Immunogenicity and biodistribution of lipid nanoparticle formulated self-amplifying mRNA vaccines against H5 avian influenza.

This study reports on the immunogenicity and biodistribution of H5 hemagglutinin (HA)-based self-amplifying (sa) mRNA vaccines in mice. Four sa-mRNA vaccines encoding either a secreted full-length HA, a secreted HA head domain, a secreted HA stalk domain, or a full-length membrane-anchored HA were investigated. All vaccines elicited an adaptive immune response. However, the full-length HA sa-RNA vaccines demonstrated superior performance compared to head and stalk domain vaccines. The antibody titers positively correlated with the vaccine dose. Cellular immune responses and antigen-specific IgA antibodies in the lungs were also observed. The comparison of the sa-mRNA vaccines encoding the secreted and membrane-anchored full-length HA revealed that anchoring of the HA to the membrane significantly enhanced the antibody and cellular responses. In addition to the injection site, the intramuscularly injected sa-mRNA-LNPs were also detected in the draining lymph nodes, spleen, and to a lesser extent, in the lung, kidney, liver, and heart.

Novel Two-Terminal Synapse/Neuron Based on an Antiferroelectric Hafnium Zirconium Oxide Device for Neuromorphic Computing.

Functionally diverse devices with artificial neuron and synapse properties are critical for neuromorphic systems. We present a two-terminal artificial leaky-integrate-fire (LIF) neuron based on 6 nm Hf0.1Zr0.9O2 (HZO) antiferroelectric (AFE) thin films and develop a synaptic device through work function (WF) engineering. LIF neuron characteristics, including integration, firing, and leakage, are achieved in W/HZO/W devices due to the accumulated polarization and spontaneous depolarization of AFE HZO films. By engineering the top electrode with asymmetric WFs, we found that Au/Ti/HZO/W devices exhibit synaptic weight plasticity, such as paired-pulse facilitation and long-term potentiation/depression, achieving >90% accuracy in digit recognition within constructed artificial neural network systems. These findings suggest that AFE HZO capacitor-based neurons and WF-engineered artificial synapses hold promise for constructing efficient spiking neuron networks and artificial neural networks, thereby advancing neuromorphic computing applications based on emerging AFE HZO devices.

Effects of Benzo[α]pyrene on Mucus Secretion and Tissue Remodeling in a Rat Model of Allergic Rhinitis.

OBJECTIVES: Exposure to benzo[α]pyrene (BaP) increases the incidence and severity of allergic rhinitis (AR), but the underlying mechanisms remain unclear. Thus, we investigated the in vivo effects of BaP exposure on mucus hypersecretion and tissue remodeling in a rat model of AR. METHODS: Female Sprague-Dawley rats were randomly divided into 4 groups: a negative control group, a group of healthy rats exposed to BaP, a group of rats with ovalbumin (OVA)-induced AR, and a group of AR model rats exposed to BaP. Nasal symptoms and levels of OVA-specific serum immunoglobulin E (IgE) were measured in each individual rat. Moreover, examination of goblet cell hyperplasia and collagen deposition was carried out with periodic acid-Schiff (PAS) staining and Masson trichrome (MT) staining. Mucin 5AC (MUC5AC) expression was assessed by immunohistochemistry. RESULTS: BaP significantly increased the number of sneezes, the number of nasal rubs and the levels of OVA-specific serum IgE in rats with AR. Statistically significant differences in goblet cell hyperplasia and collagen deposition were observed between the BaP-exposed AR model group and the AR model group. Immunohistochemical results showed that the nasal mucosa of AR model rats displayed markedly elevated MUC5AC expression after BaP exposure. CONCLUSION: Our data indicate that mucus hypersecretion and the development of nasal remodeling might be pathophysiologic mechanisms underlying increased susceptibility to AR after exposure to BaP.

Theoretical Insights into the Mechanism and Origin of Solvent-Dependent Selectivity in the Cyclization of Propargyl Alcohols for the Divergent Synthesis of N-Heterocycles.

This study elucidates the mechanisms and principles governing chemoselectivity in synthesizing two distinct N-heterocycles, benzimidazole thiazine and benzothiazole imidazole, through BF3•OEt2-catalyzed cyclization reactions of propargyl alcohols with benzimidazole thiols. Employing density functional theory calculations, we highlight the crucial role of fluorine source in influencing chemoselectivity. In DCM, BF3, as the catalytic center, coordinates with propargyl alcohol's hydroxyl group to form a precursor. Conversely, in DMF, [BF2•DMF]+, formed from DMF and BF3•OEt2, acts as the catalytic center, activating the propargyl alcohol's hydroxyl group. The mechanisms in both solvents involve sequential steps: B-O bond formation, C-O bond cleavage, S-C bond formation, hydrogen atom transfer (HAT), cyclization, and deprotonation. A notable difference is the HAT process: in DCM, it follows a 1,5-HAT process, while in DMF, BF4- formation from DMF and BF3•OEt2 provides a fluorine source and introduces steric hindrance, favoring a 1,6-HAT process and leading to unique chemoselectivity. This pioneering research showcases the impact of DMF on cyclization reactions, offering valuable insights for comprehending and designing reactions driven by fluorine sources. Crucially, our results propose an innovative reaction mechanism featuring lower potential energy surfaces, enhancing our understanding of the intricate interplay among reactants, catalysts, and solvents.

Targeting Decidual CD16+ Immune Cells with Exosome-Based Glucocorticoid Nanoparticles for Miscarriage.

Immune dysfunction in early pregnancy including overactivation of cytotoxic CD16+ NK cells and proinflammatory M1 macrophages at the maternal-fetal interface interferes with trophoblast invasion, spiral artery remodeling, and decidualization, potentially leading to miscarriage. Immunosuppressants like glucocorticoids (GCs) are used to regulate the immune microenvironment in clinical treatment, but the lack of safe and efficient tissue-specific drug delivery systems, especially immune cell-specific vectors, limits their widespread clinical application. Here, a previously uncharacterized delivery system is reported, termed GC-Exo-CD16Ab, in which GCs are loaded into purified exosomes derived from human umbilical cord mesenchymal stem cells, and subsequently decorated with antibody CD16Ab. GC-Exo-CD16Ab is biocompatible and has remarkable delivery efficiency toward CD16+ decidual natural killer (NK) cells and CD16+ macrophages in mice. This innovative approach effectively suppresses the cytotoxicity of decidual NK cells, inhibits M1 macrophage polarization, and regulates the decidual microenvironment, thereby enhancing placental and fetal morphology, and ultimately mitigating miscarriage risk in the abortion-prone mice. The developed GC-Exo-CD16Ab provides a feasible platform for precise and tissue-specific therapeutic strategies for miscarriage and pregnancy-related diseases.

Lys-63-specific deubiquitinase BRCC36 enhances the sensitivity of multiple myeloma cells to lenalidomide by inhibiting lysosomal degradation of cereblon.

Multiple myeloma (MM) is the second most common hematological tumor in adults. Immunomodulatory drugs (IMiDs), such as thalidomide and lenalidomide (Len), are effective drugs for the treatment of multiple myeloma. Len can recruit IKZF1 and IKZF3 to cereblon (CRBN), a substrate receptor of the cullin 4-RING E3 ligase (CRL4), promote their ubiquitination and degradation, and finally inhibit the proliferation of myeloma cells. However, MM patients develop resistance to IMiDs over time, leading to disease recurrence and deterioration. To explore the possible approaches that may enhance the sensitivity of IMiDs to MM, in this study, we used the proximity labeling technique TurboID and quantitative proteomics to identify Lys-63-specific deubiquitinase BRCC36 as a CRBN-interacting protein. Biochemical experiments demonstrated that BRCC36 in the BRISC complex protects CRBN from lysosomal degradation by specifically cleaving the K63-linked polyubiquitin chain on CRBN. Further studies found that a small-molecule compound SHIN1, which binds to BRISC complex subunit SHMT2, can upregulate CRBN by elevating BRCC36. The combination of SHIN1 and Len can further increase the sensitivity of MM cells to IMiDs. Therefore, this study provides the basis for the exploration of a possible strategy for the SHIN1 and Len combination treatment for MM.

MEIKIN expression and its C-terminal phosphorylation by PLK1 is closely related the metaphase-anaphase transition by affecting cyclin B1 and Securin stabilization in meiotic oocyte.

Oocyte meiotic maturation failure and chromosome abnormality is one of the main causes of infertility, abortion, and diseases. The mono-orientation of sister chromatids during the first meiosis is important for ensuring accurate chromosome segregation in oocytes. MEIKIN is a germ cell-specific protein that can regulate the mono-orientation of sister chromatids and the protection of the centromeric cohesin complex during meiosis I. Here we found that MEIKIN is a maternal protein that was highly expressed in mouse oocytes before the metaphase I (MI) stage, but became degraded by the MII stage and dramatically reduced after fertilization. Strikingly, MEIKIN underwent phosphorylation modification after germinal vesicle breakdown (GVBD), indicating its possible function in subsequent cellular event regulation. We further showed that MEIKIN phosphorylation was mediated by PLK1 at its carboxyl terminal region and its C-terminus was its key functional domain. To clarify the biological significance of meikin degradation during later stages of oocyte maturation, exogenous expression of MEIKIN was employed, which showed that suppression of MEIKIN degradation resulted in chromosome misalignment, cyclin B1 and Securin degradation failure, and MI arrest through a spindle assembly checkpoint (SAC)-independent mechanism. Exogenous expression of MEIKIN also inhibited metaphase II (MII) exit and early embryo development. These results indicate that proper MEIKIN expression level and its C-terminal phosphorylation by PLK1 are critical for regulating the metaphase-anaphase transition in meiotic oocyte. The findings of this study are important for understanding the regulation of chromosome segregation and the prevention meiotic abnormality.

[Evaluation of the role of standardized periodontal probing training on the teaching of undergraduates using the Florida probe system].

PURPOSE: To evaluate the effect of standardized periodontal probing training on the teaching of periodontal clinical probing for undergraduates by using Florida probe system. METHODS: Twenty undergraduates who practiced in the Department of Periodontology of Changzhou Stomatological Hospital from May 2022 to November 2022 were selected as the study objects and randomly divided into two groups with 10 students in each group. The experimental group received standardized periodontal probing training, while the control group did not receive training. Two groups of students used the traditional probe and the Florida probe to probe the left and right half-mouth teeth of one patient. In addition, a periodontal specialist used Florida probe to conduct full oral examination of the same patient, and the results were compared with those of the two groups of students. SPSS 26.0 software package was used for statistical analysis of the obtained data. RESULTS: There was no significant difference of probing depth(PD) between undergraduates and periodontal specialist in the experimental group (P＞0.05), while there was significant difference in the control group (P＜0.05). In the control group, PD values in the anterior area were not statistically different from those of periodontal specialist (P＞0.05), while PD values in the posterior area were statistically different (P＜0.05). Both groups of patients reported that the Florida probe system was more comfortable. CONCLUSIONS: Standardized periodontal probing training is helpful to improve the clinical probing ability of undergraduates. The use of Florida probe system can not only evaluate the teaching effect, but also improve the comfort level of patients, which is worthy of further application in the teaching course of periodontal probing for undergraduates.

Stimulation of mouse hair regrowth by exosomes derived from human umbilical cord mesenchymal stem cells.

BACKGROUND: There is an urgent need for new treatments to solve hair loss problem. As mesenchymal stem cells were proved to have effects on promoting tissue repair and regeneration, in which the exosome plays a vital role, we aim to investigate the influence of umbilical cord mesenchymal stem cells exosome (UCMSC-Exos) on hair growth and its mechanism. METHODS: The hUCMSC-Exos were extracted by ultracentrifugation. Primary fibroblasts were cultured with or without hUCMSC-Exos and cell proliferation was evaluated by CCK-8 assay. C57BL/6 mice model of depilation-induced hair regrowth was treated with either hUCMSC-Exos (200 µg/mL) or PBS on one side of the dorsal back. Real time quantitative PCR, flow cytometry analysis, immunohistochemistry and Immunofluorescent staining were used to analyze the regulative effect of hUCMSC-Exos on hair follicle stem/progenitor cells and Wnt/ß-catenin pathway. RESULTS: The proliferation of fibroblasts incubated with hUCMSC-Exos at the concentration of 200 µg/mL was greater than other groups. Treatment with hUCMSC-Exos resulted in rapid reentry into anagen. Hair follicle stem/progenitor cell markers (K15, Lgr5, Lgr6, CD34 and Lrig1) and Wnt/ß-catenin pathway related factors (Wnt5, Lef1, Lrp5 and ß-catenin) were increased in hUCMSC-Exos-injected region. CONCLUSION: hUCMSC-Exos promote fibroblasts proliferation and accelerate mouse hair regrowth by upregulating hair follicle stem/progenitor cell and Wnt/ß-catenin pathway, which suggests potential therapeutic approaches for hair loss disorders.

Multimodal Machine Learning-Based Ductal Carcinoma in situ Prediction from Breast Fibromatosis.

Objective: To develop a clinical-radiomics model using a multimodal machine learning method for distinguishing ductal carcinoma in situ (DCIS) from breast fibromatosis. Methods: The clinical factors, ultrasound features, and related ultrasound images of 306 patients (198 DCIS patients) were retrospectively collected. Patients in the development and validation cohort were 184 and 122, respectively. The independent clinical and ultrasound factors identified by the multivariable logistic regression analysis were used for the clinical-ultrasound model construction. Then, the region of interest of breast lesions was delineated and radiomics features were extracted. Six machine learning algorithms were trained to develop a radiomics model. The algorithm with higher and more stable prediction ability was chosen to convert the output of the results into the Radscore. Further, the independent clinical predictors and Radscore were enrolled into the logistic regression analysis to generate a combined clinical-radiomics model. The receiver operating characteristic curve analysis, DeLong test, and decision curve analysis were adopted to compare the prediction ability and clinical efficacy of three different models. Results: Among the six classifiers, logistic regression model was selected as the final radiomics model. Besides, the combined clinical-radiomics model exhibited a superior ability in distinguishing DCIS from breast fibromatosis to the clinical-ultrasound model and the radiomics model. Conclusion: The combined model by integrating clinical-ultrasound factors and radiomics features performed well in predicting DCIS, which might promote prompt interventions to improve the early diagnosis and prognosis of the patients.

Apramycin has high in vitro activity against Mycobacterium tuberculosis.

Introduction. Aminoglycoside antibiotics such as amikacin and kanamycin are important components in the treatment of Mycobacterium tuberculosis (Mtb) infection. However, more and more clinical strains are found to be aminoglycoside antibiotic-resistant. Apramycin is another kind of aminoglycoside antibiotic that is commonly used to treat infections in animals.Hypothesis. Apramycin may have in vitro activity against Mtb.Aim. This study aims to evaluate the efficacy of apramycin against Mtb in vitro and determine its epidemiological cut-off (ECOFF) value.Methodology. One hundred Mtb isolates, including 17 pansusceptible and 83 drug-resistant tuberculosis (DR-TB) strains, were analysed for apramycin resistance using the MIC assay.Results. Apramycin exhibited significant inhibitory activity against Mtb clinical isolates, with an MIC50 of 0.5 µg ml-1 and an MIC90 of 1 µg ml-1. We determined the tentative ECOFF value as 1 µg ml-1 for apramycin. The resistant rates of multidrug-resistant tuberculosis (MDR-TB), pre-extensively drug-resistant (pre-XDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) strains were 12.12 % (4/33), 20.69 % (6/29) and 66.67 % (14/21), respectively. The rrs gene A1401G is associated with apramycin resistance, as well as the cross-resistance between apramycin and other aminoglycosides.Conclusion. Apramycin shows high in vitro activity against the Mtb clinical isolates, especially the MDR-TB clinical isolates. This encouraging discovery calls for more research on the functions of apramycin in vivo and as a possible antibiotic for the treatment of drug-resistant TB.

Reduced actual vapor pressure exerts a significant influence on maize yield through vapor pressure deficit amid climate warming.

Understanding the impact of climate warming on crop yield and its associated mechanisms is paramount for ensuring food security. Here, we conduct a thorough analysis of the impact of vapor pressure deficit (VPD) on maize yield, leveraging a rich dataset comprising temporal and spatial observations spanning 40 years across 31 maize-growing locations in Northeast and North China. Our investigation extends to the influencing meteorological factors that drive changes in VPD during the maize growing phase. Regression analysis reveals a linear negative relationship between VPD and maize yield, demonstrating diverse spatiotemporal characteristics. Spatially, maize yield exhibits higher sensitivity to VPD in Northeast China (NEC), despite the higher VPD levels in North China Plain (NCP). The opposite patterns reveal that high VPD not invariably lead to detrimental yield impacts. Temporal analysis sheds light on an upward trend in VPD, with values of 0.05 and 0.02 kPa/10yr, accompanied by significant abrupt changes around 1996 in NEC and 2006 in NCP, respectively. These temporal shifts contribute to the heightened sensitivity of maize yield in both regions. Importantly, we emphasize the need to pay closer attention to the substantial the impact of actual vapor pressure on abrupt VPD changes during the maize growing phase, particularly in the context of ongoing climate warming.

Effects of cadmium on the intestinal health of the snail Bradybaena ravida Benson.

The heavy metal cadmium (Cd) is a toxic and bioaccumulative metal that can be enriched in the tissues and organs of living organisms through the digestive tract. However, more research is needed to determine whether food-sourced Cd affects the homeostasis of host gut microflora. In this study, the snail Bradybaena ravida (Benson) was used as a model organism fed with mulberry leaves spiked with different concentrations of Cd (0, 0.052, 0.71, and 1.94 mg kg-1). By combining 16S rRNA high-throughput sequencing with biochemical characterization, it was found that there were increases in the overall microbial diversity and abundances of pathogenic bacteria such as Corynebacterium, Enterococcus, Aeromonas, and Rickettsia in the gut of B. ravida after exposure to Cd. However, the abundances of potential Cd-resistant microbes in the host's gut, including Sphingobacterium, Lactococcus, and Chryseobacterium, decreased with increasing Cd concentrations in the mulberry leaves. In addition, there was a significant reduction in activities of energy, nutrient metabolism, and antioxidant enzymes for gut microbiota of snails treated with high concentrations of Cd compared to those with low ones. These findings highlight the interaction of snail gut microbiota with Cd exposure, indicating the potential role of terrestrial animal gut microbiota in environmental monitoring through rapid recognition and response to environmental pollution.

Clinical features and genetic analysis of developmental and epileptic encephalopathy caused by biallelic variants of CACNA1B.

Objective: To analyze the clinical features and genetic etiology of a patient with developmental and epileptic encephalopathy. Methods: The clinical information and peripheral blood of the patient and their family members were collected before the whole exome sequencing analysis was performed and Sanger sequencing was employed to verify the potential variant. Results: The patient presented with epilepsy and cerebral palsy with his parents, brother, and sister being all healthy. Whole exome sequencing analysis revealed that the child carried the paternal c.823del (p. R275Gfs*31) heterozygous variant and the maternal c.2456del (p.V819Gfs*190) heterozygous variant of the CACNA1B gene. Pedigree verification found that the elder brother and amniotic fluid of fetus in womb carried the paternal c.823del heterozygous variant, and the elder sister carried the maternal c.2456del heterozygous variant, which conformed to the law of autosomal recessive inheritance. Neither of these two variants has been reported in the literature and has not been included in the Genomic Mutation Frequency Database (gnomAD); according to the American Academy of Medical Genetics and Genomics Variation Grading Guidelines (ACMG), both variants are classified as pathogenic variants (PVS1+PM2-Supporting + PM3). Conclusion: This study reported the first case of a child with neurodevelopmental disorder and epilepsy caused by a new compound heterozygous variant of the CACNA1B gene in China, clarified its genetic etiology, enriched the mutation spectrum and disease spectrum of CACNA1B gene, and provided a basis for prenatal diagnosis of the family.

Antibacterial Property and Mechanisms of Au@Ag Core-Shell Nanoparticles with Near-Infrared Absorption Against E. faecalis Infection of Dentin.

Background: Enterococcus faecalis (E. faecalis) is one of the main pathogens responsible for refractory root canal infections in the teeth and shows resistance against various antibacterial managements. Effective control of E. faecalis infection is a prerequisite for successful treatment of refractory apical periodontitis. This study aimed to analyze the antibacterial activity and mechanisms of Au@Ag nanoparticles (NPs) combined with photothermal therapy (PTT) against the original and Ag+-resistant E. faecalis. Methods: Au@AgNPs with optimal shell thicknesses were synthesized and characterized. The antibacterial activity of Au@AgNPs with PTT against the original or Ag+-resistant E. faecalis was evaluated, and the antibiofilm activity was tested on E. faecalis biofilm on the dentin of teeth. The potential antibacterial mechanisms of Au@AgNPs combined with PTT against E. faecalis have also been studied. Moreover, its influence on dentin microhardness and cytotoxicity was assessed. Results: This study revealed that Au@AgNPs combined with PTT showed enhanced antibacterial and antibiofilm effects, no negative effects on dentin microhardness, and low cytotoxicity toward human periodontal ligament cells (hPDLCs). Moreover, Au@AgNPs combined with PTT effectively inhibited the growth of Ag+-resistant E. faecalis. Its antibacterial effects may be exerted through the release of silver ions (Ag+), destruction of the cell membrane, production of reactive oxygen species (ROS) and inhibition of adenosine triphosphate (ATP) production. Hyperthermia generated by Au@AgNPs with PTT reduced membrane fluidity and enhanced Ag+ sensitivity by downregulating fabF expression. The upregulated expression of heat shock genes demonstrated that the Ag+ released from Au@AgNPs compromised the heat adaptation of E. faecalis. Conclusion: PTT significantly enhanced Ag+ sensitivity of the original and Ag+-resistant E. faecalis. Au@AgNPs combined with PTT may have the potential to be developed as a new antibacterial agent to control E. faecalis infections in teeth.

P300 regulates histone crotonylation and preimplantation embryo development.

Histone lysine crotonylation, an evolutionarily conserved modification differing from acetylation, exerts pivotal control over diverse biological processes. Among these are gene transcriptional regulation, spermatogenesis, and cell cycle processes. However, the dynamic changes and functions of histone crotonylation in preimplantation embryonic development in mammals remain unclear. Here, we show that the transcription coactivator P300 functions as a writer of histone crotonylation during embryonic development. Depletion of P300 results in significant developmental defects and dysregulation of the transcriptome of embryos. Importantly, we demonstrate that P300 catalyzes the crotonylation of histone, directly stimulating transcription and regulating gene expression, thereby ensuring successful progression of embryo development up to the blastocyst stage. Moreover, the modification of histone H3 lysine 18 crotonylation (H3K18cr) is primarily localized to active promoter regions. This modification serves as a distinctive epigenetic indicator of crucial transcriptional regulators, facilitating the activation of gene transcription. Together, our results propose a model wherein P300-mediated histone crotonylation plays a crucial role in regulating the fate of embryonic development.

Unveiling microglia heterogeneity in intracerebral hemorrhage.

Microglia are important innate immune cells in the brain, and a rich diversity of subtypes has recently been discovered that expand beyond the traditional classification of traditional M1 (pro-inflammatory) and M2 (anti-inflammatory) classifications. Intracerebral hemorrhage (ICH) is a devastating form of stroke, and the understanding of its later-stage pathological mechanisms remains incomplete. In this study, through the analysis of single-cell transcripts from mice brains 14 days post-ICH, three disease-associated expression patterns of microglia were identified. These include a lipid metabolism and phagocytosis phenotype reminiscent of Disease-Associated Microglia (DAM) initially discovered in Alzheimer's disease models, a phenotype associated with angiogenesis, and a relatively independent phenotype similar to the pro-inflammatory M1 state. These findings were further validated through immunofluorescence in both mouse and human specimens. In addition, analysis of single-cell transcripts from mice brains 3 days post-ICH suggested that microglia involved in lipid metabolism and phagocytosis likely emerge from early proliferating populations. Given the distinct origins and phenotypic characteristics of pro-inflammatory and reparative microglia, interventions targeting these cells hold the potential to modulate the delicate balance between injury and repair during the pathophysiological process of ICH, highlighting a pivotal direction for future therapeutic strategies.

Loss-of-function mutations in Keratin 32 gene disrupt skin immune homeostasis in pityriasis rubra pilaris.

Pityriasis rubra pilaris (PRP) is an inflammatory papulosquamous dermatosis, characterized by hyperkeratotic follicular papules and erythematous desquamative plaques. The precise pathogenic mechanism underlying PRP remains incompletely understood. Herein, we conduct a case-control study involving a cohort of 102 patients with sporadic PRP and 800 healthy controls of Han Chinese population and identify significant associations (P = 1.73 × 10-6) between PRP and heterozygous mutations in the Keratin 32 gene (KRT32). KRT32 is found to be predominantly localized in basal keratinocytes and exhibits an inhibitory effect on skin inflammation by antagonizing the NF-κB pathway. Mechanistically, KRT32 binds to NEMO, promoting excessive K48-linked polyubiquitination and NEMO degradation, which hinders IKK complex formation. Conversely, loss-of-function mutations in KRT32 among PRP patients result in NF-κB hyperactivation. Importantly, Krt32 knockout mice exhibit a PRP-like dermatitis phenotype, suggesting compromised anti-inflammatory function of keratinocytes in response to external pro-inflammatory stimuli. This study proposes a role for KRT32 in regulating inflammatory immune responses, with damaging variants in KRT32 being an important driver in PRP development. These findings offer insights into the regulation of skin immune homeostasis by keratin and open up the possibility of using KRT32 as a therapeutic target for PRP.

Global net climate effects of anthropogenic reactive nitrogen.

Anthropogenic activities have substantially enhanced the loadings of reactive nitrogen (Nr) in the Earth system since pre-industrial times1,2, contributing to widespread eutrophication and air pollution3-6. Increased Nr can also influence global climate through a variety of effects on atmospheric and land processes but the cumulative net climate effect is yet to be unravelled. Here we show that anthropogenic Nr causes a net negative direct radiative forcing of -0.34 [-0.20, -0.50] W m-2 in the year 2019 relative to the year 1850. This net cooling effect is the result of increased aerosol loading, reduced methane lifetime and increased terrestrial carbon sequestration associated with increases in anthropogenic Nr, which are not offset by the warming effects of enhanced atmospheric nitrous oxide and ozone. Future predictions using three representative scenarios show that this cooling effect may be weakened primarily as a result of reduced aerosol loading and increased lifetime of methane, whereas in particular N2O-induced warming will probably continue to increase under all scenarios. Our results indicate that future reductions in anthropogenic Nr to achieve environmental protection goals need to be accompanied by enhanced efforts to reduce anthropogenic greenhouse gas emissions to achieve climate change mitigation in line with the Paris Agreement.