Cage-based sensors for circular dichroism analysis.

Quantitative chiral sensing relying on circular dichroism (CD) is very important for determining the enantiomeric excess or concentration of small molecules without strong chromophores, because they form chiral complexes with sensors, yielding strong CD signals. Three-dimensional cages are promising platforms for chiral CD due to their stereochemical flexibility and their variety of cavity and external binding sites that can be used as chiral CD sensors. In this minireview, we discuss recent advances, future challenges, and opportunities in the quantitative sensing of small molecules in host-guest and peripheral complexes with cage sensors by chiral CD. We aim to provide inspiration for the rational design of cage sensors for quantitative chiral sensing of small molecules based on CD.

Genetic dissection of mutual interference between two consecutive learning tasks in Drosophila.

Animals can continuously learn different tasks to adapt to changing environments and, therefore, have strategies to effectively cope with inter-task interference, including both proactive interference (Pro-I) and retroactive interference (Retro-I). Many biological mechanisms are known to contribute to learning, memory, and forgetting for a single task, however, mechanisms involved only when learning sequential different tasks are relatively poorly understood. Here, we dissect the respective molecular mechanisms of Pro-I and Retro-I between two consecutive associative learning tasks in Drosophila. Pro-I is more sensitive to an inter-task interval (ITI) than Retro-I. They occur together at short ITI (<20 min), while only Retro-I remains significant at ITI beyond 20 min. Acutely overexpressing Corkscrew (CSW), an evolutionarily conserved protein tyrosine phosphatase SHP2, in mushroom body (MB) neurons reduces Pro-I, whereas acute knockdown of CSW exacerbates Pro-I. Such function of CSW is further found to rely on the γ subset of MB neurons and the downstream Raf/MAPK pathway. In contrast, manipulating CSW does not affect Retro-I as well as a single learning task. Interestingly, manipulation of Rac1, a molecule that regulates Retro-I, does not affect Pro-I. Thus, our findings suggest that learning different tasks consecutively triggers distinct molecular mechanisms to tune proactive and retroactive interference.

Fractional-Order Active Disturbance Rejection Control with Fuzzy Self-Tuning for Precision Stabilized Platform.

In this paper, a novel fractional-order active disturbance rejection control with fuzzy self-tuning method (FSFOADRC) is proposed for photoelectric tracking system (PTS). Firstly, aiming at the internal uncertainty of PTS and external disturbance, a fraction-order extended state observer (FOESO) is designed, and the FOESO can transform the plant into a simple form, which greatly simplifies the mathematical model. Secondly, a fuzzy regulator is applied to the proportion-differentiation controller (PD), increasing the flexibility and adaptivity of the controller. In addition, the stability of the whole control system can be guaranteed. Eventually, numerical comparative simulations are implemented to verify the feasibility and superiority of the proposed method. Compared with the integral-order active disturbance rejection control (IOADRC), fractional-order active disturbance rejection control (FOADRC) without the fuzzy regulator and proportion-integration-differentiation (PID) controller, the proposed method performs better with faster response, smaller overshoot, and stronger disturbance suppression capability.

Prognostic Significance of the Systemic Immune-Inflammation Index in Patients With Cholangiocarcinoma: A Meta-Analysis.

Background: The systemic immune-inflammation index (SII) is a significant prognostic factor for neoplastic diseases. However, the prognostic value of SII in patients with cholangiocarcinoma (CCA) remains unclear. This meta-analysis aimed to investigate the prognostic value of preoperative SII in patients with CCA. Method: We systematically searched for relevant studies in PubMed, Scopus, EMBASE, Web of Science, PROSPERO, and Cochrane Library databases up to March 22, 2022. Hazard ratios (HRs) and 95% confidence intervals (CIs) were used to estimate the association between SII and survival outcomes, including overall survival (OS) and recurrence-free survival. Results: Five studies with 1402 patients were included in this meta-analysis to determine the prognostic value of preoperative SII. The results showed that a higher SII was associated with poor OS in patients with CCA who underwent invasive surgery (HR=1.916; 95% CI, 1.566-2.343; Z=6.329; P<0.001). The results were reliable in the subgroup analysis according to country, age, sample size, SII cutoff values, and treatment methods. Conclusions: A high preoperative SII appears to be an effective and practical method for monitoring survival in patients with CCA. Systematic Review Registration: International Platform of Registered Systematic. Review and Meta-Analysis Protocols (INPLASY), identifier INPLASY202240015.

Folded Propeller Chiral Structures Exclusively Adaptive to Chloroform.

Intramolecular folding is a strategy to construct aryl chiral compounds with applications in chiroptical materials and asymmetrical catalysts. However, beyond polarity the role of solvent in controlling the folded chirality is ambiguous. Here, we report a simple folding protocol to build chiral benzimidazole skeleton with propeller chirality, which could be adaptive to chloroform (CHCl3) with high selectivity. Benzimidazole conjugated with diamino acid arms underwent folding driven by hydrogen bonds, exhibiting propeller chirality of which handedness could be tuned by the absolute chirality of amino acids. Reversible unfolding/folding behavior was realized by heating/cooling process, giving rise to the thermomediated chiroptical switch. Among up to 32 common solvents, chloroform exclusively inverted the propeller chirality. The geometry and hydrogen bonding sites of chloroform allow rearrangement of diamino acid arms into an opposite packing propensity. The chloroform behaves as an invasive linker between diamino acid arms to replace the pristine hydrogen bonds. This work reports the fabrication of chiral aryl compounds by simple folding, which shows the adaptiveness to the chloroform. It demonstrates that not only polarity but also the active participation of solvent could change the chirality and optical activities of small folded molecules.

Arene-perfluoroarene interaction induced chiroptical inversion and precise ee% detection of chiral acids in a benzimidazole-involved ternary coassembly.

Flexible regulation of chirality and handedness of chiral functional materials and quantitative sensing of natural chiral compounds remains a considerable challenge. Herein, an achiral fluorescent 1-pyrenecarboxylic acid-benzimidazole derivative (PBI) was synthesized and its chiroptical properties upon coassembly with chiral acids (TA and MA) and octafluoronaphthalene (OFN) through hydrogen bonds between benzimidazole and chiral acids as well as an arene-perfluoroarene (AP) interaction between a pyrene moiety and OFN were systemically studied. The binary assemblies of PBI/TA and PBI/MA displayed opposite chiroptical properties including circular dichroism (CD) and circularly polarized luminescence (CPL) signals. Interestingly, the handedness of CPL was further inverted in ternary assemblies due to the synergistic effect of the AP interaction and hydrogen bonds. Besides, the highly accurate chiral sensing of chiral acids via binary assemblies was successfully achieved with a high correlation coefficient. This work provides a simple method for regulating the handedness of chiroptical active materials and quantitative sensing of chiral acids through orthogonal multiple component coassemblies.

Supramolecular Chirality Suppresses Molecular Chirality: Selective Chiral Recognition in Hierarchically Coassembled Pyridine-Benzimidazole Conjugates with Precise ee% Detection.

Incorporation of aromatic chiral species with axial, helical, or propeller chirality in surapmolecular chiral motifs would potentially facilitate the chiroptical applications such as enantiomeric excess detection, chiral sensing, and displays, which however suffer from inevitable competition between supramolecular chirality and molecular chirality and remain major challenges. Here, we show the programmable coassembly of pyridine-cored benzimidazole derivatives with intrinsic propeller chirality, which shall form binary and ternary aggregates with chiral acids as well as metal ions though H-bonds and metal-ligand coordination interactions in an orthogonal manner, to enhance and flexibly control the chiroptical properties. Solid-state X-ray structures of pyridine-benzimidazole derivatives suggested they adopted the propeller molecular chirality. Competition between molecular and supramolecular chirality and dynamic binding toward enantiomers of pyridine-benzimidazole derivatives was observed in the coassembly systems based on the chiroptical responses and molecular dynamic simulation. Compared to the intrinsic racemic assembly, coassembly systems produced chiroptical responses including the Cotton effect and circularly polarized luminescence (CPL) with relatively high dissymmetry factor (gabs up to 4.9 × 10-2, glum up to 9.6 × 10-3). Furthermore, chiroptical responses were further controlled by introducing metal ions, achieving inverted handedness and tunable dissymmetry factors. This work provides feasible strategies to efficiently regulate and enhance the chiroptical properties of intrinsic aromatics via multiple interactions, which also expressed great potential in quantitative ee% sensing for chiral acids.

Enhancing Optical Activities of Benzimidazole Derivatives through Coassembly for High-Efficiency Synthesis of Chiroptical Nanomaterials and Accurate ee % Detection of Natural Acids.

Developing efficient protocols to enhance the optical activities of chiral self-assemblies is a key to realizing their chiroptical functions such as chiral sensing and displays. Here, we have reported a coassembly protocol to efficiently boost the chiroptical responses, whereby the synthesis of chiroptical nanomaterials and highly accurate detection of enantiomeric excess (ee %) were achieved. A series of benzimidazole derivatives with different topologies underwent spontaneous aggregation and symmetry breaking in solution, generating silent Cotton effects, yet exclusive weak left-handed circularly polarized luminescence (CPL). The coassembly with natural hydroxyl acids via complementary H bonds afforded chiral nanostructures with emerged Cotton effects and enhanced CPL. Dissymmetry g-factors were dramatically boosted (glum from 1 × 10-3 to 5.5 × 10-2, gabs from 0 to 6.7 × 10-3). In addition, proof of concept of recognition and detection of natural chiral molecules was realized with high accuracy.

Helical Nanostructures with Circularly Polarized Luminescence from the Multicomponent Assembly of π-Conjugated N-terminal Amino Acids.

Self-assembled structures with circularly polarized luminescence (CPL) have attracted great attention in recent years. π-conjugated N-terminal amino acids with chiral amino acid residues and luminophores are capable of forming self-assembled structures at hierarchical levels, whereby chirality can be transferred to the macroscopic scale with easily modulated CPL properties. Due to the presence of multiple noncovalent binding sites, including hydrogen bonding and aromatic interactions, π-conjugated N-terminal amino acids are emerging core candidates for incorporation into multicomponent self-assembled architectures, accomplishing rational control over supramolecular chirality as well as showing rich chiroptical properties. In this Minireview, we provide a brief summary of multiple-component coassembled systems comprising π-conjugated N-terminal amino acids, small organic species and metal ions. The synthesis of helical structures and manipulation of supramolecular chirality by controlling the self-assembled species is introduced, and the CPL properties of multiple-component π-conjugated N-terminal amino acids are also briefly summarized.

The mechanism and role of intracellular α-ketoglutarate reduction in hepatic stellate cell activation.

BACKGROUND: The activation of hepatic stellate cells (HSCs) plays a central role in liver fibrosis. α-ketoglutarate is a natural metabolite and previous studies have shown that increase in intracellular α-ketoglutarate can inhibit HSC activation. AIM: The aim of the present study is to determine the changes and role of intracellular α-ketoglutarate in HSC activation and clarify its mechanism of action. METHODS: A human HSC cell line (LX-2) and the primary mouse HSC were used in the present study. We detected the changes of intracellular α-ketoglutarate levels and the expression of enzymes involved in the metabolic processes during HSC activation. We used siRNA to determine the role of intracellular α-ketoglutarate in HSC activation and elucidate the mechanism of the metabolic changes. RESULTS: Our results demonstrated that intracellular α-ketoglutarate levels decreased with an HSC cell line and primary mouse HSC activation, as well as the expression of isocitrate dehydrogenase 2 (IDH2), an enzyme that catalyzes the production of α-ketoglutarate. In addition, knockdown of IDH2 efficiently promoted the activation of HSCs, which was able to be reversed by introduction of an α-ketoglutarate analogue. Furthermore, we demonstrated that α-ketoglutarate regulated HSC activation is independent of transforming growth factor-ß1 (TGF-ß1). CONCLUSIONS: Our findings demonstrated that decrease in IDH2 expression limits the production of α-ketoglutarate during HSC activation and in turn promotes the activation of HSCs through a TGF-ß1 independent pathway. The present study suggests that IDH2 and α-ketoglutarate may be potential new targets for the prevention and treatment of liver fibrosis.

High-Throughput Synthesis of Chiroptical Nanostructures from Synergistic Hydrogen-Bonded Coassemblies.

The emergence, amplification, and manipulation of chiroptical activity in self-assembled nanostructures, including circularly polarized absorbance and luminescence (CPL), remain considerable challenges. Here, we report the high-throughput synthesis of nanostructures with finely tailored chiroptical activities. Two fully π-conjugated benzimidazoles formed H-bonded complexes with natural hydroxyl acids (tartaric acid and mandelic acid), which self-assembled into diversified macroscopically chiral nanostructures. Synergistic coassembly allows for the emergence of Cotton effects and CPL with high dissymmetry g-factors (gabs up to 8 × 10-3, glum up to 3 × 10-3). The tartaric acid coassembled system exhibits enantiomer-independent left-handed CPL, which transforms into a cooperative ternary coassembly appended with enantiomer-resolved CPL with extended emission wavelength upon selective transition metal ion chelation. This H-boned coassembly system provides a vast number of chiral nanostructures with flexibly tuned Cotton effects and CPL, which also behaves as a selective chiroptical sensor to metal ions.

The receptor channel formed by ppk25, ppk29 and ppk23 can sense the Drosophila female pheromone 7,11-heptacosadiene.

In Drosophila, pheromones play a crucial role in regulating courtship behaviors. In males, female aphrodisiac pheromones promote male-female courtship, and male antiaphrodisiac pheromones inhibit male-male courtship. Previous studies have reported that receptor proteins belonging to the pickpocket (ppk) family, ionotropic receptor family and gustatory receptor family are required for pheromone detection and normal courtship. However, none of them has been shown to be sufficient for sensing pheromones after ectopic expression in originally unresponsive cells. "M" cells are activated by male antiaphrodisiac pheromones but not female aphrodisiac pheromones, and the activated cells inhibit male-male courtship. In our study, male flies with ectopic expression of ppk25, ppk29 and ppk23 in "M" cells showed decreased male-female courtship. Using an in vivo calcium imaging approach, we found that the "M" cells expressing these three ppks were significantly activated by the female aphrodisiac pheromone 7,11-heptacosadiene (7,11-HD). Our results indicate that a sodium channel consisting, at minimum, of ppk25, ppk29 and ppk23, can sense 7,11-HD, most likely as a receptor. Our findings may help us gain insights into the molecular mechanisms of pheromonal functions.

Interplay between α2-chimaerin and Rac1 activity determines dynamic maintenance of long-term memory.

Memory consolidation theory suggests that once memory formation has been completed, memory is maintained at a stable strength and is incapable of further enhancement. However, the current study reveals that even long after formation, contextual fear memory could be further enhanced. Such unexpected enhancement is possible because memory is dynamically maintained at an intermediate level that allows for bidirectional regulation. Here we find that both Rac1 activation and expression of α2-chimaerin are stimulated by single-trial contextual fear conditioning. Such sustained Rac1 activity mediates reversible forgetting, and α2-chimaerin acts as a memory molecule that reverses forgetting to sustain memory through inhibition of Rac1 activity during the maintenance stage. Therefore, the balance between activated Rac1 and expressed α2-chimaerin defines dynamic long-term memory maintenance. Our findings demonstrate that consolidated memory maintains capacity for bidirectional regulation.

Substance P promotes hepatic stellate cell proliferation and activation via the TGF-ß1/Smad-3 signaling pathway.

Prolonged activation and proliferation of hepatic stellate cells (HSCs) usually results in the initiation and progression of liver fibrosis following injury. Recent studies have shown that Substance P (SP) participates in the development of fibrosis. However, whether SP is involved in liver fibrosis, especially in the activation and proliferation of HSCs, is largely unknown. In the present study, we measured the effects of a series of concentrations of SP on the cell viability and activation of HSC-T6 cells and LX2 cells. The underlying mechanism was also investigated. We found that SP effectively increased cell viability, both in an MTT assay (p<0.05) and in a lactate dehydrogenase activity assay (LDH) (p<0.05). Moreover, SP upregulated the protein expression of α-SMA and Collagen I (both p<0.05) and decreased the release of lipid droplets (LDs) (p<0.05), all of which are associated with HSC activation. Apoptosis analysis revealed that SP can attenuate the increase of cell apoptosis induced by serum withdrawal (p<0.05). Furthermore, these effects were all blocked by an SP receptor antagonist, L732138. More importantly, L732138 decreased the activation of the TGF-ß1/Smad3 signaling pathway, which is highly associated with liver fibrosis. Taken together, our results demonstrate that SP can promote HSC proliferation and induce HSC activation via the TGF-ß1/Smad3 signaling pathway.

Dimethyl α-ketoglutarate reduces CCl4-induced liver fibrosis through inhibition of autophagy in hepatic stellate cells.

Sustained activation of hepatic stellate cells (HSCs) leads to liver fibrosis. Autophagy fuels the activation of HSCs by generation of ATP. Our previous research demonstrated an inhibitory effect of dimethyl α-ketoglutarate (DMKG) on HSCs activation in vitro. In the current study, we demonstrated that DMKG reduced CCl4-induced liver fibrosis in Wistar rats. Then, with the use of the HSC-T6 cell lines and double immunofluorescent staining of liver sections, we showed that the anti-fibrotic effect occurred through the inhibition of the autophagy of HSCs. Both experiments showed that DMKG could inhibit autophagy and activation of HSCs, and that the activation of HSCs was down-regulated with autophagy. In addition, we showed that DMKG could lead to lipid droplet accumulation and decrease cellular ATP content in HSCs. Furthermore, the mechanism of how DMKG inhibited autophagy of HSCs was explored in vitro with the use of c646 (a competitive inhibitor of acetyl-coenzyme A which binds to the acetyltransferase EP300) and lipoic acid (an alternative acetyl-coenzyme A -replenishing agent to DMKG), and showed that both acetyl-coenzyme A and EP300 were involved. Collectively, our study investigated the possible role of DMKG in preventing liver fibrosis and HSCs activation. We showed that DMKG may be a potential therapeutic agent for the treatment of liver fibrosis.

Corosolic acid protects hepatocytes against ethanol-induced damage by modulating mitogen-activated protein kinases and activating autophagy.

The reactive oxygen species(ROS)/mitogen-activated protein kinase (MAPK) destroyed autophagy and the reactive oxygen species/mitogen-activated protein kinase (MAPK) pathway are considered closely related to ethanol-induced hepatocellular injury. Previous work indicated that corosolic acid, the natural extracts of leaves of the banaba tree, Lagerstroemia speciosa L., could protect the liver against ethanol-induced damage, but the underlying mechanism is unclear. In the study we found that corosolic acid significantly inhibited ethanol-induced apoptosis, increased level of tumor necrosis factor-α(TNF-α) and reactive oxygen species accumulation in vitro. Corosolic acid inhibited ethanol-activated p38 and c-Jun N-terminal kinase MAPK signaling in BRL-3A and HepG2 cells as well as in experimental rats. Corosolic acid restored the ethanol-suppressed expression of autophagy-related genes, including beclin-1 and the ratio of microtubule-associated protein light chain 3II/I (LC3II/I) via AMP-activated protein kinase (AMPK) activation both in vitro and in vivo. In experimental rats, corosolic acid ameliorated the detrimental histopathological findings. Corosolic acid may protect the liver against ethanol-induced injury by modulation of MAPK signaling and autophagy activation. These findings suggested that corosolic acid might be a promising agent in treatment of alcoholic liver diseases.

Association of genetic polymorphisms in PRKDC and XRCC4 with risk of ESCC in a high-incidence region of North China.

BACKGROUND: The nonhomologous end-joining (NHEJ) pathway is the main mechanism repairing DNA double-strand breaks (DSBs) in human cells. This research was designed to study the association between selected variants in NHEJ members and esophageal squamous cell carcinoma (ESCC). METHODS: Two single nucleotide polymorphisms (SNPs), PRKDC (rs7003908) and X-ray repair cross complementing group 4 (XRCC4; rs1805377), were genotyped in a total of 189 patients with ESCC and 189 unrelated control individuals in a high-risk area for ESCC in North China, and the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was applied. RESULTS: A significantly different distribution was found in the frequency of PRKDC (rs7003908) genotype between the ESCC group and controls. Individuals homozygous for the C allele had a significant (3.185-fold) increased risk of ESCC. As for XRCC4 (rs1805377) polymorphism, no difference was found in distribution between the ESCC and control groups. CONCLUSIONS: Our results suggest that variation in DNA repair genes may be associated with risk of ESCC.

Inhibitory effects of dimethyl α-ketoglutarate in hepatic stellate cell activation.

AIM: The activation of Hepatic stellate cell (HSC) is a pivotal event in the initiation and progression of hepatic fibrosis and a major source of collagen deposition. A recent study found that autophagy fuels the HSC activation. α-ketoglutarate (AKG), an intermediate in the Kerbs CYCLE, has been shown to regulate the level of autophagy. In this study, we aim to investigate the potential effect of dimethyl α-ketoglutarate (DMKG), a membrane-permeable esters of AKG, on the activation of HSC. METHODS: HSC and hepatocyte cell lines were treated with DMKG at gradient concentrations, MTT assay was used to assess the cell viability. Concentrations of DMKG that did not affect the cell survival were added to the culture media of HSC cells. Real-time PCR and western blot analysis was carried out to evaluate the expression of fibrogenic genes in HSC after culture for 24 hours. RESULTS: Low dose of DMKG had little cytotoxicity to both HSCs and hepatocytes, while HSCs were more vulnerable to high dose of DMKG than hepatocytes. More importantly, DMKG inhibited the expression of α-SMA and collagen I significantly in HSCs detected by real-time PCR and western blot analysis at the concentrations that didn't decrease cell viability. CONCLUSIONS: DMKG has a significant role of inhibiting the activation of HSC and may attenuate hepatic fibrosis safely.

Association of the genetic polymorphisms in XRCC6 and XRCC5 with the risk of ESCC in a high-incidence region of North China.

BACKGROUND: The XRCC6 and XRCC5 genes are part of the nonhomologous end-joining (NHEJ) pathway, which is the main mechanism repairing DNA double-strand breaks (DSBs) in human cells. Genetic variations of XRCC6 and XRCC5 might contribute to esophageal squamous cell carcinoma (ESCC) susceptibility. METHODS: ESCC patients (n = 189) and cancer-free controls (n = 189) were recruited in an ESCC high-risk area of north China. Then the rs2267437 (XRCC6), rs3835 (XRCC5) and rs16855458 (XRCC5) polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. RESULTS: A significant difference in genotype distribution and allele frequency of rs2267437 (XRCC6) was observed between the cases and controls. The CG carriers were at higher risk of ESCC (p = 0.001, odds ratio [OR] = 2.040, 95% confidence interval [95% CI], 1.323-3.147). G allele carriers were also associated with an increased ESCC risk (p = 0.003, OR = 1.868, 95% CI, 1.230-2.836). In the 2 polymorphisms of XRCC5, no significant difference was found between both groups in the distribution of either genotype or allelic frequency. But in the haplotypes established by the single nucleotide polymorphisms (SNPs) of XRCC5, the haplotype AT and CC separately increased by 4.28- and 2.31-fold the risk ratio of ESCC (p = 0.01, OR = 4.28, 95% CI, 1.40-13.05; p = 0.03, OR = 2.31, 95% CI, 1.11-4.80, respectively). In addition, gene-smoking or gene-drinking interactions, and their effect on the risk of ESCC were observed, but no significant gene-environment interaction was demonstrated. CONCLUSIONS: In conclusion, both the CG carriers/G allele carriers of rs2267437 (XRCC6) and the haplotype AT/CC established by the SNPs of XRCC5 are associated with ESCC susceptibility.