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Long-term potentiation (LTP) is the persistent increase in the strength of the synapses. However, the neural networks would become saturated if there is only synaptic strenghthening. Synaptic weakening could be facilitated by active processes like long-term depression (LTD). Molecular mechanisms that facilitate the weakening of synapses and thereby stabilize the synapses are also important in learning and memory. Here we show that blockade of dopaminergic D4 receptors (D4R) promoted the formation of late-LTP and transformed early-LTP into late-LTP. This effect was dependent on protein synthesis, activation of NMDA-receptors and CaMKII. We also show that GABA A -receptor mediated mechanisms are involved in the enhancement of late-LTP. We could show that short-term plasticity and baseline synaptic transmission were unaffected by D4R inhibition. On the other hand, antagonizing D4R prevented both early and late forms of LTD, showing that activation of D4Rs triggered a dual function. Synaptic tagging experiments on LTD showed that D4Rs act as plasticity related proteins rather than the setting of synaptic tags. D4R activation by PD 168077 induced a slow-onset depression that was protein synthesis, NMDAR and CaMKII dependent. The D4 receptors, thus exert a bidirectional modulation of CA1 pyramidal neurons by restricting synaptic strengthening and facilitating synaptic weakening.

A novel dehydrogenation-driven assembly method was proposed to fabricate durable superhydrophobic SiO2/PMHS ORMOSIL (organically modified silica) coatings on cellulose-based substrates. Poly(methylhydrogen)siloxane (PMHS) played the key role in the durability of ORMOSIL coatings and the assembly process. The dehydrogenation-driven assembly mechanism of ORMOSIL was discussed in detail. Results indicated that the chemical property and microstructure of ORMOSIL could be controlled easily by varying the weight ratio of SiO2 to PMHS. The lotus-like ORMOSIL coating could be realized as the weight ratio of SiO2 to PMHS was 1:1. The ORMOSIL coating on wood surface was of self-cleaning property, good transparency and durability (including water-repellency and dimensional stability, mechanical and chemical stability, and UV-resistance). In addition, the SiO2/PMHS ORMOSIL gave cotton good oil/water separation ability. Finally, the dehydrogenation-driven assembly method was simple and low-cost, and it can be applied to fabricate durable superhydrophobic coatings on any other hydroxyl-containing substrates besides the cellulose-based substrates.Graphic abstract

Background Mesenchymal stem cells (MSCs) can improve cutaneous wound healing via the secretion of growth factors. However, the therapeutic efficacy of MSCs varies depending upon their source. Induced pluripotent stem cells are emerging as a promising source of MSCs with the potential to overcome several limitations of adult MSCs. This study compared the effectiveness of conditioned medium of MSCs derived from induced pluripotent stem cells (iMSC-CdM) with that derived from umbilical cord MSCs (uMSC-CdM) in a mouse cutaneous wound healing model. We also investigated the mechanisms of protection. Methods The iMSC-CdM or uMSC-CdM were topically applied to mice cutaneous wound model. The recovery rate, scar formation, inflammation and angiogenesis were measured. We compared angiogenesis cytokine expression between iMSC-CdM and uMSC-CdM and their protective effects on human umbilical vein endothelial cells (HUVECs) under H 2 O 2 -induced injury. The effects of iMSC-CdM on energy metabolism, mitochondria fragmentation and apoptosis were measured. Results Topical application of iMSC-CdM was superior to the uMSC-CdM in accelerating wound closure and enhancing angiogenesis. Expression levels of angiogenetic cytokines were higher in iMSC-CdM than they were in uMSC-CdM. The iMSC-CdM protected HUVECs from H 2 O 2 induced injury more effectively than uMSC-CdM did. Administration of iMSC-CdM stimulated HUVEC proliferation, tube formation and energy metabolism via the ERK pathway. Mechanistically, iMSC-CdM inhibited H 2 O 2 -induced mitochondrial fragmentation and apoptosis of HUVECs. Conclusion Collectively, these findings indicate that iMSC-CdM is more effective than uMSC-CdM in treating cutaneous wounds, and in this way, iMSC-CdM may serve as a more constant and sustainable source for cell-free therapeutic approach. Graphical abstract

Global mega-bay systems are experiencing intensive estuarine engineering (e.g. dredging and reclamation), yet the compound effects and underlying mechanisms driving flood risk amplification remain insufficiently quantified. This study investigates flood risk changes in the Bay-Inlet-Channel system of China’s Greater Bay Area (ranked as the world's fourth largest mega-bay) through extreme value analysis of 1965–2017 water level records using generalized extreme value (GEV) theory and max-stable process modelling. Our results demonstrate spatially heterogeneity in flood risk trends, with differential extreme water level rise changes: 0.22 cm/yr at the bay mouth, 0.65 cm/yr in the inner bay, and 0.56 cm/yr in the upper tidal reach (Shiziyang), coinciding with a risk escalation from Category II (strong) to Category I (extreme). Hydrodynamic analysis reveals that deposition-induced tidal range attenuation at the bay mouth partially moderates flood risk acceleration, whereas synergistic effects of erosional dredging and convergent reclamation amplify both tidal and surge dynamics, consequently exacerbating flood risk in the inner bay, with the tidal reach exhibiting intermediate trends due to energy dissipation through Humen Inlet. Numerical simulations quantify maximum impacts on extreme high water levels, with 9.61% rising associated with slower-propagating waves from reclamation and 3.33% decreased with faster-propagating waves induced by dredging. Projections under SSP5-8.5 sea-level rise scenarios indicate that extreme high water levels will surpass optimized 300-yr return levels defense standards by 2080 (outer bay), 2090 (inner bay), and 2100 (tidal reach). These findings provide critical insights into global flood risk management in engineered mega-bay systems and advance methodological frameworks for extreme water level assessment.

Background Numerous studies have confirmed the involvement of extracellular vesicles (EVs) in various physiological processes, including cellular death and tissue damage. Recently, we reported that EVs derived from ischemia-reperfusion heart exacerbate cardiac injury. However, the role of EVs from healthy heart tissue (heart-derived EVs, or cEVs) on myocardial ischemia-reperfusion (MI/R) injury remains unclear. Results Here, we demonstrated that intramyocardial administration of cEVs significantly enhanced cardiac function and reduced cardiac damage in murine MI/R injury models. cEVs treatment effectively inhibited ferroptosis and maintained mitochondrial homeostasis in cardiomyocytes subjected to ischemia-reperfusion injury. Further results revealed that cEVs can transfer ATP5a1 into cardiomyocytes, thereby suppressing mitochondrial ROS production, alleviating mitochondrial damage, and inhibiting cardiomyocyte ferroptosis. Knockdown of ATP5a1 abolished the protective effects of cEVs. Furthermore, we found that the majority of cEVs are derived from cardiomyocytes, and ATP5a1 in cEVs primarily originates from cardiomyocytes of the healthy murine heart. Moreover, we demonstrated that adipose-derived stem cells (ADSC)-derived EVs with ATP5a1 overexpression showed much better efficacy on the therapy of MI/R injury compared to control ADSC-derived EVs. Conclusions These findings emphasized the protective role of cEVs in cardiac injury and highlighted the therapeutic potential of targeting ATP5a1 as an important approach for managing myocardial damage induced by MI/R injury. Graphical Abstract

The efficacy and safety of chidamide, a new subtype-selective histone deacetylase (HDAC) inhibitor, have been demonstrated in a pivotal phase II clinical trial, and chidamide has been approved by the China Food and Drug Administration (CFDA) as a treatment for relapsed or refractory peripheral T cell lymphoma (PTCL). This study sought to further evaluate the real-world utilization of chidamide in 383 relapsed or refractory PTCL patients from April 2015 to February 2016 in mainland China. For patients receiving chidamide monotherapy ( n  = 256), the overall response rate (ORR) and disease control rate (DCR) were 39.06 and 64.45%, respectively. The ORR and DCR were 51.18 and 74.02%, respectively, for patients receiving chidamide combined with chemotherapy ( n  = 127). For patients receiving chidamide monotherapy and chidamide combined with chemotherapy, the median progression-free survival (PFS) was 129 (95% CI 82 to 194) days for the monotherapy group and 152 (95% CI 93 to 201) days for the combined therapy group ( P  = 0.3266). Most adverse events (AEs) were of grade 1 to 2. AEs of grade 3 or higher that occurred in ≥5% of patients receiving chidamide monotherapy included thrombocytopenia (10.2%) and neutropenia (6.2%). For patients receiving chidamide combined with chemotherapy, grade 3 to 4 AEs that occurred in ≥5% of patients included thrombocytopenia (18.1%), neutropenia (12.6%), anemia (7.1%), and fatigue (5.5%). This large real-world study demonstrates that chidamide has a favorable efficacy and an acceptable safety profile for refractory and relapsed PTCL patients. Chidamide combined with chemotherapy may be a new treatment choice for refractory and relapsed PTCL patients but requires further investigation.

Background Human umbilical cord-derived mesenchymal stem cells (HucMSCs) have been recognized as a promising cell for treating myocardial infarction (MI). Inflammatory response post MI is critical in determining the cardiac function and subsequent adverse left ventricular remodeling. However, the local inflammatory effect of HucMSCs after intramyocardial injection in murine remains unclear. Methods HucMSCs were cultured and transplanted into the mice after MI surgery. Cardiac function of mice were analyzed among MI-N.S, MI-HucMSC and MI-HucMSC-C–C Motif Chemokine receptor 5 (CCR5) antagonist groups, and angiogenesis, fibrosis and hypertrophy, and immune cells infiltration of murine hearts were evaluated between MI-N.S and MI-HucMSC groups. We detected the expression of inflammatory cytokines and their effects on CD4 + T cells migration . Results HucMSCs treatment can significantly improve the cardiac function and some cells can survive at least 28 days after MI. Intramyocardial administration of HucMSCs also improved angiogenesis and alleviated cardiac fibrosis and hypertrophy. Moreover, we found the much higher numbers of CD4 + T cells and CD4 + FoxP3 + regulatory T cells (Tregs) in the heart with HucMSCs than that with N.S treatment on day 7 post MI. In addition, the protein level of C–C Motif Chemokine Ligand 5 (CCL5) greatly increased in HucMSCs treated heart compared to MI-N.S group. In vitro, HucMSCs inhibited CD4 + T cells migration and addition of CCL5 antibody or CCR5 antagonist significantly reversed this effect. In vivo results further showed that addition of CCR5 antagonist can reduce the cardioprotective effect of HucMSCs administration on day 7 post MI injury. Conclusion These findings indicated that HucMSCs contributed to cardiac functional recovery and attenuated cardiac remodeling post MI. Intramyocardial injection of HucMSCs upregulated the CD4 + FoxP3 + Tregs and contributed to the migration of CD4 + T cells into the injured heart via CCL5/CCR5 pathway.

Background Extracellular vesicles (EVs) derived from various cell sources exert cardioprotective effects during cardiac ischemic injury. Our previous study confirmed that EVs derived from ischemic-reperfusion injured heart tissue aggravated cardiac inflammation and dysfunction. However, the role of EVs derived from normal cardiac tissue in myocardial ischemic injury remains elusive. Results In the present study, normal heart-derived EVs (cEVs) and kidney-derived EVs (nEVs) were isolated and intramyocardially injected into mice after myocardial infarction (MI). We demonstrated that administration of both cEVs and nEVs significantly improved cardiac function, reduced the scar size, and alleviated inflammatory infiltration into the heart. In addition, cardiomyocyte apoptosis was inhibited, whereas angiogenesis was enhanced in the hearts receiving cEVs or nEVs treatment. Moreover, intramyocardial injection of cEVs displayed much better cardiac protective efficacy than nEVs in murine MI models. RNA-seq and protein-protein interaction (PPI) network analysis revealed the protective mRNA clusters in both cEVs and nEVs. These mRNAs were involved in multiple signaling pathways, which may synergistically orchestrate to prevent the heart from further damage post MI. Conclusions Collectively, our results indicated that EVs derived from normal heart tissue may represent a promising strategy for cardiac protection in ischemic heart diseases.

Background: This study aimed to describe the technique and outcomes of hemostasis for ultrasound-guided lauromacrogol injection for active bleeding after renal biopsy. Methods: Data from patients with active bleeding after renal biopsy between January 2018 and December 2020 were retrospectively collected. Patients who still had active bleeding after 30 min of compression were then injected with lauromacrogol under ultrasound guidance. The patient’s symptoms before and after operation were collected to assess whether they had severe complications. Changes in hemoglobin and serum creatinine values were collected. Results: Data from a total of 15 patients with active bleeding after renal biopsy were collected, including data of 6 men and 9 women. After the operation, there were 11 cases of mild back pain; 1 case of chills, cold sweats, and back pain; 1 case of cold sweats and blood pressure reduction, and 2 cases with no obvious symptoms. No severe complications occurred in this study, and active bleeding was stopped in all patients. After the operation, compared with before the operation, there was no statistically significant difference in the hemoglobin value and serum creatinine value ( p = 0.10 > 0.05, p = 0.78 > 0.05). Conclusion: Ultrasound-guided lauromacrogol injection is a relatively simple, safe and feasible method, which could be helpful in treating active bleeding in the immediate post-procedure period after renal biopsy.