The Brook rearrangement has already become established as one of the most important molecular rearrangements in synthetic chemistry and has been applied in the generation of complexes, drug ...discovery, material science, and natural products synthesis. Compared to the widely known ionic mechanism, the radical Brook rearrangement is less explored because of the difficulty in generating alkoxyl radical species. This Minireview summarizes the early developments and general concept of the radical Brook rearrangement and highlights recent advances in photocatalytic reactions and transition‐metal‐catalyzed cross‐coupling reactions involving radical Brook rearrangements. We hope this survey will inspire further developments in this emerging area.
The radical Brook rearrangement is a unique molecular arrangement, but it is not highly explored in synthetic chemistry. This Minireview summarizes the early developments and general concept of radical Brook rearrangements and highlights the recent advances in photocatalytic reactions and transition‐metal catalyzed cross‐coupling reactions involving radical Brook rearrangements.
The challenge in the artificial CO2 reduction to fuel is achieving high selective electrocatalysts. Here, a highly selective Cu2O/CuO heterostructure electrocatalyst is developed for CO2 ...electroreduction. The Cu2O/CuO nanowires modified by Ni nanoparticles exhibit superior catalytic performance with high faradic efficiency (95% for CO). Theoretical and experimental analyses show that the hybridization of Cu2O/CuO nanowires and Ni nanoparticles can not only adjust the d‐band center of electrocatalysts to enhance the intrinsic catalytic activity but also improve the adsorption of COOH* intermediates and suppress the hydrogen evolution reaction to promote the CO conversion efficiency during CO2 reduction reaction. An in situ Raman spectroscopic study further confirms the existence of COOH* species and the engineering intermediates adsorption. This work offers new insights for facile designing of nonprecious transition metal compound heterostructure for CO2 reduction reaction through adjusting the reaction pathway.
A highly selective Cu2O/CuO heterostructure electrocatalyst is developed for CO2 electroreduction, which exhibits faradic efficiency (95% for CO). The hybridization of Cu2O/CuO nanowires and Ni nanoparticles could improve the adsorption of COOH* intermediates to promote the CO conversion efficiency. An in situ Raman spectroscopic study further confirms the existence of COOH* species and the engineering intermediates adsorption.
Herein, we report a modular photocatalytic platform for the site‐selective pyridination of saturated hydrocarbon compounds employing organic photoredox catalysis to forge new carbon‐carbon bonds. The ...site‐selective C−H pyridination could couple benzylic/allylic C−H bonds with pyridylphosphonium salts, which installed directly and regioselectively from C−H heteroarenes through a radical‐radical cross coupling mechanism. This synthetic methodology could tolerate a variety of functional groups, complex heteroarenes, even late‐stage functionalization of pharmaceuticals selectively.
Angiogenesis plays an important role in the occurrence, development and metastasis of hepatocellular carcinoma (HCC). According to previous studies, miR-378a participates in tumorigenesis and tumor ...metastasis, but its exact role in HCC angiogenesis remains poorly understood.
qRT-PCR was used to investigate the expression of miR-378a-3p in HCC tissues and cell lines. The effects of miR-378a-3p on HCC in vitro and in vivo were examined by Cell Counting Kit-8 (CCK-8), Transwell, tube formation and Matrigel plug assays, RNA sequencing, bioinformatics, luciferase reporter, immunofluorescence and chromatin immunoprecipitation (ChIP) assays were used to detect the molecular mechanism by which miR-378a-3p inhibits angiogenesis.
We confirmed that miR-378a-3p expression was significantly downregulated and associated with higher microvascular density (MVD) in HCC; miR-378a-3p downregulation indicated a short survival time in HCC patients. miR-378a-3p knockdown led to a significant increase in angiogenesis in vitro and in vivo. We found that miR-378a-3p directly targeted TNF receptor associated factor 1 (TRAF1) to attenuate NF-κB signaling, and then downregulated secreted vascular endothelial growth factor. DNA methyltransferase 1 (DNMT1)-mediated hypermethylation of miR-378a-3p was responsible for downregulating miR-378a-3p. Moreover, a series of investigations indicated that p65 initiated a positive feedback loop that could upregulate DNMT1 to promote hypermethylation of the miR-378a-3p promoter.
Our study indicates a novel DNMT1/miR-378a-3p/TRAF1/NF-κB positive feedback loop in HCC cells, which may become a potential therapeutic target for HCC.
For complex financial systems, the negative and positive return-volatility correlations, i.e., the so-called leverage and anti-leverage effects, are particularly important for the understanding of ...the price dynamics. However, the microscopic origination of the leverage and anti-leverage effects is still not understood, and how to produce these effects in agent-based modeling remains open. On the other hand, in constructing microscopic models, it is a promising conception to determine model parameters from empirical data rather than from statistical fitting of the results.
To study the microscopic origination of the return-volatility correlation in financial systems, we take into account the individual and collective behaviors of investors in real markets, and construct an agent-based model. The agents are linked with each other and trade in groups, and particularly, two novel microscopic mechanisms, i.e., investors' asymmetric trading and herding in bull and bear markets, are introduced. Further, we propose effective methods to determine the key parameters in our model from historical market data.
With the model parameters determined for six representative stock-market indices in the world, respectively, we obtain the corresponding leverage or anti-leverage effect from the simulation, and the effect is in agreement with the empirical one on amplitude and duration. At the same time, our model produces other features of the real markets, such as the fat-tail distribution of returns and the long-term correlation of volatilities.
We reveal that for the leverage and anti-leverage effects, both the investors' asymmetric trading and herding are essential generation mechanisms. Among the six markets, however, the investors' trading is approximately symmetric for the five markets which exhibit the leverage effect, thus contributing very little. These two microscopic mechanisms and the methods for the determination of the key parameters can be applied to other complex systems with similar asymmetries.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Metastasis is the leading cause of death for patients with colorectal cancer (CRC). The development of therapeutic regimens that selectively inhibit the biological processes involved in CRC cell ...dissemination is important. We used multiple Affymetrix DNA microarray hybridization datasets to identify genes related to metastasis and have significant prognostic value for patients with CRC. Quantitative real-time PCR, immunofluorescent and immunohistochemical staining were used to evaluate mRNA and protein expression. The function of aldehyde dehydrogenase 1A3 (ALDH1A3) in invasion was assessed by performing transwell assays and animal experiments. Real-time PCR, luciferase reporter assays, and western blotting were used to identify the genes regulated by ALDH1A3. Molecular docking, MTS assays, cellular thermal shift assays, isothermal titration calorimetry, microscale thermophoresis, and enzymatic activity assays were used to screen and verify the efficacy of the ALDH1A3-specific inhibitor YD1701 (dibenzo-30-crown10-ether). Finally, subcutaneous or orthotopic xenograft models were established to investigate the therapeutic potential of YD1701. Human ALDH1A3 was identified to correlate with a metastatic phenotype in CRC cells and a poor patient prognosis. Moreover, ALDH1A3 upregulated the expression of ZEB1 and SNAI2 by inhibiting miR-200 family members. The ALDH1A3-specific inhibitor YD1701 was screened, attenuated the invasion of CRC cells in vitro, and prolonged the survival of mice bearing subcutaneous or orthotopic xenografts. Our results show that ALDH1A3 promotes invasion and metastasis via the miR-200-ZEB1/SANI2 axis and is thus a plausible marker for predicting CRC progression. Inhibiting ALDH1A3 with the identified compound YD1701 might represent an effective therapeutic approach to prevent the metastasis of CRC.
Display omitted
•ALDH1A3 promote the invasion of CRC cells and plays a predominant role in the regulation of CRC dissemination.•High level of ALDH1A3 promotes the expression of ZEB1/SNAI2 and is correlated with poor prognosis of CRC patients.•ALDH1A3 specific inhibitor YD1701 displays therapeutic effects on the metastasis of CRC.
Autoimmune diseases such as ankylosing spondylitis (AS) can be driven by emerging neoantigens that disrupt immune tolerance. Here, we developed a workflow to profile posttranslational modifications ...involved in neoantigen formation. Using mass spectrometry, we identified a panel of cysteine residues differentially modified by carboxyethylation that required 3-hydroxypropionic acid to generate neoantigens in patients with AS. The lysosomal degradation of integrin αIIb ITGA2B (CD41) carboxyethylated at Cys96 (ITGA2B-ceC96) generated carboxyethylated peptides that were presented by HLA-DRB1*04 to stimulate CD4
T cell responses and induce autoantibody production. Immunization of HLA-DR4 transgenic mice with the ITGA2B-ceC96 peptide promoted colitis and vertebral bone erosion. Thus, metabolite-induced cysteine carboxyethylation can give rise to pathogenic neoantigens that lead to autoreactive CD4
T cell responses and autoantibody production in autoimmune diseases.
Gastric cancer (GC) is the most prevalent gastrointestinal tumor with an unfavorable clinical prognosis. GC patients are largely threatened owing to metastasis and drug resistance. Tumor angiogenesis ...plays an important role in the development of gastric cancer and is a challenge in the treatment of gastric cancer.
Mouse xenograft models were used for screening of therapeutic peptides on GC growth and metastasis. Routine laboratory experimental methods including conditional cell culture, tube formation assay, qRT-PCR, Western blotting, immunohistochemistry (IHC), ubiquitination assay, and immunofluorescence (IF) were used in mechanism investigation; protein docking analysis and coimmunoprecipitation (Co-IP) were used for prediction and confirmation of interactions between JP3/SP1 and TRIM25/MEK1/2.
We identified an MMP2-targeted peptide JP3 that plays inhibiting roles in modulating growth and metastasis of GC in vivo and has no observable toxic side effects. JP3 reduced tumor microvessel density (MVD) in vivo and human umbilical vein endothelial cells (HUVECs) tube formation in vitro. Mechanistic studies revealed that JP3 reduces polyubiquitination-mediated degradation of TRIM25 by increasing the stability of TRIM25 through phosphorylating it at Ser12. TRIM25, as an E3 ubiquitin ligase, promoted the ubiquitin of SP1 at K610, further suppressed expression of MMP2 and inhibited angiogenesis in GC. Importantly, the inversely association between TRIM25 and SP1 protein level was further verified in human GC tissues. Decreased TRIM25 expression and increased SP1 expression in tumor tissues were positively correlated with poor prognosis of GC patients.
MMP2-targeted peptide JP3 plays a therapeutic role in GC through anti-angiogenesis by modulating TRIM25/SP1/MMP2.
Denitratation (nitrite produced from nitrate), has the potential applications in wastewater treatment by combining with ANAMMOX process. The occurrence of denitratation has been shown to be effected ...qualitatively by various parameters in the environment. A more quantitative understanding can be obtained using enrichment cultures in lab-scale experiments, yet information on the enrichment of functional microorganisms responsible for denitratation is lacking. In this study, a stable denitratation-dominated culture was obtained from methylotrophic denitrifying culture. The results showed that, besides the substitution of acetate for methanol, the lasting starvation following saturation of electron donor was another pivotal selection pressure that favored the growth of denitratating bacteria, which was supported by the distinctive physiological strategy involving the higher growth rate combining with larger poly-hydroxybutyrate (PHB) accumulation at sufficient electron donor situation and then manage the stress of electron donor starvation by consumpiton of the PHB. High-throughput 16S rRNA gene sequencing analysis indicated that non-methylotrophic
Halomonas campisalis
(48.1 %) and
Halomonas campaniensis
(30.4 %) dominated in the denitratating community. Moreover the denitratation was driven by the nitrate inhibiting the
nirS
transcription in the
Halomonas
species.
Knee osteoarthritis (KOA) is a major cause of leg disability in the elderly population. Recently, the expression levels of circulating microRNA (miRNA) let‑7e have been reported to be significantly ...reduced in KOA. The aims of the present study were to assess the feasibility of let‑7e as a serum marker for detecting KOA and to explore the underlying mechanisms of its involvement. Based on previous studies and bioinformatics analysis, let‑7e may regulate apoptosis and autophagy of articular chondrocytes. A total of 10 patients with KOA and 10 patients with trauma without KOA were recruited to examine the levels of let‑7e in peripheral blood. Subsequently, KOA rat models were established, and the levels of let‑7e in the cartilage and serum were examined, the expression of apoptotic proteins and autophagy‑related proteins in the cartilage were investigated, and apoptotic and autophagic activities of primary cultured chondrocytes were also detected. In patients with KOA, let‑7e levels in the peripheral serum were significantly decreased compared with the control group, and this result was confirmed in the peripheral serum and cartilage of KOA rats. In addition, the expression levels of proteins involved in the apoptotic pathway were increased in the cartilage of KOA rats, and apoptotic activity was increased. The expression of autophagy‑related proteins beclin 1 and microtubule associated protein 1 light chain 3 β (LC3B) II/LC3BI in the articular cartilage of KOA rats was lower compared with the controls, and autophagy was decreased. Si‑Miao‑San (SMS) treatment restored the expression of let‑7e and reversed the changes in apoptosis and autophagy. Therefore, the present study provided additional evidence that circulating let‑7e may be a potential serum biomarker for the diagnosis and treatment of KOA. Elevated apoptosis levels and decreased autophagy levels of cartilage tissue are involved in KOA, and treatment with SMS may reverse these effects.
PDF
