This short review focuses on enantiopure planar chiral 2.2paracyclophanes (pCps), a fascinating class of molecules that possess an unusual three‐dimensional core and intriguing physicochemical ...properties. In the first part of the review, different synthetic strategies for preparing optically active pCps are described. Although classical resolution methods based on the synthesis and separation of diastereoisomeric products still dominate the field, recent advances involving the kinetic resolution of racemic compounds and the desymmetrization of meso derivatives open up new possibilities to access enantiopure key intermediates on synthetically useful scales. Due to their advantageous properties including high configurational and chemical stability, 2.2paracyclophanes are increasingly employed in various research fields, ranging from stereoselective synthesis to material sciences. The applications of 2.2paracyclophanes in asymmetric organocatalysis are described in the second part of the review. While historically enantiopure pCps have been mainly employed by organic chemists as chiral ligands in transition‐metal catalysis, these compounds can also be used as efficient catalysts in metal‐free reactions and may inspire the development of new transformations in the near future.
Planar chiral 2.2paracyclophanes (pCps) constitute a fascinating class of molecules which possesses an unusual three‐dimensional core and intriguing physicochemical properties. This short review focuses on the synthesis of enantiopure pCps and their application in asymmetric organocatalysis.
Abstract
Ionospheric chemistry plays an unexpectedly important role in the evolution of planetary habitability. This study is dedicated to a detailed modeling of the nightside Martian ionospheric ...structure and composition, a topic that has been poorly explored due to the absence of relevant measurements, but now becomes tractable owing to the unprecedented measurements made by the Mars Atmosphere and Volatile Evolution. Two-stream kinetic calculations and time-dependent fluid calculations are coupled to derive the nightside density profiles at 100–300 km for a large number of ion species, assuming solar wind electron precipitation as the only viable ionizing source in the ideal nonmagnetized atmosphere. Our calculations indicate the presence of a well-defined ionospheric peak at 146 km with a peak density of 8500 cm
−3
, as driven by the strong atmospheric “absorption” of precipitating electrons at low altitudes. The distribution of nonterminal species is roughly under chemical equilibrium below 170 km, whereas for terminal species such as NO
+
and HCO
+
, diffusion is effective at essentially all altitudes, in direct contrast to the dayside behavior. In the more realistic magnetized atmosphere, the ionospheric peak seldom exists due to the patchiness of electron precipitation. In particular, our model results agree fairly well with the MAVEN measurements, especially in view of the coincidence between electron depletion and thermal plasma void seen along many MAVEN orbits. Compared to the dayside, the nightside ionospheric composition has a much higher proportion of NO
+
and lower proportion of CO
2
+
, likely indicative of nightside enhancement of atmospheric O and N.
The cystine transporter solute carrier family 7 member 11 (SLC7A11; also called xCT) protects cancer cells from oxidative stress and is overexpressed in many cancers. Here we report a surprising ...finding that, whereas moderate overexpression of SLC7A11 is beneficial for cancer cells treated with H
O
, a common oxidative stress inducer, its high overexpression dramatically increases H
O
-induced cell death. Mechanistically, high cystine uptake in cancer cells with high overexpression of SLC7A11 in combination with H
O
treatment results in toxic buildup of intracellular cystine and other disulfide molecules, NADPH depletion, redox system collapse, and rapid cell death (likely disulfidptosis). We further show that high overexpression of SLC7A11 promotes tumor growth but suppresses tumor metastasis, likely because metastasizing cancer cells with high expression of SLC7A11 are particularly susceptible to oxidative stress. Our findings reveal that SLC7A11 expression level dictates cancer cells' sensitivity to oxidative stress and suggests a context-dependent role for SLC7A11 in tumor biology.
Gas explosion has always been an important factor restricting coal mine production safety. The application of machine learning techniques in coal mine gas concentration prediction and early warning ...can effectively prevent gas explosion accidents. Nearly all traditional prediction models use a regression technique to predict gas concentration. Considering there exist very few instances of high gas concentration, the instance distribution of gas concentration would be extremely imbalanced. Therefore, such regression models generally perform poorly in predicting high gas concentration instances. In this study, we consider early warning of gas concentration as a binary-class problem, and divide gas concentration data into warning class and non-warning class according to the concentration threshold. We proposed the probability density machine (PDM) algorithm with excellent adaptability to imbalanced data distribution. In this study, we use the original gas concentration data collected from several monitoring points in a coal mine in Datong city, Shanxi Province, China, to train the PDM model and to compare the model with several class imbalance learning algorithms. The results show that the PDM algorithm is superior to the traditional and state-of-the-art class imbalance learning algorithms, and can produce more accurate early warning results for gas explosion.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, and chemotherapy is still an important treatment. It is urgent to develop new medicines because of the limitation and ...side effects of chemotherapy. 2′-Hydroxyflavanone (2HF) is a citrus-bioflavonoid that is considered to have anti-cancer efficacy. Compared to human pancreatic ductal epithelial cells hTERT-HPNE, more significant growth-inhibitory effects were seen in PDAC cells BxPC-3 and MIA PaCa-2. We showed that apoptosis was induced and that the cell cycle was arrested when cells were treated with 2HF. The expression of the molecular proteins cleaved PARP, cleaved Caspase3, Bax, Bcl-2, CyclinD1, and p27 changed correspondingly. Also, we observed anti-metastatic effects and changes in MMP9, E-cadherin, N-cadherin and Vimentin when cells were treated with a low dose of 2HF. Suppression of STAT3 and EGFR phosphorylation was also identified as a result of treatment with a combination of 2HF and EGFR inhibitors. The in vivo antitumor effects in KPC mice were consistent with those observed in vitro. 2HF has impactful anti-cancer efficacy and sensitizes human pancreatic cancer cells to EGFR inhibitors through the inhibition of STAT3.
2′-Hydroxyflavanone (2HF), a natural flavonoid extract from oranges and citrus fruits, was confirmed to have antitumor effects in pancreatic cancer in vivo and in vitro.•2HF inhibited the viability and clonogenicity of pancreatic cancer cells•2HF induced apoptosis of pancreatic cancer cells•2HF caused the cell cycle arrest of pancreatic cancer cells•2HF suppressed the invasion and migration of pancreatic cancer cells•2HF enhanced pancreatic cancer cell chemosensitivity by inhibiting activation of STAT3
Prostate cancer (PCa) is one of the most common malignancy in men. However, the molecular mechanism of its pathogenesis has not yet been elucidated. In this study, we demonstrated that CYLD, a novel ...deubiquitinating enzyme, impeded PCa development and progression via tumor suppression. First, we found that CYLD was downregulated in PCa tissues, and its expression was inversely correlated with pathological grade and clinical stage. Moreover, we discovered that CYLD inhibited tumor cell proliferation and enhanced the sensitivity to cell ferroptosis in PCa in vitro and in vivo, respectively. Mechanistically, we demonstrated that CYLD suppressed the ubiquitination of YAP protein, then promoted ACSL4 and TFRC mRNA transcription. Then, we demonstrated that CYLD could enhance the sensitivity of PCa xenografts to ferroptosis in vivo. Furthermore, we discovered for the first time that there was a positive correlation between CYLD expression and ACSL4 or TFRC expression in human PCa specimens. The results of this study suggested that CYLD acted as a tumor suppressor gene in PCa and promoted cell ferroptosis through Hippo/YAP signaling.
Abstract Fully targeted mRNA therapeutics necessitate simultaneous organ-specific accumulation and effective translation. Despite some progress, delivery systems are still unable to fully achieve ...this. Here, we reformulate lipid nanoparticles (LNPs) through adjustments in lipid material structures and compositions to systematically achieve the pulmonary and hepatic (respectively) targeted mRNA distribution and expression. A combinatorial library of degradable-core based ionizable cationic lipids is designed, following by optimisation of LNP compositions. Contrary to current LNP paradigms, our findings demonstrate that cholesterol and phospholipid are dispensable for LNP functionality. Specifically, cholesterol-removal addresses the persistent challenge of preventing nanoparticle accumulation in hepatic tissues. By modulating and simplifying intrinsic LNP components, concurrent mRNA accumulation and translation is achieved in the lung and liver, respectively. This targeting strategy is applicable to existing LNP systems with potential to expand the progress of precise mRNA therapy for diverse diseases.
As the malignant tumor with the highest incidence in male, prostate cancer poses a significant threat to the reproductive health of elderly men. Our previous studies have shown that promoting ...necroptosis of cancer cells can effectively inhibit cancer cell proliferation. This study includes lentivirus-mediated knockdown of β2AR which resulted in stable transfectants that exhibited an increased ability to form clones compared to that of the negative control group. In the protein and mRNA levels, necroptosis associated RIP and mixed lineage kinase domain-like (MLKL) were significantly higher in the treatment group than they were in the control group. Furthermore, cells treated with propranolol exhibited necrotic morphology as observed by transmission electron microscopy. The combination of β2AR suppression and necroptosis inhibitors resulted in a more potent suppression of cell proliferation compared to that observed in the control and negative control groups. Additionally, it elevated in the necrosis rate as determined by flow cytometry. Immunofluorescence staining revealed enhanced RIP and MLKL expression in the sh-β2AR group compared to levels in the negative control group. Co-immunoprecipitation experiments detected an interaction between β2AR and RIP. MLKL and RIPK3 levels were significantly higher in xenograft tumor sections from the sh-β2AR group compared to levels in the sh-NC group. To conclude, our research indicates the proliferation of PC-3 and DU-145 cprostate cancer cells can be suppressed by inhibiting β2AR, and this occurs through the RIP/MLKL-mediated pathway of necroptosis.
This paper selects 112 listed companies in China’s a-share new energy vehicle sector from 2009 to 2018 as a research sample, and uses panel data regression analysis models to empirically test the ...effects of government subsidies on corporate R&D investment and corporate innovation performance. It shows that government subsidies have a significant promotion effect on enterprises R&D investment; government subsidies have a significant inhibition effect on enterprises’ innovation performance.
Concomitant inhibition of MAPK and PI3K signaling pathways has been recognized as a promising strategy for cancer therapy, which effectively overcomes the drug resistance of MAPK signaling ...pathway-related inhibitors. Herein, we report the scaffold-hopping generation of a series of 1
-pyrazolo3,4-
pyrimidine dual ERK/PI3K inhibitors. Compound
was the most promising candidate, with potent inhibitory activities against both ERK2 and PI3Kα which displays superior anti-proliferative profiles against HCT116 and HEC1B cancer cells. Meanwhile, compound
possessed acceptable pharmacokinetic profiles and showed more efficacious anti-tumor activity than GDDC-0980 and the corresponding drug combination (BVD-523 + GDDC-0980) in HCT-116 xenograft model, with a tumor growth inhibitory rate of 51% without causing observable toxic effects. All the results indicated that
was a highly effective anticancer compound and provided a promising basis for further optimization towards dual ERK/PI3K inhibitors.
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