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The stabilization of transition metals as isolated centres with high areal density on suitably tailored carriers is crucial for maximizing the industrial potential of single-atom heterogeneous catalysts. However, achieving single-atom dispersions at metal contents above 2 wt% remains challenging. Here we introduce a versatile approach combining impregnation and two-step annealing to synthesize ultra-high-density single-atom catalysts with metal contents up to 23 wt% for 15 metals on chemically distinct carriers. Translation to a standardized, automated protocol demonstrates the robustness of our method and provides a path to explore virtually unlimited libraries of mono- or multimetallic catalysts. At the molecular level, characterization of the synthesis mechanism through experiments and simulations shows that controlling the bonding of metal precursors with the carrier via stepwise ligand removal prevents their thermally induced aggregation into nanoparticles. The drastically enhanced reactivity with increasing metal content exemplifies the need to optimize the surface metal density for a given application. Moreover, the loading-dependent site-specific activity observed in three distinct catalytic systems reflects the well-known complexity in heterogeneous catalyst design, which now can be tackled with a library of single-atom catalysts with widely tunable metal loadings. A general versatile approach combining wet-chemistry impregnation and two-step annealing is devised for the scalable synthesis of a library of ultra-high-density single-atom catalysts with drastically enhanced reactivity.

Single-atom catalysts (SACs) have well-defined active sites, making them of potential interest for organic synthesis 1 – 4 . However, the architecture of these mononuclear metal species stabilized on solid supports may not be optimal for catalysing complex molecular transformations owing to restricted spatial environment and electronic quantum states 5 , 6 . Here we report a class of heterogeneous geminal-atom catalysts (GACs), which pair single-atom sites in specific coordination and spatial proximity. Regularly separated nitrogen anchoring groups with delocalized π-bonding nature in a polymeric carbon nitride (PCN) host 7 permit the coordination of Cu geminal sites with a ground-state separation of about 4 Å at high metal density 8 . The adaptable coordination of individual Cu sites in GACs enables a cooperative bridge-coupling pathway through dynamic Cu–Cu bonding for diverse C–X (X = C, N, O, S) cross-couplings with a low activation barrier. In situ characterization and quantum-theoretical studies show that such a dynamic process for cross-coupling is triggered by the adsorption of two different reactants at geminal metal sites, rendering homo-coupling unfeasible. These intrinsic advantages of GACs enable the assembly of heterocycles with several coordination sites, sterically congested scaffolds and pharmaceuticals with highly specific and stable activity. Scale-up experiments and translation to continuous flow suggest broad applicability for the manufacturing of fine chemicals. Heterogeneous geminal-atom catalysts, which pair single-atom sites in specific coordination and spatial proximity, offer a new avenue for the sustainable manufacture of fine chemicals.

An electrochemical sensor that can resist biofouling even when operated in complex biological medium is developed for the determination of dopamine. It is based on the use of the conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT) that is doped with the water insoluble ionic liquid (IL), 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide. A glassy carbon electrode modified with PEDOT/IL is shown to enable accurate determination of dopamine, as a model analyte in the presence of high concentrations of proteins, and resist biological fouling even in native serum. It exhibited a low limit of detection of 33 nM for the detection of dopamine, with a wide linear range from 0.2 to 328 μM (at 0.2 V vs. saturated calomel electrode). The PEDOT/IL modified glassy carbon electrode has a porous microstructure, high electrical conductivity and good stability. The sensor can be used to quantify dopamine in human urine samples with satisfying accuracy. Graphical abstract An antifouling electrochemical sensor capable of detecting target in complex biological samples was developed based on the use of a conducting polymer (PEDOT) that was doped with a water insoluble ionic liquid.

Advances in mass-spectrometry have generated increasingly large-scale proteomics datasets containing tens of thousands of phosphorylation sites (phosphosites) that require prioritization. We develop a bioinformatics tool called HotPho and systematically discover 3D co-clustering of phosphosites and cancer mutations on protein structures. HotPho identifies 474 such hybrid clusters containing 1255 co-clustering phosphosites, including RET p.S904/Y928, the conserved HRAS/KRAS p.Y96, and IDH1 p.Y139/IDH2 p.Y179 that are adjacent to recurrent mutations on protein structures not found by linear proximity approaches. Hybrid clusters, enriched in histone and kinase domains, frequently include expression-associated mutations experimentally shown as activating and conferring genetic dependency. Approximately 300 co-clustering phosphosites are verified in patient samples of 5 cancer types or previously implicated in cancer, including CTNNB1 p.S29/Y30, EGFR p.S720, MAPK1 p.S142, and PTPN12 p.S275. In summary, systematic 3D clustering analysis highlights nearly 3,000 likely functional mutations and over 1000 cancer phosphosites for downstream investigation and evaluation of potential clinical relevance. Dysregulated phosphorylation is well-known in cancers, but it has largely been studied in isolation from mutations. Here the authors introduce HotPho, a tool that can discover spatial interactions between phosphosites and mutations, which are associated with activating mutation and genetic dependencies in cancer.

Identifying tumor-cell-specific markers and elucidating their epigenetic regulation and spatial heterogeneity provides mechanistic insights into cancer etiology. Here, we perform snRNA-seq and snATAC-seq in 34 and 28 human clear cell renal cell carcinoma (ccRCC) specimens, respectively, with matched bulk proteogenomics data. By identifying 20 tumor-specific markers through a multi-omics tiered approach, we reveal an association between higher ceruloplasmin ( CP ) expression and reduced survival. CP knockdown, combined with spatial transcriptomics, suggests a role for CP in regulating hyalinized stroma and tumor-stroma interactions in ccRCC. Intratumoral heterogeneity analysis portrays tumor cell-intrinsic inflammation and epithelial-mesenchymal transition (EMT) as two distinguishing features of tumor subpopulations. Finally, BAP1 mutations are associated with widespread reduction of chromatin accessibility, while PBRM 1 mutations generally increase accessibility, with the former affecting five times more accessible peaks than the latter. These integrated analyses reveal the cellular architecture of ccRCC, providing insights into key markers and pathways in ccRCC tumorigenesis. Tumour heterogeneity in clear cell renal cell carcinoma (ccRCC) remains to be investigated. Here, the integration of spatial omics, transcriptional and chromatin accessibility profiling at the single-nucleus level and bulk proteogenomics data reveal markers and pathways important for ccRCC.

Multiple sclerosis (MS) is characterized by neuroinflammation and neurodegeneration, whose precise processes are not fully understood. Diacylglycerol kinase (DGK) isozymes of α, β, γ and ζ expressed abundantly in the brain and/or the immune system, may be regulatory targets for MS. In this study, we analyzed the four DGK isozymes along the induction, peak and recovery phases in an experimental autoimmune encephalomyelitis (EAE) rat model of MS. The expression of these DGK isozymes and the diacylglycerol (DAG) pathway in the EAE rat brainstems were analyzed by qRT-PCR, immunohistochemistry, immunofluorescence double staining, western blotting and ELISA. Our results showed that the mRNA content of the four DGK isozymes decreased significantly, and their immunoreactivity in myelin sheathes (DGKα, β) and neurons (DGKγ, ζ) became weaker at the beginning of the induction phase. With the progressive increase in clinical signs, DGKα, DGKγ and DGKζ mRNA increased and DGKβ mRNA decreased, and microglia were involved in the formation of perivascular cuffing. In the peak phase, both DGKα and DGKζ were expressed in neurons and inflammatory cells, and DGKζ was also positive in microglia. During the recovery phase, the mRNA content and immunoreactivity of these DGK isozymes generally reached normal levels. Moreover, our results revealed that changes in DAG accumulation and PKCδ phosphorylation were almost the same as those of DGKα and DGKζ mRNA. In summary, the four DGK isozymes are involved in the EAE process. The predominant and broad presence of DGKα and DGKζ suggests that they may regulate the pathological process by attenuating DAG/PKCδ pathway signaling during EAE evolution.

ObjectiveThis study aimed to assess the impact of the COVID-19 pandemic on the characteristics and outcomes of patients with burns in a burn centre situated in Northwest China.DesignA retrospective descriptive study.SettingThis study was conducted in Tangdu Hospital, a major regional burn centre in Xi'an, Shaanxi Province of China.ParticipantsA total of 1413 patients with burns were included in the study, with the admission period spanning from 2017 to 2019 (before the pandemic) and 2020 to 2022 (during the pandemic).ResultsBurn hospitalisations decreased during the pandemic for both children (9.80%) and adults (24.68%). The pandemic was associated with a decrease in work-related burns and a corresponding increase in the risk of domestic burns (both p<0.001). The proportions of burns due to scald and flame increased, while electrical injury cases and proportions decreased significantly (both p=0.001). The estimated range of % total body surface area (TBSA) for children increased from 8% (IQR: 5–12%) to 10% (IQR: 8–15%) in children (p<0.001) and from 8% (IQR: 4–18%) to 11% (IQR: 6–25%) in adults (p<0.001). In children, the number of burn cases transferred from other hospitals decreased (p=0.011). Among adults, the number of female patients with burns rose (p=0.013), and the number of patients with inhalation injury also rose (p=0.009).ConclusionDuring the COVID-19 pandemic, the number of inpatients with burns declined. Domestic burns became more common, and scald and flame burns as well as the average burn area (% TBSA) increased. These findings might highlight the significance of implementing specific public health strategies and safety measures to improve family safety both during and after the pandemic.

The basic helix–loop–helix (bHLH) transcription factor family regulates plant secondary metabolism, development and stress responses. Although triterpenoids such as betulinic acid (BA), betulin (BT) and oleanolic acid (OA) from Betula platyphylla Suk. are of pharmacological importance, the methyl jasmonate (MeJA)‐induced regulation of IVa bHLHs remains unclear. A total of 131 BpbHLH genes were identified, and functional characterisation was performed for two IVa members, BpbHLH42 and BpbHLH44, in yeast, tobacco, birch cells and transgenic plants. Both enhanced triterpenoid biosynthesis but exhibited distinct specificities: BpbHLH42 primarily promoted OA accumulation by activating BpHMGR, BpSE1/3, BpW and BpY6, while BpbHLH44 favoured BT production through BpW, BpY6 and BpY11. Both indirectly regulated BpY9 via BpMYB21, forming a bHLH–MYB complex, and the MeJA repressor BpJAZ2 disrupted the BpbHLH42–MYB21 interaction. Transgenic birch lines further revealed divergent phenotypes: BpbHLH42 overexpression enlarged and smoothed leaves and increased OA levels, whereas BpbHLH44 enhanced alkali stress tolerance by elevating secondary metabolite accumulation. These results uncover the differential regulatory roles of BpbHLH42 and BpbHLH44 in triterpenoid biosynthesis and demonstrate their potential for metabolic engineering and genetic improvement in woody plants.

Swertiamarin, a predominant iridoid glycoside from hepatoprotective Swertia herbs, is biotransformed in vivo into nitrogen-containing metabolites ( R )-gentiandiol and ( S )-gentiandiol. These metabolites may be the real active hepatoprotective agents. A high-fat diet-fed rat model was treated for 12 weeks with swertiamarin, ( R )-gentiandiol, ( S )-gentiandiol and silybin, and the therapeutic effects on non-alcoholic fatty liver disease (NAFLD) were systematically evaluated through biochemical indices and histopathological observations. Swertiamarin and ( R )-gentiandiol reversed high-fat diet-induced metabolic disturbances, reduced serum alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglyceride, low-density lipoprotein cholesterol and malondialdehyde, while elevated high-density lipoprotein cholesterol, superoxide dismutase and glutathione peroxidase. However, ( S )-gentiandiol exhibited no efficacy. The differential biomarkers in the serum of high-fat diet-fed rats were determined and identified by the metabolomics method combined with multivariate analysis. The results of enrichment analysis showed that NAFLD could be improved by swertiamarin and ( R )-gentiandiol by regulating the levels of 21 biomarkers, such as stearic acid, palmitic acid and PC (36:3). According to the pathway enrichment results, swertiamarin and ( R )-gentiandiol had potent combined effects in regulating taurine and hypotaurine metabolism, arachidonic acid metabolism, etc. This study is the first verification of the metabolite activity in the NAFLD model, and the dose-dependent effects of ( R )-gentiandiol can be used to underscore its central role in swertiamarin’s bioactivity. These findings offer valuable insights to clarify the pharmaceutical material for hepatoprotective effect of Swertia herbs.