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Pectocin M1 (PM1), the bacteriocin from phytopathogenic Pectobacterium carotovorum which causes soft rot disease, has a unique ferredoxin domain that allows it to use FusA of the plant ferredoxin uptake system. To probe the structure-based mechanism of PM1 uptake, we determined the X-ray structure of full-length PM1, containing an N-terminal ferredoxin and C-terminal catalytic domain connected by helical linker, at 2.04 Å resolution. Based on published FusA structure and NMR data for PM1 ferredoxin domain titrated with FusA, we modeled docking of the ferredoxin domain with FusA. Combining the docking models with the X-ray structures of PM1 and FusA enables us to propose the mechanism by which PM1 undergoes dynamic domain rearrangement to translocate across the target cell outer membrane.
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BACKGROUND: We recently reported that the dopamine (DA) analogue CA140 modulates neuroinflammatory responses in lipopolysaccharide-injected wild-type (WT) mice and in 3-month-old 5xFAD mice, a model of Alzheimer's disease (AD). However, the effects of CA140 on Aß/tau pathology and synaptic/cognitive function and its molecular mechanisms of action are unknown. METHODS: To investigate the effects of CA140 on cognitive and synaptic function and AD pathology, 3-month-old WT mice or 8-month-old (aged) 5xFAD mice were injected with vehicle (10% DMSO) or CA140 (30 mg/kg, i.p.) daily for 10, 14, or 17 days. Behavioral tests, ELISA, electrophysiology, RNA sequencing, real-time PCR, Golgi staining, immunofluorescence staining, and western blotting were conducted. RESULTS: In aged 5xFAD mice, a model of AD pathology, CA140 treatment significantly reduced Aß/tau fibrillation, Aß plaque number, tau hyperphosphorylation, and neuroinflammation by inhibiting NLRP3 activation. In addition, CA140 treatment downregulated the expression of cxcl10, a marker of AD-associated reactive astrocytes (RAs), and c1qa, a marker of the interaction of RAs with disease-associated microglia (DAMs) in 5xFAD mice. CA140 treatment also suppressed the mRNA levels of s100ß and cxcl10, markers of AD-associated RAs, in primary astrocytes from 5xFAD mice. In primary microglial cells from 5xFAD mice, CA140 treatment increased the mRNA levels of markers of homeostatic microglia (cx3cr1 and p2ry12) and decreased the mRNA levels of a marker of proliferative region-associated microglia (gpnmb) and a marker of lipid-droplet-accumulating microglia (cln3). Importantly, CA140 treatment rescued scopolamine (SCO)-mediated deficits in long-term memory, dendritic spine number, and LTP impairment. In aged 5xFAD mice, these effects of CA140 treatment on cognitive/synaptic function and AD pathology were regulated by dopamine D1 receptor (DRD1)/Elk1 signaling. In primary hippocampal neurons and WT mice, CA140 treatment promoted long-term memory and dendritic spine formation via effects on DRD1/CaMKIIα and/or ERK signaling. CONCLUSIONS: Our results indicate that CA140 improves neuronal/synaptic/cognitive function and ameliorates Aß/tau pathology and neuroinflammation by modulating DRD1 signaling in primary hippocampal neurons, primary astrocytes/microglia, WT mice, and aged 5xFAD mice.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Ratones Transgénicos , Enfermedades Neuroinflamatorias , Receptores de Dopamina D1 , Transducción de Señal , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Ratones , Péptidos beta-Amiloides/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Receptores de Dopamina D1/metabolismo , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Sinapsis/patología , Cognición/efectos de los fármacos , Dopamina/metabolismo , Ratones Endogámicos C57BL , Masculino , HumanosRESUMEN
Background: Kawasaki disease (KD), an acute febrile illness and systemic vasculitis, is the leading cause of acquired heart disease in children in industrialized countries. KD leads to the development of coronary artery aneurysms (CAA) in affected children, which may persist for months and even years after the acute phase of the disease. There is an unmet need to characterize the immune and pathological mechanisms of the long-term complications of KD. Methods: We examined cardiovascular complications in the Lactobacillus casei cell wall extract (LCWE) mouse model of KD-like vasculitis over 4 months. The long-term immune, pathological, and functional changes occurring in cardiovascular lesions were characterized by histological examination, flow cytometric analysis, immunofluorescent staining of cardiovascular tissues, and transthoracic echocardiogram. Results: CAA and abdominal aorta dilations were detected up to 16 weeks following LCWE injection and initiation of acute vasculitis. We observed alterations in the composition of circulating immune cell profiles, such as increased monocyte frequencies in the acute phase of the disease and higher counts of neutrophils. We determined a positive correlation between circulating neutrophil and inflammatory monocyte counts and the severity of cardiovascular lesions early after LCWE injection. LCWE-induced KD-like vasculitis was associated with myocarditis and myocardial dysfunction, characterized by diminished ejection fraction and left ventricular remodeling, which worsened over time. We observed extensive fibrosis within the inflamed cardiac tissue early in the disease and myocardial fibrosis in later stages. Conclusion: Our findings indicate that increased circulating neutrophil counts in the acute phase are a reliable predictor of cardiovascular inflammation severity in LCWE-injected mice. Furthermore, long-term cardiac complications stemming from inflammatory cell infiltrations in the aortic root and coronary arteries, myocardial dysfunction, and myocardial fibrosis persist over long periods and are still detected up to 16 weeks after LCWE injection.
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Pared Celular , Modelos Animales de Enfermedad , Fibrosis , Lacticaseibacillus casei , Síndrome Mucocutáneo Linfonodular , Vasculitis , Animales , Ratones , Pared Celular/inmunología , Vasculitis/inmunología , Vasculitis/etiología , Vasculitis/patología , Síndrome Mucocutáneo Linfonodular/inmunología , Síndrome Mucocutáneo Linfonodular/complicaciones , Masculino , Miocarditis/etiología , Miocarditis/patología , Miocarditis/inmunología , Inflamación/inmunologíaRESUMEN
Piezo1 mechanosensitive ion channel plays a important role in vascular physiology and disease. This study aimed to elucidate the altered signaling elicited by Piezo1 activation in the arteries of type 2 diabetes. Ten- to 12-week-old male C57BL/6 (control) and type 2 diabetic mice (db-/db-) were used. The second-order mesenteric arteries (~ 150 µm) were used for isometric tension experiments. Western blot analysis and immunofluorescence staining were performed to observe protein expression. Piezo1 was significantly decreased in mesenteric arteries of type 2 diabetic mice compared to control mice, as analyzed by western blot and immunofluorescence staining. Piezo1 agonist, Yoda1, concentration-dependently induced relaxation of mesenteric arteries in both groups. Interestingly, the relaxation response was significantly greater in control mice than in db-/db- mice. The removal of endothelium reduced relaxation responses induced by Yoda1, which was greater in control mice than db-/db- mice. Furthermore, the relaxation response was reduced by pre-treatment with various types of K+ channel blockers in endothelium-intact arteries in control mice. In endothelium-denuded arteries, pre-incubation with charybdotoxin, an Ca2+-activated K+ channel (BKCa channel) blocker, significantly attenuated Yoda1-induced relaxation in db-/db- mice, while there was no effect in control mice. Co-immunofluorescence staining showed co-localization of Piezo1 and BKCa channel was more pronounced in db-/db- mice than in control mice. These results indicate that the vascular responses induced by Piezo1 activation are different in the mesenteric resistance arteries in type 2 diabetic mice.
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Alterations in the intestinal microbiota contribute to the pathogenesis of various cardiovascular disorders, but how they affect the development of Kawasaki disease (KD), an acute pediatric vasculitis, remains unclear. We report that depleting the gut microbiota reduces the development of cardiovascular inflammation in a murine model mimicking KD vasculitis. The development of cardiovascular lesions was associated with alterations in the intestinal microbiota composition and, notably, a decreased abundance of Akkermansia muciniphila and Faecalibacterium prausnitzii. Oral supplementation with either of these live or pasteurized individual bacteria, or with short-chain fatty acids (SCFAs) produced by them, attenuated cardiovascular inflammation. Treatment with Amuc_1100, the TLR-2 signaling outer membrane protein from A. muciniphila , also decreased the severity of vascular inflammation. This study reveals an underappreciated gut microbiota-cardiovascular inflammation axis in KD vasculitis pathogenesis and identifies specific intestinal commensals that regulate vasculitis in mice by producing metabolites or via extracellular proteins acting on gut barrier function. IN BRIEF: It remains unclear whether changes in the intestinal microbiota composition are involved in the development of cardiovascular lesions associated with Kawasaki disease (KD), an immune-mediated vasculitis. Jena et al. observe alterations in the intestinal microbiota composition of mice developing vasculitis, characterized by reduced A. muciniphila and F. prausnitzii . Oral supplementation with either of these bacteria, live or pasteurized, or with bacteria-produced short-chain fatty acids (SCFAs) or Amuc_1100, the TLR-2 signaling outer membrane protein of A. muciniphila , was sufficient to alleviate the development of cardiovascular lesions in mice by promoting intestinal barrier function. HIGHLIGHTS: Absence or depletion of the microbiota decreases the severity of vasculitis in a murine model mimicking KD vasculitis. Supplementation of B. wadsworthia and B. fragilis promotes murine KD vasculitis. Decreased abundances of F. prausnitzii and A. muciniphila are associated with the development of cardiovascular lesions in mice. Supplementation with either live or pasteurized A. muciniphila and F. prausnitzii, or the TLR-2 signaling Amuc_1100, reduces the severity of vasculitis by promoting gut barrier function.
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Tauopathies exhibit a characteristic accumulation of misfolded tau aggregates in the brain. Tau pathology shows disease-specific spatiotemporal propagation through intercellular transmission, which is closely correlated with the progression of clinical manifestations. Therefore, identifying molecular mechanisms that prevent tau propagation is critical for developing therapeutic strategies for tauopathies. The various innate immune receptors, such as complement receptor 3 (CR3) and complement receptor 4 (CR4), have been reported to play a critical role in the clearance of various extracellular toxic molecules by microglia. However, their role in tau clearance has not been studied yet. In the present study, we investigated the role of CR3 and CR4 in regulating extracellular tau clearance. We found that CR4 selectively binds to tau fibrils but not to tau monomers, whereas CR3 does not bind to either of them. Inhibiting CR4, but not CR3, significantly reduces the uptake of tau fibrils by BV2 cells and primary microglia. By contrast, inhibiting CR4 has no effect on the uptake of tau monomers by BV2 cells. Furthermore, inhibiting CR4 suppresses the clearance of extracellular tau fibrils, leading to more seed-competent tau fibrils remaining in the extracellular space relative to control samples. We also provide evidence that the expression of CR4 is upregulated in the brains of human Alzheimer's disease patients and the PS19 mouse model of tauopathy. Taken together, our data strongly support that CR4 is a previously undescribed receptor for the clearance of tau fibrils in microglia and may represent a novel therapeutic target for tauopathy.
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Microglía , Proteínas tau , Microglía/metabolismo , Microglía/patología , Proteínas tau/metabolismo , Proteínas tau/genética , Animales , Humanos , Ratones , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Tauopatías/metabolismo , Tauopatías/patología , Tauopatías/genética , Antígeno de Macrófago-1/metabolismo , Antígeno de Macrófago-1/genética , Encéfalo/metabolismo , Encéfalo/patología , MasculinoRESUMEN
PURPOSE: Virtual reality technology has been used to establish a risk-free environment in which students can practice psychiatric nursing. A quasi-experimental study was conducted to examine the effects of a virtual reality (VR) based mental health nursing simulation on practice performance of undergraduate nursing students. METHODS: A quasi-experimental, pre- and post-test design was used. A total of 68 students were randomly assigned to an experimental group (n = 32) and a control group (n = 36). The control group received conventional simulation using text scenario-based role play. The intervention group received VR software consisting of 360° video clips and related quiz questions. RESULTS: The self-reported perceived competency in nursing performance showed no statistically significant improvement in the experimental group, whereas the control group showed a statistically significant improvement in symptom management (t = 2.84, p = 0.007) and nurse-patient interaction (t = 2.10, p = 0.043). Scores from the assessor showed better performance scores in the experimental group in symptom management (t = -2.62, p = 0.011), violence risk management (t = -3.42, p = 0.001), and nurse-patient interaction (t = -3.12, p = 0.003). CONCLUSIONS: The findings of this study indicate the potential of using VR for optimized mental health nursing simulation. VR technology allowed realistic experiences which may ensure students have a more comprehensive understanding of mentally ill patients and in doing so, overcome barriers of traditional simulation, resulting in better learning outcomes.
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Enfermería Psiquiátrica , Realidad Virtual , Humanos , Enfermería Psiquiátrica/educación , Enfermería Psiquiátrica/métodos , Femenino , Masculino , Adulto Joven , Adulto , Bachillerato en Enfermería/métodos , Estudiantes de Enfermería/psicología , Estudiantes de Enfermería/estadística & datos numéricosRESUMEN
Over the past several decades, significant criticism of the categorical classification system for personality disorders has highlighted the need to transition to a dimensional classification system. This study reviewed key issues involved in the potential conversion of the diagnostic system of personality disorders from a categorical to a dimensional model. The result suggests that Kernberg's concept of personality organization can be used to indicate the overall severity of personality pathology.
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Formación de Concepto , Trastornos de la Personalidad , Humanos , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Trastornos de la Personalidad/diagnóstico , Personalidad , Inventario de PersonalidadRESUMEN
BACKGROUND: Kawasaki disease (KD) is an acute febrile illness and systemic vasculitis often associated with cardiac sequelae, including arrhythmias. Abundant evidence indicates a central role for IL (interleukin)-1 and TNFα (tumor necrosis factor-alpha) signaling in the formation of arterial lesions in KD. We aimed to investigate the mechanisms underlying the development of electrophysiological abnormalities in a murine model of KD vasculitis. METHODS: Lactobacillus casei cell wall extract-induced KD vasculitis model was used to investigate the therapeutic efficacy of clinically relevant IL-1Ra (IL-1 receptor antagonist) and TNFα neutralization. Echocardiography, in vivo electrophysiology, whole-heart optical mapping, and imaging were performed. RESULTS: KD vasculitis was associated with impaired ejection fraction, increased ventricular tachycardia, prolonged repolarization, and slowed conduction velocity. Since our transcriptomic analysis of human patients showed elevated levels of both IL-1ß and TNFα, we asked whether either cytokine was linked to the development of myocardial dysfunction. Remarkably, only inhibition of IL-1 signaling by IL-1Ra but not TNFα neutralization was able to prevent changes in ejection fraction and arrhythmias, whereas both IL-1Ra and TNFα neutralization significantly improved vasculitis and heart vessel inflammation. The treatment of L casei cell wall extract-injected mice with IL-1Ra also restored conduction velocity and improved the organization of Cx43 (connexin 43) at the intercalated disk. In contrast, in mice with gain of function of the IL-1 signaling pathway, L casei cell wall extract induced spontaneous ventricular tachycardia and premature deaths. CONCLUSIONS: Our results characterize the electrophysiological abnormalities associated with L casei cell wall extract-induced KD and show that IL-1Ra is more effective in preventing KD-induced myocardial dysfunction and arrhythmias than anti-TNFα therapy. These findings support the advancement of clinical trials using IL-1Ra in patients with KD.
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Cardiomiopatías , Síndrome Mucocutáneo Linfonodular , Taquicardia Ventricular , Vasculitis , Humanos , Animales , Ratones , Síndrome Mucocutáneo Linfonodular/complicaciones , Síndrome Mucocutáneo Linfonodular/tratamiento farmacológico , Proteína Antagonista del Receptor de Interleucina 1/farmacología , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Factor de Necrosis Tumoral alfa , Modelos Animales de Enfermedad , Interleucina-1beta/metabolismo , Arritmias Cardíacas/etiología , Arritmias Cardíacas/prevención & control , Taquicardia Ventricular/prevención & control , Taquicardia Ventricular/complicacionesRESUMEN
Background: Artificial intelligence (AI) technology can enable more efficient decision-making in healthcare settings. There is a growing interest in improving the speed and accuracy of AI systems in providing responses for given tasks in healthcare settings. Objective: This study aimed to assess the reliability of ChatGPT in determining emergency department (ED) triage accuracy using the Korean Triage and Acuity Scale (KTAS). Methods: Two hundred and two virtual patient cases were built. The gold standard triage classification for each case was established by an experienced ED physician. Three other human raters (ED paramedics) were involved and rated the virtual cases individually. The virtual cases were also rated by two different versions of the chat generative pre-trained transformer (ChatGPT, 3.5 and 4.0). Inter-rater reliability was examined using Fleiss' kappa and intra-class correlation coefficient (ICC). Results: The kappa values for the agreement between the four human raters and ChatGPTs were .523 (version 4.0) and .320 (version 3.5). Of the five levels, the performance was poor when rating patients at levels 1 and 5, as well as case scenarios with additional text descriptions. There were differences in the accuracy of the different versions of GPTs. The ICC between version 3.5 and the gold standard was .520, and that between version 4.0 and the gold standard was .802. Conclusions: A substantial level of inter-rater reliability was revealed when GPTs were used as KTAS raters. The current study showed the potential of using GPT in emergency healthcare settings. Considering the shortage of experienced manpower, this AI method may help improve triaging accuracy.
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Intracellular C-terminal cleavage of the amyloid precursor protein (APP) is elevated in the brains of Alzheimer's disease (AD) patients and produces a peptide labeled APP-C31 that is suspected to be involved in the pathology of AD. But details about the role of APP-C31 in the development of the disease are not known. Here, this work reports that APP-C31 directly interacts with the N-terminal and self-recognition regions of amyloid-ß40 (Aß40 ) to form transient adducts, which facilitates the aggregation of both metal-free and metal-bound Aß40 peptides and aggravates their toxicity. Specifically, APP-C31 increases the perinuclear and intranuclear generation of large Aß40 deposits and, consequently, damages the nucleus leading to apoptosis. The Aß40 -induced degeneration of neurites and inflammation are also intensified by APP-C31 in human neurons and murine brains. This study demonstrates a new function of APP-C31 as an intracellular promoter of Aß40 amyloidogenesis in both metal-free and metal-present environments, and may offer an interesting alternative target for developing treatments for AD that have not been considered thus far.
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Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Humanos , Ratones , Animales , Precursor de Proteína beta-Amiloide/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Apoptosis , Regiones Promotoras Genéticas/genética , Metales/toxicidadRESUMEN
Dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, is an antidiabetic medication that reduces blood glucose. Although it is well known that dapagliflozin has additional benefits beyond glycemic control, such as reducing blood pressure and lowering the risk of cardiovascular events, no sufficient research data are available on the direct effect of dapagliflozin on cardiovascular function. Thus, in this study, we investigated the direct vascular effect of dapagliflozin on isolated rat coronary arteries. The left descending coronary arteries of 13-week-old male Sprague Dawley rats were cut into segments 2-3 mm long and mounted in a multi-wire myography system to measure isometric tension. Dapagliflozin effectively reduced blood vessel constriction induced by U-46619 (500 nM) in coronary arteries regardless of the endothelium. Treatment with an eNOS inhibitor (L-NNA, 100 µM), sGC inhibitor (ODQ, 5 µM), or COX inhibitor (indomethacin, 3 µM) did not affect the vasodilation induced by dapagliflozin. The application of a Ca2+-activated K+ channel (KCa) blocker (TEA, 2 mM), voltage-dependent K+ channel (KV) blocker (4-AP, 2 mM), ATP-sensitive K+ channel blocker (KATP) glibenclamide (3 µM), and inward-rectifier K+ channel (KIR) blocker (BaCl2, 30 µM) did not affect the dapagliflozin-induced vasodilation either. The treatment with dapagliflozin decreased contractile responses induced by the addition of Ca2+, which suggested that the extracellular Ca2+ influx was inhibited by dapagliflozin. Treatment with dapagliflozin decreased the phosphorylation level of the 20 kDa myosin light chain (MLC20) in vascular smooth muscle cells. In the present study, we found that dapagliflozin has a significant vasodilatory effect on rat coronary arteries. Our findings suggest a novel pharmacologic approach for the treatment of cardiovascular diseases in diabetic patients through the modulation of Ca2+ homeostasis via dapagliflozin administration.
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Vasos Coronarios , Vasodilatación , Humanos , Ratas , Masculino , Animales , Ratas Sprague-Dawley , Adenosina Trifosfato/farmacología , Endotelio Vascular , Vasodilatadores/farmacologíaRESUMEN
Hydroxycarboxylic acid receptors (HCAR1, HCAR2, and HCAR3) transduce Gi/o signaling upon biding to molecules such as lactic acid, butyric acid and 3-hydroxyoctanoic acid, which are associated with lipolytic and atherogenic activity, and neuroinflammation. Although many reports have elucidated the function of HCAR2 and its potential as a therapeutic target for treating not only dyslipidemia but also neuroimmune disorders such as multiple sclerosis and Parkinson's disease, the structural basis of ligand recognition and ligand-induced Gi-coupling remains unclear. Here we report three cryo-EM structures of the human HCAR2-Gi signaling complex, each bound with different ligands: niacin, acipimox or GSK256073. All three agonists are held in a deep pocket lined by residues that are not conserved in HCAR1 and HCAR3. A distinct hairpin loop at the HCAR2 N-terminus and extra-cellular loop 2 (ECL2) completely enclose the ligand. These structures also reveal the agonist-induced conformational changes propagated to the G-protein-coupling interface during activation. Collectively, the structures presented here are expected to help in the design of ligands specific for HCAR2, leading to new drugs for the treatment of various diseases such as dyslipidemia and inflammation.
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Receptores Acoplados a Proteínas G , Transducción de Señal , Humanos , Ácidos Carboxílicos , Ligandos , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
Seleno-insulin, a class of artificial insulin analogs, in which one of the three disulfide-bonds (S-S's) of wild-type insulin (Ins) is replaced by a diselenide-bond (Se-Se), is attracting attention for its unique chemical and physiological properties that differ from those of Ins. Previously, we pioneered the development of a [C7UA,C7UB] analog of bovine pancreatic insulin (SeIns) as the first example, and demonstrated its high resistance against insulin-degrading enzyme (IDE). In this study, the conditions for the synthesis of SeIns via native chain assembly (NCA) were optimized to attain a maximum yield of 72%, which is comparable to the in vitro folding efficiency for single-chain proinsulin. When the resistance of BPIns to IDE was evaluated in the presence of SeIns, the degradation rate of BPIns became significantly slower than that of BPIns alone. Furthermore, the investigation on the intermolecular association properties of SeIns and BPIns using analytical ultracentrifugation suggested that SeIns readily forms oligomers not only with its own but also with BPIns. The hypoglycemic effect of SeIns on diabetic rats was observed at a dose of 150 µg/300 g rat. The strategy of replacing the solvent-exposed S-S with Se-Se provides new guidance for the design of long-acting insulin formulations.
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BACKGROUND: The in-depth understanding of human anatomy is the foundation for safety in nursing practice. Augmented reality is an emerging technology that can be used for integrative learning in nursing education. OBJECTIVE: The study aimed to develop a human anatomy-based skill training system and pilot test its usability and feasibility. METHODS: Twenty-seven nursing students participated in 3D anatomy-based skill training for intramuscular injection and Levin tube feeding using HoloLens 2. Various user interfaces including pictures, videos, animation graphics, and annotation boxes assisted users with a comprehensive understanding of the step-by-step procedures for these techniques. A one-group pre-post test was conducted to observe changes in skill performance competency, usability, and learning satisfaction. RESULTS: After study participation, a statistically significant improvement in skill performance competency (p< 0.05) was observed. The usability results showed that students were satisfied with the usefulness of the program (9.55 ± 0.49) and scored highly for the intention to participate in other educational programs (9.62 ± 0.59). A high level of learning satisfaction was achieved (9.55 ± 0.49), with positive responses in fostering students' engagement and excitement in the application of cutting-edge technology. CONCLUSION: The 3D anatomy-based nursing skill training demonstrated good potential to improve learning outcomes and facilitate engagement in self-directed practice. This can be integrated into undergraduate nursing education as an assistant teaching tool, contributing to the combination of knowledge and practice.
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The underlying causes of Alzheimer's disease (AD) remain a mystery, with multiple pathological components, including oxidative stress, acetylcholinesterase, amyloid-ß, and metal ions, all playing a role. Here we report a strategic approach to designing flavonoids that can effectively tackle multiple pathological elements involved in AD. Our systematic investigations revealed key structural features for flavonoids to simultaneously target and regulate pathogenic targets. Our findings led to the development of a highly promising flavonoid that exhibits a range of functions, based on a complete structure-activity relationship analysis. Furthermore, our mechanistic studies confirmed that this flavonoid's versatile reactivities are driven by its redox potential and direct interactions with pathogenic factors. This work highlights the potential of multi-target-directed flavonoids as a novel solution in the fight against AD.
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BACKGROUND: Monkeypox is endemic to African region and has become of Global concern recently due to its outbreaks in non-endemic countries. Although, the disease was first recorded in 1970, no monkeypox specific drug or vaccine exists as of now. METHODS: We applied drug repositioning method, testing effectiveness of currently approved drugs against emerging disease, as one of the most affordable approaches for discovering novel treatment measures. Techniques such as virtual ligand-based and structure-based screening were applied to identify potential drug candidates against monkeypox. RESULTS: We narrowed down our results to 6 antiviral and 20 anti-tumor drugs that exhibit theoretically higher potency than tecovirimat, the currently approved drug for monkeypox disease. CONCLUSIONS: Our results indicated that selected drug compounds displayed strong binding affinity for p37 receptor of monkeypox virus and therefore can potentially be used in future studies to confirm their effectiveness against the disease.
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Ezetimibe is a lipid-lowering agent that selectively inhibits cholesterol absorption by binding to the Niemann-Pick C1-like 1 (NPC1L1) protein. Although it is well known that administration of ezetimibe in hypercholesterolemia patients reduces the risk of cardiovascular events through attenuation of atherosclerosis, studies on the direct effect of ezetimibe on vascular function are not sufficient. The aim of the present study was to investigate the vascular effects of ezetimibe in rat mesenteric arteries. In the present study, 12-week-old male Sprague Dawley rats were used. After the rats were sacrificed, the second branches of the mesenteric arteries were isolated and cut into 2-3 mm segments and mounted in a multi-wire myography system to measure isometric tension. Ezetimibe reduced vasoconstriction induced by U46619 (500 nM) in endothelium-intact and endothelium-denuded arteries. Ezetimibe-induced vasodilation was not affected by the endothelial nitric oxide synthase (eNOS) inhibitor Nω-Nitro-L-arginine (L-NNA, 300 µM) or the non-selective potassium channel blocker, tetraethylammonium (TEA, 10 mM). Moreover, ezetimibe also completely blocked the contraction induced by an increase in external calcium concentration. Ezetimibe significantly reduced vascular contraction induced by L-type Ca2+ channel activator (Bay K 8644, 30 nM). Treatment with ezetimibe decreased the phosphorylation level of 20 kDa myosin light chain (MLC20) in vascular smooth muscle cells. In the present study, we found that ezetimibe has a significant vasodilatory effect in rat mesenteric resistance arteries. These results suggest that ezetimibe may have beneficial cardiovascular effects beyond its cholesterol-lowering properties.
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Arterias Mesentéricas , Vasodilatación , Humanos , Ratas , Masculino , Animales , Ezetimiba/farmacología , Ratas Sprague-Dawley , Fosforilación , Proteínas de Transporte de MembranaRESUMEN
Thermococcus onnurineus NA1, a hyperthermophilic carboxydotrophic archaeon, produces H2 through CO oxidation catalyzed by proteins encoded in a carbon monoxide dehydrogenase (CODH) gene cluster. TON_1525 with a DNA-binding helix-turn-helix (HTH) motif is a putative repressor regulating the transcriptional expression of the codh gene cluster. The T55I mutation in TON_1525 led to enhanced H2 production accompanied by the increased expression of genes in the codh cluster. Here, TON_1525 was demonstrated to be a dimer. Monomeric TON_1525 adopts a novel 'eighth note' symbol-like fold (referred to as 'eighth note' fold regulator, EnfR), and the dimerization mode of EnfR is unique in that it has no resemblance to structures in the Protein Data Bank. According to footprinting and gel shift assays, dimeric EnfR binds to a 36-bp pseudo-palindromic inverted repeat in the promoter region of the codh gene cluster, which is supported by an in silico EnfR/DNA complex model and mutational studies revealing the implication of N-terminal loops as well as HTH motifs in DNA recognition. The DNA-binding affinity of the T55I mutant was lowered by â¼15-fold, for which the conformational change of N-terminal loops is responsible. In addition, transcriptome analysis suggested that EnfR could regulate diverse metabolic processes besides H2 production.
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T cells expressing chimeric antigen receptors (CAR-T cells) have shown unprecedented clinical responses against hematological malignancies. However, some patients relapse after CAR-T cell therapy due to antigen-negative escape variants. Additionally, CAR-T cell therapies showed limited clinical efficacy in solid tumors with high antigen heterogeneity. To overcome this, we metabolically labeled the glycans on cancer cells to redirect CAR-T cell cytotoxicity regardless of the endogenous antigen expression status of the cancer cells. We found that modifying cancer cells with N-azidoacetylmannosamine and bicyclo[6.1.0]non-4-yne-fluorescein isothiocyanate can elicit selective and durable cytotoxicity of anti-FITC CAR-T cells. Furthermore, we demonstrated that dinitrophenyl-conjugated sialic acid (Sia-DNP) generated DNP-modified glycans on cancer cells in situ that could be effectively targeted by anti-DNP CAR-T cells to eradicate established tumors in xenograft models. Our study illustrates that metabolic glycan labeling using unnatural sugars can be combined with CAR-T cell therapy to provide novel cancer immunotherapy for solid tumors that lack viable target antigens.