Efficient hydrogen evolution via electrocatalytic water splitting holds great promise in modern energy devices. Herein, we demonstrate that the localized surface plasmon resonance (LSPR) excitation ...of Au nanorods (NRs) dramatically improves the electrocatalytic hydrogen evolution activity of CoFe‐metal–organic framework nanosheets (CoFe‐MOFNs), leading to a more than 4‐fold increase of current density at −0.236 V (vs. RHE) for Au/CoFe‐MOFNs composite under light irradiation versus in dark. Mechanistic investigations reveal that the hydrogen evolution enhancement can be largely attributed to the injection of hot electrons from AuNRs to CoFe‐MOFNs, raising the Fermi level of CoFe‐MOFNs, facilitating the reduction of H2O and affording decreased activation energy for HER. This study highlights the superiority of plasmonic excitation on improving electrocatalytic efficiency of MOFs and provides a novel avenue towards the design of highly efficient water‐splitting systems under light irradiation.
Some like it hot: A composite of Au nanorods/CoFe‐MOF nanosheets (Au/CoFe‐MOFNs) was used as an electrocatalyst for the hydrogen evolution reaction (HER). Au/CoFe‐MOFNs give a four‐fold increase of current density and a much reduced activation energy upon light irradiation as a result of hot‐electron injection from plasmonic Au to CoFe‐MOFNs.
Targeting CD47/SIRPα axis has emerged as a promising strategy in cancer immunotherapy. Despite the encouraging clinical efficacy observed in hematologic malignancies through CD47-SIRPα blockade, ...there are safety concerns related to the binding of anti-CD47 antibodies to CD47 on the membrane of peripheral blood cells.
In order to enhance the selectivity and therapeutic efficacy of the antibody, we developed a humanized anti-CD47 monoclonal antibody called Gentulizumab (GenSci059). The binding capacity of GenSci059 to CD47 was evaluated using flow cytometry and surface plasmon resonance (SPR) methods, the inhibitory effect of GenSci059 on the CD47-SIRPα interaction was evaluated through competitive ELISA assays. The anti-tumor activity of GenSci059 was assessed using in vitro macrophage models and in vivo patient-derived xenograft (PDX) models. To evaluate the safety profile of GenSci059, binding assays were conducted using blood cells. Additionally, we investigated the underlying mechanisms contributing to the weaker binding of GenSci059 to erythrocytes. Finally, toxicity studies were performed in non-human primates to assess the potential risks associated with GenSci059.
GenSci059 displayed strong binding to CD47 in both human and monkey, and effectively inhibited the CD47-SIRPα interaction. With doses ranging from 5 to 20 mg/kg, GenSci059 demonstrated potent inhibition of the growth of subcutaneous tumor with the inhibition rates ranged from 30.3% to complete regression. Combination of GenSci059 with 2.5 mg/kg Rituximab at a dose of 2.5 mg/kg showed enhanced tumor inhibition compared to monotherapy, exhibiting synergistic effects. GenSci059 exhibited minimal binding to hRBCs compared to Hu5F9-G4. The binding of GenSci059 to CD47 depended on the cyclization of N-terminal pyroglutamic acid and the spatial conformation of CD47, but was not affected by its glycosylation modifications. A maximum tolerated dose (MTD) of 450 mg/kg was observed for GenSci059, and no significant adverse effects were observed in repeated dosages up to 10 + 300 mg/kg, indicating a favorable safety profile.
GenSci059 selectively binds to CD47, effectively blocks the CD47/SIRPα axis signaling pathway and enhances the phagocytosis effects of macrophages toward tumor cells. This monoclonal antibody demonstrates potent antitumor activity and exhibits a favorable safety profile, positioning it as a promising and effective therapeutic option for cancer.
We report that continuous MOF films with highly controlled thickness (from 44 to 5100 nm) can be deposited over length scales greater than 80 centimeters by a facile, fast, and cost‐effective ...spray‐coating method. Such success relies on our discovery of unprecedented perfectly dispersed colloidal solutions consisting of amorphous MOF nanoparticles, which we adopted as precursors that readily converted to the crystalline films upon low‐temperature in situ heating. The colloidal solutions allow for the fabrication of compact and uniform MOF films on a great deal of substrates such as fluorine‐doped tin oxide, glass, SiO2, Al2O3, Si, Cu, and even flexible polycarbonate, widening their technological applications where substrates are essential. Despite the present work focuses on the fabrication of uniform cobalt‐(2‐methylimidazole)2 and zinc‐(2‐methylimidazole)2 films, our findings mark a great possibility in producing other high‐quality MOF thin films on a large scale.
An unconventional ZIF‐67 colloidal dispersion consisting of amorphous nanoparticles has been discovered, which was used as precursors to yield uniform films that deposited onto a number of substrates by a facile, fast, and cost‐effective spray‐coating approach, enabling fabrication of large‐area ZIF‐67 thin films with highly controlled thickness. This method can be extended to fabricate ZIF‐8 thin film.
The major energy source for most cells is glucose, from which ATP is generated via glycolysis and/or oxidative metabolism. Glucose deprivation activates AMP-activated protein kinase (AMPK), but it is ...unclear whether this activation occurs solely via changes in AMP or ADP, the classical activators of AMPK. Here, we describe an AMP/ADP-independent mechanism that triggers AMPK activation by sensing the absence of fructose-1,6-bisphosphate (FBP), with AMPK being progressively activated as extracellular glucose and intracellular FBP decrease. When unoccupied by FBP, aldolases promote the formation of a lysosomal complex containing at least v-ATPase, ragulator, axin, liver kinase B1 (LKB1) and AMPK, which has previously been shown to be required for AMPK activation. Knockdown of aldolases activates AMPK even in cells with abundant glucose, whereas the catalysis-defective D34S aldolase mutant, which still binds FBP, blocks AMPK activation. Cell-free reconstitution assays show that addition of FBP disrupts the association of axin and LKB1 with v-ATPase and ragulator. Importantly, in some cell types AMP/ATP and ADP/ATP ratios remain unchanged during acute glucose starvation, and intact AMP-binding sites on AMPK are not required for AMPK activation. These results establish that aldolase, as well as being a glycolytic enzyme, is a sensor of glucose availability that regulates AMPK.
Chronic visceral pain is a major challenge for both patients and health providers. Although the central sensitization of the brain is thought to play an important role in the development of visceral ...pain, the detailed neural circuits remain largely unknown. Using a well-established chronic visceral hypersensitivity model induced by neonatal maternal deprivation (NMD) in male mice, we identified a distinct pathway whereby the claustrum (CL) glutamatergic neuron projecting to the anterior cingulate cortex (ACC) is critical for visceral pain but not for CFA-evoked inflammatory pain. By a combination of
circuit-dissecting extracellular electrophysiological approaches and visceral pain related electromyographic (EMG) recordings, we demonstrated that optogenetic inhibition of CL glutamatergic activity suppressed the ACC neural activity and visceral hypersensitivity of NMD mice whereas selective activation of CL glutamatergic activity enhanced the ACC neural activity and evoked visceral pain of control mice. Further, optogenetic studies demonstrate a causal link between such neuronal activity and visceral pain behaviors. Chemogenetic activation or inhibition of ACC neural activities reversed the effects of optogenetic manipulation of CL neural activities on visceral pain responses. Importantly, molecular detection showed that NMD significantly enhances the expression of NMDA receptors and activated CaMKIIα in the ACC postsynaptic density (PSD) region. Together, our data establish a functional role for CL→ACC glutamatergic neurons in gating visceral pain, thus providing a potential treatment strategy for visceral pain.
Studies have shown that sensitization of anterior cingulate cortex (ACC) plays an important role in chronic pain. However, it is as yet unknown whether there is a specific brain region and a distinct neural circuit that helps the ACC to distinguish visceral and somatic pain. The present study demonstrates that claustrum (CL) glutamatergic neurons maybe responding to colorectal distention (CRD) rather than somatic stimulation and that a CL glutamatergic projection to ACC glutamatergic neuron regulates visceral pain in mice. Furthermore, excessive NMDA receptors and overactive CaMKIIα in the ACC postsynaptic density (PSD) region were observed in mice with chronic visceral pain. Together, these findings reveal a novel neural circuity underlying the central sensitization of chronic visceral pain.
Aims
Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive dysfunction and memory impairment. AD pathology involves protein acetylation. Previous studies have ...mainly focused on histone acetylation in AD, however, the roles of nonhistone acetylation in AD are less explored.
Methods
The protein acetylation and expression levels were detected by western blotting and co‐immunoprecipitation. The stoichiometry of acetylation was measured by home‐made and site‐specific antibodies against acetylated‐CaM (Ac‐CaM) at K22, K95, and K116. Hippocampus‐dependent learning and memory were evaluated by using the Morris water maze, novel object recognition, and contextual fear conditioning tests.
Results
We showed that calmodulin (CaM) acetylation is reduced in plasma of AD patients and mice. CaM acetylation and its target Ca2+/CaM‐dependent kinase II α (CaMKIIα) activity were severely impaired in AD mouse brain. The stoichiometry showed that Ac‐K22, K95‐CaM acetylation were decreased in AD patients and mice. Moreover, we screened and identified that lysine deacetylase 9 (HDAC9) was the main deacetylase for CaM. In addition, HDAC9 inhibition increased CaM acetylation and CaMKIIα activity, and hippocampus‐dependent memory in AD mice.
Conclusions
HDAC9‐mediated CaM deacetylation induces memory impairment in AD, HDAC9, or CaM acetylation may become potential therapeutic targets for AD.
HDAC9 is the CaM deacetylase, which is upregulated in APP/PS1 mouse forebrain neurons, causing CaM hyperdeacetylation. The latter impairs CaMKIIα activity and memory in APP/PS1 mice. HDAC9 inhibition enhances CaMKIIα activity via increasing CaM acetylation, thus improving the memory deficits of APP/PS1 mice.
•A mesoporous carbon with ultrahigh pore volume was prepared from chitosan.•The carbon was physically impregnated with polymeric amines for CO2 capture.•The amine/carbon composites showed superior ...CO2 capacities and selectivities.•The CO2 capacities were reserved very well throughout regeneration cycles.
Amine-impregnated adsorbents have promising application for selective CO2 capture from dilute sources in the industry. It is of great significance to develop a support exhibiting not only large pore width but also high pore volume, that can be prepared from renewable and low-cost raw materials. In this work, a mesoporous carbon exhibiting the total pore volume of 3.04 cm3/g was prepared from chitosan by a hard-template route. The mesoporous carbon was then physically impregnated with pentaethylenehexamine, which is rich in amine density and of extremely low volatility. It is demonstrated that the adsorption capacities for CO2 and selectivities for CO2/N2 on mesoporous carbon are significantly improved after the amine impregnation. The highest CO2 uptake of 3.72 mmol/g at 100 °C under atmospheric pressure was achieved in amine-impregnated carbons, being higher than most of other amine-impregnated adsorbents that have ever been reported in the literature. Furthermore, the CO2 adsorbed by amine-impregnated carbon can be facilely stripped out by concentration swing at 75 °C, and the amine-impregnated carbon exhibit high stability throughout consecutive adsorption-desorption cycles.
Genetic alterations drive metabolic reprograming to meet increased biosynthetic precursor and energy demands for cancer cell proliferation and survival in unfavorable environments. A systematic study ...of gene‐metabolite regulatory networks and metabolic dysregulation should reveal the molecular mechanisms underlying prostate cancer (PCa) pathogenesis. Herein, we performed gas chromatography–mass spectrometry (GC–MS)‐based metabolomics and RNA‐seq analyses in prostate tumors and matched adjacent normal tissues (ANTs) to elucidate the molecular alterations and potential underlying regulatory mechanisms in PCa. Significant accumulation of metabolic intermediates and enrichment of genes in the tricarboxylic acid (TCA) cycle were observed in tumor tissues, indicating TCA cycle hyperactivation in PCa tissues. In addition, the levels of fumarate and malate were highly correlated with the Gleason score, tumor stage and expression of genes encoding related enzymes and were significantly related to the expression of genes involved in branched chain amino acid degradation. Using an integrated omics approach, we further revealed the potential anaplerotic routes from pyruvate, glutamine catabolism and branched chain amino acid (BCAA) degradation contributing to replenishing metabolites for TCA cycle. Integrated omics techniques enable the performance of network‐based analyses to gain a comprehensive and in‐depth understanding of PCa pathophysiology and may facilitate the development of new and effective therapeutic strategies.
What's new?
Although many studies have reported accelerated tricarboxylic acid (TCA) cycle in prostate cancer (PCa) cells, the underlying metabolic reprogramming and molecular mechanisms remain elusive. Here, the authors systematically investigated the molecular changes in TCA cycle through metabolomics and transcriptomics analysis of matched normal and PCa tissues. Fumarate and malate were found to be highly correlated with tumor progression and expression of related genes. Potential anaplerotic routes from pyruvate, glutamine catabolism, and BCAA degradation contributed to replenishing metabolites for TCA cycle. These observations provide new molecular insight into PCa carcinogenesis and may facilitate the development of new and effective therapeutic strategies.
Massively parallel simulation of large-scale electromagnetic problems is performed on a supercomputer using an in-house developed high-performance computing scheme together with a domain ...decomposition method, where parallel adaptive unstructured mesh generation is at first performed for modeling an arbitrary multiscale structure. The accuracy, speedup, as well as scalability of such parallel scheme are numerically tested and validated during its implementation for simulating electromagnetic environmental effects (E3) on a ship platform using the TianHe-II supercomputer. It is demonstrated that this method can overcome the convergence deficiency of conventional iterative solver. In addition, numerical experiments are also carried out to show its adaptability to the number of subdomains and object electrical size. It is believed that our developed solver can be further used for solving various E3 or electromagnetic compatibility problems for the design of many large-scale platforms.
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