Nature Communications最新文献

Myelin loss induces neural dysfunction and contributes to the pathophysiology of neurodegenerative diseases, injury conditions, and aging. Because remyelination is often incomplete, better understanding endogenous remyelination and developing remyelination therapies that restore neural function are clinical imperatives. Here, we use in vivo two-photon microscopy and electrophysiology to study the dynamics of endogenous and therapeutic-induced cortical remyelination and functional recovery after cuprizone-mediated demyelination in mice. We focus on the visual pathway, which is uniquely positioned to provide insights into structure-function relationships during de/remyelination. We show endogenous remyelination is driven by recent oligodendrocyte loss and is highly efficacious following mild demyelination, but fails to restore the oligodendrocyte population when high rates of oligodendrocyte loss occur quickly. Testing a thyromimetic (LL-341070) compared to clemastine, we find it better enhances oligodendrocyte gain and hastens recovery of neuronal function. The therapeutic benefit of the thyromimetic is temporally restricted, and it acts exclusively following moderate to severe demyelination, eliminating the endogenous remyelination deficit. However, we find regeneration of oligodendrocytes and myelin to healthy levels is not necessary for recovery of visual neuronal function. These findings advance our understanding of remyelination and its impact on functional recovery to inform future therapeutic strategies.

Silencers, the yin to enhancers’ yang, play a pivotal role in fine-tuning gene expression throughout the genome. However, despite their recognized importance, comprehensive identification of these regulatory elements in the genome is still in its early stages. We developed a method called Ss-STARR-seq to directly determine the activity of silencers in the whole genome. In this study, we applied Ss-STARR-seq to human cell lines K562, LNCaP, and 293 T, and identified 134,171, 137,753, and 125,307 silencers on a genome-wide scale, respectively, these silencers function in various cells in a cell-specific manner. Silencers exhibited a substantial enrichment of transcriptional-inhibitory motifs, including REST, and demonstrated overlap with the binding sites of repressor transcription factors within the endogenous environment. Interestingly, H3K27me3 did not reflect silencer activity but facilitated the silencer’s inhibitory role on gene expression. Additionally, the silencer did not have any significant histone markers at the genome-wide level. Our findings unveil that aspect-silencers not only transition into enhancers throughout diverse cell lines but also achieve functional conversion with insulators. Regarding to biological effects, knockout experiments underscored the functional redundancy and specificity of silencers in regulating gene expression and cell proliferation. In summary, this study pioneers the elucidation of the genome-wide silencer landscape in human cells, delineates their global regulatory features, and identifies specific silencers influencing cancer cell proliferation.

Although rare non-coding variants (RVs) play crucial roles in complex traits and diseases, understanding their mechanisms and identifying disease-associated RVs continue to be major challenges. Here we constructed a comprehensive atlas of alternative polyadenylation (APA) outliers (aOutliers), including 1334 3′ UTR and 200 intronic aOutliers, from 15,201 samples across 49 human tissues. These aOutliers exhibit unique characteristics from transcription or splicing outliers, with a pronounced RV enrichment. Mechanistically, aOutlier-RVs alter poly(A) signals and splicing sites, and perturbation indeed triggers APA events. Furthermore, we developed a Bayesian-based APA RV prediction model, which successfully pinpointed a specific set of 1799 RVs impacting 278 genes with significantly large disease effect sizes. Notably, we observed a convergence effect between rare and common cancer variants, exemplified by regulation in the DDX18 gene. Together, this study introduced an APA-enhanced framework for genome annotation, underscoring APA’s role in uncovering functional RVs linked to complex traits and diseases.

Heavy precipitation, drought, and other hydroclimatic extremes occur more frequently than in the past climate reference period (1961–1990). Given their strong effect on groundwater recharge dynamics, these phenomena increase the vulnerability of groundwater quantity and quality. Over the course of the past decade, we have documented changes in the composition of dissolved organic matter in groundwater. We show that fractions of ingressing surface-derived organic molecules increased significantly as groundwater levels declined, whereas concentrations of dissolved organic carbon remained constant. Molecular composition changeover was accelerated following 2018’s extreme summer drought. These findings demonstrate that hydroclimatic extremes promote rapid transport between surface ecosystems and groundwaters, thereby enabling xenobiotic substances to evade microbial processing, accrue in greater abundance in groundwater, and potentially compromise the safe nature of these potable water sources. Groundwater quality is far more vulnerable to the impact of recent climate anomalies than is currently recognized, and the molecular composition of dissolved organic matter can be used as a comprehensive indicator for groundwater quality deterioration.

Dysregulated microglia activation, leading to neuroinflammation, is crucial in neurodegenerative disease development and progression. We constructed an atlas of human brain immune cells by integrating nineteen single-nucleus RNA-seq and single-cell RNA-seq datasets from multiple neurodegenerative conditions, comprising 241 samples from patients with Alzheimer’s disease, autism spectrum disorder, epilepsy, multiple sclerosis, Lewy body diseases, COVID-19, and healthy controls. The integrated Human Microglia Atlas (HuMicA) included 90,716 nuclei/cells and revealed nine populations distributed across all conditions. We identified four subtypes of disease-associated microglia and disease-inflammatory macrophages, recently described in mice, and shown here to be prevalent in human tissue. The high versatility of microglia is evident through changes in subset distribution across various pathologies, suggesting their contribution in shaping pathological phenotypes. A GPNMB-high subpopulation was expanded in AD and MS. In situ hybridization corroborated this increase in AD, opening the question on the relevance of this population in other pathologies.

Solar driven energetic particle precipitation (EPP) is an important factor in polar atmospheric ozone balance and has been linked to ground-level regional climate variability. However, the linking mechanism has remained ambiguous. The observed and simulated ground-level changes start well before the processes from the main candidate, the so-called EPP-indirect effect, would start. Here we show that initial reduction of polar mesospheric ozone and the resulting change in atmospheric heating rapidly couples to dynamics, transferring the signal downwards, shifting the tropospheric jet polewards. This pathway is not constrained to the polar vortex. Rather, a subtropical route initiated by a changing wind shear plays a key role. Our results show that the signal propagates downwards in timescales consistent with observed tropospheric level climatic changes linked to EPP. This pathway, from mesospheric ozone to regional climate, is independent of the EPP-indirect effect, and solves the long-standing mechanism problem for EPP effects on climate.

Gypsum (CaSO₄·2H₂O) plays a critical role in numerous natural and industrial processes. Nevertheless, the underlying mechanisms governing the formation of gypsum crystals on surfaces with diverse chemical properties remain poorly understood due to a lack of sufficient temporal-spatial resolution. Herein, we use in situ microscopy to investigate the real-time gypsum nucleation on self-assembled monolayers (SAMs) terminated with −CH₃, −hybrid (a combination of NH₂ and COOH), −COOH, −SO₃, −NH₃, and −OH functional groups. We report that the rate of gypsum formation is regulated by the surface functional groups and hydrophobicity, in the order of −CH₃ > −hybrid > −COOH > −SO₃ ≈ − NH₃ > − OH. Results based on classical nucleation theory and molecular dynamics simulations reveal that nucleation pathways for hydrophilic surfaces involve surface-induced nucleation, with ion adsorption sites (i.e., functional groups) serving as anchors to facilitate the growth of vertically oriented clusters. Conversely, hydrophobic surfaces involve bulk nucleation with ions near the surface that coalesce into larger horizontal clusters. These findings provide new insights into the spatial and temporal characteristics of gypsum formation on various surfaces and highlight the significance of surface functional groups and hydrophobicity in governing gypsum formation mechanisms, while also acknowledging the possibility of alternative nucleation pathways due to the limitations of experimental techniques.

The deep oceans are environments of complex carbon dynamics that have the potential to significantly impact the global carbon cycle. However, the role of hadal zones, particularly hadal trenches (water depth > 6 km), in the oceanic dissolved organic carbon (DOC) cycle is not thoroughly investigated. Here we report distinct DOC signatures in the Japan Trench bottom water. We find that up to 34% ± 7% of the DOC in the trench bottom is removed during the northeastward transport of dissolved carbon along the trench axis. This DOC removal increases the overall DOC recalcitrance of the deep Pacific DOC pool, and is potentially enhanced by the earthquake-triggered physical and biogeochemical processes in the hadal trenches. Radiocarbon analysis on representative oceanic transects further reveals that the Pacific deep-water DOC undergoes distinct removal compared to those in the Atlantic and Indian Oceans along the thermohaline transport. Our findings highlight hadal trenches as previously unrecognized DOC sinks in the deep ocean system, with varying dynamics that warrant further investigation.

The floating phase, a critical incommensurate phase, has been theoretically predicted as a potential intermediate phase between crystalline ordered and disordered phases. In this study, we investigate the different quantum phases that arise in ladder arrays comprising up to 92 neutral-atom qubits and experimentally observe the emergence of the quantum floating phase. We analyze the site-resolved Rydberg state densities and the distribution of state occurrences. The site-resolved measurement reveals the formation of domain walls within the commensurate ordered phase, which subsequently proliferate and give rise to the floating phase with incommensurate quasi-long-range order. By analyzing the Fourier spectra of the Rydberg density-density correlations, we observe clear signatures of the incommensurate wave order of the floating phase. Furthermore, as the experimental system sizes increase, we show that the wave vectors approach a continuum of values incommensurate with the lattice. Our work motivates future studies to further explore the nature of commensurate-incommensurate phase transitions and their non-equilibrium physics.

The Tonian Period (1000–720 Ma) bore witness to the transition from a prokaryote-dominated marine ecosystem to one characterized by the proliferation of eukaryotes. This fundamental shift has generally been attributed to evolving marine redox states. Here, we present sedimentological and geochemical analyses of the early Tonian Huainan, Feishui, and Huaibei groups in the Xuhuai basin of the North China craton. Multiple redox proxies show consistent, water depth-dependent variations across the Xuhuai basin. Excess barium contents and Ba/Al ratios further highlight spatial variations in primary productivity which ultimately regulate basinal redox structures. We propose that a shallow-water oxygen minimum zone sandwiched between the oxic/suboxic mid-depth and surface layer water masses occur in the oligotrophic Xuhuai basin, which is analogous to, but much shallower than modern oxygen minimum zones. Such marine redox architectures may benefit the maintenance of a bioavailable nitrate reservoir in the ocean, foreboding the subsequent expansion of eukaryotes.