Microglia are the primary immune cells in the brain. Under physiological conditions, they typically stay in a “resting” state, with ramified processes continuously extending to and retracting from ...surrounding neural tissues. Whether and how such highly dynamic resting microglia functionally interact with surrounding neurons are still unclear. Using in vivo time-lapse imaging of both microglial morphology and neuronal activity in the optic tectum of larval zebrafish, we found that neuronal activity steers resting microglial processes and facilitates their contact with highly active neurons. This process requires the activation of pannexin-1 hemichannels on neurons. Reciprocally, such resting microglia-neuron contact reduces both spontaneous and visually evoked activities of contacted neurons. Our findings reveal an instructive role for neuronal activity in resting microglial motility and suggest the function for microglia in homeostatic regulation of neuronal activity in the healthy brain.
► Resting microglial processes dynamically contact neuronal soma via bulbous endings ► Neuronal activity instructs resting microglial processes to contact active neurons ► Pannexin-1 hemichannel in neurons and Rac in microglia are required for this effect ► Resting microglia-neuron contact downregulates the activity of contacted neurons
Little is known about the role of resting microglia in the healthy brain. Looking in vivo in zebrafish, Li et al. uncover reciprocal regulation between neurons and resting microglia in which neuronal activity provokes the formation of microglial contacts that, in turn, downregulate the activity of contacted neurons.
Several observational studies have reported an association between obesity and primary liver cancer (PLC), while the causality behind this association and the comparison of the risk effects of ...different obesity indicators on PLC remain unclear. In this study, we performed two‐sample Mendelian randomization (MR) analyses to assess the associations of genetically determined liver fat, visceral adipose tissue (VAT), and body mass index (BMI) with the risk of PLC. The summary statistics of exposures were obtained from two genome‐wide association studies (GWASs) based on the UK Biobank (UKB) imaging cohort and the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. GWAS summary statistics for PLC were obtained from FinnGen consortium R7 release data, including 304 PLC cases and 218 488 controls. Inverse‐variance weighted (IVW) was used as the primary analysis, and a series of sensitivity analyses were performed to further verify the robustness of these findings. IVW analysis highlighted a significant association of genetically determined liver fat (OR per SD increase: 7.14; 95% CI: 5.10‐9.99; P = 2.35E‐30) and VAT (OR per SD increase: 5.70; 95% CI: 1.32‐24.72; P = .020) with PLC but not of BMI with PLC. The findings were further confirmed by a series of MR methods. No evidence of horizontal pleiotropy between these associations existed. Our study suggested that genetically determined liver fat and VAT rather than BMI were associated with an increased risk of PLC, which suggested that visceral fat distribution is more predictive of the clinical risk of PLC than common in vitro measures.
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Obesity is associated with increased risk of primary liver cancer (PLC). However, the causality of obesity in PLC is difficult to determine based on existing observational studies, and little is known about whether specific fat distribution impacts PLC risk. Here, the authors employed Mendelian randomization to investigate associations between PLC risk and genetically determined liver fat deposition and visceral fat distribution. Genetically predicted liver fat and visceral adipose tissue (VAT) distribution were more strongly linked to increased PLC risk than body mass index. VAT and especially fat deposition in the liver are promising clinical measures for predicting PLC risk.
Successful bench‐to‐bedside translation of nanomedicine relies heavily on the development of nanocarriers with superior therapeutic efficacy and high biocompatibility. However, the optimal strategy ...for improving one aspect often conflicts with the other. Herein, we report a tactic of designing tumor‐pH‐labile linkage‐bridged copolymers of clinically validated poly(d,l‐lactide) and poly(ethylene glycol) (PEG‐Dlinkm‐PDLLA) for safe and effective drug delivery. Upon arriving at the tumor site, PEG‐Dlinkm‐PDLLA nanoparticles will lose the PEG layer and increase zeta potential by responding to tumor acidity, which significantly enhances cellular uptake and improves the in vivo tumor inhibition rate to 78.1 % in comparison to 47.8 % of the non‐responsive control. Furthermore, PEG‐Dlinkm‐PDLLA nanoparticles show comparable biocompatibility with the clinically used PEG‐b‐PDLLA micelle. The improved therapeutic efficacy and safety demonstrate great promise for our strategy in future translational studies.
PEG‐detachable delivery micelles: A chemotherapeutic vector with superior therapeutic efficacy and high biocompatibility is obtained by designing bridged PEGylated polylactide‐containing tumor‐acidity‐responsive linkages. The decreased PEGylation and increased zeta potential in the tumor matrix enhanced cellular uptake of the vector, enabling safe and effective antitumor drug delivery.
A principal goal of cancer nanomedicine is to deliver therapeutics effectively to cancer cells within solid tumors. However, there are a series of biological barriers that impede nanomedicine from ...reaching target cells. Here, we report a stimuli-responsive clustered nanoparticle to systematically overcome these multiple barriers by sequentially responding to the endogenous attributes of the tumor microenvironment. The smart polymeric clustered nanoparticle (iCluster) has an initial size of ∼100 nm, which is favorable for long blood circulation and high propensity of extravasation through tumor vascular fenestrations. Once iCluster accumulates at tumor sites, the intrinsic tumor extracellular acidity would trigger the discharge of platinum prodrug-conjugated poly(amidoamine) dendrimers (diameter ∼5 nm). Such a structural alteration greatly facilitates tumor penetration and cell internalization of the therapeutics. The internalized dendrimer prodrugs are further reduced intracellularly to release cisplatin to kill cancer cells. The superior in vivo antitumor activities of iCluster are validated in varying intractable tumor models including poorly permeable pancreatic cancer, drug-resistant cancer, and metastatic cancer, demonstrating its versatility and broad applicability.
Vascular integrity helps maintain brain microenvironment homeostasis, which is critical for the normal development and function of the central nervous system. It is known that neural cells can ...regulate brain vascular integrity. However, due to the high complexity of neurovascular interactions involved, understanding of the neural regulation of brain vascular integrity is still rudimentary. Using intact zebrafish larvae and cultured rodent brain cells, we find that neurons transfer miR-132, a highly conserved and neuron-enriched microRNA, via secreting exosomes to endothelial cells (ECs) to maintain brain vascular integrity. Following translocation to ECs through exosome internalization, miR-132 regulates the expression of vascular endothelial cadherin (VE-cadherin), an important adherens junction protein, by directly targeting eukaryotic elongation factor 2 kinase (eef2k). Disruption of neuronal miR-132 expression or exosome secretion, or overexpression of vascular eef2k impairs VE-cadherin expression and brain vascular integrity. Our study indicates that miR-132 acts as an intercellular signal mediating neural regulation of the brain vascular integrity and suggests that the neuronal exosome is a novel avenue for neurovascular communication.
Modulating effector immune cells via monoclonal antibodies (mAbs) and facilitating the co-engagement of T cells and tumor cells via chimeric antigen receptor- T cells or bispecific T cell-engaging ...antibodies are two typical cancer immunotherapy approaches. We speculated that immobilizing two types of mAbs against effector cells and tumor cells on a single nanoparticle could integrate the functions of these two approaches, as the engineered formulation (immunomodulating nano-adaptor, imNA) could potentially associate with both cells and bridge them together like an 'adaptor' while maintaining the immunomodulatory properties of the parental mAbs. However, existing mAbs-immobilization strategies mainly rely on a chemical reaction, a process that is rough and difficult to control. Here, we build up a versatile antibody immobilization platform by conjugating anti-IgG (Fc specific) antibody (αFc) onto the nanoparticle surface (αFc-NP), and confirm that αFc-NP could conveniently and efficiently immobilize two types of mAbs through Fc-specific noncovalent interactions to form imNAs. Finally, we validate the superiority of imNAs over the mixture of parental mAbs in T cell-, natural killer cell- and macrophage-mediated antitumor immune responses in multiple murine tumor models.
The CRISPR/Cas9 gene editing technology holds promise for the treatment of multiple diseases. However, the inability to perform specific gene editing in targeted tissues and cells, which may cause ...off-target effects, is one of the critical bottlenecks for therapeutic application of CRISPR/Cas9. Herein, macrophage-specific promoter-driven Cas9 expression plasmids (pM458 and pM330) were constructed and encapsulated in cationic lipid-assisted PEG-b-PLGA nanoparticles (CLAN). The obtained nanoparticles encapsulating the CRISPR/Cas9 plasmids were able to specifically express Cas9 in macrophages as well as their precursor monocytes both in vitro and in vivo. More importantly, after further encoding a guide RNA targeting Ntn1 (sgNtn1) into the plasmid, the resultant CLANpM330/sgNtn1 successfully disrupted the Ntn1 gene in macrophages and their precursor monocytes in vivo, which reduced expression of netrin-1 (encoded by Ntn1) and subsequently improved type 2 diabetes (T2D) symptoms. Meanwhile, the Ntn1 gene was not disrupted in other cells due to specific expression of Cas9 by the CD68 promoter. This strategy provides alternative avenues for specific in vivo gene editing with the CRISPR/Cas9 system.
Mussel-inspired approach was attempted to non-covalently functionalize the surfaces of boron nitride (BN) with self-polymerized dopamine coatings in order to reduce the interfacial thermal barrier ...and enhance the thermal conductivity of BN-containing composites. Compared to the polypropylene (PP) composites filled with pristine BN at the same filler content, thermal conductivity was much higher for those filled with both functionalized BN (f-BN) and maleic anhydride grafted PP (PP-g-ma) due to the improved filler dispersion and better interfacial filler-matrix compatibility, which facilitated the development of more thermal paths. Theoretical models were also applied to predict the composite thermal conductivity in which the Nielsen model was found to fit well with the experimental results, and the estimated effective aspect ratio of fillers well corresponded to the degree of filler aggregation as observed in the morphological study.
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•CW-MFC could generate electricity combined with purification of wastewater.•TN removal rate in CW-MFC was highly significant (p < 0.01) higher than that in CW.•Voltage was ...265.77 ± 12.66 mV and power density was 3714.08 mW·m−2 in CW-MFC.•The diversity and richness of the CW-MFC were higher than those of the CW.
Constructed wetlands combined with microbial fuel cell (CW-MFC) could purify the wastewater while using microorganisms to generate electricity. Our study investigated pollutant removal and microorganism evolution in CW and CW-MFC. The average removal rate of total nitrogen (82.46 ± 4.74%) in the CW-MFC was highly significant (p < 0.01) higher than that in the CW. The average removal rate of chemical oxygen demand (82.32 ± 12.85%) and total phosphorus (95.06 ± 5.45%) in the CW-MFC were higher than those in the CW. In the CW-MFC, the average voltage was 265.77 ± 12.66 mV and the highest power density was 3714.08 mW·m−2. The microbial community diversity and richness of the CW-MFC system were higher than those of the CW system. The read number of ammonia oxidizing (149 ± 7), nitrite-oxidizing (144 ± 8, 132 ± 18) and anammox bacteria (281 ± 8) were the highest in the CW-MFC (Anode). The contents of denitrification, dissimilatory nitrate reduction to ammonium, and electrochemically active bacteria in the CW-MFC (Cathode) were significantly (p < 0.05) higher than others.
The circadian clock orchestrates a wide variety of physiological and behavioral processes, enabling animals to adapt to daily environmental changes, particularly the day-night cycle. However, the ...circadian clock's role in the developmental processes remains unclear. Here, we employ the in vivo long-term time-lapse imaging of retinotectal synapses in the optic tectum of larval zebrafish and reveal that synaptogenesis, a fundamental developmental process for neural circuit formation, exhibits circadian rhythm. This rhythmicity arises primarily from the synapse formation rather than elimination and requires the hypocretinergic neural system. Disruption of this synaptogenic rhythm, by impairing either the circadian clock or the hypocretinergic system, affects the arrangement of the retinotectal synapses on axon arbors and the refinement of the postsynaptic tectal neuron's receptive field. Thus, our findings demonstrate that the developmental synaptogenesis is under hypocretin-dependent circadian regulation, suggesting an important role of the circadian clock in neural development.
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