Identifying the Spatial Architecture That Restricts the Proximity of CD8+ T Cells to Tumor Cells in Pancreatic Ductal Adenocarcinoma.

The anti-tumor function of CD8+ T cells is dependent on their proximity to tumor cells. Current studies have focused on the infiltration level of CD8+ T cells in the tumor microenvironment, while further spatial information, such as spatial localization and inter-cellular communication, have not been defined. In this study, co-detection by indexing (CODEX) was designed to characterize PDAC tissue regions with seven protein markers in order to identify the spatial architecture that regulates CD8+ T cells in human pancreatic ductal adenocarcinoma (PDAC). The cellular neighborhood algorithm was used to identify a total of six conserved and distinct cellular neighborhoods. Among these, one unique spatial architecture of CD8+ T and CD4+ T cell-enriched neighborhoods enriched the majority of CD8+ T cells, but heralded a poor prognosis. The proximity analysis revealed that the CD8+ T cells in this spatial architecture were significantly closer to themselves and the CD4+ T cells than to the tumor cells. Collectively, we identified a unique spatial architecture that restricted the proximity of CD8+ T cells to tumor cells in the tumor microenvironment, indicating a novel immune evasion mechanism of pancreatic ductal adenocarcinoma in a topologically regulated manner and providing new insights into the biology of PDAC.

In situ synergistic halogen passivation of semiconducting PbS quantum dot inks for efficient photovoltaics.

Lead sulfide colloidal quantum dots (PbS CQDs) show great potential in next-generation photovoltaics. However, their high specific surface area and complex surface crystallography lead to a high surface trap density, which normally requires more than one type of capping ion or ligand to achieve effective surface passivation. In this study, we performed in situ mixed halogen passivation (MHP) during the direct synthesis of semiconducting PbS CQD inks by using different lead halogens. The different halogens can bind with the surface of the CQD throughout the nucleation/growth process, resulting in optimal surface configuration. As a result, the MHP CQD exhibited superior surface passivation compared to the conventionally iodine-capped CQDs. Finally, we achieved a substantial improvement in efficiency from 10.64% to 12.58% after the MHP treatment. Our work demonstrates the advantages of exploring efficient passivation in the directly synthesized CQD inks.

The modern scientific mystery of traditional Chinese medicine processing--take some common traditional Chinese medicine as examples.

The processing of traditional Chinese medicine (TCM) is a unique traditional pharmaceutical technology in China, which is the most important feature that distinguishes Chinese medicine from natural medicine and plant medicine. Since the record in Huangdi Neijing (Inner Canon of the Yellow Emperor), till now, the processing of TCM has experienced more than 2000 years of inheritance, innovation, and development, which is a combination of TCM theory and clinical practice, and plays an extremely important position in the field of TCM. In recent years, as a clinical prescription of TCM, Chinese herbal pieces have played a significant role in the prevention and control of the COVID-19 and exhibited their unique value, and therefore they have become the highlight of China's clinical treatment protocol and provided Chinese experience and wisdom for the international community in the prevention and control of the COVID-19 epidemic. This paper outlines the research progress in the processing of representative TCM in recent years, reviews the mechanism of the related effects of TCM materials after processing, such as changing the drug efficacy and reducing the toxicity, puts forward the integration and application of a variety of new technologies and methods, so as to reveal the modern scientific mystery of the processing technology of TCM.

Exposure to Airborne PM2.5 Water-Soluble Inorganic Ions Induces a Wide Array of Reproductive Toxicity.

Water-soluble inorganic ions (WSIIs, primarily NH4+, SO42-, and NO3-) are major components in ambient PM2.5, but their reproductive toxicity remains largely unknown. An animal study was conducted where parental mice were exposed to PM2.5 WSIIs or clean air during preconception and the gestational period. After delivery, all maternal and offspring mice lived in a clean air environment. We assessed reproductive organs, gestation outcome, birth weight, and growth trajectory of the offspring mice. In parallel, we collected birth weight and placenta transcriptome data from 150 mother-infant pairs from the Rhode Island Child Health Study. We found that PM2.5 WSIIs induced a broad range of adverse reproductive outcomes in mice. PM2.5 NH4+, SO42-, and NO3- exposure reduced ovary weight by 24.22% (p = 0.005), 14.45% (p = 0.048), and 16.64% (p = 0.022) relative to the clean air controls. PM2.5 SO42- exposure reduced the weight of testicle by 5.24% (p = 0.025); further, mice in the PM2.5 SO42- exposure group had 1.81 (p = 0.027) fewer offspring than the control group. PM2.5 NH4+, SO42-, and NO3- exposure all led to lower birth than controls. In mice, 557 placenta genes were perturbed by exposure. Integrative analysis of mouse and human data suggested hypoxia response in placenta as an etiological mechanism underlying PM2.5 WSII exposure's reproductive toxicity.

Framework nucleic acids as promising reactive oxygen species scavengers for anti-inflammatory therapy.

Reactive oxygen species (ROS) are an array of derivatives of molecular oxygen that participate in multiple physiological processes under the control of redox homeostasis. However, under pathological conditions, the over-production of ROS often leads to oxidative stress and inflammatory reactions, indicating a potential therapeutic target. With the rapid development of nucleic acid nanotechnology, scientists have exploited various DNA nanostructures with remarkable biocompatibility, programmability, and structural stability. Among these novel organic nanomaterials, a group of skeleton-like framework nucleic acid (FNA) nanostructures attracts the most interest due to their outstanding self-assembly, cellular endocytosis, addressability, and functionality. Surprisingly, different FNAs manifest similarly satisfactory antioxidative and anti-inflammatory effects during their biomedical application process. First, they are intrinsically endowed with the ability to neutralize ROS due to their DNA nature. Therefore, they are extensively involved in the complicated inflammatory signaling network. Moreover, the outstanding editability of FNAs also allows for flexible modifications with nucleic acids, aptamers, peptides, antibodies, low-molecular-weight drugs, and so on, thus further strengthening the targeting and therapeutic ability. This review focuses on the ROS-scavenging potential of three representative FNAs, including tetrahedral framework nucleic acids (tFNAs), DNA origami, and DNA hydrogels, to summarize the recent advances in their anti-inflammatory therapy applications. Although FNAs exhibit great potential in treating inflammatory diseases as promising ROS scavengers, massive efforts still need to be made to overcome the emerging challenges in their clinical translation.

Blockade of pan-viral propagation by inhibition of host cell PNPT1.

For successful viral propagation within infected cells, the virus needs to overcome the cellular integrated stress response (ISR), triggered during viral infection, which, in turn, inhibits general protein translation. This paper reports a tactic employed by viruses to suppress the ISR by upregulating host cell polyribonucleotide nucleotidyltransferase 1 (PNPT1). The propagation of adenovirus, murine cytomegalovirus and hepatovirus within their respective host cells induces PNPT1 expression. Notably, when PNPT1 is knocked down, the propagation of all three viruses is prevented. Mechanistically, the inhibition of PNPT1 facilitates the relocation of mitochondrial double-stranded RNAs (mt-dsRNAs) to the cytoplasm, where they activate RNA-activated protein kinase (PKR). This activation leads to eukaryotic initiation factor 2α (eIF2α) phosphorylation, resulting in the suppression of translation. Furthermore, by scrutinizing the PNPT1 recognition element and screening 17,728 drugs and bioactive compounds approved by the US Food and Drug Administration, lanatoside C was identified as a potent PNPT1 inhibitor. This compound impedes the propagation of adenovirus, murine cytomegalovirus and hepatovirus, and suppresses production of the severe acute respiratory syndrome coronavirus-2 spike protein. These discoveries shed light on a novel strategy to impede pan-viral propagation by activating the host cell mt-dsRNA-PKR-eIF2α signalling axis.

Interior-Confined Vacancy in Potassium Manganese Hexacyanoferrate for Ultra-Stable Potassium-Ion Batteries.

Metal hexacyanoferrates (HCFs) are viewed as promising cathode materials for potassium-ion batteries (PIBs) because of their high theoretical capacities and redox potentials. However, the development of an HCF cathode with high cycling stability and voltage retention is still impeded by the unavoidable Fe(CN)6 vacancies (VFeCN) and H2O in the materials. Here, a repair method is proposed that significantly reduces the VFeCN content in potassium manganese hexacyanoferrate (KMHCF) enabled by the reducibility of sodium citrate and removal of ligand H2O at high temperature (KMHCF-H). The KMHCF-H obtained at 90 °C contains only 2% VFeCN, and the VFeCN is concentrated in the lattice interior. Such an integrated Fe-CN-Mn surface structure of the KMHCF-H cathode with repaired surface VFeCN allows preferential decomposition of potassium bis(fluorosulfonyl)imide (KFSI) in the electrolyte, which constitutes a dense anion-dominated cathode electrolyte interphase (CEI) , inhibiting effectively Mn dissolution into the electrolyte. Consequently, the KMHCF-H cathode exhibits excellent cycling performance for both half-cell (95.2 % at 0.2 Ag-1 after 2000 cycles) and full-cell (99.4 % at 0.1 Ag-1 after 200 cycles). This thermal repair method enables scalable preparation of KMHCF with a low content of vacancies, holding substantial promise for practical applications of PIBs.

Gel-mediated recruitment of conventional type 1 dendritic cells potentiates the therapeutic effects of radiotherapy.

The efficacy of radiotherapy has not yet achieved optimal results, partially due to insufficient priming and infiltration of effector immune cells within the tumor microenvironment (TME), which often exhibits suppressive phenotypes. In particular, the infiltration of X-C motif chemokine receptor 1 (XCR1)-expressing conventional type-1 dendritic cells (cDC1s), which are critical in priming CD8+ cytotoxic T cells, within the TME is noticeably restricted. Hence, we present a facile methodology for the efficient fabrication of a calcium phosphate hydrogel loaded with X-C motif chemokine ligand 1 (XCL1) to selectively recruit cDC1s. Manganese phosphate microparticles were also loaded into this hydrogel to reprogram the TME via cGAS-STING activation, thereby facilitating the priming of cDC1s propelled specific CD8+ T cells. They also polarize tumor-associated macrophages towards the M1 phenotype and reduce the proportion of regulatory cells, effectively reversing the immunosuppressive TME into an immune-active one. The yielded XCL1@CaMnP gel exhibits significant efficacy in enhancing the therapeutic outcomes of radiotherapy, particularly when concurrently administered with postoperative radiotherapy, resulting in an impressive 60 % complete response rate. Such XCL1@CaMnP gel, which recruits cDC1s to present tumor antigens generated in situ, holds great potential as a versatile platform for enhanced cancer treatment through modulating the immunosuppressive TME.

Surface Energy Engineering of Buried Interface for Highly Stable Perovskite Solar Cells with Efficiency Over 25.

The abundant oxygen-related defects (e.g., O vacancies, O-H) in the TiO2 electron transport layer results in high surface energy, which is detrimental to effective carrier extraction and seriously impairs the photovoltaic performance and stability of perovskite solar cells. Here, novel surface energy engineering (SEE) is developed by applying a surfactant of heptadecafluorooctanesulfonate tetraethylammonium (HFSTA) on the surface of the TiO2 . Theoretical calculations show that the HFSTA-TiO2 is less prone to form O vacancies, leading to lower surface energy, thus improving the carrier-extraction efficiency. The experimental results show that superior perovskite film is obtained due to the reduced heterogeneous nucleation sites and improved crystallization process on the modified TiO2 . Furthermore, the flexible long alkyl chains in HFSTA considerably relieve the compressive stresses at the buried interface. By combining the passivation of TiO2 , crystallization process modulation, and stress relief, a champion PCE up to 25.03% is achieved. The device without encapsulation sustains 92.2% of its initial PCE after more than 2500 h storage under air ambient with relative humidity of 25-30%. The SEE of a buried interface paves a new way toward high-efficiency, stable perovskite solar cells.

Autonomous indication of electrical degradation in polymers.

Dielectric polymers are ubiquitous as electrical insulation in electronic devices and electrical systems. Electrical degradation of dielectric polymers tends to initiate catastrophic failure of numerous devices and systems, but its detection and early warning remain challenging. Here we report a general material strategy that signals the electrical degradation of dielectric polymers by autonomously presenting a visually discernible warning in the form of a pronounced colour change. This colour change is induced by the chromogenic response of molecular indicators blended with the polymer, which are chemically activated by the oxygen radicals generated in situ during the electrical degradation of the polymer. We unveil that the structural degradation and electrical properties of the dielectric polymer are quantitatively correlated with the colour difference. Such a chromogenic process is autonomous without the need of human intervention or other external energy, thus offering the convenience to lower or even eliminate the risk of dielectric failure.

Enhanced formation of methane hydrate from active ice with high gas uptake.

Gas hydrates provide alternative solutions for gas storage & transportation and gas separation. However, slow formation rate of clathrate hydrate has hindered their commercial development. Here we report a form of porous ice containing an unfrozen solution layer of sodium dodecyl sulfate, here named active ice, which can significantly accelerate gas hydrate formation while generating little heat. It can be readily produced via forming gas hydrates with water containing very low dosage (0.06 wt% or 600 ppm) of surfactant like sodium dodecyl sulfate and dissociating it below the ice point, or by simply mixing ice powder or natural snow with the surfactant. We prove that the active ice can rapidly store gas with high storage capacity up to 185 Vg Vw-1 with heat release of ~18 kJ mol-1 CH4 and the active ice can be easily regenerated by depressurization below the ice point. The active ice undergoes cyclic ice-hydrate-ice phase changes during gas uptake/release, thus removing most critical drawbacks of hydrate-based technologies. Our work provides a green and economic approach to gas storage and gas separation and paves the way to industrial application of hydrate-based technologies.

A High-Entropy Prussian Blue Analog for Aqueous Potassium-Ion Batteries.

Aqueous potassium-ion batteries (AKIBs) are considered promising electrochemical energy storage systems owing to their high safety and cost-effectiveness. However, the structural degradation resulting from the repeated accommodation of large K-ions and the dissolution of active electrode materials in highly dielectric aqueous electrolytes often lead to unsatisfactory electrochemical performance. This study introduces a high-entropy Prussian blue analog (HEPBA) cathode material for AKIBs, demonstrating significantly enhanced structural stability and reduced dissolution. The HEPBA exhibits a highly reversible specific capacity of 102.4 mAh g-1 , with 84.4% capacity retention after undergoing 3448 cycles over a duration of 270 days. Mechanistic insights derived from comprehensive experimental investigations, supported by theoretical calculations, reveal that the HEPBA features a robust structure resistant to dissolution, a solid-solution reaction pathway with negligible volume variation during charge-discharge, and efficient ion transport kinetics characterized by a reduced band gap and a low energy barrier. This study represents a measurable step forward in the development of long-lasting electrode materials for aqueous AKIBs.

Characteristics and Complete Genome Analysis of a Pathogenic Aeromonas Veronii SJ4 from Diseased Siniperca Chuatsi.

As an opportunistic pathogen, Aeromonas veronii can cause hemorrhagic septicemia of various aquatic animals. In our present study, a dominant strain SJ4, isolated from naturally infected mandarin fish (Siniperca chuatsi), was identified as A. veronii according to the morphological, physiological, and biochemical features, as well as molecular identification. Intraperitoneal injection of A. veronii SJ4 into S. chuatsi revealed clinical signs similar to the natural infection, and the median lethal dosage (LD50) of the SJ4 to S. chuatsi in a week was 3.8 × 105 CFU/mL. Histopathological analysis revealed that the isolate SJ4 could cause cell enlargement, obvious hemorrhage, and inflammatory responses in S. chuatsi. Detection of virulence genes showed the isolate SJ4 carried act, fim, flgM, ompA, lip, hly, aer, and eprCAL, and the isolate SJ4 also produce caseinase, dnase, gelatinase, and hemolysin. In addition, the complete genome of A. veronii SJ4 was sequenced, and the size of the genome of A. veronii SJ4 was 4,562,694 bp, within a G + C content of 58.95%, containing 4079 coding genes. Nine hundred ten genes encoding for several virulence factors, such as type III and VI secretion systems, flagella, motility, etc., were determined based on the VFDB database. Besides, 148 antibiotic resistance-related genes in 27 categories related to tetracyclines, fluoroquinolones, aminoglycosides, macrolides, chloramphenicol, and cephalosporins were also annotated. The present results suggested that A. veronii was etiological agent causing the bacterial septicemia of S. chuatsi in this time, as well as provided a valuable base for revealing pathogenesis and resistance mechanism of A. veronii.

[Analysis of a Chinese pedigree affected with van der Woude syndrome due to variant of IRF6 gene].

OBJECTIVE: To explore the genetic characteristics of a Chinese pedigree affected with van der Woude syndrome (VWS). METHODS: A proband who had visited the Drum Tower Hospital Affiliated to Nanjing University Medical School in May 2020 for "two previous pregnancies with cleft lip and palate" was selected as the study subject. Trio-whole exome sequencing (trio-WES) was carried out for the patient. Candidate variants were verified by Sanger sequencing of her pedigree members (8 individuals from four generations) and bioinformatic analysis. Chromosomal microarray analysis (CMA) was used to rule out copy number variations in the fetuses. RESULTS: Trio-WES revealed that the proband and her father had both harbored a heterozygous c.742G>T (p.G248C) missense variant of the IRF6 gene, for which her mother was of the wild type. The variant was located in a region with important functions and has not been reported previously. Prediction with several software suggested that it is likely to have a significant impact on the protein structure/function and is highly correlated with the specific phenotypes in this pedigree. Sanger sequencing confirmed co-segregation of the genotypes and phenotypes in the pedigree. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), this variant was rated as likely pathogenic (PM1+PM2_Supporting+PP1+PP3+PP4). Based on the above results, pre-implantation genetic diagnosis was carried out for the proband, which has led to birth of a healthy offspring with normal results for both site testing and CMA. CONCLUSION: The IRF6: c.742G>T (p.G248C) heterozygous variant probably underlay the VWS in this pedigree. Above finding has also enabled reproductive guidance for the proband.

The relationship between social support and academic engagement among university students: the chain mediating effects of life satisfaction and academic motivation.

BACKGROUND: University students' academic engagement has a significant impact on their academic performance and career development. METHODS: In order to explore the influential mechanisms of social support on university students' academic engagement and the mediating role of academic motivation and life satisfaction, this study used the Adolescent Social Support Scale, University Students' Academic Engagement Scale Questionnaire, Adolescent Student Life Satisfaction Scale and University Students' Academic Motivation Questionnaire, to conduct a questionnaire survey and empirical analysis on 2106 Chinese university students. RESULTS: (1) social support significantly and positively predicts academic engagement; (2) social support influences academic engagement through the mediating effect of life satisfaction; (3) social support influences academic engagement through the mediating effect of academic motivation; (4) life satisfaction and academic motivation play a chain mediating role in the effect of social support on academic engagement. CONCLUSIONS: This study contributes to understanding the underlying mechanisms of the relationship between social support and academic engagement, which in turn provides insights for universities and the departments concerned to make measures to improve the level of university students' academic engagement.

Academic Motivation and Social Support: Mediating and Moderating the Life Satisfaction and Learning Burnout Link.

Background: The phenomenon of university students' learning burnout has attracted the research of many scholars because of its typicality. This study aims to explore the relationship between life satisfaction, academic motivation, social support and learning burnout among university students and its underlying mechanisms. Methods: A total of 1917 university students participated in this cross-sectional study. Research instruments included the Adolescent Student Life Satisfaction Scale, University Students' Academic Motivation Questionnaire, Adolescent Learning Burnout Scale and Adolescent Social Support Scale. The data analysis comprised descriptive statistics, correlation analyses, and assessment of multicollinearity through Variance Inflation Factor (VIF). Advanced analyses were conducted using Model 4 for mediation and Model 1 for moderation from the PROCESS macro. Results: (1) life satisfaction significantly and positively predicts academic motivation; (2) academic motivation significantly and negatively predicts learning burnout; and (3) life satisfaction significantly and negatively predicts learning burnout; (4) academic motivation partially mediates the effect of life satisfaction on learning burnout; and (5) social support plays a moderating role in the effect of academic motivation on learning burnout. Discussions: These results illuminate the complex web of relationships among life satisfaction, academic motivation, social support, and learning burnout. The partial mediating role of academic motivation underscores its significance in the link between life satisfaction and learning burnout. Additionally, the moderating impact of social support emphasizes its role in ameliorating or exacerbating the effects of academic motivation on learning burnout. Conclusion: These findings can help researchers and educators better understand the underlying mechanisms between life satisfaction and learning burnout. Meanwhile, the results of the study can provide practical and effective operational suggestions for preventing and intervening in university students' learning burnout and improving their academic motivation.

Carbon budget of different forests in China estimated by an individual-based model and remote sensing.

Forests play a key role in the regional or global carbon cycle. Determining the forest carbon budget is of great significance for estimating regional carbon budgets and formulating forest management policies to cope with climate change. However, the carbon budget of Chinese different forests and their relative contributions are not completely clear so far. We evaluated the carbon budget of different forests from 1981 to 2020 in China through combining model with remote sensing observation. In addition, we also determined the relative contribution of carbon budget of each forest type to all forests in China. Eight forest types were studied: evergreen coniferous forest (ECF), deciduous coniferous forest (DCF), coniferous and broad-leaved mixed forest (CBF), deciduous broad-leaved forest (DBF), evergreen broad-leaved forest (EBF), evergreen deciduous broad-leaved mixed forest (EDBF), seasonal rain forest (SRF), and rain forest (RF). The results indicated that the Chinese forests were mainly carbon sink from 1981 to 2020, particularly the annual average carbon budget of forest from 2011 to 2020 was 0.191 PgC·a-1. Spatially, the forests' carbon budget demonstrated obvious regional differences, gradually decreasing from Southeast China to Northwest China. The relative contributions of carbon budget in different forests to all forests in China were different. During 2011-2020, the ECF forests contributed the most carbon budget (34.45%), followed by DBF forests (25.89%), EBF forests (24.82%), EDBF forests (13.10%), RF forests (2.23%), SRF forests (3.14%) and CBF forests (1.14%). However, the DCF forests were found mainly as carbon source. These results contribute to our understanding of regional carbon budget of forests.

Study on acoustic properties of hydrate-bearing sediments with reconstructed CO2 hydrate in different layers during CH4 hydrate mining.

Natural gas hydrate (NGH), a clean energy source with huge reserves in nature, and its safe and efficient exploitation fits perfectly with the UN Sustainable Development Goals (SDG-7). However, large-scale NGH decomposition frequently results in subsea landslides, reservoir subsidence, and collapse. In this work, in order to achieve safe and efficient exploitation of NGHs, the stability variation of different reservoir layers by depressurization/intermittent CO2/N2 injection (80:20 mol%, 50:50 mol%) was investigated using acoustic properties (P-wave velocity, elastic modulus), as well as reservoir subsidence under an overburden stress of 10 MPa. The P-wave velocity increased from 1282 m/s to 2778 m/s in the above-reservoir and from 1266 m/s to 2564 m/s in the below-reservoir, significantly increasing reservoir strength after CO2 hydrate formation. The P-wave velocity and elastic modulus in the top reconstructed reservoir were continually decreased by the shear damage of the overlying stress, while they remained stable in the bottom reconstructed reservoir during hydrate mining. However, due to superior pressure-bearing ability of the top CO2 hydrate reservoir, which was lacking in the bottom CO2 hydrate reservoir, the reservoir subsidence was relieved greatly. Despite the stiffness strength of reconstructed reservoir was ensured with CO2/N2 sweeping, the skeletal structure of CH4 hydrate reservoir was destroyed, and only the formation of CO2 hydrate could guarantee the stability of P-wave velocity and elastic modulus which was most beneficial to relieve reservoir subsidence. A large amount of CO2 was used in reservoir reconstruction and CH4 hydrate mining, which achieved the geological storage of CO2 (SDG-13). This work provided a new idea for safe and efficient NGHs mining in the future, and the application of acoustic properties served as a guide for the efficient construction of reconstructed reservoirs and offers credible technical assistance for safe exploitation of NGHs.

Efferocytosis Nanoinhibitors to Promote Secondary Necrosis and Potentiate the Immunogenicity of Conventional Cancer Therapies for Improved Therapeutic Benefits.

Efferocytosis of apoptotic cancer cells by tumor-associated macrophages or other phagocytes is reported to promote tumor immunosuppression by preventing them from secondary necrosis, which would lead to the release of intracellular components and thus enhanced immunogenicity. Therefore, current apoptosis-inducing cancer treatments (e.g., chemotherapy and radiotherapy) are less satisfactory in eliciting antitumor immunity. Herein, a nanoparticulate inhibitor of efferocytosis is prepared by encapsulating BMS777607, a hydrophobic inhibitor of receptors in macrophages responsible for phosphatidylserine-dependent efferocytosis, with biocompatible poly(lactic-co-glycolic acid) and its amphiphilic derivatives. The yielded nano-BMS can inhibit the efferocytosis of apoptotic cancer cells, thus redirecting them to immunogenic secondary necrosis. As a result, intratumorally injected nano-BMS is capable of activating both innate and adaptive antitumor immunity to achieve greatly improved therapeutic responses, when synergized with nonimmunogenic chemotherapy by cisplatin, immunogenic chemotherapy by oxaliplatin, or radiotherapy by external beams. Moreover, we further demonstrate that the inhalation of nano-BMS could significantly promote the efficacy of cisplatin chemotherapy to suppress tumor lung metastases. Therefore, this study highlights a general strategy to potentiate the immunogenicity of different cancer treatments by suppressing efferocytosis-propelled tumor immunosuppression, showing tremendous clinical potential in rescuing existing cancer therapies for more effective treatment.

NAD+ rescues aging-induced blood-brain barrier damage via the CX43-PARP1 axis.

Blood-brain barrier (BBB) function deteriorates during aging, contributing to cognitive impairment and neurodegeneration. It is unclear what drives BBB leakage in aging and how it can be prevented. Using single-nucleus transcriptomics, we identified decreased connexin 43 (CX43) expression in cadherin-5+ (Cdh5+) cerebral vascular cells in naturally aging mice and confirmed it in human brain samples. Global or Cdh5+ cell-specific CX43 deletion in mice exacerbated BBB dysfunction during aging. The CX43-dependent effect was not due to its canonical gap junction function but was associated with reduced NAD+ levels and mitochondrial dysfunction through NAD+-dependent sirtuin 3 (SIRT3). CX43 interacts with and negatively regulates poly(ADP-ribose) polymerase 1 (PARP1). Pharmacologic inhibition of PARP1 by olaparib or nicotinamide mononucleotide (NMN) supplementation rescued NAD+ levels and alleviated aging-associated BBB leakage. These findings establish the endothelial CX43-PARP1-NAD+ pathway's role in vascular aging and identify a potential therapeutic strategy to combat aging-associated BBB leakage with neuroprotective implications.