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The encapsulation and/or surface modification can stabilize and protect the phosphorescence bio‐probes but impede their intravenous delivery across biological barriers. Here, a new class of biocompatible rhenium (ReI) diimine carbonyl complexes is developed, which can efficaciously permeate normal vessel walls and then functionalize the extravascular collagen matrixes as in situ oxygen sensor. Without protective agents, ReI‐diimine complex already exhibits excellent emission yield (34%, λem = 583 nm) and large two‐photon absorption cross‐sections (σ2 = 300 GM @ 800 nm) in water (pH 7.4). After extravasation, remarkably, the collagen‐bound probes further enhanced their excitation efficiency by increasing the deoxygenated lifetime from 4.0 to 7.5 µs, paving a way to visualize tumor hypoxia and tissue ischemia in vivo. The post‐extravasation functionalization of extracellular matrixes demonstrates a new methodology for biomaterial‐empowered phosphorescence sensing and imaging. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to investigate the significance of circulating micro RNAs (miRNAs) in the pathogenesis of reversible cerebral vasoconstriction syndrome (RCVS). Methods: We prospectively recruited 3 independent cohorts of patients with RCVS and age‐matched and sex‐matched controls in a single medical center. Next‐generation small RNA sequencing followed by quantitative polymerase chain reaction (PCR) was used to identify and validate differentially expressed miRNAs, which was cross‐validated in migraine patients in ictal stage or interictal stage. Computational analysis was used to predict the target genes of miRNAs, followed by in vitro functional analysis. Results: We identified a panel of miRNAs including miR‐130a‐3p, miR‐130b‐3p, let‐7a‐5p, let‐7b‐5p, and let‐7f‐5p that well differentiated patients with RCVS from controls (area under the receiver operating characteristics curve [AUC] was 0.906, 0.890, and 0.867 in the 3 cohorts, respectively). The abundance of let‐7a‐5p, let‐7b‐5p, and let‐7f‐5p, but not miR‐130a‐3p nor miR‐130b‐3p, was significantly higher in patients with ictal migraine compared with that of controls and patients with interictal migraine. Target prediction and pathway enrichment analysis suggested that the transforming growth factor‐β signaling pathway and endothelin‐1 responsible for vasomotor control might link these miRNAs to RCVS pathogenesis, which was confirmed in vitro by transfecting miRNAs mimics or incubating the patients' cerebrospinal fluid (CSF) in 3 different vascular endothelial cells. Moreover, miR‐130a‐3p was associated with imaging‐proven disruption of the blood‐brain barrier (BBB) in patients with RCVS and its overexpression led to reduced transendothelial electrical resistance (ie, increased permeability) in in vitro human BBB model. Interpretation: We identified the circulating miRNA signatures associated with RCVS, which may be functionally linked to its headache, BBB integrity, and vasomotor function. ANN NEUROL 2021;89:459–473 [ABSTRACT FROM AUTHOR]

CDGSH iron-sulfur domain-containing protein 2 (Cisd2) is pivotal to mitochondrial integrity and intracellular Ca2+ homeostasis. In the heart of Cisd2 knockout mice, Cisd2 deficiency causes intercalated disc defects and leads to degeneration of the mitochondria and sarcomeres, thereby impairing its electromechanical functioning. Furthermore, Cisd2 deficiency disrupts Ca2+ homeostasis via dysregulation of sarco/endoplasmic reticulum Ca2+-ATPase (Serca2a) activity, resulting in an increased level of basal cytosolic Ca2+ and mitochondrial Ca2+ overload in cardiomyocytes. Most strikingly, in Cisd2 transgenic mice, a persistently high level of Cisd2 is sufficient to delay cardiac aging and attenuate age-related structural defects and functional decline. In addition, it results in a younger cardiac transcriptome pattern during old age. Our findings indicate that Cisd2 plays an essential role in cardiac aging and in the heart’s electromechanical functioning. They highlight Cisd2 as a novel drug target when developing therapies to delay cardiac aging and ameliorate age-related cardiac dysfunction. [ABSTRACT FROM AUTHOR]

Polydopamine (PDA) preserves universal coating and metal-binding ability, and is suitable for application in synthesizing multifunctional agents. Herein, utilizing mesoporous silica assisted deposition to enhance both heterogeneous nucleation and loading amounts of PDA, the magnetic resonance (MR) T1 component (PDA-Fe3+) and MR T2/computed tomography (CT)/multiphoton luminescence (MPL) component (FePt) have been successfully integrated in aqueous solution. This four-in-one (T1, T2, CT, MPL) imaging nanocomposite, FePt@mSiO2 @PDA-polyethylene glycol (PEG), demonstrated its multi-imaging power both in vitro/in vivo. According to our in vitro/in vivo results, FePt@mSiO2@PDA-PEG reveals water-content-dependent property in T1 MR imaging, which suggests the necessity of having dual-modal MR ability in a single particle for the precision diagnosis. Most importantly, this dual (T1,T2)-MRI/CT contrast agent is demonstrated complementary to each other in the in vivo testing. PDA coated mesoporous silica also offers an advantage of delayed degradation that prevents adverse effects caused by silica fragments before excretion. The potential of this nanocomposites in both drug carrier and photothermal agent was further evaluated by using doxorubicin and monitoring solution temperature after irradiating 808 nm continuous-wave, respectively The merits of controlled polymerization, enhanced PDA loading, and biofavorable degradation make this methodology promising to other nanoparticle@mSiO2 for a wide range of bioapplications. [ABSTRACT FROM AUTHOR]

The pathogenesis of Parkinson's disease (PD) is not completely understood, Zinc (Zn2+) and dopamine (DA) have been shown to involve in the degeneration of dopaminergic cells. By microarray analysis, we identified Gadd45b as a candidate molecule that mediates Zn2+ and DA-induced cell death; the mRNA and protein levels of Gadd45b are increased by Zn2+ treatment and raised to an even higher level by Zn2+ plus DA treatment. Zn2+ plus DA treatment-induced PC12 cell death was enhanced when there was over-expression of Gadd45b and was decreased by knock down of Gadd45b. MAPK p38 and JNK signaling was able to cross-talk with Gadd45b during Zn2+ and DA treatment. The synergistic effects of Zn2+ and DA on PC12 cell death can be accounted for by an activation of the Gadd45b-induced cell death pathway and an inhibition of p38/JNK survival pathway. Furthermore, the in vivo results show that the levels of Gadd45b protein expression and phosphorylation of p38 were increased in the substantia nigra by the infusion of Zn2+/DA in the mouse brain and the level of Gadd45b mRNA is significantly higher in the substantia nigra of male PD patients than normal controls. The novel role of Gadd45b and its interactions with JNK and p38 will help our understanding of the pathogenesis of PD and help the development of future treatments for PD. [ABSTRACT FROM AUTHOR]

Midbrain dopaminergic (DA) neurons are the key to finely tune the voluntary movement, habit and motivation. The progressive and selective degeneration of these neurons is a pathological hallmark of Parkinson’s disease (PD). The susceptibility of DA neurons in the SNpc may result from differences in how Ca 2+ is handled. However, very little information is available about the mechanisms involved in the regulation of intracellular Ca 2+ concentration ([Ca 2+ ] i ) in DA neurons. In this study, the relative contributions of various Na + /Ca 2+ exchangers and their interplay with internal Ca 2+ stores, endoplasmic reticulum (ER) and the mitochondria, in the regulation of the [Ca 2+ ] i of mouse mesencephalic neurons were characterized. Both the K + -dependent Na + /Ca 2+ exchanger (NCKX) and the K + -independent Na + /Ca 2+ exchanger (NCX) can be detected and are functional in DA and non-DA neurons. NCX accounts for the larger component of Na + /Ca 2+ exchange activity. Single-cell RT-PCR analysis showed each individual neuron expressed a distinct set of the Na + /Ca 2+ exchangers. Furthermore, the Na + /Ca 2+ exchangers play prominent roles in removing [Ca 2+ ] i induced by glutamate but not [Ca 2+ ] i induced by depolarization. The mitochondria serve as a major Ca 2+ sink and are functionally located close to NCX. In contrast, the ER is functionally located close to NCKX and acts primarily as a Ca 2+ source with marginal effects. This study reveals that the Na + /Ca 2+ exchangers, the ER and the mitochondria, which cooperate interactively, act similarly when regulating [Ca 2+ ] i in mesencephalic DA and non-DA neurons. The heterogeneous expression of multiple types of Na + /Ca 2+ exchangers and the quantitative differences found in [Ca 2+ ] i regulation, together with other risk factors specific to DA neurons such as dopamine oxidation resulting in oxidative stress, may drive these cells to undergo selective degeneration. [ABSTRACT FROM AUTHOR]

Using in vivo second harmonic generation (SHG) and third harmonic generation (THG) microscopies, we tracked the course of collagen remodeling over time in the same melanoma microenvironment within an individual mouse. The corresponding structural and morphological changes were quantitatively analyzed without labeling using an orientation index (OI), the gray level co-occurrence matrix (GLCM) method, and the intensity ratio of THG to SHG (RTHG/SHG). In the early stage of melanoma development, we found that collagen fibers adjacent to a melanoma have increased OI values and SHG intensities. In the late stages, these collagen networks have more directionality and less homogeneity. The corresponding GLCM traces showed oscillation features and the sum of squared fluctuation VarGLCM increased with the tumor sizes. In addition, the THG intensities of the extracellular matrices increased, indicating an enhanced optical inhomogeneity. Multiplying OI, VarGLCM, and RTHG/SHG together, the combinational collagen remodeling (CR) index at 4 weeks post melanoma implantation showed a 400-times higher value than normal ones. These results validate that our quantitative indices of SHG and THG microscopies are sensitive enough to diagnose the collagen remodeling in vivo. We believe these indices have the potential to help the diagnosis of skin cancers in clinical practice. [ABSTRACT FROM AUTHOR]

The bioactivity screening of fractions from two inter-tidal sponges collected from the north of China Yellow Sea and one sponge collected from the South Chinese Sea was reported in this study. In sponge Hymeniacidon perleve there were 9 fractions out of 15 from CHCl3 extract with anti Staphylococcus aureus activity, 9 fractions out of 19 from BuOH extract with anti Escherichia coli activity, and three fractions from CHCl3 extract which had moderate to strong activity in inhibiting Bacillus subtilis, Candida albicans, and Aspergilus niger. The fractions of Reniochalina sp. showed bioactivity against bacteria and fungi. The fractions of Acanthella acuta Schmidt showed bioactivity against S. aureus and fungi. One compound from H. perleve obtained by the bioactively directing isolation was tested for bioactivity against the human hepatoma cell line Qgy7701 (IC50 10.1 μg/ml), Burkitt''s lymphoma cell line Raji (IC50 9.76 μg/ml) and chronic myelogenous leukemia K562 (IC50 1.90 μg/ml). [Copyright &y& Elsevier]