Surface ligand-regulated renal clearance of MRI/SPECT dual-modality nanoprobes for tumor imaging.

BACKGROUND: The general sluggish clearance kinetics of functional inorganic nanoparticles tend to raise potential biosafety concerns for in vivo applications. Renal clearance is a possible elimination pathway for functional inorganic nanoparticles delivered through intravenous injection, but largely depending on the surface physical chemical properties of a given particle apart from its size and shape. RESULTS: In this study, three small-molecule ligands that bear a diphosphonate (DP) group, but different terminal groups on the other side, i.e., anionic, cationic, and zwitterionic groups, were synthesized and used to modify ultrasmall Fe3O4 nanoparticles for evaluating the surface structure-dependent renal clearance behaviors. Systematic studies suggested that the variation of the surface ligands did not significantly increase the hydrodynamic diameter of ultrasmall Fe3O4 nanoparticles, nor influence their magnetic resonance imaging (MRI) contrast enhancement effects. Among the three particle samples, Fe3O4 nanoparticle coated with zwitterionic ligands, i.e., Fe3O4@DMSA, exhibited optimal renal clearance efficiency and reduced reticuloendothelial uptake. Therefore, this sample was further labeled with 99mTc through the DP moieties to achieve a renal-clearable MRI/single-photon emission computed tomography (SPECT) dual-modality imaging nanoprobe. The resulting nanoprobe showed satisfactory imaging capacities in a 4T1 xenograft tumor mouse model. Furthermore, the biocompatibility of Fe3O4@DMSA was evaluated both in vitro and in vivo through safety assessment experiments. CONCLUSIONS: We believe that the current investigations offer a simple and effective strategy for constructing renal-clearable nanoparticles for precise disease diagnosis.

LILRB2-containing small extracellular vesicles from glioblastoma promote tumor progression by promoting the formation and expansion of myeloid-derived suppressor cells.

BACKGROUND: Leukocyte immunoglobulin-like receptor subfamily B2 (LILRB2) was reported to be an inhibitory molecule with suppressive functions. sEVs mediate communication between cancer cells and other cells. However, the existence of LILRB2 on sEVs in circulation and the function of sEVs-LILRB2 are still unknown. This study aims to investigate the role of LILRB2 in GBM and determine how LILRB2 in sEVs regulates tumor immunity. METHODS: LILRB2 expression in normal brain and GBM tissues was detected by immunohistochemistry, and the effect of LILRB2 on prognosis was evaluated in an orthotopic brain tumor model. Next, a subcutaneous tumor model was constructed to evaluate the function of pirb in vivo. The immune cells in the tumor sites and spleen were detected by immunofluorescence staining and flow cytometry. Then, the presence of pirb in sEVs was confirmed by WB. The percentage of immune cells after incubation with sEVs from GL261 (GL261-sEVs) or sEVs from GL261-pirb+ (GL261-sEVs-pirb) was detected by flow cytometry. Then, the effect of pirb on sEVs was evaluated by a tumor-killing assay and proliferation assay. Finally, subcutaneous tumor models were constructed to evaluate the function of pirb on sEVs. RESULTS: LILRB2 was overexpressed in human GBM tissue and was closely related to an immunosuppressive TME in GBM. Then, a protumor ability of LILRB2 was observed in subcutaneous tumor models, which was related to lower CD8 + T cells and higher MDSCs (myeloid-derived suppressor cells) in the tumor and spleen compared to those of the control group. Next, we found that pirb on sEVs (sEVs-pirb) inhibits the function of CD8 + T cells by promoting the formation and expansion of MDSCs. Furthermore, the protumor function of sEVs-pirb was demonstrated in subcutaneous tumor models. CONCLUSION: We discovered that LILRB2/pirb can be transmitted between GBM cells via sEVs and that pirb on sEVs induces the formation and expansion of MDSCs. The induced MDSCs facilitate the formation of an immunosuppressive TME.

Ultra-compact on-chip spectrometer based on thermally tuned topological miniaturized bound states in the continuum cavity.

On-chip spectrometers are key components in many spectral sensing applications owing to their unique advantages in size and in situ detection. In this work, we propose and demonstrate a class of thermally tunable spectrometers by utilizing topological miniaturized bound states in the continuum (mini-BIC) cavities in a photonic crystal (PhC) slab combined with a metal micro-ring heater. We achieve a resolution of 0.19 nm in a spectral range of ∼6 nm, while the device's footprint is only 42×42µm2. The mini-BIC spectrometer works in nearly vertical incidence and is compatible with array operation. Our work sheds light on the new possibilities of high-performance on-chip spectrometers for applications ranging from bio-sensing to medicine.

Effects of novel mRNA-VEGF@USPIO nanoparticles on human brain microvascular endothelial cell injury.

We investigated the effect of mRNA-VEGF@ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles on the repair of human brain microvascular endothelial cell (HBMECs) injury and its related mechanisms. mRNA-VEGF@USPIO nanoparticles were designed, prepared, and characterized using NTA and UV spectrophotometry. Cell viability was determined using the CCK-8. Cells in the control, TNF-α, and mRNA-VEGF@USPIO groups were sequenced and the differentially expressed genes (DEGs) were identified. Finally, a functional analysis of the DEGs was performed. Both NTA and spectrophotometry results indicated that mRNA-VEGF@USPIO was successfully constructed. TNF-α significantly reduced cell viability and promoted apoptosis compared with the control group (p < 0.05), whereas mRNA-VEGF@USPIO nanoparticles reversed the changes caused by TNF-α. Via sequencing, 9063 DEGs were identified between the control and TNF-α groups, 9125 DEGs were identified between the control and mRNA-VEGF@USPIO groups, and 211 DEGs were identified between the TNF-α and mRNA-VEGF@USPIO groups. Additionally, 71 overlapping DEGs were identified in the three groups using Venn diagrams. These overlapping DEGs were mainly enriched in cytokine-cytokine receptor interactions and the TNF signaling pathway, NF-κB signaling pathway, and NOD-like receptor signaling pathway. This study shows that mRNA-VEGF@USPIO nanoparticles can repair HBMECs injury.

Molecular characteristics of single patient-derived glioma stem-like cells from primary and recurrent glioblastoma.

Glioblastoma has high recurrence, while the sensitivity of recurrent glioblastoma to chemotherapy is lower than that of primary glioblastoma. Moreover, there is no standardized treatment for recurrent glioblastoma. Unfortunately, the biological mechanism of recurrent glioblastoma is still unclear, and there are few related studies. We compared the phenotypes of clinical glioblastoma specimens, in-vitro cultured glioma stem-like cells (GSCs) and patient-derived xenograft tumor (PDX) models to explore the molecular genetic characteristics of primary and recurrent glioblastoma from the same patient. In vitro, SU5-2, GSCs derived from recurrent glioblastoma specimens, had stronger proliferative activity and self-renewal ability. Meanwhile, SU5-2 was more resistant to temozolomide and invasive than SU5-1, which derived from primary glioblastoma specimens. Further analysis of the expression of costimulatory molecules showed that the expression of B7-H1, B7-H2 and B7-H3 of SU5-2 were upregulated. In vivo, Kaplan-Meier survival curve analysis showed that the median survival of the recurrent PDX group was worse. The results of gene detection in vitro, PDX model and clinical samples were consistent. Our results showed that the GSCs based on glioblastoma specimens and the PDX models could replicate the main molecular genetic characteristics of original tumors, which provided a reliable experimental platform for both tumor translation kinds of research and screening of molecular therapeutic targets.

Absorption Reduction of Large Purcell Enhancement Enabled by Topological State-Led Mode Coupling.

We propose the mechanism of edge state-led mode coupling under topological protection; i.e., localized surface plasmons almost do not have any influence on the edge state, while the edge state greatly changes the local field distribution of surface plasmons. Based on this mechanism, in the well-designed topological photonic structure containing a resonant plasmon nanoantenna, an obvious absorption reduction in the spontaneous emission spectra appears due to the near-field deformation around the antenna induced by the edge state. Because a plasmon antenna with ultrasmall mode volume provides large Purcell enhancement and simultaneously the photonic crystal guides almost all scattering light into its edge state, the rate of nonscattering single photons reaches more than 10^{4}γ_{0}. This topological state-led mode coupling mechanism and induced absorption reduction, which are based on topological protection, will have a profound effect on the study of composite topological photonic structures and related micro- and nanoscale cavity quantum electrodynamics. Also, nonscattering large Purcell enhancement will provide practical use for on-chip quantum light sources, such as single-photon sources and nanolasers.

Serum Neuropeptide Y Level is Associated with Post-Ischemic Stroke Epilepsy.

BACKGROUND AND PURPOSE: Post-ischemic stroke epilepsy (PISE) is one of the common complications of stroke. MATERIALS AND METHODS: Methods To determine the risk factors of PISE, in this study, 78 patients with PISE and 86 patients without PISE were recruited. Clinical data and serum neuropeptide Y (NPY) levels were collected and the relative factors including clinical data and serum were analyzed. RESULTS: Logistic regression showed that low serum NPY was significantly associated with PISE. Every 5 ng/ml increment of serum NPY was associated with 62% risk decrease in patients with PISE. The area under curve of serum NPY was 0.910 with a sensitivity of 84.62% and a specificity of 86.05%. The cut-off value of serum NPY was 90 ng/ml. According to cut-off value of serum NPY, the percentage of patients with PISE decreased from 84.6% in low serum NPY group to 14.0% in high serum NPY group. Furthermore, patients were divided into different tertiles according to serum NPY. The percentage of patients with PISE reduced from 90.0% in the lowest tertile (NPY < 85 ng/ml) to 3.5% in the highest tertile (NPY ≥ 105 ng/ml). Compared with patients with normal video-electroencephalogram (VEEG), serum NPY levels significantly decreased in patients with abnormal VEEG; however, serum NPY levels were not associaated with epileptic seizure subtypes. CONCLUSIONS: Serum NPY was an independent risk factor for PISE. Targeting serum NPY may be used to the prevention and treatment of PISE.

MicroRNA regulatory networks in the pathogenesis of sarcopenia.

Sarcopenia is an age-related disease characterized by disturbed homeostasis of skeletal muscle, leading to a decline in muscle mass and function. Loss of muscle mass and strength leads to falls and fracture, and is often accompanied by other geriatric diseases, including osteoporosis, frailty and cachexia, resulting in a general decrease in quality of life and an increase in mortality. Although the underlying mechanisms of sarcopenia are still not completely understood, there has been a marked improvement in the understanding of the pathophysiological changes leading to sarcopenia in recent years. The role of microRNAs (miRNAs), especially, has been clearer in skeletal muscle development and homeostasis. miRNAs form part of a gene regulatory network and have numerous activities in many biological processes. Intervention based on miRNAs may develop into an innovative treatment strategy to conquer sarcopenia. This review is divided into three sections: firstly, the latest understanding of the pathogenesis of sarcopenia is summarized; secondly, increasing evidence for the involvement of miRNAs in the regulation of muscle quantity or quality and muscle homeostasis is highlighted; and thirdly, the possibilities and limitations of miRNAs as a treatment for sarcopenia are explored.

Melanocortin type 4 receptor-mediated inhibition of A-type K+ current enhances sensory neuronal excitability and mechanical pain sensitivity in rats.

α-Melanocyte-stimulating hormone (α-MSH) has been shown to be involved in nociception, but the underlying molecular mechanisms remain largely unknown. In this study, we report that α-MSH suppresses the transient outward A-type K+ current (IA) in trigeminal ganglion (TG) neurons and thereby modulates neuronal excitability and peripheral pain sensitivity in rats. Exposing small-diameter TG neurons to α-MSH concentration-dependently decreased IA This α-MSH-induced IA decrease was dependent on the melanocortin type 4 receptor (MC4R) and associated with a hyperpolarizing shift in the voltage dependence of A-type K+ channel inactivation. Chemical inhibition of phosphatidylinositol 3-kinase (PI3K) with wortmannin or of class I PI3Ks with the selective inhibitor CH5132799 prevented the MC4R-mediated IA response. Blocking Gi/o-protein signaling with pertussis toxin or by dialysis of TG neurons with the Gßγ-blocking synthetic peptide QEHA abolished the α-MSH-mediated decrease in IA Further, α-MSH increased the expression levels of phospho-p38 mitogen-activated protein kinase, and pharmacological or genetic inhibition of p38α abrogated the α-MSH-induced IA response. Additionally, α-MSH significantly increased the action potential firing rate of TG neurons and increased the sensitivity of rats to mechanical stimuli applied to the buccal pad area, and both effects were abrogated by IA blockade. Taken together, our findings suggest that α-MSH suppresses IA by activating MC4R, which is coupled sequentially to the Gßγ complex of the Gi/o-protein and downstream class I PI3K-dependent p38α signaling, thereby increasing TG neuronal excitability and mechanical pain sensitivity in rats.

Nanoscale quantum plasmon sensing based on strong photon-exciton coupling.

We propose a scheme of quantum plasmon sensing system based on strong photon-exciton coupling in the gap surface plasmon nanostructure. The system's sensitivity is characterized as Rabi splitting, which is sensitive to a slight change in environmental permittivity and determined by the coupling coefficient and detuning between the emitter and plasmon nanocavity. By increasing the dipole moment of the emitter, the sensitivity can exceed that of a traditional plasmon sensing system while only depending on the resonance spectral shift. Quantum plasmon sensing provides a unique mechanism in the application of bio-sensing, opto-chemical sensing, and quantum photonics at the nanoscale.

Effectiveness of exercise intervention on fall-related fractures in older adults: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Exercise intervention can significantly improve physical function and bone strength; however, the effect of exercise on fall-related fractures in older adults remains controversial. This study aimed to assess the effectiveness of exercise intervention on fall-related fractures in older adults by conducting a meta-analysis of randomized controlled trials (RCTs). METHODS: PubMed, EMBASE, and Cochrane databases were systematically searched for RCTs through November 24, 2019 to investigate the effectiveness of exercise intervention on fall-related fractures in older adults. Pooled relative risk (RR) with 95% confidence interval (CI) was calculated using the random-effects model. Sensitivity, subgroup, and publication bias analyses were also conducted. RESULTS: A total of 7704 older adults and 428 fall-related fracture events from 20 RCTs were selected for the final meta-analysis. The follow-up duration across included trials ranged from 6.0 months to 7.0 years. The pooled RR suggested that exercise intervention was associated with a reduced fall-related fracture risk in older adults (RR: 0.74; 95% CI: 0.59-0.92; P = 0.007; I2 = 12.6%). The pooled conclusion was robust and not affected by any individual trial. Subgroup analysis revealed that the significant effect of exercise intervention on fall-related fractures was mainly detected when the study reported results from both male and female subjects, when it did not report the baseline body mass index, when individuals received both home- and center-based interventions, when the follow-up duration was > 1.0 year, and when it was a high-quality study. CONCLUSIONS: Regular exercise intervention could prevent fall-related fractures in older adults. Further large-scale RCTs should be conducted to assess the effectiveness of different exercise programs on fall-related fractures at various sites.

The role of intestinal microbiota in cardiovascular disease.

Accumulating evidence has indicated that intestinal microbiota is involved in the development of various human diseases, including cardiovascular diseases (CVDs). In the recent years, both human and animal experiments have revealed that alterations in the composition and function of intestinal flora, recognized as gut microflora dysbiosis, can accelerate the progression of CVDs. Moreover, intestinal flora metabolizes the diet ingested by the host into a series of metabolites, including trimethylamine N-oxide, short chain fatty acids, secondary bile acid and indoxyl sulfate, which affects the host physiological processes by activation of numerous signalling pathways. The aim of this review was to summarize the role of gut microbiota in the pathogenesis of CVDs, including coronary artery disease, hypertension and heart failure, which may provide valuable insights into potential therapeutic strategies for CVD that involve interfering with the composition, function and metabolites of the intestinal flora.

The nuclear localization signal is required for the function of squamosa promoter binding protein-like gene 9 to promote vegetative phase change in Arabidopsis.

KEY MESSAGE: A mutation in the nuclear localization signal of squamosa promoter binding like-protein 9 (SPL9) delays vegetative phase change by disrupting its nuclear localization. The juvenile-to-adult phase transition is a critical developmental process in plant development, and it is regulated by a decrease in miR156/157 and a corresponding increase in their targets, squamosa promoter binding protein-like (SPL) genes. SPL proteins contain a conserved SBP domain with putative nuclear localization signals (NLSs) at their C-terminals. Some SPLs promote vegetative phase change by promoting miR172 expression, but the function of nuclear localization signals in those SPLs remains unknown. Here, we identified a loss-of-function mutant, which we named del6, with delayed vegetative phase change phenotypes in a forward genetic screen. Map-based cloning, the whole genome resequencing, and allelic complementation test demonstrate that a G-to-A substitution in the SPL9 gene is responsible for the delayed vegetative phase change phenotypes. In del6, the mutation causes a substitution of the glutamine (Gln) for the conserved basic amino acid arginine (Arg) in the NLS of the SBP domain, and disrupts the normal nuclear localization and function of SPL9. Therefore, our work demonstrates that the NLSs in the SBP domain of SPL9 are indispensable for its nuclear localization and normal function in Arabidopsis.

Age-dependent heteroblastic development of leaf hairs in Arabidopsis.

Higher plants progress through a juvenile and an adult phase of development before they enter the reproductive phase. The transition from the juvenile to the adult phase is referred to as vegetative phase change, and this is signified by the production of trichomes on the abaxial side of leaf blades in Arabidopsis; however, the molecular mechanism underlying this process is poorly understood. We identified a dominant mutation (gl1-D) in a forward genetic screen that accelerates abaxial trichome production during shoot development. This phenotype is the result of a G-to-A substitution in the 3' noncoding region in the GLABRA1(GL1) gene. We show that TOE1, an AP2-like transcription factor that acts downstream of the miR156-SPL pathway, represses GL1 expression by directly binding to this site, and that gl1-D prevents TOE1 binding. Our work reveals a molecular link between vegetative phase change and abaxial trichome production in Arabidopsis, and answers a long-standing question of how the vegetative phase change pathway regulates vegetative traits.

Accumulation and directionality of large spontaneous emission enabled by epsilon-near-zero film.

We demonstrate the spectral accumulation of large spontaneous emission (SE) for nanocavities with different sizes in the coupled Ag nanorod and epsilon-near-zero (ENZ) film system. This effect originates from the slowing down of the spectral shift of resonant nanocavities at the wavelength where the permittivity of the substrate vanishes, i.e., the resonance "pinning" near the ENZ frequency. In addition, most far field radiation of the emitter is concentrated in the forward field with small solid angle due to the impedance mismatch between the ENZ film and the free space. This kind of size-relaxed nanocavity for directional SE has potential applications in the bright single photon sources, plasmon-based nanolasers, and on-chip nanodevices.

Prognostic value of NUSAP1 in progression and expansion of glioblastoma multiforme.

Nucleolar and spindle-associated protein (NUSAP1) is a microtubule and chromatin-binding protein that stabilizes microtubules to prevent depolymerization, maintains spindle integrity. NUSAP1 could cross-link spindles into aster-like structures, networks and fibers. It has also been found to play roles in progression of several cancers. However, the potential correlation between NUSAP1 and clinical outcome in patients with glioblastoma multiforme (GBM) remains largely unknown. In the current study, we demonstrated that NUSAP1 was significantly up-regulated in GBM tissues compared with adult non-tumor brain tissues both in a validated cohort and a TCGA cohort. In addition, Kaplan-Meier analysis indicated that patients with high NUSAP1 expression had significantly lower OS (P = 0.0027). Additionally, in the TCGA cohort, NUSAP1 expression was relatively lower in GBM patients within the neural and mesenchymal subtypes compared to other subtypes, and associated with the status of several genetic aberrations such as PTEN deletion and wild type IDH1. The present study provides new insights and evidence that NUSAP1 over-expression was significantly correlated with progression and prognosis of GBM. Furthermore, knockdown of NUSAP1 revealed its regulation on G2/M progression and cell proliferation (both in vitro and in vivo). These data demonstrate that NUSAP1 could serve as a novel prognostic biomarker and a potential therapeutic target for GBM.

Melatonin-mediated inhibition of Cav3.2 T-type Ca2+ channels induces sensory neuronal hypoexcitability through the novel protein kinase C-eta isoform.

Recent studies implicate melatonin in the antinociceptive activity of sensory neurons. However, the underlying mechanisms are still largely unknown. Here, we identify a critical role of melatonin in functionally regulating Cav3.2 T-type Ca2+ channels (T-type channel) in trigeminal ganglion (TG) neurons. Melatonin inhibited T-type channels in small TG neurons via the melatonin receptor 2 (MT2 receptor) and a pertussis toxin-sensitive G-protein pathway. Immunoprecipitation analyses revealed that the intracellular subunit of the MT2 receptor coprecipitated with Gαo . Both shRNA-mediated knockdown of Gαo and intracellular application of QEHA peptide abolished the inhibitory effects of melatonin. Protein kinase C (PKC) antagonists abolished the melatonin-induced T-type channel response, whereas inhibition of conventional PKC isoforms elicited no effect. Furthermore, application of melatonin increased membrane abundance of PKC-eta (PKCη ) while antagonism of PKCη or shRNA targeting PKCη prevented the melatonin-mediated effects. In a heterologous expression system, activation of MT2 receptor strongly inhibited Cav3.2 T-type channel currents but had no effect on Cav3.1 and Cav3.3 current amplitudes. The selective Cav3.2 response was PKCη dependent and was accompanied by a negative shift in the steady-state inactivation curve. Furthermore, melatonin decreased the action potential firing rate of small TG neurons and attenuated the mechanical hypersensitivity in a mouse model of complete Freund's adjuvant-induced inflammatory pain. These actions were inhibited by T-type channel blockade. Together, our results demonstrated that melatonin inhibits Cav3.2 T-type channel activity through the MT2 receptor coupled to novel Gßγ -mediated PKCη signaling, subsequently decreasing the membrane excitability of TG neurons and pain hypersensitivity in mice.

Low-voltage-activated T-type Ca2+ channel inhibitors as new tools in the treatment of glioblastoma: the role of endostatin.

Ca(2+) plays a key role in intracellular signaling and controls various cellular processes such as proliferation, differentiation, cell growth, death, and apoptosis. Aberrant changes in intracellular Ca(2+) levels can promote undesired cell proliferation and migration and are therefore associated with certain tumor types. Many research groups have suggested a potential role for voltage-gated Ca(2+) channels in the regulation of tumor growth and progression, particularly T-type channels due to their unique biophysical properties. T-type channels are expressed in normal tissues throughout the body and in different types of tumors such as breast carcinoma, retinoblastoma, neuroblastoma, and glioma. It has been demonstrated that increased functional expression of the α1 subunit of T-type channels plays a role in the abnormal proliferation of glioblastoma cells. As such, siRNA-mediated knockdown of the expression of the α1 subunit of T-type channels decreases the proliferation of these cells. Moreover, pharmacological blockade of T-type channels significantly decreases tumor growth. In this review, we focus on the use of T-type channel blockers for the potential treatment of cancers, particularly highly proliferative tumors such as glioblastoma. We conclude that T-type channel blockers such as endostatin can serve as a potential therapeutic tool for tumors whose proliferation depends on increased T-type channel expression.

Low-Shear Stress Promotes Atherosclerosis via Inducing Endothelial Cell Pyroptosis Mediated by IKKε/STAT1/NLRP3 Pathway.

Atherosclerosis is initiated by vascular endothelial dysfunction, and low-shear stress (LSS) of blood flow is a key factor leading to endothelial dysfunction. Growing evidence suggests that endothelial cell pyroptosis plays an important role in the development of atherosclerosis. Studies have shown that low-shear stress can induce endothelial cell pyroptosis, but the exact mechanism remains unclear. Our experiments demonstrated that low-shear stress induced endothelial cell pyroptosis and the phosphorylation of IκB kinase ε (IKKε). IKKε knockdown not only significantly attenuated atherosclerosis lesions of aortic arch areas in ApoE-/- mice fed with high cholesterol diets, but also markedly reduced endothelial cell pyroptosis and NLRP3 expression triggered by low-shear stress. Further mechanism studies showed that IKKε promoted the expression of NLRP3 via activating signal transducer and activator of transcription 1 (STAT1) and the subsequent binding of STAT1 to NLRP3 promoter region. These results suggest that low-shear stress plays a pro-atherosclerotic role by promoting endothelial cell pyroptosis through the IKKε/STAT1/NLRP3 pathway, which provides new insights into the formation of atherosclerosis.