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Neoplasia (New York, N.Y.) Jun 2024
PubMed: 38943994
DOI: 10.1016/j.neo.2024.101018 -
STAR Protocols Jun 2024Super-resolution imaging provides unprecedented visualization of sub-cellular structures, but the two main techniques used, single-molecule localization microscopy...
Super-resolution imaging provides unprecedented visualization of sub-cellular structures, but the two main techniques used, single-molecule localization microscopy (SMLM) and stimulated emission depletion (STED), are not easily reconciled. We present a protocol to super-impose nanoscale protein distribution reconstructed with SMLM to sub-cellular morphology obtained in STED. We describe steps for tracking cells on etched coverslips and registering images from two different microscopes with 30-nm accuracy. In this protocol, synaptic proteins are mapped in the dendritic spines of primary neurons. For complete details on the use and execution of this protocol, please refer to Inavalli et al..
PubMed: 38943646
DOI: 10.1016/j.xpro.2024.103160 -
Cell Reports Jun 2024Basal dendrites of layer 5 cortical pyramidal neurons exhibit Na and N-methyl-D-aspartate receptor (NMDAR) regenerative spikes and are uniquely poised to influence...
Basal dendrites of layer 5 cortical pyramidal neurons exhibit Na and N-methyl-D-aspartate receptor (NMDAR) regenerative spikes and are uniquely poised to influence somatic output. Nevertheless, due to technical limitations, how multibranch basal dendritic integration shapes and enables multiplexed barcoding of synaptic streams remains poorly mapped. Here, we combine 3D two-photon holographic transmitter uncaging, whole-cell dynamic clamp, and biophysical modeling to reveal how synchronously activated synapses (distributed and clustered) across multiple basal dendritic branches are multiplexed under quiescent and in vivo-like conditions. While dendritic regenerative Na spikes promote millisecond somatic spike precision, distributed synaptic inputs and NMDAR spikes regulate gain. These concomitantly occurring dendritic nonlinearities enable multiplexed information transfer amid an ongoing noisy background, including under back-propagating voltage resets, by barcoding the axo-somatic spike structure. Our results unveil a multibranch dendritic integration framework in which dendritic nonlinearities are critical for multiplexing different spatial-temporal synaptic input patterns, enabling optimal feature binding.
PubMed: 38943640
DOI: 10.1016/j.celrep.2024.114413 -
Journal of the American Chemical Society Jun 2024Ascorbic acid (AA) has been attracting great attention with its emerging potential in T cell-dependent antitumor immunity. However, premature blood clearance and...
Ascorbic acid (AA) has been attracting great attention with its emerging potential in T cell-dependent antitumor immunity. However, premature blood clearance and immunologically "cold" tumors severely compromise its immunotherapeutic outcomes. As such, the reversal of the immunosuppressive tumor microenvironment (TME) has been the premise for improving the effectiveness of AA-based immunotherapy, which hinges upon advanced AA delivery and amplified immune-activating strategies. Herein, a novel coli ( ) outer membrane vesicle (OMV)-red blood cell (RBC) hybrid membrane (ERm)-camouflaged immunomodulatory nanoturret is meticulously designed based on gating of an AA-immobilized metal-organic framework (MOF) onto bortezomib (BTZ)-loaded magnesium-doped mesoporous silica (MMS) nanovehicles, which can realize immune landscape remodeling by chemotherapy-assisted ascorbate-mediated immunotherapy (CAMIT). Once reaching the acidic TME, the acidity-sensitive MOF gatekeeper and MMS core within the nanoturret undergo stepwise degradation, allowing for tumor-selective sequential release of AA and BTZ. The released BTZ can evoke robust immunogenic cell death (ICD), synergistically promote dendritic cell (DC) maturation in combination with OMV, and ultimately increase T cell tumor infiltration together with Mg. The army of T cells is further activated by AA, exhibiting remarkable antitumor and antimetastasis performance. Moreover, the CD8-deficient mice model discloses the T cell-dependent immune mechanism of the AA-based CAMIT strategy. In addition to providing a multifunctional biomimetic hybrid nanovehicle, this study is also anticipated to establish a new immunomodulatory fortification strategy based on the multicomponent-driven nanoturret for highly efficient T cell-activation-enhanced synergistic AA immunotherapy.
PubMed: 38943624
DOI: 10.1021/jacs.4c04840 -
Computer Methods in Biomechanics and... Jun 2024The effective reconstruction of osteochondral biomimetic structures is a key factor in guiding the regeneration of full-thickness osteochondral defects. Due to the...
The effective reconstruction of osteochondral biomimetic structures is a key factor in guiding the regeneration of full-thickness osteochondral defects. Due to the avascular nature of hyaline cartilage, the greatest challenge in constructing this scaffold lies in both utilizing the biomimetic structure to promote vascular differentiation for nutrient delivery to hyaline cartilage, thereby enhancing the efficiency of osteochondral reconstruction, and effectively blocking vascular ingrowth into the cartilage layer to prevent cartilage mineralization. However, the intrinsic relationship between the planning of the microporous pipe network and the flow resistance in the biomimetic structure, and the mechanism of promoting cell adhesion to achieve vascular differentiation and inhibiting cell adhesion to block the growth of blood vessels are still unclear. Inspired by the structure of tree trunks, this study designed a biomimetic tree-like tubular network structure for osteochondral scaffolds based on Murray's law. Utilizing computational fluid dynamics, the study investigated the influence of the branching angle of micro-pores on the flow velocity, pressure distribution, and scaffold permeability within the scaffold. The results indicate that when the differentiation angle exceeds 50 degrees, the highest flow velocity occurs at the confluence of tributaries at the ninth fractal position, forming a barrier layer. This structure effectively guides vascular growth, enhances nutrient transport capacity, increases flow velocity to promote cell adhesion, and inhibits cell infiltration into the cartilage layer.
PubMed: 38943424
DOI: 10.1080/10255842.2024.2372612 -
Journal of Alzheimer's Disease : JAD Jun 2024The Montreal Cognitive Assessment (MoCA) is a valuable assessment of the patient's awareness of time and place. We show that bacille Calmette-Guerin (BCG) significantly...
The Montreal Cognitive Assessment (MoCA) is a valuable assessment of the patient's awareness of time and place. We show that bacille Calmette-Guerin (BCG) significantly affects MoCA testing when administered by the intravesical route. MoCA scores were lower with increasing age and higher in more formally educated individuals. Patients receiving BCG tended to maintain their MoCA scores, whereas almost half the control cases tended to show reduced scores. This benefit is supported by reduced pre-amyloid biomarkers in BCG-injected healthy volunteers and a favorable effect on neuronal dendritic development in animal models. Our results suggest that BCG has a beneficial impact on the cognitive status of older individuals.
PubMed: 38943393
DOI: 10.3233/JAD-240307 -
Nature Immunology Jun 2024The immunological mechanisms underlying chronic colitis are poorly understood. T follicular helper (T) cells are critical in helping B cells during germinal center...
The immunological mechanisms underlying chronic colitis are poorly understood. T follicular helper (T) cells are critical in helping B cells during germinal center reactions. In a T cell transfer colitis model, a lymphoid structure composed of mature dendritic cells (DCs) and T cells was found within T cell zones of colonic lymphoid follicles. T cells were required for mature DC accumulation, the formation of DC-T cell clusters and colitis development. Moreover, DCs promoted T cell differentiation, contributing to colitis development. A lineage-tracing analysis showed that, following migration to the lamina propria, T cells transdifferentiated into long-lived pathogenic T1 cells, promoting colitis development. Our findings have therefore demonstrated the reciprocal regulation of T cells and DCs in colonic lymphoid follicles, which is critical in chronic colitis pathogenesis.
PubMed: 38942990
DOI: 10.1038/s41590-024-01882-1 -
Nature Communications Jun 2024Cancer treatment continues to shift from utilizing traditional therapies to targeted ones, such as protein kinase inhibitors and immunotherapy. Mobilizing dendritic...
Cancer treatment continues to shift from utilizing traditional therapies to targeted ones, such as protein kinase inhibitors and immunotherapy. Mobilizing dendritic cells (DC) and other myeloid cells with antigen presenting and cancer cell killing capacities is an attractive but not fully exploited approach. Here, we show that PIKFYVE is a shared gene target of clinically relevant protein kinase inhibitors and high expression of this gene in DCs is associated with poor patient response to immune checkpoint blockade (ICB) therapy. Genetic and pharmacological studies demonstrate that PIKfyve ablation enhances the function of CD11c cells (predominantly dendritic cells) via selectively altering the non-canonical NF-κB pathway. Both loss of Pikfyve in CD11c cells and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively regulates the function of CD11c cells, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.
Topics: Animals; Humans; Dendritic Cells; Mice; Phosphatidylinositol 3-Kinases; CD11c Antigen; Morpholines; Cell Line, Tumor; Immunotherapy; Neoplasms; Mice, Inbred C57BL; Female; Immune Checkpoint Inhibitors; NF-kappa B; T-Lymphocytes; Protein Kinase Inhibitors; Hydrazones; Pyrimidines
PubMed: 38942798
DOI: 10.1038/s41467-024-48931-9 -
International Journal of Pharmaceutics Jun 2024We have recently witnessed that considerable progresses have been made in the rapid detection and appropriate treatments of COVID-19, but still this virus remains one of...
We have recently witnessed that considerable progresses have been made in the rapid detection and appropriate treatments of COVID-19, but still this virus remains one of the main targets of world research. Based on the knowledge of the complex mechanism of viral infection we designed peptide-dendrimer inhibitors of SARS-CoV-2with the aim to block cell infection through interfering with the host-pathogen interactions. We used two different strategies: i) the first one aims at hindering the virus anchorage to the human cell; ii) the second -strategy points to interfere with the mechanism of virus-cell membrane fusion. We propose the use of different nanosized carriers, formed by several carbosilane dendritic wedges to deliver two different peptides designed to inhibit host interaction or virus entry. The antiviral activity of the peptide-dendrimers, as well as of free peptides and free dendrimers was evaluated through the use of SARS-CoV-2 pseudotyped lentivirus. The results obtained show that peptides designed to block host-pathogen interaction represent a valuable strategy for viral inhibition.
PubMed: 38942185
DOI: 10.1016/j.ijpharm.2024.124389 -
Journal of Ethnopharmacology Jun 2024The traditional medicinal formulation, Qifu-yin (QFY), has been widely prescribed for Alzheimer's disease (AD) treatment in China, yet the comprehensive mechanisms...
ETHNOPHARMACOLOGICAL RELEVANCE
The traditional medicinal formulation, Qifu-yin (QFY), has been widely prescribed for Alzheimer's disease (AD) treatment in China, yet the comprehensive mechanisms through which QFY mitigates AD pathology remain to be fully delineated.
AIM OF THE STUDY
This study aimed to explore the therapeutic implications of QFY on the synaptic injury and oxidative stress in the hippocampus of APPswe/PS1dE9 (APP/PS1) mice, with a concerted effort to elucidate the molecular mechanisms related to synaptic preservation and memory improvement.
MATERIALS AND METHODS
The components of QFY were identified by ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The neuroprotective effects of QFY was evaluated using six-month-old male APP/PS1 mice. Subsequent to a 15 days of QFY regimen, spatial memory was assessed utilizing the Morris water maze (MWM) test. Amyloid-beta (Aβ) aggregation was detected via immunostaining, while the quantification of Aβ and Aβ was achieved through enzyme-linked immunosorbent assay (ELISA). Transmission electron microscopy (TEM) was used to investigate the synaptic structure and mitochondrial morphology. Golgi staining was applied to examine dendritic spine density. Reactive oxygen species (ROS), 3-nitrotyrosine (3-NT) and 4-hydroxy-nonenal (4-HNE) assays were employed to assess oxidative stress. The expression profiles of Aβ metabolism-associated enzymes and the Keap1/Nrf2/ARE signaling pathway were determined by Western blot.
RESULTS
A total of 20 principal compounds in QFY were identified. QFY mitigated memory deficits of APP/PS1 mice, including reducing escape latency and search distance and increasing the time and distance spent in the target quadrant. In addition, QFY increased platform crossings of APP/PS1 mice in the probe trial of MWM tests. TEM analysis showed that QFY increased synapse number in the CA1 region of APP/PS1 mice. Further studies indicated that QFY elevated the expression levels of Post synaptic density protein 95 (PSD95) and synaptophysin, and mitigated the loss of dendritic spine density in the hippocampus of APP/PS1 mice. QFY has been shown to ameliorated the structural abnormalities of mitochondria, including mitochondrial dissolution and degradation, up-regulate ATP synthesis and membrane potential in the hippocampus of APP/PS1 mice. Moreover, QFY activated the Keap1/Nrf2/ARE signaling pathway in the hippocampus of APP/PS1 mice, which might contribute to the neuroprotective effects of QFY.
CONCLUSION
QFY activates the Keap1/Nrf2/ARE signaling, and protects against synaptic and mitochondrial dysfunction in APP/PS1 mice, proposing a potential alternative therapeutic strategy for AD management.
PubMed: 38942156
DOI: 10.1016/j.jep.2024.118497