Insights into vaccines for elderly individuals: from the impacts of immunosenescence to delivery strategies.

Immunosenescence increases the risk and severity of diseases in elderly individuals and leads to impaired vaccine-induced immunity. With aging of the global population and the emerging risk of epidemics, developing adjuvants and vaccines for elderly individuals to improve their immune protection is pivotal for healthy aging worldwide. Deepening our understanding of the role of immunosenescence in vaccine efficacy could accelerate research focused on optimizing vaccine delivery for elderly individuals. In this review, we analyzed the characteristics of immunosenescence at the cellular and molecular levels. Strategies to improve vaccination potency in elderly individuals are summarized, including increasing the antigen dose, preparing multivalent antigen vaccines, adding appropriate adjuvants, inhibiting chronic inflammation, and inhibiting immunosenescence. We hope that this review can provide a review of new findings with regards to the impacts of immunosenescence on vaccine-mediated protection and inspire the development of individualized vaccines for elderly individuals.

SETDB1: Progress and prospects in cancer treatment potential and inhibitor research.

SET domain bifurcated methyltransferase 1 (SETDB1) serves as a histone lysine methyltransferase, catalyzing the di- and tri-methylation of histone H3K9. Mounting evidence indicates that the abnormal expression or activity of SETDB1, either through amplification or mutation, plays a crucial role in tumorigenesis and progression. This is particularly evident in the context of tumor immune evasion and resistance to immune checkpoint blockade therapy. Furthermore, there is a robust association between SETDB1 dysregulation and an unfavorable prognosis across various types of tumors. The oncogenic role of SETDB1 primarily arises from its methyltransferase function, which contributes to the establishment of a condensed and transcriptionally inactive heterochromatin state. This results in the inactivation of genes that typically hinder cancer development and silencing of retrotransposons that could potentially trigger an immune response. These findings underscore the substantial potential for SETDB1 as an anti-tumor therapeutic target. Nevertheless, despite significant strides in recent years in tumor biology research, challenges persist in SETDB1-targeted therapy. To better facilitate the development of anti-tumor therapy targeting SETDB1, we have conducted a comprehensive review of SETDB1 in this account. We present the structure and function of SETDB1, its role in various tumors and immune regulation, as well as the advancements made in SETDB1 antagonists. Furthermore, we discuss the challenges encountered and provide perspectives for the development of SETDB1-targeted anti-tumor therapy.

Development and Validation of an ADA-Tolerant Assay for Quantification of an Exatecan-Based ADC in Monkey Plasma.

BACKGROUND: The development of an anti-drug antibody (ADA)-tolerant pharmacokinetic (PK) assay is important when the drug exposure is irrelevant to toxicity in the presence of ADA. We aimed to develop and validate an ADA-tolerant assay for an exatecan-based antibody-drug conjugate (ADC) in monkey plasma. RESULTS: The assay tolerated 5.00 µg/mL of ADA at 12 µg/mL of ADC. Its accuracy and precision results satisfied the acceptance criteria. Furthermore, the assay was free from hook and matrix effects and exhibited good dilutional linearity. Additionally, the ADC in plasma samples was stable under different storage conditions. METHOD: An ADA-tolerant ADC assay was configured with an anti-payload antibody for capture, and a drug-target protein combined with a horseradish peroxidase (HRP)-labeled antibody against a drug-target-protein tag for detection. Samples were firstly acidified to dissociate drug and ADA complexes, and to convert the carboxylate form to the lactone form of exatecan molecules; then, the ADAs in the samples were removed with a naked antibody-coated microplate. The treated samples were further incubated with coated anti-payload antibody and captured ADC molecules were quantified by the detection reagent. The developed assay was optimized and validated against regulatory guidelines. CONCLUSIONS: The assay met both methodological and sample-related ADA tolerance requirements, and was applicable to a nonclinical study in cynomolgus monkeys.

Eliminating drug target interference with specific antibody or its F(ab')2 fragment in the bridging immunogenicity assay.

Background: DB-1003 is a humanized anti-IgE monoclonal antibody with higher affinity than omalizumab. In the affinity capture elution (ACE)-based bridging electrochemiluminescent immunoassay (ECLIA) for antibodies to DB-1003, monkey serum IgE caused false-positive results. Materials & methods: The target-specific antibody or its F(ab')2 fragment was used to mitigate drug target interference in an ACE-based bridging ECLIA for the detection of anti-DB-1003 antibodies. Results: The sensitivity of the developed assay was at least 100 ng/ml. When the anti-drug antibody concentration was 250 ng/ml, the assay tolerated at least 20.0 µg/ml of the monkey IgE. Conclusion: Incorporating the target-specific antibody or its F(ab')2 fragment can overcome the interference from monkey serum IgE in ACE-based bridging ECLIA for anti-DB-1003 antibody detection.

Characteristics of the complete chloroplast genome of Swertia divaricata Harry Sm. (Gentianaceae) and its phylogenetic inference.

Swertia divaricata Harry Sm., 1965, (Gentianaceae) is a perennial herb endemic to Northwest Yunnan, China, belonging to the species-rich genus Swertia. It possesses unique morphological features but its systematic position remains uncertain. To determine its phylogenetic placement, the complete plastid genome of S. divaricata was assembled utilizing high-throughput sequencing data. The genome is circular, spanning 152,073 bp, and comprises a large single-copy (LSC) region of 82,470 bp, a small single-copy (SSC) region of 18,153 bp, and two inverted repeats (IR) regions, each 25,725 bp. A total of 130 genes were annotated, including 85 protein-coding genes, 37 tRNA genes, and eight rRNA genes. The plastome of S. divaricata exhibits a structure and gene composition highly similar to those of other Swertia plastomes. Phylogenetic analysis indicated that S. divaricata is closely related to S. erythrosticta, sister to a subclade comprising species from sections Swertia and Apterae. The plastome sequence described herein constitutes a valuable contribution to phylogenetic and evolutionary research on Swertia.

Advances in volumetric bioprinting.

The three-dimensional (3D) bioprinting technologies are suitable for biomedical applications owing to their ability to manufacture complex and high-precision tissue constructs. However, the slow printing speed of current layer-by-layer (bio)printing modality is the major limitation in biofabrication field. To overcome this issue, volumetric bioprinting (VBP) is developed. VBP changes the layer-wise operation of conventional devices, permitting the creation of geometrically complex, centimeter-scale constructs in tens of seconds. VBP is the next step onward from sequential biofabrication methods, opening new avenues for fast additive manufacturing in the fields of tissue engineering, regenerative medicine, personalized drug testing, and soft robotics, etc. Therefore, this review introduces the printing principles and hardware designs of VBP-based techniques; then focuses on the recent advances in VBP-based (bio)inks and their biomedical applications. Lastly, the current limitations of VBP are discussed together with future direction of research.

Effect of chewing ability on in vivo oral digestive characteristics and in vitro gastrointestinal starch hydrolysis of three different types of cooked rice.

Chewing ability has a strong effect on food digestion. However, little is known about the relationship between the food mastication degree and the subsequent gastric emptying. This study was to explore the effects of individual chewing ability (strong and weak) on the in vivo oral processing characteristics and in vitro dynamic gastrointestinal starch hydrolysis of three types of rice (japonica rice, indica rice and waxy rice). Results showed that the swallowable bolus in the weak chewing group had larger holes and a looser microstructure with more small rice particles, while the strong chewing ones obtained a bolus with higher saliva content (up to 28%) and starch hydrolysis degree (up to 13.55%). Moreover, the gastric retention and starch hydrolysis of the strong chewing ability group were higher in the artificial gastric dynamic system (AGDS). The indica rice particles with the higher degree of fragmentation contacted enzymes easier and hydrolyzed quicker, thus emptying through the stomach faster (81.76%). However, the oral chewing properties of rice mainly influenced the starch digestion in the stomach and the initial stage of the small intestine (∼5 min). This study suggested that the chewing ability and rice variety can influence the bolus properties, which in turn affected the gastric emptying and the degree of starch hydrolysis during digestion.

An antigen self-assembled and dendritic cell-targeted nanovaccine for enhanced immunity against cancer.

The rise of nanotechnology has opened new horizons for cancer immunotherapy. However, most nanovaccines fabricated with nanomaterials suffer from carrier-related concerns, including low drug loading capacity, unpredictable metabolism, and potential systemic toxicity, which bring obstacles for their clinical translation. Herein, we developed an antigen self-assembled nanovaccine, which was resulted from a simple acryloyl modification of the antigen to induce self-assembly. Furthermore, a dendritic cell targeting head mannose monomer and a mevalonate pathway inhibitor zoledronic acid (Zol) were integrated or absorbed onto the nanoparticles (denoted as MEAO-Z) to intensify the immune response. The synthesized nanovaccine with a diameter of around 70 nm showed successful lymph node transportation, high dendritic cell internalization, promoted costimulatory molecule expression, and preferable antigen cross-presentation. In virtue of the above superiorities, MEAO-Z induced remarkably higher titers of serum antibody, stronger cytotoxic T lymphocyte immune responses and IFN-γ secretion than free antigen and adjuvants. In vivo, MEAO-Z significantly suppressed EG7-OVA tumor growth and prolonged the survival time of tumor-bearing mice. These results indicated the translation promise of our self-assembled nanovaccine for immune potentiation and cancer immunotherapy.

Advanced subunit vaccine delivery technologies: From vaccine cascade obstacles to design strategies.

Designing and manufacturing safe and effective vaccines is a crucial challenge for human health worldwide. Research on adjuvant-based subunit vaccines is increasingly being explored to meet clinical needs. Nevertheless, the adaptive immune responses of subunit vaccines are still unfavorable, which may partially be attributed to the immune cascade obstacles and unsatisfactory vaccine design. An extended understanding of the crosstalk between vaccine delivery strategies and immunological mechanisms could provide scientific insight to optimize antigen delivery and improve vaccination efficacy. In this review, we summarized the advanced subunit vaccine delivery technologies from the perspective of vaccine cascade obstacles after administration. The engineered subunit vaccines with lymph node and specific cell targeting ability, antigen cross-presentation, T cell activation properties, and tailorable antigen release patterns may achieve effective immune protection with high precision, efficiency, and stability. We hope this review can provide rational design principles and inspire the exploitation of future subunit vaccines.

Surgical outcomes of percutaneous endoscopic thoracic decompression in the treatment of multi-segment thoracic ossification of the ligamentum flavum.

BACKGROUND: Previous studies have demonstrated satisfactory outcomes of percutaneous endoscopic thoracic decompression (PETD) for single-segment thoracic ossification of the ligamentum flavum (TOLF). However, the clinical outcomes of PETD in patients with multi-segment TOLF (mTOLF) remain unclear. The aim of the present study was to evaluate the efficacy and safety of PETD for patients with multi-segment mTOLF. METHODS: Eighteen consecutive patients (41 segments) with mTOLF were treated with PETD between January 2020 and December 2021. The clinical outcomes were evaluated using the modified Japanese Orthopaedic Association (mJOA) score and Visual Analog Scale (VAS), whereas radiographic parameters were measured by cross-section area of the spinal canal and anteroposterior diameter of the spinal cord. RESULTS: The follow-up period ranged from 14 to 34 months. The mean operation time and blood loss were 154.06 ± 32.14 min and 61.72 ± 12.72 ml, respectively. Hospital stay after first-stage operation was 10.89 ± 2.42 days. The mJOA score and VAS score significantly improved at the final follow-up, with a mean mJOA recovery rate of 63.3 ± 21.90%. The incidence of complications was 12.2% per level. The radiographic outcomes showed adequate decompression of the spinal cord. CONCLUSIONS: The present study demonstrates that PETD is effective and safe as a minimally invasive procedure to treat patients with mTOLF. All patients showed relief of their symptoms and improvement in neurological function.

An Adaptive Model Filtering Algorithm Based on Grubbs Test in Federated Learning.

Federated learning has been popular for its ability to train centralized models while protecting clients' data privacy. However, federated learning is highly susceptible to poisoning attacks, which can result in a decrease in model performance or even make it unusable. Most existing defense methods against poisoning attacks cannot achieve a good trade-off between robustness and training efficiency, especially on non-IID data. Therefore, this paper proposes an adaptive model filtering algorithm based on the Grubbs test in federated learning (FedGaf), which can achieve great trade-offs between robustness and efficiency against poisoning attacks. To achieve a trade-off between system robustness and efficiency, multiple child adaptive model filtering algorithms have been designed. Meanwhile, a dynamic decision mechanism based on global model accuracy is proposed to reduce additional computational costs. Finally, a global model weighted aggregation method is incorporated, which improves the convergence speed of the model. Experimental results on both IID and non-IID data show that FedGaf outperforms other Byzantine-robust aggregation rules in defending against various attack methods.

A Lightweight Intelligent Network Intrusion Detection System Using One-Class Autoencoder and Ensemble Learning for IoT.

Network intrusion detection technology is key to cybersecurity regarding the Internet of Things (IoT). The traditional intrusion detection system targeting Binary or Multi-Classification can detect known attacks, but it is difficult to resist unknown attacks (such as zero-day attacks). Unknown attacks require security experts to confirm and retrain the model, but new models do not keep up to date. This paper proposes a Lightweight Intelligent NIDS using a One-Class Bidirectional GRU Autoencoder and Ensemble Learning. It can not only accurately identify normal and abnormal data, but also identify unknown attacks as the type most similar to known attacks. First, a One-Class Classification model based on a Bidirectional GRU Autoencoder is introduced. This model is trained with normal data, and has high prediction accuracy in the case of abnormal data and unknown attack data. Second, a multi-classification recognition method based on ensemble learning is proposed. It uses Soft Voting to evaluate the results of various base classifiers, and identify unknown attacks (novelty data) as the type most similar to known attacks, so that exception classification becomes more accurate. Experiments are conducted on WSN-DS, UNSW-NB15, and KDD CUP99 datasets, and the recognition rates of the proposed models in the three datasets are raised to 97.91%, 98.92%, and 98.23% respectively. The results verify the feasibility, efficiency, and portability of the algorithm proposed in the paper.

Liquid-embedded (bio)printing of alginate-free, standalone, ultrafine, and ultrathin-walled cannular structures.

While there has been considerable success in the three-dimensional bioprinting of relatively large standalone filamentous tissues, the fabrication of solid fibers with ultrafine diameters or those cannular featuring ultrathin walls remains a particular challenge. Here, an enabling strategy for (bio)printing of solid and hollow fibers whose size ranges could be facilely adjusted across a broad spectrum, is reported, using an aqueous two-phase embedded (bio)printing approach combined with specially designed cross-linking and extrusion methods. The generation of standalone, alginate-free aqueous architectures using this aqueous two-phase strategy allowed freeform patterning of aqueous bioinks, such as those composed of gelatin methacryloyl, within the immiscible aqueous support bath of poly(ethylene oxide). Our (bio)printing strategy revealed the fabrication of standalone solid or cannular structures with diameters as small as approximately 3 or 40 µm, respectively, and wall thicknesses of hollow conduits down to as thin as <5 µm. With cellular functions also demonstrated, we anticipate the methodology to serve as a platform that may satisfy the needs for the different types of potential biomedical and other applications in the future, especially those pertaining to cannular tissues of ultrasmall diameters and ultrathin walls used toward regenerative medicine and tissue model engineering.

An evolving view on food viscosity regulating gastric emptying.

Viscosity is a property of most foods. The consumption of the high-viscosity food is associated with a variety of physiological responses, one of which is their ability to regulate gastric emptying and modulate postprandial glycemic response. Gastric emptying has been proven to be a key step affecting the digestion and absorption of food, whereas, the relationship between viscosity and gastric emptying is still far away from being understood. Here, we reviewed the factors that influence food viscosity and food viscosity changes during digestion. Besides, the effect of food viscosity on gastric emptying and food-viscosity-physiological response were highlighted. Finally, "quantitative relationship" of viscosity and gastric emptying was discussed. This review can contribute to the understanding that how food viscosity affects gastric emptying, and help for developing foods that could control satiety and manage body weight for the specific populations.

Group polarization calls for group-level brain communication.

Group of people shows the shift towards extreme of decision-making as opposed to individuals. Previous studies have revealed two directions of group polarization, i.e., risky shift and cautious shift, but how group of brains drive these shifts remains unknown. In the current study, we arranged risk advantage and disadvantage situations to elicit group polarization of risky shift and cautious shift respectively, and examined the averaged inter-brain synchronization (ABS) among participant triads during group decision making versus individual decision making. The elicited group polarizations were accompanied by the enhanced ABS at bilateral prefrontal areas and left temporoparietal junction (TPJ). Specifically, the TPJ ABS was equivalent in risky shift and cautious shift, and based on machine learning analyses, could predict the extent of group polarization; for two shifts, it negatively correlated with negative emotion. However, the right prefrontal ABS was stronger in risky shift than in cautious shift, and the same area showed the larger brain deactivation in former shift, indicating weaker executive control. For the left prefrontal ABS, only the equivalent ABS was found for two shifts. In sum, group polarization of risky shift and cautious shift calls for inter-brain communication at the group level, and the former shift is with deactivation and more brain synchronization. Our study suggests emotional and cognitive adjustment in decision making of the group compared with individuals.

[Applying Chitosan-Modified Nanoemulsion in Nasal Vaccine Delivery].

OBJECTIVE: To prepare a chitosan-modified cationic nanoemulsion that could be used to prolong the residence time of nasal vaccines in the nasal cavity and improve the cellular uptake efficiency so as to enhance the immune efficacy of nasal vaccines. METHODS: A nanoemulsion-based vaccine coated with chitosan was prepared, and the particle size, potential, antigen encapsulation efficiency, stability as well as cytotoxicity were examined. The uptake efficiency of vaccine on different cells and the residence time of vaccine in the nasal cavity were measured. Finally, nasal vaccine was administered on mice and the antibody levels in the serum and in the nasal lavage fluids of the immunized mice were examined. RESULTS: The nanoemulsion-based vaccine had an average particle size of (167.2±0.75) nm, a polydispersity index (PDI) of 0.21±0.01, and an average potential of (13.7±0.85) mV. The encapsulation efficiency of antigen was 92.7%. The nanoemulsion-based vaccine had good stability and did not show obvious cytotoxicity in Madin-Darby canine kidney (MDCK) epithelial cells. The vaccine demonstrated relatively high cellular uptake of antigens on DC2.4 and MDCK cells at (49.7±3.45)% and (59.7±2.19)%, respectively. Besides, the cationic nanoemulsion also significantly increased the residence time of the antigen, and a considerable amount of nanoemulsion-based vaccine was found remaining in the nasal cavity 60 minutes after administration. Compared with free antigen and the nanoemulsion without chitosan modification, the chitosan-modified nanoemulsion vaccine induced higher systemic and mucosal antibody levels in mice after nasal immunization ( P<0.01). CONCLUSION: The chitosan-modified nanoemulsion vaccine prepared in the study can enhance the immune efficacy of nasal vaccines, showing great potential to be used as a delivery carrier for nasal vaccines.

Engineering a sustained release vaccine with a pathogen-mimicking manner for robust and durable immune responses.

Sustained release vaccine carriers can facilitate an increased interaction time between the antigen and immune system to strengthen immune responses, but their promotion on adaptive immune responses, especially cellular immunity, are still unfavorable. Herein, we report a sustained antigen delivery vector, which carries abundant antigens, a nucleic acid adjuvant and pathogen-associated molecular patterns to simulate a natural pathogen to reinforce immune responses. Specifically, murine colorectal cancer cells MC38 lysate and Toll-like receptor 9 agonist CpG are loaded into yeast derived ß-glucan particles (GPs). After vaccination, these particles can form a vaccine depot that continuously release the antigen similar to the traditional aluminum hydroxide gel, but recruit more immune cells and induce more cytokine secretion at the injection site. Stronger antibody responses, Th1 and Th17 biased cellular immunity and immune memory are achieved compared with aluminum hydroxide gel. More importantly, treatment with these particles significantly suppress tumor growth in a therapeutic tumor model. This work shed light on the efficacy of combining sustained antigen release with pathogen-mimicking manner in vaccine design.

Mechanisms, physiology, and recent research progress of gastric emptying.

Gastric emptying refers to a process in which the stomach discharges its contents into the small intestine to further digest and absorb nutrients. Understanding the mechanisms of gastric emptying and relationships between food and individuals is of paramount importance for the design and manufacture of novel and healthy foods. For ethical and cost reasons, in vivo tests are not always possible. In vitro digestion models therefore play a key role in current exploration of gastric emptying. This review outlines the mechanisms and physiology of gastric emptying, including calories, viscosity, composition of the food, age and gender of the individual. In addition, recent progress on in vitro static and dynamic gastric digestion models and future research trends are included in this review.

Co-delivery of antigen and dual adjuvants by aluminum hydroxide nanoparticles for enhanced immune responses.

Adjuvants that contain pathogen-associated molecular patterns (PAMPs) can enhance vaccination efficacy by binding to pattern recognition receptors (PRRs), thereby stimulating immune responses. Particularly effective may be the combination of multiple PAMPs that activate different PRRs, which occurs with natural pathogens. Here we hypothesized the enhanced effects would occur in two adjuvants that stimulate different PRRs: CpG oligodeoxynucleotide (CpG-ODN), which is Toll-like receptor 9 agonist; and 5'-triphosphate, short, double-stranded RNA (3pRNA), which activates retinoic acid-inducible gene I (RIG-I). The model antigen ovalbumin (OVA) was loaded and adjuvants were surface-adsorbed to aluminum hydroxide nanoparticles (hereafter NP-3pRNA-CpG) by electrostatic interaction with an average size of 120 nm and a negative surface charge for targeting lymph nodes. These nanoparticles were efficiently internalized by antigen-presenting cells (APCs) in the lymph nodes, and the resulting APC activation and antigen cross-presentation generated strong humoral immunity and cytotoxic T lymphocyte responses and IFN-γ secretion. NP-3pRNA-CpG significantly suppressed B16-OVA tumor growth and prolonged survival of tumor-bearing mice in therapeutic and prophylactic models, illustrating the enhanced effects of CpG-ODN and 3pRNA. Our study highlights the potential of combining multiple adjuvants for effective vaccine design.

The pore size of mesoporous silica nanoparticles regulates their antigen delivery efficiency.

Subunit vaccines generally proceed through a 4-step in vivo cascade-the DUMP cascade-to generate potent cell-mediated immune responses: (1) drainage to lymph nodes; (2) uptake by dendritic cells (DCs); (3) maturation of DCs; and (4) Presentation of peptide-MHC I complexes to CD8+ T cells. How the physical properties of vaccine carriers such as mesoporous silica nanoparticles (MSNs) influence this cascade is unclear. We fabricated 80-nm MSNs with different pore sizes (7.8 nm, 10.3 nm, and 12.9 nm) and loaded them with ovalbumin antigen. Results demonstrated these MSNs with different pore sizes were equally effective in the first three steps of the DUMP cascade, but those with larger pores showed higher cross-presentation efficiency (step 4). Consistently, large-pore MSNs loaded with B16F10 tumor antigens yielded the strongest antitumor effects. These results demonstrate the promise of our lymph node-targeting large-pore MSNs as vaccine-delivery vehicles for immune activation and cancer vaccination.