Akt/mTOR Pathway Agonist SC79 Inhibits Autophagy and Apoptosis of Oligodendrocyte Precursor Cells Associated with Neonatal White Matter Dysplasia.

White matter dysplasia (WMD) in preterm infants due to intrauterine inflammation is caused by excessive apoptosis of oligodendrocyte precursor cells (OPCs). In recent years, studies have found that excessive autophagy and apoptosis are highly interconnected and important in infection and inflammatory diseases in general. Therefore, in this study, we aimed to confirm whether regulation of autophagy by using the Akt phosphorylation agonist SC79 can inhibit abnormal apoptosis of OPCs and promote myelin maturation and white matter development in neonatal rats with WMD. We investigated the effect of inflammation on oligodendrocyte development in P0 neonatal rats by intracerebellar injection of LPS, and collected brain tissue at P2 and P5. Immunohistochemical and immunofluorescence staining were used to evaluate white matter damage, while immunofluorescence staining, terminal deoxynucleotidyl transferase dUTP nick end labeling analysis (TUNEL), and western blotting were used to evaluate autophagy and apoptosis. First, we observed that white matter development was arrested and white matter fiber maturation was impaired in LPS-inflicted pups compared with those in the sham-operated group. Second, treatment with SC79 reduced the levels of LC3II, caspase 3, caspase 9, and Bax/Bcl-2 and increased the levels of p62, p-Akt, and p-mTOR in the brain tissue of neonatal rats. Finally, SC79 treatment inhibited OPC apoptosis by increasing the binding of Beclin 1 to Bcl-2, which promoted OPC differentiation and maturation. However, the opposite results were observed after rapamycin administration. Taken together, our results suggest that SC79 can inhibit the abnormal apoptosis of OPCs caused by excessive autophagy through the Akt/mTOR pathway and that SC79 is a potential therapeutic agent for WMD in preterm infants.

Enhanced Biological Imaging via Aggregation-Induced Emission Active Porous Organic Cages.

Porous organic cages (POCs) have many advantages, including superior microenvironments, good monodispersity, and shape homogeneity, excellent molecular solubility, high chemical stability, and intriguing host-guest chemistry. These properties enable POCs to overcome the limitations of extended porous networks such as metal-organic frameworks (MOFs) and covalent organic frameworks (COFs). However, the applications of POCs in bioimaging remain limited due to the problems associated with their rigid and hydrophobic structures, thus leading to strong aggregation-caused quenching (ACQ) in aqueous biological media. To address this challenge, we report the preparation of aggregation-induced emission (AIE)-active POCs capable of stimuli responsiveness for enhanced bioimaging. We rationally design a hydrophilic, structurally flexible tetraphenylethylene (TPE)-based POC that is almost entirely soluble in aqueous solutions. This POC's conformationally flexible superstructure allows the dynamic rotation of the TPE-based phenyl rings, thus endowing impressive AIE characteristics for responses to environmental changes such as temperature and viscosity. We employ these notable features in the bioimaging of living cells and obtain good performance, demonstrating that the present AIE-active POCs are suitable candidates for further biological applications.

Differential Collective Cell Migratory Behaviors Modulated by Phospholipid Nanocarriers.

Phospholipid nanocarriers have been widely explored for theranostic and nanomedicine applications. These amphiphilic nanocarriers possess outstanding cargo encapsulation efficiency, high water dispersibility, and excellent biocompatibility, which render them promising for drug delivery and bioimaging applications. While the biological applications of phospholipid nanocarriers have been well documented, the fundamental aspects of the phospholipid-cell interactions beyond cytotoxicity have been less investigated. In particular, the effect of phospholipid nanocarriers on collective cell behaviors has not been elucidated. Herein, we evaluate the interactions of phospholipid nanocarriers possessing different functional groups and sizes with normal and cancerous immortalized breast epithelial cell sheets with varying metastatic potential. Specifically, we examine the impact of nanocarrier treatments on the collective migratory dynamics of these cell sheets. We observe that phospholipid nanocarriers induce differential collective cell migratory behaviors, where the migration speed of normal and cancerous breast epithelial cell sheets is retarded and accelerated, respectively. To a certain extent, the nanocarriers are able to alter the migration trajectory of the cancerous breast epithelial cells. Furthermore, phospholipid nanocarriers could modulate the stiffness of the nuclei, cytoplasm, and cell-cell junctions of the breast epithelial cell sheets, remodel their actin filament arrangement, and regulate the expressions of the actin-related proteins. We anticipate that this work will further shed light on nanomaterial-cell interactions and provide guidelines for rational and safer designs and applications of phospholipid nanocarriers for cancer theranostics and nanomedicine.

Fusobacterium nucleatum secretes amyloid-like FadA to enhance pathogenicity.

Fusobacterium nucleatum (Fn) is a Gram-negative oral commensal, prevalent in various human diseases. It is unknown how this common commensal converts to a rampant pathogen. We report that Fn secretes an adhesin (FadA) with amyloid properties via a Fap2-like autotransporter to enhance its virulence. The extracellular FadA binds Congo Red, Thioflavin-T, and antibodies raised against human amyloid ß42. Fn produces amyloid-like FadA under stress and disease conditions, but not in healthy sites or tissues. It functions as a scaffold for biofilm formation, confers acid tolerance, and mediates Fn binding to host cells. Furthermore, amyloid-like FadA induces periodontal bone loss and promotes CRC progression in mice, with virulence attenuated by amyloid-binding compounds. The uncleaved signal peptide of FadA is required for the formation and stability of mature amyloid FadA fibrils. We propose a model in which hydrophobic signal peptides serve as "hooks" to crosslink neighboring FadA filaments to form a stable amyloid-like structure. Our study provides a potential mechanistic link between periodontal disease and CRC and suggests anti-amyloid therapies as possible interventions for Fn-mediated disease processes.

Activation of Pyroptosis by Membrane-Anchoring AIE Photosensitizer Design: New Prospect for Photodynamic Cancer Cell Ablation.

Pyroptosis as a lytic and inflammatory form of cell death is a powerful tool to fight against cancer. However, pyroptosis is usually activated by chemotherapeutic drugs, which limits its anti-tumor applications due to drug resistance and severe side effects. Herein, we demonstrate that membrane targeting photosensitizers can induce pyroptosis for cancer cell ablation with noninvasiveness and low side effects. A series of membrane anchoring photosensitizers (TBD-R PSs) with aggregation-induced emission (AIE) characteristics were prepared through conjugation of TBD and phenyl ring with cationic chains. Upon light irradiation, cytotoxic ROS were produced in situ, resulting in direct membrane damage and superior cancer cell ablation. Detailed study revealed that pyroptosis gradually became the dominant cell death pathway along with the increase of TBD-R PSs membrane anchoring capability. This study offers a photo-activated pyroptosis-based intervention strategy for cancer cell ablation.

Constructing Adaptive Photosensitizers via Supramolecular Modification Based on Pillararene Host-Guest Interactions.

In order to promote the development of photodynamic therapy (PDT), undesired side effects like low tumor specificity and the "always-on" phenomenon should be avoided. An effective solution is to construct an adaptive photosensitizer that can be activated to generate reactive oxygen species (ROS) in the tumor microenvironment. Herein, we design and synthesize a supramolecular switch based on a host-guest complex containing a water-soluble pillar[5]arene (WP5) and an AIEgen photosensitizer (G). The formation of the host-guest complex WP5⊃G quenches the fluorescence and inhibits ROS generation of G. Benefitting from the pH-responsiveness of WP5, the binding site between G and WP5 changes in an acidic environment through a shuttle movement. Consequently, fluorescence and ROS generation of the host-guest complex can be switched on at pH 5.0. This work offers a new paradigm for the construction of adaptive photosensitizers by using a supramolecular method.

Mechanistic Understanding of the Biological Responses to Polymeric Nanoparticles.

Polymeric nanoparticles play important roles in the delivery of a multitude of therapeutic and imaging contrast agents. Although these nanomaterials have shown tremendous potential in disease diagnosis and therapy, there have been many reports on the failure of these nanoparticles in realizing their intended objectives due to an individual or a combination of factors, which have collectively challenged the merit of nanomedicine for disease theranostics. Herein, we investigate the interactions of polymeric nanoparticles with biological entities from molecular to organism levels. Specifically, the protein corona formation, in vitro endothelial uptake, and in vivo circulation time of these nanoparticles are systematically probed. We identify the crucial role of nanocarrier lipophilicity, zeta-potential, and size in controlling the interactions between nanoparticles and biological systems and propose a two-step framework in formulating a single nanoparticle system to regulate multiple biological effects. This study provides insight into the rational design and optimization of the performance of polymeric nanoparticles to advance their theranostic and nanomedicine applications.

Specific Near-Infrared Probe for Ultrafast Imaging of Lysosomal ß-Galactosidase in Ovarian Cancer Cells.

Reactivity based fluorescent probes have been widely investigated as a powerful and noninvasive tool for disease diagnosis in recent years. ß-Galactosidase (ß-gal), one of the typical lysosomal glycosidases, is reported to be a vital biomarker overexpressed in primary ovarian cancer cells. Fluorescent probes with excellent performance for endogenous ß-gal detection offer a unique option for visualization and diagnosis of primary ovarian cancer cells. Herein, a near-infrared fluorescent probe Lyso-Gal with lysosome-targeting ability was developed for lysosomal ß-gal detection and imaging in ovarian cancer cells (SKOV-3 cells). Lyso-Gal exhibits weak fluorescence in aqueous solution but emits bright NIR fluorescence at 725 nm after incubation with ß-gal. Highly selective imaging of ovarian cancer cells has been achieved upon incubation with Lyso-Gal for only 1 min. The detection time is extremely short. In comparison with a similar hemicyanine probe, Hx-Gal, without lysosome-targeting ability, Lyso-Gal realizes endogenous ß-gal visualization in lysosomes and shows brighter fluorescence than Hx-Gal in SKOV-3 cells. This work demonstrates the potential of Lyso-Gal for detection of primary ovarian cancer cells by using ß-gal as the biomarker.

Self-Assembly of Highly Stable Zirconium(IV) Coordination Cages with Aggregation Induced Emission Molecular Rotors for Live-Cell Imaging.

The self-assembly of highly stable zirconium(IV)-based coordination cages with aggregation induced emission (AIE) molecular rotors for in vitro bio-imaging is reported. The two coordination cages, NUS-100 and NUS-101, are assembled from the highly stable trinuclear zirconium vertices and two flexible carboxyl-decorated tetraphenylethylene (TPE) spacers. Extensive experimental and theoretical results show that the emissive intensity of the coordination cages can be controlled by restricting the dynamics of AIE-active molecular rotors though multiple external stimuli. Because the two coordination cages have excellent chemical stability in aqueous solutions (pH stability: 2-10) and impressive AIE characteristics contributed by the molecular rotors, they can be employed as novel biological fluorescent probes for in vitro live-cell imaging.

Precise Deciphering of Brain Vasculatures and Microscopic Tumors with Dual NIR-II Fluorescence and Photoacoustic Imaging.

Diagnostics of cerebrovascular structures and microscopic tumors with intact blood-brain barrier (BBB) significantly contributes to timely treatment of patients bearing neurological diseases. Dual NIR-II fluorescence and photoacoustic imaging (PAI) is expected to offer powerful strength, including good spatiotemporal resolution, deep penetration, and large signal-to-background ratio (SBR) for precise brain diagnostics. Herein, biocompatible and photostable conjugated polymer nanoparticles (CP NPs) are reported for dual-modality brain imaging in the NIR-II window. Uniform CP NPs with a size of 50 nm are fabricated from microfluidics devices, which show an emission peak at 1156 nm with a large absorptivity of 35.2 L g-1 cm-1 at 1000 nm. The NIR-II fluorescence imaging resolves hemodynamics and cerebral vasculatures with a spatial resolution of 23 µm at a depth of 600 µm. The NIR-II PAI enables successful noninvasive mapping of deep microscopic brain tumors (<2 mm at a depth of 2.4 mm beneath dense skull and scalp) with an SBR of 7.2 after focused ultrasound-induced BBB opening. This study demonstrates that CP NPs are promising contrast agents for brain diagnostics.

High-Resolution 3D NIR-II Photoacoustic Imaging of Cerebral and Tumor Vasculatures Using Conjugated Polymer Nanoparticles as Contrast Agent.

Exogenous contrast-agent-assisted NIR-II optical-resolution photoacoustic microscopy imaging (ORPAMI) holds promise to decipher wide-field 3D biological structures with deep penetration, large signal-to-background ratio (SBR), and high maximum imaging depth to depth resolution ratio. Herein, NIR-II conjugated polymer nanoparticle (CP NP) assisted ORPAMI is reported for pinpointing cerebral and tumor vasculatures. The CP NPs exhibit a large extinction coefficient of 48.1 L g-1 at the absorption maximum of 1161 nm, with an ultrahigh PA sensitivity up to 2 µg mL-1 . 3D ORPAMI of wide-field mice ear allows clear visualization of regular vasculatures with a resolution of 19.2 µm and an SBR of 29.3 dB at the maximal imaging depth of 539 µm. The margin of ear tumor composed of torsional dense vessels among surrounding normal regular vessels can be clearly delineated via 3D angiography. In addition, 3D whole-cortex cerebral vasculatures with large imaging area (48 mm2 ), good resolution (25.4 µm), and high SBR (22.3 dB) at a depth up to 1001 µm are clearly resolved through the intact skull. These results are superior to the recently reported 3D NIR-II fluorescence confocal vascular imaging, which opens up new opportunities for NIR-II CP-NP-assisted ORPAMI in various biomedical applications.

AIE Polymers: Synthesis, Properties, and Biological Applications.

Aggregation-caused quenching (ACQ) is a general phenomenon that is faced by traditional fluorescent polymers. Aggregation-induced emission (AIE) is exactly opposite to ACQ. AIE molecules are almost nonemissive in their molecularly dissolved state, but they can be induced to show high fluorescence in the aggregated or solid state. Incorporation of AIE phenomenon into polymer design has yielded various polymers with AIE characteristics. In this review, the recent progress of AIE polymers for biological applications is summarized.

Automated Segmentation of Coronary Arteries Based on Statistical Region Growing and Heuristic Decision Method.

The segmentation of coronary arteries is a vital process that helps cardiovascular radiologists detect and quantify stenosis. In this paper, we propose a fully automated coronary artery segmentation from cardiac data volume. The method is built on a statistics region growing together with a heuristic decision. First, the heart region is extracted using a multi-atlas-based approach. Second, the vessel structures are enhanced via a 3D multiscale line filter. Next, seed points are detected automatically through a threshold preprocessing and a subsequent morphological operation. Based on the set of detected seed points, a statistics-based region growing is applied. Finally, results are obtained by setting conservative parameters. A heuristic decision method is then used to obtain the desired result automatically because parameters in region growing vary in different patients, and the segmentation requires full automation. The experiments are carried out on a dataset that includes eight-patient multivendor cardiac computed tomography angiography (CTA) volume data. The DICE similarity index, mean distance, and Hausdorff distance metrics are employed to compare the proposed algorithm with two state-of-the-art methods. Experimental results indicate that the proposed algorithm is capable of performing complete, robust, and accurate extraction of coronary arteries.

An Active Contour Model Based on Adaptive Threshold for Extraction of Cerebral Vascular Structures.

Cerebral vessel segmentation is essential and helpful for the clinical diagnosis and the related research. However, automatic segmentation of brain vessels remains challenging because of the variable vessel shape and high complex of vessel geometry. This study proposes a new active contour model (ACM) implemented by the level-set method for segmenting vessels from TOF-MRA data. The energy function of the new model, combining both region intensity and boundary information, is composed of two region terms, one boundary term and one penalty term. The global threshold representing the lower gray boundary of the target object by maximum intensity projection (MIP) is defined in the first-region term, and it is used to guide the segmentation of the thick vessels. In the second term, a dynamic intensity threshold is employed to extract the tiny vessels. The boundary term is used to drive the contours to evolve towards the boundaries with high gradients. The penalty term is used to avoid reinitialization of the level-set function. Experimental results on 10 clinical brain data sets demonstrate that our method is not only able to achieve better Dice Similarity Coefficient than the global threshold based method and localized hybrid level-set method but also able to extract whole cerebral vessel trees, including the thin vessels.

Robust assessment of the expansion and retreat of Mediterranean climate in the 21st century.

The warm-temperate regions of the globe characterized by dry summers and wet winters (Mediterranean climate; MED) are especially vulnerable to climate change. The potential impact on water resources, ecosystems and human livelihood requires a detailed picture of the future changes in this unique climate zone. Here we apply a probabilistic approach to quantitatively address how and why the geographic distribution of MED will change based on the latest-available climate projections for the 21st century. Our analysis provides, for the first time, a robust assessment of significant northward and eastward future expansions of MED over both the Euro-Mediterranean and western North America. Concurrently, we show a significant 21st century replacement of the equatorward MED margins by the arid climate type. Moreover, future winters will become wetter and summers drier in both the old and newly established MED zones. Should these projections be realized, living conditions in some of the most densely populated regions in the world will be seriously jeopardized.

Multicomponent polymeric nanoparticles enhancing intracellular drug release in cancer cells.

Three kinds of amphiphilic copolymer, that is, poly(ε-caprolactone)-SS-poly(ethylene glycol) (PCL-SS-PEG), poly(ε-caprolactone)-polyethylenimine (PCL-PEI), and poly(ε-caprolactone)-polyethylenimine-folate (PCL-PEI-Fol) were synthesized and self-assembled into surface engineered hybrid nanoparticles (NPs). Morphological studies elucidated the stable, spherical, and uniform sandwich structure of the NPs. PCL-PEI and PCL-SS-PEG segments have introduced pH and reduction responsive characteristics in these NPs, while PCL-PEI-FA copolymers could provide specific targeting capability to cancer cells. The stimuli responsive capabilities of these NPs were carried out. Negative-to-positive charge reversible property, in response to the pH change, was investigated by zeta potential and nuclear magnetic resonance (NMR) measurements. The structure cleavage, due to redox gradient, was studied by dynamic light scattering (DLS) and transmission electron microscopy (TEM). These NPs showed controlled degradation, better drug release, less toxicity, and effective uptake in MCF-7 breast cancer cells. These multifunctional NPs showed promising potential in the treatment of cancer.