Browse Articles

Apolipoprotein M attenuates age-related macular degeneration phenotypes via sphingosine-1-phosphate signaling and lysosomal lipid catabolism

Evaluation of Intermolecular Weak Binding Through the Zero‐Field Splitting of an Endofullerene High‐Spin Probe

Abstract Weak binding between molecules is becoming a renowned aspect of molecular engineering, offering an alternative to the tuning of conventional chemical bonds. However, the subtle nature of these interactions poses challenges for characterization using standard techniques. Herein, an efficient method of weak binding characterization based on the zero‐field splitting of a high‐spin probe by electron paramagnetic resonance is presented. Using endofullerene as the high spin center, we achieved direct comparison of the weak binding strengths in F‐MTPP (M = H 2 , Zn, Ni, and Pd) and 2F‐3MTPP (M = H 2 , Ni, Pd, and Pt) through the zero‐field splitting parameters. The high‐spin resonance spectrum is sensitive to the small variation in the supramolecular structure. By examining fullerene–porphyrin co‐crystals with various metal centers and packing arrangements, the relation between intermolecular weak binding and microstructural strain on the fullerene cage is elucidated.

Ancient DNA reveals diverse community organizations in the 5th millennium BCE Carpathian Basin

Abstract Little is known about the genetic connection system and community organization of Late Neolithic and Early Copper Age populations of the Carpathian Basin. Here, we present a comprehensive genetic investigation of these populations, leveraging whole genome data from 125 individuals. Using population genetics, kinship analyses and the study of networks of identity-by-descent haplotype segment sharing, we elucidate the social and genetic dynamics of these communities between 4800−3900 calibrated years BCE. Despite changes in settlement patterns, burial practices, and material culture, we document a high degree of genetic continuity. While one set of individuals from a large community cemetery is genetically diverse, another site is more homogenous and closed, with numerous consanguineous relationships and evidence of patrilineality and patrilocality. In this work, we document important differences in kinship systems in contemporaneous Early Copper Age communities using similar material culture and living only about 100 km apart.

Decreased mitochondrial activity in the demyelinating cerebellum of progressive multiple sclerosis and chronic EAE contributes to Purkinje cell loss

In multiple sclerosis (MS), cerebellar gray matter atrophy, white matter demyelination, and Purkinje cell (PC) loss have been linked to tremors, impaired motor control, and loss of coordination. Similar pathologies have been observed in the mouse model of MS, experimental autoimmune encephalomyelitis (EAE). This study hypothesized that inflammatory demyelination of the cerebellum alters overall mitochondrial function and is a contributor to axon degeneration and PC loss. Postmortem cerebellar tissue from MS patients, particularly those with secondary progressive MS, showed decreased mitochondrial complex IV (COXIV) activity and significant PC loss. Inflammation, PC axon demyelination, axon degeneration, and parallel fiber loss were also evident. These findings were mirrored in late-stage EAE mice, which also showed increased inflammation and demyelination, reduced PC COXIV activity, and overall PC loss. Further analysis of EAE mice revealed altered mitochondrial structure, modified mitochondrial respiration, and reduced levels of mitochondrial genes involved in energy production. These findings indicate that both human MS and mouse EAE share similar cerebellar changes linked to mitochondrial dysfunction. Thus, late-stage EAE is a valuable model for studying MS-related cerebellar pathology, and mitochondria may be a potential therapeutic target for MS treatment.

Quantum spin Hall effect in magnetic graphene

A distinct LHCI arrangement is recruited to photosystem I in Fe-starved green algae

Iron (Fe) availability limits photosynthesis at a global scale where Fe-rich photosystem (PS) I abundance is drastically reduced in Fe-poor environments. We used single-particle cryoelectron microscopy to reveal a unique Fe starvation-dependent arrangement of light-harvesting chlorophyll (LHC) proteins where Fe starvation–induced TIDI1 is found in an additional tetramer of LHC proteins associated with PSI in Dunaliella tertiolecta and Dunaliella salina . These cosmopolitan green algae are resilient to poor Fe nutrition. TIDI1 is a distinct LHC protein that co-occurs in diverse algae with flavodoxin (an Fe-independent replacement for the Fe-containing ferredoxin). The antenna expansion in eukaryotic algae we describe here is reminiscent of the iron-starvation induced ( isiA- encoding) antenna ring in cyanobacteria, which typically co-occurs with isiB , encoding flavodoxin. Our work showcases the convergent strategies that evolved after the Great Oxidation Event to maintain PSI capacity.

In vivo self-renewal and expansion of quiescent stem cells from a non-human primate

Abstract The development of non-human primate models is essential for the fields of developmental and regenerative biology because those models will more closely approximate human biology than do murine models. Based on single cell RNAseq and fluorescence-activated cell sorting, we report the identification and functional characterization of two quiescent stem cell populations (skeletal muscle stem cells (MuSCs) and mesenchymal stem cells termed fibro-adipogenic progenitors (FAPs)) in the non-human primate Microcebus murinus (the gray mouse lemur). We demonstrate in vivo proliferation, differentiation, and self-renewal of both MuSCs and FAPs. By combining cell phenotyping with cross-species molecular profiling and pharmacological interventions, we show that mouse lemur MuSCs and FAPs are more similar to human than to mouse counterparts. We identify unexpected gene targets involved in regulating primate MuSC proliferation and primate FAP adipogenic differentiation. Moreover, we find that the cellular composition of mouse lemur muscle better models human muscle than does macaque ( Macaca fascicularis ) muscle. Finally, we note that our approach presents as a generalizable pipeline for the identification, isolation, and characterization of stem cell populations in new animal models.

Uncovering the Photochemical Conversion of Atmospheric Chlorinated Organics on Mineral Dust: In‐Field Evidence of a New Source of Dioxin

Abstract Hazardous chemicals are typically assessed based on their inherent toxicity, often neglecting the fact that their atmospheric secondary transformation products may exhibit increased toxicity and persistence, potentially exceeding the risks associated with the parent chemicals. Chlorinated volatile organic compounds (CVOCs) are a significant class of commercial chemicals, but their secondary conversion in the atmosphere remains largely unknown. Herein, by combining laboratory and in‐field experiments, we have identified a new conversion pathway that the CVOCs can be photochemically transformed into polychlorinated dibenzo‐ p ‐dioxins and dibenzofurans (PCDD/Fs) on mineral dust particulates under atmospheric conditions. We showed that mineral components, particularly Fe‐ and Al‐related oxides, can efficiently convert monochlorobenzene, dichloromethane, and perchloroethylene into PCDD/Fs under light irradiation. By combing reaction product measurements and density functional theory (DFT) calculations, we found that the α‐Fe 2 O 3 exhibited much higher propensity for dioxin formation than γ‐Al 2 O 3 , as evidenced by its lower reaction energy barriers for both the initial phenol formation and subsequent chlorination processes. In particular, histopathological assays showed the photochemically‐reacted α‐Fe 2 O 3 can cause severe damage to the lung and brain tissues of mice, underscoring the need to reassess the toxicity of commercial CVOCs and their secondary transformation products.

Increased sea-level contribution from northwestern Greenland for models that reproduce observations

State-of-the-art ice sheet model simulations used in the Ice Sheet Model Intercomparison Project (ISMIP) that informs the Intergovernmental Panel on Climate Change tend to underestimate observed mass loss from the Greenland Ice Sheet, leading to the question of whether future sea-level rise may be larger than projected. We use one of these models, the Ice-sheet and Sea-level System Model, to investigate how transient calibration impacts historical and projection simulations. Transient calibration is an emerging capability in ice flow models; it uses time series of surface observations and time-dependent physics to constrain uncertain model parameters—in this case, the basal friction coefficient in the sliding law. With more constraints than the common snapshot inversion method, transient calibration has been shown to better capture trends in ice dynamics. Here, we apply both methods to northwestern Greenland, a region undergoing rapid changes. For simulations initialized with the snapshot inversion, we find that subsequent modeled velocities are generally too slow, leading to an underestimation of the mass loss. With transient calibration, however, our simulation better matches a time series of observed velocities, bringing it within observational error for mass loss; however, the fit to observed surface elevation is slightly reduced. Together with the ISMIP results, our simulations show that reproducing the high rates of historical mass loss leads to greater projected sea-level contribution from this region over the coming century. Finally, we suggest a path forward for making transient calibration scalable to the entire Greenland Ice Sheet.

Ralph Holloway (1935–2025): Pioneering paleoneurologist

Ralph Holloway pioneered and developed the field of hominin paleoneurology. Although Holloway’s undergraduate degrees were in metallurgical engineering and geology, at graduate school his interests switched to the brain. Holloway and his graduate students explored many aspects of the macro- and microstructure of the brain of extant primates but he focused on the recent evolutionary history of the human brain. The infant skull of the first African early hominin discovered at Taungs by Raymond Dart included a natural brain endocast. Natural endocasts as well-preserved as that of the Taungs infant are rare, but Holloway reasoned that if a way could be found to reproduce the endocranial morphology of early hominin crania then he would be able to track brain evolution within the human clade. Holloway realized that if liquid latex was introduced into the cranial cavity and left to cure, it could be extracted via the foramen magnum and then be used to make a facsimile of that individual’s brain. Modern imaging methods have made Holloway’s technique redundant, but for many years, it was the only way to access the endocranial morphology of fossil hominins.

A Programmable Nanoparticle Conversion Pathway to Monodisperse Polyelemental High Entropy Alloy, Intermetallic, and Multiphase Nanoparticles

Abstract Polyelemental nanoparticles (PE NPs), those consisting of four or more elements, exhibit unique properties from synergistic compositional effects. Examples include high entropy alloys, high entropy intermetallics, and multiphase types, including Janus and core‐shell architectures. Although colloidal syntheses offer excellent structural control for mono‐ and bi‐elemental compositions, achieving the same control for PE NPs remains challenging. Here, this challenge is addressed with a NP conversion strategy wherein different types of PE NPs – including high entropy alloy, high entropy intermetallic, and multiphase Janus nanoparticles – are achieved through thermal transformation of readily synthesized colloidal core‐shell NPs. Through systematic variations in stoichiometry and metal identity to the core‐shell precursor NPs, along with atomistic simulations that probe phase stabilities, we deduce that the final mixing states of the various NPs are governed by the balance between the enthalpy and entropy of mixing. Moreover, our annealing method allows us to trap NPs at intermediate states of mixing, creating distinct surface ensembles that were evaluated as catalysts for the hydrogen evolution reaction. This study is the first, to our knowledge, to report colloidally derived precursor NPs enabling the synthesis of all types of PE NPs in a single process. This NP conversion strategy offers a general route to diverse PE NPs.

Collective artificial intelligence and evolutionary dynamics

Au ₁₄₇ (SPh) ₃₀ (PPh ₃ ) ₁₂ : A Geometrically Closed, but Electronically Open Triple‐Shell Icosahedral Gold Cluster and its Geometrically Open Counterpart

Abstract The aesthetic platonic solids have been known since ancient times, and the structure of all five platonic solids is also found in chemical compounds. While gold sub‐nanometer clusters and gold nanoparticles with an icosahedral structure have been known for a long time to exist, a multi‐shell icosahedral gold cluster at the intermediate size between 13 and thousands of atoms has been elusive. Here we present the synthesis and crystallographic characterization of the first triple‐shell icosahedral metal cluster, Au 147 (SPh) 30 (PPh 3 ) 12 1 . The gold core in 1 is stabilized by phosphines and thiolates, but surprisingly no staple motifs are formed. A second cluster, Au 146 (SPh) 30 (PPh 3 ) 12 2 , cocrystallizes and is identified as having a closed electronic shell but can be considered as a geometrically open pendant of 1 . The unique clusters are characterized experimentally by EDX, UV/vis, DLS, and EPR and theoretically by quantum chemical calculations.

Unilateral incentive alignment in two-agent stochastic games

Multiagent learning is challenging when agents face mixed-motivation interactions, where conflicts of interest arise as agents independently try to optimize their respective outcomes. Recent advancements in evolutionary game theory have identified a class of “zero-determinant” strategies, which confer an agent with significant unilateral control over outcomes in repeated games. Building on these insights, we present a comprehensive generalization of zero-determinant strategies to stochastic games, encompassing dynamic environments. We propose an algorithm that allows an agent to discover strategies enforcing predetermined linear (or approximately linear) payoff relationships. Of particular interest is the relationship in which both payoffs are equal, which serves as a proxy for fairness in symmetric games. We demonstrate that an agent can discover strategies enforcing such relationships through experience alone, without coordinating with an opponent. In finding and using such a strategy, an agent (“enforcer”) can incentivize optimal and equitable outcomes, circumventing potential exploitation. In particular, from the opponent’s viewpoint, the enforcer transforms a mixed-motivation problem into a cooperative problem, paving the way for more collaboration and fairness in multiagent systems.

Picking strategies in games of cooperation

Evolutionary game theory (EGT) has been pivotal in the study of cooperation, offering formal models that account for how cooperation may arise in groups of selfish, but simple agents. This is done by inspecting the complex dynamics arising from simple interactions between a few strategies in a large population. As such, the strategies at stake are typically hand-picked by the modeler, resulting in a system with many more individuals in the population than strategies available to them. In the presence of noise and with multiple equilibria, the choice of strategies can considerably alter the emergent dynamics. As a result, model outcomes may not be robust to how the strategy set is chosen, sometimes misrepresenting the conditions required for cooperation to emerge. We propose three principles that can lead to a more systematic choice of the strategies in EGT models of cooperation. These are the inclusion of all computationally equivalent strategies; explicit microeconomic models of interactions, and a connection between stylized facts and model assumptions. Further, we argue that new methods arising in AI may offer a promising path toward richer models. These richer models can push the field of cooperation forward together with the principles described above. At the same time, AI may benefit from connecting to the more abstract models of EGT. We provide and discuss examples to substantiate these claims.

European mammal turnover driven by a global rapid warming event preceding the Paleocene–Eocene Thermal Maximum

A brief global warming event known as the Pre-Onset Excursion (POE) occurred just before the Paleocene–Eocene Thermal Maximum (PETM, 56 Mya). The deconvolution of the evolutionary consequences of these two hyperthermal events is puzzling because of their close temporal proximity and the lack of comprehensive, well-calibrated paleontological records, especially in terrestrial environments. As a consequence, the impact of the POE on mammalian evolution and its role in shaping PETM faunas remains unclear. Here, we report from France a mammalian fauna, named Albas, which is interpreted to postdate the POE and predate the PETM. The absence of artiodactyls, perissodactyls, and euprimates at Albas lends support to the controversial hypothesis that these “modern” mammal groups appeared in the European fossil record during the PETM. In contrast, Albas yielded the European first definitive Paleocene record of metatherians, paromomyid primates, “creodonts,” and rodents, challenging the assumption that these groups migrated into Europe during the PETM. Because the majority of them originated from North American pre-POE species, we tentatively suggest that these “precursor” dispersers entered Europe during the POE. Similar to the modern orders during the PETM, these “precursor” dispersers likely entered Europe through corridors in the continuous evergreen forest belt at high latitudes. Our findings highlight how a brief warming event in the Arctic during the latest Paleocene, such as the POE (which could result in a release of carbon into the atmosphere similar to cumulative ongoing anthropogenic emissions), significantly influenced the evolutionary dynamics of European mammals.

Manganese‐Catalyzed Enantioselective Dearomative Epoxidation of Naphthalenes with Aqueous Hydrogen Peroxide

Abstract Arenes are abundantly occurring molecules of significant interest as versatile starting materials in organic reactions. Typically, oxidation of arenes yields planar molecules such as phenols and quinones. However, several iron dependent oxygenases can disrupt the aromaticity of arenes through oxidation and introduce C(sp 3 )─O stereogenic centers, resulting in precious enantioenriched epoxide or diol products. Emulating this enzymatic behavior with synthetic catalysts has met little success until now. Herein we describe a catalytic chemo‐ and enantioselective dearomative epoxidation of naphthalenes. The singular chemo‐ and enantioselectivity features of the reaction critically rely on a manganese catalyst that combines electron donating groups and steric demand on the ligand and activates hydrogen peroxide under mild conditions and short reaction times. Assisted with an N ‐protected amino acid, this catalyst epoxidizes a range of naphthalenes providing chemically versatile diepoxides in moderate to good yields and high levels of enantioselectivity. Straightforward elaboration gives diverse access to densely functionalized 3D structurally rich oxygenated molecules. The reaction constitutes a paradigmatical example of expedient access to stereochemically rich, valuable oxygenated molecules from readily available feedstocks, enabled by highly reactive yet selective biologically inspired oxidation catalysts.

Perceptual interventions ameliorate statistical discrimination in learning agents

Choosing social partners is a potentially demanding task which involves paying attention to the right information while disregarding salient but possibly irrelevant features. The resultant trade-off between cost of evaluation and quality of decisions can lead to undesired bias. Information-processing abilities mediate this trade-off, where individuals with higher ability choose better partners leading to higher performance. By altering the salience of features, technology can modulate the effect of information-processing limits, potentially increasing or decreasing undesired biases. Here, we use game theory and multiagent reinforcement learning to investigate how undesired biases emerge, and how a technological layer (in the form of a perceptual intervention) between individuals and their environment can ameliorate such biases. Our results show that a perceptual intervention designed to increase the salience of outcome-relevant features can reduce bias in agents making partner choice decisions. Individuals learning with a perceptual intervention showed less bias due to decreased reliance on features that only spuriously correlate with behavior. Mechanistically, the perceptual intervention effectively increased the information-processing abilities of the individuals. Our results highlight the benefit of using multiagent reinforcement learning to model theoretically grounded social behaviors, particularly when real-world complexity prohibits fully analytical approaches.

Mapping encounters between Antarctic krill fishing vessels and air-breathing krill predators using acoustic data from the fishery

Antarctic krill is a keystone species in the Antarctic marine ecosystem and the target of a growing fishery. Given the ecological importance of krill, concerns have been raised about potential negative impacts of fishing on the Southern Ocean ecosystem. Resource-efficient approaches to fisheries monitoring are particularly valuable in this context due to the high costs associated with data collection in Antarctica. In this study, we trained a segmentation model (U-Net) to extract dives of air-breathing krill predators from more than 30,000 h of active acoustic data collected by three krill fishing vessels over six years. We were able to characterize the temporal and spatial dynamics of predator-vessel co-occurrences, which aligned well with the findings from more costly tracking studies. For example, we found that encounters with whales consistently peaked in autumn around the Antarctic Peninsula, when whales are building up fat reserves for their migration to breeding grounds. We also demonstrated that protection measures, introduced to protect breeding penguins at the Antarctic Peninsula, have simply shifted penguin-vessel encounters to the South Orkney Islands, where the affected colonies are not currently monitored. Our approach, results, and application example demonstrate how acoustic data from fishing vessels can provide important information to support fisheries management. As a by-product of fishing operations, these data are cost-effective, offering unique temporal and spatial coverage and providing a useful basis for rapid, low-level assessments of the fishery’s interaction with the wider ecosystem. This is particularly important given the unpredictable dynamics of krill fishery management decision-making.

Caterina G. C. Marques Netto