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The mechanisms behind a lack of efficient fear extinction in some individuals are unclear. Here, by employing a principal components analysis-based approach, we differentiated the mice into extinction- resistant and susceptible groups. We determined that elevated synapsin 2a (Syn2a) in the infralimbic cortex (IL) to basolateral amygdala (BLA) circuit disrupted presynaptic orchestration, leading to an excitatory/inhibitory imbalance in the BLA region and causing extinction resistance. Overexpression or silencing of Syn2a levels in IL neurons replicated or alleviated behavioral, electrophysiological, and biochemical phenotypes in resistant mice. We further identified that the proline-rich domain H in the C-terminus of Syn2a was indispensable for the interaction with synaptogyrin-3 (Syngr3) and demonstrated that disrupting this interaction restored extinction impairments. Molecular docking revealed that ritonavir, an FDA- approved HIV drug, could disrupt Syn2a- Syngr3 binding and rescue fear extinction behavior in Syn2a-elevated mice. In summary, the aberrant elevation of Syn2a expression and its interaction with Syngr3 at the presynaptic site were crucial in fear extinction resistance, suggesting a potential therapeutic avenue for related disorders., Introduction Posttraumatic stress disorder (PTSD) is a debilitating neuropsychiatric disorder (1) with complicated psychological and neurobiological mechanisms involving varied brain circuits mediating stress and fear responses (2-4), as well as [...]

In recent years, entrepreneurial orientation (EO) has emerged as a key concept in the management literature, with various studies demonstrating its positive effects on important firm-level outcomes. However, our understanding of whether and how EO shapes dynamics within organizations is still underdeveloped. Thus, by integrating EO and social information–processing theories, this study develops and tests a cross-level contingency model that describes how and when EO cascades through an organization—bridging firm, supervisor, and employee levels. We conducted a three-source, three-wave study involving 280 supervisors and 1,214 employees from 94 organizations to test our model. The results show that firm-level EO is positively related to employees' creative performance and that supervisors' and employees' passion for inventing serves as the central serial mediators for these links. The results also reveal that these cascading effects of EO do not occur unconditionally but depend on an important boundary condition—that is, the extent to which supervisors identify with their organizations. A follow-up study of 238 supervisors from various firms provides further support for the social information–processing perspective of our model. It shows that the link between firm EO and supervisors' passion for inventing is mediated by perceived normative expectations for creativity. Taken together, these findings offer a new perspective on the internal dynamics of EO, uncover a crucial boundary condition, and provide insights for the effective implementation of EO. [ABSTRACT FROM AUTHOR]

Individuals' continuous success in competitive interactions with conspecifics strongly affects their social hierarchy. Medial prefrontal cortex (mPFC) is the key brain region mediating both social competition and hierarchy. However, the molecular regulatory mechanisms underlying the neural ensemble in the mPFC remains unclear. Here, we demonstrate that in excitatory neurons of prelimbic cortex (PL), lncRNA Sera remodels the utilization of Pkm Exon9 and Exon10, resulting in a decrease in the Pkm1/2 ratio in highly competitive mice. By employing a tet-on/off system, we disrupt or rebuild the normal Pkm1/2 ratio by controlling the expression of Pkm2 in PL excitatory neurons. We find that long-term Pkm2 modulation induces timely competition alteration and hysteretic rank change, through phosphorylating the Ser845 site of GluA1. Together, this study uncovers a crucial role of lncRNA Sera/Pkm2 pathway in the transition of social competition to rank by remodeling neural ensemble in mPFC. [ABSTRACT FROM AUTHOR]

A new ferroelectric borate, [C6N2H15]·[B5O6(OH)4] (1), has been synthesized, and a series of thin films of 1 have prepared on different substrates. Thickness of the ferroelectric film can be controlled by the number of coatings, thereby tuning the performance of the film, making it a potential application in wearable devices. [ABSTRACT FROM AUTHOR]

Sinapic acid (SA) is renowned for its many pharmacological activities as a polyphenolic compound. The cause of polycystic ovary syndrome (PCOS), a commonly encountered array of metabolic and hormonal abnormalities in females, has yet to be determined. The present experiment was performed to evaluate the antifibrotic properties of SA in rats with letrozole‐induced PCOS‐related ovarian fibrosis. SA treatment successfully mitigated the changes induced by letrozole in body weight (BW) (p <.01) and relative ovary weight (p <.05). Histological observation revealed that SA reduced the number of atretic and cystic follicles (AFs) and (CFs) (p <.01), as well as ovarian fibrosis, in PCOS rats. Additionally, SA treatment impacted the serum levels of sex hormones in PCOS rats. Luteinizing hormone (LH) and testosterone (T) levels were decreased (p <.01, p <.05), and follicle‐stimulating hormone (FSH) levels were increased (p <.05). SA administration also decreased triglyceride (TG) (p <.01) and total cholesterol (TC) levels (p <.05) and increased high‐density lipoprotein cholesterol (HDL‐C) levels (p <.01), thereby alleviating letrozole‐induced metabolic dysfunction in PCOS rats. Furthermore, SA treatment targeted insulin resistance (IR) and increased the messenger RNA (mRNA) levels of antioxidant enzymes in the ovaries of PCOS rats. Finally, SA treatment enhanced the activity of peroxisome proliferator‐activated receptor‐γ (PPAR‐γ), reduced the activation of transforming growth factor‐β1 (TGF‐β1)/Smads, and decreased collagen I, α‐smooth muscle actin (α‐SMA), and connective tissue growth factor (CTGF) levels in the ovaries of PCOS rats. These observations suggest that SA significantly ameliorates metabolic dysfunction and oxidative stress and ultimately reduces ovarian fibrosis in rats with letrozole‐induced PCOS. [ABSTRACT FROM AUTHOR]

Sporadic or late-onset Alzheimer's disease (LOAD) accounts for more than 95% of Alzheimer's disease (AD) cases without any family history. Although genome-wide association studies have identified associated risk genes and loci for LOAD, numerous studies suggest that many adverse environmental factors, such as social isolation, are associated with an increased risk of dementia. However, the underlying mechanisms of social isolation in AD progression remain elusive. In the current study, we found that 7 days of social isolation could trigger pattern separation impairments and presynaptic abnormalities of the mossy fibre-CA3 circuit in AD mice. We also revealed that social isolation disrupted histone acetylation and resulted in the downregulation of 2 dentate gyrus (DG)-enriched miRNAs, which simultaneously target reticulon 3 (RTN3), an endoplasmic reticulum protein that aggregates in presynaptic regions to disturb the formation of functional mossy fibre boutons (MFBs) by recruiting multiple mitochondrial and vesicle-related proteins. Interestingly, the aggregation of RTN3 also recruits the PP2A B subunits to suppress PP2A activity and induce tau hyperphosphorylation, which, in turn, further elevates RTN3 and forms a vicious cycle. Finally, using an artificial intelligence-assisted molecular docking approach, we determined that senktide, a selective agonist of neurokinin3 receptors (NK3R), could reduce the binding of RTN3 with its partners. Moreover, application of senktide in vivo effectively restored DG circuit disorders in socially isolated AD mice. Taken together, our findings not only demonstrate the epigenetic regulatory mechanism underlying mossy fibre synaptic disorders orchestrated by social isolation and tau pathology but also reveal a novel potential therapeutic strategy for AD. [ABSTRACT FROM AUTHOR]

In this paper, we completely characterize the distributivity between the extended conjunctive aggregation functions and the extended disjunctive aggregation functions. We give two necessary and sufficient conditions for the distributivity of the extended aggregation functions and the convexity of fuzzy truth values. Most of the current research focuses on the distributivity of the extended t-norm (resp. t-conorm), overlap function (resp. grouping function) and uninorm (resp. nullnorm), and so on. It is well-known that a conjunctive (resp. disjunctive) aggregation function is a more general aggregation function than a t-norm (resp. t-conorm). Therefore, the obtained results show that the distributivity equation is more general than the previous ones. [ABSTRACT FROM AUTHOR]

A Metal-Organic Framework (MOF) based on a tricarboxylic acid ligand (H3L = biphenyl-2,4′,5-tricarboxylic acid), namely [Cd3(L)2(H2O)4] (1), had been prepared and characterized by elemental analysis, IR spectroscopy, powder X-ray diffraction (PXRD), thermogravimetric analyses (TGA), and single-crystal X-ray diffraction. Fluorescence studies showed that 1 has high quenching efficiency for testing acetone and Fe3+ ions in aqueous systems. Therefore, it can be used as a new type of fluorescence probe to detect solvent molecules and metal ions in water. [ABSTRACT FROM AUTHOR]

Substrate access tunnel engineering is a useful strategy for enzyme modification. In this study, we improved the catalytic performance of Fe-type Nitrile hydratase (Fe-type NHase) from Pseudomonas fluorescens ZJUT001 (PfNHase) by mutating residue Q86 at the entrance of the substrate access tunnel. The catalytic activity of the mutant PfNHase-αQ86W towards benzonitrile, 2-cyanopyridine, 3-cyanopyridine, and 4-hydroxybenzonitrile was enhanced by 9.35-, 3.30-, 6.55-, and 2.71-fold, respectively, compared to that of the wild-type PfNHase (PfNHase-WT). In addition, the mutant PfNHase-αQ86W showed a catalytic efficiency (k cat /K m ) towards benzonitrile 17.32-fold higher than the PfNHase-WT. Interestingly, the substrate preference of PfNHase-αQ86W shifted from aliphatic nitriles to aromatic nitrile substrates. Our analysis delved into the structural changes that led to this altered substrate preference, highlighting an expanded entrance tunnel region, theenlarged substrate-binding pocket, and the increased hydrophobic interactions between the substrate and enzyme. Molecular dynamic simulations and dynamic cross-correlation Matrix (DCCM) further supported these findings, providing a comprehensive explanation for the enhanced catalytic activity towards aromatic nitrile substrates., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The role of periodontal ligament stem cells (PDLSCs) in repairing periodontal destruction is crucial, but their functions can be impaired by excessive oxidative stress (OS). Nocardamine (NOCA), a cyclic siderophore, has been shown to possess anti-cancer and anti-bacterial properties. This study aimed to investigate the protective mechanisms of NOCA against OS-induced cellular dysfunction in PDLSCs., Methods: The cytotoxicity of NOCA on PDLSCs was assessed using a CCK-8 assay. PDLSCs were then treated with hydrogen peroxide (H 2 O 2 ) to induce OS. ROS levels, cell viability, and antioxidant factor expression were analyzed using relevant kits after treatment. Small molecule inhibitors U0126 and XAV-939 were employed to block ERK signaling and Wnt pathways respectively. Osteogenic differentiation was assessed using alkaline phosphatase (ALP) activity staining and Alizarin Red S (ARS) staining of mineralized nodules. Expression levels of osteogenic gene markers and ERK pathway were determined via real-time quantitative polymerase chain reaction (RT-qPCR) or western blot (WB) analysis. β-catenin nuclear localization was examined by western blotting and confocal microscopy., Results: NOCA exhibited no significant cytotoxicity at concentrations below 20 µM and effectively inhibited H 2 O 2 -induced OS in PDLSCs. NOCA also restored ALP activity, mineralized nodule formation, and the expression of osteogenic markers in H 2 O 2 -stimulated PDLSCs. Mechanistically, NOCA increased p-ERK level and promoted β-catenin translocation into the nucleus; however, blocking ERK pathway disrupted the osteogenic protection provided by NOCA and impaired its ability to induce β-catenin nuclear translocation under OS conditions in PDLSCs., Conclusions: NOCA protected PDLSCs against H 2 O 2 -induced OS and effectively restored impaired osteogenic differentiation in PDLSCs by modulating the ERK/Wnt signaling pathway., (© 2024. The Author(s).)

β-Alanine is the only β-amino acid in nature and one of the most important three-carbon chemicals. This work was aimed to construct a non-inducible β-alanine producer with enhanced metabolic flux towards β-alanine biosynthesis in Escherichia coli. First of all, the assembled E. coli endogenous promoters and 5'-untranslated regions (PUTR) were screened to finely regulate the combinatorial expression of genes panD BS and aspB CG for an optimal flux match between two key pathways. Subsequently, additional copies of key genes (panD BS K104S and ppc) were chromosomally introduced into the host A1. On these bases, dynamical regulation of the gene thrA was performed to reduce the carbon flux directed in the competitive pathway. Finally, the β-alanine titer reached 10.25 g/L by strain A14-R15, 361.7% higher than that of the original strain. Under fed-batch fermentation in a 5-L fermentor, a titer of 57.13 g/L β-alanine was achieved at 80 h. This is the highest titer of β-alanine production ever reported using non-inducible engineered E. coli. This metabolic modification strategy for optimal carbon flux distribution developed in this work could also be used for the production of various metabolic products., (© 2024 Wiley Periodicals LLC.)

Objective: To investigate the toxic effect of chlorambucil combined with ibrutinib on mantle cell lymphoma (MCL) cell line Jeko-1 and its related mechanism., Methods: The MCL cell line Jeko-1 was incubated with different concentrations of chlorambucil or ibrutinib or the combination of the two drugs, respectively. CCK-8 assay was used to detect the proliferation of the cells, and Western blot was used to measure the protein expression levels of BCL-2, caspase-3, PI3K, AKT and P-AKT., Results: After Jeko-1 cells were treated with chlorambucil (3.125, 6.25, 12.5, 25, 50 μmol/L) and ibrutinib (3.125, 6.25, 12.5, 25, 50 μmol /L) alone for 24, 48, 72h respectively, the cell proliferation was inhibited in a time- and dose-dependent manner. Moreover, the two drugs were applied in combination at low doses (single drug inhibition rate<50%), and the results showed that the combination of two drugs had a more significant inhibitory effect (all P < 0.05). Compared with the control group, the apoptosis rate of the single drug group of chlorambucil (3.125, 6.25, 12.5, 25, 50 μmol/L) and ibutinib (3.125, 6.25, 12.5, 25, 50 μmol/L) was increased in a dose-dependent manner. The combination of the two drugs at low concentrations (3.125, 6.25, 12.5 μmol/L) could significantly increase the apoptosis rate compared with the corresponding concentration of single drug groups (all P < 0.05). Compared with control group, the protein expression levels of caspase-3 in Jeko-1 cells were upregulated, while the protein expression levels of BCL-2, PI3K, and p-AKT/AKT were downregulated after treatment with chlorambucil or ibrutinib alone. The combination of the two drugs could produce a synergistic effect on the expressions of the above-mentioned proteins, and the differences between the combination group and the single drug groups were statistically significant (all P < 0.05)., Conclusion: Chlorambucil and ibrutinib can promote the apoptosis of MCL cell line Jeko-1, and combined application of the two drugs shows a synergistic effect, the mechanism may be associated with the AKT-related signaling pathways.

We propose a mechanism to simultaneously enhance quantum cooling and entanglement via coupling an auxiliary microwave cavity to a magnomechanical cavity. The auxiliary cavity acts as a dissipative cold reservoir that can efficiently cool multiple localized modes in the primary system via beam-splitter interactions, which enables us to obtain strong quantum cooling and entanglement. We analyze the stability of the system and determine the optimal parameter regime for cooling and entanglement under the auxiliary-microwave-cavity-assisted (AMCA) scheme. The maximum cooling enhancement rate of the magnon mode can reach 98.53 % , which clearly reveals that the magnomechanical cooling is significantly improved in the presence of the AMCA. More importantly, the dual-mode entanglement of the system can also be significantly enhanced by AMCA in the full parameter region, where the initial magnon-phonon entanglement can be maximally enhanced by a factor of about 11. Another important result of the AMCA is that it also increases the robustness of the entanglement against temperature. Our approach provides a promising platform for the experimental realization of entanglement and quantum information processing based on cavity magnomechanics.