Size-controlled Co/CoO heterogeneous nanoparticles confined in N-doped mesoporous carbon for efficient oxygen reduction in zinc-air batteries.

The size of metal compound particles and interface electronic structure of heterojunctions in a matrix greatly affect oxygen reduction performance in zinc-air batteries. However, it is still a big challenge to precisely control or regulate the size of these metal compound particles and the heterojunction structure. Herein, cobalt complexes with different-sized ligands are chosen as cobalt resources and adsorbed onto a mesoporous carbon, after which they are coated with polydopamine and calcined. Under the confinement effect of mesopores and the isolation effect of ligands and dopamine, the as-obtained Co/CoO heterogeneous nanoparticles are restricted to nano-size and uniformly dispersed in N-doped carbon (NC). The sizes of Co/CoO are estimated to be 39.7, 24.9 and 15.6 nm with increased CoO contents, corresponding to the adopted cobalt precursors of Co(OAc)2, Co(acac)2 and Co(acac)3, respectively. The smallest Co/CoO/NC-S shows excellent catalytic activity for oxygen reduction reaction, with a half-wave potential of 0.82 V vs. RHE and a limiting current density of 4.59 mA cm-2. When applied to the cathode of zinc-air battery, a high peak power density of 131.9 mW cm-2 is achieved, which surpasses that of the battery powered by Pt/C. The excellent performance can be attributed to the formation of heterogeneous structures between Co and CoO, the smaller Co/CoO nanoparticles, and N-doped mesoporous carbon with effective charge/mass transport. This work provides an effective way to regulate the size and phase contents of heterogeneous particles in mesoporous carbon, which is highly valuable in electrocatalytic systems.

Sulfur atom-directed metal-ligand synergistic catalysis in zirconium/hafnium-oxo clusters for highly efficient amine oxidation.

The performance applications (e.g., photocatalysis) of zirconium (Zr) and hafnium (Hf) based complexes are greatly hindered by the limited development of their structures and the relatively inert metal reactivity. In this work, we constructed two ultrastable Zr/Hf-based clusters (Zr9-TC4A and Hf9-TC4A) using hydrophobic 4-tert-butylthiacalix[4]arene (H4TC4A) ligands, in which unsaturated coordinated sulfur (S) atoms on the TC4A4- ligand can generate strong metal-ligand synergy with nearby active metal Zr/Hf sites. As a result, these two functionalized H4TC4A ligands modified Zr/Hf-oxo clusters, as catalysts for the amine oxidation reaction, exhibited excellent catalytic activity, achieving very high substrate conversion (>99%) and product selectivity (>90%). Combining comparative experiments and theoretical calculations, we found that these Zr/Hf-based cluster catalysts accomplish efficient amine oxidation reactions through synergistic effect between metals and ligands: (i) the photocatalytic benzylamine (BA) oxidation reaction was achieved by the synergistic effect of the dual active sites, in which, the naked S sites on the TC4A4- ligand oxidize the BA by photogenerated hole and oxygen molecules are reduced by photogenerated electrons on the metal active sites; (ii) in the aniline oxidation reaction, aniline was adsorbed by the bare S sites on ligands to be closer to metal active sites and then oxidized by the oxygen-containing radicals activated by the metal sites, thus completing the catalytic reaction under the synergistic catalytic effect of the proximity metal-ligand. In this work, the Zr/Hf-based complexes applied in the oxidation of organic amines have been realized using active S atom-directed metal-ligand synergistic catalysis and have demonstrated very high reactivity.

Mitopherogenesis, a form of mitochondria-specific ectocytosis, regulates sperm mitochondrial quantity and fertility.

Mitochondrial export into the extracellular space is emerging as a fundamental cellular process implicated in diverse physiological activities. Although a few studies have shed light on the process of discarding damaged mitochondria, how mitochondria are exported and the functions of mitochondrial release remain largely unclear. Here we describe mitopherogenesis, a formerly unknown process that specifically secretes mitochondria through a unique extracellular vesicle termed a 'mitopher'. We observed that during sperm development in male Caenorhabditis elegans, healthy mitochondria are exported out of the spermatids through mitopherogenesis and each of the generated mitophers harbours only one mitochondrion. In mitopherogenesis, the plasma membrane first forms mitochondrion-embedding outward buds, which then promptly bud off and thereby result in the generation of mitophers. Mechanistically, extracellular protease signalling in the testis triggers mitopher formation from spermatids, which is partially mediated by the tyrosine kinase SPE-8. Moreover, mitopherogenesis requires normal microfilament dynamics, whereas myosin VI antagonizes mitopher generation. Strikingly, our three-dimensional electron microscopy analyses indicate that mitochondrial quantity requires precise modulation during sperm development, which is critically mediated by mitopherogenesis. Inhibition of mitopherogenesis causes accumulation of mitochondria in sperm, which may lead to sperm motility and fertility defects. Our findings identify mitopherogenesis as a previously undescribed process for mitochondria-specific ectocytosis, which may represent a fundamental branch of mechanisms underlying mitochondrial quantity control to regulate cell functions during development.

Recent progress in 2D bipolar magnetic semiconductors.

Bipolar magnetic semiconductor (BMS) is a class of magnetic semiconductors, whose valence band maximum and conduction band minimum are fully spin-polarized with opposite spin directions. Due to the special energy band, half-metallicity can be easily obtained in BMS by gate voltage, and the spin polarization can be reversed between spin-up and down when the gate voltage switches from positive to negative. BMSs have great potential applications in spintronic devices, such as the field-effect spin valves, spin filters and spin transistors,etc. With the rapid progress of the two-dimensional (2D) magnetic materials, researchers have identified a series of potential intrinsic 2D BMS materials using high-throughput computational methods. Additionally, methods such as doping, application of external stress, introduction of external fields, stacking of interlayer antiferromagnetic semiconductors, and construction of Janus structures have endowed existing materials with BMS properties. This paper reviews the research progress of 2D BMS. These advancements provide crucial guidance for the design and synthesis of BMS materials and offer innovative pathways for the future development of spintronics.

Gasdermin D: A Potential New Auxiliary Pan-Biomarker for the Detection and Diagnosis of Diseases.

Pyroptosis is a form of programmed cell death mediated by gasdermins, particularly gasdermin D (GSDMD), which is widely expressed in tissues throughout the body. GSDMD belongs to the gasdermin family, which is expressed in a variety of cell types including epithelial cells and immune cells. It is involved in the regulation of anti-inflammatory responses, leading to its differential expression in a wide range of diseases. In this review, we provide an overview of the current understanding of the major activation mechanisms and effector pathways of GSDMD. Subsequently, we examine the importance and role of GSDMD in different diseases, highlighting its potential as a pan-biomarker. We specifically focus on the biological characteristics of GSDMD in several diseases and its promising role in diagnosis, early detection, and differential diagnosis. Furthermore, we discuss the application of GSDMD in predicting prognosis and monitoring treatment efficacy in cancer. This review proposes a new strategy to guide therapeutic decision-making and suggests potential directions for further research into GSDMD.

p-Cresol-Enabled Nickel-Catalyzed Intermolecular Redox-Economical Coupling of Allyl Alcohols with Alkynes through oxa-Nickelacycle.

An intermolecular redox-economical coupling reaction of allyl alcohols with alkynes, catalyzed by Ni-Brønsted acid cocatalysis, has been developed. This method allows for the synthesis of a diverse range of γ,δ-unsaturated ketones with yields ranging from 40% to 94%, while maintaining excellent compatibility with various functional groups. The transformation of the resulting product demonstrates the significant practical value of this method. Further mechanistic investigations have revealed that the reaction proceeds through the formation of an oxa-nickelacycle intermediate.

Piezoionic High Performance Hydrogel Generator and Active Protein Absorber via Microscopic Porosity and Phase Blending.

Generating electricity in hydrogel is very important but remains difficult. Hydrogel with electricity generation capability is more capable in bio-relevant tasks such as tissue engineering, artificial skin, or medical treatment, because electricity is indispensable in regulating physiological activities. Here, a porous and phase blending hydrogel structure for effective piezoionic electricity generation is developed. Dynamic electric field is generated taking advantage of the difference in streaming speeds of sodium and chloride in the material. Microscopic porosity and hydrophilic-hydrophobic phase blending are the two key factors for prominent piezoionic performance. Voltages as high as 600 mV are first realized in hydrogels in response to medical ultrasound stimulation. The hydrogel structure is also subjective to effective substance exchange and can actively enrich proteins from surroundings under mechanical stimuli. Preliminary applications in neural stimulation, constructing complex spatial-temporal chemical and electric field distribution patterns, mimetic tactile sensor, sample pretreatment in fast detection, and enzyme immobilization are demonstrated.

Shared Genetic Architecture between Parkinson's Disease and Brain Structural Phenotypes.

BACKGROUND: Patients with Parkinson's disease (PD) have consistently demonstrated brain structure abnormalities, indicating the presence of shared etiological and pathological processes between PD and brain structures; however, the genetic relationship remains poorly understood. OBJECTIVE: The aim of this study was to investigate the extent of shared genetic architecture between PD and brain structural phenotypes (BSPs) and to identify shared genomic loci. METHODS: We used the summary statistics from genome-wide association studies to conduct MiXeR and conditional/conjunctional false discovery rate analyses to investigate the shared genetic signatures between PD and BSPs. Subsequent expression quantitative trait loci mapping in the human brain and enrichment analyses were also performed. RESULTS: MiXeR analysis identified genetic overlap between PD and various BSPs, including total cortical surface area, average cortical thickness, and specific brain volumetric structures. Further analysis using conditional false discovery rate (FDR) identified 21 novel PD risk loci on associations with BSPs at conditional FDR < 0.01, and the conjunctional FDR analysis demonstrated that PD shared several genomic loci with certain BSPs at conjunctional FDR < 0.05. Among the shared loci, 16 credible mapped genes showed high expression in the brain tissues and were primarily associated with immune function-related biological processes. CONCLUSIONS: We confirmed the polygenic overlap with mixed directions of allelic effects between PD and BSPs and identified multiple shared genomic loci and risk genes, which are likely related to immune-related biological processes. These findings provide insight into the complex genetic architecture associated with PD. © 2023 International Parkinson and Movement Disorder Society.

Transcriptional deciphering of the metabolic pathways associated with the bioactive ingredients of wolfberry species with different quality characteristics.

BACKGROUND: Wolfberry is rich in carotenoids, flavonoids, vitamins, alkaloids, betaines and other bioactive ingredients. For over 2,000 years, wolfberry has been used in China as a medicinal and edible plant resource. Nevertheless, the content of bioactive ingredients varies by cultivars, resulting in uneven quality across wolfberry cultivars and species. To date, research has revealed little about the underlying molecular mechanism of the metabolism of flavonoids, carotenoids, and other bioactive ingredients in wolfberry. RESULTS: In this context, the transcriptomes of the Lycium barbarum L. cultivar 'Ningqi No. 1' and Lycium chinense Miller were compared during the fruit maturity stage using the Illumina NovaSeq 6000 sequencing platform, and subsequently, the changes of the gene expression profiles in two types of wolfberries were analysed. In total, 256,228,924 clean reads were obtained, and 8817 differentially expressed genes (DEGs) were identified, then assembled by Basic Local Alignment Search Tool (BLAST) similarity searches and annotated using Gene Ontology (GO), Clusters of Orthologous Groups of proteins (KOG), and the Kyoto Encyclopedia of Genes and Genomes (KEGG). By combining these transcriptome data with data from the PubMed database, 36 DEGs related to the metabolism of bioactive ingredients and implicated in the metabolic pathway of carotenoids, flavonoids, terpenoids, alkaloids, vitamins, etc., were identified. In addition, among the 9 differentially expressed transcription factors, LbAPL, LbPHL11 and LbKAN4 have raised concerns. The protein physicochemical properties, structure prediction and phylogenetic analysis indicated that LbAPL and LbPHL11 may be good candidate genes involved in regulating the flavonoid metabolism pathway in wolfberry. CONCLUSIONS: This study provides preliminary evidence for the differences in bioactive ingredient content at the transcription level among different wolfberry species, as well as a research and theoretical basis for the screening, cloning and functional analysis of key genes involved in the metabolism of bioactive ingredients in wolfberry.

Sanhuang Xiexin Decoction Ameliorates TNBC By Modulating JAK2-STAT3 and Lipid Metabolism.

OBJECTIVE: To investigate the therapeutic effect of Sanhuang Xiexin Decoction (SXD) on triple-negative breast cancer (TNBC) in mice and its underlying mechanism. METHODS: The high-performance liquid chromatography (HPLC) was used to quantitate and qualify SXD. A total of 15 female BALB/c mice were inoculated subcutaneously on the right hypogastrium with 3×105 of 4T1-Luc cells to establish TNBC mouse model. All mice were divided randomly into 3 groups, including phosphate buffered solution (PBS), SXD and doxorubicin (DOX) groups (positive drug). Additionally, tumor growth, pathological changes, serum lipid profiles, expression of Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) signaling pathway and its key targets including inflammatory factors, cell cycle and epithelial-mesenchymal transition (EMT) markers were investigated. Besides, the biosafety of SXD was also evaluated in mice. RESULTS: Rhein, coptisine, berberine hydrochloride and baicalin were all found in SXD, and the concentrations of these 4 components were 0.57, 2.61, 2.93, and 46.04 mg/g, respectively. The mouse experiment showed that SXD could notably suppress the development of tumors and reduce the density of tumor cells (P<0.01). The serum lipid analysis and Oil-Red-O staining both showed the differences, SXD group exhibited higher serum adiponectin and HDL-C levels with lower TC and LDL-C levels compared to the PBS and DOX groups (P<0.05 or P<0.01), respectively. SXD also decreased the levels of phospho-JAK2 (p-JAK2), phospho-STAT3 (p-STAT3) expressions and its downstream factors, including mostly inflammatory cytokine, EMT markers, S phase of tumor cells and vascular endothelial growth factor (VEGF) expression (P<0.05 or P<0.01), respectively. The biosafety assessment of SXD revealed low levels of toxicity in mice. CONCLUSION: SXD could inhibit TNBC by suppressing JAK2-STAT3 phosphorylation which may be associated with modulation of lipid metabolism.

Tat-NTS peptide protects neurons against cerebral ischemia-reperfusion injury via ANXA1 SUMOylation in microglia.

Rationale: Recent studies indicate that microglial activation and the resulting inflammatory response could be potential targets of adjuvant therapy for ischemic stroke. Many studies have emphasized a well-established function of Annexin-A1 (ANXA1) in the immune system, including the regulation of microglial activation. Nevertheless, few therapeutic interventions targeting ANXA1 in microglia for ischemic stroke have been conducted. In the present study, Tat-NTS, a small peptide developed to prevent ANXA1 from entering the nucleus, was utilized. We discovered the underlying mechanism that Tat-NTS peptide targets microglial ANXA1 to protect against ischemic brain injury. Methods: Preclinical studies of ischemic stroke were performed using an oxygen-glucose deprivation and reperfusion (OGD/R) cell model in vitro and the middle cerebral artery occlusion (MCAO) animal model of ischemic stroke in vivo. Confocal imaging and 3D reconstruction analyses for detecting the protein expression and subcellular localization of microglia in vivo. Co-immunoprecipitation (Co-IP), immunoblotting, ELISA, quantitative real-time PCR (qRT-PCR), Luciferase reporter assay for determining the precise molecular mechanism. Measurement on the cytotoxicity of Tat-NTS peptide for microglia was assessed by CCK-8 and LDH assay. TUNEL staining was used to detect the microglia conditioned medium-mediated neuronal apoptosis. Adeno-associated viruses (AAVs) were injected into the cerebral cortex, striatum and hippocampal CA1 region of adult male Cx3cr1-Cre mice, to further verify the neurofunctional outcome and mechanism of Tat-NTS peptide by TTC staining, the modified Neurological Severity Score (mNSS) test, the open field test (OFT), the novel object recognition task (NORT), the Morris water maze (MWM) test, the long-term potentiation (LTP) and the Transmission electron microscopy (TEM). Results: It was observed that administration of Tat-NTS led to a shift of subcellular localization of ANXA1 in microglia from the nucleus to the cytoplasm in response to ischemic injury. Notably, this shift was accompanied by an increase in ANXA1 SUMOylation in microglia and a transformation of microglia towards an anti-inflammatory phenotype. We confirmed that Tat-NTS-induced ANXA1 SUMOylation in microglia mediated IKKα degradation via NBR1-dependent selective autophagy, then blocking the activation of the NF-κB pathway. As a result, the expression and release of the pro-inflammatory factors IL-1ß and TNF-α were reduced in both in vitro and in vivo experiments. Furthermore, we found that Tat-NTS peptide's protective effect on microglia relieved ischemic neuron apoptosis. Finally, we demonstrated that Tat-NTS peptide administration, through induction of ANXA1 SUMOylation in microglia, reduced infarct volume, improved neurological function and facilitated behavioral recovery in MCAO mice. Conclusions: Our study provides evidence for a novel mechanism of Tat-NTS peptide in regulating microglial ANXA1 function and its substantial neuroprotective effect on neurons with ischemic injuries. These findings suggest that Tat-NTS peptides have a high potential for clinical application and may be a promising therapeutic candidate for treating cerebral ischemia.

Deep learning-driven MRI trigeminal nerve segmentation with SEVB-net.

Purpose: Trigeminal neuralgia (TN) poses significant challenges in its diagnosis and treatment due to its extreme pain. Magnetic resonance imaging (MRI) plays a crucial role in diagnosing TN and understanding its pathogenesis. Manual delineation of the trigeminal nerve in volumetric images is time-consuming and subjective. This study introduces a Squeeze and Excitation with BottleNeck V-Net (SEVB-Net), a novel approach for the automatic segmentation of the trigeminal nerve in three-dimensional T2 MRI volumes. Methods: We enrolled 88 patients with trigeminal neuralgia and 99 healthy volunteers, dividing them into training and testing groups. The SEVB-Net was designed for end-to-end training, taking three-dimensional T2 images as input and producing a segmentation volume of the same size. We assessed the performance of the basic V-Net, nnUNet, and SEVB-Net models by calculating the Dice similarity coefficient (DSC), sensitivity, precision, and network complexity. Additionally, we used the Mann-Whitney U test to compare the time required for manual segmentation and automatic segmentation with manual modification. Results: In the testing group, the experimental results demonstrated that the proposed method achieved state-of-the-art performance. SEVB-Net combined with the ωDoubleLoss loss function achieved a DSC ranging from 0.6070 to 0.7923. SEVB-Net combined with the ωDoubleLoss method and nnUNet combined with the DoubleLoss method, achieved DSC, sensitivity, and precision values exceeding 0.7. However, SEVB-Net significantly reduced the number of parameters (2.20 M), memory consumption (11.41 MB), and model size (17.02 MB), resulting in improved computation and forward time compared with nnUNet. The difference in average time between manual segmentation and automatic segmentation with manual modification for both radiologists was statistically significant (p < 0.001). Conclusion: The experimental results demonstrate that the proposed method can automatically segment the root and three main branches of the trigeminal nerve in three-dimensional T2 images. SEVB-Net, compared with the basic V-Net model, showed improved segmentation performance and achieved a level similar to nnUNet. The segmentation volumes of both SEVB-Net and nnUNet aligned with expert annotations but SEVB-Net displayed a more lightweight feature.

Knockdown of SETD5 inhibited glycolysis and tumor growth in gastric cancer cells by down-regulating Akt signaling pathway.

Gastric cancer (GC) is the 5th most common cancer and the 3rd leading cause of cancer-related death worldwide. It is of great significance to study the underlying molecular mechanism of GC, and targeting glycolysis is a good strategy to treat GC. SET domain containing 5 (SETD5) contains a catalytic methyltransferase SET domain, which is known as a lysine methyltransferase that affects the progression of multiple cancers. However, its possible role in GC was still unclear. Here, we revealed that SETD5 was highly expressed in GC and was associated with a poor prognosis. Further through the in vitro experiments, we revealed that the downregulation of SETD5 inhibited the proliferation and migration of GC cells. Knockdown of SETD5 inhibited glucose consumption and glycolysis. Further studies have shown that SETD5 knockdown restrained the Akt signaling pathway. Therefore, we thought that SETD5 could act as a GC target.

NAT10 Is Involved in Cardiac Remodeling Through ac4C-Mediated Transcriptomic Regulation.

BACKGROUND: Heart failure, characterized by cardiac remodeling, is associated with abnormal epigenetic processes and aberrant gene expression. Here, we aimed to elucidate the effects and mechanisms of NAT10 (N-acetyltransferase 10)-mediated N4-acetylcytidine (ac4C) acetylation during cardiac remodeling. METHODS: NAT10 and ac4C expression were detected in both human and mouse subjects with cardiac remodeling through multiple assays. Subsequently, acetylated RNA immunoprecipitation and sequencing, thiol (SH)-linked alkylation for the metabolic sequencing of RNA (SLAM-seq), and ribosome sequencing (Ribo-seq) were employed to elucidate the role of ac4C-modified posttranscriptional regulation in cardiac remodeling. Additionally, functional experiments involving the overexpression or knockdown of NAT10 were conducted in mice models challenged with Ang II (angiotensin II) and transverse aortic constriction. RESULTS: NAT10 expression and RNA ac4C levels were increased in in vitro and in vivo cardiac remodeling models, as well as in patients with cardiac hypertrophy. Silencing and inhibiting NAT10 attenuated Ang II-induced cardiomyocyte hypertrophy and cardiofibroblast activation. Next-generation sequencing revealed ac4C changes in both mice and humans with cardiac hypertrophy were associated with changes in global mRNA abundance, stability, and translation efficiency. Mechanistically, NAT10 could enhance the stability and translation efficiency of CD47 and ROCK2 transcripts by upregulating their mRNA ac4C modification, thereby resulting in an increase in their protein expression during cardiac remodeling. Furthermore, the administration of Remodelin, a NAT10 inhibitor, has been shown to prevent cardiac functional impairments in mice subjected to transverse aortic constriction by suppressing cardiac fibrosis, hypertrophy, and inflammatory responses, while also regulating the expression levels of CD47 and ROCK2. CONCLUSIONS: Therefore, our data suggest that modulating epitranscriptomic processes, such as ac4C acetylation through NAT10, may be a promising therapeutic target against cardiac remodeling.

Lysine-372-dependent SUMOylation inhibits the enzymatic activity of glutamine synthases.

Glutamine synthetase (GS) is a crucial enzyme involved in de novo synthesis of glutamine and participates in several biological processes, including nitrogen metabolism, nucleotide synthesis, and amino acid synthesis. Post-translational modification makes GS more adaptable to the needs of cells, and acetylation modification of GS at double sites has attracted considerable attention. Despite very intensive research, how SUMOylation affects GS activity at a molecular level remains unclear. Here, we report that previously undiscovered GS SUMOylation which is deficient mutant K372R of GS exhibits more bluntness under glutamine starvation. Mechanistically, glutamine deprivation triggers the GS SUMOylation, and this SUMOylation impaired the protein stability of GS, within a concomitant decrease in enzymatic activity. In addition, we identified SAE1, Ubc9, and PIAS1 as the assembly enzymes of GS SUMOylation respectively. Furthermore, Senp1/2 functions as a SUMO-specific protease to reverse the SUMOylation of GS. This study provides the first evidence that SUMOylation serves as a regulatory mechanism for determining the GS enzymatic activity, contributing to understanding the GS regulation roles in various cellular and pathophysiological processes.

Evaluation of synovial inflammation in juvenile idiopathic arthritis using superb microvascular imaging compared with power Doppler ultrasound.

OBJECTIVES: This study aimed to investigate the diagnostic and prognostic performance of superb microvascular imaging (SMI) in evaluation of synovial inflammation in patients with juvenile idiopathic arthritis (JIA) compared with power Doppler ultrasound (PDUS). METHODS: Fifty-nine patients with active disease and 62 patients with inactive disease were enrolled. The synovial inflammation was evaluated via vascularity index (VI) of SMI and PDUS. The correlations between VIs and the inflammatory biomarkers were analysed by Spearman's coefficient. Receiver operating characteristics curves were plotted to examine the prognostic value of SMI and PDUS. RESULTS: The VI of SMI was significantly higher than that of PDUS in JIA patients regardless of the disease activity. The SMI and PDUS VI were significantly correlated with levels of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and serum amyloid A (SAA). The SMI VI was significantly higher in patients with relapse than in those with remission, and showed superior performance in predicting relapse in JIA patients with inactive disease. CONCLUSIONS: SMI may detect the synovial inflammation with greater sensitivity than PDUS in patients with JIA, and correlate well with the inflammatory biomarkers. SMI signal in the knees might play an important role in prediction of relapse in clinically inactive patients, thus allowing personalised treatment strategies for JIA patients.

The Impact of ESBLs-Positive Escherichia coli's Resistance to Cefepime and Its Guidance for Clinical Treatment.

Background: Escherichia coli (E. coli) is a common pathogen in bloodstream infections (BSI), and the production of extended-spectrum beta-lactamases (ESBLs) is its main mechanism of resistance. However, the impact of different ESBL genotypes of E. coli on the resistance to Cefepime (FEP) remains unclear. Methods: A total of 2356 cases of BSI patients were collected. The experimental group included 188 ESBL-positive E. coli strains that were resistant to FEP but sensitive to ceftazidime (CAZ). Antibiotic usage and resistance rates were evaluated through antimicrobial susceptibility testing and antibiotic usage records. The ESBL genotypes were identified, and the minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) of FEP were determined. Results: In ESBL-positive E. coli, three ESBL genotypes were identified: 188 strains of CTX-M, 130 strains of TEM-1, and 26 strains of OXA-10. Among them, 124 strains carried both CTX-M-9 and TEM-1 genotypes, 22 strains carried two CTX-M genotypes (CTX-M-1 and CTX-M-2), 20 strains carried both CTX-M-9 and OXA-10, and 6 strains carried three genotypes (CTX-M-9, CTX-TEM-1, and OXA-10). The MIC50, MIC90, MPC50, and MPC90 of the 188 ESBL-positive E. coli were 64, 256, 128, and 528, respectively. The MIC values ranged from 32 to 256, while the MPC values ranged from 64 to 528. The MIC50, MIC90, MPC50, and MPC90 of the 40 ESBL-negative E. coli were 0.5, 1, 64, and 128, respectively; the MIC values ranged from 0.25 to 4, while the MPC values ranged from 32 to 256, respectively. Conclusion: ESBL-positive E. coli induces an increase in the MIC value of FEP, leading to an increase in FEP resistance. The inoculation effect also causes a significant increase in the MPC value of FEP, especially the increase in selection index value, indicating selective enrichment and amplification of drug-resistant mutants, resulting in clinical treatment failure.

Synthesis of disulfide-rich C-terminal Cys-containing peptide acids through a photocleavable side-chain anchoring strategy.

A side-chain anchoring strategy has been developed as an effective method for the synthesis of C-terminal Cys-containing peptide acids. However, the application of this strategy to CCAs containing more than one disulfide bond is still hindered due to the trifluoroacetic acid (TFA) lability of the anchored side-chain groups. Herein, we report a photocleavable side-chain anchoring strategy using newly developed molecules having photocleavable side-chain protecting groups that are stable against TFA cleavage to assist in the formation of disulfide bonds. The utility of this new strategy was demonstrated by the synthesis of Riparin 1.1 and hCNP22 containing one disulfide bond and α-conotoxin Vc1.1 containing two disulfide bonds. This new strategy will provide new possibilities for the synthesis of disulfide-rich C-terminal Cys-containing peptide acids.

ent-Atisane Diterpenoids from Euphorbia helioscopia and Their Anti-inflammatory Activities.

Phytochemical investigation on the anti-inflammatory fraction extracted from the whole plant of Euphorbia helioscopia L. led to the isolation of three new ent-atisane diterpenoids (1-3) and five known analogues (4-8). The structures and absolute configurations of the new compounds were elucidated by comprehensive analysis of the NMR, MS, IR, ECD, and X-ray crystallography. It is worth mentioning that compound 3 belongs to a rare class of ent-atisane diterpenoid featuring a hydroxyl group at C-9. Bioactivity investigation showed that compounds 4, 7, and 8 exhibited significant inhibitory effects on LPS-induced NO production in a dose-dependent manner, which indicates their anti-inflammatory potential.