The first enantioselective construction of a new class of axially chiral naphthyl‐indole skeletons has been established by organocatalytic asymmetric coupling reactions of 2‐naphthols with ...2‐indolylmethanols (up to 99 % yield, 97:3 e.r.). This approach not only affords a new type of axially chiral heterobiaryl backbone, but also provides a new catalytic enantioselective strategy for constructing axially chiral biaryl scaffolds by making use of the C3‐electrophilicity of 2‐indolylmethanols.
Axed: The title compounds have been accessed by organocatalytic asymmetric coupling reactions of 2‐naphthols with 2‐indolylmethanols. This approach not only affords a new type of axially chiral heterobiaryl backbone, but also provides a new catalytic enantioselective strategy for constructing axially chiral biaryl scaffolds by making use of the C3‐electrophilicity of 2‐indolylmethanols. CPA=chiral phosphoric acid, M.S.=molecular sieves.
A catalytic asymmetric 4+2 cyclization of para‐quinone methide (p‐QM) derivatives with 3‐alkyl‐2‐vinylindoles in the presence of a chiral phosphoric acid has been established, and this method ...provides chiral chroman frameworks in good yields (up to 98%) with high diastereoselectivities (up to >95:5 dr) and excellent enantioselectivities (up to 96% ee). This reaction represents the first catalytic asymmetric 4+2 cyclization of p‐QM derivatives with electron‐rich alkenes, which will enrich the field of catalytic asymmetric reactions of p‐QM derivatives. In addition, this catalytic asymmetric cyclization was successfully applied to 3‐alkyl‐2‐vinylindoles. More importantly, this reaction will offer a useful method for the construction of enantioenriched chroman frameworks.
Spastic limb paralysis due to injury to a cerebral hemisphere can cause long-term disability. We investigated the effect of grafting the contralateral C7 nerve from the nonparalyzed side to the ...paralyzed side in patients with spastic arm paralysis due to chronic cerebral injury.
We randomly assigned 36 patients who had had unilateral arm paralysis for more than 5 years to undergo C7 nerve transfer plus rehabilitation (18 patients) or to undergo rehabilitation alone (18 patients). The primary outcome was the change from baseline to month 12 in the total score on the Fugl-Meyer upper-extremity scale (scores range from 0 to 66, with higher scores indicating better function). Results The mean increase in Fugl-Meyer score in the paralyzed arm was 17.7 in the surgery group and 2.6 in the control group (difference, 15.1; 95% confidence interval, 12.2 to 17.9; P<0.001). With regard to improvements in spasticity as measured on the Modified Ashworth Scale (an assessment of five joints, each scored from 0 to 5, with higher scores indicating more spasticity), the smallest between-group difference was in the thumb, with 6, 9, and 3 patients in the surgery group having a 2-unit improvement, a 1-unit improvement, or no change, respectively, as compared with 1, 6, and 7 patients in the control group (P=0.02). Transcranial magnetic stimulation and functional imaging showed connectivity between the ipsilateral hemisphere and the paralyzed arm. There were no significant differences from baseline to month 12 in power, tactile threshold, or two-point discrimination in the hand on the side of the donor graft.
The mean increase in Fugl-Meyer score in the paralyzed arm was 17.7 in the surgery group and 2.6 in the control group (difference, 15.1; 95% confidence interval, 12.2 to 17.9; P<0.001). With regard to improvements in spasticity as measured on the Modified Ashworth Scale (an assessment of five joints, each scored from 0 to 5, with higher scores indicating more spasticity), the smallest between-group difference was in the thumb, with 6, 9, and 3 patients in the surgery group having a 2-unit improvement, a 1-unit improvement, or no change, respectively, as compared with 1, 6, and 7 patients in the control group (P=0.02). Transcranial magnetic stimulation and functional imaging showed connectivity between the ipsilateral hemisphere and the paralyzed arm. There were no significant differences from baseline to month 12 in power, tactile threshold, or two-point discrimination in the hand on the side of the donor graft.
In this single-center trial involving patients who had had unilateral arm paralysis due to chronic cerebral injury for more than 5 years, transfer of the C7 nerve from the nonparalyzed side to the side of the arm that was paralyzed was associated with a greater improvement in function and reduction of spasticity than rehabilitation alone over a period of 12 months. Physiological connectivity developed between the ipsilateral cerebral hemisphere and the paralyzed hand. (Funded by the National Natural Science Foundation of China and others; Chinese Clinical Trial Registry number, 13004466 .).
In this work, we established catalytic asymmetric 4+1 cyclization of ortho‐quinone methides (o‐QMs) with 3‐chlorooxindoles and a catalytic asymmetric domino oxidation/4+1 cyclization reaction of ...2‐alkylphenols with 3‐chlorooxindoles, which constructed a spirooxindole‐based 2,3‐dihydrobenzofuran scaffold in good yield (up to 97%), with excellent diastereoselectivity (up to >95:5 dr) and high enantioselectivity (up to 99% ee). This work is not only the first highly enantioselective 4+1 cyclization of o‐QMs but has also realized the first catalytic asymmetric domino 4+1 cyclization of o‐QMs. In addition, both of the reactions provide efficient stereoselective methods for constructing spirooxindole‐based 2,3‐dihydrobenzofuran scaffolds with optical purity.
The in situ self‐assembly of exogenous molecules is a powerful strategy for manipulating cellular behavior. However, the direct self‐assembly of photochemically inert constituents into supramolecular ...nano‐photosensitizers (PSs) within cancer cells for precise photodynamic therapy (PDT) remains a challenge. Herein, we developed a glycosylated Aza‐BODIPY compound (LMBP) capable of self‐assembling into J‐aggregate nanofibers in situ for cell membrane destruction and type I PDT. LMBP selectively entered human hepatocellular carcinoma HepG2 cells and subsequently self‐assembled into intracellular J‐aggregate nanovesicles and nanofibers through supramolecular interactions. Detailed studies revealed that these J‐aggregate nanostructures generated superoxide radicals (O2−⋅) exclusively through photoinduced electron transfer, thus enabling effective PDT. Furthermore, the intracellular nanofibers exhibited an aggregation‐induced retention effect, which resulted in selective toxicity to HepG2 cells by disrupting their cellular membranes and synergizing with PDT for powerful tumor suppression efficacy in vivo.
We designed a lactosylated Aza‐BODIPY compound that self‐assembles in situ to form J‐aggregate nanofibers acting as type I photosensitizers. The J‐aggregate nanofibers exhibited remarkable superoxide anion radical (O2−.) generation efficiency, the ability to damage the tumor cell membrane, and long‐term retention at tumor sites. This efficient synergistic therapeutic effect was confirmed in HepG2 cells and tumor‐bearing mice.
The homeostatic link between oxidative stress and autophagy plays an important role in cellular responses to a wide variety of physiological and pathological conditions. However, the regulatory ...pathway and outcomes remain incompletely understood. Here, we show that reactive oxygen species (ROS) function as signaling molecules that regulate autophagy through ataxia‐telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway activated during metabolic and hypoxic stress. We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1‐Bcl‐2 autophagy‐regulatory complex formation in a ROS‐dependent fashion. We further demonstrate that CHK2‐mediated autophagy has an unexpected role in reducing ROS levels via the removal of damaged mitochondria, which is required for cell survival under stress conditions. Finally, CHK2−/− mice display aggravated infarct phenotypes and reduced Beclin 1 p‐Ser90/Ser93 in a cerebral stroke model, suggesting an in vivo role of CHK2‐induced autophagy in cell survival. Taken together, these results indicate that the ROS‐ATM‐CHK2‐Beclin 1‐autophagy axis serves as a physiological adaptation pathway that protects cells exposed to pathological conditions from stress‐induced tissue damage.
Synopsis
Whether hypoxia and nutrient starvation are coupled to cellular autophagy remains unclear. Here, DNA damage response kinases ATM and CHK2 are shown to trigger autophagy in response to reactive oxygen species (ROS) accumulation, suggesting a novel physiological adaptation pathway toward metabolic stress.
Depletion of CHK2 or ATM impairs oxidative stress‐induced autophagy in MEFs.
CHK2 binds and phosphorylates Beclin1 at Ser90/Ser93, suppressing Beclin1‐Bcl‐2 autophagy regulatory complex formation.
CHK2‐induced autophagy limits intracellular ROS levels by clearing damaged mitochondria.
CHK2‐induced autophagy protects against cell death and tissue damage following cerebral ischemia.
ROS accumulation activates protective autophagy to prevent stress‐induced tissue damage.
The distortion in machining aeronautical aluminum alloy parts (AAAPs) is one of the serious challenges in the aviation industry, and the residual stresses produced in multimanufacturing steps are the ...main cause. In order to get a comprehensive understanding of the problems about residual stresses and distortion in machining AAAPs, the state-of-the-art in several aspects including the generation reasons of residual stresses, the factors influencing distortion during machining, the measurement methods of residual stresses, the prediction and controlling methods of distortion are summarized in this paper. The generation mechanism of the bulk residual stress inner materials and the machining-induced residual stresses, as well as the factors affecting two kinds of residual stresses are stated. Also, the influences of residual stresses and machining process conditions on distortion are analyzed. Furthermore, the common residual stress measurement methods and its application scope are summarized. Significantly, the differences, advantages, and disadvantages of various prediction methods are analyzed. The methods of controlling distortion before and after machining are summarized. Finally, the paper gives out further research on the distortion in machining AAAPs in aeronautical manufacturing.
Background and Aims
NAFLD is considered as the hepatic manifestation of the metabolic syndrome, which includes insulin resistance, obesity and hyperlipidemia. NASH is a progressive stage of NAFLD ...with severe hepatic steatosis, hepatocyte death, inflammation, and fibrosis. Currently, no pharmacological interventions specifically tailored for NASH are approved. Ovarian tumor domain, ubiquitin aldehyde binding 1 (OTUB1), the founding member of deubiquitinases, regulates many metabolism‐associated signaling pathways. However, the role of OTUB1 in NASH is unclarified.
Methods and Results
We demonstrated that mice with Otub1 deficiency exhibited aggravated high‐fat diet–induced and high‐fat high‐cholesterol (HFHC) diet–induced hyperinsulinemia and liver steatosis. Notably, hepatocyte‐specific overexpression of Otub1 markedly alleviated HFHC diet–induced hepatic steatosis, inflammatory responses, and liver fibrosis. Mechanistically, we identified apoptosis signal–regulating kinase 1 (ASK1) as a key candidate target of OTUB1 through RNA‐sequencing analysis and immunoblot analysis. Through immunoprecipitation–mass spectrometry analysis, we further found that OTUB1 directly bound to tumor necrosis factor receptor–associated factor 6 (TRAF6) and suppressed its lysine 63–linked polyubiquitination, thus inhibiting the activation of ASK1 and its downstream pathway.
Conclusions
OTUB1 is a key suppressor of NASH that inhibits polyubiquitinations of TRAF6 and attenuated TRAF6‐mediated ASK1 activation. Targeting the OTUB1‐TRAF6‐ASK1 axis may be a promising therapeutic strategy for NASH.
Retrosynthesis analysis is an important task in organic chemistry with numerous industrial applications. Previously, machine learning approaches employing natural language processing techniques ...achieved promising results in this task by first representing reactant molecules as strings and subsequently predicting reactant molecules using text generation or machine translation models. Chemists cannot readily derive useful insights from traditional approaches that rely largely on atom-level decoding in the string representations, because human experts tend to interpret reactions by analyzing substructures that comprise a molecule. It is well-established that some substructures are stable and remain unchanged in reactions. In this paper, we developed a substructure-level decoding model, where commonly preserved portions of product molecules were automatically extracted with a fully data-driven approach. Our model achieves improvement over previously reported models, and we demonstrate that its performance can be boosted further by enhancing the accuracy of these substructures. Analyzing substructures extracted from our machine learning model can provide human experts with additional insights to assist decision-making in retrosynthesis analysis.
The characteristics of winter nighttime enhancement (WNE) of the midlatitude ionosphere at 300, 550, and 750 km altitude are presented, based on the radio occultation data from the Constellation ...Observing System for Meteorology, Ionosphere, and Climate. WNE at 750 km altitude has earlier start time and larger increasing rate than that at 550 km, possibly due to the downward plasma diffusion from above that dominates the most upper part of the ionosphere. Theoretical calculation of the plasma transport at 300 km altitude reveals the largest effect of downward diffusion at 45° geomagnetic latitude, consistent with the latitudinal distribution of WNE. Meanwhile, the wind‐driven plasma transport also contributes to WNE, at 30°W–180°W geographic longitude in the Southern Hemisphere. The strength and end time of WNE vary with longitude, and are correlated with the longitudinal variations of the enhancement in the conjugate (summer) hemisphere. This may be attributed to the transport processes in the interhemispheric geomagnetic flux tubes, which redistribute and balance the plasma between the conjugate hemispheres at night. The plasma flux from above is hence an important plasma source for further understanding of both the winter and summer nighttime enhancements.
Key Points
Stronger winter nighttime enhancement with earlier start time is observed at 750 km than at 550 km altitude
The downward diffusive flux dominates the formation of the enhancement, while the neutral wind also contributes at certain longitudes
The plasma flux from above could be an important plasma source for both the winter and summer nighttime enhancements
![Catalytic Asymmetric [4+2] ...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1615-4150/small "Catalytic Asymmetric [4+2] Cyclization of para‐Quinone Methide Derivatives with 3‐Alkyl‐2‐vinylindoles")
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