Injectable Hydrogel Mucosal Vaccine Elicits Protective Immunity against Respiratory Viruses.

Intranasal vaccines, eliciting mucosal immune responses, can prevent early invasion, replication, and transmission of pathogens in the respiratory tract. However, the effective delivery of antigens through the nasal barrier and boosting of a robust systematic and mucosal immune remain challenges in intranasal vaccine development. Here, we describe an intranasally administered self-healing hydrogel vaccine with a reversible strain-dependent sol-gel transition by precisely modulating the self-assembly processes between the natural drug rhein and aluminum ions. The highly bioadhesive hydrogel vaccine enhances antigen stability and prolongs residence time in the nasal cavity and lungs by confining the antigen to the surface of the nasal mucosa, acting as a "mucosal mask". The hydrogel also stimulates superior immunoenhancing properties, including antigen internalization, cross-presentation, and dendritic cell maturation. Furthermore, the formulation recruits immunocytes to the nasal mucosa and nasal-associated lymphoid tissue (NALT) while enhancing antigen-specific humoral, cellular, and mucosal immune responses. Our findings present a promising strategy for preparing intranasal vaccines for infectious diseases or cancer.

Multiwalled Carbon Nanotubes-Reprogrammed Macrophages Facilitate Breast Cancer Metastasis via NBR2/TBX1 Axis.

In recent years, carbon nanotubes have emerged as a widely used nanomaterial, but their human exposure has become a significant concern. In our former study, we reported that pulmonary exposure of multiwalled carbon nanotubes (MWCNTs) promoted tumor metastasis of breast cancer; macrophages were key effectors of MWCNTs and contributed to the metastasis-promoting procedure in breast cancer, but the underlying molecular mechanisms remain to be explored. As a follow-up study, we herein demonstrated that MWCNT exposure in breast cancer cells and macrophage coculture systems promoted metastasis of breast cancer cells both in vitro and in vivo; macrophages were skewed into M2 polarization by MWCNT exposure. LncRNA NBR2 was screened out to be significantly decreased in MWCNTs-stimulated macrophages through RNA-seq; depletion of NBR2 led to the acquisition of M2 phenotypes in macrophages by activating multiple M2-related pathways. Specifically, NBR2 was found to positively regulate the downstream gene TBX1 through H3k27ac activation. TBX1 silence rescued NBR2-induced impairment of M2 polarization in IL-4 & IL-13-stimulated macrophages. Moreover, NBR2 overexpression mitigated the enhancing effects of MWCNT-exposed macrophages on breast cancer metastasis. This study uncovered the molecular mechanisms underlying breast cancer metastasis induced by MWCNT exposure.

Protein Corona-Mediated Inhibition of Nanozyme Activity: Impact of Protein Shape.

During biomedical applications, nanozymes, exhibiting enzyme-like characteristics, inevitably come into contact with biological fluids in living systems, leading to the formation of a protein corona on their surface. Although it is acknowledged that molecular adsorption can influence the catalytic activity of nanozymes, there is a dearth of understanding regarding the impact of the protein corona on nanozyme activity and its determinant factors. In order to address this gap, we employed the AuNR@Pt@PDDAC [PDDAC, poly(diallyldimethylammonium chloride)] nanorod (NR) as a model nanozyme with multiple activities, including peroxidase, oxidase, and catalase-mimetic activities, to investigate the inhibitory effects of the protein corona on the catalytic activity. After the identification of major components in the plasma protein corona on the NR, we observed that spherical proteins and fibrous proteins induced distinct inhibitory effects on the catalytic activity of nanozymes. To elucidate the underlying mechanism, we uncovered that the adsorbed proteins assembled on the surface of the nanozymes, forming protein networks (PNs). Notably, the PNs derived from fibrous proteins exhibited a screen mesh-like structure with smaller pore sizes compared to those formed by spherical proteins. This structural disparity resulted in a reduced efficiency for the permeation of substrate molecules, leading to a more robust inhibition in activity. These findings underscore the significance of the protein shape as a crucial factor influencing nanozyme activity. This revelation provides valuable insights for the rational design and application of nanozymes in the biomedical fields.

Investigation of unexpected silane ions caused by gas-phase reactions in Orbitrap gas chromatography-mass spectrometry.

RATIONALE: The mass spectra of compounds containing dimethyl (phenyl)silyl group (-SiMe2Ph) sometimes exhibit unusual ion peaks when measured using Orbitrap gas chromatography-mass spectrometry (GC-MS). This would complicate the mass spectra and may limit the matching of spectral data with preexisting resources for compound annotation. These peaks were identified as products from reactions with residual water. METHODS: A series of dimethyl (phenyl)silyl compounds were dissolved in methanol and investigated using Orbitrap GC-MS. Certain ions reacted with residual water in the C-trap. The reaction was confirmed using accurate mass and elemental composition analysis via MS studies, and the active center of the reaction was determined using density functional theory (DFT) calculations. RESULTS: Two types of gas-phase reactions between gaseous water and cations from a series of silanes were identified. DFT calculations indicate that silicon (Si) acts as the active center for these gas-phase water reactions. Compounds with multiple Si atoms generate a larger number of additional ions, which would complicate the mass spectra. The mass spectra of vinylsilanes and alkylsilanes with -SiMe2Ph indicate that the conjugated group linked to -SiMe2Ph can affect the water adduction process. CONCLUSIONS: Silane ions could react with residual water in the C-trap of an Orbitrap mass spectrometer. The mass spectra of these compounds may exhibit unexplained peaks arising from gas-phase reactions. Although these reactions may decrease spectral matching scores for compound annotation, they offer opportunities for systematic investigations into the mechanistic and kinetic aspects of high-energy ion reactivity.

Piezocatalytically-induced controllable mineralization scaffold with bone-like microenvironment to achieve endogenous bone regeneration.

Orderly hierarchical structure with balanced mechanical, chemical, and electrical properties is the basis of the natural bone microenvironment. Inspired by nature, we developed a piezocatalytically-induced controlled mineralization strategy using piezoelectric polymer poly-L-lactic acid (PLLA) fibers with ordered micro-nano structures to prepare biomimetic tissue engineering scaffolds with a bone-like microenvironment (pcm-PLLA), in which PLLA-mediated piezoelectric catalysis promoted the in-situ polymerization of dopamine and subsequently regulated the controllable growth of hydroxyapatite crystals on the fiber surface. PLLA fibers, as analogs of mineralized collagen fibers, were arranged in an oriented manner, and ultimately formed a bone-like interconnected pore structure; in addition, they also provided bone-like piezoelectric properties. The uniformly sized HA nanocrystals formed by controlled mineralization provided a bone-like mechanical strength and chemical environment. The pcm-PLLA scaffold could rapidly recruit endogenous stem cells, and promote their osteogenic differentiation by activating cell membrane calcium channels and PI3K signaling pathways through ultrasound-responsive piezoelectric signals. In addition, the scaffold also provided a suitable microenvironment to promote macrophage M2 polarization and angiogenesis, thereby enhancing bone regeneration in skull defects of rats. The proposed piezocatalytically-induced controllable mineralization strategy provides a new idea for the development of tissue engineering scaffolds that can be implemented for multimodal physical stimulation therapy.

Radionuclide-Labeled Antisilencing Function 1a Inhibitory Peptides for Tumor Identification and Individualized Therapy.

Immune checkpoint blockade (ICB) therapy is promising to revolutionize cancer regimens, but the low response rate and the lack of a suitable patient stratification method have impeded universal profit to cancer patients. Noninvasive positron emission tomography (PET) imaging in the whole body, upon coupling with specific biomarkers closely related to the immune response, could provide spatiotemporal information to prescribe cancer therapy. Herein, we demonstrate that antisilencing function 1a (ASF1a) could serve as a biomarker target to delineate tumor immune microenvironments by immune PET (iPET). The iPET radiotracer (68Ga-AP1) is designed to target ASF1a in tumors and predict immune response, and the signal intensity predicts anti-PD-1 (αPD-1) therapy response in a negative correlation manner. The ICB-resistant tumors with a high level of ASF1a as revealed by iPET (ASF1aHigh-iPET) are prescribed to be treated by either the combined 177Lu-labeled AP1 and αPD-1 or the standalone α particle-emitting 225Ac-labeled AP1, both achieving enhanced therapeutic efficacy and prolonged survival time. Our study not only replenishes the iPET arsenal for immune-related response evaluation by designing a reliable biomarker and a facile radiotracer but also provides optional therapeutic strategies for ICB-resistant tumors with versatile radionuclide-labeled AP1 peptides, which is promising for real-time clinical diagnosis and individualized therapy planning simultaneously.

Loneliness and suicide risks in the general population before and during first-year COVID-19 in Taiwan.

PURPOSE: Loneliness is a critical issue affecting the general population. Current evidence from national surveys of loneliness is scarce. The study aimed to examine the impact of COVID-19 pandemic on the prevalence of loneliness and its associating suicide risks in Taiwan. METHODS: Four annual telephone interview surveys were performed by the Taiwan Suicide Prevention Center in 2015-2017 and 2020 during COVID outbreak. Each year the sample was randomly selected by stratifying the general public in different geographical areas and fulfilled a questionnaire collecting information including loneliness, psychological distress, and suicide risk assessment. All the data were analyzed using SPSS25 analysis. RESULTS: A total of 8460 participants were recruited. The average prevalence of loneliness was 12.6 %. Feelings of loneliness was significantly correlated with psychological distress and most risk factors relating to suicide. The odds of loneliness for lifetime suicidal ideation, lifetime suicide attempt, and future suicide intent were 4.9, 5.1, and 9.2, respectively. During the COVID-19 period, loneliness and suicidality demonstrated a noteworthy decline trend, whereas "no one trustworthy to talk to" was the only item that showed significant increase under the pandemic and also impacted on loneliness. CONCLUSION: Nearly one in ten Taiwanese people felt lonely before and during COVID-19. Loneliness was closely linked with various suicide risk factors such as lifetime suicide ideation and attempt or future intention. Although psychological distress and suicide risk were not increased during COVID-19, maintaining trustful relationships to seek support appeared to be critical to prevent the risks of loneliness or suicide.

Octadecyl Gallate and Lipid-Modified MnSe2 Nanoparticles Enhance Radiosensitivity in Esophageal Squamous Cell Carcinoma and Promote Radioprotection in Normal Tissues.

Radiotherapy, a widely used therapeutic strategy for esophageal squamous cell carcinoma (ESCC), is always limited by radioresistance of tumor tissues and side-effects on normal tissues. Herein, a signature based on four core genes of cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, is developed to predict prognosis and assess immune cell infiltration, indicating that the cGAS-STING pathway and radiotherapy efficacy are closely intertwined in ESCC. A novel lipid-modified manganese diselenide nanoparticle (MnSe2 -lipid) with extraordinarily uniform sphere morphology and tumor microenvironment (TME) responsiveness is developed to simultaneously overcome radioresistance and reduce side-effects of radiation. The uniform MnSe2 encapsulated lipid effectively achieves tumor accumulation. Octadecyl gallate on surface of MnSe2 forming pH-responsive metal-phenolic covalent realizes rapid degradation in TME. The released Mn2+ promotes radiosensitivity by generating reactive oxygen species induced by Fenton-like reaction and activating cGAS-STING pathway. Spontaneously, selenium strengthens immune response by promoting secretion of cytokines and increasing white blood cells, and performs antioxidant activity to reduce side-effects of radiotherapy. Overall, this multifunctional remedy which is responsive to TME is capable of providing radiosensitivity by cGAS-STING pathway-mediated immunostimulation and chemodynamic therapy, and radioprotection of normal tissues, is highlighted here to optimize ESCC treatment.

Characterization of carbonaceous particles by single particle aerosol mass spectrometer in the urban area of Chengdu, China.

Carbonaceous particles are an important chemical component of atmospheric fine particles. In this study, a single particle aerosol mass spectrometer was used to continuously measure the carbonaceous particles in Chengdu, one of the megacities most affected by haze in China, from January 22 to March 3, 2021. During the observation period, the average mass concentration of PM2.5 was 62.3 ± 37.2 µg m-3, and the emissions from mobile sources were more prominent. Carbonaceous particles accounted for 68.6% of the total particles and could be classified into 10 categories, with elemental carbon (EC) mixed with sulfate (EC-S) particles making the highest contribution (33.1%). EC particles rich in secondary components and organic carbon (OC) particles rich in secondary component exhibited different diurnal variations, suggesting different sources and mixing mechanisms. From "excellent" to "polluted" days, the contributions of EC-S, EC mixed with sulfate and nitrate (EC-SN) and OC mixed with EC (OC-EC) particles increased by 9.8%, 4.5% and 6.6%, respectively, and thus these particles are key targets for future pollution control. The potential source contribution of the southwest area was stronger than that of other areas, and the potential contribution of regional transport to EC-related particles was stronger than to OC-related particles. Most particles were highly mixed with sulfate or nitrate, and the level of secondary mixing further enhanced as pollution worsened.

A Meta-analysis of the Effect of Noninvasive Brain Stimulation on Dysphagia in Patients with Cerebral Stroke.

The objective of this study is to assess the efficacy of non-invasive brain stimulation (NIBS) in preventing and treating dysphagia in patients who have experienced a cerebral stroke (CS). Both Chinese and international guidelines for the management of dysphagia resulting from CS mention various non-pharmacological treatments, such as acupuncture, mechanical myoelectric stimulation, and NIBS. However, due to limited evidence, these treatments are often suggested as measures rather than interventions. Therefore, this study assesses the impact of NIBS on the severity and improvement of dysphagia in CS patients. The researchers provide evidence-based recommendations for clinical practice by conducting a comprehensive literature review and meta-analysis. The researchers analyze the impact of NIBS on the severity of dysphagia and its overall improvement in CS patients. Employing a systematic computer-based search, the researchers retrieved randomized controlled trials and cohort studies published between the inception of relevant databases and December 1, 2022, about the utilization of NIBS in managing dysphagia in CS patients. This effort included nine articles for meta-analysis, with sample sizes ranging from 14 to 59, allowing an assessment of the effectiveness of NIBS in CS patients. The analysis revealed a mean difference (MD) score of 1.05 in the NIBS studies for the prevention and treatment of dysphagia severity in stroke patients, indicating a notable alleviation of dysphagia severity in CS patients through NIBS. The MD for the dysphagia score was also 1.05, and the MD for the functional dysphagia score was 1.78, suggesting that NIBS provided relief from dysphagia in CS patients. In summary, this meta-analysis thoroughly evaluated NIBS efficacy in CS patients and provided evidence-based recommendations for clinical practice. Future research needs to collect additional indicators to elucidate the nuances of various interventions, contributing to a more robust theoretical foundation for clinical therapy.

A natural biogenic nanozyme for scavenging superoxide radicals.

Biominerals, the inorganic minerals of organisms, are known mainly for their physical property-related functions in modern living organisms. Our recent discovery of the enzyme-like activities of nanomaterials, coined as nanozyme, inspires the hypothesis that nano-biominerals might function as enzyme-like catalyzers in cells. Here we report that the iron cores of biogenic ferritins act as natural nanozymes to scavenge superoxide radicals. Through analyzing eighteen representative ferritins from three living kingdoms, we find that the iron core of prokaryote ferritin possesses higher superoxide-diminishing activity than that of eukaryotes. Further investigation reveals that the differences in catalytic capability result from the iron/phosphate ratio changes in the iron core, which is mainly determined by the structures of ferritins. The phosphate in the iron core switches the iron core from single crystalline to amorphous iron phosphate-like structure, resulting in decreased affinity to the hydrogen proton of the ferrihydrite-like core that facilitates its reaction with superoxide in a manner different from that of ferric ions. Furthermore, overexpression of ferritins with high superoxide-diminishing activities in E. coli increases the resistance to superoxide, whereas bacterioferritin knockout or human ferritin knock-in diminishes free radical tolerance, highlighting the physiological antioxidant role of this type of nanozymes.

In situ label-free X-ray imaging for visualizing the localization of nanomedicines and subcellular architecture in intact single cells.

Understanding the intracellular behaviors of nanomedicines and morphology variation of subcellular architecture impacted by nanomaterial-biology (nano-bio) interactions could help guide the safe-by-design, manufacturing and evaluation of nanomedicines for clinical translation. The in situ and label-free analysis of nano-bio interactions in intact single cells at nanoscale remains challenging. We developed an approach based on X-ray microscopy to directly visualize the 2D or 3D intracellular distribution without labeling at nanometer resolution and analyze the chemical transformation of nanomedicines in situ. Here, we describe an optimized workflow for cell sample preparation, beamline selection, data acquisition and analysis. With several model bionanomaterials as examples, we analyze the localization of nanomedicines in various primary blood cells, macrophages, dendritic cells, monocytes and cancer cells, as well as the morphology of some organelles with soft and hard X-rays. Our protocol has been successfully implemented at three beamline facilities: 4W1A of Beijing Synchrotron Radiation Facility, BL08U1A of Shanghai Synchrotron Radiation Facility and BL07W of the National Synchrotron Radiation Laboratory. This protocol can be completed in ~2-5 d, depending on the cell types, their incubation times with nanomaterials and the selected X-ray beamline. The protocol enables the in situ analysis of the varieties of metal-containing nanomaterials, visualization of intracellular endocytosis, distribution and excretion and corresponding subcellular morphological variation influenced by nanomedicines in cell lines or primary cells by using this universal and robust platform. The results facilitate the understanding of the true principle and mechanism underlying the nano-bio interaction.

Oxyhaemoglobin saturation NIR-IIb imaging for assessing cancer metabolism and predicting the response to immunotherapy.

In vivo quantitative assessment of oxyhaemoglobin saturation (sO2) status in tumour-associated vessels could provide insights into cancer metabolism and behaviour. Here we develop a non-invasive in vivo sO2 imaging technique to visualize the sO2 levels of healthy and tumour tissue based on photoluminescence bioimaging in the near-infrared IIb (NIR-IIb; 1,500-1,700 nm) window. Real-time dynamic sO2 imaging with a high frame rate (33 Hz) reveals the cerebral arteries and veins through intact mouse scalp/skull, and this imaging is consistent with the haemodynamic analysis results. Utilizing our non-invasive sO2 imaging, the tumour-associated-vessel sO2 levels of various cancer models are evaluated. A positive correlation between the tumour-associated-vessel sO2 levels and the basal oxygen consumption rate of corresponding cancer cells at the early stages of tumorigenesis suggests that cancer cells modulate the tumour metabolic microenvironment. We also find that a positive therapeutic response to the checkpoint blockade cancer immunotherapy could lead to a dramatic decrease of the tumour-associated-vessel sO2 levels. Two-plex dynamic NIR-IIb imaging can be used to simultaneously observe tumour-vessel sO2 and PD-L1, allowing a more accurate prediction of immunotherapy response.

Interannual evolution of the chemical composition, sources and processes of PM2.5 in Chengdu, China: Insights from observations in four winters.

The air quality in China has improved significantly in the last decade and, correspondingly, the characteristics of PM2.5 have also changed. We studied the interannual variation of PM2.5 in Chengdu, one of the most heavily polluted megacities in southwest China, during the most polluted season (winter). Our results show that the mass concentrations of PM2.5 decreased significantly year-by-year, from 195.8 ± 91.0 µg/m3 in winter 2016 to 96.1 ± 39.3 µg/m3 in winter 2020. The mass concentrations of organic matter (OM), SO42-, NH4+ and NO3- decreased by 49.6%, 57.1%, 49.7% and 28.7%, respectively. The differential reduction in the concentrations of chemical components increased the contributions from secondary organic carbon and NO3- and there was a larger contribution from mobile sources. The contribution of OM and NO3- not only increased with increasing levels of pollution, but also increased year-by-year at the same level of pollution. Four sources of PM2.5 were identified: combustion sources, vehicular emissions, dust and secondary aerosols. Secondary aerosols made the highest contribution and increased year-by-year, from 40.6% in winter 2016 to 46.3% in winter 2020. By contrast, the contribution from combustion sources decreased from 14.4% to 8.7%. Our results show the effectiveness of earlier pollution reduction policies and emphasizes that priority should be given to key pollutants (e.g., OM and NO3-) and sources (secondary aerosols and vehicular emissions) in future policies for the reduction of pollution in Chengdu during the winter months.

Combinational Gene Therapy toward Cancer with Nanoplatform: Strategies and Principles.

Cancer remains a significant threat to human health. While numerous therapies have been developed to combat the disease, traditional treatments such as chemotherapy and radiotherapy are suboptimal and associated with significant side effects. Gene therapy is an emerging therapeutic approach that offers improved targeting and reduced side effects compared with traditional treatments. Using siRNA and other nucleic acid-based drugs in cancer treatment has generated significant interest among researchers. Nanocarriers, such as liposomes, can effectively deliver these agents to tumor sites. However, gene therapy alone is often insufficient to eradicate tumors, and there is a risk of recurrence. Therefore, combining gene therapy with other therapies using nanocarriers, such as phototherapy and magnetic hyperthermia therapy, can lead to synergistic therapeutic effects through different mechanisms. In this review, we summarize various ways in which gene therapy can be combined with other therapies and highlight the role of nanoplatforms in mediating these combined therapies, which would inspire novel design ideas toward combination therapies. Additionally, bottlenecks and barriers to gene therapy should be addressed in the near future to achieve better clinical efficacy.

Multi-omics for COVID-19: driving development of therapeutics and vaccines.

The ongoing COVID-19 pandemic caused by SARS-CoV-2 has raised global concern for public health and economy. The development of therapeutics and vaccines to combat this virus is continuously progressing. Multi-omics approaches, including genomics, transcriptomics, proteomics, metabolomics, epigenomics and metallomics, have helped understand the structural and molecular features of the virus, thereby assisting in the design of potential therapeutics and accelerating vaccine development for COVID-19. Here, we provide an up-to-date overview of the latest applications of multi-omics technologies in strategies addressing COVID-19, in order to provide suggestions towards the development of highly effective knowledge-based therapeutics and vaccines.

Mediation Effects of Coping Styles on Fear of Progression and Reproductive Concerns in Breast Cancer Patients of Reproductive Age.

PURPOSE: This study aimed to investigate reproductive concerns among breast cancer patients of reproductive age, analyze the influencing factors, explore the relationship between coping styles, fear of progression (FOP), and reproductive concerns, and identify the multiple effects of coping styles on the relationship between FOP and reproductive concerns among Chinese breast cancer patients. METHODS: A cross-sectional, descriptive study was conducted among breast cancer patients in four tertiary grade A hospitals in Fujian, China, from January 2022 to September 2022. A total of 210 patients were recruited to complete paper-based questionnaires, which included the general data questionnaires, the Reproductive Concerns After Cancer Scale (RCACS), the Fear of Progression Questionnaire-Short Form (FOP-Q-SF), and the Medical Coping Modes Questionnaire (MCMQ). Structural equation models were utilized to evaluate the multiple effects of coping styles on FOP and reproductive concerns. RESULTS: Reproductive concerns in breast cancer patients had a mean score of 53.02 (SD, 10.69), out of a total score of 90, and coping styles for cancer (confrontation, avoidance) were closely associated with FOP and reproductive concerns. FOP showed a significant positive correlation with reproductive concerns (r = .52, p < .01). At the same time, confrontation was significantly negatively correlated with both FOP (r = -.28, p < .01) and reproductive concerns (r = -.39, p < .01). Avoidance was positively correlated to both FOP (r = .25, p < .01) and reproductive concerns (r = .34, p < .01). The impact of FOP on reproductive concerns is partially mediated by confrontation and avoidance, with effect sizes of .07 and .04, respectively. These mediating factors account for 22.0% of the total effect. CONCLUSIONS: The FOP directly impacted reproductive concerns, while coping styles could partially mediate the association between FOP and reproductive concerns. This study illustrates the role of confrontation and avoidance in alleviating reproductive concerns, suggesting that it is necessary to focus on the changes in reproductive concerns among reproductive-age breast cancer patients. Healthcare professionals can improve disease awareness and reduce patients' FOP, thereby promoting positive psychological and coping behaviors and ultimately alleviating reproductive concerns.