Lysine crotonylation has attracted widespread attention in recent years. However, little is known about bacterial crotonylation, particularly crotonyltransferase and decrotonylase, and its effects on ...antibiotic resistance. Our study demonstrates the ubiquitous presence of crotonylation in E. coli, which promotes bacterial resistance to polymyxin. We identify the crotonyltransferase YjgM and its regulatory pathways in E. coli with a focus on crotonylation. Further studies show that YjgM upregulates the crotonylation of the substrate protein PmrA, thereby boosting PmrA’s affinity for binding to the promoter of eptA, which, in turn, promotes EptA expression and confers polymyxin resistance in E. coli. Additionally, we discover that PmrA’s crucial crotonylation site and functional site is Lys 164. These significant discoveries highlight the role of crotonylation in bacterial drug resistance and offer a fresh perspective on creating antibacterial compounds.
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•YjgM functions as a crotonyltransferase in Escherichia coli•Crotonylation proteomics reveals differentially crotonylated proteins in PMB-R•YjgM promotes bacterial polymyxin resistance via the crotonylation of PmrA•Crotonylation promotes PmrA’s binding ability to the eptA promoter
Zhuang et al. find that YjgM is a crotonyltransferase in Escherichia coli. YjgM improves the binding affinity between the polymyxin-resistant protein PmrA and the eptA promoter by increasing the crotonoylation level of PmrA, thereby encouraging the expression of eptA, resulting in the development of polymyxin resistance in E. coli.
MDR Staphylococcus aureus infections, along with the severity of biofilm-associated infections, continue to threaten human health to a great extent. It necessitates the urgent development of novel ...antimicrobial and antibiofilm agents.
To reveal the mechanism and target of cinacalcet as an antibacterial and antimicrobial agent for S. aureus.
Screening of non-antibiotic drugs for antibacterial and antibiofilm properties was conducted using a small-molecule drug library. In vivo efficacy was assessed through animal models, and the antibacterial mechanism was studied using quantitative proteomics, biochemical assays, LiP-SMap, BLI detection and gene knockout techniques.
Cinacalcet, an FDA-approved drug, demonstrated antibacterial and antibiofilm activity against S. aureus, with less observed development of bacterial resistance. Importantly, cinacalcet significantly improved survival in a pneumonia model and bacterial clearance in a biofilm infection model. Moreover, the antibacterial mechanism of cinacalcet mainly involves the destruction of membrane-targeted structures, alteration of energy metabolism, and production of reactive oxygen species (ROS). Cinacalcet was found to target IcaR, inhibiting biofilm formation through the negative regulation of IcaADBC.
The findings suggest that cinacalcet has potential for repurposing as a therapeutic agent for MDR S. aureus infections and associated biofilms, warranting further investigation.
Graphene nanosheets (GNSs) were synthesized by reducing exfoliated graphite oxides. Their structure, surface morphology and lithium storage mechanism were characterized and investigated ...systematically using X-ray diffraction, atomic force microscopy, scanning electron microscopy, charge-discharge tests, cyclic voltammetry and electrochemical impedance spectroscopy. It was found that the GNSs, which were obtained via chemical synthesis, were primarily less than 10 graphene layers. The GNS electrodes, which were fabricated from the reduced GNSs, exhibited an enhanced reversible lithium storage capacity and good cyclic stability when serving as anodes in lithium-ion batteries. Also, the first-cycle irreversible capacities of the system were relatively high, because of the formation of a solid electrolyte interphase film on the surface of the GNS electrode and the spontaneous stacking of GNSs during the first lithiation. The electrochemical impedance spectroscopy results suggest that the solid electrolyte interphase film on the GNS electrode during first lithiation were primarily formed at potentials between 0.95 and 0.7 V. Also, the symmetry factor of the charge transfer was measured to be 0.446.
Highly chlorinated benzenes usually have a low efficient degradation in environment. Here we proposed a synergistic removal strategy of pentachlorobenzene (PeCB) using
sp. JS100 coupled with ...immobilized nanoscale zero-valent iron (NZVI). The structural and textural features of the synergistic system were characterized by X-ray powder diffraction, field emission scanning electron microscopy, and a specific surface area and pore size analysis. Nanoscale zero-valent iron particles were dispersed and attached to the biofilter, which increased the specific surface area to 34.5 m
g
. The batch experiment revealed that the removal efficiency of PeCB reached 80.2% in the synergistic system within 48 h. The degradation followed pseudo-first-order reaction kinetics, and the reaction rate constant was measured to be 0.0336 h
. In the degradation mechanism, PeCB was degraded by NZVI to lower chlorobenzenes, which were utilized by
sp. JS100 as nutrients, thereby achieving rapid removal of PeCB.
Obesity has been recognized as a major risk factor for the development of chronic cardiomyopathy, which is associated with increased cardiac inflammation, fibrosis, and apoptosis. We previously ...developed an anti-inflammatory compound C66, which prevented inflammatory diabetic complications via targeting JNK. In the present study, we have tested the hypothesis that C66 could prevent obesity-induced cardiomyopathy by suppressing JNK-mediated inflammation. High-fat diet (HFD)-induced obesity mouse model and palmitic acid (PA)-challenged H9c2 cells were used to develop inflammatory cardiomyopathy and evaluate the protective effects of C66. Our data demonstrate a protective effect of C66 against obesity-induced cardiac inflammation, cardiac hypertrophy, fibrosis, and dysfunction, overall providing cardio-protection. C66 administration attenuates HFD-induced myocardial inflammation by inhibiting NF-κB and JNK activation in mouse hearts. In vitro, C66 prevents PA-induced myocardial injury and apoptosis in H9c2 cells, accompanied with inhibition against PA-induced JNK/NF-κB activation and inflammation. The protective effect of C66 is attributed to its potential to inhibit JNK activation, which led to reduced pro-inflammatory cytokine production and reduced apoptosis in cardiomyocytes both in vitro and in vivo. In summary, C66 provides significant protection against obesity-induced cardiac dysfunction, mainly by inhibiting JNK activation and JNK-mediated inflammation. Our data indicate that inhibition of JNK is able to provide significant protection against obesity-induced cardiac dysfunction.
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•Compound C66 attenuated cardiomyopathy in HFD-fed mice.•C66 reduced PA-induced inflammation and apoptosis via inhibiting JNK activation.•Inhibition of inflammation prevents obesity-associated cardiomyopathy.•JNK is a promising therapeutic target for obesity-induced myocardial injury.
Mountain glaciers are retreating at an unprecedented rate due to global warming. Glacier retreat is widely believed to be driven by the physiochemical characteristics of glacier surfaces; however, ...the current knowledge of such biological drivers remains limited. An estimated 130 Tg of organic carbon (OC) is stored in mountain glaciers globally. As a result of global warming, the accelerated microbial decomposition of OC may further accelerate the melting process of mountain glaciers by heat production with the release of greenhouse gases, such as carbon dioxide (CO2) and methane. Here, using short‐term aerobic incubation data from the forefield of Urumqi Glacier No. 1, we assessed the potential climate feedback mediated by soil microbiomes at temperatures of 5°C (control), 6.2°C (RCP 2.6), 11°C (RCP 8.5), and 15°C (extreme temperature). We observed enhanced CO2‐C release and heat production under warming conditions, which led to an increase in near‐surface (2 m) atmospheric temperatures, ranging from 0.9°C to 3.4°C. Warming significantly changed the structures of the RNA‐derived (active) and DNA‐derived (total) soil microbiomes, and active microbes were more sensitive to increased temperatures than total microbes. Considering the positive effects of temperature and deglaciation age on the CO2‐C release rate, the alterations in the active microbial community structure had a negative impact on the increased CO2‐C release rate. Our results revealed that glacial melting could potentially be significantly accelerated by heat production from increased microbial decomposition of OC. This risk might be true for other high‐altitude glaciers under emerging warming, thus improving the predictions of the effects of potential feedback on global warming.
Global warming is expected to accelerate melting process in the forefield of Urumqi Glacier No. 1, with the changes in soil microbiomes and carbon cycle. Short‐term experimental warming revealed that different warming patterns significantly altered RNA‐derived microbial communities compared to those of DNA derived, and caused an increase in atmospheric temperatures by heat production from microbial respiration, which ranged from 0.9 to 3.4°C. These results have important implications when making the predictions of glacial melting in mountain regions.
Advances in the understanding of growth hormone-producing adenomas (GHomas) are ongoing, but current therapy is limited by moderate and variable efficacy and in need of life-long treatment. In this ...study, the molecular signaling pathway related to GHoma was investigated by proteomics and transcriptomics. The differentially expressed proteins and genes were significantly enriched in Extracellular Matrix-Receptor Interactions, Notch Signaling, Basal Cell Carcinoma Signaling, JAK-STAT3, Wnt Signaling, and Glioblastoma Multiforme Signaling by Ingenuity Pathway Analysis. Furthermore, the Notch2/Delta-like canonical Notch ligand (DLL) signaling pathway was identified to be associated with tumorigenesis and invasiveness of GHoma. In 76 patients, Notch2 and DLL3 were upregulated in invasive compared to those in non-invasive GHoma (
< 0.05). Disease-free survival was significantly longer in patients with low, compared with high, DLL3 expression (
= 0.027). Notch 2 knockdown inhibited cell migration in both GH3 cells and primary GHoma cells, along with downregulation of the mRNA expression of related genes. DAPT, a γ-secretase inhibitor, inhibited tumor growth and invasion
and
and suppressed the release of growth hormone in primary GHoma cells. The involvement of Notch2/DLL3 signaling in GHoma progression warrants additional study of Notch inhibitor, DAPT, as a potential GHoma treatment.
Current treatments of GH adenomas (GHomas) are limited by their moderate and variable efficacy and in need of life-long treatment. We found that the Notch2/Delta-like Notch ligand 3 (DLL3) signaling pathway was active in GHoma tumorigenesis, progression, and invasion.The γ-secretase inhibitor DAPT is of potential use in GHoma treatment targeting Notch signaling.
Recent extensive studies have promoted the imaging techniques through scattering layers to a reality but the imaging quality still needs to be improved. We demonstrate a high-speed method to image ...objects hidden behind a thin scattering medium. By analyzing the imaging degradation model of the speckle correlation methods, a memory effect (ME) based filter is proposed to improve the image quality of reconstructed images with deconvolution operation. Comparing to Wiener filter and other related methods, the ME-based filter can optimize the recovered images with the smaller mean square error, suppression of noise background, and central maximum. The proposed ME filter is also applied to improve the imaging method proposed for dynamic imaging through scattering layer with a reference object. The artifact generated by the deviation of retrieved point spread function can be effectively eliminated with a better imaging quality. This ME-based filter is promising to improve the imaging quality for other deconvolution and speckle correlation methods.
Bystander‐killing payloads can significantly overcome the tumor heterogeneity issue and enhance the clinical potential of antibody‐drug conjugates (ADC), but the rational design and identification of ...effective bystander warheads constrain the broader implementation of this strategy. Here, graph attention networks (GAT) are constructed for a rational bystander killing scoring model and ADC construction workflow for the first time. To generate efficient bystander‐killing payloads, this model is utilized for score‐directed exatecan derivatives design. Among them, Ed9, the most potent payload with satisfactory permeability and bioactivity, is further used to construct ADC. Through linker optimization and conjugation, novel ADCs are constructed that perform excellent anti‐tumor efficacy and bystander‐killing effect in vivo and in vitro. The optimal conjugate T‐VEd9 exhibited therapeutic efficacy superior to DS‐8201 against heterogeneous tumors. These results demonstrate that the effective scoring approach can pave the way for the discovery of novel ADC with promising bystander payloads to combat tumor heterogeneity.
A rational strategy for generating antibody‐drug conjugate with bystander‐killing effect through GAT‐driven bystander‐killing scoring, payload screening and linker optimization. Several potential bystander payloads and conjugates are discovered under the strategy, in which the optimal conjugate T‐VEd9 exhibited therapeutic efficacy superior to DS‐8201 against heterogeneous tumors.
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