Morphometric development of the human fetal cerebellum during the early second trimester.

The protracted nature of development makes the cerebellum vulnerable to a broad spectrum of pathologic conditions, especially during the early fetal period. This study aims to characterize normal cerebellar growth in human fetuses during the early second trimester. We manually segmented the fetal cerebellum using 7.0-T high-resolution MR images obtained in 35 specimens with gestational ages ranging from 15 to 22 weeks. Volume measurements and shape analysis were performed to quantitatively evaluate global and regional cerebellar growth. The absolute volume of the fetal cerebellum showed a quadratic growth with increasing gestational age, while the pattern of relative volume changes revealed that the cerebellum grew at a greater pace than the cerebrum after 17 gestational weeks. Shape analysis was used to examine the distinctive development of subregions of the cerebellum. The extreme lateral portions of both cerebellar hemispheres showed the lowest rate of growth. The anterior lobe grew faster than most of the posterior lobe. These findings expand our understanding of the early growth pattern of the human cerebellum and could be further used to assess the developmental conditions of the fetal brain.

Changes in Male Rat Sexual Behavior and Brain Activity Revealed by Functional Magnetic Resonance Imaging in Response to Chronic Mild Stress.

BACKGROUND: Non-organic erectile dysfunction (noED) at functional imaging has been related to abnormal brain activity and requires animal models for further research on the associated molecular mechanisms. AIM: To develop a noED animal model based on chronic mild stress and investigate brain activity changes. METHODS: We used 6 weeks of chronic mild stress to induce depression. The sucrose consumption test was used to assess the hedonic state. The apomorphine test and sexual behavior test were used to select male rats with ED. Rats with depression and ED were considered to have noED. Blood oxygen level-dependent-based resting-state functional magnetic resonance imaging (fMRI) studies were conducted on these rats, and the amplitude of low-frequency fluctuations and functional connectivity were analyzed to determine brain activity changes. OUTCOMES: The sexual behavior test and resting-state fMRI were used for outcome measures. RESULTS: The induction of depression was confirmed by the sucrose consumption test. A low intromission ratio and increased mount and intromission latencies were observed in male rats with depression. No erection was observed in male rats with depression during the apomorphine test. Male rats with depression and ED were considered to have noED. The possible central pathologic mechanism shown by fMRI involved the amygdaloid body, dorsal thalamus, hypothalamus, caudate-putamen, cingulate gyrus, insular cortex, visual cortex, sensory cortex, motor cortex, and cerebellum. Similar findings have been found in humans. CLINICAL TRANSLATION: The present study provided a novel noED rat model for further research on the central mechanism of noED. STRENGTHS AND LIMITATIONS: The present study developed a novel noED rat model and analyzed brain activity changes based at fMRI. The observed brain activity alterations might not extend to humans. CONCLUSION: The present study developed a novel noED rat model with brain activity alterations related to sexual arousal and erection, which will be helpful for further research involving the central mechanism of noED. Chen G, Yang B, Chen J, et al. Changes in Male Rat Sexual Behavior and Brain Activity Revealed by Functional Magnetic Resonance Imaging in Response to Chronic Mild Stress. J Sex Med 2018;15:136-147.

Detection of volume alterations in hippocampal subfields of rats under chronic unpredictable mild stress using 7T MRI: A follow-up study.

PURPOSE: To determine hippocampal subfields volume loss in depression, which was simulated by a rat chronic unpredictable mild stress (CUMS) model. As different cellular and molecular characteristics in hippocampal subfields, these subfields are regarded as differentially vulnerable to processes associated with stress. MATERIALS AND METHODS: Twenty male Wistar rats were exposed to various stressors until the model was successfully established. The effects of physical exercise on recovery of hippocampal volume in depressed rats were simulated using the wheel running test (WRT). These rats hippocampal volumes were dynamically measured using T2 -weighted images (T2 WIs) at 7T structural magnetic resonance imaging (MRI). RESULTS: After 4 weeks of CUMS (CUMS-4W), the behavioral tests showed that the rat model of depression was successfully established (P < 0.001). In this process, the bilateral CA1 volume was significantly atrophic after 2 weeks of CUMS (CUMS-2W) compared with controls (left: 21.09 ± 2.31 vs. 26.16 ± 3.83 mm3 , P < 0.001; right: 21.05 ± 2.36 vs. 26.12 ± 3.78 mm3 , P < 0.001), whereas the other subfields did not show a similar change (all P > 0.05). The volume of CA3, dentate gyrus (DG), and subiculum displayed atrophy after CUMS-4W (CA3: left:12.23 ± 1.10 mm3 , right: 12.20 ± 1.14 mm3 ; DG: left:8.16 ± 0.58 mm3 , right: 8.18 ± 0.92 mm3 ; subiculum: left: 4.30 ± 0.52 mm3 , right: 4.29 ± 0.44 mm3 ; all P < 0.05). The rats' (CUMS-4W) hippocampal DG volume was restored (left: 10.67 ± 1.60 mm3 , right: 10.71 ± 1.58 mm3 ), and the depression-like behaviors of these rats improved after WRT-4W (P < 0.05). CONCLUSION: In general, volume loss was demonstrated in various rat hippocampal subfields during the development and recovery from depression, which were detected by ultrahigh-field MRI. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2017;46:1456-1463.

Development of the human fetal hippocampal formation during early second trimester.

Development of the fetal hippocampal formation has been difficult to fully describe because of rapid changes in its shape during the fetal period. The aims of this study were to: (1) segment the fetal hippocampal formation using 7.0 T MR images from 41 specimens with gestational ages ranging from 14 to 22 weeks and (2) reveal the developmental course of the fetal hippocampal formation using volume and shape analyses. Differences in hemispheric volume were observed, with the right hippocampi being larger than the left. Absolute volume changes showed a linear increase, while relative volume changes demonstrated an inverted-U shape trend during this period. Together these exhibited a variable developmental rate among different regions of the fetal brain. Different sub-regional growth of the fetal hippocampal formation was specifically observed using shape analysis. The fetal hippocampal formation possessed a prominent medial-lateral bidirectional shape growth pattern during its rotation process. Our results provide additional insight into 3D hippocampal morphology in the assessment of fetal brain development and can be used as a reference for future hippocampal studies.

Effective PEGylation of Fe3O4 Nanomicelles for In Vivo MR Imaging.

A practical and effective strategy for synthesizing PEGylated Fe3O4 nanomicelles is established. In this strategy, a magnetic fluid of the Fe3O4 nanomicelles was synthesized with amphiphilic PEGylated phospholipid as surfactant and soybean oil as stabilizer under simple mechanical stirring and subsequent ultrasonication. Transmission electron microscope (TEM) measurement indicated that the sample is monodisperse spherical Fe3O4 nanoparticles with internal core size of 9 nm and external nanomicelle shell thickness of 1.5 nm. The final hydrodynamic size of the sample is 19.5 nm and its zeta potential is - 38.5 mV, suggesting good stability of the magnetic nanomicelles in water. To assess the ability of magnetic nanomicelles to escape reticuloendothelial system (RES) uptake, in vitro cell phagocytosis experiments were conducted using murine macrophages (RAW264.7). The results indicated that the PEGylation can effectively prevent the uptake of the nanomicelles by the macrophages. Using a mouse model of 4T1 breast cancer, the nanomicelles provided a good magnetic resonance imaging (MRI) capability to sensitively detect tumor by enhanced permeability and retention (EPR) effect. The PEGylated monodisperse magnetic nanomicelles would become a potential contrast agent for passive targeting diagnosis of tumor by MR imaging.

Spatial-temporal atlas of human fetal brain development during the early second trimester.

During the second trimester, the human fetal brain undergoes numerous changes that lead to substantial variation in the neonatal in terms of its morphology and tissue types. As fetal MRI is more and more widely used for studying the human brain development during this period, a spatiotemporal atlas becomes necessary for characterizing the dynamic structural changes. In this study, 34 postmortem human fetal brains with gestational ages ranging from 15 to 22 weeks were scanned using 7.0 T MR. We used automated morphometrics, tensor-based morphometry and surface modeling techniques to analyze the data. Spatiotemporal atlases of each week and the overall atlas covering the whole period with high resolution and contrast were created. These atlases were used for the analysis of age-specific shape changes during this period, including development of the cerebral wall, lateral ventricles, Sylvian fissure, and growth direction based on local surface measurements. Our findings indicate that growth of the subplate zone is especially striking and is the main cause for the lamination pattern changes. Changes in the cortex around Sylvian fissure demonstrate that cortical growth may be one of the mechanisms for gyration. Surface deformation mapping, revealed by local shape analysis, indicates that there is global anterior-posterior growth pattern, with frontal and temporal lobes developing relatively quickly during this period. Our results are valuable for understanding the normal brain development trajectories and anatomical characteristics. These week-by-week fetal brain atlases can be used as reference in in vivo studies, and may facilitate the quantification of fetal brain development across space and time.

[Mapping fetal brain development in the second trimester with 7.0T magnetic resonance imaging].

OBJECTIVE: To obtain the three dimensional visualization model with normal measurements of fetal brain in the second trimester and analyze the developmental changes with gestational age (GA), sexual dimorphisms and cerebral asymmetries. METHODS: The brains of 69 fetal specimens of 12 - 22 weeks GA were scanned by 7.0T magnetic resonance imaging (MRI). The developing structures were analyzed and a three dimensional visualization model was rebuilt with Amira 4.1 software. RESULTS: Most sulci, except for postcentral and intraparietal sulcus, were present until 22 weeks GA. And none developed secondary branches. Laminar organization, described as early as 12 weeks GA, was delineated as layers with different signal intensities and became typical after 16 weeks GA. Basal nuclei was distinctly visible. Brains had different growth rates linearly increasing with GA. But neither sexual dimorphisms nor cerebral asymmetries was detected. CONCLUSIONS: The initial developmental stage of fetal brain occurs at 12 - 22 weeks GA. The developing structures may be distinctly visualized on 7.0T post-mortem MRI. And the three dimensional visualization model aids greatly in the precise cognition of immature brain.

Camouflaged Nanoreactors Mediated Radiotherapy-Adjuvant Chemodynamic Synergistic Therapy.

Chemodynamic therapy based on the Fenton-like catalysis ability of Fe3O4 has the advantages of no involvement of chemical drugs and minimal adverse effects as well as the limitation of depletable efficacy. Radiotherapy based on high-energy radiation offers the convenience of treatment and cost-effectiveness but lacks precision and cellular adaptation of tumor cells. Approaching such dilemmas from a nanoscale materials perspective, we aim to bridge the weaknesses of both treatment methods by combining the principles of two therapeutics reciprocally. We have designed a camouflaged Fe3O4@HfO2 composite nanoreactor (FHCM), which combines a chemodynamic therapeutic agent Fe3O4 and a radiosensitizer HfO2 that both has passed clinical trials and was inspired by a cell membrane biomimetic technique. FHCM is employed as conceived radiotherapy-adjuvant chemodynamic synergistic therapy of malignant tumors, which has undergone dual scrutiny from both the physical and biological aspects. Experimental results obtained at different levels, including theory, material characterizations, and in vitro and in vivo verifications, suggest that FHCM effectively impaired tumor cells through physical and molecular biological mechanisms involving a HfO2-Fe3O4 photoelectron-electron transfer chain and DNA damage-ferroptosis-immunity chain. It is worth noting that compared to single therapies such as only chemodynamic therapy or radiotherapy, FHCM-mediated radiotherapy-adjuvant chemodynamic synergistic therapy exhibits stronger tumor inhibition efficacy. It significantly addresses the inherent limitations of chemodynamic therapy and radiotherapy and underscores the feasibility and importance of using existing clinical weapons, such as radiotherapy, as auxiliary strategies to overcome certain flaws of emerging antitumor therapeutics like chemodynamic therapy.

Development of the subcortical brain structures in the second trimester: assessment with 7.0-T MRI.

INTRODUCTION: This study aims to obtain the signal intensity changes and quantitative measurements of the subcortical brain structures of 12-22 weeks gestational age (GA). METHODS: Sixty-nine fetal specimens were selected and scanned by 7.0-T MR. The signal intensity changes of the subcortical brain structures were analyzed. The three-dimensional visualization models of the germinal matrix, caudate nucleus, lentiform nucleus, and dorsal thalamus were rebuilt with Amira 4.1, and the developmental trends between the measurements and GA were analyzed. RESULTS: The germinal matrix was delineated on 7.0-T MR images at 12 weeks GA, with high signals on T1-weighted images (WI). While at 16 weeks GA, the caudate nucleus, lentiform nucleus, and internal and external capsules could be distinguished. The caudate nucleus was high signal intensity on T1WI. The signal intensity of the putamen was high on T1WI during 15-17 weeks GA and was delineated as an area with uneven signal intensities. The signal intensity of the peripheral area of the putamen became higher after 18 weeks GA. The signal intensity of the globus pallidus was high on T1WI and low on T2WI after 20 weeks GA. At 18 weeks GA, the claustrum was delineated with low signals on T2WI. Measurements of the germinal matrix, caudate nucleus, lentiform nucleus, and dorsal thalamus linearly increased with the GA. CONCLUSION: Development of the subcortical brain structures during 12-22 weeks GA could be displayed with 7.0-T MRI. The measurement provides significant reference beneficial to the clinical evaluation of fetal brain development.

Resting-State Functional Connectivity Analyses: Brain Functional Reorganization in a Rat Model of Postherpetic Neuralgia.

Postherpetic neuralgia (PHN) is a chronic neuropathic pain syndrome, similar to other chronic pains, the mechanisms of which are not fully understood. To further understand the neural mechanism of this chronic pain and its transition, we performed functional magnetic resonance imaging (fMRI) scans on PHN rat models. Twelve PHN rat models were established by intraperitoneal injection of resiniferatoxin, with an additional 12 rats serving as controls. Nociceptive behavioral tests were performed on these rats and fMRI scans were performed on days 7 and 14 after modeling. Functional connection (FC) analysis was used to investigate the brain FC alterations associated with chronic pain in PHN rats, with the anterior cingulate cortex (ACC) as a seed. Nociceptive behavioral tests showed that PHN rats presented symptoms similar to those of PHN patients. FC analysis showed that compared to the control group, the PHN group showed different FC patterns on days 7 and 14. As can be seen, the brain FC alterations in the rat model of PHN changed dynamically, shifting from brain regions processing sensory information to regions processing emotions and motives.

Alterations to cognitive abilities and functional networks in rats post broad-band intense noise exposure.

This study aimed to investigate the alterations of cognition and functional connectivity post noise, and find the progress and neural substrates of noise induced hearing loss (NIHL)-associated cognitive impairment. We exposed rats to 122 dB broad-band noise for 2 h to induce hearing loss and the auditory function was assessed by measuring auditory brainstem response thresholds. Morris water maze test and resting state MRI were computed at 0 day, 1, 3, 6 months post noise to reveal cognitive ability and neural substrate. The interregional connections in the auditory network and default mode network, as well as the connections using the auditory cortex and cingulate cortex as seeds were also examined addtionally. The deficit in spatial learning/memory was only observed at 6 months after noise exposure. The internal connections in the auditory network and default mode network were enhanced at 0 day and decreased at 6 months post noise. The connectivity using the auditory cortex and cingulate cortex as seeds generally followed the rule of "enhancement-normal-decrease-widely decrease". A new model accounting for arousal, dementia, motor control of NIHL in is proposed. Our study highlights the fundamental flexibility of neural systems, and may also point toward novel therapeutic strategies for treating sensory disorders.

Development of the human fetal cerebellum in the second trimester: a post mortem magnetic resonance imaging evaluation.

The cerebellum is one of the most important structures in the posterior cranial fossa, but the characterization of its development by magnetic resonance imaging (MRI) is incomplete. We scanned 40 fetuses that had no morphological brain disorder at 14-22 weeks of gestation using 7.0 T MRI. Amira 4.1 software was used to determine morphological parameters of the fetal cerebellum, which included the cerebellar volume (CV), transverse cerebellar diameter (TCD), and the length and width of the vermis. The relationship between these measurements and gestational age (GA) was analysed. We found that the primary fissure was visible at week 14 of gestation. From week 16, the prepyramidal fissure, the secondary fissure and the dentate nucleus could be identified. The posterolateral fissure and the fourth ventricle were recognized at week 17, whereas the tentorium of the cerebellum was visible at week 20. The relationships between GA and CV, TCD, and the width and length of the vermis were described adequately by second-order polynomial regression curves. The ratios between TCD and vermis length and between TCD and vermis width decreased with GA. These results show that 7.0 T MRI can show the trajectory of cerebellar development clearly. They increase our understanding of normal cerebellar development in the fetus, and will facilitate the diagnosis of pathological intrauterine changes in the cerebellum.

Development of laminar organization of the fetal cerebrum at 3.0T and 7.0T: a postmortem MRI study.

INTRODUCTION: The purpose of this study is to show the condition of laminar organization on 3.0T and 7.0T postmortem magnetic resonance imaging (MRI) and analyze developmental changes. METHODS: Heads of 131 fetal specimens of 14-40 weeks gestational age (GA) were scanned by 3.0T MRI. Eleven fetal specimens of 14-27 weeks GA were scanned by 7.0T MRI. Clear images were chosen for analysis. RESULTS: On T1-weighted 3.0T MRI, layers could be visualized at 14 weeks GA and appeared clearer after 18 weeks GA. On 7.0T MRI, four zones could be recognized at 14 weeks GA. During 15-22 weeks GA, when laminar organization appeared typical, seven layers including the periventricular zone and external capsule fibers could be differentiated, which corresponded to seven zones in histological stained sections. At 23-28 weeks GA, laminar organization appeared less typical, and borderlines among them appeared obscured. After 30 weeks GA, it disappeared and turned into mature-like structures. The developing lamination appeared the most distinguishable at the parieto-occipital part of brain and peripheral regions of the hippocampus. The migrating thalamocortical afferents were probably delineated as a high signal layer located at the lower, middle, and upper part of the subplate zone at 16-28 weeks GA on T1-weighted 3.0T MRI. CONCLUSIONS: T1-weighted 3.0T MRI and T2-weighted 7.0T MRI can well demonstrate the laminar organization. Development of the lamination follows a specific spatio-temporal regularity, and postmortem MRI of the parieto-occipital part of brain obtained with 3.0T or 7.0T is an effective way to show developmental changes.

[Modeling of acute thromboembolic stroke in mice].

OBJECTIVE: To evaluate the controllability and reproducibility of a acute thromboembolic cerebral ischemia model for studying molecular imaging and thrombolysis in mice by 7.0 Tesla magnetic resonance imaging (MRI). METHODS: Twenty-four male C57BL/6J mice were randomly divided into embolic group (n = 14) and sham-operated group (n = 10). To prepare rich fibrin and optimal length of clots and measure diameters of clots under microscope, the clots were injected into internal carotid artery via a microcatheter inserted from external carotid artery to bifurcation of common carotid artery in embolic group. In sham-operated group, phosphate-buffered saline containing bovine serum albumin was injected similarly. At 1, 3 or 24 h after injection of clots or phosphate-buffered saline containing bovine serum albumin, mice underwent 7.0 Tesla magnetic resonance imaging including sequences of magnetic resonance angiography (MRA), diffusion weighted imaging (DWI) and perfusion weighted imaging (PWI) by arterial spin labeling technology (ASL) and T(2) weighted imaging (T(2)WI) so as to evaluate the occlusive rate of middle cerebral artery (MCA) and the change of relative cerebral blood flow (rCBF) and lesion volumes. Triphenyl tetrazolium chloride (TTC) stain was performed at 24 h. RESULTS: The diameters of clots were 162 ± 14 µm. In embolic group at 1, 3 or 24 h after injection of clots, the occlusive rate of MCA was 78.6%, 71.4% and 57.1% respectively. And the values of rCBF decrease in mice showing occlusion of MCA in MRA images. The percents of rCBF value in embolic group were 26% ± 10% at 1 h and 26% ± 15% at 3 h respectively. They were significantly lower than the percents of rCBF value in sham-operated group at the same time points. The percents of infarct volumes at 24 h were 30% ± 4% from T(2)WI images and 30% ± 16% from TTC images. In sham-operated groups, both MRI and TTC images were negative. CONCLUSION: A murine model of acute thromboembolic cerebral ischemia has been successfully established. The improved method is both stable and feasible. It may be readily evaluated from multi-parameter imaging by 7.0 Tesla magnetic resonance imaging.

[Manganese enhanced magnetic resonance imaging for tracing corticospinal tracts in rat brain using 7.0 T MRI].

OBJECTIVE: To investigate the methods of manganese enhanced magnetic resonance imaging in 7.0 T magnetic field for tracing corticospinal tract in rat brain in vivo. METHODS: 0.4 microl volume of 1 mol/L aqueous solution of MnCl(2) was injected into the primary motor cortex of 9 SD rats under stereotaxis. MRI studies were performed for tracing corticospinal tract and other coherent nerve tracts before injection and 24 hours, 48 hours, 72 hours, 7 days after injection respectively using 7.0T Micro-MRI. RESULTS: Corticospinal tract was visualized perfectly from primary motor cortex, thalamus, cerebral peduncle to pons at different time points after Mn(2+) administration, and the best contrast was achieved after 24-48 h. At the same time, a small quantity of Mn(2+) reached the opposite somatosensory cortex through the corpus callosum. CONCLUSION: Manganese enhanced MRI visualizes perfectly the transport of Mn(2+) through axoplasmic flow in corticospinal tracts. This method may be used to investigate the change of corticospinal tract and the functional connectivity between two sides of hemisphere in rat brain.

Rituximab conjugated iron oxide nanoparticles for targeted imaging and enhanced treatment against CD20-positive lymphoma.

Since its launch in 1997, rituximab (RTX) has extensively improved the treatment of CD20-positive follicular and diffuse large B cell non-Hodgkin lymphoma (NHL). The application of RTX is limited usually by the failed therapy because of resistance. Iron oxide nanomaterials have been explored for cancer detection and treatment in recent years. In this study, a multivalent nanoprobe comprising one Fe3O4 nanoparticle and several RTX antibodies was constructed for the targeted imaging and enhanced treatment of NHL. Poly(ethylene glycol) (PEG)-coated Fe3O4 nanoparticles were fabricated via a thermal decomposition method and ligand exchange. RTX was conjugated onto the surface of the Fe3O4-PEG nanoparticles to form Fe3O4-PEG-nAb (n = 2, 5 or 8) multivalent nanoprobes. These multivalent nanoprobes, with a core size of approximately 11 nm and a hydrodynamic diameter of about 22 nm, showed colloidal stability in buffer solution. The r2 relaxation rate of Fe3O4-PEG-nAb was similar to that of Fe3O4-PEG (309 ± 3.08 mM-1 s-1). The specificity of nanoprobes for CD20-positive Raji cells was assessed on a clinical magnetic resonance imaging scanner. The receptor binding site of one multivalent nanoprobe was more than that of one RTX, exhibiting valence-dependent induction of Raji cell apoptosis, and this effect could be enhanced by complement activation from blood serum added. A similar activity was observed in vivo in a NHL xenograft model. The multivalent nanoprobe treatment significantly reduced tumor burden and enhanced survival in comparison to the RTX group. Our studies demonstrate that the appropriate design and preparation of anticancer antibody-nanoparticle conjugates enable the generation of improved anticancer nanomedicines and could thus provide an efficient cancer theranostic strategy.

Moderate cooling coprecipitation for extremely small iron oxide as a pH dependent T1-MRI contrast agent.

Iron based nanomedicine (IBNM) has been one powerful diagnostic tool as a magnetic resonance imaging (MRI) contrast agent (CA) in the clinic for years. Conventional IBNMs are generally employed as T2-MRI CAs, but most of them are constrained in clinical indication expansion by magnetic susceptibility artifacts. In comparison, extremely small iron oxide (ESIO) with a core size less than 5 nm has demonstrated the T1-MRI effect, which provides prospects for a Gd-based agent alternative. Nevertheless, currently developed ESIOs for T1-MRI CAs always require harsh conditions such as a high temperature and high boiling point reagent. Moreover, very few of the currently developed ESIOs meet the stringent pharmaceutical standard. Herein, on the basis of a crystal nuclear precipitation-dissolution equilibrium mechanism and outer/inner sphere T1-MRI theory, monodisperse ESIOs with an average size of 3.43 nm (polydispersity index of 0.104) are fabricated using a moderate cooling procedure with mild coprecipitation reaction conditions. The as-synthesized ESIOs display around 3-fold higher T1 MRI signal intensity than that of commercial Ferumoxytol (FMT), comparable to that of Gd-based CAs in vitro. Additionally, the T1-MRI performance of the ESIOs is pH dependent and delivers bright signal augmentation. Eventually, the internalization into mesenchymal stem cells of the ESIO is realized in the absence of a transferring agent. Considering the identical structure and composition of the ESIOs as compared to that of FMT, they could meet the pharmaceutical criteria, thus providing great potential as T1-MRI Cas, for instance as stem cell tracers.

Silencing of circular RNA HIPK2 in neural stem cells enhances functional recovery following ischaemic stroke.

BACKGROUND: Circular RNAs (circRNAs) have been reported to be involved in central nervous system (CNS) diseases and to have a close connection with neuronal development. However, the role of circRNAs in neural stem cell (NSC) differentiation and the treatment of ischaemic stroke remains unknown. METHODS: Ischaemic stroke was induced in mice using transient middle cerebral artery occlusion (tMCAO). NSCs were transducted with circHIPK2 siRNA (si-circHIPK2-NSCs) or vehicle control (si-circCon-NSCs) and microinjected into lateral ventricle of brain at 7 d post-tMCAO. Magnetic resonance imaging (MRI) was used to detect brain damage, and functional deficits were evaluated with sensorimotor behavioural tests. The distribution of the transplanted NSCs was investigated by near-infrared fluorescence imaging (NIF) and immunofluorescence. The neural plasticity of si-circHIPK2-NSCs was verified by western blot and immunofluorescence in vivo and in vitro. FINDINGS: We investigated the role of circHIPK2 in NCS differentiation. In vitro, silencing of circHIPK2 facilitated NSCs directionally differentiated to neurons but had no effect on the differentiation to astrocytes. In vivo, microinjected NSCs could migrate to the ischaemic hemisphere after stroke induction. Si-circHIPK2-NSCs increased neuronal plasticity in the ischaemic brain, conferred long-lasting neuroprotection, and significantly reduced functional deficits. INTERPRETATIONS: Si-circHIPK2 regulates NSC differentiation, and microinjection of si-circHIPK2-NSCs exhibits a promising therapeutic strategy to neuroprotection and functional recovery after stroke. FUNDING: The National Key Research and Development Program of China; the International Cooperation and Exchange of the National Natural Science Foundation of China; the National Natural Science Foundation of China; the Jiangsu Innovation & Entrepreneurship Team Program.

Role of myo-inositol by magnetic resonance spectroscopy in early diagnosis of Alzheimer's disease in APP/PS1 transgenic mice.

BACKGROUND/AIMS: To explore the potential value of myo-inositol (mIns), which is regarded as a biomarker for early diagnosis of Alzheimer's disease, in APP/PS1 transgenic (tg) mice detected by (1)H-MRS. METHODS: (1)H-MRS was performed in 30 APP/PS1 tg mice and 20 wild-type (wt) littermates at 3, 5 and 8 months of age. Areas under the peak of N-acetylaspartate (NAA), mIns and creatine (Cr) in the frontal cortex and hippocampus were measured, and the NAA/Cr and mIns/Cr ratios were analyzed quantitatively. RESULTS: Compared with the wt mice, the mIns/Cr ratio of the 3-month-old tg mice was significantly higher (p < 0.05), and pathology showed activation and proliferation of astrocytes in the frontal cortex and hippocampus. The concentration of NAA was significantly lower at 8 and 8 months of age (p < 0.05). According to the threshold of mIns/Cr that was adopted to separate the tg from the wt mice, the rate of correct predictions was 82, 94 and 95%, respectively, for 3, 5 and 8 months. CONCLUSION: Of the early AD metabolites as detected by (1)H-MRS, mIns is the most valuable marker for assessment of AD. Quantitative analysis of mIns may provide important clues for early diagnosis of AD.

Magnetic targeting combined with active targeting of dual-ligand iron oxide nanoprobes to promote the penetration depth in tumors for effective magnetic resonance imaging and hyperthermia.

The combination of multi-targeting magnetic nanoprobes and multi-targeting strategies has potential to facilitate magnetic resonance imaging (MRI) and magnetic induction hyperthermia of the tumor. Although the thermo-agents based on magnetic iron oxide nanoparticles (MION) have been successfully used in the form of intratumoral injection in clinical cure of glioblastoma, the tumor-targeted thermotherapy by intravenous administration remains challenging. Herein, we constructed a c(RGDyK)- and d-glucosamine-grafted bispecific molecular nanoprobe (Fe3O4@RGD@GLU) with a magnetic iron oxide core of size 22.17 nm and a biocompatible shell of DSPE-PEG2000, which can specially target the tumor vessel and cancer cells. The selection of c(RGDyK) could make the nanoprobe enter the neovascularization endotheliocyte through αvß3-mediated endocytosis, which drastically reduced the dependence on the enhanced permeability and retention (EPR) effect in tumor. This dual-ligand nanoprobe exhibited strong magnetic properties and favorable biocompatibility. In vitro studies confirmed the anti-phagocytosis ability against macrophages and the specific targeting capability of Fe3O4@RGD@GLU. Then, the imaging effect and anti-tumor efficacy were compared using different targeting strategies with untargeted nanoprobes, dual-targeted nanoprobes, and magnetic targeting combined with dual-targeted nanoprobes. Moreover, the combination strategy of magnetic targeting and active targeting promoted the penetration depth of nanoprobes in addition to the increased accumulation in tumor tissue. Thus, the dual-targeted magnetic nanoprobe together with the combined targeting strategy could be a promising method in tumor imaging and hyperthermia through in vivo delivery of theranostic agents. STATEMENT OF SIGNIFICANCE: Magnetic induction hyperthermia based on iron oxide nanoparticles has been used in clinic for adjuvant treatment of recurrent glioblastoma. Nonetheless, this application is limited to intratumoral injection, and tumor-targeted hyperthermia by intravenous injection remains challenging. In this study, we developed a multi-targeted strategy by combining magnetic targeting with active targeting of dual-ligand magnetic nanoprobes. This combination mode acquired optimum contrast imaging effect through MRI and tumor-suppressive effect through hyperthermia under an alternating current magnetic field. The design of the nanoprobe was suitable for targeting most tumor lesions, which enabled it to be an effective theranostic agent with extensive uses. This study showed significant enhancement of the penetration depth and accumulation of nanoprobes in the tumor tissue for efficient imaging and hyperthermia.