Browse Articles

The cGAS–STING, p38 MAPK, and p53 pathways link genome instability to accelerated cellular senescence in ATM-deficient murine lung fibroblasts

Ataxia–telangiectasia (A-T) is a pleiotropic genome instability syndrome resulting from the loss of the homeostatic protein kinase ATM. The complex phenotype of A-T includes progressive cerebellar degeneration, immunodeficiency, gonadal atrophy, interstitial lung disease, cancer predisposition, endocrine abnormalities, chromosomal instability, radiosensitivity, and segmental premature aging. Cultured skin fibroblasts from A-T patients exhibit premature senescence, highlighting the association between genome instability, cellular senescence, and aging. We found that lung fibroblasts derived from ATM-deficient mice provide a versatile experimental system to explore the mechanisms driving the premature senescence of primary fibroblasts lacking ATM. Atm −/− fibroblasts failed to proliferate under ambient oxygen conditions (21%). Although they initially proliferated under physiological oxygen levels (3%), they rapidly entered senescence. In contrast, wild-type (WT) lung fibroblasts did not senesce under 3% oxygen and eventually underwent immortalization and neoplastic transformation. However, rapid senescence could be induced in WT cells either by Atm gene ablation or persistent chemical inhibition of ATM kinase activity, with senescence induced by ATM inhibition being reversible upon inhibitor removal. Moreover, the concomitant loss of ATM and p53 led to senescence evasion, vigorous growth, rampant genome instability, and subsequent immortalization and transformation. Our findings reveal that the rapid senescence of Atm −/− lung fibroblasts is driven by the collaborative action of the cGAS–STING, p38 MAPK, and p53 pathways in response to persistent DNA damage, ultimately leading to the induction of interferon-α1 and downstream interferon-stimulated genes. We propose that accelerated cellular senescence may exacerbate specific A-T symptoms, particularly contributing to the progressive, life-threatening interstitial lung disease often observed in A-T patients during adulthood.

Dynamical properties of hydrogen fluid at high pressures

The properties of the hydrogen fluid at high pressures are still of interest to the scientific community. The experimentally unreachable dynamical properties could provide new insights into this field. In 2020 [Cheng et al., Nature 585, 217–220 (2020)], the machine-learned approach allows the calculation of the self-diffusion coefficient in the warm dense hydrogen with higher precision. After that, the work [van de Bund et al., Phys. Rev. Lett. 126(22), 225701 (2021)] reports the ab initio treatment of isotopic effects on diffusion in H2/D2 and a significant increase in its value in the region of the phase transition. Both works indicate the anomalous growth of diffusion, but the reasons for this phenomenon are unclear. In the present work, we reveal the plasma-like behavior of the diffusion growth. We apply the classical molecular dynamics method using a machine learning potential developed on the ab initio modeling for the prediction of diffusion and shear viscosity coefficients. We consider dependencies of the vibrational spectrum, molecule lifetime, diffusion, and shear viscosity coefficients on density along the isotherms in the temperature range from 600 to 1100 K.

Evolutionary adaptation under climate change: <i>Aedes</i> sp. demonstrates potential to adapt to warming

Climate warming is expected to shift the distributions of mosquitoes and mosquito-borne diseases, promoting expansions at cool range edges and contractions at warm range edges. However, whether mosquito populations could maintain their warm edges through evolutionary adaptation remains unknown. Here, we investigate the potential for thermal adaptation in Aedes sierrensis , a congener of the major disease vector species that experiences large thermal gradients in its native range, by assaying tolerance to prolonged and acute heat exposure, and its genetic basis in a diverse, field-derived population. We found pervasive evidence of heritable genetic variation in mosquito heat tolerance, and phenotypic trade-offs in tolerance to prolonged versus acute heat exposure. Further, we found genomic variation associated with prolonged heat tolerance was clustered in several regions of the genome, suggesting the presence of larger structural variants such as chromosomal inversions. A simple evolutionary model based on our data estimates that the maximum rate of evolutionary adaptation in mosquito heat tolerance will exceed the projected rate of climate warming, implying the potential for mosquitoes to track warming via genetic adaptation.

Monofluorinated acetal electrolyte for high-performance lithium metal batteries

High degree of fluorination for ether electrolytes has resulted in improved cycling stability of lithium metal batteries due to stable solid electrolyte interphase (SEI) formation and good oxidative stability. However, the sluggish ion transport and environmental concerns of high fluorination degree drive the need to develop less fluorinated structures. Here, we depart from the traditional ether backbone and introduce bis(2-fluoroethoxy)methane (F2DEM), featuring monofluorination of the acetal backbone. High coulombic efficiency and stable long-term cycling in Li||Cu half cells can be achieved with F2DEM even under fast Li metal plating conditions. The performance of F2DEM is further compared with diethoxymethane (DEM) and 2-[2-(2,2-difluoroethoxy)ethoxy]-1,1,1-trifluoroethane (F5DEE). A significantly lower overpotential is observed with F2DEM, which improves energy efficiency and enables its application in high-rate conditions. Comparative studies of F2DEM with DEM and F5DEE in anode-free lithium iron phosphate (LiFePO 4 ) LFP pouch cells and high-loading LFP coin cells further show improved capacity retention of F2DEM electrolyte, demonstrating its practical applicability. More importantly, we also extensively investigate the underlying mechanism for the superior performance of F2DEM through various techniques, including X-ray photoelectron spectroscopy, scanning electron microscopy, cryogenic electron microscopy, focused ion beam, electrochemical impedance spectroscopy, and titration gas chromatography. Overall, F2DEM facilitates improved Li deposition morphology with reduced amount of dead Li. This enables F2DEM to show superior performance, especially under higher charging and slower discharging rate conditions.

APOBEC3A deaminates CTG hairpin loops to promote fragility and instability of expanded CAG/CTG repeats

CAG/CTG repeats are prone to expansion, causing several inherited human diseases. The initiating sources of DNA damage which lead to inaccurate repair of the repeat tract to cause expansions are not fully understood. Expansion-prone CAG/CTG repeats are actively transcribed and prone to forming stable R-loops with hairpin structures forming on the displaced single-stranded DNA (S-loops). We previously determined that damage by the Saccharomyces cerevisiae cytosine deaminase, Fcy1, was required for both fragility and instability of CAG/CTG tracts engaged in R-loops. To determine whether this mechanism is more universal, we expressed human cytidine deaminases APOBEC3A (A3A), APOBEC3B (A3B), or activation-induced cytidine deaminase (AID) in our yeast system. We show that mutagenic activity of Apolipoprotein B messenger RNA-editing enzyme, catalytic polypeptides causes CAG/CTG fragility and instability, with A3A having the greatest effect followed by A3B and least from AID. A3A-induced repeat fragility was exacerbated by enrichment of R-loops at the repeat site. A3A and A3B-induced instability was dependent on the MutLγ nuclease and to a lesser extent, base excision repair factors. Deaminase activity assays on hairpin substrates containing CTG and GTC triplet sequences revealed that A3A prefers cytidines within the hairpin loop, and bulges in the hairpin stem alter preferred locations. Analysis of RNA expression levels in human cortex samples revealed that A3A is expressed in brain tissue that exhibits CAG/CTG repeat expansions and its expression is elevated in Huntington’s disease (HD) patient samples. These results implicate cytidine deamination by A3A as a potential source of repeat expansions in HD and other CAG/CTG repeat expansion disorders.

Synthesis of ethane from CO ₂ by a methyl transferase–inspired molecular catalyst

Molecular catalysts with a single metal center are reported to reduce CO 2 to a wide range of valuable single-carbon products like CO, HCOOH, CH 3 OH, etc. However, these catalysts cannot reduce CO 2 to two carbon products like ethane or ethylene and the ability to form C–C from CO 2 remains mostly limited to heterogeneous material-based catalysts. We report a set of simple iron porphyrins with pendant thiol group can catalyze the reduction of CO 2 to ethane (C 2 H 6 ) with H 2 O as the proton source with a Faradaic yield &gt;40% the rest being CO. The mechanism involves a CO 2 -derived methyl group transfer to the pendant thiol akin to the proposal forwarded for methyl transferases and a follow-up C–C bond formation of the thioether thus formed and a Fe(II)–CH 3 species generated by the reduction of a second molecule of CO 2 . The availability of a “parking space” in the molecular framework for the first reduced C 1 product from CO 2 reduction allows C–C bond formation resulting in a unique case where a component of natural gas can be generated from direct electrochemical reduction of CO 2 .

Mechanically Robust Bismuth-Embedded Carbon Microspheres for Ultrafast Charging and Ultrastable Sodium-Ion Batteries

Exome sequencing identifies genes for socioeconomic status in 350,770 individuals

Socioeconomic status (SES) is a critical factor in determining health outcomes and is influenced by genetic and environmental factors. However, our understanding of the genetic structure of SES remains incomplete. Here, we conducted a large-scale exome study of SES markers (household income, occupational status, educational attainment, and social deprivation) in 350,770 individuals. For rare coding variants, we identified 56 significant associations by gene-based collapsing tests, unveiling 7 additional SES-associated genes ( NRN1 , CCDC36 , RHOB , EP400 , NCAM1, TPTEP2-CSNK1E , and LINC02881 ). Exome-wide single common variant analysis revealed nine lead single-nucleotide polymorphisms (SNPs) associated with household income and 34 lead SNPs associated with EduYears, replicating previous GWAS findings. The gene–environment correlations had a substantial impact on the genetic associations with SES, as indicated by the significantly increased P values in several associations after controlling for geographic regions. Furthermore, we observed the pleiotropic effects of SES-associated genetic factors on a wide range of health outcomes, such as cognitive function, psychosocial status, and diabetes. This study highlights the contribution of coding variants to SES and their associations with health phenotypes.

Small CAG Repeat RNA Forms a Duplex Structure with Sticky Ends That Promote RNA Condensation

Escalation of genome defense capacity enables control of an expanding meiotic driver

From RNA interference to chromatin silencing, diverse genome defense pathways silence selfish genetic elements to safeguard genome integrity. Despite their diversity, different defense pathways share a modular organization, where numerous specificity factors identify diverse targets and common effectors silence them. In the PIWI-interacting RNA (piRNA) pathway, target RNAs are first identified by complementary base pairing with piRNAs and then silenced by PIWI-clade nucleases. Such a binary architecture allows the defense systems to be readily adaptable, where new targets can be captured via innovation of specificity factors. Thus, our current understanding of genome defense against lineage-specific selfish genes has been largely limited to specificity factor innovations, while it remains poorly understood whether other types of innovations are required. Here, we describe a new type of innovation, which escalates the genome defense capacity to control a recently expanded selfish gene in Drosophila melanogaster . Through a targeted RNAi screen for repressors of Stellate —a recently evolved meiotic driver—we identified a defense factor, Trailblazer. Trailblazer is a transcription factor that promotes the expression of two PIWI-clade nucleases, Aub and AGO3, to match Stellate in abundance. Recent innovation in the DNA-binding domain of Trailblazer enabled it to elevate Aub and AGO3 expression, thereby escalating the silencing capacity of piRNA pathway to tame expanded Stellate and safeguard fertility. As copy-number expansion is a recurrent feature of diverse selfish genes across the tree of life, we envision that augmenting the defense capacity to quantitatively match selfish genes is a repeatedly employed defense strategy in evolution.

A synapse-specific refractory period for plasticity at individual dendritic spines

How newly formed memories are preserved while brain plasticity is ongoing has been a source of debate. One idea is that synapses which experienced recent plasticity become resistant to further plasticity, a type of metaplasticity often referred to as saturation. Here, we probe the local dendritic mechanisms that limit plasticity at recently potentiated synapses. We show that recently potentiated individual synapses exhibit a synapse-specific refractory period for further potentiation. We further found that the refractory period is associated with reduced postsynaptic CaMKII signaling; however, stronger synaptic activation fully restored CaMKII signaling but only partially restored the ability for further plasticity. Importantly, the refractory period is released after one hour, a timing that coincides with the enrichment of several postsynaptic proteins to preplasticity levels. Notably, increasing the level of the postsynaptic scaffolding protein, PSD95, but not of PSD93, overcomes the refractory period. Our results support a model in which potentiation at a single synapse is sufficient to initiate a synapse-specific refractory period that persists until key postsynaptic proteins regain their steady-state synaptic levels.

Molecular dynamics-guided reaction discovery reveals endoperoxide-to-alkoxy radical isomerization as key branching point in α-pinene ozonolysis

Funding rules that promote equity in climate adaptation outcomes

Many climate policies adopt improving equity as a key objective. A key challenge is that policies often conceive of equity in terms of individuals but introduce strategies that focus on spatially coarse administrative areas. For example, the Justice40 Initiative in the United States requires 518 diverse federal programs to prioritize funds for “disadvantaged” census tracts. This strategy is largely untested and contrasts with the federal government’s definition of equity as the “consistent and systematic fair, just and impartial treatment of all individuals (Executive Office of the President, Federal Register, 2021).” How well does the Justice40 approach improve equity in climate adaptation outcomes across individuals ? We analyze this question using a case study of a municipality that faces repetitive flooding and struggles to effectively manage these risks due to limited resources and public investment. We find that the way the Federal Emergency Management Agency implements the Justice40 Initiative can be an obstacle to promoting equity in household flood-risk outcomes. For example, in this case study, ensuring the majority of benefits accrue in “Justice40 Communities” does not reduce risk for the most burdened households, does not reduce risk-burden inequality, and produces net costs. In contrast, we design simple funding rules based on household risk burden that cost-effectively target the most burdened households, reduce risk-burden inequality, and accrue large net benefits. Our findings suggest that “disadvantaged community” indicators defined at coarse spatial scales face the risk of poorly capturing many climate risks and can be ineffective for meeting equity promises about climate-related investments.

Multi-omics architecture of childhood obesity and metabolic dysfunction uncovers biological pathways and prenatal determinants

The magnitude of legal wildlife trade and implications for species survival

The unsustainable use of wildlife is a primary driver of global biodiversity loss. No comprehensive global dataset exists on what species are in trade, their geographic origins, and trade’s ultimate impacts, which limits our ability to sustainably manage trade. The United States is one of the world’s largest importers of wildlife, with trade data compiled in the US Law Enforcement Management Information System (LEMIS). The LEMIS provides the most comprehensive publicly accessible wildlife trade database of non-the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) listed species. In total, 21,097 species and over 2.85 billion individuals were traded over the past 22 y (2000-2022). When LEMIS data are combined with CITES records, the United States imported over 29,445 wild species, including over 50% of all globally described species in some taxonomic groups. For most taxa, around half of the individuals are declared as sourced from the wild. Although the LEMIS provides the only means to assess trade volumes for many taxa, without any associated data on most wild populations, it is impossible to assess the impact on biodiversity, sustainability of trade, or any potential risk of pest or pathogen spread. These insights underscore the considerable underestimation of trade and the urgent need for other countries to adopt similar mechanisms to accurately record trade.

Large Language Models lack essential metacognition for reliable medical reasoning

Individualized temporal patterns drive human sleep spindle timing

Sleep spindles are cortical electrical oscillations considered critical for memory consolidation and sleep stability. The timing and pattern of sleep spindles are likely to be important in driving synaptic plasticity during sleep as well as preventing disruption of sleep by sensory and internal stimuli. However, the relative importance of factors such as sleep depth, cortical up/down-state, and temporal clustering in governing sleep spindle dynamics remains poorly understood. Here, we analyze sleep data from 1,025 participants, statistically modeling the simultaneous influences of multiple factors on moment-to-moment spindle production using a point process-generalized linear model framework. Results reveal fingerprint-like timing patterns, characterized by a refractory period followed by a period of increased spindle activity, which are highly individualized yet consistent night-to-night, with increased variability with age. Strikingly, short-term (&lt;15 s) temporal patterns of past spindle history are the main determinant of spindle timing, accounting for over 70% of the statistical deviance—surpassing the contribution of factors such as cortical up/down-state (slow oscillation phase), sleep depth, and long-term history (15 to 90 s, including ~50 s infraslow activity). Short-term history has a statistically significant influence in over 98% of the population, suggesting it is a near-universal feature of spindle activity. Short-term history and slow oscillation phase exert independent effects on spindle timing. Our results establish a robust statistical framework to examine abnormalities in sleep spindle timing observed in neurological disorders and aging, as well as the relationship between individualized sleep spindle timing, cognition, and sleep stability.

Recent changes in ENSO’s impacts on the summertime circumglobal teleconnection and mid-latitude extremes

Reconciling Archean organic-rich mudrocks with low primary productivity before the Great Oxygenation Event

The organic carbon content of ancient rocks provides a fundamental record of the biosphere on early Earth. For over 50 y, the high organic content of Archean (&gt;2.5 Ga) mudrocks has puzzled geologists and evolutionary biologists, because high biological primary productivity was unexpected for the nascent biosphere before the rise of O 2 . Here, we took a different approach to resolve this apparent paradox, by studying the accumulation rates of Archean organic-rich mudrocks. We evaluated the sedimentation rates of three sections of the Mount McRae Shale and Jeerinah Formation (2.68 to 2.48 Ga, Pilbara Craton, Australia) with new and recently published U–Pb zircon ages from intraformational ash beds. For comparison, we compiled Phanerozoic (&lt;500 Ma) data from comparable depositional settings and developed an idealized model that considers the sedimentation rates for predicting rock organic content. We found that organic-rich Archean mudrocks were deposited under exceptionally low sedimentation rates (~1 m/Ma), in sharp contrast to organic-rich rocks from the Phanerozoic Eon (10 to 100 m/Ma). Constrained by observations, model results indicated that the Archean data reflect low primary productivity (~100-fold lower than during the Phanerozoic) and enhanced preservation under anoxic conditions, with the principal control on organic carbon content provided by dilution with inorganic sediment. Thus, the high organic carbon content which is typically attributed to high productivity instead reflects slow accumulation, high preservation, and minimal inorganic dilution—reconciling the geological evidence with a slow carbon cycle cadence during Archean time.

Interplay of p23 with FKBP51 and their chaperone complex in regulating tau aggregation

Abstract The pathological deposition of tau and amyloid-beta into insoluble amyloid fibrils are pathological hallmarks of Alzheimer’s disease. Molecular chaperones are important cellular factors contributing to the regulation of tau misfolding and aggregation. Here we reveal an Hsp90-independent mechanism by which the co-chaperone p23 as well as a molecular complex formed by two co-chaperones, p23 and FKBP51, modulates tau aggregation. Integrating NMR spectroscopy, SAXS, molecular docking, and site-directed mutagenesis we reveal the structural basis of the p23-FKBP51 complex. We show that p23 specifically recognizes the TPR domain of FKBP51 and interacts with tau through its C-terminal disordered tail. We further show that the p23-FKBP51 complex binds tau to form a dynamic p23-FKBP51-tau trimeric complex that delays tau aggregation and thus may counteract Hsp90-FKBP51 mediated toxicity. Taken together, our findings reveal a co-chaperone mediated Hsp90-independent chaperoning of tau protein.