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Calciphylaxis is a rare but life-threatening disorder characterized by ectopic calcification affecting the subcutaneous tissues and blood vessels of the skin. Survival rates are less than a year after diagnosis, and yet despite the severity of the condition, the pathobiology of calciphylaxis is ill understood. Here, we created animal models of calciphylaxis that recapitulated many characteristics of the human phenotype. We demonstrate that cutaneous calcification is preceded by inflammatory cell infiltration. We show that increased local skin inflammation, regardless of the inciting cause, in the presence of hypercalcemia and hyperphosphatemia contributes to cutaneous ectopic calcification. Genetically modified rodents lacking immune activation of T and B cells or NK cells are resistant to developing cutaneous calcification. Consistent with this, administration of the immunosuppressive cyclophosphamide reduced calcific deposits, as did T cell suppression with cyclosporine. We demonstrate that IL-17 is upregulated in calcific skin and neutrophils are the predominant cell type expressing IL-17 and tissue-nonspecific alkaline phosphatase (TNAP) that are necessary for ectopic calcification. Targeting IL-17 with a monoclonal antibody or using a myeloperoxidase inhibitor to blunt neutrophil activation notably attenuated calcific deposits in vivo. Taken together, these observations provide fresh insight into the role of the immune system and the IL-17/neutrophil axis in mediating ectopic calcification in rodent models of calciphylaxis.

Dissecting the preneoplastic disease states’ biological mechanisms that precede tumorigenesis can lead to interventions that can slow down disease progression and/or mitigate disease-related comorbidities. Myelodysplastic syndromes (MDS) cannot be cured by currently available pharmacological therapies, which fail to eradicate aberrant hematopoietic stem cells (HSCs), most of which are mutated by the time of diagnosis. Here, we sought to elucidate how MDS HSCs evade immune surveillance and expand in patients with clonal cytopenias of undetermined significance (CCUS), the pre-malignant stage of MDS. We used multi-omic single-cell approaches and functional in vitro studies to show that immune escape at disease initiation is mainly mediated by mutant, dysfunctional natural killer (NK) cells with impaired cytotoxic capability against cancer cells. Preclinical in vivo studies demonstrated that injecting NK cells from healthy donors efficiently depleted CCUS mutant cells while allowing normal cells to regenerate hematopoiesis. Our findings suggest that early intervention with adoptive cell therapy can prevent or delay the development of MDS. Patients with myelodysplastic syndromes (MDS) have limited therapeutic options. Here the authors show that functionally impaired NK cells contribute to immune escape of pre-malignant clones in early stage MDS and that NK adoptive cell therapy can be considered to prevent or delay the development of MDS.

Understanding mechanisms of pathogenesis and protection in human tuberculosis (TB) remain major global health challenges. While organized granulomas have long been the focus of TB research, growing evidence for asymptomatic transmission highlights the need to study earlier disease stages, particularly TB pneumonia, which remains underexplored. Defining the alveolar immune niche that governs bacillary expansion before granuloma formation is essential for interrupting transmission. Here, we integrate spatial transcriptomics, single cell RNA sequencing, and high resolution imaging of human lung biopsies to map early TB pneumonia and compare with adjacent granulomas within the same tissues. Pneumonic alveolar spaces were dominated by TREM2-associated macrophages, characterized by sparse T cell infiltration, minimal antimicrobial gene expression, and abundant antigens and transcripts. In contrast, granuloma cores were enriched for antimicrobial pathways, were surrounded by multiple cell types that walled off infection, and contained comparatively fewer bacterial markers. Our findings identify TREM2 positive 'foamy' macrophages as a key permissive alveolar niche for survival and growth. These cells represent an attractive target for early intervention to restrict infection and limit transmission. Early TB pneumonia defines an alveolar niche that fosters bacterial persistence and transmission before granuloma formation.

Human skin is not a uniform organ but a mosaic of anatomically distinct niches, with each site finely tuned to unique environmental demands and immune pressures. Yet, the molecular determinants that define these regional identities and their relationship to site-specific vulnerability to inflammatory disease remain poorly understood. Here, we generate a high-resolution single-cell atlas of human skin, profiling 274,834 cells from 96 healthy samples across 7 anatomically distinct sites (acral, arm, axilla, back, face, leg and scalp). Our analysis reveals striking region-specific transcriptional and cellular networks, uncovering how local immune-stromal crosstalk governs tissue homeostasis and underpins anatomical susceptibility to distinct inflammatory diseases such as such as systemic lupus erythematosus (SLE), atopic dermatitis (AD), and psoriasis. These findings illuminate the tissue-intrinsic foundations of regional immune identity and provide a blueprint/resource for the development of precision therapies tailored to the distinct immunological microenvironments of specific anatomical skin sites.

Myelodysplastic syndromes (MDS) are a group of incurable hematopoietic stem cell (HSC) neoplasms characterized by peripheral blood cytopenias and a high risk of progression to acute myeloid leukemia. MDS represent the final stage in a continuum of HSCs' genetic and functional alterations and are preceded by a premalignant phase, clonal cytopenia of undetermined significance (CCUS). Dissecting the mechanisms of CCUS maintenance may uncover therapeutic targets to delay or prevent malignant transformation. Here, we demonstrate that DNMT3A and TET2 mutations, the most frequent mutations in CCUS, induce aberrant HSCs' differentiation towards the myeloid lineage at the expense of erythropoiesis by upregulating IL-1β-mediated inflammatory signaling and that canakinumab rescues red blood cell transfusion dependence in early-stage MDS patients with driver mutations in DNMT3A and TET2 . This study illuminates the biological landscape of CCUS and offers an unprecedented opportunity for MDS intervention during its initial phase, when expected survival is prolonged.Myelodysplastic syndromes (MDS) are a group of incurable hematopoietic stem cell (HSC) neoplasms characterized by peripheral blood cytopenias and a high risk of progression to acute myeloid leukemia. MDS represent the final stage in a continuum of HSCs' genetic and functional alterations and are preceded by a premalignant phase, clonal cytopenia of undetermined significance (CCUS). Dissecting the mechanisms of CCUS maintenance may uncover therapeutic targets to delay or prevent malignant transformation. Here, we demonstrate that DNMT3A and TET2 mutations, the most frequent mutations in CCUS, induce aberrant HSCs' differentiation towards the myeloid lineage at the expense of erythropoiesis by upregulating IL-1β-mediated inflammatory signaling and that canakinumab rescues red blood cell transfusion dependence in early-stage MDS patients with driver mutations in DNMT3A and TET2 . This study illuminates the biological landscape of CCUS and offers an unprecedented opportunity for MDS intervention during its initial phase, when expected survival is prolonged.

Background Different mulches have variable effects on soil physicochemical characteristics, bacterial and fungal communities and ecosystem functions. However, the information about soil microbial diversity, community structure and ecosystem function in tea plantation under different mulching patterns was limited. In this study, we investigated bacterial and fungal communities of tea plantation soils under polyethylene film and peanut hull mulching using high-throughput 16S rRNA and ITS rDNA gene Illumina sequencing. Results The results showed that the dominant bacterial phyla were Proteobacteria , Actinobacteria, Acidobacteria and Chloroflexi, and the dominant fungal phyla were Ascomycota, Mortierellomycota and Basidiomycota in all samples, but different mulching patterns affected the distribution of microbial communities. At the phylum level, the relative abundance of Nitrospirae in peanut hull mulching soils (3.24%) was significantly higher than that in polyethylene film mulching soils (1.21%) in bacterial communities, and the relative abundances of Mortierellomycota and Basidiomycota in peanut hull mulching soils (33.72, 21.93%) was significantly higher than that in polyethylene film mulching soils (14.88, 6.53%) in fungal communities. Peanut hull mulching increased the diversity of fungal communities in 0–20 cm soils and the diversity of bacterial communities in 20–40 cm soils. At the microbial functional level, there was an enrichment of bacterial functional features, including amino acid transport and metabolism and energy production and conversion, and there was an enrichment of fungal functional features, including undefined saprotrophs, plant pathogens and soils aprotrophs. Conclusions Unique distributions of bacterial and fungal communities were observed in soils under organic mulching. Thus, we believe that the organic mulching has a positive regulatory effect on the soil bacterial and fungal communities and ecosystem functions, and so, is more suitable for tea plantation.

Drought stress often affects the expression of genes and proteins in tea plants. However, the global profiling of ubiquitinated (Kub) proteins in tea plants remains unearthed. Here, we performed the ubiquitome in tea leaves under drought stress using antibody-based affinity enrichment coupled with LC-MS/MS analysis. In total, 1,409 lysine Kub sites in 781 proteins were identified, of which 14 sites in 12 proteins were up-regulated and 123 sites in 91 proteins down-regulated under drought stress. The identified Kub proteins were mainly located in the cytosol (31%), chloroplast (27%) and nuclear (19%). Moreover, 5 conserved motifs in EK ub , EXXXK ub , K ub D, K ub E and K ub A were extracted. Several Kub sites in ubiquitin-mediated proteolysis-related proteins, including RGLG2, UBC36, UEV1D, RPN10 and PSMC2, might affect protein degradation and DNA repair. Plenty of Kub proteins related to catechins biosynthesis, including PAL, CHS, CHI and F3H, were positively correlated with each other due to their co-expression and co-localization. Furthermore, some Kub proteins involved in carbohydrate and amino acid metabolism, including FBPase, FBA and GAD1, might promote sucrose, fructose and GABA accumulation in tea leaves under drought stress. Our study preliminarily revealed the global profiling of Kub proteins in metabolic pathways and provided an important resource for further study on the functions of Kub proteins in tea plants.

Electrostatic dielectric capacitors are essential components in advanced electronic and electrical power systems due to their ultrafast charging/discharging speed and high power density. A major challenge, however, is how to improve their energy densities to effectuate the next-generation applications that demand miniaturization and integration. Here, we report a high-entropy stabilized Bi 2 Ti 2 O 7 -based dielectric film that exhibits an energy density as high as 182 J cm −3 with an efficiency of 78% at an electric field of 6.35 MV cm −1 . Our results reveal that regulating the atomic configurational entropy introduces favourable and stable microstructural features, including lattice distorted nano-crystalline grains and a disordered amorphous-like phase, which enhances the breakdown strength and reduces the polarization switching hysteresis, thus synergistically contributing to the energy storage performance. This high-entropy approach is expected to be widely applicable for the development of high-performance dielectrics. Electrostatic capacitors can enable ultrafast energy storage and release, but advances in energy density and efficiency need to be made. Here, by doping equimolar Zr, Hf and Sn into Bi 4 Ti 3 O 12 thin films, a high-entropy stabilized Bi 2 Ti 2 O 7 pyrochlore phase forms with an energy density of 182 J cm −3 and 78% efficiency.

Human-wildlife conflicts in cities are becoming increasingly common worldwide and are a challenge to urban biodiversity management and landscape planning. In comparison to compensatory management, which often focuses on addressing emergency conflicts, precautionary management allows decision-makers to better allocate limited resources on prioritized areas and initiate long-term actions in advance. However, precautionary approaches have rarely been developed or applied in biodiversity conservation. Since 2020, human-raccoon dog conflicts in Shanghai, one of the largest cities in the world, have tripled in reported number due to the rapid spread of the species in the city from 70 residential districts in 2020 to 249 residential districts in 2022. Here, we use ensemble and circuit modeling to predict suitable raccoon dog habitat and identify their potential dispersal pathways to aid the development of precautionary management strategies. We find that raccoon dog distribution is positively associated with several anthropogenic factors, including residential buildings and nighttime light, which could be signs that the species’ foraging behavior has adapted to the urban environment. We find that raccoon dogs only occupy 10.1% of its suitable habitat, and thus there is a high potential for the expansion of the raccoon dog population and more frequent human-raccoon dog conflicts in the near future. We predict 60 potential dispersal pathways across Shanghai, seven of which cross densely human populated areas and are likely to trigger excessive conflicts. Based on our findings, we propose priority areas where precautionary management strategies, such as constraining stray animal feeding and wildlife-vehicle collision prevention, would potentially alleviate human-raccoon dog conflicts. We present the first study on the precautionary approach of human-wildlife conflict in China’s major cities, and provide a practical example of how comprehensive modeling approaches can be used as the foundation of precautionary management in urban landscapes.

Relaxor ferroelectrics are the primary candidates for high-performance energy storage dielectric capacitors. A common approach to tuning the relaxor properties is to regulate the local compositional inhomogeneity, but there is a lack of a quantitative evaluation way for compositional fluctuation in relaxors. Here we propose configurational entropy as an index for the quantitative evaluation of local compositional inhomogeneity. Our results reveal that the local inhomogeneity increases with the entropy via scanning transmission electron microscopy, and relaxor features are accordingly modulated. With the deliberate design of entropy, we achieve an optimal overall energy storage performance in Bi 4 Ti 3 O 12 -based medium-entropy films, featuring a high energy density of 178.1 J cm −3 with efficiency exceeding 80% and a high figure of merit of 913. By using the medium-entropy films as dielectric layers, we demonstrate a multilayer film capacitor prototype that outperforms conventional multilayer ceramic capacitors. Dielectric capacitors based on relaxor ferroelectrics are a promising energy storage technology, and an efficient design of relaxors is useful to enhance the storage performance. Here the authors quantitatively evaluate the local compositional inhomogeneity of relaxors via a configurational entropy index and realize overall high performance in a Bi 4 Ti 3 O 12 -based device.