Dysfunction of glutamate neurotransmission in the nucleus accumbens (NAc) has been implicated in the pathophysiology of alcohol use disorders (AUD). Neurogranin (Ng) is exclusively expressed in the brain and mediates N‐methyl‐d ‐aspartate receptor (NMDAR) hypo‐function by regulating the intracellular calcium‐calmodulin (Ca2+‐CaM) pathway. Ng null mice (Ng–/– mice) demonstrate increased alcohol drinking compared to wild‐type mice, while also showing less tolerance to the effect of alcohol. To identify the molecular mechanism related to alcohol seeking, both in vivo microdialysis and label‐free quantification proteomics comparing Ng genotype and effects of alcohol treatment on the NAc are utilized. There is significant difference in glutamate and gamma‐aminobutyric acid (GABA) neurotransmission between genotypes; however, alcohol administration normalizes both glutamate and GABA levels in the NAc. Using label‐free proteomics, 427 protein expression changes are identified against alcohol treatment in the NAc among 4347 total proteins detected. Bioinformatics analyses reveal significant molecular differences in Ng null mice in response to acute alcohol treatment. Ingenuity pathway analysis found that the AKT network is altered significantly between genotypes, which may increase the sensitivity of alcohol in Ng null mice. The pharmacoproteomics results presented here illustrate a possible molecular basis of the alcohol sensitivity through Ng signaling in the NAc. 相似文献
Protein arginine methyltransferase 5 (PRMT5) is a major enzyme responsible for generating monomethyl and symmetric dimethyl arginine in proteins. PRMT5 is essential for cell viability and development, and its overexpression is observed in a variety of cancers. In the present study, it is found that levels of PRMT5 protein and symmetric arginine dimethylation in colorectal cancer (CRC) tissues are increased compared to those in adjacent noncancerous tissues. Using immunoaffinity enrichment of methylated peptides combined with high‐resolution mass spectrometry, a total of 147 symmetric dimethyl‐arginine (SDMA) sites in 94 proteins are identified, many of which are RNA binding proteins and enzymes. Quantitative analysis comparing CRC and normal tissues reveals significant increase in the symmetric dimethylation of 70 arginine sites in 46 proteins and a decrease in that of four arginine sites in four proteins. Among the 94 proteins identified in this study, it is confirmed that KH‐type splicing regulatory protein is a target of PRMT5 and highly expressed in CRC tissues compared to noncancerous tissues. This study is the first comprehensive analysis of symmetric arginine dimethylation using clinical samples and extends the number of known in vivo SDMA sites. The data obtained are available via ProteomeXchange with the identifier PXD015653. 相似文献
The angle-variable tunable optical filter was strictly fabricated by two strategies of nanoimprint-coupled metal nanopatterning with improved cost-effectiveness and accessibility. The tunable optical properties and the performances of two strategies were experimentally examined and turned out to be well matched to numerical results. Tunable properties are obtained by three factors: size of fabricated Ag nanodisks, incident illumination angle, and fabrication strategies. The resonant extinction peak shifts were identified to show a large increase along with the increase in fabricated Ag disk size and increase in the incidence angle of illumination. When comparing a fabrication strategy, it was confirmed that the sample fabricated by the strip-off method has better stability on color changes with a consistent dependency on the incident angle. The presented strategies of fabrication are technically viable for obtaining well-defined plasmonic nanostructures so that it has the feasibility to apply for fascinating optical applications including display or tunable optical filters.
The growth arrest and DNA damage‐inducible beta (Gadd45β) protein have been associated with various cellular functions, but its role in progressive renal disease is currently unknown. Here, we examined the effect of Gadd45β deletion on cell proliferation and apoptosis, inflammation, and renal fibrosis in an early chronic kidney disease (CKD) mouse model following unilateral ureteral obstruction (UUO). Wild‐type (WT) and Gadd45β‐knockout (KO) mice underwent either a sham operation or UUO and the kidneys were sampled eight days later. A histological assay revealed that ablation of Gadd45β ameliorated UUO‐induced renal injury. Cell proliferation was higher in Gadd45β KO mouse kidneys, but apoptosis was similar in both genotypes after UUO. Expression of pro‐inflammatory cytokines after UUO was down‐regulated in the kidneys from Gadd45β KO mice, whereas UUO‐mediated immune cell infiltration remained unchanged. The expression of pro‐inflammatory cytokines in response to LPS stimulation decreased in bone marrow‐derived macrophages from Gadd45β KO mice compared with that in WT mice. Importantly, UUO‐induced renal fibrosis was ameliorated in Gadd45β KO mice unlike in WT mice. Gadd45β was involved in TGF‐β signalling pathway regulation in kidney fibroblasts. Our findings demonstrate that Gadd45β plays a crucial role in renal injury and may be a therapeutic target for the treatment of CKD. 相似文献
Amyotrophic lateral sclerosis (ALS) is a disorder that affects motor neurons in motor cortex and spinal cord, and the degeneration of both neuronal populations is a critical feature of the disease. Abnormalities in protein homeostasis (proteostasis) are well established in ALS. However, they have been investigated mostly in spinal cord but less so in motor cortex. Herein, we monitored the unfolded protein (UPR) and heat shock response (HSR), two major proteostasis regulatory pathways, in human post-mortem tissue derived from the motor cortex of sporadic ALS (SALS) and compared them to those occurring in spinal cord. Although the UPR was activated in both tissues, specific expression of select UPR target genes, such as PDIs, was observed in motor cortex of SALS cases strongly correlating with oligodendrocyte markers. Moreover, we found that endoplasmic reticulum-associated degradation (ERAD) and HSR genes, which were activated predominately in spinal cord, correlated with the expression of neuronal markers. Our results indicate that proteostasis is strongly and selectively activated in SALS motor cortex and spinal cord where subsets of these genes are associated with specific cell type. This study expands our understanding of convergent molecular mechanisms occurring in motor cortex and spinal cord and highlights cell type–specific contributions. 相似文献
High‐capacity Li‐rich layered oxide cathodes along with Si‐incorporated graphite anodes have high reversible capacity, outperforming the electrode materials used in existing commercial products. Hence, they are potential candidates for the development of high‐energy‐density lithium‐ion batteries (LIBs). However, structural degradation induced by loss of interfacial stability is a roadblock to their practical use. Here, the use of malonic acid‐decorated fullerene (MA‐C60) with superoxide dismutase activity and water scavenging capability as an electrolyte additive to overcome the structural instability of high‐capacity electrodes that hampers the battery quality is reported. Deactivation of PF5 by water scavenging leads to the long‐term stability of the interfacial structures of electrodes. Moreover, an MA‐C60‐added electrolyte deactivates the reactive oxygen species and constructs an electrochemically robust cathode‐electrolyte interface for Li‐rich cathodes. This work paves the way for new possibilities in the design of electrolyte additives by eliminating undesirable reactive substances and tuning the interfacial structures of high‐capacity electrodes in LIBs. 相似文献
Rechargeable batteries based on MnO2 cathodes, able to operate in mild aqueous electrolytes, have attracted attention due to their appealing features for the design of low‐cost stationary energy storage devices. However, the charge/discharge mechanism of MnO2 in such media is still a matter of debate. Here, an in‐depth quantitative spectroelectrochemical analysis of MnO2 thin‐films provides a set of unrivaled mechanistic insights. A major finding is that charge storage occurs through the reversible two‐electron faradaic conversion of MnO2 into Mn2+ in the presence of a wide range of weak Brønsted acids, including the [Zn(H2O)6]2+ or [Mn(H2O)6]2+ complexes present in aqueous Zn/MnO2 batteries. Furthermore, it is shown that buffered electrolytes loaded with Mn2+ are ideal to achieve highly reversible conversion of MnO2 with both high gravimetric capacity and remarkably stable charging/discharging potentials. In the most favorable case, a record gravimetric capacity of 450 mA·h·g?1 is obtained at a high rate of 1.6 A·g?1, with a Coulombic efficiency close to 100% and a MnO2 utilization of 84%. Overall, the present results challenge the common view on MnO2 the charge storage mechanism in mild aqueous electrolytes and underline the benefit of buffered electrolytes for high‐performance rechargeable aqueous batteries. 相似文献
Layered lithium–nickel–cobalt–manganese oxide (NCM) materials have emerged as promising alternative cathode materials owing to their high energy density and electrochemical stability. Although high reversible capacity has been achieved for Ni‐rich NCM materials when charged beyond 4.2 V versus Li+/Li, full lithium utilization is hindered by the pronounced structural degradation and electrolyte decomposition. Herein, the unexpected realization of sustained working voltage as well as improved electrochemical performance upon electrochemical cycling at a high operating voltage of 4.9 V in the Ni‐rich NCM LiNi0.895Co0.085Mn0.02O2 is presented. The improved electrochemical performance at a high working voltage at 4.9 V is attributed to the removal of the resistive Ni2+O rock‐salt surface layer, which stabilizes the voltage profile and improves retention of the energy density during electrochemical cycling. The manifestation of the layered Ni2+O rock‐salt phase along with the structural evolution related to the metal dissolution are probed using in situ X‐ray diffraction, neutron diffraction, transmission electron microscopy, and X‐ray absorption spectroscopy. The findings help unravel the structural complexities associated with high working voltages and offer insight for the design of advanced battery materials, enabling the realization of fully reversible lithium extraction in Ni‐rich NCM materials. 相似文献