CGRP Released by Corneal Sensory Nerve Maintains Tear Secretion of the Lacrimal Gland.

Purpose: This study aims to elucidate the calcitonin gene-related peptide (CGRP) mediation and primary mechanism of corneal sensory nerves on tear production of the lacrimal gland. Methods: Mouse corneal denervation models were constructed through surgical axotomy, pharmacologic treatment with capsaicin or resiniferatoxin, and Trpv1-Cre/DTR mice with diphtheria toxin injection. The capsaicin-treated mice received subconjunctival injection of CGRP or substance P, while the normal C57BL/6J mice were administered with CGRP receptor antagonist BIBN-4096. Furthermore, double immunostaining of c-FOS+ and choline acetyltransferase was used to evaluate the activation of the superior salivatory nucleus (SSN). Mouse lacrimal glands were collected for transcriptomic sequencing and subsequent RNA and protein expression analysis. Results: The corneal denervated mice exhibited a significant reduction in corneal sensitivity and tear secretion. In capsaicin-treated mice, tear secretion decreased to 2.5 ± 0.5 mm compared to 6.3 ± 0.9 mm in control mice (P < 0.0001). However, exogenous administration of CGRP in capsaicin-treated mice increased tear secretion from 2.6 ± 0.5 mm to 4.5 ± 0.5 mm (P = 0.0009), while BIBN-4096 treatment reduced tear secretion to 3.4 ± 0.5 mm when compared to 7.3 ± 0.7 mm in control mice (P = 0.0022). Furthermore, c-FOS+ cell number in the SSN increased by twofold (P = 0.0168) after CGRP administration compared with capsaicin-treated mice. In addition, the expressions of CCNA2, Ki67, PCNA, and CDK1 in acinar cells of the lacrimal gland were impaired by corneal denervation and alleviated by CGRP administration. Conclusions: CGRP released by corneal sensory nerves mediates tear secretion of the lacrimal gland, providing a new strategy for improving tear secretion in patients with neurotrophic keratitis.

Tannic Acid-Modified Decellularized Tendon Scaffold with Antioxidant and Anti-Inflammatory Activities for Tendon Regeneration.

Tendon regeneration is greatly influenced by the oxidant and the inflammatory microenvironment. Persistent inflammation during the tendon repair can cause matrix degradation, tendon adhesion, and excessive accumulation of reactive oxygen species (ROS), while excessive ROS affect extracellular matrix remodeling and tendon integration. Herein, we used tannic acid (TA) to modify a decellularized tendon slice (DTS) to fabricate a functional scaffold (DTS-TA) with antioxidant and anti-inflammatory properties for tendon repair. The characterizations and cytocompatibility of the scaffolds were examined in vitro. The antioxidant and anti-inflammatory activities of the scaffold were evaluated in vitro and further studied in vivo using a subcutaneous implantation model. It was found that the modified DTS combined with TA via hydrogen bonds and covalent bonds, and the hydrophilicity, thermal stability, biodegradability, and mechanical characteristics of the scaffold were significantly improved. Afterward, the results demonstrated that DTS-TA could effectively reduce inflammation by increasing the M2/M1 macrophage ratio and interleukin-4 (IL-4) expression, decreasing the secretion of interleukin-6 (IL-6) and interleukin-1ß (IL-1ß), as well as scavenging excessive ROS in vitro and in vivo. In summary, DTS modified with TA provides a potential versatile scaffold for tendon regeneration.

Establishment of mouse model of neurotrophic keratopathy through TRPV1 neuronal ablation.

Neurotrophic keratopathy (NK) is a challenging disease with the reduced innervation to the cornea. To establish a genetic and stable mouse model of NK, we utilized the TRPV1-DTR mice with intraperitoneal injection of diphtheria toxin (DT) to selectively eliminate TRPV1 neurons. After DT administration, the mice exhibited robust ablation of TRPV1 neurons in the trigeminal ganglion, accompanied with reduced corneal sensation and nerve density, as well as the decreased calcitonin-gene-related peptide (CGRP) and substance P levels. According to disease progression of TRPV1 neuronal ablation, tear secretion was reduced from day 3, which followed by corneal epithelial punctate lesions from day 7. From day 11 to day 16, the mice exhibited persistent corneal epithelial defects and stromal edema. By day 21, corneal ulceration and stromal melting were observed with the abundant inflammatory cell infiltration, corneal neovascularization, and enhanced cell apoptosis. Moreover, subconjunctival injection of CGRP delayed the NK progression with the characteristics of reduced severe corneal epithelial lesions and corneal inflammation. In addition, the impairments of conjunctival goblet cells, lacrimal gland, and meibomian gland were identified by the diminished expression of MUC5AC, AQP5, and PPARγ, respectively. Therefore, these results suggest that the TRPV1-DTR mice may serve as a reliable animal model for the research of NK pathogenesis.

IGFBP3 induces PD-L1 expression to promote glioblastoma immune evasion.

BACKGROUND: Glioblastoma (GBM) characterized by immune escape is the most malignant primary brain tumors, which has strong immunosuppressive effect. Programmed death ligand-1 (PD-L1) is a recognized immunosuppressive member on the surface of tumor cells, and plays a crucial role in immune evasion of tumors. Actually, little is known about the regulation of PD-L1 expression in GBM. Insulin-like growth factor binding protein 3 (IGFBP3) is upregulated in GBM and is related to poor patient prognosis. However, it remains unclear whether IGFBP3 plays a role in the regulation of PD-L1 expression in GBM. METHODS: The role of IGFBP3 in the glioma immune microenvironment was investigated using the CIBERSORT algorithm. The correlation between IGFBP3 and PD-L1 expression was analyzed using TCGA and CGGA databases. QRT-PCR, immunoblotting and RNA-seq were used to examine the regulatory effect of IGFBP3 on PD-L1 expression. Co-culture assay, cell counting kit (CCK-8), qRT-PCR, ELISA and flow cytometry were performed to explore the function of IGFBP3 in inducing immunosuppression. The biological role of IGFBP3 was verified using immunohistochemical, immunofluorescence and mice orthotopic tumor model. RESULTS: In this study, we analyzed immune cells infiltration in gliomas and found that IGFBP3 may be associated with an immunosuppressive microenvironment. Then, by analyzing TCGA and CGGA databases, our results showed that IGFBP3 and PD-L1 expression were positively correlated in GBM patients, but not in LGG patients. In vitro experiments conducted on different GBM cell lines revealed that the overexpression of IGFBP3 led to an increase in PD-L1 expression, which was reversible upon knockdown IGFBP3. Mechanistically, IGFBP3 activated the JAK2/STAT3 signaling pathway, leading to an increase in PD-L1 expression. Additionally, co-culture experiments results showed IGFBP3 overexpression induced upregulation of PD-L1 expression promoted apoptosis in Jurkat cells, and this effect was blocked by IGFBP3 antibody and PDL-1 inhibitors. Importantly, in vivo experiments targeting IGFBP3 suppressed tumor growth and significantly prolonged the survival of mice. CONCLUSIONS: This research demonstrated IGFBP3 is a novel regulator for PD-L1 expression in GBM, and identified a new mechanism by which IGFBP3 regulates immune evasion through PD-L1, suggesting that IGFBP3 may be a potential novel target for GBM therapy.

Aberrant dynamic functional connectivity of thalamocortical circuitry in major depressive disorder. / é‡åº¦æŠ‘éƒéšœç¢æ‚£è€ ä¸˜è„‘çš®å±‚çŽ¯è·¯çš„åŠ¨æ€åŠŸèƒ½è¿žæŽ¥å¼‚å¸¸.

Thalamocortical circuitry has a substantial impact on emotion and cognition. Previous studies have demonstrated alterations in thalamocortical functional connectivity (FC), characterized by region-dependent hypo- or hyper-connectivity, among individuals with major depressive disorder (MDD). However, the dynamical reconfiguration of the thalamocortical system over time and potential abnormalities in dynamic thalamocortical connectivity associated with MDD remain unclear. Hence, we analyzed dynamic FC (dFC) between ten thalamic subregions and seven cortical subnetworks from resting-state functional magnetic resonance images of 48 patients with MDD and 57 healthy controls (HCs) to investigate time-varying changes in thalamocortical FC in patients with MDD. Moreover, dynamic laterality analysis was conducted to examine the changes in functional lateralization of the thalamocortical system over time. Correlations between the dynamic measures of thalamocortical FC and clinical assessment were also calculated. We identified four dynamic states of thalamocortical circuitry wherein patients with MDD exhibited decreased fractional time and reduced transitions within a negative connectivity state that showed strong correlations with primary cortical networks, compared with the HCs. In addition, MDD patients also exhibited increased fluctuations in functional laterality in the thalamocortical system across the scan duration. The thalamo-subnetwork analysis unveiled abnormal dFC variability involving higher-order cortical networks in the MDD cohort. Significant correlations were found between increased dFC variability with dorsal attention and default mode networks and the severity of symptoms. Our study comprehensively investigated the pattern of alteration of the thalamocortical dFC in MDD patients. The heterogeneous alterations of dFC between the thalamus and both primary and higher-order cortical networks may help characterize the deficits of sensory and cognitive processing in MDD.

Diagnostic Performance of 3D-NERVE as an Adjunct to Electromyography for the Assessment of Brachial Plexus Injury in Infants.

Objective: This study aimed to explore diagnostic performance of 3D-NERVE as an adjunct to electromyography for the assessment of brachial plexus injury in infants. Methods: Imaging of infants with brachial plexus injury using 3D-NERVE and/or 3D-STIR from 2019 to 2022 were reviewed. Images were evaluated between the 2 sequences for nerve-to-fat ratio, nerve-to-muscle ratio, muscle-to-fat ratio, fat suppression homogeneity, and display rate of brachial plexus branches. Results: This study included 37 infants who were referred for a clinical diagnosis of brachial plexus injury. A total of 21 infants accepted 3D-NERVE sequence scanning, and 16 infants accepted 3D-NERVE and 3D-STIR sequences scanning. The results of examination were generally consistent with electromyography. The 2 sequences were compared, yielding the following results. There were no pulsation artifacts (0/16), and 1 case with heterogeneous fat saturation (1/16) was seen on 3D-NERVE. There were no pulsation artifacts (0/16), and 5 cases with heterogeneous fat saturation (5/16) were seen on 3D-STIR. 3D-NERVE performed better (P < .05) for nerve-to-fat and nerve-to-muscle ratios compared with 3D-STIR, and no significant difference in the muscle-to-fat ratio (P > .05). The 3D-NERVE and STIR helped depict 100% (16/16) of the brachial roots and brachial plexus trunk. Brachial plexus bundles and brachial plexus branches were observed in 93.75% (15/16) and 68.75% (11/16) of the 3D-NERVE and 93.75% (15/16) and 62.5% (10/16) of the 3D-STIR, respectively. The differences were not statistically significant (P > .05). Conclusion: Nerve trauma was better visualized with the 3D-NERVE, which is an effective adjunct to electromyography for doctors to assess brachial plexus injury and consequently helps in better treatment planning.

Decellularized tendon scaffolds loaded with collagen targeted extracellular vesicles from tendon-derived stem cells facilitate tendon regeneration.

Stem cell-based treatment of tendon injuries remains to have some inherent issues. Extracellular vesicles derived from stem cells have shown promising achievements in tendon regeneration, though their retention in vivo is low. This study reports on the use of a collagen binding domain (CBD) to bind extracellular vesicles, obtained from tendon-derived stem cells (TDSCs), to collagen. CBD-extracellular vesicles (CBD-EVs) were coupled to decellularized bovine tendon sheets (DBTS) to fabricate a bio-functionalized scaffold (CBD-EVs-DBTS). Our results show that thus obtained bio-functionalized scaffolds facilitate the proliferation, migration and tenogenic differentiation of stem cells in vitro. Furthermore, the scaffolds promote endogenous stem cell recruitment to the defects, facilitate collagen deposition and improve the biomechanics of injured tendons, thus resulting in functional regeneration of tendons.

5-Demethylnobiletin mediates cell cycle arrest and apoptosis via the ERK1/2/AKT/STAT3 signaling pathways in glioblastoma cells.

5-Demethylnobiletin is the active ingredient in citrus polymethoxyflavones that could inhibit the proliferation of several tumor cells. However, the anti-tumor effect of 5-Demethylnobiletin on glioblastoma and the underlying molecular mechanisms are remains unknown. In our study, 5-Demethylnobiletin markedly inhibited the viability, migration and invasion of glioblastoma U87-MG, A172 and U251 cells. Further research revealed that 5-Demethylnobiletin induces cell cycle arrest at the G0/G1 phase in glioblastoma cells by downregulating Cyclin D1 and CDK6 expression levels. Furthermore, 5-Demethylnobiletin significantly induced glioblastoma cells apoptosis by upregulating the protein levels of Bax and downregulating the protein level of Bcl-2, subsequently increasing the expression of cleaved caspase-3 and cleaved caspase-9. Mechanically, 5-Demethylnobiletin trigged G0/G1 phase arrest and apoptosis by inhibiting the ERK1/2, AKT and STAT3 signaling pathway. Furthermore, 5-Demethylnobiletin inhibition of U87-MG cell growth was reproducible in vivo model. Therefore, 5-Demethylnobiletin is a promising bioactive agent that might be used as glioblastoma treatment drug.

IGFBP3 induced by the TGF-ß/EGFRvIII transactivation contributes to the malignant phenotype of glioblastoma.

Dual or multi-targets therapy targeting epidermal growth factor receptor variant III (EGFRvIII) and other molecular may relax the constraint for glioblastoma (GBM), putting forward the urgent requirement of finding candidate molecules. Here, the insulin-like growth factor binding protein-3 (IGFBP3) was considered a candidate, whereas the mechanisms of IGFBP3 production remain unclear. We treated GBM cells with exogenous transforming growth factor ß (TGF-ß) to simulate the microenvironment. We found that TGF-ß and EGFRvIII transactivation induced the activation of transcription factor c-Jun, which specifically bound to the promoter region of IGFBP3 through Smad2/3 and ERK1/2 pathways and promoted the production and secretion of IGFBP3. IGFBP3 knockdown inhibited the activation of TGF-ß and EGFRvIII signals and the malignant behaviors triggered by them in vitro and in vivo. Collectively, our results indicated a positive feedback loop of p-EGFRvIII/IGFBP3 under administration of TGF-ß, blocking IGFBP3 may be an additional target in EGFRvIII-expressing GBM-selective therapeutic strategy.

Spatiotemporal Developmental Gradient of Thalamic Morphology, Microstructure, and Connectivity fromthe Third Trimester to Early Infancy.

Thalamus is a critical component of the limbic system that is extensively involved in both basic and high-order brain functions. However, how the thalamic structure and function develops at macroscopic and microscopic scales during the perinatal period development is not yet well characterized. Here, we used multishell high-angular resolution diffusion MRI of 144 preterm-born and full-term infants in both sexes scanned at 32-44 postmenstrual weeks (PMWs) from the Developing Human Connectome Project database to investigate the thalamic development in morphology, microstructure, associated connectivity, and subnucleus division. We found evident anatomic expansion and linear increases of fiber integrity in the lateral side of thalamus compared with the medial part. The tractography results indicated that thalamic connection to the frontal cortex developed later than the other thalamocortical connections (parieto-occipital, motor, somatosensory, and temporal). Using a connectivity-based segmentation strategy, we revealed that functional partitions of thalamic subdivisions were formed at 32 PMWs or earlier, and the partition developed toward the adult pattern in a lateral-to-medial pattern. Collectively, these findings revealed faster development of the lateral thalamus than the central part as well as a posterior-to-anterior developmental gradient of thalamocortical connectivity from the third trimester to early infancy.SIGNIFICANCE STATEMENT This is the first study that characterizes the spatiotemporal developmental pattern of thalamus during the third trimester to early infancy. We found that thalamus develops in a lateral-to-medial pattern for both thalamic microstructures and subdivisions; and thalamocortical connectivity develops in a posterior-to-anterior gradient that thalamofrontal connectivity appears later than the other thalamocortical connections. These findings may enrich our understanding of the developmental principles of thalamus and provide references for the atypical brain growth in neurodevelopmental disorders.

Amazing roles of extrachromosomal DNA in cancer progression.

In cancers, extrachromosomal DNA (ecDNA) has gained renewed interest since its first discovery, presenting its roles in tumorigenesis. Because of the unique structure and genetic characteristics, extrachromosomal DNA shed new light on development, early diagnosis, treatment and prognosis of cancers. Occurs in cancer cells, extrachromosomal DNA, one dissociative circular extrachromosomal element, drives the amplification of oncogenes, promotes the transcription and lifts tumor heterogeneity to participate in tumorigenesis. Given its role act as messenger, extrachromosomal DNA is connected with drug resistance, tumor microenvironment, germline and aging. The diversity of space and time gives extrachromosomal DNA a crucial role in cancer progression that has been ignored for decades. Thus, in this review, we will focus on some unique information of extrachromosomal DNA and the regulation of oncogenes as well as its roles and possible mechanisms in tumorigenesis, which are of great significance for us to understand extrachromosomal DNA comprehensively in carcinogenic mechanism.

The immunosuppressive microenvironment and immunotherapy in human glioblastoma.

Glioblastoma multiforme (GBM) is the most malignant intracranial tumor in adults, characterized by extensive infiltrative growth, high vascularization, and resistance to multiple therapeutic approaches. Among the many factors affecting the therapeutic effect, the immunosuppressive GBM microenvironment that is created by cells and associated molecules via complex mechanisms plays a particularly important role in facilitating evasion of the tumor from the immune response. Accumulating evidence is also revealing a close association of the gut microbiota with the challenges in the treatment of GBM. The gut microbiota establishes a connection with the central nervous system through bidirectional signals of the gut-brain axis, thus affecting the occurrence and development of GBM. In this review, we discuss the key immunosuppressive components in the tumor microenvironment, along with the regulatory mechanism of the gut microbiota involved in immunity and metabolism in the GBM microenvironment. Lastly, we concentrate on the immunotherapeutic strategies currently under investigation, which hold promise to overcome the hurdles of the immunosuppressive tumor microenvironment and improve the therapeutic outcome for patients with GBM.

EEG-based evaluation of motion sickness and reducing sensory conflict in a simulated autonomous driving environment.

Autonomous driving offers significant potential for changes in the automotive industry. However, sensory conflict during autonomous driving can lead to motion sickness. Quantitative evaluation and effective preventions to predict and reduce motion sickness are needed. The goal of this study is to verify the objective indicator of motion sickness level based on encephalography (EEG) that we proposed before and investigate the influence of attenuating sensory conflict on motion sickness. A 6-degree of freedom (DOF) driving simulator platform was used to provide an autonomous driving environment to the subjects, and the subjective motion sickness level (MSL), as well as the EEG signals of 15 healthy subjects, were collected simultaneously during 3 conditions, i) autonomous driving, ii) autonomous driving with eyes blindfolded and iii) active driving. The MSLs were reported by the subjects every two minutes, providing a reference to the recorded EEG signals. The EEG signals were analyzed and compared among different conditions. Average MSLs were higher in autonomous driving than in autonomous driving with eyes blindfolded and active driving, together with the increase of the mean EEG frequency of theta band in the central, parietal and occipital areas (FC5, Cz, CP5, P3, and POz). These findings validated that EEG mean frequency of theta band could be an indicator of motion sickness, besides an attenuated visual input or active control of the vehicle can effectively reduce the generation of motion sickness.

Dendrobium nobile-derived polysaccharides ameliorate spermatogenic disorders in mice with streptozotocin-induced diabetes through regulation of the glycolytic pathway.

Dysfunction of spermatogenesis is a major complication of diabetes mellitus (DM). This study characterized the protective effects of Dendrobium nobile-derived polysaccharides (DNP) against spermatogenetic dysfunction in mice with streptozotocin (STZ)-induced diabetes. The diabetic mice had lower body and testicular mass, and fewer spermatozoa with a higher incidence of malformation. The testicular histology showed disordered narrow seminiferous tubules covering a smaller area, and fewer spermatogenic cells. Moreover, the qRT-PCR analysis indicated that DM was associated with high expression of the pro-apoptotic factor Bax and low expression of the anti-apoptotic factor Bcl-2 in the testes. The qRT-PCR and immunohistochemical analysis clarified that DM was also associated with low testicular expression of the Sertoli cell (SC) markers GATA-4, WT1, and vimentin, and genes encoding the glycolytic rate-limiting enzymes LDHA, PKM2, and HK2. DNP treatment increased the body and testicular masses, sperm count, and number of spermatogenic cells of the mice, and reduced the proportion of abnormal sperm. DNP also reduced the expression of Bax, and increased that of Bcl-2, GATA-4, WT1, vimentin, LDHA, PKM2, and HK2, in the testes of the diabetic mice. Thus, DNP protects against spermatogenic dysfunction in diabetic mice by inhibiting apoptosis and activating the glycolytic pathway in their testes.

Temporal Grading Index of Functional Network Topology Predicts Pain Perception of Patients With Chronic Back Pain.

Chronic back pain (CBP) is a maladaptive health problem affecting the brain function and behavior of the patient. Accumulating evidence has shown that CBP may alter the organization of functional brain networks; however, whether the severity of CBP is associated with changes in dynamics of functional network topology remains unclear. Here, we generated dynamic functional networks based on resting-state functional magnetic resonance imaging (rs-fMRI) of 34 patients with CBP and 34 age-matched healthy controls (HC) in the OpenPain database via a sliding window approach, and extracted nodal degree, clustering coefficient (CC), and participation coefficient (PC) of all windows as features to characterize changes of network topology at temporal scale. A novel feature, named temporal grading index (TGI), was proposed to quantify the temporal deviation of each network property of a patient with CBP to the normal oscillation of the HCs. The TGI of the three features achieved outstanding performance in predicting pain intensity on three commonly used regression models (i.e., SVR, Lasso, and elastic net) through a 5-fold cross-validation strategy, with the minimum mean square error of 0.25 ± 0.05; and the TGI was not related to depression symptoms of the patients. Furthermore, compared to the HCs, brain regions that contributed most to prediction showed significantly higher CC and lower PC across time windows in the CBP cohort. These results highlighted spatiotemporal changes in functional network topology in patients with CBP, which might serve as a valuable biomarker for assessing the sensation of pain in the brain and may facilitate the development of CBP management/therapy approaches.

The Role of NcRNAs to Regulate Immune Checkpoints in Cancer.

At present, the incidence of cancer is becoming more and more common, but its treatment has always been a problem. Although a small number of cancers can be treated, the recurrence rates are generally high and cannot be completely cured. At present, conventional cancer therapies mainly include chemotherapy and radiotherapy, which are the first-line therapies for most cancer patients, but there are palliatives. Approaches to cancer treatment are not as fast as cancer development. The current cancer treatments have not been effective in stopping the development of cancer, and cancer treatment needs to be imported into new strategies. Non-coding RNAs (ncRNAs) is a hot research topic at present. NcRNAs, which include microRNAs (miRNAs), circular RNAs (circRNAs), and long non-coding RNAs (lncRNAs), participate in all aspects of cancer biology. They are involved in the progression of tumors into a new form, including B-cell lymphoma, glioma, or the parenchymal tumors such as gastric cancer and colon cancer, among others. NcRNAs target various immune checkpoints to affect tumor proliferation, differentiation, and development. This might represent a new strategy for cancer treatment.

Experimental and Numerical Study on Friction and Wear Performance of Hot Extrusion Die Materials.

For the aluminium alloys produced by the hot extrusion process, the profile is shaped according to the bearing at the exit of the extrusion die. The tribological process has significant effects on the die service life, profile dimensional tolerances, and profile surface finish. Recently, new technologies have been introduced to the hot extrusion die, such as cemented carbide insert die and surface coating. However, under hot extrusion working conditions, quantitative studies on their friction and wear performances are lacking. In this work, the friction and wear performances of three typical extrusion die materials, traditional hot tool steel (H13), cemented carbide (YG8), and chemical vapour deposition (CVD) coating, were studied. Macro and nano hardness tests, Pin-on-disk friction and wear tests, optical profiler and SEM observations, and experiments and simulations of hot extrusion were conducted. The results show that the coefficients of friction of CVD coatings and H13 hot work tool steel specimens were smaller under the hot extrusion condition than at room temperature. The wear mechanisms of H13, YG8, and CVD coatings at 500 °C are adhesion, abrasive, and fatigue, respectively. Moreover, the tribology results were validated by the extrusion experiments and the finite element analysis of hot extrusion. The conclusion of this manuscript is useful not only for the numerical simulation of the hot extrusion process but also for the surface finishing of the extrusion profile.

Nodding Duck Structure Multi-track Directional Freestanding Triboelectric Nanogenerator toward Low-Frequency Ocean Wave Energy Harvesting.

Development of ocean energy conversion technique is a strategic requirement to optimize the energy structure and expand the "blue economic" space. Triboelectric nanogenerator (TENG) provides a potential approach for efficiently capturing wave energy with its unique advantages. Herein, a nodding duck structure multi-track freestanding triboelectric-layer nanogenerator (NDM-FTENG) is developed for ocean wave energy harvesting at a low-frequency range. Configuration parameters including track numbers, connection approach, oscillation frequency, and swing amplitude on electrical output performances of NDM-FTENG are systematically investigated and optimized; the maximum instantaneous power density of 4 W/m3 is obtained by one NDM-FTENG block with 320 LEDs lighted up simultaneously. Overall, NDM-FTENG is proved to be an efficient device for driving small electronics with excellent stability and durability in a real water wave environment, and the power potential can be further magnified by combining more NDM-FTENG devices in parallel to form a network toward large-scale blue energy harvesting.

Design, synthesis and biological evaluation of imidazolopyridone derivatives as novel BRD4 inhibitors.

Bromodomain containing protein 4 (BRD4) has been demonstrated to play critical roles in cellular proliferation and cell cycle progression. In this study, using the BRD4 inhibitor Fragment 9 as a lead compound, a series of imidazolopyridone derivatives were designed and tested for their inhibitory activity against BRD4 protein in vitro. Among them, HB100-A7 showed excellent BRD4(1) inhibitory activities with an IC50 value of 0.035 µM in amplified luminescent proximity homogeneous assay (Alphascreen). The result of MTT assay showed that HB100-A7 could suppress the proliferation of pancreatic cancer cells. In addition, flow cytometry further illustrated that HB100-A7 treatment resulted in G0/G1 phase arrest and promoted apoptosis of BxPc3 cells. Furthermore, the in vivo study found that HB100-A7 displayed significant tumor growth inhibition in a pancreatic mouse tumor model (Panc-02). Moreover, IHC staining suggested that HB100-A7 induce cell apoptosis in pancreatic cancer tumor tissue. Together, this study revealed, for the first time, HB100-A7 is a promising lead compound for further development as a new generation of small molecule inhibitors targeting the BRD4 protein.

Tuning Surface Wettability of Buffer Layers by Incorporating Polyethylene Glycols for Enhanced Performance of Perovskite Solar Cells.

Phenyl-C61-butyric acid methyl ester (PCBM) has been widely researched as a passivate electron transport layer in planar n-i-p-type perovskite solar cells (PSCs). However, due to the terrible wettability of PCBM, the growth of perfect large-area perovskite films on the electron transport layer treated by PCBM is a huge challenge, which limits the commercial application of PSCs. Herein, we incorporate a hydrophilic polymer polyethylene glycol (PEG) into PCBM to ameliorate its wettability. A high-quality perovskite film can be prepared on a 2 × 2 cm substrate. Hydrogen-bonding effects between the PEG-PCBM buffer layer and the perovskite layer can further stabilize the electron transport layer/perovskite interface. Based on the improved electron transport and suppressed carrier recombination, a device with an active area of 1.03 cm2 achieves an efficiency of 18.25%. In addition, the first-principles calculations indicate that PEG has stronger adsorption (Eads = -0.37) toward H2O than the MAPbI3 perovskite (Eads = -0.25), which can prevent water molecules from infiltrating the perovskite. The unsealed device still maintains 90% of the initial efficiency under ambient conditions, with 30-40% relative humidity for 22 days. These outstanding properties are attributed to the unique molecular structure and prominent wettability of PEG.