Fe-HCOF-PEG2000 as a Hypoxia-Tolerant Photosensitizer to Trigger Ferroptosis and Enhance ROS-Based Cancer Therapy.

Background: The hypoxic tumor microenvironment and single mechanisms severely limit the photodynamic therapy (PDT) efficiency of covalent organic framework (COF) nanoparticles in cancer treatment. Purpose: Here, we propose an iron-loaded, hydrophilic 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000)-modified hollow covalent organic framework (HCOF), Fe-HCOF-PEG2000, for use in hypoxic PDT and ferroptosis therapy owing to its type I and II photodynamic ability and iron nanoparticle loading property. Results: Fe-HCOF-PEG2000 nanoparticles (Fe-HCOFs-PEG2000) with semiconducting polymers and microporous skeletons allow efficient photophysical properties. Moreover, the iron nanoparticles on Fe-HCOF-PEG2000 caused ferroptosis and further enhanced tumor elimination under normoxic and hypoxic conditions. DSPE-PEG2000 endowed Fe-HCOF-PEG2000 with hydrophilicity, allowing it to circulate and accumulate in organs rich in blood supply, especially tumors. 808 nm NIR activated Fe-HCOF-PEG2000 aggregated in tumors and significantly inhibited tumor growth under hypoxia. Conclusion: To our knowledge, Fe-HCOF-PEG2000 is the leading combination of type I/II PDT and ferroptosis. The strong antitumor effects of this nanomaterial suggest prospects for clinical translation as a tumor nanotherapy drug.

Development of an imidazole-based N,N-bidentate ligand for the manganese catalyzed direct coupling of nitriles with alcohols.

3d-Metal catalyzed borrowing hydrogen (BH) reactions represent powerful and environmentally friendly approaches for the direct coupling of alcohols with nitriles to assemble various important branched nitriles. The development of simple and efficient ligands is a crucial issue in this field. In this study, we designed a series of readily available N,N-bidentate ligands that demonstrated good efficiency in the Mn-catalyzed BH reaction of alcohols and nitrile derivatives, yielding the targeted nitriles in moderate to good yields. Remarkably, the mildness and practicality of this protocol were further demonstrated by the successful synthesis of anipamil via a two-cascade borrowing hydrogen procedure.

How effort-based self-interest motivation shapes altruistic donation behavior and brain responses.

Prosocial behaviors are central to individual and societal well-being. Although the relationship between effort and prosocial behavior is increasingly studied, the impact of effort-based self-interested motivation on prosocial behavior has received less attention. In the current study, we carried out two experiments to examine the effect of motivation to obtain a reward for oneself on donation behavior and brain response. We observed that individuals who accumulated more money in the effort-expenditure rewards task (EEfRT) donated a lower proportion of their earnings. The sigmoid model fitted participants' choices in the EEfRT task, and the effort-reward bias and sigma parameters negatively correlated with the amount of money donated in the donation task. Additionally, the effort-reward bias and sigma parameters negatively predicted N2 amplitude during processing of charitable donation-related information. We propose that individuals who exhibit a lower level of effort-based self-interest motivation may allocate more cognitive control or attentional resources when processing information related to charitable donations. Our work adds weight to understanding the relationship between effort-based self-interest motivation and prosocial behavior and provides electrophysiological evidence.

Discovery of Novel N-(Anthracen-9-ylmethyl) Benzamide Derivatives as ZNF207 Inhibitors Promising in Treating Glioma.

Targeting tumor stemness is an innovative approach to cancer treatment. Zinc Finger Protein 207 (ZNF207) is a promising target for weakening the stemness of glioma cells. Here, a series of novel N-(anthracen-9-ylmethyl) benzamide derivatives against ZNF207 were rationally designed and synthesized. The inhibitory activity was evaluated, and their structure-activity relationships were summarized. Among them, C16 exhibited the most potent inhibitory activity, as evidenced by its IC50 values ranging from 0.5-2.5 µM for inhibiting sphere formation and 0.5-15 µM for cytotoxicity. Furthermore, we found that C16 could hinder tumorigenesis and migration and promote apoptosis in vitro. These effects were attributed to the downregulation of stem-related genes. The in vivo evaluation demonstrated that C16 exhibited efficient permeability across the blood-brain barrier and potent efficacy in both subcutaneous and orthotopic glioma tumor models. Hence, C16 may serve as a potential lead compound targeting ZNF207 and has promising therapeutic potential for glioma.

Order of magnitude reduction in Joule heating of single molecular junctions between graphene electrodes.

Maintaining stability of single-molecular junctions (SMJs) in the presence of current flow is a prerequisite for their potential device applications. However, theoretical understanding of nonequilibrium heat transport in current-carrying SMJs is a challenging problem due to the different kinds of nonlinear interactions involved, including electron-vibration and anharmonic vibrational coupling. Here, we overcome this challenge by accelerating Langevin-type current-induced molecular dynamics using machine-learning potential derived from density functional theory. We show that SMJs with graphene electrodes generate an order of magnitude less heating than those with gold electrodes. This is rooted in the better phonon spectral overlap of graphene with molecular vibrations, rendering harmonic phonon heat transport being dominant. In contrast, in a spectrally mismatched junction with gold electrodes, anharmonic coupling becomes important to transport heat away from the molecule to surrounding electrodes. Our work paves the way for studying current-induced heat transport and energy redistribution in realistic SMJs.

Electrophysiological evidence for the effects of pain on the different stages of reward evaluation under a purchasing situation.

Pain and reward have crucial roles in determining human behaviors. It is still unclear how pain influences different stages of reward processing. This study aimed to assess the physical pain's impact on reward processing with event-related potential (ERP) method. In the present study, a flash sale game (reward-seeking task) was carried out, in which the participants were instructed to press a button as soon as possible to obtain the earphone (a reward) after experiencing either electric shock or not and finally evaluated the outcome of their response. High-temporal-resolution electroencephalogram data were simultaneously recorded to reveal the neural mechanism underlying the pain effect. The ERP analyses revealed that pain affected the feedback processing reflected by feedback-related negativity (FRN) and P300. Specifically, participants in the nopain situation exhibited greater FRN discrepancy between success and failure feedbacks relative to that in the pain situation. Moreover, the P300 amplitude was enhanced in the nopain condition compared to the pain condition regardless of the feedback valence. These results demonstrate that the pain reduced the sensitivity to the reward valence at the early stage and weakened the motivational salience at the late stage. Altogether, this study extends the understanding of the effect of pain on reward processing from the temporal perspective under a purchasing situation.

Autophagy-mediated negative feedback attenuates the oncogenic activity of YAP in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy in humans, and new therapeutic targets are urgently needed. Yes-associated protein (YAP) plays a significant role in cancer progression. Autophagy is also closely associated with various human cancers. However, the interplay between YAP and autophagy in PDAC remains poorly understood. In this study, we found that YAP was upregulated and activated in PDAC. Further analysis revealed that there is a YAP-autophagy feedback loop in pancreatic cancer. Mechanistically, YAP activates autophagy by promoting Atg5 transcription via TEAD1-mediated binding, while autophagy negatively regulates YAP through autophagic degradation. The hyperactivation of YAP in PDAC unbalances the YAP-autophagy circuit and promotes cancer progression. Inhibition of autophagy enhances the oncogenic activity of YAP in PDAC. The autophagy activator rapamycin promotes the antitumor effect of verteporfin, a YAP inhibitor. Therefore, our study elucidated the interaction between YAP and autophagy in PDAC and our results suggest that targeting the YAP-autophagy circuit may be a new therapeutic strategy for pancreatic cancer.

Charge Transfer Gap Tuning via Structural Distortion in Monolayer 1T-NbSe2.

The Mott state in 1T-TaS2 is predicted to host quantum spin liquids (QSLs). However, its insulating mechanism is controversial due to complications from interlayer coupling. Here, we study the charge transfer state in monolayer 1T-NbSe2, an electronic analogue to TaS2 exempt from interlayer coupling, using spectroscopic imaging scanning tunneling microscopy and first-principles calculations. Monolayer NbSe2 surprisingly displays two types of star of David (SD) motifs with different charge transfer gap sizes, which are interconvertible via temperature variation. In addition, bilayer 1T-NbSe2 shows a Mott collapse by interlayer coupling. Our calculation unveils that the two types of SDs possess distinct structural distortions, altering the effective Coulomb energies of the central Nb orbital. Our calculation suggests that the charge transfer gap, the same parameter for determining the QSL regime, is tunable with strain. This finding offers a general strategy for manipulating the charge transfer state in related systems, which may be tuned into the potential QSL regime.

YAP promotes sorafenib resistance in hepatocellular carcinoma by upregulating survivin.

BACKGROUND: Sorafenib is the standard first-line treatment for advanced hepatocellular carcinoma (HCC), but its use is hampered by secondary drug resistance. Yes-associated protein (YAP) is a downstream effector of the Hippo signaling pathway, which is crucial for liver tumorigenesis. As yet, however, the mechanism underlying sorafenib resistance and the role of YAP therein is not fully understood and needs to be explored further. METHODS: Western blotting, flow cytometry and CCK-8 assays were used to assess the role of YAP in HCC sorafenib resistance. Next, qRT-PCR and Western blotting were performed to identify survivin as a YAP downstream effector, and rescue experiments were performed to confirm that YAP induces sorafenib resistance via survivin. Additionally, Western blotting, flow cytometry and in vivo xenograft models were used to evaluate the effect of verteporfin in combination with sorafenib on HCC. RESULTS: We found that sorafenib enhances YAP nuclear accumulation and activation, thereby promoting sorafenib resistance through inhibiting apoptosis in HCC cells. In addition, we found that survivin acts as a downstream mediator of YAP to resist sorafenib-induced apoptosis. Pharmacological inhibition of YAP by verteporfin increased the sensitivity of HCC cells to sorafenib and reversed sorafenib resistance. Moreover, verteporfin in combination with sorafenib significantly suppressed in vivo HCC tumor growth. CONCLUSIONS: Our data indicate that YAP promotes sorafenib resistance through upregulation of survivin expression in HCC cells. Targeting YAP may be a therapeutic strategy to improve the antitumor effects of sorafenib in HCC.

YAP in pancreatic cancer: oncogenic role and therapeutic strategy.

Pancreatic cancer, especially pancreatic ductal adenocarcinoma (PDAC), remains a fatal disease with few efficacious treatments. The Hippo signaling pathway, an evolutionarily conserved signaling module, plays critical roles in tissue homeostasis, organ size control and tumorigenesis. The transcriptional coactivator yes-associated protein (YAP), a major downstream effector of the Hippo pathway, is associated with various human cancers including PDAC. Considering its importance in cancer, YAP is emerging as a promising therapeutic target. In this review, we summarize the current understanding of the oncogenic role and regulatory mechanism of YAP in PDAC, and the potential therapeutic strategies targeting YAP.

Weissella cibaria Attenuated LPS-Induced Dysfunction of Intestinal Epithelial Barrier in a Caco-2 Cell Monolayer Model.

The dysfunction of the intestinal epithelial barrier contributes to local or systemic infection and inflammation. Some lactic acid bacteria (LAB) strains had been shown to improve the conditions of barrier function and, for this reason, are recognized as probiotics. Weissella cibaria, a species belonging to the LAB group, is known to promote several health benefits. However, the role of W. cibaria in regulating the integrity of the intestinal epithelial barrier has not yet been investigated. In this study, W. cibaria MW01 was isolated from Chinese sauerkraut and was selected based on its functional features, such as gastric juice and bile salt tolerance, besides antagonistic activity against pathogenic bacteria. In a cellular model of the intestinal barrier, it was observed that W. cibaria was able to adhere more efficiently than Lactobacillus rhamnosus GG in Caco-2 cells. Moreover, the LPS-induced inflammation in Caco-2 cells was attenuated by the treatment with W. cibaria MW01, which reduced the synthesis of TNF-α, IL-6, and IL-8. In addition, it was noted that the treatment with W. cibaria MW01 recovered the integrity of the Caco-2 cell monolayer exposed to LPS. Furthermore, W. cibaria MW01 significantly alleviated LPS-induced downregulation of tight junction proteins (TJP) (claudin, occludin, and tight junction protein-1). Mechanistically, W. cibaria MW01 inhibited the translocation of NF-κB to the nucleus and deactivated the MLCK-pMLC pathway during LPS exposure. Thus, W. cibaria MW01, as a potential probiotic, can protect intestinal epithelial barrier function by regulating inflammation and expression of TJP via the NF-κB-mediated MLCK-pMLC pathway.

Modulating activity in the dorsolateral prefrontal cortex alter corruption behavior: A transcranial direct current stimulation study.

Corruption behavior has gained worldwide concern for its great harmfulness to public society. In order to reduce corruption, researchers have carried out numerous studies on corrupt prevention. Researchers found that except for external supervision, the internal factor such as moral judgment also have an impact on corruption behavior. Previous brain imaging and stimulation studies suggested that dorsolateral prefrontal cortex (DLPFC) is critical brain area which integrates emotional and cognitive process of moral judgments. Therefore, in the current study, we applied tDCS (transcranial direct current stimulation) over DLPFC to investigated the modulation effect of cortical excitability on corruption behavior. According to the characteristics of corruption, we designed an incomplete information invest game task based on trust game, then adopted a between-subject design to compare participants' corruption rate and reaction time (RT) among right anodal/left cathodal, left anodal/right cathodal and sham tDCS. The results showed that, in contrast to sham stimulation, left anodal/right cathodal tDCS reduced corruption rate both in high and low entrusted amount while right anodal/left cathodal tDCS only prolonged subjects' reaction time (RT) of dishonest response only in high entrusted amount. A possible explanation for the results of current study is that the left DLPFC is associated with the emotional process, which influenced the moral intuition aspect of moral judgment and reflected in the change of immoral behavior rate. While the right DLPFC is associated with cognitive control, which influenced the moral reasoning aspect of moral judgment and reflected in the change of reaction time. This explanation is also consistent with the Emotion-Evoked Collective Corruption Model and dual process theory of brain function.