This Letter presents a novel cosmic-ray scattering experiment employing a resistive plate chamber muon tomography system. By introducing the scattering angle between incident and outgoing cosmic-ray tracks as a key observable, this approach enables simultaneous studies of secondary cosmic-ray composition and searching for new physics. During a 63-day campaign, 1.18 million cosmic ray scattering events were recorded and analyzed. By performing combined template fits to the observed angular distribution, particle abundances are measured-for example, resolving the electron component at ∼2% precision. Furthermore, constraints are established on elastic muon-dark matter (DM) scattering cross sections for muonphilic dark matter. At the 95% confidence level, the limit reaches 1.61×10^{-17}  cm^{2} for 1 GeV slow DM, demonstrating the sensitivity limit to light muon-coupled slow DM, in scenarios where a strongly interacting dark matter component is captured and thermalized within Earth, leading to large surface densities.
We report a measurement of the cosmic ray helium energy spectrum in the energy interval 0.16-13 PeV, derived by subtracting the proton spectrum from the light component (proton and helium) spectrum obtained with observations made by the Large High Altitude Air Shower Observatory (LHAASO) under a consistent energy scale. The helium spectrum shows a significant hardening centered at E≃1.1  PeV, followed by a softening at ∼7  PeV, indicating the appearance of a helium "knee." Comparing the proton and helium spectra in the LHAASO energy range reveals some remarkable facts. In the lower part of this range, in contrast to the behavior at lower energies, the helium spectrum is significantly softer than the proton spectrum. This results in protons overtaking helium nuclei and becoming the largest cosmic ray component at E≃0.7  PeV. A second crossing of the two spectra is observed at E≃5  PeV, above the proton knee, when helium nuclei overtake protons to become the largest cosmic ray component again. These results have important implications for our understanding of the Galactic cosmic ray sources.
In most particle acceleration or propagation theories, the characteristic features of the cosmic ray spectra due to acceleration limits or propagation phase changes are charge-dependent1-4. Alternatively, the interaction scenario would expect mass-dependent spectral features in general. The observational verification of which relation takes effect in nature is still lacking because of the difficulty in measuring the spectra of individual particles up to very high energies. Here we report direct measurements of the carbon, oxygen and iron spectra from about 20 gigavolts to around 100 teravolts (60 teravolts for iron) with 9 years of on-orbit data collected by the Dark Matter Particle Explorer. Distinct spectral softenings have been directly detected in these spectra for the first time, to our knowledge. Combined with the updated proton and helium spectra, the spectral softening appears universally at a rigidity of about 15 teravolts. A nuclei-mass-dependent softening is rejected at a confidence level of >99.999%. Possible interpretations of these results, including a nearby cosmic ray source5-7 and other models such as the propagation effect8, are discussed.
We present the first experimental evidence for in-ice Askaryan radiation-coherent charge-excess radio emission-from high-energy particle cascades developing in the Antarctic ice sheet. In 208 days of data recorded with the phased array instrument of the Askaryan Radio Array, a previous analysis has incidentally identified 13 events with impulsive radio frequency signals originating from below the ice surface. We here present a detailed reanalysis of these events. The observed event rate, radiation arrival directions, signal shape, spectral content, and electric field polarization are consistent with in-ice Askaryan radiation from cosmic ray air shower cores impacting the ice sheet. For the brightest events, the angular radiation pattern favors an extended cascadelike emitter over a pointlike source. An origin from the geomagnetic separation of charges in cosmic ray air showers is disfavored by the arrival directions and polarization. Considering the arrival angles, timing properties, and impulsive nature of the passing events, the event rate is inconsistent with the estimation of the combined background from thermal noise events and on-surface events at the level of 5.1σ.
Background: Spaceflight stressors, including microgravity-induced unloading and galactic cosmic radiation (GCR), acutely disrupt mitochondrial function and contribute to skeletal muscle atrophy. The long-term remodeling of skeletal muscle following combined unloading and radiation exposure remains poorly understood. We investigated protein abundance changes 9-months post-exposure to combined unloading and radiation exposure. Methods: Female, 6-month old, C57Bl/6J mice underwent 5 days of hindlimb unloading (HU) or weight-bearing (WB) conditions, followed by 0Gy, 0.5Gy, or 1.5Gy of simulated GCR exposure using the simplified 5-ion beam exposure (simGCRsim) (n=5/group). The gastrocnemius muscle was collected after 9-months of WB and analyzed by data-independent acquisition mass spectrometry. Differentially abundant proteins were identified and evaluated using pathway enrichment analyses. Results: WB mice exposed to 0.5Gy exhibited increased abundance of electron transport system proteins and mitochondrial transport proteins, suggesting increased mitochondrial activity relative to control mice. HU mice exposed to 0.5Gy displayed decreased glycolytic proteins, increased reliance on oxidative pathways, and reduced antioxidant proteins (glutaredoxins, peroxiredoxin) compared to WB0.5. In HU mice, a higher radiation dose (HU1.5 vs HU0.5) led to the downregulation of 26S proteasome subunits and the upregulation of peroxisomal antioxidant, tricarboxylic acid cycle, and β-oxidation proteins, indicating dose-dependent mitochondrial adaptations. Conclusion: Long-term muscular remodeling after simGCRsim exposure is influenced by both muscle loading status and radiation dose, with prolonged shifts toward oxidative metabolism and altered protein quality control persisting months after exposure. These findings provide new insights into skeletal muscle adaptation to spaceflight stressors and have important implications for astronaut health during and after long-duration missions.
In regions of the Solar System distant from planetary magnetic fields, galactic cosmic rays (GCRs) have generally been assumed to be uniformly distributed over the Earth-Moon distance. However, our analysis of data from the LND (Lunar Lander Neutron and Dosimetry) experiment onboard the Chang'E-4 lander revealed a region of reduced GCR flux in the prenoon sector of the lunar orbit. Further investigation suggests the presence of an energetic particle cavity, formed by Earth's magnetic field acting as an obstacle to GCR propagation. This cavity indicates that the influence of Earth's magnetic field within the space environment extends unexpectedly up to and far beyond the lunar orbit. This finding offers the potential to avoid high radiation levels during future lunar exploration and deep-space missions.
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Spaceflight environments pose unique physiological challenges due to al-tered gravity and radiation exposure. To investigate how these abiotic stressors interact with viral infections, we ana-lyzed the transcriptomic response of Caenorhabditis elegans acclimated to low-shear mod-eled microgravity (LSMMG) and radiologically shielded environments (RSE), after being infected with Orsay virus (OrV). Using RNA-sequencing, we characterized gene expres-sion profiles across both single and combined stress conditions. Both LSMMG and RSE elicited distinct stress responses, including the modula-tion of oxidative stress, lipid metabolism, and immune pathways. The OrV infection alone induced robust transcriptional changes, but its impact was significantly attenuated when combined with abiotic stress, suggesting an antagonistic interaction. Notably, proviral genes such as drl-1, fat-7, and hipr-1 were downregulated under RSE and LSMMG condi-tions, potentially impairing the viral replication. Gene ontology analyses revealed enrich-ment in immune effectors, RNA metabolism, and proteostasis-related pathways, particular-ly under RSE. Viral load and RNA2/RNA1 ratios were reduced in both stress conditions, indicating a shift in viral replication dynamics. Moreover, genomic diversity and defective viral genome formation were affected differentially, with stress conditions leading to in-creased genetic diversity and structural variation. These findings suggest that acclimation to simulated off-Earth conditions primes the host for a dampened response to acute viral infections, potentially through re-source reallocation and transcriptional attenuation. This study provides transcriptomic insight into viral infections under space-relevant conditions, highlighting complex interac-tions between stressors and their implications for host-pathogen dynamics in extraterres-trial environments.
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Stellar explosions seemingly replayed as gravity bends their light could resolve a dispute over the speed of the expanding universe.
We delineate the maximal parameter space of sterile neutrino dark matter in the presence of lepton-flavor asymmetries. We focus on large flavor asymmetries with vanishing total lepton asymmetry, which are washed out by neutrino oscillations at MeV temperatures and hence are consistent with big bang nucleosynthesis and cosmic microwave background constraints. We derive a semiclassical Boltzmann equation for sterile neutrinos applicable in this regime and validate it against quantum kinetic equations. For sterile neutrino masses up to 60 keV, the viable range of mixing angles extends by up to 2 orders of magnitude, with broad prospects for tests in forthcoming x-ray, cosmic microwave background, and structure formation observations. We also release a public framework to compute the production of sterile neutrinos, and in particular their momentum distribution, enabling dedicated structure formation analyses.
Cosmic voids, the large underdense regions of our Universe, have emerged over the past decade as powerful cosmological laboratories: their simple dynamics, sensitivity to local gravitational effects and cosmic expansion, and ability to span large volumes, make them uniquely suited to test fundamental physics. Fueled by advances in theory, simulations, and observations, void science has matured into a precision tool for constraining the parameters of the standard cosmological model and its possible extensions. In this review, we provide a comprehensive description of the statistical tools developed to characterize voids, the theoretical models that link them to cosmological parameters, and the methodologies used to extract information from survey data. We highlight the growing synergy between void-based observables and other cosmological probes, and showcase the increasingly stringent constraints derived from voids measured from current and expected for upcoming surveys' data. With the advent of the next generation of galaxy surveys, voids are poised to play a central role in the future of cosmology, turning what was once regarded as emptiness into one of the most promising frontiers of fundamental science.
Cutaneous adnexal carcinomas (CACs) comprise a diverse group of malignant tumors that show morphological differentiation toward one of the four main adnexal structures in normal skin: hair follicles, sebaceous glands, sweat-apocrine glands, and sweat-eccrine glands. These tumors can arise sporadically or may be associated with rare genetic syndromes. A total of 276 CACs cases underwent hybrid capture-based comprehensive genomic profiling (CGP) to assess all classes of genomic alterations (GA). Sequencing data were used to determine microsatellite instability (MSI) status, tumor mutational burden (TMB), genomic loss of heterozygosity (gLOH), genomic ancestry, and COSMIC mutational signatures. PD-L1 expression was evaluated by immunohistochemistry (TPS; Dako 22C3). Statistical analyses were performed using Fisher's exact test, with false discovery rate correction via the Benjamini-Hochberg method. Sequencing was performed on primary cutaneous tumors in 131 cases (47.4%) and on local recurrence or metastatic site biopsies in 145 cases (52.5%). Across all groups, there was a male predominance (64-81%) and similar mean ages (59-63 years), with apocrine (APO) tumors occurring in older patients than eccrine (ECC) tumors (72 vs. 62 years; p = 0.001). Histologically, 173 tumors (62.7%) were sweat gland-derived (SWT), 55 (19.9%) sebaceous gland-derived (SEB), 14 (5.1%) hair follicle-derived (HRF), and 34 (12.3%) unclassified (UNK). Among SWT tumors, 150 (86.7%) were eccrine and 23 (13.3%) apocrine. SWT tumors included digital papillary adenocarcinomas (DPA, 6.9%), mucinous carcinomas (MC, 6.3%), porocarcinomas (POR, 11.0%), spiradenocarcinomas (SPR, 8.1%), syringoadenocarcinomas (SRNG, 5.8%), and 77 (44.5%) unclassified cases. The number of GA per tumor was highest in SEB compared with SWT tumors (7.9 vs. 4.9; p = 0.005) and lowest in DPA (2.1 vs. 5.0 in non-DPA; p = 0.03). No differences in ancestry distribution were observed. Compared with SWT tumors, SEB tumors exhibited higher frequencies of RB1 (38.2% vs. 8.1%; p < 0.0001) and TP53 alterations (76.4% vs. 43.4%; p = 0.0002), suggesting potential neuroendocrine differentiation. MC tumors showed significantly higher PTCH1 alterations than non-MC tumors (36.4% vs. 1.8%; p = 0.044). MSI-high status was most frequent in SEB tumors compared with all other groups (15.7% vs. 1.2%; p = 0.005), and gLOH > 16% was also more common in SEB than SWT tumors (19.6% vs. 7.2%; p = 0.081). The MMR signature occurred more frequently in SEB than SWT tumors (32.0% vs. 2.1%; p = 0.005). Mean TMB was elevated across most CACs types, ranging from 10.4 mutations/Mb in HRF to 38.8 mutations/Mb in MC, with the exceptions of APO (2.7 mut/Mb; p = 0.001) and DPA (1.4 mut/Mb; p = 0.003). PD-L1 expression was generally low and did not differ significantly between SWT and SEB tumors (37.0% vs. 33.3%; NS). Given the limited data on CAC treatment, this study provides a catalog of commonly observed GA. SEB tumors exhibited the highest frequency of genomic alterations. Prospective clinical trials are needed to determine the prognostic and predictive value of CAC-specific biomarkers for immune checkpoint inhibitor (ICI) response, which is essential for integrating novel therapies into the evolving treatment landscape.
Demonstrating pharmacological effects in early-phase oncology clinical trials remains challenging, largely due to the lack of robust pharmacodynamic markers. Lipopolysaccharide (LPS) is used as an immune challenge agent in healthy participants to study drugs for autoimmune conditions. We hypothesized that the intravenous LPS challenge model could be implemented in oncology drug studies in healthy participants to evaluate in vivo pharmacodynamics of new drugs. This open-label study included 13 healthy males who received a single intravenous dose of 1 or 2 ng/kg LPS. Blood and bone marrow samples were collected pre- and post-LPS for bulk RNA sequencing, multiplex cytokine measurements, immunophenotyping, and immunohistochemistry of bone marrow biopsies. Differentially expressed genes were integrated with the OpenTargets Platform and the COSMIC database to assess their tractability and relation to cancer hallmarks. The LPS challenge and bone marrow sampling were safe and well tolerated. In peripheral blood, LPS induced a rapid, transient inflammatory response, with myeloid cell activation and enrichment of inflammation-related pathways. Conversely, bone marrow showed an attenuated cellular response and activation of hematopoietic and cell cycle-related transcriptional programs. We identified 91 LPS-induced oncology-relevant targets in blood and 24 targets in bone marrow. The oncogenic transcription factor MYC was upregulated in the bone marrow, which was confirmed at the protein level by a dose-dependent increase in c-Myc expression. Our findings highlight the potential of immune challenges in healthy participants to pharmacodynamically profile novel oncology agents, with the aim of generating early pharmacological data ahead of pivotal clinical trials in cancer patients.
Matter in the early Universe was nearly uniform, and galaxies emerged through the gravitational growth of small primordial density fluctuations. Astrophysics has been trying to unveil the complex physical phenomena that have caused the formation and evolution of galaxies throughout the 13-billion-year history of the Universe using the first principles of physics. However, since present-day astrophysical big data contain more than 100 explanatory variables, such a conventional methodology faces limits in dealing with such data. We, instead, elucidate the physics of galaxy evolution by applying manifold learning, one of the latest methods of data science, to a feature space spanned by galaxy luminosities and cosmic time. We discovered a low-dimensional nonlinear structure of data points in this space, referred to as the galaxy manifold. We found that the galaxy evolution in the ultraviolet-optical-near-infrared luminosity space is well described by two parameters, star formation and stellar mass evolution, on the manifold. We also discuss a possible way to connect the manifold coordinates to physical quantities.
We investigate proteinoid systems formed on olivine mineral substrates, focusing on self-organization, electrochemical properties, and information-processing capacity. Olivine's ubiquity in meteorites, planetary surfaces, and protoplanetary disks makes it a geochemically relevant template for prebiotic chemistry across cosmic environments. Glu:Phe:Asp proteinoids synthesized in olivine-rich acidic solutions─mimicking early Earth hydrothermal conditions─were characterized using scanning electron microscopy (SEM), electrochemical impedance spectroscopy (EIS), cyclic voltammetry (CV), and differential pulse voltammetry (DPV). The proteinoids self-assembled into spherical microspheres (2-15 μm in diameter), dendritic networks, and complex mineral-templated architectures. Budding-like reproduction and neuron-like branching morphologies emerged spontaneously. Electrochemical analysis revealed stable impedance profiles that, when thresholded, enabled Boolean logic operations (AND, OR, XOR, and NOT). Galvanostatic measurements showed spontaneous electrical oscillations with burst dynamics, heavy-tailed distributions, and non-Poissonian statistics, which are signatures of complex adaptive systems. Olivine substrates stabilized the electrical behavior while preserving computational functionality. These findings suggest that proteinoid-olivine hybrids can perform unconventional computing tasks while simultaneously exhibiting biomimetic self-assembly and primitive reproductive behaviors. This work illuminates mineral-organic interactions relevant to both terrestrial and extraterrestrial prebiotic chemistry and provides a foundation for bioinspired computing systems that merge organic self-organization with mineral-based information processing.
Ice grains emitted by the Saturnian moon Enceladus were sampled by Cassini's Cosmic Dust Analyser (CDA) using impact ionization mass spectrometry. CDA revealed that Enceladus hosts a rich organic and inorganic chemical inventory in its subsurface ocean, hinting at its potential habitability. Analysis of fragmentation patterns with laser desorption experiments for the interpretation of CDA data has been essential; however, theoretical insights regarding both fragmentation and ionization processes are often missing. Here, we use density functional theory methods to investigate the energies for dissociation channels of phenol, a model aromatic compound for the features observed by CDA. The fragmentation channels are compared to experimental spectra obtained by using laser-induced liquid beam ion desorption (LILBID) mass spectrometry, an analogue for ice impact mass spectra. Our findings suggest that protonation is the dominant mechanism of ionization, that dissociation from the radical cation and neutral phenol molecule is limited, and that multiple isomers of the protonated molecule act as starting points for dissociation. The highest-intensity organic fragments observed in the LILBID spectrumarising from the losses of CO, [M + H-CO]+, and water, [M + H-H2O]+are found to be both thermodynamically and kinetically accessible. We examined water-molecule interactions during the initial production of the protonated molecule. The presence of water significantly influences the preferred site of protonation and causes variation in the relative energy ordering of the protomers. This work builds toward a computational model of ice grain impact ionization mass spectrometry, relevant for missions such as Europa Clipper and ESA's L4 mission to Enceladus.