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Wnt signaling pathways are transmitted via 10 homologous frizzled receptors (FZD1-10) in humans. Reagents broadly inhibiting Wnt signaling pathways reduce growth and metastasis of many tumors, but their therapeutic development has been hampered by the side effect. Inhibitors targeting specific Wnt-FZD pair(s) enriched in cancer cells may reduce side effect, but the therapeutic effect of narrow-spectrum Wnt-FZD inhibitors remains to be established in vivo. Here, we developed a fragment of C. difficile toxin B (TcdBFBD), which recognizes and inhibits a subclass of FZDs, FZD1/2/7, and examined whether targeting this FZD subgroup may offer therapeutic benefits for treating breast cancer models in mice. Utilizing 2 basal-like and 1 luminal-like breast cancer models, we found that TcdBFBD reduces tumor-initiating cells and attenuates growth of basal-like mammary tumor organoids and xenografted tumors, without damaging Wnt-sensitive tissues such as bones in vivo. Furthermore, FZD1/2/7-positive cells are enriched in chemotherapy-resistant cells in both basal-like and luminal mammary tumors treated with cisplatin, and TcdBFBD synergizes strongly with cisplatin in inhibiting both tumor types. These data demonstrate the therapeutic value of narrow-spectrum Wnt signaling inhibitor in treating breast cancers.

Objective To explore the regulatory mechanism of microglia apoptosis in neuroinflammation. Methods LPS was used to establish mouse microglia cell line BV2 cells as a neuroinflammatory microglia model, IL-6 antagonist siltuximab was applied to treat LPS-induced BV2 cells. CCK-8 was used to detect the proliferation of cells. Cell apoptosis was detected by flow cytometry. ELISA kit was used to detect the content of pro-inflammatory related factors IL-6 and TNF-α. The expression of M1 polarization markers IL-1β, IFN-γ and M2 polarization markers CD206, Arg-1 in BV2 cell was detected by qRT-PCR. The expression of JAK-STAT3 signaling pathway key proteins and necroptosis related proteins RIP1 and RIP3 was detected by Western blot. Results After LPS induction, the proliferation of BV2 cells decreased, apoptosis increased, and the contents of inflammatory factors IL-6 and TNF-α increased (P＜0.01). The expression of M1 polarization markers IL-1β and IFN-γ increased, and the expression of M2 polarization markers CD206 and Arg-1 decreased(P＜0.01). The phosphorylation of JAK-STAT3 key protein increased, and the relative protein expression of RIP1 and RIP3 (P＜0.01). After treatment with IL-6 antagonist siltuximab, phosphorylation of JAK-STAT3 key proteins decreased, and RIP1 and RIP3 protein decreased (P＜0.01). Conclusions IL-6 may activate JAK-STAT3 signaling pathway to promote necroptosis of mouse microglia in neuroinflammation.

Acquired brain injury (ABI) is an injury that affects the brain structure and function. Traditional ABI treatment strategies, including medications and rehabilitation therapy, exhibit their ability to improve its impairments in cognition, emotion, and physical activity. Recently, near-infrared (NIR) photobiomodulation (PBM) has emerged as a promising physical intervention method for ABI, demonstrating that low-level light therapy can modulate cellular metabolic processes, reduce the inflammation and reactive oxygen species of ABI microenvironments, and promote neural repair and regeneration. Preclinical studies using ABI models have been carried out, revealing the potential of PBM in promoting brain injury recovery although its clinical application is still in its early stages. In this review, we first inspected the possible physical and biological mechanisms of NIR-PBM, and then reported the pathophysiology and physiology of ABI underlying NIR-PBM intervention. Therefore, the potential of NIR-PBM as a therapeutic intervention in ABI was demonstrated and it is also expected that further work can facilitate its clinical applications. [ABSTRACT FROM AUTHOR]

Previous studies have found a processing difference between unaccusative sentences and unergative sentences. Theyargued that the difference is derived from a syntactic difference, i.e. an unaccusative sentence involves movement whereas anunergative sentence does not. In this study, we are going to show that those studies are uninterpretable due to uncontrolledstimuli and confounds in the materials. After examining their data anlysis, we argue that the effects they found does seem to bestable. This reopens the question whether there is a syntactic difference between unaccusative and unergative verbs.

The consumption of low-mineral water has been increasing worldwide. Drinking low-mineral water is associated with cardiovascular disease, osteopenia, and certain neurodegenerative diseases. However, the specific mechanism remains unclear. The liver metabolic alterations in rats induced by drinking purified water for 3 months were investigated with a metabolomics-based strategy. Compared with the tap water group, 74 metabolites were significantly changed in the purified water group (6 increased and 68 decreased), including 29 amino acids, 11 carbohydrates, 10 fatty acids, 7 short chain fatty acids (SCFAs), and 17 other biomolecules. Eight metabolic pathways were significantly changed, namely aminoacyl–tRNA biosynthesis; nitrogen metabolism; alanine, aspartate and glutamate metabolism; arginine and proline metabolism; histidine metabolism; biosynthesis of unsaturated fatty acids; butanoate metabolism; and glycine, serine and threonine metabolism. These changes suggested that consumption of purified water induced negative nitrogen balance, reduced expression of some polyunsaturated fatty acids and SCFAs, and disturbed energy metabolism in rats. These metabolic disturbances may contribute to low-mineral-water-associated health risks. The health risk of consuming low-mineral water requires attention. [ABSTRACT FROM AUTHOR]

The interdependence of various energy forms and flexible cooperative operation between different units in an integrated energy system (IES) are essential for carbon emission reduction. To address the planning problem of an electric–thermal integrated energy system under low-carbon conditions and to fully consider the low carbon and construction sequence of the integrated energy system, a low-carbon-oriented capacity optimization method for the electric–thermal integrated energy system that considers construction time sequence (CTS) and uncertainty is proposed. A calculation model for the carbon transaction cost under the ladder carbon trading mechanism was constructed, and a multi-stage planning model of the integrated energy system was established with the minimum life cycle cost, considering carbon transaction cost as the objective function, to make the optimal decision on equipment configuration in each planning stage. Finally, a case study was considered to verify the advantages of the proposed capacity optimization method in terms of economy and environmental friendliness through a comparative analysis of different planning cases. Simulation results show that, compared with the scenario of completing planning at the beginning of the life cycle at one time, the proposed low-carbon-oriented capacity optimization method that considers construction time sequence and uncertainty can not only reduce the cost of the integrated energy system, but also help to enhance renewable energy utilization and reduce the system's carbon emissions; the total cost of phased planning is reduced by 11.91% compared to the total cost of one-time planning at the beginning of the year. [ABSTRACT FROM AUTHOR]

The Unaccusative Hypothesis (UH) predicts that the subject of an unaccusative is mentally reactivated in the objectposition. Previous psycholinguistic studies have reported evidence of reactivation (Friedmann et al 2008, Koring et al 2012).However, these studies did not equate the unaccusative and unergative stimuli, resulting in confounds which jeopardize theirconclusions. We reexamined UH with two Visual World Paradigm experiments carefully controlled for the potential confoundsin the previous studies. On each trial, participants (n=40; n=52) saw 4 black-and-white drawings and heard a sentence. In thetest condition, but not the control condition, one image was semantically related to subject of the sentence. We measured theproportion of looks to the target image at three time regions after the verb onset and found a robust match-effect (p’s