Chemokine receptor CXCR5-mediated control of B cell trafficking in the lymphoid tissues plays a central role in orchestrating the B cell function, which not only guides the colocalization of B cells with follicular helper T cells in the follicular mantle zone but also determines the position of germinal center dark and light zones. However, the mechanisms that regulate the expression of CXCR5 in B cells remain unclear. Here, we show that the expression level of CXCR5 in B cells was substantially reduced in vitro culture conditions, while being maintained in the presence of CD40 signals. Furthermore, CD40 signaling promotes CXCR5 expression in B cells at least partially through noncanonical NF- κ B signaling pathway activation. However, other non-B cells also contributed to the optimal expression of CXCR5 in B cells through cell-cell contact and cytokine secretion. Our findings suggest that CD40 signaling-mediated activation of the noncanonical NF- κ B pathway promotes the expression of CXCR5 in a B cell-intrinsic way to orchestrate the trafficking of B cells.
Spinal cord injury (SCI) remains a formidable challenge in the clinic. In the current study, we examined the effects of the TLX gene on the proliferation and neu- ronal differentiation of dermal multipotent stem cells (DMSCs) in vitro and the potential of these cells to improve SCI in rats in vivo. DMSCs were stably trans- fected with TLX-expressing plasmid (TLX/DMSCs). Cell proliferation was examined using the MTT assay, and neuronal differentiation was characterized by morphologi- cal observation combined with immunocytochemical/ immunofluorescent staining. The in vivo functions of these cells were evaluated by transplantation into rats with SCI, followed by analysis of hindlimb locomotion and post- mortem histology. Compared to parental DMSCs, TLX/ DMSCs showed enhanced proliferation and preferential differentiation into NF200-positive neurons in contrast to GFAP-positive astrocytes. When the undifferentiated cells were transplanted into rats with SCI injury, TLX/DMSCs led to significant improvement in locomotor recovery and healing of SCI, as evidenced by reduction in scar tissues and cavities, increase in continuous nerve fibers/axons and enrichment of NF200-positive neurons on the histological level. In conclusion, TLX promotes the proliferation and neuronal differentiation of DMSCs and thus, may serve as a promising therapy for SCI in the clinic.
Brain organoids are widely used to model brain development and diseases. However, a major challenge in their application is the insufficient supply of oxygen and nutrients to the core region, restricting the size and maturation of the organoids. In order to vascularize brain organoids and enhance the nutritional supply to their core areas, two-photon polymerization (TPP) 3D printing is employed to fabricate high-resolution meshed vessels in this study. These vessels made of photoresist with densely distributed micropores with a diameter of 20 μm on the sidewall, are cocultured with brain organoids to facilitate the diffusion of culture medium into the organoids. The vascularized organoids exhibit dimensional breaking growth and enhanced proliferation, reduced hypoxia and apoptosis, suggesting that the 3D-printed meshed vessels partially mimic vascular function to promote the culture of organoids. Furthermore, cortical, striatal and medial ganglionic eminence (MGE) organoids are respectively differentiated to generate Cortico-Striatal-MGE assembloids by 3D-printed vessels. The enhanced migration, projection and excitatory signaling transduction are observed between different brain regional organoids in the assembloids. This study presents an approach using TPP 3D printing to construct vascularized brain organoids and assembloids for enhancing the development and assembly, offering a research model and platform for neurological diseases.
Synaptic damage is a crucial pathological process in traumatic brain injury. However, the mechanisms driving this process remain poorly understood. In this report, we demonstrate that the accumulation of damaged mitochondria, resulting from impaired mitphagy, plays a significant role in causing synaptic damage. Moreover, copper induced downregulation of BNIP3 is a key player in regulating mitophagy. DMSA alleviates synaptic damage and mitochondrial dysfunction by promoting urinary excretion of copper. Mechanistically, we find that copper downregulate BNIP3 by increasing the nuclear translocation of NFKB, which is triggered by TRIM25-mediated ubiquitination-dependent degradation of NFKBIA. Our study underscores the importance of copper accumulation in the regulation of BNIP3-mediated mitophagy and suggests that therapeutic targeting of the copper-TRIM25-NFKB-BNIP3 axis holds promise to attenuate synaptic damage after traumatic brain injury.
Abstract Although the neurotransmitter dopamine (DA) plays a crucial pathophysiologic role after traumatic brain injury (TBI), its function and specific underlying mechanisms of action remain unclear. In this study, DA inhibits neural death induced by TBI or stretch injury, which is mediated via the dopamine receptor D1 (DRD1). Our results showed that DRD1 signaling promotes receptor interacting protein kinase 1 (RIPK1) ubiquitination via the E3 ubiquitin ligase Chip and degradation through autophagy. Importantly, in vivo data revealed that DRD1 signaling prevented neuronal death, suppressed neuroinflammation, and restored many TBI-related functional sequelae through an autophagy-dependent mechanism. These data reveal a novel mechanism involving dopamine, and suggest that DRD1 activation positively regulates Chip-mediated ubiquitylation of RIPK1—leading to its autophagic degradation.
We report the generation, trapping and sympathetic cooling of individual conformers of molecular ions with the example of cis- and trans-meta-aminostyrene. Following conformationally selective photoionization, the incorporation of the conformers into a Coulomb crystal of laser-cooled calcium ions was confirmed by fluorescence imaging, mass spectrometry and molecular dynamics simulations. We deduce the molecules to be stable in the trap environment for more than ten minutes. The present results pave the way for the spectroscopy and controlled chemistry of distinct ionic conformers in traps.
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