten source at high temperature on substrates. The R-stacked configuration is achieved by the symmetry breaking in a-plane sapphire, where the influence of atomic steps passes through the lower TMD layer and controls the R-stacking of the upper layer. The as-grown R-stacked bilayers show up-to-30-fold enhancements in carrier mobility (34 cm2V−1s−1), nearly doubled circular helicity (61%) and interfacial ferroelectricity, in contrast to monolayer films. Our work reveals a growth mechanism to obtain stacking-controlled bilayer TMD single crystals, and promotes large-scale applications of R-stacked TMD.
ADAM9 promotes type I interferon-mediated innate immunity during encephalomyocarditis virus infection
Authors: Bazzone Lindsey E. , Zhu Junji , King Michael , Liu GuanQun , Guo Zhiru , MacKay Christopher R. , Kyawe Pyae P. , Qaisar Natasha , Rojas-Quintero Joselyn , Owen Caroline A. , Brass Abraham L. , McDougall William , Baer Christina E. , Cashman Timothy , Trivedi Chinmay M. , Gack Michaela U. , Finberg Robert W. , Kurt-Jones Evelyn A. 
Published: May 2024

AbstractViral myocarditis, an inflammatory disease of the heart, causes significant morbidity and mortality. Type I interferon (IFN)-mediated antiviral responses protect against myocarditis, but the mechanisms are poorly understood. We previously identified A Disintegrin And Metalloproteinase domain 9 (ADAM9) as an important factor in viral pathogenesis. ADAM9 is implicated in a range of human diseases, including inflammatory diseases; however, its role in viral infection is unknown. Here, we demonstrate that mice lacking ADAM9 are more susceptible to encephalomyocarditis virus (EMCV)-induced death and fail to mount a characteristic type I IFN response. This defect in type I IFN induction is specific to positive-sense, single-stranded RNA (+ ssRNA) viruses and involves melanoma differentiation-associated protein 5 (MDA5)—a key receptor for +ssRNA viruses. Mechanistically, ADAM9 binds to MDA5 and promotes its oligomerization and thereby downstream mitochondrial antiviral-signaling protein (MAVS) activation in response to EMCV RNA stimulation. Our findings identify a role for ADAM9 in the innate antiviral response, specifically MDA5-mediated IFN production, which protects against virus-induced cardiac damage, and provide a potential therapeutic target for treatment of viral myocarditis.