A nickel‐catalyzed 1,4‐carbofluoroalkylation of 1,3‐enynes to access structurally diverse fluoroalkylated allenes has been established. This method has demonstrated high catalytic reactivity, mild ...reaction conditions, broad substrate scope, and excellent functional‐group tolerance. The key to success is the use of a nickel catalyst to generate different fluoroalkyl radicals from readily available and structurally diverse fluoroalkyl halides to access 1,4‐difunctionalization of 1,3‐enynes by a radical relay. This strategy provides facile synthesis of structurally diverse multisubstituted allenes, and offers a solution for batch production of various fluorinated bioactive molecules for drug discovery by further transformations.
Radical relay: A nickel‐catalyzed 1,4‐carbofluoroalkylation of 1,3‐enynes provides fluoroalkylated allenes under mild reaction conditions and with excellent functional‐group tolerance. The key to success is the use of the nickel catalyst to generate different fluoroalkyl radicals from fluoroalkyl halides to realize the 1,4‐difunctionalization by a radical relay.
Abstract
Fast, low-cost, reliable, and multi-component nanopatterning techniques for functional colloidal nanoparticles have been dreamed about by scientists and engineers for decades. Although ...countless efforts have been made, it is still a daunting challenge to organize different nanocomponents into a predefined structure with nanometer precision over the millimeter and even larger scale. To meet the challenge, we report a nanoprinting technique that can print various functional colloidal nanoparticles into arbitrarily defined patterns with a 200 nm (or smaller) pitch (>125,000 DPI), 30 nm (or larger) pixel size/linewidth, 10 nm position accuracy and 50 nm overlay precision. The nanopatterning technique combines dielectrophoretic enrichment and deep surface-energy modulation and therefore features high efficiency and robustness. It can form nanostructures over the millimeter-scale by simply spinning, brushing or dip coating colloidal nanoink onto a substrate with minimum error (error ratio < 2 × 10
−6
). This technique provides a powerful yet simple construction tool for large-scale positioning and integration of multiple functional nanoparticles toward next-generation optoelectronic and biomedical devices.
Monofluorinated alkyl compounds are of great importance in pharmaceuticals, agrochemicals and materials. Herein, we describe a direct nickel‐catalyzed monofluoromethylation of unactivated alkyl ...halides using a low‐cost industrial raw material, bromofluoromethane, by demonstrating a general and efficient reductive cross‐coupling of two alkyl halides. Results with 1‐bromo‐1‐fluoroalkane also demonstrate the viability of monofluoroalkylation, which further established the first example of reductive C(sp3)‐C(sp3) cross‐coupling fluoroalkylation. These transformations demonstrate high efficiency, mild conditions, and excellent functional‐group compatibility, especially for a range of pharmaceuticals and biologically active compounds. Mechanistic studies support a radical pathway. Kinetic studies reveal that the reaction is first‐order dependent on catalyst and alkyl bromide whereas the generation of monofluoroalkyl radical is not involved in the rate‐determining step. This strategy provides a general and efficient method for the synthesis of aliphatic fluorides.
A direct nickel‐catalyzed monofluoroalkylation of unactivated alkyl halides has been established, by demonstrating the first example of reductive C(sp3)−C(sp3) cross‐coupling fluoroalkylation. These transformations exhibited high efficiency, mild conditions, and excellent functional‐group compatibility, especially for a range of pharmaceuticals and biologically active compounds.
Monofluoroalkanes are important in many pharmaceuticals, agrochemicals and functional materials. However, the lack of easily available and transformable monofluoroalkylating reagents that facilitate ...a broad array of transformations has hampered the application of monofluoroalkylation. Herein, we report a general and efficient method of preparing diverse aliphatic monofluorides with monofluoroalkyl triflate as the synthetic scaffold. Using both nickel‐catalyzed hydromonofluoroalkylation of unactivated alkenes and copper‐catalyzed C−C bond formation, the general diversification of the monofluoroalkylating scaffold has been exhibited. The broad utility of this monofluoroalkylating reagent is shown by concise conversion into various conventional fluoroalkylating reagents and construction of monofluoro‐alkoxy, ‐alkylamino motifs with commercially available heteroatom‐based coupling partners.
A general method allows preparation of diverse monofluorides based on the monofluoroalkyl triflate scaffold. Both nickel‐catalyzed hydromonofluoroalkylation of unactivated alkenes and copper‐catalyzed monofluoroalkylation of Grignard reagents were studied. Further utilities including conversion into conventional fluoroalkylating reagents and construction of monofluoro‐alkoxy, ‐alkylamino motifs.
Dendritic spines are postsynaptic compartments of excitatory synapses that undergo dynamic changes during development, including rapid spinogenesis in early postnatal life and significant pruning ...during adolescence. Spine pruning defects have been implicated in developmental neurological disorders such as autism, yet much remains to be uncovered regarding its molecular mechanism. Here, we show that spine pruning and maturation in the mouse somatosensory cortex are coordinated via the cadherin/catenin cell adhesion complex and bidrectionally regulated by sensory experience. We further demonstrate that locally enhancing cadherin/catenin-dependent adhesion or photo-stimulating a contacting channelrhodopsin-expressing axon stabilized the manipulated spine and eliminated its neighbors, an effect requiring cadherin/catenin-dependent adhesion. Importantly, we show that differential cadherin/catenin-dependent adhesion between neighboring spines biased spine fate in vivo. These results suggest that activity-induced inter-spine competition for β-catenin provides specificity for concurrent spine maturation and elimination and thus is critical for the molecular control of spine pruning during neural circuit refinement.
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•Spine pruning and maturation in the mammalian brain are coordinated events•Competition for cadherins and catenins mediates spine maturation and elimination•Inter-spine competition for β-catenin in vivo biases spine fate during pruning•Activity-dependent acceleration of spine pruning and maturation requires β-catenin
The pruning or elimination of dendritic spines is always coordinated with the maturation of surviving neighboring spines. This process is bidirectionally regulated by neural activity and mediated by inter-spine competition for cadherin/catenin cell adhesion complexes.
Circular dichroism spectroscopy is one of the most important tools in nanoscopic chiroptics. However, there is lack of simple, fast and reliable method for measuring the circular dichroism responses ...of single nanostructures. To tackle this issue, we report a polarization-dispersive imaging spectrometer which is capable of measuring the scattering circular dichroism response of a single chiral nanostructure with a single shot. Using this technique, we studied the scattering circular dichroism spectra of a model system, the vertically coupled plasmonic nanorod pair. Both experimental and theoretical results indicate that the polarization-dispersive spectrometer measures the imaginary part of nonlocal susceptibility of the structure. We further applied the technique to 3-dimensional Au nanorod structures assembled on DNA origami templates together with correlated scanning electron microscopic measurements. Rich chiroptical phenomena were unveiled at the single nanostructure level.
Sleep quality declines with age; however, the underlying mechanisms remain elusive. We found that hyperexcitable hypocretin/orexin (Hcrt/OX) neurons drive sleep fragmentation during aging. In aged ...mice, Hcrt neurons exhibited more frequent neuronal activity epochs driving wake bouts, and optogenetic activation of Hcrt neurons elicited more prolonged wakefulness. Aged Hcrt neurons showed hyperexcitability with lower KCNQ2 expression and impaired M-current, mediated by KCNQ2/3 channels. Single-nucleus RNA-sequencing revealed adaptive changes to Hcrt neuron loss in the aging brain. Disruption of
genes in Hcrt neurons of young mice destabilized sleep, mimicking aging-associated sleep fragmentation, whereas the KCNQ-selective activator flupirtine hyperpolarized Hcrt neurons and rejuvenated sleep architecture in aged mice. Our findings demonstrate a mechanism underlying sleep instability during aging and a strategy to improve sleep continuity.
Abstract
Shank3 is a shared risk gene for autism spectrum disorders and schizophrenia. Sleep defects have been characterized for autism models with Shank3 mutations; however, evidence has been ...lacking for the potential sleep defects caused by Shank3 mutation associated with schizophrenia and how early in development these defects may occur. Here we characterized the sleep architecture of adolescent mice carrying a schizophrenia-linked, R1117X mutation in Shank3. We further employed GRABDA dopamine sensor and fiber photometry to record dopamine release in the nucleus accumbens during sleep/wake states. Our results show that homozygous mutant R1117X mice have significantly reduced sleep in the dark phase during adolescence, altered electroencephalogram power, especially during the rapid-eye-movement sleep, and dopamine hyperactivity during sleep but not during wakefulness. Further analyses suggest that these adolescent defects in sleep architecture and dopaminergic neuromodulation tightly correlate with the social novelty preference later in adulthood and predict adult social performance during same-sex social interactions. Our results provide novel insights into the sleep phenotypes in mouse models of schizophrenia and the potential use of developmental sleep as a predictive metric for adult social symptoms. Together with recent studies in other Shank3 models, our work underscores the idea that Shank3-involved circuit disruptions may be one of the shared pathologies in certain types of schizophrenia and autism. Future research is needed to establish the causal relationship among adolescent sleep defects, dopaminergic dysregulation, and adult behavioral changes in Shank3 mutation animals and other models.
Graphical abstract
Graphical Abstract
Aims
Ischemic stroke is a life‐threatening disease with limited therapeutic strategies. Blood‐brain barrier (BBB) disruption is a critical pathological process that contributes to poor outcomes in ...ischemic stroke. We previously showed that the microglial inhibition of the inflammasome sensor absent in melanoma 2 (AIM2) suppressed the inflammatory response and protected against ischemic stroke. However, whether AIM2 is involved in BBB disruption during cerebral ischemia is unknown.
Methods
Middle cerebral artery occlusion (MCAO) and oxygen‐glucose deprivation/reoxygenation (OGD/R) were used to mimic cerebral ischemia in mice and brain microvascular endothelial cells (HBMECs), respectively. The infarct volume, neurological deficits, and BBB permeability were measured in mice after MCAO. Transendothelial electrical resistance (TEER) and neutrophil adhesion to the HBMEC monolayer were assessed after OGD/R treatment. Western blot and immunofluorescence analyses were conducted to evaluate the expression of related proteins.
Results
AIM2 was shown to be expressed in brain endothelial cells and upregulated after ischemic stroke in the mouse brain. AIM2 deletion reduced the infarct volume, improved neurological and motor functions, and decreased BBB disruption. In vitro, OGD/R significantly increased the protein levels of AIM2 and ICAM‐1 and decreased those of the tight junction (TJ) proteins ZO‐1 and occludin. AIM2 knockdown effectively protected BBB integrity by promoting the expression of TJ proteins and decreasing ICAM‐1 expression and neutrophil adhesion. Mechanistically, AIM2 knockdown reversed the OGD/R‐induced increases in ICAM‐1 expression and STAT3 phosphorylation in brain endothelial cells. Furthermore, treatment with the p‐STAT3 inhibitor AG490 mitigated the effect of AIM2 on BBB breakdown.
Conclusion
Our findings indicated that inhibiting AIM2 preserved the BBB integrity after ischemic stroke, at least partially by modulating STAT3 activation and that AIM2 may be a promising therapeutic target for cerebral ischemic stroke.
AIM2 deletion in brain endothelial cells reversed ischemia‐induced BBB injury by suppressing ICAM‐1 expression and neutrophil adhesion in a STAT3 signaling‐ dependent manner.
Purpose
This study aimed to evaluate the Ki-67 proliferation state in patients with gastrointestinal stromal tumors (GISTs) using radiomics prediction signatures based on contrast-enhanced computed ...tomography (CE-CT).
Materials and methods
This single-center, retrospective study involved 103 patients (48 men and 55 women, mean age 61.1 ± 10.6 years) who had pathologically confirmed GISTs after curative resection, including 63 with low Ki-67 proliferation level (Ki-67 labeling index ≤ 6%) and 40 with high Ki-67 proliferation level (Ki-67 labeling index > 6%). Radiomics features of the delineated lesions were preoperatively extracted from three-phase CE-CT images, including the arterial, venous, and delayed phases. The most relevant features were selected to construct the radiomics signatures using a logistic regression algorithm. Significant demographic characteristics and semantic features on CT were selected to develop a nomogram along with the optimal radiomics feature. We calculated the sensitivity, specificity, accuracy, F1 score, and area under the receiver operating characteristic (ROC) curve to evaluate the predictive performance of radiomics signatures.
Results
Ten quantitative radiomics features (two first-order and eight texture features) were selected to construct radiomics signatures. The radiomics signature based on the three-phase CE-CT images showed better predictive performance than that based on the single-phase CE-CT images, with an area under the curve (AUC) of 0.83 (95% CI 0.73–0.92) and F1 score of 82% in the training dataset and an AUC of 0.80 (95% CI 0.63–0.95) and F1 score of 75% in the testing dataset. The nomogram showed good calibration.
Conclusion
Radiomics signatures using CE-CT images are generalizable and could be used in clinical practice to determine the proliferation state of Ki-67 in GISTs.
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