C-X-C motif chemokine receptor 4 (CXCR4) is a promising therapeutic target of breast cancer because it is overexpressed on cell surface of all molecular subtypes of breast cancer including triplenegative breast cancer (TNBC). Herein, CXCR4 antagonistic peptide-NaGdF4 nanodot conjugates (termed as anti-CXCR4-NaGdF4 NDs) have been constructed for magnetic resonance imaging (MRI)-guided biotherapy of TNBC through conjugation of the C-X-C Motif Chemokine 12 (CXCL12)-derived cyclic peptide with tryptone coated NaGdF4 nanodots (5 ± 0.5 nm in diameter, termed as Try-NaGdF4 NDs). The as-prepared anti-CXCR4-NaGdF4 NDs exhibits high longitudinal relaxivity (r1) value (21.87 mM-1S-1), reasonable biocompatibility and good tumor accumulation ability. The features of anti-CXCR4-NaGdF4 NDs improve the tumor-MRI sensitivity and facilitate tumor biotherapy after injection in mouse-bearing MDA-MB-231 tumor model in vivo. MRI-guided biotherapy using anti-CXCR4-NaGdF4 NDs enables to suppress 46% tumor growth. In addition, about 47% injection dose of anti-CXCR4-NaGdF4 NDs is found in the mouse urine at 24 h post-injection. These findings demonstrate that anti-CXCR4-NaGdF4 NDs enable to be used as renal clearable nanomedicine for biotherapy and MRI of breast cancer.

Ferroptosis therapy (FT) efficacy of tumors suffers from a relatively low concentration of Fenton agents, limited hydrogen peroxide (H2O2) content, and insufficient acidity in the tumor environment (TME), which are unfavorable for reactive oxygen species (ROS) generation based on Fenton or Fenton-like reactions. The glutathione (GSH) overexpression in TME can scavenge ROS and abate the FT performance. In this study, a strategy of ROS storm generation specifically initiated by the TME and our developed nanoplatforms (TAF-HMON-CuP@PPDG) is proposed for high-performance FT of tumors. The GSH in the TME initiates HMON degradation, resulting in tamoxifen (TAF) and copper peroxide (CuP) release from TAF3-HMON-CuP3@PPDG. The released TAF leads to enhanced acidification within tumor cells, which reacts with the released CuP producing Cu2+ and H2O2. The Fenton-like reaction between Cu2+ and H2O2 generates ROS and Cu+, and that between Cu+ and H2O2 generates ROS and Cu2+, forming a cyclic catalysis effect. Cu2+ reacts with GSH to generate Cu+ and GSSG. The increased acidification by TAF can accelerate the Fenton-like reaction between Cu+ and H2O2. The GSH consumption decreases the glutathione peroxidase 4 (GPX4) expression. All of the above reactions generate a ROS storm in tumor cells for high-performance FT, which is demonstrated in cancer cells and tumor-bearing mice.

Serine protease is linked to a wide range of diseases, prompting the development of robust, selective, and sensitive protease assays and sensing methods. However, the clinical needs for serine protease activity imaging have not yet been met, and the efficient in vivo detection and imaging of serine protease remain challenging. Here, we report the development of the gadolinium-cyclic 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-click-Sulfonyl Fluoride (Gd-DOTA-click-SF) MRI contrast agent targeting serine protease. The HR-FAB mass spectrum confirmed the successful formation of our designed chelate. The molar longitudinal relaxivity (r1) of the Gd-DOTA-click-SF probe (r1 = 6.82 mM-1 s-1) was significantly higher than that of Dotarem (r1 = 4.63 mM-1 s-1), in the range of 0.01-0.64 mM at 9.4 T. The in vitro cellular study and the transmetallation kinetics study showed that the safety and stability of this probe are comparable to those of conventional Dotarem. Ex vivo abdominal aortic aneurysm (AAA) MRI revealed that this probe has a contrast-agent-to-noise ratio (CNR) that is approximately 51 ± 23 times greater than that of Dotarem. This study of superior visualization of AAA suggests that it has the potential to detect elastase in vivo and supports the feasibility of probing serine protease activity in T1-weighted MRI.

The emerging tumor ferroptosis therapy confronts impediments of the tumor microenvironment (TME) with weak intrinsic acidity, inadequate endogenous H2 O2 , and a powerful intracellular redox balance system that eliminates toxic reactive oxygen species (ROS). Herein, a strategy of Fenton reaction cycloacceleration initiated by remodeling the TME for magnetic resonance imaging (MRI)-guided high-performance ferroptosis therapy of tumors is proposed. The synthesized nanocomplex exhibits enhanced accumulation at carbonic anhydrase IX (CAIX)-positive tumors based on the CAIX-mediated active targeting, and increased acidification via the inhibition of CAIX by 4-(2-aminoethyl) benzene sulfonamide (ABS) (remodeling TME). This accumulated H+ and abundant glutathione in TME synergistically trigger biodegradation of the nanocomplex to release the loaded cuprous oxide nanodots (CON), β-lapachon (LAP), Fe3+ , and gallic acid-ferric ions coordination networks (GF). The Fenton and Fenton-like reactions are cycloaccelerated via the catalytic loop of Fe-Cu, and the LAP-triggered and nicotinamide adenine dinucleotide phosphate quinone oxidoreductase1-mediated redox cycle, generating robust ROS and plenitudinous lipid peroxides accumulation for ferroptosis of tumor cells. The detached GF network has improved relaxivities in response to the TME. Therefore, the strategy of Fenton reaction cycloacceleration initiated by remodeling the TME is promising for MRI-guided high-performance ferroptosis therapy of tumors.

Increasingly intricate in their multilevel multiscale microarchitecture, metamaterials with unique physical properties are challenging the inherent constraints of natural materials. Their applicability in the nanomedicine field still suffers because nanomedicine requires a maximum size of tens to hundreds of nanometers; however, this size scale has not been achieved in metamaterials. Therefore, \"nano-metamaterials,\" a novel class of metamaterials, are introduced, which are rationally designed materials with multilevel microarchitectures and both characteristic sizes and whole sizes at the nanoscale, investing in themselves remarkably unique and significantly enhanced material properties as compared with conventional nanomaterials. Microarchitectural regulation through conventional thermodynamic strategy is limited since the thermodynamic process relies on the frequency-dependent effective temperature, Teff (ω), which limits the architectural regulation freedom degree. Here, a novel dual-kinetic control strategy is designed to fabricate nano-metamaterials by freezing a high-free energy state in a Teff (ω)-constant system, where two independent dynamic processes, non-solvent induced block copolymer (BCP) self-assembly and osmotically driven self-emulsification, are regulated simultaneously. Fe3+ -\"onion-like core@porous corona\" (Fe3+ -OCPCs) nanoparticles (the products) have not only architectural complexity, porous corona and an onion-like core but also compositional complexity, Fe3+ chelating BCP assemblies. Furthermore, by using Fe3+ -OCPCs as a model material, a microstructure-biological performance relationship is manifested in nano-metamaterials.

Observations of short-term changes in the neural health of youth athletes participating in collision sports (e.g., football and soccer) have highlighted a need to explore potential structural alterations in brain tissue volumes for these persons. Studies have shown biochemical, vascular, functional connectivity, and white matter diffusivity changes in the brain physiology of these athletes that are strongly correlated with repetitive head acceleration exposure. Here, research is presented that highlights regional anatomical volumetric measures that change longitudinally with accrued subconcussive trauma. A novel pipeline is introduced that provides simplified data analysis on standard-space template to quantify group-level longitudinal volumetric changes within these populations. For both sports, results highlight incremental relative regional volumetric changes in the subcortical cerebrospinal fluid that are strongly correlated with head exposure events greater than a 50-G threshold at the short-term post-season assessment. Moreover, longitudinal regional gray matter volumes are observed to decrease with time, only returning to baseline/pre-participation levels after sufficient (5-6 months) rest from collision-based exposure. These temporal structural volumetric alterations are significantly different from normal aging observed in sex- and age-matched controls participating in non-collision sports. Future work involves modeling repetitive head exposure thresholds with multi-modal image analysis and understanding the underlying physiological reason. A possible pathophysiological pathway is presented, highlighting the probable metabolic regulatory mechanisms. Continual participation in collision-based activities may represent a risk wherein recovery cannot occur. Even when present, the degree of the eventual recovery remains to be explored, but has strong implications for the well-being of collision-sport participants.

Multimodal imaging studies targeting preschoolers and low-functioning autism spectrum disorder (ASD) patients are scarce. We applied machine learning classifiers to parameters from T1-weighted MRI and DTI data of 58 children with ASD (age 3-6 years) and 48 typically developing controls (TDC). Classification performance reached an accuracy, sensitivity, and specificity of 88.8%, 93.0%, and 83.8%, respectively. The most prominent features were the cortical thickness of the right inferior occipital gyrus, mean diffusivity of the middle cerebellar peduncle, and nodal efficiency of the left posterior cingulate gyrus. Machine learning-based analysis of MRI data was useful in distinguishing low-functioning ASD preschoolers from TDCs. Combination of T1 and DTI improved classification accuracy about 10%, and large-scale multi-modal MRI studies are warranted for external validation.

Morphometric analyses in the early foetal phase (9-13 postconceptional week) are critical for evaluating normal brain growth. In this study, we assessed sequential morphological and morphometric changes in the foetal brain during this period using high-resolution T1-weighted magnetic resonance imaging (MRI) scans from 21 samples preserved at Kyoto University. MRI sectional views (coronal, mid-sagittal, and horizontal sections) and 3D reconstructions of the whole brain revealed sequential changes in its external morphology and internal structures. The cerebrum\'s gross external view, lateral ventricle and choroid plexus, cerebral wall, basal ganglia and thalamus, and corpus callosum were assessed. The development of the cerebral cortex, white matter microstructure, and basal ganglia can be well-characterized using MRI scans. The insula became apparent and deeply impressed as brain growth progressed. A thick, densely packed cellular ventricular/subventricular zone and ganglionic eminence became apparent at high signal intensity. We detected the emergence of important landmarks which may be candidates in the subdivision processes during the early foetal period; the corpus callosum was first detected in the sample with crown-rump length (CRL) 62 mm. A primary sulcus on the medial part of the cortex (cingulate sulcus) was observed in the sample with CRL 114 mm. In the cerebellum, the hemispheres, posterolateral fissure, union of the cerebellar halves, and definition of the vermis were observed in the sample with CRL 43.5 mm, alongside the appearance of a primary fissure in the sample with CRL 56 mm and the prepyramidal fissure in the sample with CRL 75 mm. The volumetric, linear, and angle measurements revealed the comprehensive and regional development, growth, and differentiation of brain structures during the early foetal phase. The early foetal period was neither morphologically nor morphometrically uniform. The cerebral proportion (length/height) and the angle of cerebrum to the standard line at the lateral view of the cerebrum, which may reflect the growth and C-shape formation of the cerebrum, may be a candidate for subdividing the early foetal period. Future precise analyses must establish a staging system for the brain during the early foetal period. This study provides insights into brain structure, allowing for a correlation with functional maturation and facilitating the early detection of brain damage and abnormal development.

Gadolinium-based contrast agents (GBCAs) are widely used for T1-weighted magnetic resonance imaging (MRI) in clinic diagnosis. However, a major drawback of GBCAs is that they can increase the toxicological risk of nephrogenic systemic fibrosis (NSF) in patients with advanced renal dysfunction. Hence, safer alternatives to GBCAs are currently in demand, especially for patients with renal diseases. Here we investigated the potential of polyethylene glycol (PEG)-stabilized iron oxide nanoclusters (IONCs) as biocompatible T1MRI contrast agents and systematically evaluated their NSF-related risk in rats with renal failure. We profiled the distribution, excretion, histopathological alterations, and fibrotic gene expressions after administration of IONCs and GBCAs. Our results showed that, compared with GBCAs, IONCs exhibited dramatically improved biosafety and a much lower risk of causing NSF, suggesting the feasibility of substituting GBCAs with IONCs in clinical MRI diagnosis of patients with renal diseases.

Medial temporal lobe (MTL) substructures are the earliest regions affected by neurofibrillary tangle pathology-and thus are promising biomarkers for Alzheimer\'s disease (AD). However, automatic segmentation of the MTL using only T1-weighted (T1w) magnetic resonance imaging (MRI) is challenging due to the large anatomical variability of the MTL cortex and the confound of the dura mater, which is commonly segmented as gray matter by state-of-the-art algorithms because they have similar intensity in T1w MRI. To address these challenges, we developed a novel atlas set, consisting of 15 cognitively normal older adults and 14 patients with mild cognitive impairment with a label explicitly assigned to the dura, that can be used by the multiatlas automated pipeline (Automatic Segmentation of Hippocampal Subfields [ASHS-T1]) for the segmentation of MTL subregions, including anterior/posterior hippocampus, entorhinal cortex (ERC), Brodmann areas (BA) 35 and 36, and parahippocampal cortex on T1w MRI. Cross-validation experiments indicated good segmentation accuracy of ASHS-T1 and that the dura can be reliably separated from the cortex (6.5% mislabeled as gray matter). Conversely, FreeSurfer segmented majority of the dura mater (62.4%) as gray matter and the degree of dura mislabeling decreased with increasing disease severity. To evaluate its clinical utility, we applied the pipeline to T1w images of 663 ADNI subjects and significant volume/thickness loss is observed in BA35, ERC, and posterior hippocampus in early prodromal AD and all subregions at later stages. As such, the publicly available new atlas and ASHS-T1 could have important utility in the early diagnosis and monitoring of AD and enhancing brain-behavior studies of these regions.