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The abuse of antibiotics leads to the rapid spread of bacterial resistance, which seriously threatens human life and health. Now, 8 resorcylic acid derivatives, including 4 new compounds (1-4) were isolated from Lysimachia tengyuehensis by bio-guided isolation, and they inhibited both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) (MIC = 4-8 µg/mL). Notably, 1 and 2 rapidly killed MRSA and VRE within 40 min without drug resistance in 20 days. Mechanically, they potently disrupted biofilm and cell membrane by interfering with bacterial metabolic imbalance. The structure-activity relationship (SAR) revealed that the lipophilic long carbon chains (C-5/C-6) and hydrophilic hydroxyl/carboxyl groups were essential for the anti-MRSA and VRE bioactivity. Additionally, they effectively recovered MRSA-infected skin wounds and VRE-infected peritoneal in vivo. Resorcylic acid derivatives showed significant anti-MRSA and VRE bioactivity in vitro and in vivo with potential application for the first time.
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BACKGROUND: Understanding the mechanism behind sepsis-associated encephalopathy (SAE) remains a formidable task. This study endeavors to shed light on the complex cellular and molecular alterations that occur in the brains of a mouse model with SAE, ultimately unraveling the underlying mechanisms of this condition. METHODS: We established a murine model using intraperitoneal injection of lipopolysaccharide (LPS) in wild type and Anxa1-/- mice and collected brain tissues for analysis at 0-hour, 12-hour, 24-hour, and 72-hour post-injection. Utilizing advanced techniques such as single-nucleus RNA sequencing (snRNA-seq) and Stereo-seq, we conducted a comprehensive characterization of the cellular responses and molecular patterns within the brain. RESULTS: Our study uncovered notable temporal differences in the response to LPS challenge between Anxa1-/- (annexin A1 knockout) and wild type mice, specifically at the 12-hour and 24-hour time points following injection. We observed a significant increase in the proportion of Astro-2 and Micro-2 cells in these mice. These cells exhibited a colocalization pattern with the vascular subtype Vas-1, forming a distinct region known as V1A2M2, where Astro-2 and Micro-2 cells surrounded Vas-1. Moreover, through further analysis, we discovered significant upregulation of ligands and receptors such as Timp1-Cd63, Timp1-Itgb1, Timp1-Lrp1, as well as Ccl2-Ackr1 and Cxcl2-Ackr1 within this region. In addition, we observed a notable increase in the expression of Cd14-Itgb1, Cd14-Tlr2, and Cd14-C3ar1 in regions enriched with Micro-2 cells. Additionally, Cxcl10-Sdc4 showed broad upregulation in brain regions containing both Micro-2 and Astro-2 cells. Notably, upon LPS challenge, there was an observed increase in Anxa1 expression in the mouse brain. Furthermore, our study revealed a noteworthy increase in mortality rates following Anxa1 knockdown. However, we did not observe substantial differences in the types, numbers, or distribution of other brain cells between Anxa1-/- and wildtype mice over time. Nevertheless, when comparing the 24-hour post LPS injection time point, we observed a significant decrease in the proportion and distribution of Micro-2 and Astro-2 cells in the vicinity of blood vessels in Anxa1-/- mice. Additionally, we noted reduced expression levels of several ligand-receptor pairs including Cd14-Tlr2, Cd14-C3ar1, Cd14-Itgb1, Cxcl10-Sdc4, Ccl2-Ackr1, and Cxcl2-Ackr1. CONCLUSIONS: By combining snRNA-seq and Stereo-seq techniques, our study successfully identified a distinctive cellular colocalization, referred to as a special pathological niche, comprising Astro-2, Micro-2, and Vas-1 cells. Furthermore, we observed an upregulation of ligand-receptor pairs within this niche. These findings suggest a potential association between this cellular arrangement and the underlying mechanisms contributing to SAE or the increased mortality observed in Anxa1 knockdown mice.
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Astrocitos , Encéfalo , Modelos Animales de Enfermedad , Lipopolisacáridos , Ratones Noqueados , Microglía , Encefalopatía Asociada a la Sepsis , Animales , Ratones , Lipopolisacáridos/toxicidad , Encefalopatía Asociada a la Sepsis/patología , Encefalopatía Asociada a la Sepsis/genética , Encefalopatía Asociada a la Sepsis/metabolismo , Microglía/metabolismo , Microglía/patología , Encéfalo/patología , Encéfalo/metabolismo , Astrocitos/metabolismo , Astrocitos/patología , Análisis de Secuencia de ARN/métodos , Ratones Endogámicos C57BL , Transcriptoma , MasculinoRESUMEN
OBJECTIVES: To establish and validate scoring models for predicting vessels encapsulating tumor clusters (VETC) in hepatocellular carcinoma (HCC) using computed tomography (CT) and magnetic resonance imaging (MRI), and to intra-individually compare the predictive performance between the two modalities. METHODS: We retrospectively included 324 patients with surgically confirmed HCC who underwent preoperative dynamic CT and MRI with extracellular contrast agent between June 2019 and August 2020. These patients were then divided into a discovery cohort (n = 227) and a validation cohort (n = 97). Imaging features and Liver Imaging Reporting and Data System (LI-RADS) categories of VETC-positive HCCs were evaluated. Logistic regression analyses were conducted on the discovery cohort to identify clinical and imaging predictors associated with VETC-positive cases. Subsequently, separate CT-based and MRI-based scoring models were developed, and their diagnostic performance was compared using generalized estimating equations. RESULTS: On both CT and MRI, VETC-positive HCCs exhibited a higher frequency of size > 5.0 cm, necrosis or severe ischemia, non-smooth tumor margin, targetoid appearance, intratumor artery, and heterogeneous enhancement with septations or irregular ring-like structure compared to VETC-negative HCCs (all p < 0.05). Regarding LI-RADS categories, VETC-positive HCCs were more frequently categorized as LR-M than VETC-negative cases (all p < 0.05). In the validation cohort, the CT-based model showed similar sensitivity (76.7% vs. 86.7%, p = 0.375), specificity (83.6% vs. 74.6%, p = 0.180), and area under the curve value (0.80 vs. 0.81, p = 0.910) to the MRI-based model in predicting VETC-positive HCCs. CONCLUSION: Preoperative CT and MRI demonstrated comparable performance in the identification of VETC-positive HCCs, thus displaying promising predictive capabilities. CLINICAL RELEVANCE STATEMENT: Both computed tomography and magnetic resonance imaging demonstrated promise in preoperatively identifying the vessel-encapsulating tumor cluster pattern in hepatocellular carcinoma, with no statistically significant difference between the two modalities, potentially adding additional prognostic value. KEY POINTS: Computed tomography (CT) and magnetic resonance imaging (MRI) show promise in the preoperative identification of vessels encapsulating tumor clusters-positive hepatocellular carcinoma (HCC). HCC with vessels encapsulating tumor cluster patterns were more frequently LR-M compared to those without. These CT and MRI models showed comparable ability in identifying vessels encapsulating tumor clusters-positive HCC.
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Although the photoresponse cut-off wavelength of Si is about 1100 nm due to the Si bandgap energy, the internal photoemission effect (IPE) of the Au/Si junction in Schottky detector can extend the absorption wavelength, which makes it a promising candidate for the Si-based infrared detector. However, due to low light absorption, low photon-electron interaction, and poor electron injection efficiency, the near-infrared light detection efficiency of the Schottky detector is still insufficient. The synergistic effect of Si nano/microstructures with a strong light trapping effect and nanoscale Au films with surface plasmon enhanced absorption may provide an effective solution for improving the detection efficiency. In this paper, a large-area periodic Si microcone array covered by an Au film has successfully been fabricated by one-time dry etching based on the mature polystyrene microspheres lithography technique and vacuum thermal deposition, and its properties for hot electron-based near infrared photodetection are investigated. Optical measurements show that the 20 nm-thick Au covered Si microcone array exhibits a low reflectance and a strong absorption (about 85%) in wide wavelength range (900-2500 nm), and the detection responsivity can reach a value as high as 17.1 and 7.0 mA W-1at 1200 and 1310 nm under the front illumination, and 35.9 mA W-1at 1310 nm under the back illumination respectively. Three-dimensional finite difference time domain (3D-FDTD) simulation results show that the enhanced local electric field in the Au layer distributes near the air/Au interface under the front illumination and close to the Au/Si interface under the back illumination. The back illumination favors the injection of photo-generated hot electrons in Au layer into Si, which can explain the higher responsivity under the back illumination. Our research is expected to promote the practical application of Schottky photodetectors to Si-compatible near infrared photodetectors.
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PURPOSE: The Functional Assessment of Cancer Therapy item (FACT-GP5) has the potential to provide an understanding of global treatment tolerability from the patient perspective. Longitudinal evaluations of the FACT-GP5 and challenges posed by data missing-not-at-random (MNAR) have not been explored. Robustness of the FACT-GP5 to missing data assumptions and the responsiveness of the FACT-GP5 to key side-effects are evaluated. METHODS: In a randomized, double-blind study (NCT00065325), postmenopausal women (n = 618) with hormone receptor-positive (HR+), advanced breast cancer received either fulvestrant or exemestane and completed FACT measures monthly for seven months. Cumulative link mixed models (CLMM) were fit to evaluate: (1) the trajectory of the FACT-GP5 and (2) the responsiveness of the FACT-GP5 to CTCAE grade, Eastern Cooperative Oncology Group (ECOG) Performance Status scale, and key side-effects from the FACT. Sensitivity analyses of the missing-at-random (MAR) assumption were conducted. RESULTS: Odds of reporting worse side-effect bother increased over time. There were positive within-person relationships between level of side-effect bother (FACT-GP5) and severity of other FACT items, as well as ECOG performance status and Common Terminology Criteria for Adverse Events (CTCAE) grade. The number of missing FACT-GP5 assessments impacted the trajectory of the FACT-GP5 but did not impact the relationships between the FACT-GP5 and other items (except for nausea [FACT-GP2]). CONCLUSIONS: Results support the responsiveness of the FACT-GP5. Generally speaking, the responsiveness of the FACT-GP5 is robust to missing assessments. Missingness should be considered, however, when evaluating change over time of the FACT-GP5. TRIAL REGISTRATION: NCT00065325. TRIAL REGISTRATION YEAR: 2003.
Researchers have been exploring the use of a single question, FACT-GP5 ("I am bothered by side effects of treatment"), as a quick way to learn about drug tolerability from the patients' perspective. This study explores if this single question can capture changes in tolerability during treatment, and if the assessment is missed by patients, whether that impacts the interpretation of tolerability. In our study, we found that the FACT-GP5 can be used to understand how tolerability changes during treatment. Missing assessments of the FACT-GP5 are important to account for when interpreting results. The FACT-GP5 may be a useful question for capturing the patient experience of drug tolerability.
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The study aims to investigate the predictive capability of machine learning algorithms for omental metastasis in locally advanced gastric cancer (LAGC) and to compare the performance metrics of various machine learning predictive models. A retrospective collection of 478 pathologically confirmed LAGC patients was undertaken, encompassing both clinical features and arterial phase computed tomography images. Radiomic features were extracted using 3D Slicer software. Clinical and radiomic features were further filtered through lasso regression. Selected clinical and radiomic features were used to construct omental metastasis predictive models using support vector machine (SVM), decision tree (DT), random forest (RF), K-nearest neighbors (KNN), and logistic regression (LR). The models' performance metrics included accuracy, area under the curve (AUC) of the receiver operating characteristic curve, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). In the training cohort, the RF predictive model surpassed LR, SVM, DT, and KNN in terms of accuracy, AUC, sensitivity, specificity, PPV, and NPV. Compared to the other four predictive models, the RF model significantly improved PPV. In the test cohort, all five machine learning predictive models exhibited lower PPVs. The DT model demonstrated the most significant variation in performance metrics relative to the other models, with a sensitivity of 0.231 and specificity of 0.990. The LR-based predictive model had the lowest PPV at 0.210, compared to the other four models. In the external validation cohort, the performance metrics of the predictive models were generally consistent with those in the test cohort. The LR-based model for predicting omental metastasis exhibited a lower PPV. Among the machine learning algorithms, the RF predictive model demonstrated higher accuracy and improved PPV relative to LR, SVM, KNN, and DT models.
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Aprendizaje Automático , Epiplón , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patología , Neoplasias Gástricas/diagnóstico por imagen , Masculino , Femenino , Epiplón/patología , Epiplón/diagnóstico por imagen , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Neoplasias Peritoneales/secundario , Neoplasias Peritoneales/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Máquina de Vectores de Soporte , Curva ROC , Algoritmos , Adulto , Árboles de Decisión , RadiómicaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Sarcococca hookeriana var. digyna Franch. has been widely utilized in folk medicine by the Miao people in the southwestern region of China for treating skin sores which may be associated with microbial infection. AIM OF THE STUDY: To investigate the antifungal bioactivity of S. hookeriana var. digyna against fluconazole-resistant Candida albicans in vitro and in vivo, as well as its underlying mechanism and the key bioactive component. MATERIALS AND METHODS: The antifungal bioactivity of 80% ethanol extract of S. hookeriana var. digyna (SHE80) was investigated in vitro using the broth microdilution method, time-growth curve, and time-kill assay. Its key functional component and antifungal mechanism were explored with combined approaches including UPLC-Q-TOF-MS, network pharmacology and metabolomics. The antifungal pathway was further supported via microscopic observation of fungal cell morphology and examination of its effects on fungal biofilm and cell membranes using fluorescent staining reagents. In vivo assessment of antifungal bioactivity was conducted using a mouse model infected with C. albicans on the skin. RESULTS: S. hookeriana var. digyna suppressed fluconazole-resistant C. albicans efficiently (MIC = 16 µg/mL, MFC = 64 µg/mL). It removed fungal biofilm, increased cell membrane permeability, induced protein leakage, reduced membrane fluidity, disrupted mitochondrial membrane potential, induced the release of reactive oxygen species, promoted cell apoptosis, and inhibited the transformation of fungi from the yeast state to the hyphal state significantly. In terms of mechanism, it affected sphingolipid metabolism and signaling pathway. Moreover, the predicted bioactive component, sarcovagine D, was supported by antifungal bioactivity evaluation in vitro (MIC = 4 µg/mL, MFC = 16 µg/mL). Furthermore, S. hookeriana var. digyna promoted wound healing, reduced the number of colony-forming units, and reduced inflammation effectively in vivo. CONCLUSIONS: The traditional use of S. hookeriana var. digyna for fungal skin infections was supported by antifungal bioactivity investigated in vitro and in vivo. Its mechanism and bioactive component were predicted and confirmed by experiments, which also provided a new antifungal agent for future research.
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Antifúngicos , Biopelículas , Candida albicans , Farmacorresistencia Fúngica , Fluconazol , Pruebas de Sensibilidad Microbiana , Extractos Vegetales , Antifúngicos/farmacología , Antifúngicos/aislamiento & purificación , Candida albicans/efectos de los fármacos , Animales , Fluconazol/farmacología , Farmacorresistencia Fúngica/efectos de los fármacos , Extractos Vegetales/farmacología , Extractos Vegetales/química , Ratones , Biopelículas/efectos de los fármacos , Candidiasis/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Femenino , Potencial de la Membrana Mitocondrial/efectos de los fármacosRESUMEN
1-Nitropyrene (1-NP) is a neurodevelopmental toxicant. This study was to evaluate the impact of exposure to 1-NP after weaning on anxiety-like behavior. Five-week-old mice were administered with 1-NP (0.1 or 1 mg/kg) daily for 4 weeks. Anxiety-like behaviour was measured using elevated-plus maze (EPM) and open field test (OFT). In EPM test, time spending in open arm and times entering open arm were reduced in 1-NP-treated mice. In OFT test, time spent in the center region and times entering the center region were diminished in 1-NP-treated mice. Prefrontal dendritic length and number of dendrite branches were decreased in 1-NP-treated mice. Prefrontal PSD95, an excitatory postsynaptic membrane protein, and gephyrin, an inhibitory postsynaptic membrane protein, were downregulated in 1-NP-treated mice. Further analysis showed that peripheral steroid hormones, including serum testosterone (T) and estradiol (E2), testicular T, and ovarian E2, were decreased in 1-NP-treated mice. Interestingly, T and E2 were diminished in 1-NP-treated prefrontal cortex. Prefrontal T and E2 synthases were diminished in 1-NP-treated mice. Mechanistically, GCN2-eIF2α, a critical pathway that regulates ribosomal protein translation, was activated in 1-NP-treated prefrontal cortex. These results indicate that exposure to 1-NP after weaning induces anxiety-like behaviour partially by inhibiting steroid hormone synthesis in prefrontal cortex.
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Ansiedad , Corteza Prefrontal , Pirenos , Destete , Animales , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ansiedad/inducido químicamente , Masculino , Pirenos/toxicidad , Femenino , Ratones , Conducta Animal/efectos de los fármacos , Testosterona/sangre , EstradiolRESUMEN
Tuning the oxygen activity in perovskite oxides (ABO3) is promising to surmount the trade-off between activity and selectivity in redox reactions. However, this remains challenging due to the limited understanding in its activation mechanism. Herein, we propose the discovery that generating subsurface A-site cation (Lasub.) vacancy beneath surface Fe-O layer greatly improved the oxygen activity in LaFeO3, rendering enhanced methane conversion that is 2.9-fold higher than stoichiometric LaFeO3 while maintaining high syngas selectivity of 98% in anaerobic oxidation. Experimental and theoretical studies reveal that absence of Lasub.-O interaction lowered the electron density over oxygen and improved the oxygen mobility, which reduced the barrier for C-H bond cleavage and promoted the oxidation of C-atom, substantially boosting methane-to-syngas conversion. This discovery highlights the importance of A-site cations in modulating electronic state of oxygen, which is fundamentally different from the traditional scheme that mainly credits the redox activity to B-site cations and can pave a new avenue for designing prospective redox catalysts.
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Autism spectrum disorder (ASD) is a neurodevelopmental disorder, characterized by social communication disability and stereotypic behavior. This study aims to investigate the impact of prenatal exposure to 1-nitropyrene (1-NP), a key component of motor vehicle exhaust, on autism-like behaviors in a mouse model. Three-chamber test finds that prenatal 1-NP exposure causes autism-like behaviors during the weaning period. Patch clamp shows that inhibitory synaptic transmission is reduced in medial prefrontal cortex of 1-NP-exposed weaning pups. Immunofluorescence finds that prenatal 1-NP exposure reduces the number of prefrontal glutamate decarboxylase 67 (GAD67) positive interneurons in fetuses and weaning pups. Moreover, prenatal 1-NP exposure retards tangential migration of GAD67-positive interneurons and downregulates interneuron migration-related genes, such as Nrg1, Erbb4, and Sema3F, in fetal forebrain. Mechanistically, prenatal 1-NP exposure reduces hydroxymethylation of interneuron migration-related genes through inhibiting ten-eleven translocation (TET) activity in fetal forebrain. Supplement with alpha-ketoglutarate (α-KG), a cofactor of TET enzyme, reverses 1-NP-induced hypohydroxymethylation at specific sites of interneuron migration-related genes. Moreover, α-KG supplement alleviates 1-NP-induced migration retardation of interneurons in fetal forebrain. Finally, maternal α-KG supplement improves 1-NP-induced autism-like behaviors in weaning offspring. In conclusion, prenatal 1-NP exposure causes autism-like behavior partially by altering DNA hydroxymethylation of interneuron migration-related genes in developing brain.
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Encéfalo , Modelos Animales de Enfermedad , Efectos Tardíos de la Exposición Prenatal , Animales , Ratones , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/genética , Femenino , Embarazo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Trastorno Autístico/genética , Trastorno Autístico/inducido químicamente , Trastorno Autístico/metabolismo , Metilación de ADN/efectos de los fármacos , Metilación de ADN/genética , Conducta Animal/efectos de los fármacos , Masculino , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/inducido químicamente , Trastorno del Espectro Autista/metabolismo , Pirenos/toxicidad , Ratones Endogámicos C57BLRESUMEN
Fruit ripening is associated with the degreening process (loss of chlorophyll) that occurs in most fruit species. Kiwifruit is one of the special species whose fruits may maintain green flesh by accumulating a large amount of chlorophyll even after ripening. However, little is known about the genetic variations related to the fruit degreening process. Here, a graph-based kiwifruit pangenome by analyzing 14 chromosome-scale haplotype-resolved genome assemblies from seven representative cultivars or lines in Actinidia chinensis is built. A total of 49,770 non-redundant gene families are identified, with core genes constituting 46.6%, and dispensable genes constituting 53.4%. A total of 84,591 non-redundant structural variations (SVs) are identified. The pangenome graph integrating both reference genome sequences and variant information facilitates the identification of SVs related to fruit color. The SV in the promoter of the AcBCM gene determines its high expression in the late developmental stage of fruits, which causes chlorophyll accumulation in the green-flesh fruits by post-translationally regulating AcSGR2, a key enzyme of chlorophyll catabolism. Taken together, a high-quality pangenome is constructed, unraveled numerous genetic variations, and identified a novel SV mediating fruit coloration and fruit quality, providing valuable information for further investigating genome evolution and domestication, QTL genes function, and genomics-assisted breeding.
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Actinidia , Frutas , Genoma de Planta , Actinidia/genética , Actinidia/metabolismo , Frutas/genética , Frutas/metabolismo , Genoma de Planta/genética , Clorofila/metabolismo , Clorofila/genética , Variación Genética/genéticaRESUMEN
Molybdenum disulfide nanoflowers (MoS2 NFs) were prepared by hydrothermal method. The prepared MoS2 NFs was characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), specific surface areas, Raman and X-ray photoelectron spectroscopy (XPS). The characterization results show that the flower-like spherical MoS2 is composed of many ultra-thin nanosheets with an average diameter of about 300-400â nm. MoS2 NFs also exhibits excellent UV-vis absorption and high fluorescence intensity. In order to explore the biological behavior of MoS2 NFs, the interaction between MoS2 NFs and bovine serum albumin (BSA) was studied by UV-Vis absorption, fluorescence, synchronous fluorescence spectra, and cyclic voltammetry. The results of absorption and fluorescence show that MoS2 NFs and BSA interact strongly through the formation of complexes in the ground state, and the static quenching is the main mechanism. The Stern-Volmer constant and the quenching constant was calculated about 3.79×107â L mol-1 and 3.79×1015â L mol-1 s-1, respectively. The synchronous fluorescence implied that MoS2 in the complex may mainly bind to tryptophan residues of BSA. The cyclic voltammograms indicated that the addition of BSA makes electron reduction of MoS2 NFs more difficult than the corresponding free state. The results show that hydrophobic forces play a major role in the binding interaction between BSA and MoS2 NFs.
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Disulfuros , Molibdeno , Nanoestructuras , Albúmina Sérica Bovina , Espectrometría de Fluorescencia , Albúmina Sérica Bovina/química , Albúmina Sérica Bovina/metabolismo , Molibdeno/química , Disulfuros/química , Animales , Bovinos , Nanoestructuras/química , Espectrofotometría Ultravioleta , Tamaño de la Partícula , Espectroscopía de Fotoelectrones , Propiedades de SuperficieRESUMEN
Metal sulfides have attracted extensive attention due to their excellent electrochemical performance. However, issues such as poor conductivity and severe volume expansion during charge and discharge processes affect the applications of sulfides as electrode materials. Here, a combination of coprecipitation and high-temperature sulfidation methods are employed to synthesize a ZnS-SnS2 composite with a hollow cubic structure, which is further composited with reduced graphene oxide (RGO) to form ZnS-SnS2 hollow cubic boxes encapsulated in a conductive framework of reduced graphene oxide (RGO) (denoted as ZnS-SnS2@RGO) for electrode materials. The hollow structure effectively alleviates the pulverization of ZnS-SnS2@RGO caused by volume expansion during charge and discharge processes. The heterogeneous structure formed by ZnS and SnS2 effectively reduces the electron transfer resistance of the material. The use of RGO wrapping enhances the conductivity of the ZnS-SnS2 hollow cubic boxes, and RGO's dispersion effect on the ZnS-SnS2 cubes improves particle agglomeration, further mitigating volume expansion of the material. These results indicate the outstanding electrochemical performance of heterostructural ZnS-SnS2 hollow cubic electrodes encapsulated with reduced graphene oxide as a conductive framework. The fabrication process provides a novel approach for addressing volume expansion and poor conductivity issues in other pseudocapacitive materials.
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Clostridium perfringens has emerged as a growing public health concern due to its ability to cause various infections and its increasing resistance to antibiotics. To assess its current epidemiology in clinical settings, we conducted a survey involving 426 healthy individuals and 273 ICU inpatients at a provincial hospital in China. Our findings revealed a high prevalence of C. perfringens in healthy individuals (45.77%, 95% CI: 41.0%-50.6%) and ICU patients (12.82%, 95% CI: 9.1%-17.4%). The identified 220 C. perfringens isolates displayed substantial resistance to erythromycin (57.9%), clindamycin (50.7%), and tetracycline (32.0%), primarily attributed to the presence of erm(Q) (54.4%), lnu(P) (13.8%), tetB(P) (83.6%), and tetA(P) (66.7%). Notably, C. perfringens isolates from this particular hospital demonstrated a high degree of sequence type diversity and phylogenic variation, suggesting that the potential risk of infection primarily arises from the bacteria's gut colonization rather than clonal transmissions within the clinical environment. This study provides an updated analysis of the current epidemiology of C. perfringens in healthy individuals and ICU patients in China and emphasizes the need to optimize intervention strategies against its public health threat. IMPORTANCE: Clostridium perfringens is a bacterium of growing public health concern due to its ability to cause infections and its increasing resistance to antibiotics. Understanding its epidemiology in clinical settings is essential for intervention strategies. This study surveyed healthy individuals and ICU inpatients in a provincial hospital in China. It found a high prevalence of C. perfringens, indicating infection risk. The isolates also showed significant antibiotic resistance. Importantly, the study revealed diverse sequence types and phylogenetic variation, suggesting infection risk from intestinal colonization rather than clonal transmission in hospitals. This analysis emphasizes the need to optimize intervention strategies against this public health threat.
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Antibacterianos , Portador Sano , Infecciones por Clostridium , Clostridium perfringens , Unidades de Cuidados Intensivos , Humanos , Clostridium perfringens/genética , Clostridium perfringens/aislamiento & purificación , Clostridium perfringens/efectos de los fármacos , Clostridium perfringens/clasificación , China/epidemiología , Infecciones por Clostridium/epidemiología , Infecciones por Clostridium/microbiología , Infecciones por Clostridium/transmisión , Masculino , Femenino , Persona de Mediana Edad , Adulto , Antibacterianos/farmacología , Portador Sano/microbiología , Portador Sano/epidemiología , Anciano , Prevalencia , Adulto Joven , Filogenia , Intestinos/microbiología , Pruebas de Sensibilidad Microbiana , Adolescente , Farmacorresistencia BacterianaRESUMEN
Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) cause more than 100,000 deaths each year, which need efficient and non-resistant antibacterial agents. SAR analysis of 162 flavonoids from the plant in this paper suggested that lipophilic group at C-3 was crucial, and then 63 novel flavonoid derivatives were designed and total synthesized. Among them, the most promising K15 displayed potent bactericidal activity against clinically isolated MRSA and VRE (MICs = 0.25-1.00 µg/mL) with low toxicity and high membrane selectivity. Moreover, mechanism insights revealed that K15 avoided resistance by disrupting biofilm and targeting the membrane, while vancomycin caused 256 times resistance against MRSA, and ampicillin caused 16 times resistance against VRE by the same 20 generations inducing. K15 eliminated residual bacteria in mice skin MRSA-infected model (>99 %) and abdominal VRE-infected model (>92 %), which was superior to vancomycin and ampicillin.
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Antibacterianos , Flavonoides , Staphylococcus aureus Resistente a Meticilina , Pruebas de Sensibilidad Microbiana , Enterococos Resistentes a la Vancomicina , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Flavonoides/farmacología , Flavonoides/química , Flavonoides/síntesis química , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Enterococos Resistentes a la Vancomicina/efectos de los fármacos , Animales , Ratones , Relación Estructura-Actividad , Estructura Molecular , Relación Dosis-Respuesta a Droga , Infecciones Estafilocócicas/tratamiento farmacológico , HumanosRESUMEN
Autophagy, a lysosome-dependent degradation process, plays a crucial role in maintaining cell homeostasis. It serves as a vital mechanism for adapting to stress and ensuring intracellular quality control. Autophagy deficiencies or defects are linked to numerous human disorders, especially those associated with neuronal degeneration or metabolic diseases. Yoshinori Ohsumi was honored with the Nobel Prize in Physiology or Medicine in 2016 for his groundbreaking discoveries regarding autophagy mechanisms. Over the past few decades, autophagy research has predominantly concentrated on the early stages of autophagy, with relatively limited attention given to the late stages. Nevertheless, recent studies have witnessed substantial advancements in understanding the molecular intricacies of the late stages, which follows autophagosome formation. This review provides a comprehensive summary of the recent progresses in comprehending the molecular mechanisms of the late stages of autophagy.
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Transthyretin (TTR) is a tetrameric homologous protein that can dissociate into monomers. Misfolding and aggregation of TTR can lead to amyloid transthyretin amyloidosis (ATTR), which can cause many diseases (e.g., senile systemic amyloidosis, familial amyloid cardiomyopathy, and familial amyloid polyneuropathy). Despite growing evidence indicating that small oligomers play a critical role in regulating cytotoxicity, the structures of these oligomeric intermediates and their conformational transformations are still unclear, impeding our understanding of neurodegenerative mechanisms and the development of therapeutics targeting early aggregation species. The TTR monomer protein consists of various fragments prone to self-aggregation, including the residue 105-115 sequence. Therefore, our study investigated the assembly progress of ATTR (105-115) peptides using all-atom molecular dynamics simulations. The findings indicate that the probability of ß-sheet content increases with increasing numbers of peptides. Additionally, interactions between hydrophobic residues L110 and L111 are crucial for the formation of a ß-rich oligomer formation. These ß-rich oligomers may adopt ß-barrel conformations, potentially toxic oligomer species. Free-energy analysis reveals that ß-barrel conformations serve as intermediates for these ß-rich oligomers. Our insights into the structural ensemble dynamics of ATTR (105-115) contribute to understanding the physical mechanisms underlying the ß-barrel oligomers of ATTR. These findings may shed light on the pathological role of ATTR in neurodegenerative diseases and offer potential therapeutic targets.
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Neuropatías Amiloides Familiares , Amiloide , Prealbúmina , Amiloide/metabolismo , Simulación de Dinámica Molecular , Proteínas Amiloidogénicas , Péptidos/química , EntropíaRESUMEN
BACKGROUND: Anxiety and depression can influence adherence to Pre-exposure Prophylaxis (PrEP). However, there is limited research on the temporal dynamics of anxiety and depression among men who have sex with men (MSM) using PrEP. METHODS: From December 2018 to November 2020, we administered the Hospital Anxiety and Depression Scale (HADS) to participants in the China Real-World Oral Intake of PrEP (CROPrEP) to measure their anxiety and depression levels. The group-based trajectory model (GBTM) depicted the dynamic changes of anxiety and depression scores over time. RESULTS: A total of 1023 MSM were included, with 4523 follow-up assessments. The GBTM categorized the trajectories into three distinct patterns: consistently low (54.8% for anxiety, 60.7% for depression), consistently moderate (39.3% for anxiety, 31.4% for depression), and high but bell-shaped (5.9% for anxiety, 7.9% for depression). Higher anxiety levels were associated with being aged 18-30 years old, earning less than US$619 per month, female-identifying, adopting the bottom sexual role with men, and having two or more anal sex partners in the past three months; similarly, higher depression levels correlated with a monthly income under US$619, female-identifying, sexual behavior as bottom and a positive syphilis at baseline. PrEP adherence was notably lower in the high but bell-shaped anxiety and depression group compared to the other groups, particularly at the 12th-month follow-up. CONCLUSIONS: Close monitoring of anxiety and depression levels in MSM on PrEP is crucial. Provision of targeted mental health support is essential to enhance PrEP effectiveness.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Profilaxis Pre-Exposición , Minorías Sexuales y de Género , Masculino , Humanos , Femenino , Adolescente , Adulto Joven , Adulto , Homosexualidad Masculina , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Infecciones por VIH/tratamiento farmacológico , Tenofovir/uso terapéutico , Depresión/epidemiología , Fármacos Anti-VIH/uso terapéutico , Cumplimiento de la Medicación , Conducta Sexual , Ansiedad/epidemiología , China/epidemiologíaRESUMEN
Objective: To assess the alteration of individual brain morphological and functional network topological properties and their clinical significance in patients with neuromyelitis optica spectrum disorder (NMOSD). Materials and methods: Eighteen patients with NMOSD and twenty-two healthy controls (HCs) were included. The clinical assessment of NMOSD patients involved evaluations of disability status, cognitive function, and fatigue impact. For each participant, brain images, including high-resolution T1-weighted images for individual morphological brain networks (MBNs) and resting-state functional MR images for functional brain networks (FBNs) were obtained. Topological properties were calculated and compared for both MBNs and FBNs. Then, partial correlation analysis was performed to investigate the relationships between the altered network properties and clinical variables. Finally, the altered network topological properties were used to classify NMOSD patients from HCs and to analyses time- to-progression of the patients. Results: The average Expanded Disability Status Scale score of NMOSD patients was 1.05 (range from 0 to 2), indicating mild disability. Compared to HCs, NMOSD patients exhibited a higher normalized characteristic path length (λ) in their MBNs (P = 0.0118, FDR corrected) but showed no significant differences in the global properties of FBNs (p: 0.405-0.488). Network-based statistical analysis revealed that MBNs had more significantly altered connections (P< 0.01, NBS corrected) than FBNs. Altered nodal properties of MBNs were correlated with disease duration or fatigue scores (P< 0.05/6 with Bonferroni correction). Using the altered nodal properties of MBNs, the accuracy of classification of NMOSD patients versus HCs was 96.4%, with a sensitivity of 93.3% and a specificity of 100%. This accuracy was better than that achieved using the altered nodal properties of FBNs. Nodal properties of MBN significantly predicted Expanded Disability Status Scale worsening in patients with NMOSD. Conclusion: The results indicated that patients with mild disability NMOSD exhibited compensatory increases in local network properties to maintain overall stability. Furthermore, the alterations in the morphological network nodal properties of NMOSD patients not only had better relevance for clinical assessments compared with functional network nodal properties, but also exhibited predictive values of EDSS worsening.