A combinatorial nickel‐catalyzed monofluoroalkylation of aryl halides with unactivated fluoroalkyl halides by reductive cross‐coupling has been developed. This method demonstrated high efficiency, ...mild conditions, and excellent functional‐group tolerance, thus enabling the late‐stage monofluoroalkylation of diverse drugs. The key to success was the combination of diverse readily available bidentate and monodentate pyridine‐type nitrogen ligands with nickel, which in situ generated a variety of readily tunable catalysts to promote fluoroalkylation with broad scope with respect to both coupling partners. This combinatorial catalysis strategy offers a solution for nickel‐catalyzed reductive cross‐coupling reactions and provides an efficient way to synthesize fluoroalkylated druglike molecules for drug discovery.
Combining forces: Aryl halides undergo efficient monofluoroalkylation with unactivated fluoroalkyl halides by reductive cross‐coupling with excellent functional‐group tolerance (see scheme). The mild and efficient transformation was developed by the combination of diverse readily available bidentate and monodentate pyridine‐type nitrogen ligands with nickel to generate a variety of readily tunable catalysts in situ.
As a kind of coming-of-age story with the theme of narrating the growth of characters, Bildungsroman mainly reflects the protagonist’s mental journey after a series of challenging events. This ...perspective has been widely used by scholars to interpret characters in literary works. This paper creatively applies this perspective to character analysis in Japanese epidemic film
I am a Hero
. The thesis makes an in-depth discussion on the protagonist image in the film from multiple structural elements of the Bildungsroman, such as people guiding the way and spiritual construction of personal consciousness, then analyzes the process of protagonist Hideo’s spiritual growth and finally summarize the characteristics of Bildungsroman.
The recent development in the nanotechnology has paved the way for large number of new materials and devices of desirable properties which have useful functions for electrochemical sensor and ...biosensor applications. In this paper, a novel enzymeless glucose sensor is developed on the discovery that the FeOOH nanowire in fact possesses an intrinsic enzyme mimetic electrocatalytic activity similar to that found in natural peroxidases. The electrode modified with FeOOH nanowires showed a wide linear range (15
μM–3
mM) and high sensitivity (12.13
μA
mM
−
1
) for glucose sensing. Other excellent performances such as highly reproducible response, long-term stability, sound mechanical and chemical stability are also observed, and the interferences of ascorbic acid and dopamine can almost be completely avoided. The good analytical performance, low cost and straightforward preparation method made this novel electrode material promising for the development of effective glucose sensors.
Although the Trans-Himalayan region (THR) is an important endemic and rendezvous area of peste des petits ruminants (PPR), monitoring and prevention measurements are difficult to execute because of ...the rough geographical conditions. Besides, a heterogeneous breeding system and the poor veterinary service of susceptible animals compound the existing problems. Here, we propose a forecasting system to define the key points of PPR prevention and aid the countries in saving time, labor, and products to achieve the goal of the global eradication project of PPR. The spatial distribution of PPR was predicted in the THR for the first time using a niche model that was constructed with a combination of eco-geographical, anthropoid, meteorological, and host variables. The transboundary least-cost paths (LCPs) of small ruminants in the THR were also calculated. Our results reveal that the low-elevation area of the THR had a higher PPR risk and was mainly dominated by human variables. The high-elevation area had lower risk and was mainly dominated by natural variables. Eight LCPs representing corridors among India, Nepal, Bhutan, Bangladesh, and China were obtained. This confirmed the potential risk of transboundary communication by relying on PPR contamination on the grasslands for the first time. The predicted potential risk communication between the two livestock systems and landscapes (high and low elevation) might play a role in driving PPR transboundary transmission.
Understanding the neural substrates of depression is crucial for diagnosis and treatment. Here, we review recent studies of functional and effective connectivity in depression, in terms of functional ...integration in the brain. Findings from these studies, including our own, point to the involvement of at least four networks in patients with depression. Elevated connectivity of a ventral limbic affective network appears to be associated with excessive negative mood (dysphoria) in the patients; decreased connectivity of a frontal‐striatal reward network has been suggested to account for loss of interest, motivation, and pleasure (anhedonia); enhanced default mode network connectivity seems to be associated with depressive rumination; and diminished connectivity of a dorsal cognitive control network is thought to underlie cognitive deficits especially ineffective top‐down control of negative thoughts and emotions in depressed patients. Moreover, the restoration of connectivity of these networks—and corresponding symptom improvement—following antidepressant treatment (including medication, psychotherapy, and brain stimulation techniques) serves as evidence for the crucial role of these networks in the pathophysiology of depression.
Aristolactam I (ALI) is an active component derived from some Traditional Chinese medicines (TCMs), and also the important metabolite of aristolochic acid. Long-term administration of ...medicine-containing ALI was reported to be related to aristolochic acid nephropathy (AAN), which was attributed to ALI-induced nephrotoxicity. However, the toxic mechanism of action involved is still unclear. Recently, pathogenic ferroptosis mediated lipid peroxidation was demonstrated to cause kidney injury. Therefore, this study explored the role of ferroptosis induced by mitochondrial iron overload in ALI-induced nephrotoxicity, aiming to identify the possible toxic mechanism of ALI-induced chronic nephropathy. Our results showed that ALI inhibited HK-2 cell activity in a dose-dependent manner and significantly suppressed glutathione (GSH) levels, accompanying by significant increases in intracellular 4-hydroxynonenal (4-HNE) and intracellular iron ions. Moreover, the ALI-mediated cytotoxicity could be reversed by deferoxamine mesylate (DFO). Compared with other inhibitors, Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, obviously alleviated ALI-induced cytotoxicity. Furthermore, we have shown that ALI could remarkably increase the levels of superoxide anion and ferrous ions in mitochondria, and induce mitochondrial damage and condensed mitochondrial membrane density, the morphological characteristics of ferroptosis, all of which could be reversed by DFO. Interestingly, ALI dose-dependently inhibited these protein contents of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutathione peroxidase 4 (GPX4), which could be partly rescued by Tin-protoporphyrin IX (SnPP) and mitoTEMPO co-treatment. In conclusion, our results demonstrated that mitochondrial iron overload-mediated antioxidant system inhibition would assist ALI-induced ferroptosis in renal tubular epithelial cells, and Nrf2-HO-1/GPX4 antioxidative system could be an important intervention target to prevent medicine containing ALI-induced nephropathy.
Considerable signal crosstalk exists in the regulatory network of senescence and stress response. Numerous senescence‐associated genes are also involved in plant stress tolerance. However, the ...underlying mechanisms and application potential of these genes in stress‐tolerant crop breeding remain poorly explored. We found that overexpression of SENESCENCE‐SUPPRESSED PROTEIN PHOSPHATASE (SSPP), a negative regulator of leaf senescence, significantly improved plant salt tolerance by increasing reactive oxygen species (ROS) scavenging in both Arabidopsis and soybean. However, overexpression of SSPP severely suppressed normal plant growth, limiting its direct use in agriculture. We previously revealed that the N‐terminal 1–14 residues of ACS7 (termed ‘N7’) negatively regulated its protein stability through the ubiquitin/proteasome pathway, and the N7‐mediated protein degradation was suppressed by environmental and senescence signals. To avoid the adverse effects of SSPP, the N7 element was fused to the N‐terminus of SSPP. We demonstrated that N7‐SSPP fusion gene effectively rescued SSPP‐induced growth suppression but maintained enhanced salt tolerance in Arabidopsis and soybean. Particularly, N7‐SSPP enhanced tolerance to long‐term salt stress and increased seed yield in soybean. These results suggest that N7‐SSPP overcomes the disadvantages of SSPP on plant growth inhibition and effectively improves salt tolerance through enhanced ROS scavenging, providing an effective strategy of using posttranslational regulatory element for salt‐tolerant crop breeding.
Numerous senescence‐associated genes are also involved in stress tolerance, but the underlying mechanisms and application potentials are poorly investigated. We found that SSPP, a negative regulator of leaf senescence, enhances plant salt tolerance through ROS scavenging. Fusing N7, a regulatory element in the N‐degron pathway, to SSPP rescued SSPP‐induced growth suppression but did not affect salt tolerance in Arabidopsis and soybean. Notably, N7‐SSPP enhanced long‐term salt tolerance and increased yield in soybean. This study supported that manipulation of key senescence‐associated genes can effectively modulate plant stress responses and provided an effective strategy of using regulatory elements in the N‐degron pathway for salt‐tolerant crop breeding.
Drug–drug interaction (DDI) often causes serious adverse reactions and thus results in inestimable economic and social loss. Currently, comprehensive DDI evaluation has become a major challenge in ...pharmaceutical research due to the time-consuming and costly process of the experimental assessment and it is of high necessity to develop effective in silico methods to predict and evaluate DDIs accurately and efficiently. In this study, based on a large number of substrates and inhibitors related to five important CYP450 isozymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4), a series of high-performance predictive models for metabolic DDIs were constructed by two machine learning methods (random forest and XGBoost) and 4 different types of descriptors (MOE_2D, CATS, ECFP4 and MACCS). To reduce the uncertainty of individual models, the consensus method was applied to yield more reliable predictions. A series of evaluations illustrated that the consensus models were more reliable and robust for the DDI predictions of new drug combination. For the internal validation, the whole prediction accuracy and AUC value of the DDI models were around 0.8 and 0.9, respectively. When it was applied to the external datasets, the model accuracy was 0.793 and 0.795 for multi-level validation and external validation, respectively. Furthermore, we also compared our model with some recently published tools and then applied the final model to predict FDA-approved drugs and proposed 54,013 possible drug pairs with potential DDIs. In summary, we developed a powerful DDI predictive model from the perspective of the CYP450 enzyme family and it will help a lot in the future drug development and clinical pharmacy research.
Graphical Abstract
Fe(2)O(3) was generally considered to be biologically and electrochemically inert, and its electrocatalytic functionality has been rarely realized directly in the past. In this work, Fe(2)O(3) ...nanowire arrays were synthesized and electrochemically characterized. The as prepared Fe(2)O(3) nanomaterial was proved to be an ideal electrode material due to the intrinsic peroxidase-like catalytic activity. The Fe(2)O(3) nanowire array modified glucose sensor exhibited excellent biocatalytic performance towards the oxidation of glucose with a response time of <6 s, a linear range between 0.015-8 mM, and sensitivity of 726.9 μA mM(-1)cm(-1). Additionally, a high sensing selectivity towards glucose oxidation in the presence of ascorbic acid (AA) and dopamine (DA) has also been obtained at their maximum physiological concentrations, which makes the Fe(2)O(3) nanomaterial promising for the development of effective electrochemical sensors for practical applications.
The Chinese Government has introduced numerous policy incentives to promote the development and adoption of electric vehicles (EVs), especially aggressive subsidization policies. Stimulated by such ...policies, sales of EVs exceeded 500,000 in 2016. However, the subsidies for EVs will be abrogated after 2020. In order to maintain market stability, the EV-related policy system needs innovation. Nonetheless, it is still unclear how effective different policy incentives are.
By conducting a discrete choice experiment involving 247 respondents and using a mixed logit model, this paper investigates the effectiveness of several potential policy incentives except subsidization policies, as well as the influence of socio-psychologist determinants. The results help to offer suggestions for the EV-related policy reformation.
As expected, the probability of stated EV-acceptance increases if policy incentives are provided in the choice experiment. EVs are exempted from purchase restrictions (license plate control policy) and driving restrictions in China, and these two transport policy incentives have the most significant positive effects on the EV-acceptance. Discounted/free electric charging also has great contribution. Preferential bus lane access gains increasing attention. Vehicle purchase tax exemption should be resumed because of its positive influence. Comparatively speaking, the financial incentives (e.g., reduced parking fees) in the EV using stage play a weaker role.
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