bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural basis of p53 inactivation by cavity-creating cancer mutations and its implications for the development of mutant p53 reactivators
Authors: Balourdas Dimitrios-Ilias , Markl Anja M. , Krämer Andreas , Settanni Giovanni , Joerger Andreas C. 
Published: June 2024

SummaryThe cavity-creating p53 cancer mutation Y220C is an ideal paradigm for developing small-molecule drugs based on protein stabilization. Here, we have systematically analyzed the structural and stability effects of all oncogenic Tyr-to-Cys mutations (Y126C, Y163C, Y205C, Y220C, Y234C, and Y236C) in the p53 DNA-binding domain (DBD). They were all highly destabilizing, drastically lowering the melting temperature of the protein by 8–17 °C. In contrast, two non-cancerous mutations, Y103C and Y107C, had only a moderate effect on protein stability. Differential stabilization of the mutants upon treatment with the anticancer agent arsenic trioxide and stibogluconate revealed an interesting proximity effect. Crystallographic studies complemented by MD simulations showed that two of the mutations, Y234C and Y236C, create internal cavities of different size and shape, whereas the others induce unique surface lesions. The mutation-induced pockets in the Y126C and Y205C mutant were, however, relatively small compared with that of the already druggable Y220C mutant. Intriguingly, our structural studies suggest a pronounced plasticity of the mutation-induced pocket in the frequently occurring Y163C mutant, which may be exploited for the development of small-molecule stabilizers. We point out general principles for reactivating thermolabile cancer mutants and highlight special cases where mutant-specific drugs are needed for the pharmacological rescue of p53 function in tumors.
Heat stress induces calcium dyshomeostasis to subsequent cognitive impairment through ERS-mediated apoptosis via SERCA/PERK/eIF2α pathway
Authors: Li Hongxia , Pan Wenlan , Li Chenqi , Cai Mengyu , Shi Wenjing , Ren Zifu , Lu Hongtao , Zhou Qicheng , Shen Hui 
Published: June 2024

AbstractHeat exposure is an environmental stressor that has been associated with cognitive impairment. However, the neural mechanisms that underlie this phenomenon have yet to be extensively investigated. The Morris water maze test was utilized to assess cognitive performance. RNA sequencing was employed to discover the primary regulators and pathological pathways involved in cognitive impairment caused by heat. Before heat exposure in vivo and in vitro, activation of the sarco/endoplasmic reticulum (SR/ER) calcium (Ca2+)-ATPase (SERCA) was achieved by CDN1163. Hematoxylin-Eosin, Nissl staining, calcium imaging, transmission electron microscopy, western blot, and immunofluorescence were utilized to visualize histological changes, intracellular calcium levels, endoplasmic reticulum stress (ERS) markers, apoptosis, and synaptic proteins alterations. Heat stress (HS) significantly induced cognitive decline and neuronal damage in mice. By the transcriptome sequencing between control (n = 5) and heat stress (n = 5) mice in hippocampal tissues, we identified a reduction in the expression of the atp2a gene encoding SERCA, accompanied by a corresponding decrease in its protein level. Consequently, this dysregulation resulted in an excessive accumulation of intracellular calcium ions. Furthermore, HS exposure also activated ERS and apoptosis, as evidenced by the upregulation of p-PERK, p-eIF2α, CHOP, and caspase-3. Consistently, a reduction in postsynaptic density protein 95 (PSD95) and synaptophysin (SYN) expressions indicated modifications in synaptic function. Notably, the impacts on neurons caused by HS were found to be mitigated by CDN1163 treatment both in vivo and in vitro. Additionally, SERCA-mediated ERS-induced apoptosis was attenuated by GSK2606414 treatment via inhibiting PERK-eIF2α-CHOP axis that not only curtailed the level of caspase-3 but also elevated the levels of PSD95 and SYN. These findings highlight the significant impact of heat stress on cognitive impairment, and further elucidate the underlying mechanism involving SERCA/PERK/eIF2α pathway.
Novel meriolin derivatives potently inhibit cell cycle progression and transcription in leukemia and lymphoma cells via inhibition of cyclin-dependent kinases (CDKs)
Authors: Schmitt Laura , Hoppe Julia , Cea-Medina Pablo , Bruch Peter-Martin , Krings Karina S. , Lechtenberg Ilka , Drießen Daniel , Peter Christoph , Bhatia Sanil , Dietrich Sascha , Stork Björn , Fritz Gerhard , Gohlke Holger , Müller Thomas J. J. , Wesselborg Sebastian 
Published: June 2024

AbstractA key feature of cancer is the disruption of cell cycle regulation, which is characterized by the selective and abnormal activation of cyclin-dependent kinases (CDKs). Consequently, targeting CDKs via meriolins represents an attractive therapeutic approach for cancer therapy. Meriolins represent a semisynthetic compound class derived from meridianins and variolins with a known CDK inhibitory potential. Here, we analyzed the two novel derivatives meriolin 16 and meriolin 36 in comparison to other potent CDK inhibitors and could show that they displayed a high cytotoxic potential in different lymphoma and leukemia cell lines as well as in primary patient-derived lymphoma and leukemia cells. In a kinome screen, we showed that meriolin 16 and 36 prevalently inhibited most of the CDKs (such as CDK1, 2, 3, 5, 7, 8, 9, 12, 13, 16, 17, 18, 19, 20). In drug-to-target modeling studies, we predicted a common binding mode of meriolin 16 and 36 to the ATP-pocket of CDK2 and an additional flipped binding for meriolin 36. We could show that cell cycle progression and proliferation were blocked by abolishing phosphorylation of retinoblastoma protein (a major target of CDK2) at Ser612 and Thr82. Moreover, meriolin 16 prevented the CDK9-mediated phosphorylation of RNA polymerase II at Ser2 which is crucial for transcription initiation. This renders both meriolin derivatives as valuable anticancer drugs as they target three different Achilles’ heels of the tumor: (1) inhibition of cell cycle progression and proliferation, (2) prevention of transcription, and (3) induction of cell death.
Release of CD36-associated cell-free mitochondrial DNA and RNA as a hallmark of space environment response
Authors: Husna Nailil , Aiba Tatsuya , Fujita Shin-Ichiro , Saito Yoshika , Shiba Dai , Kudo Takashi , Takahashi Satoru , Furukawa Satoshi , Muratani Masafumi 
Published: June 2024

AbstractA detailed understanding of how spaceflight affects human health is essential for long-term space exploration. Liquid biopsies allow for minimally-invasive multi-omics assessments that can resolve the molecular heterogeneity of internal tissues. Here, we report initial results from the JAXA Cell-Free Epigenome Study, a liquid biopsy study with six astronauts who resided on the International Space Station (ISS) for more than 120 days. Analysis of plasma cell-free RNA (cfRNA) collected before, during, and after spaceflight confirms previously reported mitochondrial dysregulation in space. Screening with 361 cell surface marker antibodies identifies a mitochondrial DNA-enriched fraction associated with the scavenger receptor CD36. RNA-sequencing of the CD36 fraction reveals tissue-enriched RNA species, suggesting the plasma mitochondrial components originated from various tissues. We compare our plasma cfRNA data to mouse plasma cfRNA data from a previous JAXA mission, which had used on-board artificial gravity, and discover a link between microgravity and the observed mitochondrial responses.
Astronaut omics and the impact of space on the human body at scale
Authors: Rutter Lindsay A. , Cope Henry , MacKay Matthew J. , Herranz Raúl , Das Saswati , Ponomarev Sergey A. , Costes Sylvain V. , Paul Amber M. , Barker Richard , Taylor Deanne M. , Bezdan Daniela , Szewczyk Nathaniel J. , Muratani Masafumi , Mason Christopher E. , Giacomello Stefania 
Published: June 2024

AbstractFuture multi-year crewed planetary missions will motivate advances in aerospace nutrition and telehealth. On Earth, the Human Cell Atlas project aims to spatially map all cell types in the human body. Here, we propose that a parallel Human Cell Space Atlas could serve as an openly available, global resource for space life science research. As humanity becomes increasingly spacefaring, high-resolution omics on orbit could permit an advent of precision spaceflight healthcare. Alongside the scientific potential, we consider the complex ethical, cultural, and legal challenges intrinsic to the human space omics discipline, and how philosophical frameworks may benefit from international perspectives.
Studying phonon coherence with a quantum sensor
Authors: Cleland Agnetta Y. , Wollack E. Alex , Safavi-Naeini Amir H. 
Published: June 2024

AbstractNanomechanical oscillators offer numerous advantages for quantum technologies. Their integration with superconducting qubits shows promise for hardware-efficient quantum error-correction protocols involving superpositions of mechanical coherent states. Limitations of this approach include mechanical decoherence processes, particularly two-level system (TLS) defects, which have been widely studied using classical fields and detectors. In this manuscript, we use a superconducting qubit as a quantum sensor to perform phonon number-resolved measurements on a piezoelectrically coupled phononic crystal cavity. This enables a high-resolution study of mechanical dissipation and dephasing in coherent states of variable size ($$\bar{n}\simeq 1-10$$

n

¯

≃
1
−
10
phonons). We observe nonexponential relaxation and state size-dependent reduction of the dephasing rate, which we attribute to TLS. Using a numerical model, we reproduce the dissipation signatures (and to a lesser extent, the dephasing signatures) via emission into a small ensemble (N = 5) of rapidly dephasing TLS. Our findings comprise a detailed examination of TLS-induced phonon decoherence in the quantum regime.
Observation of a spontaneous anomalous Hall response in the Mn5Si3 d-wave altermagnet candidate
Authors: Reichlova Helena , Lopes Seeger Rafael , González-Hernández Rafael , Kounta Ismaila , Schlitz Richard , Kriegner Dominik , Ritzinger Philipp , Lammel Michaela , Leiviskä Miina , Birk Hellenes Anna , Olejník Kamil , Petřiček Vaclav , Doležal Petr , Horak Lukas , Schmoranzerova Eva , Badura Antonín , Bertaina Sylvain , Thomas Andy , Baltz Vincent , Michez Lisa , Sinova Jairo , Goennenwein Sebastian T. B. , Jungwirth Tomáš , Šmejkal Libor 
Published: June 2024

AbstractPhases with spontaneous time-reversal ($${{{{{{{\mathcal{T}}}}}}}}$$
T
) symmetry breaking are sought after for their anomalous physical properties, low-dissipation electronic and spin responses, and information-technology applications. Recently predicted altermagnetic phase features an unconventional and attractive combination of a strong $${{{{{{{\mathcal{T}}}}}}}}$$
T
-symmetry breaking in the electronic structure and a zero or only weak-relativistic magnetization. In this work, we experimentally observe the anomalous Hall effect, a prominent representative of the $${{{{{{{\mathcal{T}}}}}}}}$$
T
-symmetry breaking responses, in the absence of an external magnetic field in epitaxial thin-film Mn5Si3 with a vanishingly small net magnetic moment. By symmetry analysis and first-principles calculations we demonstrate that the unconventional d-wave altermagnetic phase is consistent with the experimental structural and magnetic characterization of the Mn5Si3 epilayers, and that the theoretical anomalous Hall conductivity generated by the phase is sizable, in agreement with experiment. An analogy with unconventional d-wave superconductivity suggests that our identification of a candidate of unconventional d-wave altermagnetism points towards a new chapter of research and applications of magnetic phases.
Mapping the landscape of histomorphological cancer phenotypes using self-supervised learning on unannotated pathology slides
Authors: Claudio Quiros Adalberto , Coudray Nicolas , Yeaton Anna , Yang Xinyu , Liu Bojing , Le Hortense , Chiriboga Luis , Karimkhan Afreen , Narula Navneet , Moore David A. , Park Christopher Y. , Pass Harvey , Moreira Andre L. , Le Quesne John , Tsirigos Aristotelis , Yuan Ke 
Published: June 2024

AbstractCancer diagnosis and management depend upon the extraction of complex information from microscopy images by pathologists, which requires time-consuming expert interpretation prone to human bias. Supervised deep learning approaches have proven powerful, but are inherently limited by the cost and quality of annotations used for training. Therefore, we present Histomorphological Phenotype Learning, a self-supervised methodology requiring no labels and operating via the automatic discovery of discriminatory features in image tiles. Tiles are grouped into morphologically similar clusters which constitute an atlas of histomorphological phenotypes (HP-Atlas), revealing trajectories from benign to malignant tissue via inflammatory and reactive phenotypes. These clusters have distinct features which can be identified using orthogonal methods, linking histologic, molecular and clinical phenotypes. Applied to lung cancer, we show that they align closely with patient survival, with histopathologically recognised tumor types and growth patterns, and with transcriptomic measures of immunophenotype. These properties are maintained in a multi-cancer study.
Ultra-high spin emission from antiferromagnetic FeRh
Authors: Hamara Dominik , Strungaru Mara , Massey Jamie R. , Remy Quentin , Chen Xin , Nava Antonio Guillermo , Alves Santos Obed , Hehn Michel , Evans Richard F. L. , Chantrell Roy W. , Mangin Stéphane , Ducati Caterina , Marrows Christopher H. , Barker Joseph , Ciccarelli Chiara 
Published: June 2024

AbstractAn antiferromagnet emits spin currents when time-reversal symmetry is broken. This is typically achieved by applying an external magnetic field below and above the spin-flop transition or by optical pumping. In this work we apply optical pump-THz emission spectroscopy to study picosecond spin pumping from metallic FeRh as a function of temperature. Intriguingly we find that in the low-temperature antiferromagnetic phase the laser pulse induces a large and coherent spin pumping, while not crossing into the ferromagnetic phase. With temperature and magnetic field dependent measurements combined with atomistic spin dynamics simulations we show that the antiferromagnetic spin-lattice is destabilised by the combined action of optical pumping and picosecond spin-biasing by the conduction electron population, which results in spin accumulation. We propose that the amplitude of the effect is inherent to the nature of FeRh, particularly the Rh atoms and their high spin susceptibility. We believe that the principles shown here could be used to produce more effective spin current emitters. Our results also corroborate the work of others showing that the magnetic phase transition begins on a very fast picosecond timescale, but this timescale is often hidden by measurements which are confounded by the slower domain dynamics.
Spatially resolved multiomics on the neuronal effects induced by spaceflight in mice
Authors: Masarapu Yuvarani , Cekanaviciute Egle , Andrusivova Zaneta , Westholm Jakub O. , Björklund Åsa , Fallegger Robin , Badia-i-Mompel Pau , Boyko Valery , Vasisht Shubha , Saravia-Butler Amanda , Gebre Samrawit , Lázár Enikő , Graziano Marta , Frapard Solène , Hinshaw Robert G. , Bergmann Olaf , Taylor Deanne M. , Wallace Douglas C. , Sylvén Christer , Meletis Konstantinos , Saez-Rodriguez Julio , Galazka Jonathan M. , Costes Sylvain V. , Giacomello Stefania 
Published: June 2024

AbstractImpairment of the central nervous system (CNS) poses a significant health risk for astronauts during long-duration space missions. In this study, we employed an innovative approach by integrating single-cell multiomics (transcriptomics and chromatin accessibility) with spatial transcriptomics to elucidate the impact of spaceflight on the mouse brain in female mice. Our comparative analysis between ground control and spaceflight-exposed animals revealed significant alterations in essential brain processes including neurogenesis, synaptogenesis and synaptic transmission, particularly affecting the cortex, hippocampus, striatum and neuroendocrine structures. Additionally, we observed astrocyte activation and signs of immune dysfunction. At the pathway level, some spaceflight-induced changes in the brain exhibit similarities with neurodegenerative disorders, marked by oxidative stress and protein misfolding. Our integrated spatial multiomics approach serves as a stepping stone towards understanding spaceflight-induced CNS impairments at the level of individual brain regions and cell types, and provides a basis for comparison in future spaceflight studies. For broader scientific impact, all datasets from this study are available through an interactive data portal, as well as the National Aeronautics and Space Administration (NASA) Open Science Data Repository (OSDR).
Sopa: a technology-invariant pipeline for analyses of image-based spatial omics
Authors: Blampey Quentin , Mulder Kevin , Gardet Margaux , Christodoulidis Stergios , Dutertre Charles-Antoine , André Fabrice , Ginhoux Florent , Cournède Paul-Henry 
Published: June 2024

AbstractSpatial omics data allow in-depth analysis of tissue architectures, opening new opportunities for biological discovery. In particular, imaging techniques offer single-cell resolutions, providing essential insights into cellular organizations and dynamics. Yet, the complexity of such data presents analytical challenges and demands substantial computing resources. Moreover, the proliferation of diverse spatial omics technologies, such as Xenium, MERSCOPE, CosMX in spatial-transcriptomics, and MACSima and PhenoCycler in multiplex imaging, hinders the generality of existing tools. We introduce Sopa (https://github.com/gustaveroussy/sopa), a technology-invariant, memory-efficient pipeline with a unified visualizer for all image-based spatial omics. Built upon the universal SpatialData framework, Sopa optimizes tasks like segmentation, transcript/channel aggregation, annotation, and geometric/spatial analysis. Its output includes user-friendly web reports and visualizer files, as well as comprehensive data files for in-depth analysis. Overall, Sopa represents a significant step toward unifying spatial data analysis, enabling a more comprehensive understanding of cellular interactions and tissue organization in biological systems.
Optimizing the design of spatial genomic studies
Authors: Jones Andrew , Cai Diana , Li Didong , Engelhardt Barbara E. 
Published: June 2024

AbstractSpatial genomic technologies characterize the relationship between the structural organization of cells and their cellular state. Despite the availability of various spatial transcriptomic and proteomic profiling platforms, these experiments remain costly and labor-intensive. Traditionally, tissue slicing for spatial sequencing involves parallel axis-aligned sections, often yielding redundant or correlated information. We propose structured batch experimental design, a method that improves the cost efficiency of spatial genomics experiments by profiling tissue slices that are maximally informative, while recognizing the destructive nature of the process. Applied to two spatial genomics studies—one to construct a spatially-resolved genomic atlas of a tissue and another to localize a region of interest in a tissue, such as a tumor—our approach collects more informative samples using fewer slices compared to traditional slicing strategies. This methodology offers a foundation for developing robust and cost-efficient design strategies, allowing spatial genomics studies to be deployed by smaller, resource-constrained labs.
Strength dependency of frequency–magnitude distribution in earthquakes and implications for stress state criticality
Authors: Matsumoto Satoshi , Iio Yoshihisa , Sakai Shinichi , Kato Aitaro 
Published: June 2024

AbstractEarthquake size distribution is characterized by the “b-value” of the power law decay, which exhibits spatiotemporal variations. These variations are sometimes evident before a large earthquake. Understanding spatiotemporal variations is key to developing a model for large-earthquake generation. Previous studies have shown that changes in the b-value are caused by the tectonic stress regime. Furthermore, lab experiments have demonstrated the b-value dependency of acoustic emissions on the criticality of the failure condition. However, the factors controlling the b-values during natural seismic activity are unclear. In this study, changes in the b-value in small earthquake sequences are investigated, focusing on failure criticality. Based on our high-precision focal mechanism dataset, we conclude that the b-value decreases as it nears a critical failure condition, providing a physical explanation for the reduction in b-value before a major earthquake. Our findings elucidate fault failure models, facilitating improvement in earthquake alerts and disaster mitigation.
An antiferromagnetic spin phase change memory
Authors: Yan Han , Mao Hongye , Qin Peixin , Wang Jinhua , Liang Haidong , Zhou Xiaorong , Wang Xiaoning , Chen Hongyu , Meng Ziang , Liu Li , Zhao Guojian , Duan Zhiyuan , Zhu Zengwei , Fang Bin , Zeng Zhongming , Bettiol Andrew A. , Zhang Qinghua , Tang Peizhe , Jiang Chengbao , Liu Zhiqi 
Published: June 2024

AbstractThe electrical outputs of single-layer antiferromagnetic memory devices relying on the anisotropic magnetoresistance effect are typically rather small at room temperature. Here we report a new type of antiferromagnetic memory based on the spin phase change in a Mn-Ir binary intermetallic thin film at a composition within the phase boundary between its collinear and noncollinear phases. Via a small piezoelectric strain, the spin structure of this composition-boundary metal is reversibly interconverted, leading to a large nonvolatile room-temperature resistance modulation that is two orders of magnitude greater than the anisotropic magnetoresistance effect for a metal, mimicking the well-established phase change memory from a quantum spin degree of freedom. In addition, this antiferromagnetic spin phase change memory exhibits remarkable time and temperature stabilities, and is robust in a magnetic field high up to 60 T.
An optical study on the enhanced light trapping performance of the perovskite solar cell using nanocone structure
Authors: Gu Xiaowei , Li Zeyu , E Rusli , Xu Xiaoxiao , Tao Zhi , Pan Jiangyong , Yu Xuechao , Yu Linwei , Mokkapati Sudha 
Published: June 2024

AbstractPhoton management strategies are crucial to improve the efficiency of perovskite thin film (PTF) solar cell. In this work, a nano-cone (NC) based 2D photonic nanostructure is designed and simulated aiming at achieve superior light trapping performance by introducing strong light scattering and interferences within perovskite active layer. Compared to the planar PTF solar cell, the NC nanostructured device with 45 degrees half apex angle obtains highest short-circuit current density, which improved over 20% from 15.00 mA/cm2 to 18.09 mA/cm2. This work offers an alternative design towards effective light trapping performance using 2D photonic nanostructure for PTF solar cell and could potentially be adopted as the nano-structuring strategy for the future perovskite solar cell industry.