Flexible use of commercial rhenium disulfide for various theranostic applications.

Rhenium disulfide (ReS2) with distinct physicochemical properties has shown promising potential in disease theranostics, such as drug delivery, computed tomography (CT), radiotherapy, and photothermal therapy (PTT). However, the synthesis and post-modification of ReS2 agents for different application scenarios are time- and energy-consuming, which seriously hinders the clinical translation of ReS2. Herein, we proposed three facile excipient strategies for different theranostic applications of ReS2 just through the flexible use of commercial ReS2 powder. Three excipients, including sodium alginate (ALG), xanthan gum (XG), and ultraviolet-cured resin (UCR), were used to prepare different dosage forms of commercial ReS2 powder, like hydrogel, suspension, and capsule, respectively. These dosage forms of ReS2 with distinct characteristics showed great potential for second near-infrared window PTT against tumours, gastric spectral CT imaging, and functional evaluation of the digestive tract in vivo. In addition, these ReS2 formulations exhibited good biocompatibility both in vitro and in vivo, showing a promising prospect for clinical transformation. More importantly, the facile excipient strategies for commercial agents pave a bridge to the development and wide bioapplication of many other theranostic biomaterials.

Monitoring Nitric Oxide-Induced Hypoxic Tumor Radiosensitization by Radiation-Activated Nanoagents under BOLD/DWI Imaging.

Tumor heterogeneity leads to unpredictable radiotherapeutic outcomes although multiple sensitization strategies have been developed. Real-time monitoring of treatment response through noninvasive imaging methods is critical and a great challenge in optimizing radiotherapy. Herein, we propose a combined functional magnetic resonance imaging approach (blood-oxygen-level-dependent/diffusion-weighted (BOLD/DWI) imaging) for monitoring tumor response to nitric oxide (NO)-induced hypoxic radiosensitization achieved by radiation-activated nanoagents (NSC@SiO2-SNO NPs). This nanoagent carrying NO donors can efficiently concentrate in tumors and specifically produce high concentrations of NO under radiation. In vitro and in vivo studies show that this nanoagent can effectively reduce tumor hypoxia, promote radiation-induced apoptosis and DNA damage under hypoxia, and ultimately inhibit tumor growth. In vivo BOLD/DWI imaging enables noninvasive monitoring of improvements in tumor oxygen levels and radiosensitivity during treatment with this nanostrategy by quantifying functional parameters. This work demonstrates that BOLD/DWI imaging is a useful tool for evaluating tumor response and monitoring the effectiveness of radiotherapeutic strategies aimed at improving hypoxia, with great clinical potential.

Biocompatible BSA-MnO2 nanoparticles for in vivo timely permeability imaging of blood-brain barrier and prediction of hemorrhage transformation in acute ischemic stroke.

Hemorrhage transformation (HT) is a frequent but maybe fatal complication following acute ischemic stroke due to severe damage of the blood-brain barrier (BBB). Quantitative BBB permeability imaging is a promising method to predict HT in stroke patients for a favorable prognosis. However, clinical gadolinium chelate-based magnetic resonance (MR) imaging of the stroke suffers from a relatively low sensitivity and potential side effects of nephrogenic systemic fibrosis and intracranial gadolinium deposition. Herein, BSA-MnO2 nanoparticles (BM NPs) fabricated by a facile disinfection-mimic method were employed for the permeability imaging of BBB in the stroke for the first time. The BM NPs showed a high T1 relaxivity (r1 = 5.9 mM-1 s-1), remarkable MR imaging ability, and good biocompatibility, allowing the noninvasive timely visualization of BBB permeability in the model rats of middle cerebral artery occlusion (MCAO). Furthermore, increased peak intensity, extended imaging duration, and expanded imaging region indicated by BM NPs in MR imaging showed a good prediction for the onset of HT in MCAO rats. Therefore, BM NPs hold an attractive potential to be an alternative biocompatible MR contrast agent for the noninvasive BBB permeability imaging in vivo, benefiting the fundamental research of diverse neurological disorders and the clinical treatment for stroke patients.

Prefrontal Granule Cell-Related Genes and Schizophrenia.

Although both the granular layer of the prefrontal cortex (PFC) and schizophrenia are unique in primates, especially humans, their linkage is unclear. Here, we tested whether schizophrenia is associated with expression profiles of the granule cell (GC)-related genes in the human PFC. We identified 14 candidate GC-related genes with gradually increased expression levels along the gradient of the agranular, dysgranular, light-granular, and granular prefrontal regions based on the densely sampled gene expression data of 6 postmortem human brains, and with more than 10-fold expression in neurons than other cell types based on the single-cell RNA-sequencing data of the human PFC. These GC-related genes were functionally associated with synaptic transmission and cell development and differentiation. The identified 14 GC-related genes were significantly enriched for schizophrenia, but not for depression and bipolar disorder. The expression levels of the 4 stable schizophrenia- and GC-related genes were spatially correlated with gray matter volume differences in the PFC between patients with schizophrenia and healthy controls. This study provides a set of candidate genes for the human prefrontal GCs and links expression profiles of the GC-related genes to the prefrontal structural impairments in schizophrenia.

Long-term Pingju Opera Training Induces Plasticity Changes in Cerebral Blood Flow: An Arterial Spin Labelling MRI Study.

Professional Pingju actors have been shown to exhibit practice-induced plastic changes in spontaneous regional brain activity; however, whether these changes are present in resting-state regional cerebral blood flow (CBF) remains largely unclear. Here, twenty professional Pingju opera actors and 20 age-, sex-, and handedness-matched untrained subjects were recruited, and resting-state CBF maps were obtained by using a three-dimensional pseudocontinuous arterial spin labelling sequence. Voxel-based comparisons of the CBF maps between the two groups were performed with two-sample t-tests, and correlation analyses between the CBF changes and years of training in the actor group were conducted. In addition, the CBF connectivity between regions with CBF alterations and the whole brain was computed and compared between the two groups. Compared with untrained subjects, the actors showed significantly higher CBF in the right inferior temporal gyrus, right middle temporal gyrus, left temporal pole, and left inferior frontal gyrus, whereas significantly lower CBF was not found in the actor group (voxel-level uncorrected p < 0.001, cluster-level family-wise error corrected p < 0.05). Furthermore, there was no correlation between the mean CBF values from significantly different clusters and the years of training, and no significant alterations in CBF connectivity were found in the actor group. Overall, these results provided preliminary evidence that neural plastic changes in CBF are present in professional Pingju opera actors, which may correspond to specific experiences associated with Pingju opera training.

Rhenium Sulfide Nanoparticles as a Biosafe Spectral CT Contrast Agent for Gastrointestinal Tract Imaging and Tumor Theranostics in Vivo.

Spectral computed tomography (CT) imaging as a novel imaging technique shows promising prospects in the accurate diagnosis of various diseases. However, clinically iodinated contrast agents suffer from poor signal-to-noise ratio, and emerging heavy-metal-based CT contrast agents arouse great biosafety concern. Herein, we show the fabrication of rhenium sulfide (ReS2) nanoparticles, a clinic radiotherapy sensitizer, as a biosafe spectral CT contrast agent for the gastrointestinal tract imaging and tumor theranostics in vivo by teaching old drugs new tricks. The ReS2 nanoparticles were fabricated in a one-pot facile method at room temperature, and exhibited sub-10 nm size, favorable monodispersity, admirable aqueous solubility, and strong X-ray attenuation capability. More importantly, the proposed nanoparticles possess an outstanding spectral CT imaging ability and undoubted biosafety as a clinic therapeutic agent. Besides, the ReS2 nanoparticles possess appealing photothermal performance due to their intense near-infrared absorption. The proposed nano-agent not only guarantees obvious contrast enhancement in gastrointestinal tract spectral CT imaging in vivo, but also allows effective CT imaging-guided tumor photothermal therapy. The proposed "teaching old drugs new tricks" strategy shortens the time and cuts the cost required for clinical application of nano-agents based on existing clinical toxicology testing and trial results, and lays down a low-cost, time-saving, and energy-saving method for the development of multifunctional nano-agents toward clinical applications.

Altered Spontaneous Regional Brain Activity in the Insula and Visual Areas of Professional Traditional Chinese Pingju Opera Actors.

Recent resting-state fMRI studies have revealed neuroplastic alterations after long-term training. However, the neuroplastic changes that occur in professional traditional Chinese Pingju opera actors remain unclear. Twenty professional traditional Chinese Pingju opera actors and 20 age-, sex-, and handedness-matched laymen were recruited. Resting-state fMRI was obtained by using an echo-planar imaging sequence, and two metrics, amplitude of low frequency fluctuation (ALFF) and regional homogeneity (ReHo), were utilized to assess spontaneous neural activity during resting state. Our results demonstrated that compared with laymen, professional traditional Chinese Pingju actors exhibited significantly decreased ALFF in the bilateral calcarine gyrus and cuneus; decreased ReHo in the bilateral superior occipital and calcarine gyri, cuneus, and right middle occipital gyrus; and increased ReHo in the left anterior insula. In addition, no significant association was found between spontaneous neural activity and Pingju opera training duration. Overall, the changes observed in spontaneous brain activity in professional traditional Chinese Pingju opera actors may indicate their superior performance of multidimensional professional skills, such as music and face perception, dancing, and emotional representation.

ZNF804A rs1344706 interacts with COMT rs4680 to affect prefrontal volume in healthy adults.

The biological function of ZNF804A rs1344706, the first genome-wide supported risk variant of schizophrenia, remains largely unknown. Based on the upregulating effect of ZNF804A on the expression of COMT, we hypothesize that ZNF804A may affect grey matter volume (GMV) by interacting with COMT. Voxel-based morphometry was applied to analyze the main and interaction effects of ZNF804A rs1344706 and COMT rs4680 on brain GMV in 274 healthy young human subjects. The GMV of the left dorsolateral prefrontal cortex (DLPFC) showed a significant COMT rs4680 × ZNF804A rs1344706 interaction, manifesting as an inverted U-shape modulation by the presumed dopamine signaling. In COMT Met-allele carriers, the ZNF804A TG heterozygotes showed greater GMV in the left DLPFC than both GG and TT homozygotes. In COMT Val/Val homozygotes, however, the ZNF804A TG heterozygotes exhibited smaller GMV in the left DLPFC than GG homozygotes and comparable GMV with TT homozygotes. These findings suggest that ZNF804A affects the GMV of the prefrontal cortex by interacting with COMT, which may improve our understanding of neurobiological effect of ZNF804A and its association with schizophrenia.

Radiation-responsive scintillating nanotheranostics for reduced hypoxic radioresistance under ROS/NO-mediated tumor microenvironment regulation.

Hypoxia-induced radioresistance is the primary reason for failure of tumor radiotherapy (RT). Changes within the irradiated tumor microenvironment (TME) including oxygen, reactive oxygen species (ROS) and nitric oxide (NO) are closely related to radioresistance. Therefore, there is an urgent need to develop new approaches for overcoming hypoxic radioresistance by incorporating TME regulation into current radiotherapeutic strategies. METHODS: Herein, we explored a radiation-responsive nanotheranostic system to enhance RT effects on hypoxic tumors by multi-way therapeutic effects. This system was developed by loading S-nitrosothiol groups (SNO, a NO donor) and indocyanine green (ICG, a photosensitizer) onto mesoporous silica shells of Eu3+-doped NaGdF4 scintillating nanocrystals (NSC). RESULTS: Under X-ray radiation, this system can increase the local dosage by high-Z elements, promote ROS generation by X-ray-induced photodynamic therapy, and produce high levels of NO to enhance tumor-killing effects and improve hypoxia via NO-induced vasodilation. In vitro and in vivo studies revealed that this combined strategy can greatly reinforce DNA damage and apoptosis of hypoxic tumor cells, while significantly suppressing tumor growth, improving tumor hypoxia and promoting p53 up-regulation and HIF1α down-regulation. In addition, this system showed pronounced tumor contrast performance in T1-weighted magnetic resonance imaging and computed tomography. CONCLUSION: This work demonstrates the great potential of scintillating nanotheranostics for multimodal imaging-guided X-ray radiation-triggered tumor combined therapy to overcome radioresistance.

Network-Dependent Modulation of COMT and DRD2 Polymorphisms in Healthy Young Adults.

Nonlinear modulation of the dopamine signaling on brain functions can be estimated by the interaction effects of dopamine-related genetic variations. We aimed to explore the interaction effects of COMT rs4680 and DRD2 rs1076560 on intra-network connectivity using independent component analysis. In 250 young healthy adults, we identified 11 meaningful resting-state networks (RSNs), including the salience, visual, auditory, default-mode, sensorimotor, attention and frontoparietal networks. A two-way analysis of covariance was used to investigate COMT×DRD2 interactions on intra-network connectivity in each network, controlling for age, gender and education. Significant COMT×DRD2 interaction was found in intra-network connectivity in the left medial prefrontal cortex of the anterior default-mode network, in the right dorsolateral frontal cortex of the right dorsal attention network, and in the left dorsal anterior cingulate cortex of the salience network. Post hoc tests revealed that these interactions were driven by the differential effects of DRD2 genotypes on intra-network connectivity in different COMT genotypic subgroups. Moreover, even in the same COMT subgroup, the modulation effects of DRD2 on intra-network connectivity were different across RSNs. These findings suggest a network-dependent modulation of the DA-related genetic variations on intra-network connectivity.