Bacterial γ-glutamyltranspeptidases (γ-GT) is a well-known metabolic enzyme, which could cleave the γ-glutamyl amide bond of γ-glutamyl analogues. As a key metabolic enzyme of bacteria and a ...virulence factor for the host, bacterial γ-GT was determined to be a novel pharmaceutical target for new antibiotics development. However, there is no efficient method for the sensing of γ-GT activity in bacteria and the recognition of γ-glutamyltransferase rich-bacteria. In the present work, a dicyanoisophorone derivative (ADMG) has been designed and developed to be a sensitive and selective near-infrared fluorescent probe for the sensing of bacterial γ-GT. ADMG not only sensed bacterial γ-GT in vitro, but also imaged intestinal bacteria in vivo. More interesting, the intestinal bacteria existed in the duodenum section of mouse displayed significant fluorescence emission. Under the guidance of the sensing of γ-GT using ADMG, three intestinal bacteria strains K. pneumoniae CAV1042, K. pneumoniae XJRML-1, and E. faecalis were isolated successfully, which expressed the bacterial γ-GT. Therefore, the fluorescent probe ADMG not only sensed the endogenous bacterial γ-GT and imaged the intestinal bacteria but also guided the isolation of intestinal bacteria possessing γ-GT efficiently, which suggested a novel biological tool for the rapid isolation of special bacteria from a mixed sample.
Integrated geochemical analysis was conducted on oil and gas samples from the LG7 block, Tarim Basin, China, to investigate the causal mechanisms for the complex petroleum phase. Consistency in ...biomarker derived parameters suggest that heavy oil, black oil, and condensate, though vary in physical properties and phase state, share a genetic affinity and are all mature oil generated at peak oil window. However, mass loss and double-peaks pattern in n-paraffins of black oil and heavy oil, and much higher maturity of gas and some oil fractions (diamondoids) jointly suggest the oil samples in the study site have suffered secondary alteration process including phase fractionation and mixing. In combination with tectonic evolution analysis, the study site experienced severe uplift after primary oil accumulation and thus formed biodegraded heavy oil in local highs. Since Neogene, the introduction of oil-cracking gas from deeper strata charged early oil accumulations and caused phase fractionation, during which primary oil was fractionated into vaporized light oil and heavy oil residue. Vaporized light oil continued to migrate towards higher positions and were readily to either mix with other oil residue and heavy oil, or to be trapped to form secondary condensate in favorable reservoirs. Thus, the complex disordered distribution of heavy oil, black oil, and condensate is observed within a relatively small area. Our reconstruction of the petroleum accumulation and alteration process speculates future exploration endeavors to potential oil-cracking gas/condensate accumulations in the study area.
•Causal mechanisms for complex petroleum phase in the LG7 block were proposed.•Vaporized light oil and oil residue formed during the phase fractionation of primary oil.•Two types of oil mixing scenarios led to complex n-alkane distribution.•Petroleum accumulation and alteration process in the LG7 block was reconstructed.
Mitochondria, the only semiautonomous organelles in mammalian cells, possess a circular, double-stranded genome termed mitochondrial DNA (mtDNA). While nuclear genomic DNA compaction, chromatin ...compartmentalization and transcription are known to be regulated by phase separation, how the mitochondrial nucleoid, a highly compacted spherical suborganelle, is assembled and functions is unknown. Here we assembled mitochondrial nucleoids in vitro and show that mitochondrial transcription factor A (TFAM) undergoes phase separation with mtDNA to drive nucleoid self-assembly. Moreover, nucleoid droplet formation promotes recruitment of the transcription machinery via a special, co-phase separation that concentrates transcription initiation, elongation and termination factors, and retains substrates to facilitate mtDNA transcription. We propose a model of mitochondrial nucleoid self-assembly driven by phase separation, and a pattern of co-phase separation involved in mitochondrial transcriptional regulation, which orchestrates the roles of TFAM in both mitochondrial nucleoid organization and transcription.
In the process of diagenesis and burial of sedimentary basins, basin fluid activities participate in the process of hydrocarbon accumulation and metal mineralization. Understanding the evolution of ...basin fluid is of great significance in revealing the related hydrocarbon accumulation and mineralization. Paleo-reservoirs are closely associated with Carlin-type gold deposits in the Nanpanjiang-Youjiang Basin, South China. Calcite, the fluid activity product, is closely related to bitumen and gold-bearing pyrite. By integrating petrographic, cathode luminescence, and fluid inclusion analysis, as well as the relevant chronological results of predecessors, this paper attempts to establish the relationship between fluid evolution, hydrocarbon accumulation, and gold mineralization. Two types of calcite (black/gray and white) developed in the Banqi-Yata-Laizishan area, the Nanpanjiang-Youjiang Basin. Black/gray calcite is symbiotic with bitumen and features dark red colors in cathode luminescence. Many hydrocarbon inclusions developed along with fluid inclusion analysis at low homogenization temperatures (65.7~173.1 °C). Combining the previously reported U-Pb ages (~250–230 Ma) of this kind of calcite with some geochemistry data on the associated reservoir and gold deposit, this calcite records the consecutive hydrocarbon accumulation and Carlin-type gold mineralization from the Late Permian to the Late Triassic periods controlled by Indosinian tectonic movement. The white calcite featuring bright red in cathodoluminescence is symbiotic with gold-bearing pyrite and realgar, and the associated fluid inclusions have high homogenization temperatures (128.2~299.9 °C). Combined with regional tectonic background and isotopic chronology (~140–106 Ma), it seems to record the early Cretaceous Carlin-type gold mineralization controlled by the subduction of the paleo-Pacific plate in the late Yanshanian period.
Recently, the cicada-inspired nanostructured surfaces have attracted much interest because they possess remarkable bactericidal ability. However, Gram-positive bacteria are less damageable by the ...nanopillar structure of a cicada wing surface compared to Gram-negative species. To overcome this shortcoming, fluoridated hydroxyapatite (FHA) is employed owing to its effective antibacterial ability against both Gram-negative and Gram-positive bacteria. Here, we design a novel potential antibacterial surface by combining the cicada wing-like nanopillar structure and the FHA together to potentially exert the advantages of physical and chemical antibacterial strategies simultaneously for battling the antibiotic-resistant pathogenic bacteria more effectively. Cicada-inspired FHA nanostructured surfaces have been successfully fabricated on acid-etched titanium (AETi) plates using an electrochemical additive manufacturing (ECAM) method for the first time. The as-prepared FHA nanopillar array consists of close-packed individual nanopillars with diameters, heights, and aspect ratios of ~65–95 nm, ~380–510 nm, and ~4.5–7.5, respectively. The chemical composition of the FHA nanopillar array is similar to that of the Ca10(PO4)6(OH)F. Individual FHA nanopillars possess high crystallinity, long-range regularity, and flaw-free lattices with the 0001 orientation. Our new, cost-effective, and time-saving method for fabricating cicada-inspired FHA nanostructured surfaces could potentially endow orthopedic and dental implants with enhanced antibacterial performance for biomedical applications.
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•We firstly proposed an electrochemical additive manufacturing method for preparing cicada-inspired nanostructured surfaces.•This promising synthesis method is novel, cost-effective, and time-saving.•This study focused on fabricating nanostructures with bioactive and biocompatible fluoridated hydroxyapatite pioneeringly.•We designed the biomimetic nanostructures by combining the advantages of physical and chemical antibacterial strategies.•The nanostructures could potentially endow medical implants with more effective non-antibiotic antibacterial activity.
This paper proposes a novel hyperspectral image classification method that combines dynamic semi-supervised multiple-kernel collaborative representation ensemble selection with superpixel (SP) ...consistency constraints. The method is based on the consistency principle of labels within SP blocks, where the hyperspectral image is divided into different SP blocks, and each block is treated as an independent classification task. It applies a dynamic ensemble selection strategy to select high-confidence samples from the unlabeled data and assigns pseudo-labels to expand the available training sample set. Additionally, it employs a multiple-kernel collaborative representation classifier as the base classifier to better capture sample similarities and correlations, thereby improving the classification performance. Experimental results demonstrate that the proposed method achieves superior classification accuracy on various datasets such as Indian Pines, Purdue, and KSC, outperforming the traditional Meta-DES method significantly.
Nine new monoterpenoid indole alkaloids, uncarialins A–I (1–9), were isolated from Uncaria rhynchophylla as well as 14 known analogues (10–23). Their structures were determined by HRESIMS, 1D and 2D ...NMR, and experimental and calculated electronic circular dichroism data. Compounds 5, 7, 15, and 22 displayed significant agonistic effects against the 5-HT1A receptor with EC50 values of 2.2 ± 0.1, 0.1 ± 0.1, 1.6 ± 0.3, and 2.0 ± 0.5 μM, respectively. The mechanisms of action of these four compounds with the 5-HT1A receptor were investigated by molecular docking, and the results suggested that amino acid residues Asp116, Thr196, Asn386, and Tyr390 played critical roles in the observed activity of the above-mentioned compounds.
This study aimed to develop a novel therapeutic vaccine based on a unique B cell epitope and investigate its therapeutic potential against chronic hepatitis B (CHB) in animal models.
A series of ...peptides and carrier proteins were evaluated in HBV-tolerant mice to obtain an optimised therapeutic molecule. The immunogenicity, therapeutic efficacy and mechanism of the candidate were investigated systematically.
Among the HBsAg-aa119-125-containing peptides evaluated in this study, HBsAg-aa113-135 (SEQ13) exhibited the most striking therapeutic effects. A novel immunoenhanced virus-like particle carrier (CR-T3) derived from the roundleaf bat HBV core antigen (RBHBcAg) was created and used to display SEQ13, forming candidate molecule CR-T3-SEQ13. Multiple copies of SEQ13 displayed on the surface of this particulate antigen promote the induction of a potent anti-HBs antibody response in mice, rabbits and cynomolgus monkeys. Sera and purified polyclonal IgG from the immunised animals neutralised HBV infection in vitro and mediated efficient HBV/hepatitis B virus surface antigen (HBsAg) clearance in the mice. CR-T3-SEQ13-based vaccination induced long-term suppression of HBsAg and HBV DNA in HBV transgenic mice and eradicated the virus completely in hydrodynamic-based HBV carrier mice. The suppressive effects on HBsAg were strongly correlated with the anti-HBs level after vaccination, suggesting that the main mechanism of CR-T3-SEQ13 vaccination therapy was the induction of a SEQ13-specific antibody response that mediated HBV/HBsAg clearance.
The novel particulate protein CR-T3-SEQ13 suppressed HBsAg effectively through induction of a humoural immune response in HBV-tolerant mice. This B cell epitope-based therapeutic vaccine may provide a novel immunotherapeutic agent against chronic HBV infection in humans.
Background
Chronic primary pain (CPP) is an intractable pain of unknown cause with significant emotional distress and/or dysfunction that is a leading factor of disability globally. The lack of a ...suitable animal model that mimic CPP in humans has frustrated efforts to curb disease progression. 2R, 6R-hydroxynorketamine (2R, 6R-HNK) is the major antidepressant metabolite of ketamine and also exerts antinociceptive action. However, the analgesic mechanism and whether it is effective for CPP are still unknown.
Methods
Based on nociplastic pain is evoked by long-term potentiation (LTP)-inducible high- or low-frequency electrical stimulation (HFS/LFS), we wanted to develop a novel CPP mouse model with mood and cognitive comorbidities by noninvasive low-frequency percutaneous electrical nerve stimulation (LF-PENS). Single/repeated 2R, 6R-HNK or other drug was intraperitoneally (i.p.) or intrathecally (i.t.) injected into naïve or CPP mice to investigate their analgesic effect in CPP model. A variety of behavioral tests were used to detect the changes in pain, mood and memory. Immunofluorescent staining, western blot, reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) and calcium imaging of in cultured dorsal root ganglia (DRG) neurons by Fluo-8-AM were used to elucidate the role and mechanisms of 2R, 6R-HNK in vivo or in vitro.
Results
Intrathecal 2R, 6R-HNK, rather than intraperitoneal 2R, 6R-HNK or intrathecal S-Ketamine, successfully mitigated HFS-induced pain. Importantly, intrathecal 2R, 6R-HNK displayed effective relief of bilateral pain hypersensitivity and depressive and cognitive comorbidities in a dose-dependent manner in LF-PENS-induced CPP model. Mechanically, 2R, 6R-HNK markedly attenuated neuronal hyperexcitability and the upregulation of calcitonin gene-related peptide (CGRP), transient receptor potential ankyrin 1 (TRPA1) or vanilloid-1 (TRPV1), and vesicular glutamate transporter-2 (VGLUT2) in peripheral nociceptive pathway. In addition, 2R, 6R-HNK suppressed calcium responses and CGRP overexpression in cultured DRG neurons elicited by the agonists of TRPA1 or/and TRPV1. Strikingly, the inhibitory effects of 2R, 6R-HNK on these pain-related molecules and mechanical allodynia were substantially occluded by TRPA1 antagonist menthol.
Conclusions
In the newly designed CPP model, our findings highlighted the potential utility of intrathecal 2R, 6R-HNK for preventing and therapeutic modality of CPP. TRPA1-mediated uprgulation of CGRP and neuronal hyperexcitability in nociceptive pathways may undertake both unique characteristics and solving process of CPP.
Highlights
1) We first establish the CPP mouse model by LF-PENS to mimic nociplastic pain.
2) Intrathecal 2R, 6R-HNK effectively alleviates LF-PENS-induced CPP in mouse models by inhibiting TRPA1 in DRG neurons.
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