The efficient construction of enantiomerically enriched molecules from simple starting materials via catalytic asymmetric synthesis strategies is a key challenge in synthetic chemistry. Metallated ...azomethine ylides are commonly-used synthons for the preparation of N-heterocycles and α-amino acids. Remarkably, to date, the utilization of azomethine ylides for the facile access to chiral amines has proven elusive. Here, we report that a synergistic Cu/Ir-catalytic system combined with careful tuning of the steric congestion can be used to convert aldimine esters to a variety of chiral homoallylic amines via a cascade allylation/2-aza-Cope rearrangement. The elucidation of the distinct effects of each stereogenic center of the allylation intermediates on the stereochemical outcome and chirality transfer in the rearrangement further guided the selection of catalysts combination.
Background
Accurate glioma grading plays an important role in the clinical management of patients and is also the basis of molecular stratification nowadays.
Purpose/Hypothesis
To verify the ...superiority of radiomics features extracted from multiparametric MRI to glioma grading and evaluate the grading potential of different MRI sequences or parametric maps.
Study Type
Retrospective; radiomics.
Population
A total of 153 patients including 42, 33, and 78 patients with Grades II, III, and IV gliomas, respectively.
Field Strength/Sequence
3.0T MRI/T1‐weighted images before and after contrast‐enhanced, T2‐weighted, multi‐b‐value diffusion‐weighted and 3D arterial spin labeling images.
Assessment
After multiparametric MRI preprocessing, high‐throughput features were derived from patients' volumes of interests (VOIs). The support vector machine‐based recursive feature elimination was adopted to find the optimal features for low‐grade glioma (LGG) vs. high‐grade glioma (HGG), and Grade III vs. IV glioma classification tasks. Then support vector machine (SVM) classifiers were established using the optimal features. The accuracy and area under the curve (AUC) was used to assess the grading efficiency.
Statistical Tests
Student's t‐test or a chi‐square test were applied on different clinical characteristics to confirm whether intergroup significant differences exist.
Results
Patients' ages between LGG and HGG groups were significantly different (P < 0.01). For each patient, 420 texture and 90 histogram parameters were derived from 10 VOIs of multiparametric MRI. SVM models were established using 30 and 28 optimal features for classifying LGGs from HGGs and grades III from IV, respectively. The accuracies/AUCs were 96.8%/0.987 for classifying LGGs from HGGs, and 98.1%/0.992 for classifying grades III from IV, which were more promising than using histogram parameters or using the single sequence MRI.
Data Conclusion
Texture features were more effective for noninvasively grading gliomas than histogram parameters. The combined application of multiparametric MRI provided a higher grading efficiency. The proposed radiomic strategy could facilitate clinical decision‐making for patients with varied glioma grades.
Level of Evidence: 3
Technical Efficacy: Stage 2
J. Magn. Reson. Imaging 2018;48:1518–1528
Rational utilization of the rich light‐bio‐matter interplay taking place in single‐cell analysis represents a new technological direction in the field. The light‐fueled operation is expected to ...achieve advanced photoelectrochemical (PEC) single‐cell analysis with unknown possibilities. Here, a PEC nanoreactor capable of single‐cell sampling and near zero‐background Faradaic detection of intracellular microRNA (miR) is devised by the construction of a small reaction chamber accommodating the target‐triggered hybridization chain reaction for binding the metallointercalator of Ru(bpy)2(dppz)2+ as the signal reporter. Light stimulation of the dsDNA/metallointercalator adduct will induce the generation of photocurrents, underpinning a zero‐biased and near zero‐background PEC method toward Faradaic detection of non‐electrogenic miR at the single‐cell level. Using this nanotool, lower miR concentration in the near‐nucleus region than that in the main cytosol was revealed.
A photoelectrochemical nanoreactor was devised for single‐cell sampling and near zero‐background faradic detection of intracellular microRNA. This platform provided a new perspective for exploring light‐biomatter interplay toward single‐cell studies.
Ischemic stroke leads to neuronal damage induced by excitotoxicity, inflammation, and oxidative stress. Astrocytes play diverse roles in stroke and ischemia‐induced inflammation, and autophagy is ...critical for maintaining astrocytic functions. Our previous studies showed that the activation of G protein‐coupled receptor 30 (GPR30), an estrogen membrane receptor, protected neurons from excitotoxicity. However, the role of astrocytic GPR30 in maintaining autophagy and neuroprotection remained unclear. In this study, we found that the neuroprotection induced by G1 (GPR30 agonist) in wild‐type mice after a middle cerebral artery occlusion was completely blocked in GPR30 conventional knockout (KO) mice but partially attenuated in astrocytic or neuronal GPR30 KO mice. In cultured primary astrocytes, glutamate exposure induced astrocyte proliferation and decreased astrocyte autophagy by activating mammalian target of rapamycin (mTOR) and c‐Jun N‐terminal kinase (JNK) and inhibiting p38 mitogen‐activated protein kinase (MAPK) pathway. G1 treatment restored autophagy to its basal level by regulating the p38 pathway but not the mTOR and JNK signaling pathways. Our findings revealed a key role of GPR30 in neuroprotection via the regulation of astrocyte autophagy and support astrocytic GPR30 as a potential drug target against ischemic brain damage.
Main Points
Astrocytic GPR30 was involved in the neuroprotection.
Autophagic deficiency of astrocytes induced by glutamate promoted inflammatory cytokine release.
GPR30 activation restored autophagy balance in astrocytes by regulating the p38 MAPK pathway.
Hypoxic microenvironment severely reduces therapeutic efficacy of oxygen‐dependent photodynamic therapy in solid tumor due to the hampered cytotoxic oxygen radicals generation. Herein, a ...biocompatible nanoparticle (NP) is developed by combining bovine serum albumin, indocyanine green (ICG), and an oxygen‐independent radicals generator (AIPH) for efficient sequential cancer therapy, denoted as BIA NPs. Upon near‐infrared irradiation, the photothermal effect generated by ICG will induce rapid decomposition of AIPH to release cytotoxic alkyl radicals, leading to cancer cell death in both normoxic and hypoxic environments. Moreover, such nanosystem provides the highest AIPH loading capacity (14.9%) among all previously reported radical nanogenerators (generally from 5–8%). Additionally, the aggregation‐quenched fluorescence of ICG molecules in the NPs can be gradually released and recovered upon irradiation enabling real‐time drug release monitoring. More attractively, these BIA NPs exhibit remarkable anticancer effects both in vitro and in vivo, achieving 100% tumor elimination and 100% survival rate among 50 days treatment. These results highlight that this albumin‐based nanoplatform is promising for high‐performance cancer therapy circumventing hypoxic tumor environment and possessing great potential for future clinical translation.
A biocompatible free radical nanogenerator is developed based on albumin, indocyanine green, and thermal‐labile molecules for effective hypoxic cancer therapy. Under laser irradiation, this nanoagent can generate toxic free radicals in both normoxia and hypoxia. Meanwhile, the nanogenerator provides a high drug loading capability and real‐time drug release monitoring ability a which enables it with multifunctionality and high therapeutic performance.
Transforming growth factor beta (TGF‐β) plays an important role in the viral liver disease progression via controlling viral propagation and mediating inflammation‐associated responses. However, the ...antiviral activities and mechanisms of TGF‐β isoforms, including TGF‐β1, TGF‐β2 and TGF‐β3, remain unclear. Here, we demonstrated that all of the three TGF‐β isoforms were increased in Huh7.5 cells infected by hepatitis C virus (HCV), but in turn, the elevated TGF‐β isoforms could inhibit HCV propagation with different potency in infectious HCV cell culture system. TGF‐β isoforms suppressed HCV propagation through interrupting several different stages in the whole HCV life cycle, including virus entry and intracellular replication, in TGF‐β/SMAD signalling pathway–dependent and TGF‐β/SMAD signalling pathway–independent manners. TGF‐β isoforms showed additional anti‐HCV activities when combined with each other. However, the elevated TGF‐β1 and TGF‐β2, not TGF‐β3, could also induce liver fibrosis with a high expression of type I collagen alpha‐1 and α‐smooth muscle actin in LX‐2 cells. Our results showed a new insight into TGF‐β isoforms in the HCV‐related liver disease progression.
New tools for single‐cell interrogation enable deeper understanding of cellular heterogeneity and associated cellular behaviors and functions. Information of RNA expression in single cell could ...contribute to our knowledge of the genetic regulatory circuits and molecular mechanism of disease development. Although significant progresses have been made for intracellular RNA analysis, existing methods have a trade‐off between operational complexity and practical feasibility. We address this challenge by combining the ionic current rectification property of nanopipette reactor with duplex‐specific nuclease‐assisted hybridization chain reaction for signal amplification to realize a simple and practical intracellular nanosensor with minimal invasiveness, which enables single‐cell collection and electrochemical detection of intracellular RNA with cell‐context preservation. Systematic studies on differentiation of oncogenic miR‐10b expression levels in non‐malignant breast cells, metastatic breast cancer cells as well as non‐metastatic breast cancer cells were then realized by this nanotool accompanied by assessment of different drugs effects. This work has unveiled the ability of electrochemistry to probe intracellular RNA and opened new opportunities to study the gene expression and heterogeneous complexity under physiological conditions down to single‐cell level.
A DSN‐assisted ICR‐nanopipette was fabricated for tracking the drug‐induced variation of the oncogenic miR‐10b expression levels of a dynamic manner. This method unveils the ability of electrochemistry to probe intracellular RNA and to study the gene expression and heterogeneous complexity under physiological conditions down to single‐cell level.
Animal studies implicate meningeal lymphatic dysfunction in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (PD). However, there is no direct ...evidence in humans to support this role
. In this study, we used dynamic contrast-enhanced magnetic resonance imaging to assess meningeal lymphatic flow in cognitively normal controls and patients with idiopathic PD (iPD) or atypical Parkinsonian (AP) disorders. We found that patients with iPD exhibited significantly reduced flow through the meningeal lymphatic vessels (mLVs) along the superior sagittal sinus and sigmoid sinus, as well as a notable delay in deep cervical lymph node perfusion, compared to patients with AP. There was no significant difference in the size (cross-sectional area) of mLVs in patients with iPD or AP versus controls. In mice injected with α-synuclein (α-syn) preformed fibrils, we showed that the emergence of α-syn pathology was followed by delayed meningeal lymphatic drainage, loss of tight junctions among meningeal lymphatic endothelial cells and increased inflammation of the meninges. Finally, blocking flow through the mLVs in mice treated with α-syn preformed fibrils increased α-syn pathology and exacerbated motor and memory deficits. These results suggest that meningeal lymphatic drainage dysfunction aggravates α-syn pathology and contributes to the progression of PD.
Coordinatively unsaturated ferrous (CUF) sites confined in nanosized matrices are active centers in a wide range of enzyme and homogeneous catalytic reactions. Preparation of the analogous active ...sites at supported catalysts is of great importance in heterogeneous catalysis but remains a challenge. On the basis of surface science measurements and density functional calculations, we show that the interface confinement effect can be used to stabilize the CUF sites by taking advantage of strong adhesion between ferrous oxides and metal substrates. The interface-confined CUF sites together with the metal supports are active for dioxygen activation, producing reactive dissociated oxygen atoms. We show that the structural ensemble was highly efficient for carbon monoxide oxidation at low temperature under typical operating conditions of a proton-exchange membrane fuel cell.
Ylides at a crossing: An unprecedented 1,3‐dipolar cycloaddition (cross‐cycloaddition) between two different ylides (see scheme) was realized by using the chiral CuI/tBu‐Phosferrox complex as the ...catalyst under mild reaction conditions. This catalytic system provides an expeditious approach to the construction of highly functionalized 1,2,4‐triazinane derivatives in good yields with excellent diastereoselectivities and enantioselectivities.
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