ABSTRACT
The CCAAT/enhancer-binding proteins (C/EBPs) constitute a family of pivotal transcription factors involved in tissue development, cellular function, proliferation, and differentiation. NFIL3, as one of them, plays an important role in regulating immune cell differentiation, circadian clock system, and neural regeneration, yet its specific DNA recognition mechanism remains enigmatic. In this study, we showed by the ITC binding experiments that NFIL3 prefers to bind to the TTACGTAA DNA motif. Our structural studies revealed that the α-helical NFIL3 bZIP domain dimerizes through its leucine zipper region, and binds to DNA via its basic region. The two basic regions of the NFIL3 bZIP dimer were pushed apart upon binding to DNA, facilitating the snug accommodation of the two basic regions within the major grooves of the DNA. Remarkably, our binding and structural data also revealed that both NFIL3 and C/EBPα/ß demonstrate a shared preference for the TTACGTAA sequence. Furthermore, our study revealed that disease-associated mutations within the NFIL3 bZIP domain result in either reduction or complete disruption of its DNA binding ability. These discoveries not only provide valuable insights into the DNA binding mechanisms of NFIL3 but also elucidate the causal role of NFIL3 mutations in disease pathogenesis.
Subject(s)
Basic-Leucine Zipper Transcription Factors , DNA , Amino Acid Sequence , Base Sequence , Basic-Leucine Zipper Transcription Factors/genetics , Basic-Leucine Zipper Transcription Factors/metabolism , CCAAT-Enhancer-Binding Proteins/metabolism , DNA/metabolism , Transcription Factors/metabolism , HumansABSTRACT
RNase P and RNase mitochondrial RNA processing (MRP) are ribonucleoproteins (RNPs) that consist of a catalytic RNA and a varying number of protein cofactors. RNase P is responsible for precursor tRNA maturation in all three domains of life, while RNase MRP, exclusive to eukaryotes, primarily functions in rRNA biogenesis. While eukaryotic RNase P is associated with more protein cofactors and has an RNA subunit with fewer auxiliary structural elements compared to its bacterial cousin, the double-anchor precursor tRNA recognition mechanism has remarkably been preserved during evolution. RNase MRP shares evolutionary and structural similarities with RNase P, preserving the catalytic core within the RNA moiety inherited from their common ancestor. By incorporating new protein cofactors and RNA elements, RNase MRP has established itself as a distinct RNP capable of processing ssRNA substrates. The structural information on RNase P and MRP helps build an evolutionary trajectory, depicting how emerging protein cofactors harmonize with the evolution of RNA to shape different functions for RNase P and MRP. Here, we outline the structural and functional relationship between RNase P and MRP to illustrate the coevolution of RNA and protein cofactors, a key driver for the extant, diverse RNP world.
Subject(s)
Endoribonucleases , Evolution, Molecular , Protein Subunits , RNA, Catalytic , Ribonuclease P , Coenzymes , Endoribonucleases/chemistry , Endoribonucleases/metabolism , Protein Subunits/chemistry , Protein Subunits/metabolism , Ribonuclease P/chemistry , Ribonuclease P/metabolism , RNA Processing, Post-Transcriptional , RNA, Catalytic/genetics , RNA, Catalytic/metabolism , RNA, Transfer/genetics , RNA, Transfer/metabolism , Substrate Specificity , Eukaryota/enzymologyABSTRACT
BACKGROUND: Telomere length is a critical metric linked to aging, health, and disease. Currently, the exploration of target proteins related to telomere length is usually limited to the context of aging and specific diseases, which limits the discovery of more relevant drug targets. This study integrated large-scale plasma cis-pQTLs data and telomere length GWAS datasets. We used Mendelian randomization(MR) to identify drug target proteins for telomere length, providing essential clues for future precision therapy and targeted drug development. METHODS: Using plasma cis-pQTLs data from a previous GWAS study (3,606 Pqtls associated with 2,656 proteins) and a GWAS dataset of telomere length (sample size: 472,174; GWAS ID: ieu-b-4879) from UK Biobank, using MR, external validation, and reverse causality testing, we identified essential drug target proteins for telomere length. We also performed co-localization, Phenome-wide association studies and enrichment analysis, protein-protein interaction network construction, search for existing intervening drugs, and potential drug/compound prediction for these critical targets to strengthen and expand our findings. RESULTS: After Bonferron correction (p < 0.05/734), RPN1 (OR: 0.96; 95%CI: (0.95, 0.97)), GDI2 (OR: 0.94; 95%CI: (0.92, 0.96)), NT5C (OR: 0.97; 95%CI: (0.95, 0.98)) had a significant negative causal association with telomere length; TYRO3 (OR: 1.11; 95%CI: (1.09, 1.15)) had a significant positive causal association with telomere length. GDI2 shared the same genetic variants with telomere length (coloc.abf-PPH 4 > 0.8). CONCLUSION: Genetically determined plasma RPN1, GDI2, NT5C, and TYRO3 have significant causal effects on telomere length and can potentially be drug targets. Further exploration of the role and mechanism of these proteins/genes in regulating telomere length is needed.
Subject(s)
Drug Delivery Systems , Genome-Wide Association Study , Phenomics , Telomere/genetics , Mendelian Randomization AnalysisABSTRACT
Partitioning the pores of covalent organic frameworks (COFs) is an attractive strategy for introducing microporosity and achieving new functionality, but it is technically challenging to achieve. Herein, we report a simple strategy for partitioning the micropores/mesopores of multivariate COFs. Our approach relies on the predesign and synthesis of multicomponent COFs through imine condensation reactions with aldehyde groups anchored in the COF pores, followed by inserting additional symmetric building blocks (with C2 or C3 symmetries) as pore partition agents. This approach allowed tetragonal or hexagonal pores to be partitioned into two or three smaller micropores, respectively. The synthesized library of pore-partitioned COFs was then applied for the capture of iodine pollutants (i.e., I2 and CH3I). This rich inventory allowed deep exploration of the relationships between the COF adsorbent composition, pore architecture, and adsorption capacity for I2 and CH3I capture under wide-ranging conditions. Notably, one of our developed pore-partitioned COFs (COF 3-2P) exhibited greatly enhanced dynamic I2 and CH3I adsorption performances compared to its parent COF (COF 3) in breakthrough tests, setting a new benchmark for COF-based adsorbents. Results present an effective design strategy toward functional COFs with tunable pore environments, functions, and properties.
ABSTRACT
BACKGROUND: Previous studies of non-small cell lung cancer (NSCLC) focused on CEA measured at a single time point, ignoring serial CEA measurements. METHODS: This retrospective cohort included 2959 patients underwent surgery for stage I-III NSCLC. CEA trajectory patterns and long-term cumulative CEA burden were evaluated using the latent class growth mixture model. RESULTS: Four CEA trajectory groups were identified, named as low-stable, decreasing, early-rising and later-rising. Compared with the low-stable group, the adjusted hazard ratios associated with death were 1.27, 4.50, and 3.68 for the other groups. Cumulative CEA burden were positively associated with the risk of death in patients not belonging to the low-stable group. The 5-year overall survival (OS) rates decreased from 62.3% to 33.0% for the first and fourth quantile groups of cumulative CEA burden. Jointly, patients with decreasing CEA trajectory could be further divided into the decreasing & low and decreasing & high group, with 5-year OS rates to be 77.9% and 47.1%. Patients with rising CEA trajectory and high cumulative CEA were found to be more likely to develop bone metastasis. CONCLUSIONS: Longitudinal trajectory patterns and long-term cumulative burden of CEA were independent prognostic factors of NSCLC. We recommend CEA in postoperative surveillance of NSCLC.
Subject(s)
Carcinoembryonic Antigen , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/surgery , Carcinoma, Non-Small-Cell Lung/mortality , Lung Neoplasms/surgery , Lung Neoplasms/pathology , Lung Neoplasms/mortality , Male , Female , Retrospective Studies , Middle Aged , Carcinoembryonic Antigen/blood , Aged , Longitudinal Studies , Follow-Up Studies , Prognosis , Survival Rate , Neoplasm StagingABSTRACT
As the aging population increases, the focus on elderly patients with acute respiratory distress syndrome (ARDS) is also increasing. In this article, we found progranulin (PGRN) differential expression in ARDS patients and healthy controls, even in young and old ARDS patients. Its expression strongly correlates with several cytokines in both young and elderly ARDS patients. PGRN has comparable therapeutic effects in young and elderly mice with lipopolysaccharide-induced acute lung injury, manifesting as lung injury, apoptosis, inflammation, and regulatory T cells (Tregs) differentiation. Considering that Tregs differentiation relies on metabolic reprogramming, we discovered that Tregs differentiation was mediated by mitochondrial function, especially in the aged population. Furthermore, we demonstrated that PGRN alleviated the mitochondrial damage during Tregs differentiation through the AMPK/PGC-1α pathway in T cells. Collectively, PGRN may regulate mitochondria function to promote Tregs differentiation through the AMPK/PGC-1α pathway to improve ARDS.
Subject(s)
Acute Lung Injury , Respiratory Distress Syndrome , Humans , Aged , Mice , Animals , Progranulins/metabolism , Progranulins/pharmacology , AMP-Activated Protein Kinases/metabolism , AMP-Activated Protein Kinases/pharmacology , T-Lymphocytes, Regulatory/metabolism , Mitochondria/metabolism , Acute Lung Injury/metabolismABSTRACT
Aptamers are single-stranded RNA or DNA molecules that can specifically bind to targets and have found broad applications in cancer early-stage detection, accurate drug delivery, and precise treatment. Although various aptamer screening methods have been developed over the past several decades, the accurate binding site between the target and the aptamer cannot be characterized during a typical aptamer screening process. In this research, we chose a widely used aptamer screened by our group, sgc8c, and its target protein tyrosine kinase 7 (PTK7) as the model aptamer and target and tried to determine the binding site between aptamer sgc8c and PTK7. Through sequential protein truncation, we confirmed that the exact binding site of sgc8c was within the region of Ig 3 to Ig 4 in the extracellular domain of PTK7. Using in vitro expressed Ig (3-4), we successfully acquired the crystal of an sgc8c-Ig (3-4) binding complex. The possible sgc8c-binding amino acid residues on PTK7 and PTK7-binding nucleotide residues on sgc8c were further identified and simulated by mass spectrometry and molecular dynamics simulation and finally verified by aptamer/protein truncation and mutation.
Subject(s)
Aptamers, Nucleotide , Cell Adhesion Molecules , Receptor Protein-Tyrosine Kinases , Aptamers, Nucleotide/chemistry , Aptamers, Nucleotide/metabolism , Binding Sites , Humans , Receptor Protein-Tyrosine Kinases/metabolism , Receptor Protein-Tyrosine Kinases/chemistry , Cell Adhesion Molecules/metabolism , Cell Adhesion Molecules/chemistry , Molecular Dynamics SimulationABSTRACT
The covalent organic frameworks (COFs) possessing high crystallinity and capability to capture low-concentration CO2 (400 ppm) from air are still underdeveloped. The challenge lies in simultaneously incorporating high-density active sites for CO2 insertion and maintaining the ordered structure. Herein, a structure engineering approach is developed to afford an ionic pair-functionalized crystalline and stable fluorinated COF (F-COF) skeleton. The ordered structure of the F-COF is well maintained after the integration of abundant basic fluorinated alcoholate anions, as revealed by synchrotron X-ray scattering experiments. The breakthrough test demonstrates its attractive performance in capturing (400 ppm) CO2 from gas mixtures via OâC bond formation, as indicated by the in situ spectroscopy and operando nuclear magnetic resonance spectroscopy using 13C-labeled CO2 sources. Both theoretical and experimental thermodynamic studies reveal the reaction enthalpy of ≈-40 kJ mol-1 between CO2 and the COF scaffolds. This implies weaker interaction strength compared with state-of-the-art amine-derived sorbents, thus allowing complete CO2 release with less energy input. The structure evolution study from synchrotron X-ray scattering and small-angle neutron scattering confirms the well-maintained crystalline patterns after CO2 insertion. The as-developed proof-of-concept approach provides guidance on anchoring binding sites for direct air capture (DAC) of CO2 in crystalline scaffolds.
ABSTRACT
Immunotherapy has emerged as a potent strategy in cancer treatment, with many approved drugs and modalities in the development stages. Despite its promise, immunotherapy is not without its limitations, including side effects and suboptimal efficacy. Using nanoparticles (NPs) as delivery vehicles to target immunotherapy to lymph nodes (LNs) can improve the efficacy of immunotherapy drugs and reduce side effects in patients. In this context, this paper reviews the development of LN-targeted immunotherapeutic NP strategies, the mechanisms of NP transport during LN targeting, and their related biosafety risks. NP targeting of LNs involves either passive targeting, influenced by NP physical properties, or active targeting, facilitated by affinity ligands on NP surfaces, while alternative methods, such as intranodal injection and high endothelial venule (HEV) targeting, have uncertain clinical applicability and require further research and validation. LN targeting of NPs for immunotherapy can reduce side effects and increase biocompatibility, but risks such as toxicity, organ accumulation, and oxidative stress remain, although strategies such as biodegradable biomacromolecules, polyethylene glycol (PEG) coating, and impurity addition can mitigate these risks. Additionally, this work concludes with a future-oriented discussion, offering critical insights into the field.
Subject(s)
Immunotherapy , Lymph Nodes , Nanoparticles , Neoplasms , Immunotherapy/methods , Humans , Neoplasms/therapy , Neoplasms/immunology , Nanoparticles/chemistry , AnimalsABSTRACT
The unique physical and chemical properties make metallic nanoparticles promising for broad applications in many fields. Exploring the dynamics of metallic nanoparticles in optical traps is crucial for exploiting optical tweezers to advance the applications of metallic particles. In this paper, we present a detailed study of the annular optical trapping of gold nanoparticles with azimuthal polarization. Theoretical analysis based on the T-matrix method shows that the gold nanoparticles experience optical forces pointing to the equilibrium position along the radial direction, while there is no force along the azimuthal direction at this equilibrium position. Therefore, a tightly focused azimuthally polarized beam captures gold nanoparticles in an annular region. Experimental measurements of the motion trajectory of the confined gold nanoparticles reveal a donut profile consistent with the theoretical predictions. Our work reported in this paper is expected to deepen our understanding of the interactions between metallic nanoparticles and light and promote the application of metallic nanoparticles.
ABSTRACT
Appreciating reactivity in terms of physicochemical effects for chemical processes is one of the most important undertakings in chemistry. While transition state (TS) theory provides the framework enabling the reliable calculation of the barrier height for a given elementary step, analytical tools are necessary to gain insight into key factors governing the different processes during chemical reactions. In this contribution, we partition the potential energy surface of an elementary step along the intrinsic coordinate into three segments, the so-called Pre-TS, TS, and Post-TS regions, and then determine the most important factors dictating each segment. This analysis is based on the use of both reactivity descriptors from conceptual density functional theory and concepts from the information-theoretic approach in density functional theory. We found that in both Pre-TS and Post-TS regions, steric effects are the dominant factors, whereas in the TS region, it is the intrinsic electrophilic and nucleophilic propensity of the transition state structure that governs the reactivity. The wide applicability of our approach is shown by a validation for a total of 37 organic and inorganic reactions. This work thus, in our view, provides a novel perspective on how chemical reactivity can be quantified at different stages of chemical reactions.
ABSTRACT
Experimental and theoretical study of the regioselectivity and mechanism of polycyclic aromatic amine (PAA) electrochemical oxidation is important for designing nitrogen doped large π-conjugated functional molecules. Herein, we used binary-, ternary-, and quaternary-fused PAAs as electro-oxidative reaction substrates to investigate the yield changes of carbazole and phenazine based aza-helicene other than oligomers, which were obtained through pyrrole and pyrazine annulation pathways. Combined with the restrained electrostatic potential (RESP) and steric hindrance factor analysis of the substrate, the electron spin density distribution of free radical resonance hybrid and the spin population analysis of the atoms in the structure of each free radical tautomer indicate that the degree of delocalized dispersion of N free radical and the resulting change in the spin density distribution of C free radical tautomers determine the reaction regioselectivity. The potential charge of the K-region, Bay-region, and L-region adjacent to the C(α)-C(ß1) bond is higher than that of other regions within the molecule, and the charge in these high RESP regions tends to delocalize more strongly toward electron-deficient N free radicals. Thus, the activity of N-C(α)-C(ß1) region is increased, which supports the proposed free radical addition and free radical coupling mechanism for the electro-oxidative reaction of PAA.
ABSTRACT
Previous epidemiological evidence suggests rheumatoid arthritis is associated with sarcopenia-related features. However, most of the current evidence is from cross-sectional studies, and the causal link of this association is still to be determined. Therefore, this study was committed to a two-sample Mendelian randomization analysis to assess the causal effect of rheumatoid arthritis on sarcopenia-related features. In this two-sample Mendelian randomization study, instrumental variables for rheumatoid arthritis were obtained from the Non-Cancer Disease Study, and data for the five relevant characteristics of sarcopenia were pooled from UKBiobank. Inverse variance weighting is the primary analysis method for assessing causal effects. MR-Egger regression and weighted median are complementary analysis methods for causal effects. Leave-one-out analysis, horizontal pleiotropy test, and Heterogeneity test are applied as a sensitivity analysis to assess the robustness of causal effect estimates. The inverse variance weighted results for the five characteristics associated with sarcopenia and rheumatoid arthritis were: hand grip strength (right) (beta = - 2.309, se = 0.206, p = 3.340E-29), hand grip strength (left) (beta = - 2.046, se = 0.205, p = 2.166E-23), whole body lean mass (beta = - 0.843, se = 0.135, p = 4.67E-10), appendicular lean mass (beta = - 2.444, se = 0.208, p = 6.069E-32), Usual walking pace (OR 0.340, 95% CI (0.238, 0.484), p = 2.471E-09). The sensitivity analyses did not support that horizontal pleiotropy distorted causal effect estimates. The beta coefficient quantifies the number of standard deviations of the continuous outcome variables (hand grip strength, whole body lean mass, and appendicular lean mass) that change on average with each increase in the standard deviation of the binary exposure variable (rheumatoid arthritis). The odds ratios indicate the increased risk of the binary outcome variable (usual walking pace) per rheumatoid arthritis standard deviation increase. This study has demonstrated a negative causal effect of rheumatoid arthritis with five major sarcopenia-related features in a European population.
Subject(s)
Arthritis, Rheumatoid , Sarcopenia , Humans , Sarcopenia/complications , Sarcopenia/epidemiology , Sarcopenia/genetics , Mendelian Randomization Analysis/methods , Hand Strength , Cross-Sectional Studies , Polymorphism, Single Nucleotide , Genome-Wide Association Study , Arthritis, Rheumatoid/complications , Arthritis, Rheumatoid/geneticsABSTRACT
Diabetes, characterized as a well-known chronic metabolic syndrome, with its associated complications pose a substantial and escalating health and healthcare challenge on a global scale. Current strategies addressing diabetes are mainly symptomatic and there are fewer available curative pharmaceuticals for diabetic complications. Thus, there is an urgent need to identify novel pharmacological targets and agents. The impaired mitochondria have been associated with the etiology of diabetes and its complications, and the intervention of mitochondrial dysfunction represents an attractive breakthrough point for the treatments of diabetes and its complications. Natural products (NPs), with multicenter characteristics, multi-pharmacological activities and lower toxicity, have been caught attentions as the modulators of mitochondrial functions in the therapeutical filed of diabetes and its complications. This review mainly summarizes the recent progresses on the potential of 39 NPs and 2 plant-extracted mixtures to improve mitochondrial dysfunction against diabetes and its complications. It is expected that this work may be useful to accelerate the development of innovative drugs originated from NPs and improve upcoming therapeutics in diabetes and its complications.
Subject(s)
Biological Products , Diabetes Complications , Diabetes Mellitus , Mitochondrial Diseases , Humans , Biological Products/pharmacology , Biological Products/therapeutic use , Biological Products/metabolism , Diabetes Mellitus/drug therapy , Diabetes Mellitus/metabolism , Diabetes Complications/drug therapy , Diabetes Complications/metabolism , Mitochondria/metabolism , Mitochondrial Diseases/metabolism , Multicenter Studies as TopicABSTRACT
The development of homogeneous metal catalysts for the efficient hydrogenation of carbon dioxide (CO2) into methanol (CH3OH) remains a significant challenge. In this study, a new cyclopentadienone diphosphine ligand (CPDDP ligand) was designed, which could coordinate with ruthenium to form a Ru-CPDDP complex to efficiently catalyze the CO2-to-methanol process using dihydrogen (H2) as the hydrogen resource based on density functional theory (DFT) mechanistic investigation. This process consists of three catalytic cycles, stage I (the hydrogenation of CO2 to HCOOH), stage II (the hydrogenation of HCOOH to HCHO), and stage III (the hydrogenation of HCHO to CH3OH). The calculated free energy barriers for the hydrogen transfer (HT) steps of stage I, stage II, and stage III are 7.5, 14.5, and 3.5 kcal/mol, respectively. The most favorable pathway of the dihydrogen activation (DA) steps of three stages to regenerate catalytic species is proposed to be the formate-assisted DA step with a free energy barrier of 10.4 kcal/mol. The calculated results indicate that the designed Ru-CPDDP and Ru-CPDDPEt complexes could catalyze hydrogenation of CO2 to CH3OH (HCM) under mild conditions and that the transition-metal owning designed CPDDP ligand framework be one kind of promising potential efficient catalysts for HCM.
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BACKGROUND: To analyze the economic benefits of paliperidone palmitate in the treatment of schizophrenia. METHODS: We collected 546 patients who met the diagnostic criteria for schizophrenia according to the ãInternational Statistical Classification of Diseases and Related Health Problems,10thã(ICD-10). We gathered general population data such as gender, age, marital status, and education level, then initiated treatment with paliperidone palmitate. Then Follow-up evaluations were conducted at 1, 3, 6, 9, and 12 months after the start of treatment to assess clinical efficacy, adverse reactions, and injection doses. We also collected information on the economic burden before and after 12 months of treatment, as well as the number of outpatient visits and hospitalizations in the past year to analyze economic benefits. RESULTS: The baseline patients totaled 546, with 239 still receiving treatment with paliperidone palmitate 12 months later. After 12 months of treatment, the number of outpatient visits per year increased compared to before (4 (2,10) vs. 12 (4,12), Z=-5.949, P < 0.001), while the number of hospitalizations decreased (1 (1,3) vs. 1 (1,2), Z = 5.625, P < 0.001). The inpatient costs in the direct medical expenses of patients after 12 months of treatment decreased compared to before (5000(2000,12000) vs. 3000 (1000,8050), P < 0.05), while there was no significant change in outpatient expenses and direct non-medical expenses (transportation, accommodation, meal, and family accompanying expenses, etc.) (P > 0.05); the indirect costs of patients after 12 months of treatment (lost productivity costs for patients and families, economic costs due to destructive behavior, costs of seeking non-medical assistance) decreased compared to before (300(150,600) vs. 150(100,200), P < 0.05). CONCLUSION: Palmatine palmitate reduces the number of hospitalizations for patients, as well as their direct and indirect economic burdens, and has good economic benefits.
Subject(s)
Antipsychotic Agents , Paliperidone Palmitate , Schizophrenia , Humans , Paliperidone Palmitate/therapeutic use , Paliperidone Palmitate/economics , Paliperidone Palmitate/administration & dosage , Schizophrenia/drug therapy , Schizophrenia/economics , Male , Female , Antipsychotic Agents/economics , Antipsychotic Agents/therapeutic use , Adult , Middle Aged , Hospitalization/economics , Hospitalization/statistics & numerical data , Cohort Studies , Cost of Illness , Treatment OutcomeABSTRACT
The deployment of imaging examinations has evolved into a robust approach for the diagnosis of lymph node metastasis (LNM). The advancement of technology, coupled with the introduction of innovative imaging drugs, has led to the incorporation of an increasingly diverse array of imaging techniques into clinical practice. Nonetheless, conventional methods of administering imaging agents persist in presenting certain drawbacks and side effects. The employment of controlled drug delivery systems (DDSs) as a conduit for transporting imaging agents offers a promising solution to ameliorate these limitations intrinsic to metastatic lymph node (LN) imaging, thereby augmenting diagnostic precision. Within the scope of this review, we elucidate the historical context of LN imaging and encapsulate the frequently employed DDSs in conjunction with a variety of imaging techniques, specifically for metastatic LN imaging. Moreover, we engage in a discourse on the conceptualization and practical application of fusing diagnosis and treatment by employing DDSs. Finally, we venture into prospective applications of DDSs in the realm of LNM imaging and share our perspective on the potential trajectory of DDS development.
Subject(s)
Drug Delivery Systems , Lymph Nodes , Humans , Lymphatic Metastasis/pathology , Lymph Nodes/diagnostic imaging , Lymph Nodes/pathologyABSTRACT
Research into mRNA vaccines is advancing rapidly, with proven efficacy against coronavirus disease 2019 and promising therapeutic potential against a variety of solid tumors. Adjuvants, critical components of mRNA vaccines, significantly enhance vaccine effectiveness and are integral to numerous mRNA vaccine formulations. However, the development and selection of adjuvant platforms are still in their nascent stages, and the mechanisms of many adjuvants remain poorly understood. Additionally, the immunostimulatory capabilities of certain novel drug delivery systems (DDS) challenge the traditional definition of adjuvants, suggesting that a revision of this concept is necessary. This review offers a comprehensive exploration of the mechanisms and applications of adjuvants and self-adjuvant DDS. It thoroughly addresses existing issues mentioned above and details three main challenges of immune-related adverse event, unclear mechanisms, and unsatisfactory outcomes in old age group in the design and practical application of cancer mRNA vaccine adjuvants. Ultimately, this review proposes three optimization strategies which consists of exploring the mechanisms of adjuvant, optimizing DDS, and improving route of administration to improve effectiveness and application of adjuvants and self-adjuvant DDS.
Subject(s)
Adjuvants, Immunologic , Cancer Vaccines , Nanotechnology , Neoplasms , mRNA Vaccines , Humans , Cancer Vaccines/immunology , Nanotechnology/methods , Neoplasms/therapy , Neoplasms/immunology , Animals , Drug Delivery Systems/methods , COVID-19/prevention & control , Adjuvants, Vaccine , RNA, Messenger/genetics , SARS-CoV-2/immunology , Vaccines, Synthetic/immunologyABSTRACT
OBJECTIVE: Tooth agenesis is a common craniofacial malformation, which is often associated with gene mutations. The purpose of this research was to investigate and uncover ectodysplasin A (EDA) gene variants in eight Chinese families affected with tooth agenesis. METHODS: Genomic DNA was extracted from tooth agenesis families and sequenced using whole-exome sequencing. The expression of ectodysplasin A1 (EDA1) protein was studied by western blot, binding activity with receptor was tested by pull-down and the NF-κB transcriptional activity was analyzed by Dual luciferase assay. RESULTS: Eight EDA missense variants were discovered, of which two (c.T812C, c.A1073G) were novel. The bioinformatics analysis indicated that these variants might be pathogenic. The tertiary structure analysis revealed that these eight variants could cause structural damage to EDA proteins. In vitro functional studies demonstrated that the variants greatly affect protein stability or impair the EDA-EDAR interaction; thereby significantly affecting the downstream NF-κb transcriptional activity. In addition, we summarized the genotype-phenotype correlation caused by EDA variants and found that EDA mutations leading to NSTA are mostly missense mutations located in the TNF domain. CONCLUSION: Our results broaden the variant spectrum of the EDA gene associated with tooth agenesis and provide valuable information for future genetic counseling.
ABSTRACT
BACKGROUND: Patients with idiopathic scoliosis commonly present with an imbalance of the paraspinal muscles. However, it is unclear whether this muscle imbalance is an underlying cause or a result of idiopathic scoliosis. This study aimed to investigate the role of paraspinal muscles in the development of idiopathic scoliosis based on surface electromyography (sEMG) and radiographic analyses. METHODS: This was a single-center prospective study of 27 patients with single-curve idiopathic scoliosis. Posteroanterior whole-spine radiographs and sEMG activity of the erector spinae muscles were obtained for all patients in the habitual standing position (HSP), relaxed prone position (RPP), and prone extension position (PEP). The Cobb angle, symmetrical index (SI) of the sEMG activity (convex/concave), and correlation between the two factors were analyzed. RESULTS: In the total cohort, the mean Cobb angle in the HSP was significantly greater than the mean Cobb angle in the RPP (RPP-Cobb) (p < 0.001), whereas the mean Cobb angle in the PEP (PEP-Cobb) did not differ from the RPP-Cobb. Thirteen patients had a PEP-Cobb that was significantly smaller than their RPP-Cobb (p = 0.007), while 14 patients had a PEP-Cobb that was significantly larger than their RPP-Cobb (p < 0.001). In the total cohort and two subgroups, the SI of sEMG activity at the apex vertebra (AVSI) in the PEP was significantly greater than 1, revealing significant asymmetry, and was also significantly larger than the AVSI in the RPP. In the RPP, the AVSI was close to 1 in the total cohort and two subgroups, revealing no significant asymmetry. CONCLUSION: The coronal Cobb angle and the SI of paraspinal muscle activity in AIS patients vary with posture changes. Asymmetrical sEMG activity of the paraspinal muscles may be not an inherent feature of AIS patients, but is evident in the challenging tasks. The potential significance of asymmetric paraspinal muscle activity need to be explored in further research.