Murepavadin promotes the killing efficacies of aminoglycoside antibiotics against Pseudomonas aeruginosa by enhancing membrane potential.

Murepavadin is a peptidomimetic that specifically targets the lipopolysaccharide transport protein LptD of Pseudomonas aeruginosa. Here, we found that murepavadin enhances the bactericidal efficacies of tobramycin and amikacin. We further demonstrated that murepavadin enhances bacterial respiration activity and subsequent membrane potential, which promotes intracellular uptake of aminoglycoside antibiotics. In addition, the murepavadin-amikacin combination displayed a synergistic bactericidal effect in a murine pneumonia model.

Fontisubflavum oceani gen. nov., sp. nov., isolated from the deep-sea cold seep water of South China Sea.

In this study, we report a Gram-stain-negative, rod-shaped, atrichous and aerobic bacterial strain named CSW1921T, which was isolated from the deep-sea water of a cold seep in South China Sea. Growth of strain CSW1921T occurred at 10.0-35.0 °C (optimum, 30 °C), pH 5.0-10.0 (optimum, pH 8.0-9.0) and with 0-9.0 % (w/v) NaCl (optimum, 1.0-2.0 %). Phylogenetic tree analysis based on 16S rRNA gene sequence or the genomic sequence indicated that strain CSW1921T belonged to the family Rhodobacteraceae and was closely related to Rhodophyticola porphyridii MA-7-27T (97.5 % sequence similarity). Genomic analysis indicated that strain CSW1921T contains a circular chromosome of 3 592 879 bp with G+C content of 60.5 mol%. The predominant respiratory quinone of CSW1921T was ubiquinone-10. The polar lipids of CSW1921T contained phosphatidylglycerol, three unidentified aminolipids, two unidentified phospholipids and two unidentified lipids. The major fatty acids of strain CSW1921T contained C16 : 0, C18 : 1 ω7c 11-methyl and summed feature 8 (C18 : 1 ω7c). The average nucleotide identity, DNA-DNA hybridization and average amino acid identity values between strain CSW1921T and members of its related species were 68.02-69.08 %, 12.7-12.9 % and 46.87-48.08 %, respectively, which were lower than the recommended threshold values for bacterial species or genus delineation. Phylogenetic, physiological, biochemical and morphological analyses suggested that strain CSW1921T represents a novel genus and a novel species of the family Rhodobacteraceae, and the name Fontisubflavum oceani gen. nov., sp. nov. is proposed with the type strain CSW1921T (=MCCC 1K08371T=KCTC 92834T).

Tetraspanin CD53 regulates peripheral blood leucocytes vitality and pathogen infection in turbot (Scophthalmus maximus).

Cluster of differentiation 53 (CD53) also known as OX44 or tetraspanin 25 (TSPAN25) is a glycoprotein belonging to the tetraspanin family. Members of the tetraspanin family are characterized by four transmembrane domains, including intracellular N- and C-termini, and small and large extracellular domains. Currently, the function of CD53 in teleost is not well understood. In this study, we identified a CD53 (named SmCD53) from turbot (Scophthalmus maximus) and examined its expression and biological activity. SmCD53 contained 231 amino acid residues and was predicted to be a tetraspanin with small and large extracellular domains. SmCD53 expression was observed in different tissues, particularly in immune-related organs. Experimental infection with bacterial or viral pathogen significantly up-regulated SmCD53 expression in a time-dependent manner. Immunofluorescence microscopy analysis showed that SmCD53 was localized on the surface of PBL and was recognized by antibody against its large extracellular domain. Ligation of SmCD53 onto PBLs with antibodies suppressed the respiratory burst activity, inflammatory reaction, and enhanced cell viability. SmCD53 knockdown significantly enhanced bacterial dissemination and proliferation in turbot. Overall, these results underscore the importance of CD53 in the maintenance of the function and homeostasis of the immune system.

NO3- as an electron acceptor elevates antibiotic resistance gene and human bacterial pathogen risks in managed aquifer recharge (MAR): A comparison with O2.

Managed aquifer recharge (MAR) stands out as a promising strategy for ensuring water resource sustainability. This study delves into the comparative impact of nitrate (NO3-) and oxygen (O2) as electron acceptors in MAR on water quality and safety. Notably, NO3-, acting as an electron acceptor, has the potential to enrich denitrifying bacteria, serving as hosts for antibiotic resistance genes (ARGs) and enriching human bacterial pathogens (HBPs) compared to O2. However, a direct comparison between NO3- and O2 remains unexplored. This study assessed risks in MAR effluent induced by NO3- and O2, alongside the presence of the typical refractory antibiotic sulfamethoxazole. Key findings reveal that NO3- as an electron acceptor resulted in a 2 times reduction in dissolved organic carbon content compared to O2, primarily due to a decrease in soluble microbial product production. Furthermore, NO3- significantly enriched denitrifying bacteria, the primary hosts of major ARGs, by 747%, resulting in a 66% increase in the overall abundance of ARGs in the effluent of NO3- MAR compared to O2. This escalation was predominantly attributed to horizontal gene transfer mechanisms, as evidenced by a notable 78% increase in the relative abundance of mobile ARGs, alongside a minor 27% rise in chromosomal ARGs. Additionally, the numerous denitrifying bacteria enriched under NO3- influence also belong to the HBP category, resulting in a significant 114% increase in the abundance of all HBPs. The co-occurrence of ARGs and HBPs was also observed to intensify under NO3- influence. Thus, NO3- as an electron acceptor in MAR elevates ARG and HBP risks compared to O2, potentially compromising groundwater quality and safety.

Description of Fuscovulum ytuae sp. nov, a facultative autotroph isolated from the intertidalite of Yangma island, China.

In this study, we reported a Gram-stain-negative, ovoid to rod-shaped, atrichous, and facultative anaerobe bacteria strain named YMD61T, which was isolated from the intertidal sediment of Yangma island, China. Growth of strain YMD61T occurred at 10.0-45.0 °C (optimum, 30.0 °C), pH 7.0-10.0 (optimum, 8.0) and with 0-3.0% (w/v) NaCl (optimum, 2.0%). Phylogenetic tree analysis based on 16 S rRNA gene or genomic sequence indicated that strain YMD61T belonged to the genus Fuscovulum and was closely related to Fuscovulum blasticum ATCC 33,485T (96.6% sequence similarity). Genomic analysis indicated that strain YMD61T contains a circular chromosome of 3,895,730 bp with DNA G + C content of 63.3%. The genomic functional analysis indicated that strain YMD61T is a novel sulfur-metabolizing bacteria, which is capable of fixing carbon through an autotrophic pathway by integrating the processes of photosynthesis and sulfur oxidation. The predominant respiratory quinone of YMD61T was ubiquinone-10 (Q-10). The polar lipids of YMD61T contained phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, five unidentified lipids, unidentified aminolipid and unidentified aminophospholipid. The major fatty acids of strain YMD61T contained C18:1ω7c 11-methyl and summed feature 8 (C18:1 ω 7c or/and C18:1 ω 6c). Phylogenetic, physiological, biochemical and morphological analyses suggested that strain YMD61T represents a novel species of the genus Fuscovulum, and the name Fuscovulum ytuae sp. nov. is proposed. The type strain is YMD61T (= MCCC 1K08483T = KCTC 43,537T).

Surface ligand-regulated renal clearance of MRI/SPECT dual-modality nanoprobes for tumor imaging.

BACKGROUND: The general sluggish clearance kinetics of functional inorganic nanoparticles tend to raise potential biosafety concerns for in vivo applications. Renal clearance is a possible elimination pathway for functional inorganic nanoparticles delivered through intravenous injection, but largely depending on the surface physical chemical properties of a given particle apart from its size and shape. RESULTS: In this study, three small-molecule ligands that bear a diphosphonate (DP) group, but different terminal groups on the other side, i.e., anionic, cationic, and zwitterionic groups, were synthesized and used to modify ultrasmall Fe3O4 nanoparticles for evaluating the surface structure-dependent renal clearance behaviors. Systematic studies suggested that the variation of the surface ligands did not significantly increase the hydrodynamic diameter of ultrasmall Fe3O4 nanoparticles, nor influence their magnetic resonance imaging (MRI) contrast enhancement effects. Among the three particle samples, Fe3O4 nanoparticle coated with zwitterionic ligands, i.e., Fe3O4@DMSA, exhibited optimal renal clearance efficiency and reduced reticuloendothelial uptake. Therefore, this sample was further labeled with 99mTc through the DP moieties to achieve a renal-clearable MRI/single-photon emission computed tomography (SPECT) dual-modality imaging nanoprobe. The resulting nanoprobe showed satisfactory imaging capacities in a 4T1 xenograft tumor mouse model. Furthermore, the biocompatibility of Fe3O4@DMSA was evaluated both in vitro and in vivo through safety assessment experiments. CONCLUSIONS: We believe that the current investigations offer a simple and effective strategy for constructing renal-clearable nanoparticles for precise disease diagnosis.

Intranasal Pathway for Nanoparticles to Enter the Central Nervous System.

Intranasal administration was previously proposed for delivering drugs for central nervous system (CNS) diseases. However, the delivery and elimination pathways, which are very imperative to know for exploring the therapeutic applications of any given CNS drugs, remain far from clear. Because lipophilicity has a high priority in the design of CNS drugs, the as-prepared CNS drugs tend to form aggregates. Therefore, a PEGylated Fe3O4 nanoparticle labeled with a fluorescent dye was prepared as a model drug and studied to elucidate the delivery pathways of intranasally administered nanodrugs. Through magnetic resonance imaging, the distribution of the nanoparticles was investigated in vivo. Through ex vivo fluorescence imaging and microscopy studies, more precise distribution of the nanoparticles across the entire brain was disclosed. Moreover, the elimination of the nanoparticles from cerebrospinal fluid was carefully studied. The temporal dose levels of intranasally delivered nanodrugs in different parts of the brain were also investigated.

Tunable Fluorine-Functionalized Scholl-Coupled Microporous Polymer for the Selective Adsorption and Ultrasensitive Analysis of Environmental Liquid-Crystal Monomers.

Liquid-crystal monomers (LCMs), especially fluorinated biphenyls and analogues (FBAs), are identified to be an emerging generation of persistent organic pollutants. However, there is a dearth of information about their occurrence and distribution in environmental water and lacustrine soil samples. Herein, a series of fluorine-functionalized Scholl-coupled microporous polymers (FSMP-X, X = 1-3) were designed and synthesized for the highly efficient and selective enrichment of FABs. Their hydrophobicity, porosity, chemical stability, and adsorption performance (capacity, rate, and selectivity) were regulated preciously. The best-performing material (FSMP-2) was employed as the on-line fluorous solid-phase extraction (on-line FSPE) adsorbent owing to its high adsorption capacity (313.68 mg g-1), fast adsorption rate (1.05 g h-1), and specific selectivity for FBAs. Notably, an enrichment factor of up to 590.2 was obtained for FSMP-2, outperforming commercial C18 (12.6-fold). Also, the underlying adsorption mechanism was uncovered by density functional theory calculations and experiments. Based on this, a novel and automated on-line FSPE-high-performance liquid chromatography method was developed for ultrasensitive (detection limits: 0.0004-0.0150 ng mL-1) and low matrix effect (73.79-113.3%) determination of LCMs in lake water and lacustrine soils. This study offers new insight into the highly selective quantification of LCMs and the first evidence for their occurrence and distribution in these environmental samples.

Effects and mechanisms of natural products on Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia in elderly people with a high incidence rate and complicated pathogenesis, and causes progressive cognitive deficit and memory impairment. Some natural products and bioactive compounds from natural sources show great potential in the prevention and treatment of AD, such as apple, blueberries, grapes, chili pepper, Monsonia angustifolia, cruciferous vegetables, Herba epimedii, Angelica tenuissima, Embelia ribes, sea cucumber, Cucumaria frondosa, green tea, Puer tea, Amanita caesarea and Inonotus obliquus, via reducing amyloid beta (Aß) deposition, decreasing Tau hyperphosphorylation, regulating cholinergic system, reducing oxidative stress, inhibiting apoptosis and ameliorating inflammation. This review mainly summarizes the effects of some natural products and their bioactive compounds on AD with the potential molecular mechanisms.

Dietary sources, health benefits, and risks of caffeine.

Dietary intake of caffeine has significantly increased in recent years, and beneficial and harmful effects of caffeine have been extensively studied. This paper reviews antioxidant and anti-inflammatory activities of caffeine as well as its protective effects on cardiovascular diseases, obesity, diabetes mellitus, cancers, and neurodegenerative and liver diseases. In addition, we summarize the side effects of long-term or excessive caffeine consumption on sleep, migraine, intraocular pressure, pregnant women, children, and adolescents. The health benefits of caffeine depend on the amount of caffeine intake and the physical condition of consumers. Moderate intake of caffeine helps to prevent and modulate several diseases. However, the long-term or over-consumption of caffeine can lead to addiction, insomnia, migraine, and other side effects. In addition, children, adolescents, pregnant women, and people who are sensitive to caffeine should be recommended to restrict/reduce their intake to avoid potential adverse effects.

Application of postmortem MRI for identification of medulla oblongata contusion as a cause of death: a case report.

Whiplash injury is common in traffic accidents, and severe whiplash is characterized by cervical spinal cord injuries with cervical dislocation or fracture, that can be diagnosed by postmortem computed tomography (PMCT), postmortem magnetic resonance (PMMR), or conventional autopsy. However, for cervical spinal cord injury without fracture and dislocation, PMMR can be more informative because it provides higher resolution of soft tissues. We report the case of a 29-year-old male who died immediately following a traffic accident, in which the vehicle hit an obstacle at a high speed, causing deformation of the bumper and severe damage of the vehicle body. PMCT indicated no significant injuries or diseases related to death, but PMMR showed patchy abnormal signals in the medulla oblongata, and the lower edge of the cerebellar tonsil was herniated out of the foramen magnum. The subsequent pathological and histological results confirmed that death was caused by medulla oblongata contusion combined with cerebellar tonsillar herniation. Our description of this case of a rare but fatal whiplash injury in which there was no fracture or dislocation provides a better understanding of the potentially fatal consequences of cervical spinal cord whiplash injury without fracture or dislocation and of the underlying lethal mechanisms. Compared with PMCT, PMMR provides important diagnostic information in forensic practice for the identification of soft tissue injuries, and is therefore an important imaging modality for diagnosis of whiplash injury when there is no fracture or dislocation.

Exploring an Efficient and Eco-Friendly Signaling Molecule and Its Quorum Quenching Ability for Controlling Microcystis Blooms.

Globally, cyanobacterial blooms have become serious problems in eutrophic water. Most previous studies have focused on environmental factors but have neglected the role of quorum sensing (QS) in bloom development and control. This study explored a key quorum sensing molecule (QSM) that promotes cell growth and then proposed a targeted quorum quencher to control blooms. A new QSM 3-OH-C4-HSL was identified with high-resolution mass spectrometry. It was found to regulate cellular carbon metabolism and energy metabolism as a means to promote Microcystis aeruginosa growth. To quench the QS induced by 3-OH-C4-HSL, three furanone-like inhibitors were proposed based on molecular structure, of which dihydro-3-amino-2-(3H)-furanone (FN) at a concentration of 20 µM exhibited excellent inhibition of M. aeruginosa growth (by 67%). Molecular docking analysis revealed that the inhibitor strongly occupied the QSM receptor protein LuxR by binding with Asn164(A) and His167(A) via two hydrogen bonds (the bond lengths were 3.04 and 4.04 Å) and the binding energy was -5.9 kcal/mol. The inhibitor blocked signaling regulation and induced programmed cell death in Microcystis. Importantly, FN presented little aquatic biotoxicity and negligibly affected aquatic microbial function. This study provides a promising new and eco-friendly strategy for controlling cyanobacterial blooms.

Coremoval of Energetics and Oxyanions via the In Situ Coupling of Catalytic and Enzymatic Destructions: A Solution to Ammunition Wastewater Treatment.

Ammunition wastewater contains toxic nitrated explosives like RDX and oxyanions like nitrate and perchlorate. Its treatment is challenged by low efficiency due to contaminant recalcitrance and high cost due to multiple processes needed for separately removing different contaminant types. This paper reports a H2-based low-energy strategy featuring the treatment of explosives via catalytic denitration followed by microbial mineralization coupled with oxyanion reduction. After a nitrate- and perchlorate-reducing biofilm incapable of RDX biodegradation was coated with palladium nanoparticles (Pd0NPs), RDX was rapidly denitrated with a specific catalytic activity of 8.7 gcat-1 min-1, while biological reductions of nitrate and perchlorate remained efficient. In the subsequent 30-day continuous test, >99% of RDX, nitrate, and perchlorate were coremoved, and their effluent concentrations were below their respective regulation levels. Detected intermediates and shallow metagenome analysis suggest that the intermediates after Pd-catalytic denitration of RDX ultimately were enzymatically utilized by the nitrate- and perchlorate-reducing bacteria as additional electron donor sources.

Tropicibacter oceani sp. nov., a novel sulfur-metabolizing bacteria isolated from the intertidal zone sediment of Chinese Yellow Sea.

In this study, we reported a Gram-stain-negative, rod-shaped, atrichous, and aerobic bacterial strain named YMD87T, which was isolated from the intertidal zone sediment of Chinese Yellow Sea. Growth of strain YMD87T occurred at 10.0-40.0 °C (optimum, 25-30 °C), pH 4.0-12.0 (optimum, 8.0) and with 0-6.0% (w/v) NaCl (optimum, 0.0-2.0%). Phylogenetic tree analysis based on 16S rRNA gene sequence indicated that strain YMD87T belonged to the genus Tropicibacter and was closely related to Tropicibacter alexandrii LMIT003T (97.2% sequence similarity). Genomic analysis indicated that strain YMD87T contains a circular chromosome of 3,932,460 bp with G + C content of 63.8% and three circular plasmids of 116,492 bp, 49,209 bp and 49,673 bp, with G + C content of 64.3%. Genomic functional analysis revealed that strain YMD87T is potential a novel sulfur-metabolizing bacteria. The predominant respiratory quinone of YMD87T was ubiquinone-10 (Q-10). The major polar lipids of YMD87T contained phosphatidylglycerol, phosphatidylethanolamine, five unidentified lipids, five unidentified phospholipids, phosphatidylcholine, unidentified glycolipid and five unidentified aminolipids. The major fatty acids of strain YMD87T contained C12:1 3-OH, C16:0, and summed feature 8 (C18:1 ω7c or/and C18:1 ω6c). Phylogenetic, physiological, biochemical and morphological analyses suggested that strain YMD87T represents a novel species of the genus Tropicibacter, and the name Tropicibacter oceani sp. nov is proposed. The type strain is YMD87T (= MCCC 1K08473T = KCTC 92856 T).

Micro-matrix cartridge extraction followed by online micro-solid phase extraction based on polystyrene@hydroxypropyl-ß-cyclodextrin nanofibers for selective determination of fipronil and its metabolites in soil.

Micro-matrix cartridge extraction coupled on-line to micro-solid phase extraction-high performance liquid chromatography-mass spectrometry (µ-MCE-online-µ-SPE-HPLC-MS) is presented. Micro-matrix cartridge extraction (µ-MCE) was applied to highly efficient desorption of adsorbed pesticides from contaminated soil with favorable extraction efficiency (100%). Novel polystyrene@hydroxypropyl-ß-cyclodextrin (PS@HPCD) electrospun nanofibers with 3D network structure were prepared to selectively capture fipronil and its metabolites. High selectivity was obtained with adsorption efficiency ≥ 86.64% via complexation, hydrophobic affinity, and π-π interactions. PS@HPCD nanofibers exhibited remarkable advantages such as excellent enrichment factors (24-55), superior permeability, and long service life (> 65 times). Under the optimum conditions, wide linear range (0.1-1000 ng g-1), low detection limits (0.0032-0.0067 ng g-1), high recoveries (84-124.5%), favorable repeatability (RSD ≤ 10.4%, n = 5), and reproducibility (RSD ≤ 7.2%, n = 3) were acquired for fipronil and three metabolites. The developed method was applied to the pesticide determination in actual soils and the ISO-certified soil with satisfactory recoveries (96.5%). The method developed provides a green, efficient, and miniaturized method for the determination of trace pesticide residues in soil.

Diagnosis of Acute Pancreatitis Using Postmortem Computed Tomography and Postmortem Magnetic Resonance Imaging: A Case Report and a Review of Literature.

ABSTRACT: Acute pancreatitis (AP) is inflammation of the pancreas, which may be due to a wide variety of etiologies that share a final common pathway of premature activation of pancreatic enzymes and resultant autodigestion of pancreatic parenchyma. Acute pancreatitis is easy to diagnose clinically, with the presence of at least 2 of the 3 criteria (upper abdominal pain, serum amylase or lipase level greater than 3 times the upper limit of normal, or characteristic findings on imaging studies) of the revised Atlanta classification. However, postmortem imaging examinations of pancreatitis are extremely rare, and very few successful cases have been reported. Here, we present a case report of a single patient who underwent autopsy and postmortem imaging. Postmortem computed tomography (PMCT) and postmortem magnetic resonance imaging (PMMRI) showed peripancreatic inflammation and acute peripancreatic fluid collection in the left anterior pararenal space, which is consistent with the examination by autopsy. The advantages of PMMRI in AP have also been demonstrated. Our study also confirmed the advantage of PMCT angiography in the diagnosis of AP. To the best of our knowledge, this is the first report of PMCT and PMMRI combined with postmortem pathology in the diagnosis of AP.

Identifying Explainable Machine Learning Models and a Novel SFRP2+ Fibroblast Signature as Predictors for Precision Medicine in Ovarian Cancer.

Ovarian cancer (OC) is a type of malignant tumor with a consistently high mortality rate. The diagnosis of early-stage OC and identification of functional subsets in the tumor microenvironment are essential to the development of patient management strategies. However, the development of robust models remains unsatisfactory. We aimed to utilize artificial intelligence and single-cell analysis to address this issue. Two independent datasets were screened from the Gene Expression Omnibus (GEO) database and processed to obtain overlapping differentially expressed genes (DEGs) in stage II-IV vs. stage I diseases. Three explainable machine learning algorithms were integrated to construct models that could determine the tumor stage and extract important characteristic genes as diagnostic biomarkers. Correlations between cancer-associated fibroblast (CAF) infiltration and characteristic gene expression were analyzed using TIMER2.0 and their relationship with survival rates was comprehensively explored via the Kaplan-Meier plotter (KM-plotter) online database. The specific expression of characteristic genes in fibroblast subsets was investigated through single-cell analysis. A novel fibroblast subset signature was explored to predict immune checkpoint inhibitor (ICI) response and oncogene mutation through Tumor Immune Dysfunction and Exclusion (TIDE) and artificial neural network algorithms, respectively. We found that Support Vector Machine-Shapley Additive Explanations (SVM-SHAP), Extreme Gradient Boosting (XGBoost), and Random Forest (RF) successfully diagnosed early-stage OC (stage I). The area under the receiver operating characteristic curves (AUCs) of these models exceeded 0.990. Their overlapping characteristic gene, secreted frizzled-related protein 2 (SFRP2), was a risk factor that affected the overall survival of OC patients with stage II-IV disease (log-rank test: p < 0.01) and was specifically expressed in a fibroblast subset. Finally, the SFRP2+ fibroblast signature served as a novel predictor in evaluating ICI response and exploring pan-cancer tumor protein P53 (TP53) mutation (AUC = 0.853, 95% confidence interval [CI]: 0.829-0.877). In conclusion, the models based on SVM-SHAP, XGBoost, and RF enabled the early detection of OC for clinical decision making, and SFRP2+ fibroblast signature used in diagnostic models can inform OC treatment selection and offer pan-cancer TP53 mutation detection.

Effect of Intense Pulsed Light to Mitigate Meibomian Gland Dysfunction for Dry Eye Disease.

BACKGROUND: This retrospective study aimed to evaluate the effect of intense pulsed light treatment (IPL) combined with meibomian gland expression (MGX) in treating meibomian gland dysfunction (MGD) related dry eye disease (DED) for the first time in Northeast China. METHODS: Thirty-one MGD-related dry eye patients were managed by IPL-MGX from October to December 2019 in The First Hospital of Jilin University. Those patients had single IPL-MGX treatment with one follow-up visit, and no topical eye drops used were included in the study. General checkup and data collection helped in determining the age, sex, diagnosis, status of the MG, first noninvasive tear break-up time (1st NIBUT), average NIBUT, the height of tear film, and additional medical history. RESULTS: There was an improvement in the function of the meibomian gland (MG), with a significant decrease in the MG dropouts in the upper eyelid (Rt eye, p = 0.0047; Lt eye, p = 0.0158) and lower eyelid (Rt eye, p = 0.0017; Lt eye, p = 0.0027) plus the average NIBUT (Rt eye, p = 0.0264) also showed improvement after the IPL-MGX treatment. Though no significant difference was reached with the average NIBUT of the Lt eye (p = 0.5256) and the NIBUT grade (Rt eye, p = 0.0578; Lt eye, p = 0.0588), there was an increased duration of the average NIBUT and improved NIBUT grading. The negative results may be because of the maximum severity of DED and the limited treatment times. CONCLUSIONS: The result suggests that IPL-MGX was effective in treating MGD-related DED.

Designing Hierarchically Porous Single Atoms of Fe-N5 Catalytic Sites with High Oxidase-like Activity for Sensitive Detection of Organophosphorus Pesticides.

Recently, single-atom catalysts (SACs) have been used to construct biosensors for the determination of organophosphorus pesticides (OPs). However, most nanozymes including SACs are peroxidase-like enzymes and require highly toxic and unstable hydrogen peroxide (H2O2) as a co-reactant to generate reactive oxygen species. Inspired by the heme site of cytochrome c oxidases (Ccos), the construction of Fe-N5-coordinated SACs by introducing axial N ligands is expected to bind O2 to generate active metal-oxygen intermediates. Herein, a SAC with an Fe-N5 active center confined by hierarchically porous carbon nanoframes (Fe SAs/N5-pC-4) was prepared by a polymerization-pyrolysis-evaporation-etching strategy, and its underlying enzyme-like mechanism was uncovered through experiments and density functional theory calculations. The 100% metal atom utilization, increased accessible active sites, accelerated mass transfer, excellent hydrophilicity, and an electron-driven mechanism of axial N endow the SAC with enhanced oxidase-like activity. Notably, its catalytic rate constant (0.398 s-1) is 569 times greater than that of the commercial Pt/C catalyst. Similar to the catalytic mechanism of Ccos, O2 can be converted into reactive oxygen species, avoiding the use of co-reactant H2O2 effectively. In addition, based on the inhibitory effect of thiols on the active site of Fe SAs/N5-pC-4, a biosensor was constructed and applied to the colorimetric analysis of OPs. This provides a facile, cost-effective method for efficient OP screening at sites to help control their contamination.

Loss of endothelial EMCN drives tumor lung metastasis through the premetastatic niche.

BACKGROUND: Metastasis is the primary cause of cancer-related mortality. Metastasis involves a complex multistep process during which individual tumor cells spread primarily through destruction of the endothelial barrier, entering the circulatory system to colonize distant organs. However, the role of the endothelial barrier as the rate-limiting process in tumor metastasis and how these processes affect the regulation of the host microenvironment at the molecular level are poorly understood. METHODS: Here, we analyzed differentially expressed genes in breast cancer and lung adenocarcinoma, including metastatic and recurrent specimens, using TCGA dataset. The effects of EMCN on endothelial cells in vitro and in vivo were analyzed by assessing angiogenesis and vascular permeability, respectively. We established a syngeneic mouse model of endothelial cell-specific knockout of EMCN (EMCNecko) to study the role of EMCN in tumor growth and metastasis. Transcriptome sequencing, Western blotting, qPCR and immunofluorescence confirmed important factors in the premetastatic niche. A mouse model of allograft tumor resection with lung metastasis was established to confirm the therapeutic effect of a notch inhibitor combined with an anti-TGF-ß antibody. RESULTS: We found a strong correlation of EMCN deficiency with tumor recurrence and metastasis. Comparative experiments in WT and EMCNecko mice revealed that endothelial EMCN deficiency did not affect primary tumor growth significantly but strongly promoted spontaneous metastasis. EMCN deficiency was associated with gene profiles that regulate cell junctions in vitro and enhance vascular permeability in vivo. Mechanistically, EMCN deficiency mainly affected the host microenvironment and led to the formation of a lung premetastatic niche by recruiting Ly6G+ neutrophils and upregulating MMP9, S100A8/A9 and TGF-ß expression. Anti-TGF-ß antibody effectively eliminated TGF-ß-induced neutrophil polarization, thereby reducing lung metastasis. Notably, the combination of a Notch inhibitor and an anti-TGF-ß antibody effectively inhibited tumor growth and lung metastasis and prolonged the survival time of mice. CONCLUSIONS: We present a new translational strategy of EMCN as a new key player in tumor lung metastasis by affecting the host microenvironment. These findings could provide a sound theoretical basis for clinical treatment.