Nature Communications最新文献

Active and stable electrocatalysts are essential for hydrogen production from alkaline water electrolysis. However, precisely controlling the interaction between electrocatalysts and reaction intermediates (H₂O*, H*, and *OH) remains challenging. Here, we demonstrate an yttrium-doped NiMo-MoO₂ heterogenous electrocatalyst that efficiently promotes water dissociation and accelerates the intermediate adsorption/desorption dynamics in alkaline electrolytes. Introducing yttrium into the NiMo/MoO₂ heterostructure induces lattice expansion and optimizes the d-band center of NiMo alloy component, enhancing water dissociation and H* desorption. Yttrium doping also increases the concentration of oxygen vacancies in MoO_2−x, which in turn accelerates the charge kinetics and the swift evacuation of *OH intermediates from the active sites. Consequently, the Y-NiMo/MoO_2−x heterostructure exhibits notable performance by requiring only 189 and 220 mV overpotentials to achieve current density of 2.0 A cm⁻² in alkaline water and seawater, respectively. This work provides a strategy to modulate heterostructure catalysts for scalable, economically viable hydrogen production from low-quality waters.

Accidental ingestion of lead (Pb)-contaminated soils represents a major route of Pb exposure for both adults and children, and the development of accessible and cost-effective solutions to reduce Pb poisoning is urgently required. Here, we present an effective and straightforward technique, involving the consumption of cola beverages, for the purpose of lowering blood Pb levels following the ingestion of contaminated soils in animal models. This method facilitated the direct passage of Pb in contaminated soil through the digestive system, enhancing its elimination without absorption into systemic circulation. Our results demonstrated that cola effectively reduced Pb bioaccessibility in 22 contaminated soils by 32.6%–98.8%. In male rats and swine exposed to Pb-contaminated soils, cola treatment decreased blood Pb concentrations by 32.9%–96.0% and 31.5%–81.5%, respectively. This cola-induced reduction in Pb bioaccessibility and bioavailability was attributed to the rich phosphoric acid content in cola, which promoted the formation of insoluble Pb phosphate precipitate (pyromorphite [Pb₅(PO₄)₃Cl]) during the gastric phase. The precipitate was directly excreted in feces, resulting in lower Pb absorption in the blood. These findings suggest that the consumption of cola beverages may be a practical strategy to mitigate the risk of Pb poisoning following the accidental ingestion of contaminated soils. However, the applicability of this approach in humans remains uncertain in the absence of population-based studies. While these findings underscore the potential for cola beverages to reduce Pb absorption following soil ingestion in animal models, further research is necessary to evaluate its safety, efficacy, and possible risks in humans before any such protocols are initiated.

The MCM motor of the eukaryotic replicative helicase is loaded as a double hexamer onto DNA by the Origin Recognition Complex (ORC), Cdc6, and Cdt1. ATP binding supports formation of the ORC-Cdc6-Cdt1-MCM (OCCM) helicase-recruitment complex where ORC-Cdc6 and one MCM hexamer form two juxtaposed rings around duplex DNA. ATP hydrolysis by MCM completes MCM loading but the mechanism is unknown. Here, we used cryo-EM to characterise helicase loading with ATPase-dead Arginine Finger variants of the six MCM subunits. We report the structure of two MCM complexes with different DNA grips, stalled as they mature to loaded MCM. The Mcm2 Arginine Finger-variant stabilises DNA binding by Mcm2 away from ORC/Cdc6. The Arginine Finger-variant of the neighbouring Mcm5 subunit stabilises DNA engagement by Mcm5 downstream of the Mcm2 binding site. Cdc6 and Orc1 progressively disengage from ORC as MCM translocates along DNA. We observe that duplex DNA translocation by MCM involves a set of leading-strand contacts by the pre-sensor 1 ATPase hairpins and lagging-strand contacts by the helix-2-insert hairpins. Mutating any of the MCM residues involved impairs high-salt resistant DNA binding in vitro and double-hexamer formation assessed by electron microscopy. Thus, ATPase-powered duplex DNA translocation away from ORC underlies MCM loading.

Oxidative stress plays a critical role in postmenopausal osteoporosis, yet its impact on osteoblasts remains underexplored, limiting therapeutic advances. Our study identifies phospholipid peroxidation in osteoblasts as a key feature of postmenopausal osteoporosis. Estrogen regulates the transcription of glutathione peroxidase 4 (GPX4), an enzyme crucial for reducing phospholipid peroxides in osteoblasts. The deficiency of estrogen reduces GPX4 expression and increases phospholipid peroxidation in osteoblasts. Inhibition or knockout of GPX4 impairs osteoblastogenesis, while the elimination of phospholipid peroxides rescues bone formation and mitigates osteoporosis. Mechanistically, 4-hydroxynonenal, an end-product of phospholipid peroxidation, binds to integrin-linked kinase and triggers its protein degradation, disrupting RUNX2 signaling and inhibiting osteoblastogenesis. Importantly, we identified two natural allosteric activators of GPX4, 6- and 8-Gingerols, which promote osteoblastogenesis and demonstrate anti-osteoporotic effects. Our findings highlight the detrimental role of phospholipid peroxidation in osteoblastogenesis and underscore GPX4 as a promising therapeutic target for osteoporosis treatment.

Mice have evolved a new dental plan with two additional cusps on the upper molar, while hamsters were retaining the ancestral plan. By comparing the dynamics of molar development with transcriptome time series, we found at least three early changes in mouse upper molar development. Together, they redirect spatio-temporal dynamics to ultimately form two additional cusps. The mouse lower molar has undergone much more limited phenotypic evolution. Nevertheless, its developmental trajectory evolved as much as that of the upper molar and co-evolved with it. Among the coevolving changes, some are clearly involved in the new upper molar phenotype. We found a similar level of coevolution in bat limbs. In conclusion, our study reveals how serial organ morphology has adapted through organ-specific developmental changes, as expected, but also through shared changes that have organ-specific effects on the final phenotype. This highlights the important role of developmental system drift in one organ to accommodate adaptation in another.

Aggregation intermediates play a pivotal role in the assembly of amyloid fibrils, which are central to the pathogenesis of neurodegenerative diseases. The structures of filamentous intermediates and mature fibrils are now efficiently determined by single-particle cryo-electron microscopy. By contrast, smaller pre-fibrillar α-Synuclein (αS) oligomers, crucial for initiating amyloidogenesis, remain largely uncharacterized. We report an atomic-resolution structural characterization of a toxic pre-fibrillar aggregation intermediate (I1) on pathway to the formation of lipidic fibrils, which incorporate lipid molecules on protofilament surfaces during fibril growth on membranes. Super-resolution microscopy reveals a tetrameric state, providing insights into the early oligomeric assembly. Time resolved nuclear magnetic resonance (NMR) measurements uncover a structural reorganization essential for the transition of I1 to mature lipidic L2 fibrils. The reorganization involves the transformation of anti-parallel β-strands during the pre-fibrillar I1 state into a β-arc characteristic of amyloid fibrils. This structural reconfiguration occurs in a conserved structural kernel shared by a vast number of αS-fibril polymorphs including extracted fibrils from Parkinson’s and Lewy Body Dementia patients. Consistent with reports of anti-parallel β-strands being a defining feature of toxic αS pre-fibrillar intermediates, I1 impacts viability of neuroblasts and disrupts cell membranes, resulting in an increased calcium influx. Our results integrate the occurrence of anti-parallel β-strands as salient features of toxic oligomers with their significant role in the amyloid fibril assembly pathway. These structural insights have implications for the development of therapies and biomarkers.

Biological ion channels exhibit strong gating effects due to their zero-current closed states. However, the gating capabilities of artificial nanochannels have typically fallen short of biological channels, primarily owing to the larger nanopores that fail to completely block ion transport in the off-states. Here, we demonstrate solid-state hydrogen-bonded organic frameworks-based membranes to achieve high-performance ambient humidity-controlled proton gating, accomplished by switching the proton transport pathway instead of relying on conventional ion blockage/activation effects. Density functional theory calculations reveal that the reversible formation and disruption of humidity-induced water bridges within the frameworks facilitates the switching of proton transport mode from the adsorption site hopping to the Grotthuss mechanism. This transition, coupled with the introduction of bacterial cellulose to enhance desorption/adsorption of water clusters, enables us to achieve a superior proton gating ratio of up to 5740, surpassing state-of-the-art solid-state gating devices. Moreover, the developed membrane operates entirely on solid-state principles, rendering it highly versatile for a myriad of applications from environmental detection to human health monitoring. This study offers perspectives for the design of efficient proton gating systems.

Interferon (IFN)-α is the earliest cytokine signature observed in individuals at risk for type 1 diabetes (T1D), but the effect of IFN-α on the antigen repertoire of HLA Class I (HLA-I) in pancreatic β-cells is unknown. Here we characterize the HLA-I antigen presentation in resting and IFN-α-exposed β-cells and find that IFN-α increases HLA-I expression and expands peptide repertoire to those derived from alternative mRNA splicing, protein cis-splicing and post-translational modifications. While the resting β-cell immunopeptidome is dominated by HLA-A-restricted peptides, IFN-α largely favors HLA-B and only marginally upregulates HLA-A, translating into increased HLA-B-restricted peptide presentation and activation of HLA-B-restricted CD8⁺ T cells. Lastly, islets of patients with T1D show preferential HLA-B hyper-expression when compared with non-diabetic donors, and islet-infiltrating CD8⁺ T cells reactive to HLA-B-restricted granule peptides are found in T1D donors. Thus, the inflammatory milieu of insulitis may skew the autoimmune response toward alternative epitopes presented by HLA-B, hence recruiting T cells with a distinct repertoire that may be relevant to T1D pathogenesis.

A fundamental obstacle to tackling the antimicrobial resistance crisis is identifying mutations that lead to resistance in a given genomic background and environment. We present a high-throughput technique – Quantitative Mutational Scan sequencing (QMS-seq) – that enables quantitative comparison of which genes are under antibiotic selection and captures how genetic background influences resistance evolution. We compare four E. coli strains exposed to ciprofloxacin, cycloserine, or nitrofurantoin and identify 812 resistance mutations, many in genes and regulatory regions not previously associated with resistance. We find that multi-drug and antibiotic-specific resistance are acquired through categorically different types of mutations, and that minor genotypic differences significantly influence evolutionary routes to resistance. By quantifying mutation frequency with single base pair resolution, QMS-seq informs about the underlying mechanisms of resistance and identifies mutational hotspots within genes. Our method provides a way to rapidly screen for resistance mutations while assessing the impact of multiple confounding factors.

Mediator25 (MED25) has been ascribed as a signal-processing and -integrating center that controls jasmonate (JA)-induced and MYC2-dependent transcriptional output. A better understanding of the regulation of MED25 stability will undoubtedly advance our knowledge of the precise regulation of JA signaling-related transcriptional output. Here, we report that Arabidopsis MED16 activates JA-responsive gene expression by promoting MED25 stability. Conversely, two homologous E3 ubiquitin ligases, MED25-BINDING RING-H2 PROTEIN1 (MBR1) and MBR2, negatively regulate JA-responsive gene expression by promoting MED25 degradation. MED16 competes with MBR1&2 to bind to the von Willebrand Factor A (vWF-A) domain of MED25, thereby antagonizing the MBR1&2-mediated degradation of MED25 in vivo. In addition, we show that MED16 promotes hormone-induced interactions between MYC2 and MED25, leading to the activation of JA-responsive gene expression. Collectively, our findings reveal a multiprotein regulatory module that robustly and tightly maintains MED25 homeostasis, which determines the strength of the transcriptional output of JA signaling.