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Antimicrobial resistance presents us with a potential global crisis as it undermines the abilities of conventional antibiotics to combat pathogenic microbes. The history of antimicrobial agents is replete with examples of scaffolds containing halogens. In this review, we discuss the impacts of halogen atoms in various antibiotic types and antimicrobial scaffolds and their modes of action, structure-activity relationships, and the contributions of halogen atoms in antimicrobial activity and drug resistance. Other halogenated molecules, including carbohydrates, peptides, lipids, and polymeric complexes, are also reviewed, and the effects of halogenated scaffolds on pharmacokinetics, pharmacodynamics, and factors affecting antimicrobial and antivirulence activities are presented. Furthermore, the potential of halogenation to circumvent antimicrobial resistance and rejuvenate impotent antibiotics is addressed. This review provides an overview of the significance of halogenation, the abilities of halogens to interact in biomolecular settings and enhance pharmacological properties, and their potential therapeutic usages in preventing a postantibiotic era. SIGNIFICANCE STATEMENT: Antimicrobial resistance and the increasing impotence of antibiotics are critical threats to global health. The roles and importance of halogen atoms in antimicrobial drug scaffolds have been established, but comparatively little is known of their pharmacological impacts on drug resistance and antivirulence activities. This review is the first to extensively evaluate the roles of halogen atoms in various antibiotic classes and pharmacological scaffolds and to provide an overview of their ability to overcome antimicrobial resistance.
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Antibacterianos , Anti-Infecciosos , Humanos , Antibacterianos/farmacologia , Antibacterianos/química , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Halogênios/química , Halogenação , Relação Estrutura-AtividadeRESUMO
In alignment with the ICH guideline for Good Clinical Practice [ICH E6(R2)], quality tolerance limit (QTL) monitoring has become a standard component of risk-based monitoring of clinical trials by sponsor companies. Parameters that are candidates for QTL monitoring are critical to participant safety and quality of trial results. Breaching the QTL of a given parameter could indicate systematic issues with the trial that could impact participant safety or compromise the reliability of trial results. Methods for QTL monitoring should detect potential QTL breaches as early as possible while limiting the rate of false alarms. Early detection allows for the implementation of remedial actions that can prevent a QTL breach at the end of the trial. We demonstrate that statistically based methods that account for the expected value and variability of the data generating process outperform simple methods based on fixed thresholds with respect to important operating characteristics. We also propose a Bayesian method for QTL monitoring and an extension that allows for the incorporation of partial information, demonstrating its potential to outperform frequentist methods originating from the statistical process control literature.
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Staphylococcus aureus, particularly drug-resistant strains, poses significant challenges in healthcare due to its ability to form biofilms, which confer increased resistance to antibiotics and immune responses. Building on previous knowledge that several flavonoids exhibit antibiofilm activity, this study sought to identify a novel flavonoid capable of effectively inhibiting biofilm formation and virulence factor production in S. aureus strains including MRSA. Among the 19 flavonoid-like compounds tested, 3,2'-dihydroxyflavone (3,2'-DHF) was identified for the first time as inhibiting biofilm formation and virulence factors in S. aureus with an MIC 75 µg/mL. The antibiofilm activity was further confirmed by microscopic methods. Notably, 3,2'-DHF at 5 µg/mL was effective in inhibiting both mono- and polymicrobial biofilms involving S. aureus and Candida albicans, a common co-pathogen. 3,2'-DHF reduces hemolytic activity, slime production, and the expression of key virulence factors such as hemolysin gene hla and nuclease gene nuc1 in S. aureus. These findings highlight the potential of 3,2'-DHF as a novel antibiofilm and antivirulence agent against both bacterial and fungal biofilms, offering a promising alternative to traditional antibiotics in the treatment of biofilm-associated infections.
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Antibacterianos , Biofilmes , Testes de Sensibilidade Microbiana , Staphylococcus aureus , Fatores de Virulência , Biofilmes/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/patogenicidade , Fatores de Virulência/genética , Antibacterianos/farmacologia , Candida albicans/efeitos dos fármacos , Candida albicans/patogenicidade , Flavonas/farmacologia , Flavonoides/farmacologia , Virulência/efeitos dos fármacos , HumanosRESUMO
Skin microbiota, such as acne-related Cutibacterium acnes, Staphylococcus aureus, and fungal Candida albicans, can form polymicrobial biofilms with greater antimicrobial tolerance to traditional antimicrobial agents and host immune systems. In this study, the phytopigment shikonin was investigated against single-species and multispecies biofilms under aerobic and anaerobic conditions. Minimum inhibitory concentrations of shikonin were 10 µg/mL against C. acnes, S. aureus, and C. albicans, and at 1-5 µg/mL, shikonin efficiently inhibited single biofilm formation and multispecies biofilm development by these three microbes. Shikonin increased porphyrin production in C. acnes, inhibited cell aggregation and hyphal formation by C. albicans, decreased lipase production, and increased hydrophilicity in S. aureus. In addition, shikonin at 5 or 10 µg/mL repressed the transcription of various biofilm-related genes and virulence-related genes in C. acnes and downregulated the gene expression levels of the quorum-sensing agrA and RNAIII, α-hemolysin hla, and nuclease nuc1 in S. aureus, supporting biofilm inhibition. In addition, shikonin prevented multispecies biofilm development on porcine skin, and the antimicrobial efficacy of shikonin was recapitulated in a mouse infection model, in which it promoted skin regeneration. The study shows that shikonin inhibits multispecies biofilm development by acne-related skin microbes and might be useful for controlling bacterial infections.
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Acne Vulgar , Anti-Infecciosos , Naftoquinonas , Infecções Estafilocócicas , Animais , Camundongos , Candida albicans/genética , Staphylococcus aureus , Biofilmes , Anti-Infecciosos/farmacologiaRESUMO
BACKGROUND: Emotion recognition is essential to the social adjustment and social interaction of people with intellectual and developmental disabilities (IDDs). Given that music is a medium for expressing and conveying human emotion, we conducted this preliminary study to identify musical passages representing the basic human emotions of happiness, sadness, and anger, with the goal of developing a music-based emotion perception scale for IDDs. METHODS: To identify musical passages for emotion perception, 20 certified music therapists evaluated 100 selected musical passages and established 60 pieces that yielded the highest agreement for each emotion category. During the second phase of this study, 300 neurotypical participants rated 60 passages in terms of the perceived type and intensity of emotions expressed. RESULTS: The 60 passages showed high reliability and were statistically classified into three factors: happiness, sadness, and anger. The k-means cluster analysis yielded a cut-off score of 41 for the low emotion perception group (F = 1120.63, P < 0.001). The hierarchical logistic regression analysis revealed that only model 3 (musical passages) was significantly associated with low emotion perception (step χ² = 227.8, P < 0.001). CONCLUSION: The selected musical passages demonstrated high reliability and established three factors for identifying perceptions of happiness, sadness, and anger. Neither psychological status nor individual demographic characteristics affected the emotion perception results.
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Música , Humanos , Criança , Música/psicologia , Deficiências do Desenvolvimento , Reprodutibilidade dos Testes , Emoções , PercepçãoRESUMO
BACKGROUND: Music is regarded as a beneficial tool for assessing the clinical symptoms and communication skills in individuals with autism spectrum disorder (ASD) or autism. The present study developed a music-based attention test (MAT) for individuals with autism using music parameters and the algorithm of the comprehensive attention test (CAT). METHODS: We recruited 51 autistic individuals and 50 neurotypical individuals to participate in the CAT, MAT, and social intelligence tests. The reliability and validity of the MAT were assessed using exploratory factor analysis, concurrent validity, and criterion-related validity. RESULTS: The MAT had sound internal consistency (high Cronbach's α = 0.948). In addition, the MAT had suitable concurrent validity in the correlation between CAT and MAT, as well as good criterion validity when attention was measured using the MAT and was compared between autistic individuals and neurotypical individuals. Attention evaluated using the MAT was associated with the social quotient in individuals with autism. CONCLUSIONS: The MAT could be a relevant tool for gauging attention in individuals with ASD. Furthermore, attention determined using the MAT may be correlated with social quotient in autistic individuals. Future studies should consider that using music in the field of attention could improve the social quotient of individuals with autism.
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Transtorno do Espectro Autista , Transtorno Autístico , Humanos , Reprodutibilidade dos Testes , Algoritmos , Análise FatorialRESUMO
Small RNA (sRNA) has become an alternate biotechnology tool for sustaining eco-agriculture by enhancing plant solidity and managing environmental hazards over traditional methods. Plants synthesize a variety of sRNA to silence the crucial genes of pests or plant immune inhibitory proteins and counter adverse environmental conditions. These sRNAs can be cultivated using biotechnological methods to apply directly or through bacterial systems to counter the biotic stress. On the other hand, through synthesizing sRNAs, microbial networks indicate toxic elements in the environment, which can be used effectively in environmental monitoring and management. Moreover, microbes possess sRNAs that enhance the degradation of xenobiotics and maintain bio-geo-cycles locally. Selective bacterial and plant sRNA systems can work symbiotically to establish a sustained eco-agriculture system. An sRNA-mediated approach is becoming a greener tool to replace xenobiotic pesticides, fertilizers, and other chemical remediation elements. The review focused on the applications of sRNA in both sustained agriculture and bioremediation. It also discusses limitations and recommends various approaches toward future improvements for a sustained eco-agriculture system.
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Agricultura , Pequeno RNA não Traduzido , RNA Bacteriano/genética , Biotecnologia , Plantas/metabolismo , Bactérias/genética , Bactérias/metabolismo , Pequeno RNA não Traduzido/genética , Pequeno RNA não Traduzido/metabolismoRESUMO
Primary motor cortex (M1) consists of a stack of interconnected but distinct layers (L1-L6) which affect motor control through large-scale networks. However, the brain-wide functional influence of each layer is poorly understood. We sought to expand our knowledge of these layers' circuitry by combining Cre-driver mouse lines, optogenetics, fMRI, and electrophysiology. Neuronal activities initiated in Drd3 neurons (within L2/3) were mainly confined within M1, while stimulation of Scnn1a, Rbp4, and Ntsr1 neurons (within L4, L5, and L6, respectively) evoked distinct responses in M1 and motor-related subcortical regions, including striatum and motor thalamus. We also found that fMRI responses from targeted stimulations correlated with both local field potentials (LFPs) and spike changes. This study represents a step forward in our understanding of how different layers of primary motor cortex are embedded in brain-wide circuitry.
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Córtex Motor , Camundongos , Animais , Córtex Motor/fisiologia , Optogenética , Neurônios/fisiologia , Tálamo/fisiologia , EncéfaloRESUMO
Affinity chromatography utilizing specific interactions between therapeutic proteins and bead-immobilized capturing agents is a standard method for protein purification, but its scalability is limited by long purification times, activity loss by the capturing molecules and/or purified protein, and high costs. Here, we report a platform for purifying therapeutic antibodies via affinity precipitation using the endogenous calcium ion-binding protein, calsequestrin (CSQ), which undergoes a calcium ion-dependent phase transition. In this method, ZZ-CSQ fusion proteins with CSQ and an affinity protein (Z domain of protein A) capture antibodies and undergo multimerization and subsequent aggregation in response to calcium ions, enabling the antibody to be collected by affinity precipitation. After robustly validating and optimizing the performance of the platform, the ZZ-CSQ platform can rapidly purify therapeutic antibodies from industrial harvest feedstock with high purity (>97%) and recovery yield (95% ± 3%). In addition, the ZZ-CSQ platform outperforms protein A-based affinity chromatography (PAC) in removing impurities, yielding â¼20-fold less DNA and â¼4.8-fold less host cell protein (HCP) contamination. Taken together, this platform is rapid, recyclable, scalable, and cost-effective, and it shows antibody-purification performance superior or comparable to that of the standard affinity chromatography method.
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Cálcio , Calsequestrina , Anticorpos/metabolismo , Cálcio/metabolismo , Proteínas de Ligação ao Cálcio , Calsequestrina/química , Calsequestrina/genética , Calsequestrina/metabolismo , Cromatografia de Afinidade/métodos , Proteína Estafilocócica A/metabolismoRESUMO
Staphylococcus aureus is one of the major pathogens responsible for antimicrobial resistance-associated death. S. aureus can secrete various exotoxins, and staphylococcal biofilms play critical roles in antibiotic tolerance and the persistence of chronic infections. Here, we investigated the inhibitory effects of 18 hydroquinones on biofilm formation and virulence factor production by S. aureus. It was found that 2,5-bis(1,1,3,3-tetramethylbutyl) hydroquinone (TBHQ) at 1 µg/mL efficiently inhibits biofilm formation by two methicillin-sensitive and two methicillin-resistant S. aureus strains with MICs of 5 µg/mL, whereas the backbone compound hydroquinone did not (MIC > 400 µg/mL). In addition, 2,3-dimethylhydroquinone and tert-butylhydroquinone at 50 µg/mL also exhibited antibiofilm activity. TBHQ at 1 µg/mL significantly decreased the hemolytic effect and lipase production by S. aureus, and at 5−50 µg/mL was non-toxic to the nematode Caenorhabditis elegans and did not adversely affect Brassica rapa seed germination or growth. Transcriptional analyses showed that TBHQ suppressed the expression of RNAIII (effector of quorum sensing). These results suggest that hydroquinones, particularly TBHQ, are potentially useful for inhibiting S. aureus biofilm formation and virulence.
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Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Antibacterianos/farmacologia , Biofilmes , Exotoxinas/farmacologia , Humanos , Hidroquinonas/farmacologia , Lipase , Meticilina/farmacologia , Testes de Sensibilidade Microbiana , Staphylococcus aureus , Fatores de Virulência/farmacologiaRESUMO
Bacterial biofilm formation is a major cause of drug resistance and bacterial persistence; thus, controlling pathogenic biofilms is an important component of strategies targeting infectious bacterial diseases. Cinnamaldehyde (CNMA) has broad-spectrum antimicrobial and antibiofilm activities. In this study, we investigated the antibiofilm effects of ten CNMA derivatives and trans-CNMA against Gram-negative uropathogenic Escherichia coli (UPEC) and Gram-positive Staphylococcus aureus. Among the CNMA analogs tested, 4-nitrocinnamaldehyde (4-nitroCNMA) showed antibacterial and antibiofilm activities against UPEC and S. aureus with minimum inhibitory concentrations (MICs) for cell growth of 100 µg/mL, which were much more active than those of trans-CNMA. 4-NitroCNMA inhibited UPEC swimming motility, and both trans-CNMA and 4-nitroCNMA reduced extracellular polymeric substance production by UPEC. Furthermore, 4-nitroCNMA inhibited the formation of mixed UPEC/S. aureus biofilms. Collectively, our observations indicate that trans-CNMA and 4-nitroCNMA potently inhibit biofilm formation by UPEC and S. aureus. We suggest efforts be made to determine the therapeutic scope of CNMA analogs, as our results suggest CNMA derivatives have potential therapeutic use for biofilm-associated diseases.
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Escherichia coli Uropatogênica , Acroleína/análogos & derivados , Antibacterianos/farmacologia , Biofilmes , Matriz Extracelular de Substâncias Poliméricas , Testes de Sensibilidade Microbiana , Staphylococcus aureusRESUMO
The widespread outbreak of the novel coronavirus called severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused the main health challenge worldwide. This pandemic has attracted the attention of the research communities in various fields, prompting efforts to discover rapid drug molecules for the treatment of the life-threatening COVID-19 disease. This study is aimed at investigating 4H-chromen-4-one scaffold-containing flavonoids that combat the SARS-CoV-2 virus using computational and in vitro approaches. Virtual screening studies of the molecule's library for 4H-chromen-4-one scaffold were performed with the recently reported coronavirus main protease (Mpro, also called 3CLpro) because it plays an essential role in the maturation and processing of the viral polyprotein. Based on the virtual screening, the top hit molecules such as isoginkgetin and afzelin molecules were selected for further estimating in vitro antiviral efficacies against SARS-CoV-2 in Vero cells. Additionally, these molecules were also docked with RNA-dependent RNA Polymerase (RdRp) to reveal the ligands-protein molecular interaction. In the in vitro study, isoginkgetin showed remarkable inhibition potency against the SARS-CoV-2 virus, with an IC50 value of 22.81 µM, compared to remdesivir, chloroquine, and lopinavir with IC50 values of 7.18, 11.63, and 11.49 µM, respectively. Furthermore, the complex stability of isoginkgetin with an active binding pocket of the SARS-CoV-2 Mpro and RdRp supports its inhibitory potency against the SARS-CoV-2. Thus, isoginkgetin is a potent leading drug candidate and needs to be used in in vivo trials for the treatment of SARS-CoV-2 infected patients.
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Whole-brain imaging approaches and optogenetic manipulations are powerful tools to map brain-wide neural circuits in vivo. To date, functional magnetic resonance imaging (fMRI) provides the most comprehensive evaluation of such large-scale circuitry. However, functional ultrasound imaging (fUSI) has recently emerged as a complementary imaging modality that can extend such measurements towards the context of diverse behavioral states and tasks. Nevertheless, in order to properly interpret the fUSI signal during these complicated scenarios, it must first be carefully validated against well-established technologies, such as fMRI, in highly controlled experimental settings. Here, to address this need, we compared subsequent fMRI and fUSI recordings in response to direct neuronal activation via optogenetics in the same animals under an identical anesthetic protocol. Specifically, we applied various intensities of light stimulation to the primary motor cortex (M1) of mice and compared the spatiotemporal dynamics of the elicited fMRI and fUSI signals. Overall, our general linear model analysis (t-scores) and time series analysis (z-scores) revealed that fUSI was more sensitive than fMRI for detecting optogenetically-induced neuronal activation. Local field potential recordings in the bilateral M1 and striatum also better co-localized with fUSI activation patterns than those of fMRI. Finally, the fUSI response contained distinct arterial and venous components that provide vascular readouts of neuronal activity with vessel-type specificity.
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Neuroimagem Funcional/métodos , Córtex Motor/diagnóstico por imagem , Optogenética/métodos , Ultrassonografia/métodos , Animais , Feminino , Imageamento por Ressonância Magnética , Masculino , Camundongos , Neurônios/fisiologiaRESUMO
BACKGROUND. Potential approaches for abbreviated knee MRI, including prospective acceleration with deep learning, have achieved limited clinical implementation. OBJECTIVE. The objective of this study was to evaluate the interreader agreement between conventional knee MRI and a 5-minute 3D quantitative double-echo steady-state (qDESS) sequence with automatic T2 mapping and deep learning super-resolutionaugmentation and to compare the diagnostic performance of the two methods regarding findings from arthroscopic surgery. METHODS. Fifty-one patients with knee pain underwent knee MRI that included an additional 3D qDESS sequence with automatic T2 mapping. Fourier interpolation was followed by prospective deep learning super resolution to enhance qDESS slice resolution twofold. A musculoskeletal radiologist and a radiology resident performed independent retrospective evaluations of articular cartilage, menisci, ligaments, bones, extensor mechanism, and synovium using conventional MRI. Following a 2-month washout period, readers reviewed qDESS images alone followed by qDESS with the automatic T2 maps. Interreader agreement between conventional MRI and qDESS was computed using percentage agreement and Cohen kappa. The sensitivity and specificity of conventional MRI, qDESS alone, and qDESS plus T2 mapping were compared with arthroscopic findings using exact McNemar tests. RESULTS. Conventional MRI and qDESS showed 92% agreement in evaluating all tissues. Kappa was 0.79 (95% CI, 0.76-0.81) across all imaging findings. In 43 patients who underwent arthroscopy, sensitivity and specificity were not significantly different (p = .23 to > .99) between conventional MRI (sensitivity, 58-93%; specificity, 27-87%) and qDESS alone (sensitivity, 54-90%; specificity, 23-91%) for cartilage, menisci, ligaments, and synovium. For grade 1 cartilage lesions, sensitivity and specificity were 33% and 56%, respectively, for conventional MRI; 23% and 53% for qDESS (p = .81); and 46% and 39% for qDESS with T2 mapping (p = .80). For grade 2A lesions, values were 27% and 53% for conventional MRI, 26% and 52% for qDESS (p = .02), and 58% and 40% for qDESS with T2 mapping (p < .001). CONCLUSION. The qDESS method prospectively augmented with deep learning showed strong interreader agreement with conventional knee MRI and near-equivalent diagnostic performance regarding arthroscopy. The ability of qDESS to automatically generate T2 maps increases sensitivity for cartilage abnormalities. CLINICAL IMPACT. Using prospective artificial intelligence to enhance qDESS image quality may facilitate an abbreviated knee MRI protocol while generating quantitative T2 maps.
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Meios de Contraste , Aumento da Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodos , Traumatismos do Joelho/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Adolescente , Adulto , Idoso , Inteligência Artificial , Estudos de Avaliação como Assunto , Feminino , Humanos , Imageamento Tridimensional/métodos , Articulação do Joelho/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Tempo , Adulto JovemRESUMO
Biofilm formation by Staphylococcus aureus plays a critical role in the persistence of chronic infections due to its tolerance against antimicrobial agents. Here, we investigated the antibiofilm efficacy of six phorbaketals: phorbaketal A (1), phorbaketal A acetate (2), phorbaketal B (3), phorbaketal B acetate (4), phorbaketal C (5), and phorbaketal C acetate (6), isolated from the Korean marine sponge Phorbas sp. Of these six compounds, 3 and 5 were found to be effective inhibitors of biofilm formation by two S. aureus strains, which included a methicillin-resistant S. aureus. In addition, 3 also inhibited the production of staphyloxanthin, which protects microbes from reactive oxygen species generated by neutrophils and macrophages. Transcriptional analyses showed that 3 and 5 inhibited the expression of the biofilm-related hemolysin gene hla and the nuclease gene nuc1.
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Antibacterianos/farmacologia , Poríferos/química , Sesterterpenos/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Animais , Antibacterianos/isolamento & purificação , Proteínas de Bactérias/genética , Biofilmes/efeitos dos fármacos , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Genes Bacterianos , Sesterterpenos/isolamento & purificação , Staphylococcus aureus/genética , Staphylococcus aureus/metabolismo , Staphylococcus aureus/fisiologia , Xantofilas/metabolismoRESUMO
BACKGROUND: Super-resolution is an emerging method for enhancing MRI resolution; however, its impact on image quality is still unknown. PURPOSE: To evaluate MRI super-resolution using quantitative and qualitative metrics of cartilage morphometry, osteophyte detection, and global image blurring. STUDY TYPE: Retrospective. POPULATION: In all, 176 MRI studies of subjects at varying stages of osteoarthritis. FIELD STRENGTH/SEQUENCE: Original-resolution 3D double-echo steady-state (DESS) and DESS with 3× thicker slices retrospectively enhanced using super-resolution and tricubic interpolation (TCI) at 3T. ASSESSMENT: A quantitative comparison of femoral cartilage morphometry was performed for the original-resolution DESS, the super-resolution, and the TCI scans in 17 subjects. A reader study by three musculoskeletal radiologists assessed cartilage image quality, overall image sharpness, and osteophytes incidence in all three sets of scans. A referenceless blurring metric evaluated blurring in all three image dimensions for the three sets of scans. STATISTICAL TESTS: Mann-Whitney U-tests compared Dice coefficients (DC) of segmentation accuracy for the DESS, super-resolution, and TCI images, along with the image quality readings and blurring metrics. Sensitivity, specificity, and diagnostic odds ratio (DOR) with 95% confidence intervals compared osteophyte detection for the super-resolution and TCI images, with the original-resolution as a reference. RESULTS: DC for the original-resolution (90.2 ± 1.7%) and super-resolution (89.6 ± 2.0%) were significantly higher (P < 0.001) than TCI (86.3 ± 5.6%). Segmentation overlap of super-resolution with the original-resolution (DC = 97.6 ± 0.7%) was significantly higher (P < 0.0001) than TCI overlap (DC = 95.0 ± 1.1%). Cartilage image quality for sharpness and contrast levels, and the through-plane quantitative blur factor for super-resolution images, was significantly (P < 0.001) better than TCI. Super-resolution osteophyte detection sensitivity of 80% (76-82%), specificity of 93% (92-94%), and DOR of 32 (22-46) was significantly higher (P < 0.001) than TCI sensitivity of 73% (69-76%), specificity of 90% (89-91%), and DOR of 17 (13-22). DATA CONCLUSION: Super-resolution appears to consistently outperform naïve interpolation and may improve image quality without biasing quantitative biomarkers. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;51:768-779.
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Aprendizado Profundo , Osteoartrite , Biomarcadores , Humanos , Imageamento por Ressonância Magnética , Osteoartrite/diagnóstico por imagem , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
Microbial biofilms are associated with persistent infections because of their high tolerance to antimicrobial agents and host defenses. The effects of centipede oil from Scolopendra subspinipes mutilans and its main components were investigated to identify non-toxic biofilm inhibitors. Centipede oil and linoleic acid at 20 µg ml-1 markedly inhibited biofilm formation by two fluconazole-resistant Candida albicans strains and three Staphylococcus aureus strains without affecting their planktonic cell growth. Also, both centipede oil and linoleic acid inhibited hyphal growth and cell aggregation by C. albicans. In addition, centipede oil and linoleic acid showed anti-biofilm activities against mixed C. albicans and S. aureus biofilms. Transcriptomic analysis showed that centipede oil and linoleic acid downregulated the expressions of several hypha/biofilm-related genes in C. albicans and α-hemolysin in S. aureus. Furthermore, both compounds effectively reduced C. albicans virulence in a nematode infection model with minimal toxicity.
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Anti-Infecciosos/farmacologia , Biofilmes/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Ácido Linoleico/farmacologia , Óleos Voláteis/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Animais , Anti-Infecciosos/toxicidade , Artrópodes/química , Biofilmes/crescimento & desenvolvimento , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/microbiologia , Candida albicans/crescimento & desenvolvimento , Candida albicans/patogenicidade , Hifas/crescimento & desenvolvimento , Ácido Linoleico/toxicidade , Testes de Sensibilidade Microbiana , Óleos Voláteis/toxicidade , Staphylococcus aureus/crescimento & desenvolvimento , Staphylococcus aureus/patogenicidade , Virulência/efeitos dos fármacosRESUMO
Extracellular electrophysiology and functional MRI are complementary techniques that provide information about cellular and network-level neural activity, respectively. However, electrodes for electrophysiology are typically made from metals, which cause significant susceptibility artifacts on MR images. Previous work has demonstrated that insulated carbon fiber bundle electrodes reduce the volume of magnetic susceptibility artifacts and can be used to record local field potentials (LFP), but the relatively large diameter of the probes make them unsuitable for multi- and single-unit recordings. Although single carbon fiber electrodes have recently been used to record single-unit activity, these probes require modifications in order to aid insertion and the use of these probes in fMRI has yet to be validated. Therefore, there is a need for a single-carbon fiber electrode design that (1) minimizes the volume of the susceptibility artifact, (2) can record from a wide frequency band that includes LFP and multi- and single-unit recording, and (3) is practical to insert without additional modifications. Here, we demonstrate that carbon-fiber electrodes made from single carbon monofilaments (35⯵m in diameter) meet all of these criteria. Carbon monofilament electrodes modified with the conductive polymer poly(3,4-ethylenedioxythiophene) (PEDOT) have lower impedances and higher signal-to-noise ratio recordings than platinum-iridium electrodes, a current gold standard for chronic single-unit recording. Furthermore, these probes distort a significantly smaller volume of voxels compared to tungsten and platinum-iridium electrodes in agarose phantom and in vivo MR images, leading to higher contrast-to-noise ratio in regions proximal to the electrode implantation site during fMRI. Collectively, this work establishes that carbon monofilaments are a practical choice for combined electrophysiology-fMRI experiments.
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Compostos Bicíclicos Heterocíclicos com Pontes , Fibra de Carbono , Córtex Cerebral/fisiologia , Eletrodos Implantados , Eletroencefalografia/instrumentação , Fenômenos Eletrofisiológicos , Desenho de Equipamento , Neuroimagem Funcional , Imageamento por Ressonância Magnética , Polímeros , Animais , Eletroencefalografia/métodos , Feminino , Ratos , Ratos Sprague-DawleyRESUMO
Uropathogenic Escherichia coli (UPEC) is the primary causative agent of urinary tract infections, which are one of the most common infectious disease types in humans. UPEC infections involve bacterial cell adhesion to bladder epithelial cells, and UPEC can also form biofilms on indwelling catheters that are often tolerant to common antibiotics. In this study, the anti-biofilm activities of t-stilbene, stilbestrol, t-resveratrol, oxyresveratrol, ε-viniferin, suffruticosol A, and vitisin A were investigated against UPEC. t-Resveratrol, oxyresveratrol, and ε-viniferin, suffruticosol A, and vitisin A significantly inhibited UPEC biofilm formation at subinhibitory concentrations (10-50 µg ml-1). These findings were supported by observations that t-resveratrol and oxyresveratrol reduced fimbriae production and the swarming motility in UPEC. Furthermore, t-resveratrol and oxyresveratrol markedly diminished the hemagglutinating ability of UPEC, and enhanced UPEC killing by human whole blood. The findings show that t-resveratrol, oxyresveratrol, and resveratrol oligomers warrant further attention as antivirulence strategies against persistent UPEC infections.
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Biofilmes , Extratos Vegetais/farmacologia , Resveratrol/farmacologia , Estilbenos/farmacologia , Escherichia coli Uropatogênica/efeitos dos fármacos , Aderência Bacteriana/efeitos dos fármacos , Proteínas de Escherichia coli/metabolismo , Fímbrias Bacterianas/metabolismo , Escherichia coli Uropatogênica/fisiologia , Virulência/efeitos dos fármacosRESUMO
Neurological disease drives symptoms through pathological changes to circuit functions. Therefore, understanding circuit mechanisms that drive behavioral dysfunction is of critical importance for quantitative diagnosis and systematic treatment of neurological disease. Here, we describe key technologies that enable measurement and manipulation of neural activity and neural circuits. Applying these approaches led to the discovery of circuit mechanisms underlying pathological motor behavior, arousal regulation, and protein accumulation. Finally, we discuss how optogenetic functional magnetic resonance imaging reveals global scale circuit mechanisms, and how circuit manipulations could lead to new treatments of neurological diseases.