Post-translational modifications: The potential ways for killing cancer stem cells.

While strides in cancer treatment continue to advance, the enduring challenges posed by cancer metastasis and recurrence persist as formidable contributors to the elevated mortality rates observed in cancer patients. Among the multifaceted factors implicated in tumor recurrence and metastasis, cancer stem cells (CSCs) emerge as noteworthy entities due to their inherent resistance to conventional therapies and heightened invasive capacities. Characterized by their notable abilities for self-renewal, differentiation, and initiation of tumorigenesis, the eradication of CSCs emerges as a paramount objective. Recent investigations increasingly emphasize the pivotal role of post-translational protein modifications (PTMs) in governing the self-renewal and replication capabilities of CSCs. This review accentuates the critical significance of several prevalent PTMs and the intricate interplay of PTM crosstalk in regulating CSC behavior. Furthermore, it posits that the manipulation of PTMs may offer a novel avenue for targeting and eliminating CSC populations, presenting a compelling perspective on cancer therapeutics with substantial potential for future applications.

D-π-A type fluorescent dyes: Effect of π-bridge units on optical and G4 DNA binding properties.

Fluorescent solvatochromic dyes that are sensitive to the nature of local microenvironmental, have been explored as probes in applications ranging from the imaging biomolecules to understanding of basic biomolecule functions. To expand the scope of fluorescent solvatochromic dyes for G-quadruplex (G4) DNA structures, and to illustrate the relationship between structure and properties, three newly designed D-π-A type fluorescent dyes were synthesized by introducing diarylimidazole to carbazole skeleton linked to benzene, furan or thiophene π-conjugated bridge and connected with pyridinium acceptor, respectively. Their structural characteristics, optical properties, and G4 DNA binding properties were discussed in detail. In general, the incorporation of furan and thiophene as π-conjugated bridges leads the better conjugation and molecular coplanarity with more efficient intramolecular charge transfer (ICT) effect compared with benzene bridge. The fluorescence intensities induced upon interaction were found that TP-6 with thiophene π-conjugated bridge had the strongest response toward G4 DNAs. In addition, the application of this dye as a fluorescent agent for living cell imaging was also demonstrated.

Brain macrophage senescence in glioma.

Gliomas are a diverse group of primary central nervous system neoplasms with no curative therapies available. Brain macrophages comprise microglia in the brain parenchyma, border-associated macrophages in the meningeal-choroid plexus-perivascular space and monocyte-derived macrophages infiltrating the brain. With the great improvement of our recognition of brain macrophages, diverse macrophage populations have been found in the context of glioma, which exhibit functional and phenotypic heterogeneity. We have long thought that brain macrophage senescence is detrimental, manifested by specialized forms of persistent cell cycle arrest and chronic low-grade inflammation. Persistent senescence of macrophages may result in immune dysfunction, potentially contributing to glioma initiation and development. Given the crucial roles played by brain macrophages in glioma, we unravel how brain macrophages undergo reprogramming and their contribution to glioma. We outline general molecular alterations and specific biomarkers in senescent brain macrophages, as well as functional changes (such as metabolism, autophagy, phagocytosis, antigen presentation, and infiltration and recruitment). In addition, recent advances in genetic regulation and mechanisms linked to senescent brain macrophages are discussed. In particular, this review emphasizes the contribution of senescent brain macrophages to glioma, which may drive translational efforts to utilize brain macrophages as a prognostic marker or/and treatment target in glioma. An in-depth comprehending of how brain macrophage senescence functionally influences the tumor microenvironment will be key to our development of innovative therapeutics for glioma.

The jacktree genome and population genomics provides insights for the mechanisms of the germination obstacle and the conservation of endangered ornamental plants.

Sinojackia Hu represents the first woody genus described by Chinese botanists, with all species classified as endangered ornamental plants endemic to China. Their characteristic spindle-shaped fruits confer high ornamental value to the plants, making them favored in gardens and parks. Nevertheless, the fruits likely pose a germination obstacle, contributing to the endangered status of this lineage. Here we report the chromosome-scale genome of S. xylocarpa, and explore the mechanisms underlying its endangered status, as well as its population dynamics throughout evolution. Population genomic analysis has indicated that S. xylocarpa experienced a bottleneck effect following the recent glacial period, leading to a continuous population reduction. Examination of the pericarp composition across six stages of fruit development revealed a consistent increase in the accumulation of lignin and fiber content, responsible for the sturdiness of mature fruits' pericarps. At molecular level, enhanced gene expression in the biosynthesis of lignin, cellulose and hemicellulose was detected in pericarps. Therefore, we conclude that the highly lignified and fibrotic pericarps of S. xylocarpa, which inhibit its seed germination, should be its threatening mechanism, thus proposing corresponding strategies for improved conservation and restoration. This study serves as a seminal contribution to conservation biology, offering valuable insights for the study of other endangered ornamental plants.

The predictive value of TyG and lipid ratios on the development of complications and hyperuricemia in patients with type 2 diabetes mellitus.

Investigate the predictive value of TyG and lipid ratios on the development of complications and HUA in patients with T2DM. A retrospective cross-sectional study involving 9488 T2DM patients was conducted. They were divided into HUA and NUA group base on SUA level and divided into with and without complications groups according to the diagnosis of the endocrinologist. Necessary information and biochemical parameters were recorded during outpatient visit. TyG index and lipid ratios were calculated, and statistical analysis was carried out to correlate the calculated values and HUA using SPSS version 26.0 for Windows. TyG and lipid ratios were significantly higher in T2DM with HUA or with complications than those with NUA or without complications (p < 0.05). Regression analysis adjusting for confounding factors found TyG (adjusted OR = 1.54; 95% CI: 1.31-1.82; p < 0.05), TG/HDL-C (adjusted OR = 1.21; 95% CI: 1.04-1.40; p < 0.05) and TC/HDL (adjusted OR = 1.36; 95% CI: 1.17-1.57; p < 0.05) was risk factor of HUA in T2DM patients. TyG (adjusted OR = 1.21; 95% CI: 1.02-1.44; p < 0.05), TG/HDL (adjusted OR = 1.19; 95% CI: 1.03-1.38; p < 0.05) and Apo A/Apo B (adjusted OR = 1.41; 95% CI: 1.26-1.58; p < 0.05) was risk factor of complications in T2DM patients. TyG, TG/HDL-C, and TC/HDL can be used as early sensitive target in the occurrence of HUA in T2DM patients and TyG was the most influential risk factor. TyG, TG/HDL-C, and Apo A/Apo B can be used as early sensitive target in the occurrence of complications in T2DM patients and Apo A/Apo B was the most influential risk factor.

Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells.

Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. In this study, we investigated functional drivers of post-treatment recurrent GBM through integrative genomic analyses, genome-wide genetic perturbation screens in patient-derived GBM models and independent lines of validation. Specific genetic dependencies were found consistent across recurrent tumor models, accompanied by increased mutational burden and differential transcript and protein expression compared to its primary GBM predecessor. Our observations suggest a multi-layered genetic response to drive tumor recurrence and implicate PTP4A2 (protein tyrosine phosphatase 4A2) as a modulator of self-renewal, proliferation and tumorigenicity in recurrent GBM. Genetic perturbation or small-molecule inhibition of PTP4A2 acts through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1) and its downstream molecular players, exploiting a functional dependency on ROBO signaling. Because a pan-PTP4A inhibitor was limited by poor penetrance across the blood-brain barrier in vivo, we engineered a second-generation chimeric antigen receptor (CAR) T cell therapy against ROBO1, a cell surface receptor enriched across recurrent GBM specimens. A single dose of ROBO1-targeted CAR T cells doubled median survival in cell-line-derived xenograft (CDX) models of recurrent GBM. Moreover, in CDX models of adult lung-to-brain metastases and pediatric relapsed medulloblastoma, ROBO1 CAR T cells eradicated tumors in 50-100% of mice. Our study identifies a promising multi-targetable PTP4A-ROBO1 signaling axis that drives tumorigenicity in recurrent GBM, with potential in other malignant brain tumors.

Etiologies of Persistent Aminotransferase Elevations in Chronic Hepatitis B Patients Treated with Nucleos(t)ide Analogs.

Background/Aims: Recent studies revealed that patients with persistent aminotransferase elevations after antiviral treatment had higher risk of hepatic events; yet its underlying causes remain unclear. Our study aimed to investigate the etiologies of persistent aminotransferase elevations in patients treated with nucleos(t)ide analogs (NAs). Materials and Methods: A retrospective study was conducted on chronic hepatitis B (CHB) patients who had been receiving NA treatment for over a year and had an aminotransferase level greater than 40 IU/mL (more than twice, with a 3-month interval) and subsequently underwent a liver biopsy. Results: The study group included 46 patients (34 males) with a mean age of 44.8 ± 20.3 years (range: 24-71 years).The average dura- tion of NA therapy was 3.7 years (1.1-10.6 years). The etiologies of persistant transaminase elevation were categorized into 4 groups: patients with low hepatitis B virus (HBV) viral load (LVL, n = 11); concurrent non-alcoholic fatty liver disease (NAFLD, n = 12); concurrent other liver diseases (OLD, n = 12); and unknown liver dysfunction (ULD, n = 11). The proportion of G ≥ 2 inflammation was significantly higher in the LVL group (90.9%) compared to NAFLD (33.3%), OLD (50%), and ULD (27.2%) groups (P = .012). The hepatitis B e-antigen (HBeAg)-positive group exhibited a younger age (34.5 ± 10.2 vs. 48.1 ± 9.4 years, P < .001), a lower proportion of fibrosis F ≥ 2 (36.3% vs. 77.1%, P = .012), and a higher prevalence of detectable HBV DNA (54.5% vs.14.2%, P = .00632) compared to the HBeAg-negative group. Conclusion: The etiology of persistent aminotransferase elevations in CHB patients undergoing NAs treatment warrants investigation. Besides the commonly observed NAFLD and low HBV viral load, concurrent presence of other liver diseases requires elucidation.The proportion of G≥2 inflammation was higher in the LVL group.

Transcriptional regulation mechanism of PARP1 and its application in disease treatment.

Poly (ADP-ribose) polymerase 1 (PARP1) is a multifunctional nuclear enzyme that catalyzes poly-ADP ribosylation in eukaryotic cells. In addition to maintaining genomic integrity, this nuclear enzyme is also involved in transcriptional regulation. PARP1 can trigger and maintain changes in the chromatin structure and directly recruit transcription factors. PARP1 also prevents DNA methylation. However, most previous reviews on PARP1 have focused on its involvement in maintaining genome integrity, with less focus on its transcriptional regulatory function. This article comprehensively reviews the transcriptional regulatory function of PARP1 and its application in disease treatment, providing new ideas for targeting PARP1 for the treatment of diseases other than cancer.

Hypericum perforatum-derived exosomes-like nanovesicles for adipose tissue photodynamic therapy.

BACKGROUND: Recent investigations underscore the capacity of photodynamic therapy (PDT) to induce adipocyte apoptosis, thereby mitigating obesity. Nonetheless, extant synthetic photosensitizers manifest limitations that hinder their clinical viability. PURPOSE: In the current study, we used Hypericum perforatum-derived exosomes-like nanovesicles (HPExos) as a novel photosensitizer, and investigated its PDT effects in adipose tissue during obesity. METHOD: HPExos-were administered to high fat diet mice via intraperitoneal injection, followed by targeted irradiation with specialized LED lights. Mass spectrometric analysis was analyzed in adipose tissues. CCK8 assay and Oil Red O staining were used to investigate lipid accumulation in 3T3-L1 cells to clarify adipocyte differentiation. The expression levels of related markers associated with adipogenesis and lipogenesis were assessed by RT-PCR. Apoptosis analysis was performed by TUNEL staining of and western blotting. RESULTS: HPExos combined with PDT accumulated in visceral white adipose tissues results in a reduced body weight and improved insulin sensitivity. HPExos combined with PDT induced apoptosis by driving high levels of ROS. In addition, HPExos combined with PDT significantly downregulated the expression of transcription factors, PPARγ, C/EBPα, and SREBP and lipogenesis protein FABP4 both in vitro and in vivo, associated with a decreased FFA levels. CONCLUSION: These findings suggest that HPExos could act as an effective photosensitizer in regulating glucose hemostasis by inhibiting adipocyte differentiation and lipogenesis, offering a promising approach for obesity treatment.

Novel audio characteristic-dependent feature extraction and data augmentation methods for cough-based respiratory disease classification.

Respiratory diseases are one of the major health problems worldwide. Early diagnosis of the disease types is of vital importance. As one of the main symptoms of many respiratory diseases, cough may contain information about different pathological changes in the respiratory system. Therefore, many researchers have used cough sounds to diagnose different diseases through artificial intelligence in recent years. The acoustic features and data augmentation methods commonly used in speech tasks are used to achieve better performance. Although these methods are applicable, previous studies have not considered the characteristics of cough sound signals. In this paper, we designed a cough-based respiratory disease classification system and proposed audio characteristic-dependent feature extraction and data augmentation methods. Firstly, according to the short durations and rapid transition of different cough stages, we proposed maximum overlapping mel-spectrogram to avoid missing inter-frame information caused by traditional framing methods. Secondly, we applied various data augmentation methods to mitigate the problem of limited labeled data. Based on the frequency energy distributions of different diseased cough audios, we proposed a parameter-independent self-energy-based augmentation method to enhance the differences between different frequency bands. Finally, in the model testing stage, we leveraged test-time augmentation to further improve the classification performance by fusing the test results of the original and multiple augmented audios. The proposed methods were validated on the Coswara dataset through stratified four-fold cross-validation. Compared to the baseline model using mel-spectrogram as input, the proposed methods achieved an average absolute performance improvement of 3.33% and 3.10% in macro Area Under the Receiver Operating Characteristic (macro AUC) and Unweighted Average Recall (UAR), respectively. The visualization results through Gradient-weighted Class Activation Mapping (Grad-CAM) showed the contributions of different features to model decisions.

Performance analysis of non-invasive prenatal testing for trisomy 13, 18, and 21: A large-scale retrospective study (2018-2021).

Background: Non-invasive prenatal tests (NIPT) are used to screen for trisomy 21, 18, and 13. This study investigated NIPT performance and the clinical significance of its results. Methods: Pregnant women (n = 282,911) participating in a free NIPT (April 2018-December 2021) were screened for common trisomies, and the results were retrospectively analyzed. NIPT performance was evaluated by its positive predictive value (PPV), sensitivity, and specificity. Results were analyzed using number, percentage, and chi-squared/t-test analyses. Results: After NIPT screening, patients with common trisomies (n = 746) included 457 with T21, 160 with T18, and 129 with T13. Seven false negative cases were identified. High PPV (86.81 %, 56.81 %, 18.18 %), sensitivity (99.25 %, 98.33 %, 100.00 %), and specificity (99.98 %, 99.98 %, 99.97 %) values were detected for trisomy 21, 18, and 13, respectively. The PPVs of common trisomies were significantly different between pregnant women older than 35 (85.53 %, 136/159) and those aged 35 or younger (58.90 %, 311/528) (χ2 = 125.02, P = 2.20e-16). As the NIPT uptake increased from 2018 to 2021, live-born birth defect incidence decreased. Conclusion: NIPT performed well in screening for T21, T18, and T13. Our discoveries offer an important and useful guideline in laboratory and clinical genetic counseling.

Clofazimine inhibits innate immunity against Mycobacterium tuberculosis by NF-κB.

Tuberculosis (TB) remains one of the infectious diseases with high incidence and high mortality. About a quarter of the population has been latently infected with Mycobacterium tuberculosis. At present, the available TB treatment strategies have the disadvantages of too long treatment duration and serious adverse reactions. The sustained inflammatory response leads to permanent tissue damage. Unfortunately, the current selection of treatment regimens does not consider the immunomodulatory effects of various drugs. In this study, we preliminarily evaluated the effects of commonly used anti-tuberculosis drugs on innate immunity at the cellular level. The results showed that clofazimine (CFZ) has a significant innate immunosuppressive effect. CFZ significantly inhibited cytokines and type I interferons (IFNα and IFNß) expression under both lipopolysaccharide stimulation and CFZ-resistant strain infection. In further mechanistic studies, CFZ strongly inhibited the phosphorylation of nuclear factor kappa B (NF-κB) p65 and had no significant effect on the phosphorylation of p38. In conclusion, our study found that CFZ suppresses innate immunity against Mycobacterium tuberculosis by NF-κB, which should be considered in future regimen development. IMPORTANCE: The complete elimination of Mycobacterium tuberculosis (Mtb), the etiologic agent of TB, from TB patients is a complicated process that takes a long time. The excessive immune inflammatory response of the host for a long time causes irreversible organic damage to the lungs and liver. Current antibiotic-based treatment options involve multiple complex drug combinations, often targeting different physiological processes of Mtb. Given the high incidence of post-tuberculosis lung disease, we should also consider the immunomodulatory properties of other drugs when selecting drug combinations.

[Quality control mode between Lonicera macranthoides and L. japonica based on multi-elemental difference through inductively coupled plasma mass spectrometry].

Numerous studies show that Lonicera macranthoides and L. japonica have significant differences in organic matter. However, there is still a lack of research on inorganic elements between them. In this study, a non-targeted elemental metabolomics method was established by inductively coupled plasma mass spectrometry(ICP-MS), so as to compare the overall differences of inorganic elements between L. macranthoides and L. japonica. In addition, the differential markers were screened, and these differential markers were quantitatively analyzed by the targeted method. The non-targeted elemental metabolomics showed that the established mathematical model could reflect the difference in element content between L. macranthoides and L. japonica. Four inorganic elements such as ~(55)Mn, ~(209)Bi, ~(111)Cd, and ~(85)Rb were confirmed as the differential markers of L. macranthoides and L. japonica based on the screening principles of variable importance in the projection(VIP) value>2.0, P<0.01 and fold change(FC) value>1.2 or <0.80. The targeted quantitative results showed that the content of ~(209)Bi in L. japonica was significantly higher than that in L. macranthoides, while ~(55)Mn, ~(111)Cd, and ~(85)Rb in L. macranthoides were significantly higher than that in L. japonica. The non-targeted and targeted elemental metabolomics methods based on ICP-MS can significantly reflect the overall differences in inorganic elements between L. macranthoides and L. japonica. Exploring the differences between them from the perspective of elements can partly reflect the differences in their drug properties and lay a foundation for further study on the quality control mode of inorganic elements in L. macranthoides and L. japonica and their pharmacological effects.

LC-MS characterization of N/O-glycans of α- and ß-subunits of chicken ovomucin separated by SDS-PAGE.

As the main active glycoprotein of egg white, the biological functions of chicken ovomucin α- and ß-subunit are closely related to the structure of glycans. However, the exact composition and structure of the subunit glycans are still unknown. We obtained highly pure chicken ovomucin α-subunit and ß-subunit protein bands by the strategy combined with two-step isoelectric precipitation and SDS-PAGE gel electrophoresis. The ammonia-catalyzed one-pot procedure was then used to release and capture α-and ß-subunit protein glycans with 1-phenyl- 3-Methyl-5-pyrazolone (PMP). The N/O-glycans of bis-PMP derivatives were purified and analyzed by LC-MS. More importantly, an effective dual modification was performed to accurately quantify neutral and sialylated O-glycans through methylamidation of sialic acid residues and simultaneously through carbonyl condensation reactions of reducing ends with PMP. We first showed that the α-subunit protein has only N-glycosylation modification, and the ß-subunit only O-glycosylation, a total of 22 N-glycans and 20 O-glycans were identified in the α- and ß-subunit, respectively. In addition, the complex N-glycan (47 %) and the sialylated O-glycan (77 %) are each major types of the above subunits. Such findings in this study provide a basis for studying the functional and biological activities of chicken ovomucin glycans.

Association Between Handgrip Strength and Mortality of Patients With Coronary Artery Disease: A Meta-Analysis.

BACKGROUND: Muscular strength has been linked to increased risk of cardiovascular disease in the community population. The aim of this systematic review and meta-analysis is to evaluate the association between weak handgrip strength (HGS) and mortality risk in patients with coronary artery disease (CAD). METHODS: To carry out the meta-analysis, an extensive search was conducted on databases such as PubMed, Embase, Web of Science, Cochrane Library, Wanfang, and CNKI to identify observational studies with longitudinal follow-up. Random-effects models were used to combine the findings, taking into account the potential influence of heterogeneity. RESULTS: Eight observational studies involving 10 543 patients with CAD were included. During a mean follow-up duration of 20.4 months, 1327 (12.6%) patients died. Pooled results showed that weak HGS at baseline was associated with an increased risk of all-cause mortality during follow-up (risk ratio [RR]: 1.95, 95% confidence interval: 1.50 to 2.55, p < 0.001; I2 = 62%). Subgroup analysis suggested a stronger association between weak HGS and increased mortality in older patients with CAD as compared to that of overall adult patients with CAD (RR: 3.01 vs. 1.60, p for subgroup difference = 0.004). Subgroup analyses according to study location, design, subtype of CAD, follow-up duration, analytical model, and study quality scores showed similar results (p for subgroup difference all > 0.05). CONCLUSIONS: Weak HGS at baseline is associated with an increased risk of mortality in patients with CAD, particularly in older patients with CAD.

Enhanced editing efficiency in Arabidopsis with a LbCas12a variant harboring D156R and E795L mutations.

Cas12a (Cpf1), a Class 2 Type V CRISPR/Cas nuclease, has several unique attributes for genome editing and may provide a valuable alternative to Cas9. However, a low editing efficiency due to temperature sensitivity and insufficient cleavage activity of the Cas12a nuclease are major obstacles to its broad application. In this report, we generated two variants, ttAsCas12 Ultra and ttLbCas12a Ultra harboring three (E174R, M537R, and F870L) or two (D156R and E795L) mutations, respectively, by combining the mutations from the temperature-tolerant variants ttAsCas12a (E174R) and ttLbCas12a (D156R), and those from the highly active variants AsCas12a Ultra (M537R and F870L) and LbCas12a Ultra (E795L). We compared editing efficiencies of the five resulting Cas12a variants (LbCas12a, ttLbCas12a, ttLbCas12a Ultra, AsCas12a Ultra, and ttAsCas12 Ultra) at six target sites of four genes in Arabidopsis (Arabidopsis thaliana). The variant ttLbCas12a Ultra, harboring the D156R and E795L mutations, exhibited the highest editing efficiency of all variants tested in Arabidopsis and can be used to generate homozygous or biallelic mutants in a single generation in Arabidopsis plants grown at 22 °C. In addition, optimization of ttLbCas12a Ultra, by varying nuclear localization signal sequences and codon usage, further greatly improved editing efficiency. Collectively, our results indicate that ttLbCas12a Ultra is a valuable alternative to Cas9 for editing genes or promoters in Arabidopsis. Supplementary Information: The online version contains supplementary material available at 10.1007/s42994-024-00144-w.

PE6c greatly enhances prime editing in transgenic rice plants.

Prime editing is a versatile CRISPR/Cas-based precise genome-editing technique for crop breeding. Four new types of prime editors (PEs) named PE6a-d were recently generated using evolved and engineered reverse transcriptase (RT) variants from three different sources. In this study, we tested the editing efficiencies of four PE6 variants and two additional PE6 constructs with double-RT modules in transgenic rice (Oryza sativa) plants. PE6c, with an evolved and engineered RT variant from the yeast Tf1 retrotransposon, yielded the highest prime-editing efficiency. The average fold change in the editing efficiency of PE6c compared with PEmax exceeded 3.5 across 18 agronomically important target sites from 15 genes. We also demonstrated the feasibility of using two RT modules to improve prime-editing efficiency. Our results suggest that PE6c or its derivatives would be an excellent choice for prime editing in monocot plants. In addition, our findings have laid a foundation for prime-editing-based breeding of rice varieties with enhanced agronomically important traits.

Stereochemical Control of Redox CoII/CoIII-Cages with Switchable Cotton Effects Based on Labile-Static States.

The structural dynamics of artificial assemblies, in aspects such as molecular recognition and structural transformation, provide us with a blueprint to achieve bioinspired applications. Here, we describe the assembly of redox-switchable chiral metal-organic cages Λ8/Δ8-[Pd6(CoIIL3)8]28+ and Λ8/Δ8-[Pd6(CoIIIL3)8]36+. These isomeric cages demonstrate an on-off chirality logic gate controlled by their chemical and stereostructural dynamics tunable through redox transitions between the labile CoII-state and static CoIII-state with a distinct Cotton effect. The transition between different states is enabled by a reversible redox process and chiral recognition originating in the tris-chelate Co-centers. All cages in two states are thoroughly characterized by NMR, ESI-MS, CV, CD, and X-ray crystallographic analysis, which clarify their redox-switching behaviors upon chemical reduction/oxidation. The stereochemical lability of the CoII-center endows the Λ8/Δ8-CoII-cages with efficient chiral-induction by enantiomeric guests, leading to enantiomeric isomerization to switch between Λ8/Δ8-CoII-cages, which can be stabilized by oxidation to their chemically inert forms of Λ8/Δ8-CoIII-cages. Kinetic studies reveal that the isomerization rate of the Δ8-CoIII-cage is at least an order of magnitude slower than that of the Δ8-CoII-cage even at an elevated temperature, while its activation energy is 16 kcal mol-1 higher than that of the CoII-cage.

Multivalent mRNA Vaccine Elicits Broad Protection against SARS-CoV-2 Variants of Concern.

SARS-CoV-2 new waves are primarily caused by changes to the spike protein (S), which can substantially decrease the efficacy of vaccines. Therefore, we tested several multivalent mRNA-LNP vaccines, targeting the full-length S proteins of different variants, and identified an optimal combination for protection against VOCs in BALB/c mice. The tested formulations included trivalent (WT + BA.5 + XBB.1.5), pentavalent (WT + BA.5 + XBB.1.5 + BQ.1.1 + CH.1.1), and octavalent (WT + BA.5 + XBB.1.5 + BQ.1.1 + CH.1.1 + Alpha + Delta + BA.2) vaccines. Among these multivalent vaccines, the pentavalent vaccine showed superior protection for almost all tested variants. Despite this, each multivalent vaccine elicited greater broad-spectrum neutralizing antibodies than the previously evaluated bivalent vaccine (WT + BA.5). Subsequently, we redesigned the multivalent vaccine to efficiently generate neutralizing antibodies against recent VOCs, including EG.5.1. Immunization with the redesigned pentavalent vaccine (WT + EG.5.1 + XBB.1.16 + Delta + BA.5) showed moderate levels of protection against recent Omicron VOCs. Results suggest that the neutralization activity of multivalent vaccines is better than those of the tested bivalent vaccines against WT + BA.5 and WT + EG.5.1. Moreover, the pentavalent vaccine we developed may be highly useful for neutralizing new Omicron VOCs.

Icariside I enhances the effects of immunotherapy in gastrointestinal cancer via targeting TRPV4 and upregulating the cGAS-STING-IFN-I pathway.

Gastrointestinal cancer is among the most common cancers worldwide. Immune checkpoint inhibitor-based cancer immunotherapy has become an innovative approach in cancer treatment; however, its efficacy in gastrointestinal cancer is limited by the absence of infiltration of immune cells within the tumor microenvironment. Therefore, it is therefore urgent to develop a novel therapeutic drug to enhance immunotherapy. In this study, we describe a previously unreported potentiating effect of Icariside I (ICA I, GH01), the main bioactive compound isolated from the Epimedium species, on anti-tumor immune responses. Mechanistically, molecular docking and SPR assay result show that ICA I binding with TRPV4. ICA I induced intracellular Ca2+ increasing and mitochondrial DNA release by targeting TRPV4, which triggered cytosolic ox-mitoDNA release. Importantly, these intracellular ox-mitoDNA fragments were taken up by immune cells in the tumor microenvironment, which amplified the immune response. Moreover, our study shows the remarkable efficacy of sequential administration of ICA I and anti-α-PD-1 mAb in advanced tumors and provides a strong scientific rationale for recommending such a combination therapy for clinical trials. ICA I enhanced the anti-tumor effects with PD-1 inhibitors by regulating the TRPV4/Ca2+/Ox-mitoDNA/cGAS/STING axis. We expect that these findings will be translated into clinical therapies, which will benefit more patients with cancer in the near future.