bluuebunny/crossref_metadata_2025 huggingface dataset:
AffineMortality: An R package for estimation, analysis, and projection of affine mortality models
Authors: Ungolo Francesco , Garces Len Patrick Dominic M. , Sherris Michael , Zhou Yuxin
Published: May 2024

This paper presents the AffineMortality R package which performs parameter estimation, goodness-of-fit analysis, simulation, and projection of future mortality rates for a set of affine mortality models for use in pricing and reserving. The computational routines build on the univariate Kalman Filtering approach of Koopman and Durbin ((2000). Journal of Time Series Analysis,21(3), 281–296.) along other numerical methods to enhance the robustness of the results. This paper provides a discussion of how the package works in order to effectively estimate and project survival curves, and describes the available functions. Illustration of the package for mortality analysis of the US male data set is provided.
On the benefits of pension plan consolidation: Understanding the impact of full plan mergers
Authors: Bégin Jean-François , Sanders Barbara , Zhou Wenyuan
Published: May 2024

This study investigates the benefits and drawbacks of pension plan consolidation by quantifying the impact of mergers of heterogeneous plans on different stakeholders in a unique Canadian implementation of defined benefit plans. Using a comprehensive framework that combines a realistic economic scenario generator, a stochastic mortality model that captures differences among subpopulations, a cost model with economies of scale, and a dynamic asset allocation methodology, we evaluate the combined effect of asset- and liability-side changes on three groups of measures: plan-related risk measures assessing profits from an economic capital perspective, consumption-based metrics to understand the impact on members, and contribution risk measures capturing the risk from the employer’s viewpoint. We apply the framework to a hypothetical and empirically relevant merger and find that consolidation is favorable under most circumstances: the positive impacts of better diversification and economies of scale continue to outweigh the negative effects of heterogeneity even when the merging plans have different mortality expectations, different maturity levels, or modest differences in initial funded ratios.
Pockmarks Offshore Big Sur, California Provide Evidence for Recurrent, Regional, and Unconfined Sediment Gravity Flows
Authors: Lundsten E. , Paull C. K. , Gwiazda R. , Dobbs S. , Caress D. W. , Kuhnz L. A. , Walton M. , Nieminski N. , McGann M. , Lorenson T. , Cochrane G. , Addison J.
Published: May 2024

Recent surface ship multibeam surveys of the Sur Pockmark Field, offshore Central California, reveal >5,000 pockmarks in an area that is slated to host a wind farm, between 500‐ and 1,500‐m water depth. Extensive fieldwork was conducted to characterize the seafloor environment and its recent geologic history, including visual observations with remotely operated vehicles, sediment core sampling, and high‐resolution, near‐bottom Chirp and multibeam surveys collected with autonomous underwater vehicles to capture the morphology and stratigraphy of the pockmarks. No evidence of high methane concentrations in sediments, chemosynthetic biological communities, or methane‐derived diagenetic byproducts was found. Chirp data and sediment cores showed alternating layers of slowly accumulating hemipelagic drapes interrupted by more reflective turbidite horizons that extend throughout the pockmark field and beyond. Chirp data showed multiple episodes of lateral migration over time in some of the pockmarks in association with erosion and infilling events. Laterally continuous turbidite horizons that overlay erosional surfaces indicated that pockmark migration occurred synchronously in multiple pockmarks separated by tens of kilometers. These shifts are presumed to be the result of asymmetrical erosion of the pockmark flanks caused by passing sediment gravity flows. While some pockmarks occur in chains, most are not clustered or randomly spaced but are regularly dispersed within the pockmark field. We hypothesize that intermittent, unconfined sediment gravity flows occurring over at least the last 280,000 years are the source of the regionally continuous turbidite deposits and the mechanism that maintained the regularly dispersed pockmarks.
δ18O of Marine‐Influenced Tectona grandis L. f. From Equatorial Indonesia: A Local Rainfall Amount and Remote ENSO Indicator
Authors: Nurhati I. S. , Evans M. N. , Cahyarini S. Y. , D’Arrigo R. D. , Yoshimura K. , Herho S. H. S.
Published: May 2024

The hydroclimatic response of the El Niño‐Southern Oscillation (ENSO) to external radiative forcing remains controversial and difficult to project with confidence for the 21st century. Annually resolved paleoclimatic reconstructions spanning the pre‐ and post‐industrial eras from the Indonesian maritime continent may provide hindcasting and diagnostic targets. Here we report δ18O observations from dendrochronologically dated teak (Tectona grandis L. f.) α‐cellulose samples collected at Muna Island, Sulawesi (5.3°S, 123°E, elevation 10 m), for November‐April growing seasons during the period 1969/70–2004/5. Age‐modeled, annually averaged α‐cellulose δ18O anomalies are significantly correlated with simulated α‐cellulose δ18O at the study site. We show that the correlation is largely explained by the amount effect in local and regional precipitation δ18O. Significant correlation with SST anomalies over the study period suggest that replicated multicentury α‐cellulose records from this archive may be interpreted as ENSO indicators.
Combustion Completeness and Sample Location Determine Wildfire Ash Leachate Chemistry
Authors: Campbell Micheline , Treble Pauline C. , McDonough Liza K. , Naeher Sebastian , Baker Andy , Grierson Pauline F. , Wong Henri , Andersen Martin S.
Published: May 2024

Understanding past fire regimes and how they vary with climate, human activity, and vegetation patterns is fundamental to the mitigation and management of changing fire regimes as anthropogenic climate change progresses. Ash‐derived trace elements and pyrogenic biomarkers from speleothems have recently been shown to record past fire activity in speleothems from both Australia and North America. This calls for an empirical study of ash geochemistry to aid the interpretation of speleothem palaeofire proxy records. Here we present analyses of leached ashes collected following fires in southwest and southeast Australia. We include a suite of inorganic elemental data from the water‐soluble fraction of ash as well as a selection of organic analytes (pyrogenic lipid biomarkers). We also present elemental data from leachates of soils collected from sites in southwest Australia. We demonstrate that the water‐soluble fraction of ash differs from the water‐soluble fraction of soils, with trace and minor element concentrations in ash leachates varying with combustion completeness (burn severity) and sample location. Changes in some lipid biomarker concentrations extracted from ashes may reflect burn severity. Our results contribute to building a process‐based understanding of how speleothem geochemistry may record fire frequency and severity, and suggest that more research is needed to understand the transport pathways for the inclusion of pyrogenic biomarkers in speleothems. Our results also demonstrate that potential contaminant loads from ashes are much higher than from soils, with implications for the management of karst catchments, which are a critical water resource.
Transcription factor activating enhancer-binding protein 2ε (AP2ε) modulates phenotypic plasticity and progression of malignant melanoma
Authors: Staebler Sebastian , Rottensteiner-Brandl Ulrike , El Ahmad Zubeir , Kappelmann-Fenzl Melanie , Arkudas Andreas , Kengelbach-Weigand Annika , Bosserhoff Anja-Katrin , Schmidt Sonja K.
Published: May 2024

Malignant melanoma, the most aggressive form of skin cancer, is often incurable once metastatic dissemination of cancer cells to distant organs has occurred. We investigated the role of Transcription Factor Activating Enhancer-Binding Protein 2ε (AP2ε) in the progression of metastatic melanoma. Here, we observed that AP2ε is a potent activator of metastasis and newly revealed AP2ε to be an important player in melanoma plasticity. High levels of AP2ε lead to worsened prognosis of melanoma patients. Using a transgenic melanoma mouse model with a specific loss of AP2ε expression, we confirmed the impact of AP2ε to modulate the dynamic switch from a migratory to a proliferative phenotype. AP2ε deficient melanoma cells show a severely reduced migratory potential in vitro and reduced metastatic behavior in vivo. Consistently, we revealed increased activity of AP2ε in quiescent and migratory cells compared to heterogeneously proliferating cells in bioprinted 3D models. In conclusion, these findings disclose a yet-unknown role of AP2ε in maintaining plasticity and migration in malignant melanoma cells.
Energy stress-induced circDDX21 promotes glycolysis and facilitates hepatocellular carcinogenesis
Authors: Luo Jingjing , Yang Yang , Zhang Guang , Fang Debao , Liu Kaiyue , Mei Yide , Wang Fang
Published: May 2024

Cancer cells undergo metabolic reprogramming in response to hostile microenvironments, such as energy stress; however, the underlying mechanisms remain largely unclear. It is also unknown whether energy stress-responsive circular RNA (circRNA) is involved in the regulation of glucose metabolism. Here we report that circDDX21 is upregulated in response to glucose deprivation by the transcription factor c-Myc. Functionally, circDDX21 is shown to promote glycolysis by increasing PGAM1 expression. Mechanistically, circDDX21 interacts with the RNA binding protein PABPC1, disrupting its association with the ubiquitin E3 ligase MKRN3. This disassociation attenuates MKRN3-mediated PABPC1 ubiquitination and enhances the binding of PABPC1 to PGAM1 mRNA, thereby leading to PGAM1 mRNA stabilization. The ability of the circDDX21-PGAM1 axis to promote hepatocellular carcinogenesis is validated in a xenograft mouse model. Additionally, in clinical hepatocellular carcinoma tissues, there is a positive correlation between circDDX21 and PGAM1 expression. These findings establish circDDX21 as an important regulator of glycolysis and suggest circDDX21 as a potential therapeutic target for hepatocellular carcinoma.
Ferroptosis exacerbates hyperlipidemic acute pancreatitis by enhancing lipid peroxidation and modulating the immune microenvironment
Authors: Gu Xinyi , Huang Zhicheng , Ying Xiuzhiye , Liu Xiaodie , Ruan Kaiyi , Hua Sijia , Zhang Xiaofeng , Jin Hangbin , Liu Qiang , Yang Jianfeng
Published: May 2024

Abnormal activation of ferroptosis worsens the severity of acute pancreatitis and intensifies the inflammatory response and organ damage, but the detailed underlying mechanisms are unknown. Compared with other types of pancreatitis, hyperlipidemic acute pancreatitis (HLAP) is more likely to progress to necrotizing pancreatitis, possibly due to peripancreatic lipolysis and the production of unsaturated fatty acids. Moreover, high levels of unsaturated fatty acids undergo lipid peroxidation and trigger ferroptosis to further exacerbate inflammation and worsen HLAP. This paper focuses on the malignant development of hyperlipidemic pancreatitis with severe disease combined with the core features of ferroptosis to explore and describe the mechanism of this phenomenon and shows that the activation of lipid peroxidation and the aberrant intracellular release of many inflammatory mediators during ferroptosis are the key processes that regulate the degree of disease development in patients with HLAP. Inhibiting the activation of ferroptosis effectively reduces the intensity of the inflammatory response, thus reducing organ damage in patients and preventing the risk of HLAP exacerbation. Additionally, this paper summarizes the key targets and potential therapeutic agents of ferroptosis associated with HLAP deterioration to provide new ideas for future clinical applications.
TAF2, within the TFIID complex, regulates the expression of a subset of protein-coding genes
Authors: Cheng I-Hsin , Pi Wen-Chieh , Hsu Chung-Hao , Guo Yiran , Lai Jun-Lin , Wang Gang G. , Chung Bon-chu , Roeder Robert G. , Chen Wei-Yi
Published: May 2024

TFIID, one of the general transcription factor (GTF), regulates transcriptional initiation of protein-coding genes through direct binding to promoter elements and subsequent recruitment of other GTFs and RNA polymerase II. Although generally required for most protein-coding genes, accumulated studies have also demonstrated promoter-specific functions for several TFIID subunits in gene activation. Here, we report that TBP-associated factor 2 (TAF2) specifically regulates TFIID binding to a small subset of protein-coding genes and is essential for cell growth of multiple cancer lines. Co-immunoprecipitation assays revealed that TAF2 may be sub-stoichiometrically associated with the TFIID complex, thus indicating a minor fraction of TAF2-containing TFIID in cells. Consistently, integrated genome-wide profiles show that TAF2 binds to and regulates only a small subset of protein-coding genes. Furthermore, through the use of an inducible TAF2 degradation system, our results reveal a reduction of TBP/TFIID binding to several ribosomal genes upon selective ablation of TAF2. In addition, depletion of TAF2, as well as the TAF2-regulated ribosomal protein genes RPL30 and RPL39, decreases ribosome assembly and global protein translation. Collectively, this study suggests that TAF2 within the TFIID complex is of functional importance for TBP/TFIID binding to and expression of a small subset of protein-coding genes, thus establishing a previously unappreciated promoter-selective function for TAF2.
Emergent disorder and mechanical memory in periodic metamaterials
Authors: Sirote-Katz Chaviva , Shohat Dor , Merrigan Carl , Lahini Yoav , Nisoli Cristiano , Shokef Yair
Published: May 2024

Ordered mechanical systems typically have one or only a few stable rest configurations, and hence are not considered useful for encoding memory. Multistable and history-dependent responses usually emerge from quenched disorder, for example in amorphous solids or crumpled sheets. In contrast, due to geometric frustration, periodic magnetic systems can create their own disorder and espouse an extensive manifold of quasi-degenerate configurations. Inspired by the topological structure of frustrated artificial spin ices, we introduce an approach to design ordered, periodic mechanical metamaterials that exhibit an extensive set of spatially disordered states. While our design exploits the correspondence between frustration in magnetism and incompatibility in meta-mechanics, our mechanical systems encompass continuous degrees of freedom, and thus generalize their magnetic counterparts. We show how such systems exhibit non-Abelian and history-dependent responses, as their state can depend on the order in which external manipulations were applied. We demonstrate how this richness of the dynamics enables to recognize, from a static measurement of the final state, the sequence of operations that an extended system underwent. Thus, multistability and potential to perform computation emerge from geometric frustration in ordered mechanical lattices that create their own disorder.
3D ocean assessments reveal that fisheries reach deep but marine protection remains shallow
Authors: Jacquemont Juliette , Loiseau Charles , Tornabene Luke , Claudet Joachim
Published: May 2024

The wave of new global conservation targets, the conclusion of the High Seas Treaty negotiations, and the expansion of extractive use into the deep sea call for a paradigm shift in ocean conservation. The current reductionist 2D representation of the ocean to set targets and measure impacts will fail at achieving effective biodiversity conservation. Here, we develop a framework that overlays depth realms onto marine ecoregions to conduct the first three-dimensional spatial analysis of global marine conservation achievements and fisheries footprint. Our novel approach reveals conservation gaps of mesophotic, rariphotic, and abyssal depths and an underrepresentation of high protection levels across all depths. In contrast, the 3D footprint of fisheries covers all depths, with benthic fishing occurring down to the lower bathyal and mesopelagic fishing peaking in areas overlying abyssal depths. Additionally, conservation efforts are biased towards areas where the lowest fishing pressures occur, compromising the effectiveness of the marine conservation network. These spatial mismatches emphasize the need to shift towards 3D thinking to achieve ocean sustainability.
Post-resolution macrophages shape long-term tissue immunity and integrity in a mouse model of pneumococcal pneumonia
Authors: Feehan Karen T. , Bridgewater Hannah E. , Stenkiewicz-Witeska Jan , De Maeyer Roel P. H. , Ferguson John , Mack Matthias , Brown Jeremy , Ercoli Giuseppe , Mawer Connar M. , Akbar Arne N. , Glanville James R. W. , Jalali Parinaaz , Bracken Olivia V. , Nicolaou Anna , Kendall Alexandra C. , Sugimoto Michelle A. , Gilroy Derek W.
Published: May 2024

Resolving inflammation is thought to return the affected tissue back to homoeostasis but recent evidence supports a non-linear model of resolution involving a phase of prolonged immune activity. Here we show that within days following resolution of Streptococcus pneumoniae-triggered lung inflammation, there is an influx of antigen specific lymphocytes with a memory and tissue-resident phenotype as well as macrophages bearing alveolar or interstitial phenotype. The transcriptome of these macrophages shows enrichment of genes associated with prostaglandin biosynthesis and genes that drive T cell chemotaxis and differentiation. Therapeutic depletion of post-resolution macrophages, inhibition of prostaglandin E2 (PGE2) synthesis or treatment with an EP4 antagonist, MF498, reduce numbers of lung CD4+/CD44+/CD62L+ and CD4+/CD44+/CD62L-/CD27+ T cells as well as their expression of the α-integrin, CD103. The T cells fail to reappear and reactivate upon secondary challenge for up to six weeks following primary infection. Concomitantly, EP4 antagonism through MF498 causes accumulation of lung macrophages and marked tissue fibrosis. Our study thus shows that PGE2 signalling, predominantly via EP4, plays an important role during the second wave of immune activity following resolution of inflammation. This secondary immune activation drives local tissue-resident T cell development while limiting tissue injury
Spatiotemporal brain hierarchies of auditory memory recognition and predictive coding
Authors: Bonetti L. , Fernández-Rubio G. , Carlomagno F. , Dietz M. , Pantazis D. , Vuust P. , Kringelbach M. L.
Published: May 2024

Our brain is constantly extracting, predicting, and recognising key spatiotemporal features of the physical world in order to survive. While neural processing of visuospatial patterns has been extensively studied, the hierarchical brain mechanisms underlying conscious recognition of auditory sequences and the associated prediction errors remain elusive. Using magnetoencephalography (MEG), we describe the brain functioning of 83 participants during recognition of previously memorised musical sequences and systematic variations. The results show feedforward connections originating from auditory cortices, and extending to the hippocampus, anterior cingulate gyrus, and medial cingulate gyrus. Simultaneously, we observe backward connections operating in the opposite direction. Throughout the sequences, the hippocampus and cingulate gyrus maintain the same hierarchical level, except for the final tone, where the cingulate gyrus assumes the top position within the hierarchy. The evoked responses of memorised sequences and variations engage the same hierarchical brain network but systematically differ in terms of temporal dynamics, strength, and polarity. Furthermore, induced-response analysis shows that alpha and beta power is stronger for the variations, while gamma power is enhanced for the memorised sequences. This study expands on the predictive coding theory by providing quantitative evidence of hierarchical brain mechanisms during conscious memory and predictive processing of auditory sequences.
Receptor-like cytoplasmic kinases of different subfamilies differentially regulate SOBIR1/BAK1-mediated immune responses in Nicotiana benthamiana
Authors: Huang Wen R. H. , Braam Ciska , Kretschmer Carola , Villanueva Sergio Landeo , Liu Huan , Ferik Filiz , van der Burgh Aranka M. , Boeren Sjef , Wu Jinbin , Zhang Lisha , Nürnberger Thorsten , Wang Yulu , Seidl Michael F. , Evangelisti Edouard , Stuttmann Johannes , Joosten Matthieu H. A. J.
Published: May 2024

Cell-surface receptors form the front line of plant immunity. The leucine-rich repeat (LRR)-receptor-like kinases SOBIR1 and BAK1 are required for the functionality of the tomato LRR-receptor-like protein Cf-4, which detects the secreted effector Avr4 of the pathogenic fungus Fulvia fulva. Here, we show that the kinase domains of SOBIR1 and BAK1 directly phosphorylate each other and that residues Thr522 and Tyr469 of the kinase domain of Nicotiana benthamiana SOBIR1 are required for its kinase activity and for interacting with signalling partners, respectively. By knocking out multiple genes belonging to different receptor-like cytoplasmic kinase (RLCK)-VII subfamilies in N. benthamiana:Cf-4, we show that members of RLCK-VII-6, −7, and −8 differentially regulate the Avr4/Cf-4-triggered biphasic burst of reactive oxygen species. In addition, members of RLCK-VII-7 play an essential role in resistance against the oomycete pathogen Phytophthora palmivora. Our study provides molecular evidence for the specific roles of RLCKs downstream of SOBIR1/BAK1-containing immune complexes.
Uncovering the spin ordering in magic-angle graphene via edge state equilibration
Authors: Hoke Jesse C. , Li Yifan , May-Mann Julian , Watanabe Kenji , Taniguchi Takashi , Bradlyn Barry , Hughes Taylor L. , Feldman Benjamin E.
Published: May 2024

The flat bands in magic-angle twisted bilayer graphene (MATBG) provide an especially rich arena to investigate interaction-driven ground states. While progress has been made in identifying the correlated insulators and their excitations at commensurate moiré filling factors, the spin-valley polarizations of the topological states that emerge at high magnetic field remain unknown. Here we introduce a technique based on twist-decoupled van der Waals layers that enables measurement of their electronic band structure and–by studying the backscattering between counter-propagating edge states–the determination of the relative spin polarization of their edge modes. We find that the symmetry-broken quantum Hall states that extend from the charge neutrality point in MATBG are spin unpolarized at even integer filling factors. The measurements also indicate that the correlated Chern insulator emerging from half filling of the flat valence band is spin unpolarized and suggest that its conduction band counterpart may be spin polarized.
Determinants of gastric cancer immune escape identified from non-coding immune-landscape quantitative trait loci
Authors: Miliotis Christos , Ma Yuling , Katopodi Xanthi-Lida , Karagkouni Dimitra , Kanata Eleni , Mattioli Kaia , Kalavros Nikolas , Pita-Juárez Yered H. , Batalini Felipe , Ramnarine Varune R. , Nanda Shivani , Slack Frank J. , Vlachos Ioannis S.
Published: May 2024

The landscape of non-coding mutations in cancer progression and immune evasion is largely unexplored. Here, we identify transcrptome-wide somatic and germline 3′ untranslated region (3′-UTR) variants from 375 gastric cancer patients from The Cancer Genome Atlas. By performing gene expression quantitative trait loci (eQTL) and immune landscape QTL (ilQTL) analysis, we discover 3′-UTR variants with cis effects on expression and immune landscape phenotypes, such as immune cell infiltration and T cell receptor diversity. Using a massively parallel reporter assay, we distinguish between causal and correlative effects of 3′-UTR eQTLs in immune-related genes. Our approach identifies numerous 3′-UTR eQTLs and ilQTLs, providing a unique resource for the identification of immunotherapeutic targets and biomarkers. A prioritized ilQTL variant signature predicts response to immunotherapy better than standard-of-care PD-L1 expression in independent patient cohorts, showcasing the untapped potential of non-coding mutations in cancer.
Towards silent and efficient flight by combining bioinspired owl feather serrations with cicada wing geometry
Authors: Wei Zixiao , Wang Stanley , Farris Sean , Chennuri Naga , Wang Ningping , Shinsato Stara , Demir Kahraman , Horii Maya , Gu Grace X.
Published: May 2024

As natural predators, owls fly with astonishing stealth due to the serrated feather morphology that produces advantageous flow characteristics. Traditionally, these serrations are tailored for airfoil edges with simple two-dimensional patterns, limiting their effect on noise reduction while negotiating tradeoffs in aerodynamic performance. Conversely, the intricately structured wings of cicadas have evolved for effective flapping, presenting a potential blueprint for alleviating these aerodynamic limitations. In this study, we formulate a synergistic design strategy that harmonizes noise suppression with aerodynamic efficiency by integrating the geometrical attributes of owl feathers and cicada forewings, culminating in a three-dimensional sinusoidal serration propeller topology that facilitates both silent and efficient flight. Experimental results show that our design yields a reduction in overall sound pressure levels by up to 5.5 dB and an increase in propulsive efficiency by over 20% compared to the current industry benchmark. Computational fluid dynamics simulations validate the efficacy of the bioinspired design in augmenting surface vorticity and suppressing noise generation across various flow regimes. This topology can advance the multifunctionality of aerodynamic surfaces for the development of quieter and more energy-saving aerial vehicles.
Heavy-atom tunnelling in singlet oxygen deactivation predicted by instanton theory with branch-point singularities
Authors: Ansari Imaad M. , Heller Eric R. , Trenins George , Richardson Jeremy O.
Published: May 2024

The reactive singlet state of oxygen (O2) can decay to the triplet ground state nonradiatively in the presence of a solvent. There is a controversy about whether tunnelling is involved in this nonadiabatic spin-crossover process. Semiclassical instanton theory provides a reliable and practical computational method for elucidating the reaction mechanism and can account for nuclear quantum effects such as zero-point energy and multidimensional tunnelling. However, the previously developed instanton theory is not directly applicable to this system because of a branch-point singularity which appears in the flux correlation function. Here we derive a new instanton theory for cases dominated by the singularity, leading to a new picture of tunnelling in nonadiabatic processes. Together with multireference electronic-structure theory, this provides a rigorous framework based on first principles that we apply to calculate the decay rate of singlet oxygen in water. The results indicate a new reaction mechanism that is 27 orders of magnitude faster at room temperature than the classical process through the minimum-energy crossing point. We find significant heavy-atom tunnelling contributions as well as a large temperature-dependent H2O/D2O kinetic isotope effect of approximately 20, in excellent agreement with experiment.
Cell of origin epigenetic priming determines susceptibility to Tet2 mutation
Authors: Schiroli Giulia , Kartha Vinay , Duarte Fabiana M. , Kristiansen Trine A. , Mayerhofer Christina , Shrestha Rojesh , Earl Andrew , Hu Yan , Tay Tristan , Rhee Catherine , Buenrostro Jason D. , Scadden David T.
Published: May 2024

Hematopoietic stem cell (HSC) mutations can result in clonal hematopoiesis (CH) with heterogeneous clinical outcomes. Here, we investigate how the cell state preceding Tet2 mutation impacts the pre-malignant phenotype. Using an inducible system for clonal analysis of myeloid progenitors, we find that the epigenetic features of clones at similar differentiation status are highly heterogeneous and functionally respond differently to Tet2 mutation. Cell differentiation stage also influences Tet2 mutation response indicating that the cell of origin’s epigenome modulates clone-specific behaviors in CH. Molecular features associated with higher risk outcomes include Sox4 that sensitizes cells to Tet2 inactivation, inducing dedifferentiation, altered metabolism and increasing the in vivo clonal output of mutant cells, as confirmed in primary GMP and HSC models. Our findings validate the hypothesis that epigenetic features can predispose specific clones for dominance, explaining why identical genetic mutations can result in different phenotypes.
Human CD4-binding site antibody elicited by polyvalent DNA prime-protein boost vaccine neutralizes cross-clade tier-2-HIV strains
Authors: Wang Shixia , Chan Kun-Wei , Wei Danlan , Ma Xiuwen , Liu Shuying , Hu Guangnan , Park Saeyoung , Pan Ruimin , Gu Ying , Nazzari Alexandra F. , Olia Adam S. , Xu Kai , Lin Bob C. , Louder Mark K. , McKee Krisha , Doria-Rose Nicole A. , Montefiori David , Seaman Michael S. , Zhou Tongqing , Kwong Peter D. , Arthos James , Kong Xiang-Peng , Lu Shan
Published: May 2024

The vaccine elicitation of HIV tier-2-neutralization antibodies has been a challenge. Here, we report the isolation and characterization of a CD4-binding site (CD4bs) specific monoclonal antibody, HmAb64, from a human volunteer immunized with a polyvalent DNA prime-protein boost HIV vaccine. HmAb64 is derived from heavy chain variable germline gene IGHV1-18 and light chain germline gene IGKV1-39. It has a third heavy chain complementarity-determining region (CDR H3) of 15 amino acids. On a cross-clade panel of 208 HIV-1 pseudo-virus strains, HmAb64 neutralized 20 (10%), including tier-2 strains from clades B, BC, C, and G. The cryo-EM structure of the antigen-binding fragment of HmAb64 in complex with a CNE40 SOSIP trimer revealed details of its recognition; HmAb64 uses both heavy and light CDR3s to recognize the CD4-binding loop, a critical component of the CD4bs. This study demonstrates that a gp120-based vaccine can elicit antibodies capable of tier 2-HIV neutralization.
Superlative mechanical energy absorbing efficiency discovered through self-driving lab-human partnership
Authors: Snapp Kelsey L. , Verdier Benjamin , Gongora Aldair E. , Silverman Samuel , Adesiji Adedire D. , Morgan Elise F. , Lawton Timothy J. , Whiting Emily , Brown Keith A.
Published: May 2024

Energy absorbing efficiency is a key determinant of a structure’s ability to provide mechanical protection and is defined by the amount of energy that can be absorbed prior to stresses increasing to a level that damages the system to be protected. Here, we explore the energy absorbing efficiency of additively manufactured polymer structures by using a self-driving lab (SDL) to perform >25,000 physical experiments on generalized cylindrical shells. We use a human-SDL collaborative approach where experiments are selected from over trillions of candidates in an 11-dimensional parameter space using Bayesian optimization and then automatically performed while the human team monitors progress to periodically modify aspects of the system. The result of this human-SDL campaign is the discovery of a structure with a 75.2% energy absorbing efficiency and a library of experimental data that reveals transferable principles for designing tough structures.
Explainable chemical artificial intelligence from accurate machine learning of real-space chemical descriptors
Authors: Gallegos Miguel , Vassilev-Galindo Valentin , Poltavsky Igor , Martín Pendás Ángel , Tkatchenko Alexandre
Published: May 2024

Machine-learned computational chemistry has led to a paradoxical situation in which molecular properties can be accurately predicted, but they are difficult to interpret. Explainable AI (XAI) tools can be used to analyze complex models, but they are highly dependent on the AI technique and the origin of the reference data. Alternatively, interpretable real-space tools can be employed directly, but they are often expensive to compute. To address this dilemma between explainability and accuracy, we developed SchNet4AIM, a SchNet-based architecture capable of dealing with local one-body (atomic) and two-body (interatomic) descriptors. The performance of SchNet4AIM is tested by predicting a wide collection of real-space quantities ranging from atomic charges and delocalization indices to pairwise interaction energies. The accuracy and speed of SchNet4AIM breaks the bottleneck that has prevented the use of real-space chemical descriptors in complex systems. We show that the group delocalization indices, arising from our physically rigorous atomistic predictions, provide reliable indicators of supramolecular binding events, thus contributing to the development of Explainable Chemical Artificial Intelligence (XCAI) models.
Priming with LSD1 inhibitors promotes the persistence and antitumor effect of adoptively transferred T cells
Authors: Qiu Fengqi , Jiang Peishan , Zhang Guiheng , An Jie , Ruan Kexin , Lyu Xiaowen , Zhou Jianya , Sheng Wanqiang
Published: May 2024

The antitumor efficacy of adoptively transferred T cells is limited by their poor persistence, in part due to exhaustion, but the underlying mechanisms and potential interventions remain underexplored. Here, we show that targeting histone demethylase LSD1 by chemical inhibitors reshapes the epigenome of in vitro activated and expanded CD8+ T cells, and potentiates their antitumor efficacy. Upon T cell receptor activation and IL-2 signaling, a timely and transient inhibition of LSD1 suffices to improve the memory phenotype of mouse CD8+ T cells, associated with a better ability to produce multiple cytokines, resist exhaustion, and persist in both antigen-dependent and -independent manners after adoptive transfer. Consequently, OT1 cells primed with LSD1 inhibitors demonstrate an enhanced antitumor effect in OVA-expressing solid tumor models implanted in female mice, both as a standalone treatment and in combination with PD-1 blockade. Moreover, priming with LSD1 inhibitors promotes polyfunctionality of human CD8+ T cells, and increases the persistence and antitumor efficacy of human CD19-CAR T cells in both leukemia and solid tumor models. Thus, pharmacological inhibition of LSD1 could be exploited to improve adoptive T cell therapy.
Parental experiences orchestrate locust egg hatching synchrony by regulating nuclear export of precursor miRNA
Authors: Zhu Ya′nan , He Jing , Wang Jiawen , Guo Wei , Liu Hongran , Song Zhuoran , Kang Le
Published: May 2024

Parental experiences can affect the phenotypic plasticity of offspring. In locusts, the population density that adults experience regulates the number and hatching synchrony of their eggs, contributing to locust outbreaks. However, the pathway of signal transmission from parents to offspring remains unclear. Here, we find that transcription factor Forkhead box protein N1 (FOXN1) responds to high population density and activates the polypyrimidine tract-binding protein 1 (Ptbp1) in locusts. FOXN1–PTBP1 serves as an upstream regulator of miR-276, a miRNA to control egg-hatching synchrony. PTBP1 boosts the nucleo-cytoplasmic transport of pre-miR-276 in a “CU motif”-dependent manner, by collaborating with the primary exportin protein exportin 5 (XPO5). Enhanced nuclear export of pre-miR-276 elevates miR-276 expression in terminal oocytes, where FOXN1 activates Ptbp1 and leads to egg-hatching synchrony in response to high population density. Additionally, PTBP1-prompted nuclear export of pre-miR-276 is conserved in insects, implying a ubiquitous mechanism to mediate transgenerational effects.
Pressure stabilizes ferrous iron in bridgmanite under hydrous deep lower mantle conditions
Authors: Zhang Li , Chen Yongjin , Yang Ziqiang , Liu Lu , Yang Yanping , Dalladay-Simpson Philip , Wang Junyue , Mao Ho-kwang
Published: May 2024

Earth’s lower mantle is a potential water reservoir. The physical and chemical properties of the region are in part controlled by the Fe3+/ΣFe ratio and total iron content in bridgmanite. However, the water effect on the chemistry of bridgmanite remains unclear. We carry out laser-heated diamond anvil cell experiments under hydrous conditions and observe dominant Fe2+ in bridgmanite (Mg, Fe)SiO3 above 105 GPa under the normal geotherm conditions corresponding to depth > 2300 km, whereas Fe3+-rich bridgmanite is obtained at lower pressures. We further observe FeO in coexistence with hydrous NiAs-type SiO2 under similar conditions, indicating that the stability of ferrous iron is a combined result of H2O effect and high pressure. The stability of ferrous iron in bridgmanite under hydrous conditions would provide an explanation for the nature of the low-shear-velocity anomalies in the deep lower mantle. In addition, entrainment from a hydrous dense layer may influence mantle plume dynamics and contribute to variations in the redox conditions of the mantle.
Multiregional transcriptomics identifies congruent consensus subtypes with prognostic value beyond tumor heterogeneity of colorectal cancer
Authors: Langerud Jonas , Eilertsen Ina A. , Moosavi Seyed H. , Klokkerud Solveig M. K. , Reims Henrik M. , Backe Ingeborg F. , Hektoen Merete , Sjo Ole H. , Jeanmougin Marine , Tejpar Sabine , Nesbakken Arild , Lothe Ragnhild A. , Sveen Anita
Published: May 2024

Intra-tumor heterogeneity compromises the clinical value of transcriptomic classifications of colorectal cancer. We investigated the prognostic effect of transcriptomic heterogeneity and the potential for classifications less vulnerable to heterogeneity in a single-hospital series of 1093 tumor samples from 692 patients, including multiregional samples from 98 primary tumors and 35 primary-metastasis sets. We show that intra-tumor heterogeneity of the consensus molecular subtypes (CMS) is frequent and has poor-prognostic associations independently of tumor microenvironment markers. Multiregional transcriptomics uncover cancer cell-intrinsic and low-heterogeneity signals that recapitulate the intrinsic CMSs proposed by single-cell sequencing. Further subclassification identifies congruent CMSs that explain a larger proportion of variation in patient survival than intra-tumor heterogeneity. Plasticity is indicated by discordant intrinsic phenotypes of matched primary and metastatic tumors. We conclude that multiregional sampling reconciles the prognostic power of tumor classifications from single-cell and bulk transcriptomics in the context of intra-tumor heterogeneity, and phenotypic plasticity challenges the reconciliation of primary and metastatic subtypes.
Neuroprotective gap-junction-mediated bystander transformations in the adult zebrafish spinal cord after injury
Authors: Pedroni Andrea , Dai Yu-Wen E. , Lafouasse Leslie , Chang Weipang , Srivastava Ipsit , Del Vecchio Lisa , Ampatzis Konstantinos
Published: May 2024

The adult zebrafish spinal cord displays an impressive innate ability to regenerate after traumatic insults, yet the underlying adaptive cellular mechanisms remain elusive. Here, we show that while the cellular and tissue responses after injury are largely conserved among vertebrates, the large-size fast spinal zebrafish motoneurons are remarkably resilient by remaining viable and functional. We also reveal the dynamic changes in motoneuron glutamatergic input, excitability, and calcium signaling, and we underscore the critical role of calretinin (CR) in binding and buffering the intracellular calcium after injury. Importantly, we demonstrate the presence and the dynamics of a neuron-to-neuron bystander neuroprotective biochemical cooperation mediated through gap junction channels. Our findings support a model in which the intimate and dynamic interplay between glutamate signaling, calcium buffering, gap junction channels, and intercellular cooperation upholds cell survival and promotes the initiation of regeneration.
Astrocytic ALKBH5 in stress response contributes to depressive-like behaviors in mice
Authors: Guo Fang , Fan Jun , Liu Jin-Ming , Kong Peng-Li , Ren Jing , Mo Jia-Wen , Lu Cheng-Lin , Zhong Qiu-Ling , Chen Liang-Yu , Jiang Hao-Tian , Zhang Canyuan , Wen You-Lu , Gu Ting-Ting , Li Shu-Ji , Fang Ying-Ying , Pan Bing-Xing , Gao Tian-Ming , Cao Xiong
Published: May 2024

Epigenetic mechanisms bridge genetic and environmental factors that contribute to the pathogenesis of major depression disorder (MDD). However, the cellular specificity and sensitivity of environmental stress on brain epitranscriptomics and its impact on depression remain unclear. Here, we found that ALKBH5, an RNA demethylase of N6-methyladenosine (m6A), was increased in MDD patients’ blood and depression models. ALKBH5 in astrocytes was more sensitive to stress than that in neurons and endothelial cells. Selective deletion of ALKBH5 in astrocytes, but not in neurons and endothelial cells, produced antidepressant-like behaviors. Astrocytic ALKBH5 in the mPFC regulated depression-related behaviors bidirectionally. Meanwhile, ALKBH5 modulated glutamate transporter-1 (GLT-1) m6A modification and increased the expression of GLT-1 in astrocytes. ALKBH5 astrocyte-specific knockout preserved stress-induced disruption of glutamatergic synaptic transmission, neuronal atrophy and defective Ca2+ activity. Moreover, enhanced m6A modification with S-adenosylmethionine (SAMe) produced antidepressant-like effects. Our findings indicate that astrocytic epitranscriptomics contribute to depressive-like behaviors and that astrocytic ALKBH5 may be a therapeutic target for depression.
Physics-informed neural network for lithium-ion battery degradation stable modeling and prognosis
Authors: Wang Fujin , Zhai Zhi , Zhao Zhibin , Di Yi , Chen Xuefeng
Published: May 2024

Accurate state-of-health (SOH) estimation is critical for reliable and safe operation of lithium-ion batteries. However, reliable and stable battery SOH estimation remains challenging due to diverse battery types and operating conditions. In this paper, we propose a physics-informed neural network (PINN) for accurate and stable estimation of battery SOH. Specifically, we model the attributes that affect the battery degradation from the perspective of empirical degradation and state space equations, and utilize neural networks to capture battery degradation dynamics. A general feature extraction method is designed to extract statistical features from a short period of data before the battery is fully charged, enabling our method applicable to different battery types and charge/discharge protocols. Additionally, we generate a comprehensive dataset consisting of 55 lithium-nickel-cobalt-manganese-oxide (NCM) batteries. Combined with three other datasets from different manufacturers, we use a total of 387 batteries with 310,705 samples to validate our method. The mean absolute percentage error (MAPE) is 0.87%. Our proposed PINN has demonstrated remarkable performance in regular experiments, small sample experiments, and transfer experiments when compared to alternative neural networks. This study highlights the promise of physics-informed machine learning for battery degradation modeling and SOH estimation.
OsMAPK6 phosphorylation and CLG1 ubiquitylation of GW6a non-additively enhance rice grain size through stabilization of the substrate
Authors: Bai Chen , Wang Gao-Jie , Feng Xiao-Hui , Gao Qiong , Wang Wei-Qing , Xu Ran , Guo Su-Jie , Shen Shao-Yan , Ma Ming , Lin Wen-Hui , Liu Chun-Ming , Li Yunhai , Song Xian-Jun
Published: May 2024

The chromatin modifier GRAIN WEIGHT 6a (GW6a) enhances rice grain size and yield. However, little is known about its gene network determining grain size. Here, we report that MITOGEN-ACTIVED PROTEIN KINASE 6 (OsMAPK6) and E3 ligase CHANG LI GENG 1 (CLG1) interact with and target GW6a for phosphorylation and ubiquitylation, respectively. Unexpectedly, however, in vitro and in vivo assays reveal that both of the two post-translational modifications stabilize GW6a. Furthermore, we uncover two major GW6a phosphorylation sites (serine142 and threonine186) targeted by OsMAPK6 serving an important role in modulating grain size. In addition, our genetic and molecular results suggest that the OsMAPK6-GW6a and CLG1-GW6a axes are crucial and operate in a non-additive manner to control grain size. Overall, our findings identify a previously unknown mechanism by which phosphorylation and ubiquitylation non-additively stabilize GW6a to enhance grain size, and reveal correlations and interactions of these posttranslational modifications during rice grain development.
Digital non-Foster-inspired electronics for broadband impedance matching
Authors: Yang Xin , Zhang Zhihe , Xu Mengwei , Li Shuxun , Zhang Yuanhong , Zhu Xue-Feng , Ouyang Xiaoping , Alù Andrea
Published: May 2024

Narrow bandwidths are a general bottleneck for applications relying on passive, linear, subwavelength resonators. In the past decades, several efforts have been devoted to overcoming this challenge, broadening the bandwidth of small resonators by the means of analog non-Foster matching networks for radiators, antennas and metamaterials. However, most non-Foster approaches present challenges in terms of tunability, stability and power limitations. Here, by tuning a subwavelength acoustic transducer with digital non-Foster-inspired electronics, we demonstrate five-fold bandwidth enhancement compared to conventional analog non-Foster matching. Long-distance transmission over airborne acoustic channels, with approximately three orders of magnitude increase in power level, validates the performance of the proposed approach. We also demonstrate convenient reconfigurability of our non-Foster-inspired electronics. This implementation provides a viable solution to enhance the bandwidth of sub-wavelength resonance-based systems, extendable to the electromagnetic domain, and enables the practical implementation of airborne and underwater acoustic radiators.
Investigating nutrient biomarkers of healthy brain aging: a multimodal brain imaging study
Authors: Zwilling Christopher E. , Wu Jisheng , Barbey Aron K.
Published: May 2024

The emerging field of Nutritional Cognitive Neuroscience aims to uncover specific foods and nutrients that promote healthy brain aging. Central to this effort is the discovery of nutrient profiles that can be targeted in nutritional interventions designed to promote brain health with respect to multimodal neuroimaging measures of brain structure, function, and metabolism. The present study therefore conducted one of the largest and most comprehensive nutrient biomarker studies examining multimodal neuroimaging measures of brain health within a sample of 100 older adults. To assess brain health, a comprehensive battery of well-established cognitive and brain imaging measures was administered, along with 13 blood-based biomarkers of diet and nutrition. The findings of this study revealed distinct patterns of aging, categorized into two phenotypes of brain health based on hierarchical clustering. One phenotype demonstrated an accelerated rate of aging, while the other exhibited slower-than-expected aging. A t-test analysis of dietary biomarkers that distinguished these phenotypes revealed a nutrient profile with higher concentrations of specific fatty acids, antioxidants, and vitamins. Study participants with this nutrient profile demonstrated better cognitive scores and delayed brain aging, as determined by a t-test of the means. Notably, participant characteristics such as demographics, fitness levels, and anthropometrics did not account for the observed differences in brain aging. Therefore, the nutrient pattern identified by the present study motivates the design of neuroscience-guided dietary interventions to promote healthy brain aging.