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Macromolecules Jun 2024Polymer vitrimers are a new class of materials that combine the advantages of thermoplastics and thermosets. This is due to the dynamic nature of the chemical bonds...
Polymer vitrimers are a new class of materials that combine the advantages of thermoplastics and thermosets. This is due to the dynamic nature of the chemical bonds linking different chains. However, how this property affects the polymer dynamics at different length scales is still an open question. Here, we investigate the dynamics of model vitrimers based on well-defined polyisoprene (PI) chains using broadband dielectric spectroscopy. In this way, we study the polymer dynamics from the segmental to the whole chain scale, taking advantage of the fact that PI belongs to the class of molecules that exhibit a net dipole moment associated with the end-to-end vector. Three distinct relaxation phenomena are identified. The fastest relaxation is attributed to the segmental PI dynamics with a small influence of the cross-linking. An intermediate relaxation attributed to the dipolar character of the cross-linker is also observed. The slower identified relaxation component, corresponding to limited fluctuations of the end-to-end PI chains, is found to be determined by the dynamics of the clusters formed by the cross-linkers with an average time scale orders of magnitude faster than that of the terminal relaxation as inferred from the viscous flow.
PubMed: 38948182
DOI: 10.1021/acs.macromol.3c02558 -
MLife Jun 2024The microbial synthesis of sulfonolipids within the human body is likely involved in maintaining human health or causing diseases. However, the enzymes responsible for...
The microbial synthesis of sulfonolipids within the human body is likely involved in maintaining human health or causing diseases. However, the enzymes responsible for their biosynthesis remain largely unknown. In this study, we identified and verified the role of 3-ketocapnine reductase, the third-step enzyme, in the four-step conversion of l-phosphoserine into sulfobacin B both in vivo and in vitro. This finding builds upon our previous research into sulfonolipid biosynthesis, which focused on the vaginal bacterium DSM 16776 and the gut bacterium DSM 17242. Through comprehensive gene mapping, we demonstrate the widespread presence of potential sulfonolipid biosynthetic genes across diverse bacterial species inhabiting various regions of the human body. These findings shed light on the prevalence of sulfonolipid-like metabolites within the human microbiota, suggesting a potential role for these lipid molecules in influencing the intricate biointeractions within the complex microbial ecosystem of the human body.
PubMed: 38948141
DOI: 10.1002/mlf2.12134 -
World Journal of Stem Cells Jun 2024Pelvic organ prolapse (POP) involves pelvic organ herniation into the vagina due to pelvic floor tissue laxity, and vaginal structure is an essential factor. In POP, the...
BACKGROUND
Pelvic organ prolapse (POP) involves pelvic organ herniation into the vagina due to pelvic floor tissue laxity, and vaginal structure is an essential factor. In POP, the vaginal walls exhibit abnormal collagen distribution and decreased fibroblast levels and functions. The intricate etiology of POP and the prohibition of transvaginal meshes in pelvic reconstruction surgery present challenges in targeted therapy development. Human umbilical cord mesenchymal stromal cells (hucMSCs) present limitations, but their exosomes (hucMSC-Exo) are promising therapeutic tools for promoting fibroblast proliferation and extracellular matrix remodeling.
AIM
To investigate the effects of hucMSC-Exo on the functions of primary vaginal fibroblasts and to elucidate the underlying mechanism involved.
METHODS
Human vaginal wall collagen content was assessed by Masson's trichrome and Sirius blue staining. Gene expression differences in fibroblasts from patients with and without POP were assessed RNA sequencing (RNA-seq). The effects of hucMSC-Exo on fibroblasts were determined functional experiments . RNA-seq data from fibroblasts exposed to hucMSC-Exo and microRNA (miRNA) sequencing data from hucMSC-Exo were jointly analyzed to identify effective molecules.
RESULTS
In POP, the vaginal wall exhibited abnormal collagen distribution and reduced fibroblast 1 quality and quantity. Treatment with 4 or 6 μg/mL hucMSC-Exo suppressed inflammation in POP group fibroblasts, stimulated primary fibroblast growth, and elevated collagen I (Col1) production . High-throughput RNA-seq of fibroblasts treated with hucMSC-Exo and miRNA sequencing of hucMSC-Exo revealed that abundant exosomal miRNAs downregulated matrix metalloproteinase 11 (MMP11) expression.
CONCLUSION
HucMSC-Exo normalized the growth and function of primary fibroblasts from patients with POP by promoting cell growth and Col1 expression . Abundant miRNAs in hucMSC-Exo targeted and downregulated MMP11 expression. HucMSC-Exo-based therapy may be ideal for safely and effectively treating POP.
PubMed: 38948096
DOI: 10.4252/wjsc.v16.i6.708 -
Theranostics 2024Immunotherapy has demonstrated its potential to improve the prognosis of patients with hepatocellular carcinoma (HCC); however, patients' responses to immunotherapy...
Immunotherapy has demonstrated its potential to improve the prognosis of patients with hepatocellular carcinoma (HCC); however, patients' responses to immunotherapy vary a lot. A comparative analysis of the tumor microenvironment (TME) in responders and non-responders is expected to unveil the mechanisms responsible for the immunotherapy resistance and provide potential treatment targets. We performed sequencing analyses using 10x Genomics technology on six HCC patients who responded to anti-PD-1 therapy and one HCC patient who did not respond. Additionally, we obtained single cell data from untreated, responsive, and nonresponsive HCC patients from public databases, and used part of the datasets as a validation cohort. These data were integrated using algorithms such as Harmony. An independent validation cohort was established. Furthermore, we performed spatial transcriptomic sequencing on the tumor adjacent tissues of three HCC responsive patients using 10x Genomics spatial transcriptomic technology. Additionally, we analyzed data about three HCC patients obtained from public databases. Finally, we validated our conclusions using immunofluorescence, flow cytometry, and experiments. Our findings confirmed the presence of "immune barrier" partially accounting for the limited efficacy of immunotherapy. Our analysis revealed a significant increase in TREM2 Macrophages among non-responsive patients expressing multiple immunosuppressive signals. anti-Csf1r monoclonal antibodies effectively eliminated these macrophages and augmented the therapeutic effects of anti-PD-1 therapy. TCR Macrophages possessed direct tumor-killing capabilities. IL1B cDC2 was the primary functional subtype of cDC2 cells. Absence of THEMIS CD8 T subtypes might diminish immunotherapeutic effects. Furthermore, CD8 T cells entered a state of stress after anti-PD-1 treatment, which might be associated with CD8 T cell exhaustion and senescence. The profiles of immune TMEs showed differences in HCC patients responsive, non-responsive and untreated. These differences might explain the discounted efficacy of immunotherapy in some HCC patients. The cells and molecules, which we found to carry unique capabilities, may be targeted to enhance immunotherapeutic outcomes in patients with HCC.
Topics: Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Single-Cell Analysis; Tumor Microenvironment; Programmed Cell Death 1 Receptor; Immune Checkpoint Inhibitors; Immunotherapy; Animals; Male; Mice; Female; Middle Aged
PubMed: 38948071
DOI: 10.7150/thno.95971 -
Theranostics 2024Trophoblast cell surface antigen 2 (Trop2) is overexpressed in a range of solid tumors and participants in multiple oncogenic signaling pathways, making it an attractive... (Review)
Review
Trophoblast cell surface antigen 2 (Trop2) is overexpressed in a range of solid tumors and participants in multiple oncogenic signaling pathways, making it an attractive therapeutic target. In the past decade, the rapid development of various Trop2-targeted therapies, notably marked by the advent of the antibody-drug conjugate (ADC), revolutionized the outcome for patients facing Trop2-positive tumors with limited treatment opinions, such as triple-negative breast cancer (TNBC). This review provides a comprehensive summary of advances in Trop2-targeted therapies, including ADCs, antibodies, multispecific agents, immunotherapy, cancer vaccines, and small molecular inhibitors, along with in-depth discussions on their designs, mechanisms of action (MOAs), and limitations. Additionally, we emphasize the clinical research progress of these emerging Trop2-targeted agents, focusing on their clinical application and therapeutic efficacy against tumors. Furthermore, we propose directions for future research, such as enhancing our understanding of Trop2's structure and biology, exploring the best combination strategies, and tailoring precision treatment based on Trop2 testing methodologies.
Topics: Humans; Antigens, Neoplasm; Cell Adhesion Molecules; Immunoconjugates; Molecular Targeted Therapy; Neoplasms; Immunotherapy; Animals; Cancer Vaccines
PubMed: 38948057
DOI: 10.7150/thno.98178 -
Heliyon Jun 2024The GIMAP family genes play a key role in immune function. Increasing evidence suggests that GIMAP genes were implicated in the tumorigenesis of lung adenocarcinoma...
BACKGROUND
The GIMAP family genes play a key role in immune function. Increasing evidence suggests that GIMAP genes were implicated in the tumorigenesis of lung adenocarcinoma (LUAD). This study aimed to investigate the clinical significance of GIMAP family genes in LUAD.
METHODS
In this study, we explored the expression, mutation, prognostic value of GIMAP family genes and the correlation with immune microenvironment in LUAD. We further investigated the relationship between GIMAP family genes expression and immunotherapy response in GEO LUAD and melanoma cohorts.
RESULTS
Among the GIMAP family genes, the expression levels of GIMAP1, GIMAP2, GIMAP4, GIMAP5, GIMAP6, GIMAP7, and GIMAP8 were significantly lower in LUAD tumor tissues than normal tissues. Most GIMAP genes were closely related to age, tumor grade and T stage, but not significantly related to sex, N stage and M stage. In the overall population, patients with high expression of GIMAP family genes had a significant longer overall survival (OS). GO and KEGG enrichment analysis showed that GIMAP family genes were highly enriched in immune-related biological process. The expression of GIMAP family genes was positively correlated with immune cell infiltration and immune checkpoint molecules. Furthermore, high expression of GIMAP family genes were correlated with therapeutic response to immunotherapy in LUAD and melanoma patients.
CONCLUSION
In this study, we identified that GIMAP family genes were significantly associated with immune cell infiltration and immune checkpoint molecules. They potentially play a critical role in anti-tumor immunity and serve as immunotherapy biomarkers.
PubMed: 38948046
DOI: 10.1016/j.heliyon.2024.e33111 -
Chemistry of Materials : a Publication... Jun 2024A previously unreported polymorph of 5,11-bis(triisopropylsilylethynyl)anthradithiophene (TIPS ADT), Form II, crystallizes from melt-processed TIPS ADT films blended...
A previously unreported polymorph of 5,11-bis(triisopropylsilylethynyl)anthradithiophene (TIPS ADT), Form II, crystallizes from melt-processed TIPS ADT films blended with 16 ± 1 wt % medium density polyethylene (PE). TIPS ADT/PE blends that initially are crystallized from the melt produce twisted TIPS ADT crystals of a metastable polymorph (Form IV, space group 1̅) with a brickwork packing motif distinct from the slipstack packing by solution-processed TIPS ADT crystals (Form I, space group 2/) at room temperature. When these films were cooled to room temperature and subsequently annealed at 100 °C, near a PE melting temperature of 110 °C, Form II crystals nucleated and grew while consuming Form IV. The growth rate and orientations of Form II crystals were predetermined by the twisting pitch and growth direction of the original banded spherulites in the melt-processed films of the blends. Notably, the Form IV → II transition was not observed during thermal annealing of neat TIPS ADT films without PE. The presence of the mobile PE phase during thermal annealing of TIPS ADT/PE blend films increases the diffusion rate of TIPS ADT molecules, and the rate of nucleation of Form II. Form IV crystals are more conductive but less emissive compared to Form II crystals.
PubMed: 38947980
DOI: 10.1021/acs.chemmater.4c00418 -
ACS Applied Electronic Materials Jun 2024We report a semiconducting triindole-based discotic liquid crystal () functionalized with six -methylthiophenyl groups at its periphery. While initially a crystalline...
We report a semiconducting triindole-based discotic liquid crystal () functionalized with six -methylthiophenyl groups at its periphery. While initially a crystalline solid at room temperature, transitions to a columnar hexagonal mesophase upon heating and retains this supramolecular organization upon subsequent cooling, despite having only three flexible alkyl chains attached to the core's nitrogens. The incorporation of methylthio groups effectively hinders tight molecular packing, stabilizing the columnar arrangement of this disk-shaped molecule. Single crystal analysis confirmed the high tendency of this compound to organize into a columnar architecture and the role played by the methylthio groups in reinforcing such structure. The mesomorphic behavior of provides an opportunity for processing from its molten state. Notably, our research reveals significant differences in charge transport depending on the processing method, whether solution drop-casting or melt-based. shows hole mobility values averaging 3 × 10 cm V s when incorporated in diode-type devices from the isotropic melt and annealed at the mesophase temperature, estimated by SCLC (space-charge-limited current) measurements. However, when integrated into solution-processed organic field-effect transistors (OFETs), crystalline exhibits a hole mobility of 3 × 10 cm V s. The observed differences can be attributed to a beneficial supramolecular assembly achieved in the mesophase in spite of its lower order. These results emphasize the material's potential for applications in easy-to-process electronic devices and highlight the potential of methylthio moieties in promoting columnar mesophases.
PubMed: 38947954
DOI: 10.1021/acsaelm.4c00693 -
ArXiv Jun 2024Predicting drug efficacy and safety in vivo requires information on biological responses (e.g., cell morphology and gene expression) to small molecule perturbations....
Predicting drug efficacy and safety in vivo requires information on biological responses (e.g., cell morphology and gene expression) to small molecule perturbations. However, current molecular representation learning methods do not provide a comprehensive view of cell states under these perturbations and struggle to remove noise, hindering model generalization. We introduce the Information Alignment (InfoAlign) approach to learn molecular representations through the information bottleneck method in cells. We integrate molecules and cellular response data as nodes into a context graph, connecting them with weighted edges based on chemical, biological, and computational criteria. For each molecule in a training batch, InfoAlign optimizes the encoder's latent representation with a minimality objective to discard redundant structural information. A sufficiency objective decodes the representation to align with different feature spaces from the molecule's neighborhood in the context graph. We demonstrate that the proposed sufficiency objective for alignment is tighter than existing encoder-based contrastive methods. Empirically, we validate representations from InfoAlign in two downstream tasks: molecular property prediction against up to 19 baseline methods across four datasets, plus zero-shot molecule-morphology matching.
PubMed: 38947938
DOI: No ID Found -
Journal of Extracellular Biology Jul 2024Extracellular vesicle (EV) secretion is mediated by purinergic receptor P2X (P2RX7), an ATP-gated cation channel highly expressed in microglia. We have previously shown...
Extracellular vesicle (EV) secretion is mediated by purinergic receptor P2X (P2RX7), an ATP-gated cation channel highly expressed in microglia. We have previously shown that administration of GSK1482160, a P2RX7 selective inhibitor, suppresses EV secretion from murine microglia and prevents tauopathy development, leading to the recovery of the hippocampal function in PS19 mice, expressing P301S tau mutant. It is yet unknown, however, whether the effect of GSK1482160 on EV secretion from glial cells is specifically regulated through P2RX7. Here we tested GSK1482160 on primary microglia and astrocytes isolated from C57BL/6 (WT) and mice and evaluated their EV secretion and phagocytotic activity of aggregated human tau (hTau) under ATP stimulation. GSK1482160 treatment and deletion of significantly reduced secretion of small and large EVs in microglia and astrocytes in both ATP stimulated or unstimulated condition as determined by nanoparticle tracking analysis, CD9 ELISA and immunoblotting of Tsg101 and Flotilin 1 using isolated EVs. GSK1482160 treatment had no effect on EV secretion from microglia while we observed significant reduction in the secretion of small EVs from astrocytes, suggesting its specific targeting of P2RX7 in EV secretion except small EV secretion from astrocytes. Finally, deletion of suppressed IL-1β secretion and phagocytosed misfolded tau from both microglia and astrocytes. Together, these findings show that GSK1482160 suppresses EV secretion from microglia and astrocytes in P2RX7-dependment manner, and P2RX7 critically regulates secretion of IL-1β and misfolded hTau, demonstrating as the viable target of suppressing EV-mediated neuroinflammation and tau propagation.
PubMed: 38947879
DOI: 10.1002/jex2.155