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Diagnosing malignant skin tumors accurately at an early stage can be challenging due to ambiguous and even confusing visual characteristics displayed by various categories of skin tumors. To improve diagnosis precision, all available clinical data from multiple sources, particularly clinical images, dermoscopy images, and medical history, could be considered. Aligning with clinical practice, we propose a novel Transformer model, named Remix-Former++ that consists of a clinical image branch, a dermoscopy image branch, and a metadata branch. Given the unique characteristics inherent in clinical and dermoscopy images, specialized attention strategies are adopted for each type. Clinical images are processed through a top-down architecture, capturing both localized lesion details and global contextual information. Conversely, dermoscopy images undergo a bottom-up processing with two-level hierarchical encoders, designed to pinpoint fine-grained structural and textural features. A dedicated metadata branch seamlessly integrates non-visual information by encoding relevant patient data. Fusing features from three branches substantially boosts disease classification accuracy. RemixFormer++ demonstrates exceptional performance on four single-modality datasets (PAD-UFES-20, ISIC 2017/2018/2019). Compared with the previous best method using a public multi-modal Derm7pt dataset, we achieved an absolute 5.3% increase in averaged F1 and 1.2% in accuracy for the classification of five skin tumors. Furthermore, using a large-scale in-house dataset of 10,351 patients with the twelve most common skin tumors, our method obtained an overall classification accuracy of 92.6%. These promising results, on par or better with the performance of 191 dermatologists through a comprehensive reader study, evidently imply the potential clinical usability of our method.
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BACKGROUND: The relationship between lifestyle and migraine is complex, as it remains uncertain which specific lifestyle factors play the most prominent role in the development of migraine, or which modifiable metabolic traits serve as mediators in establishing causality. METHODS: Independent genetic variants strongly associated with 20 lifestyle factors were selected as instrumental variables from corresponding genome-wide association studies (GWASs). Summary-level data for migraine were obtained from the FinnGen consortium (18,477 cases and 287,837 controls) as a discovery set and the GWAS meta-analysis data (26,052 cases and 487,214 controls) as a replication set. Estimates derived from the two datasets were combined using fixed-effects meta-analysis. Two-step univariable MR (UVMR) and multivariable Mendelian randomization (MVMR) analyses were conducted to evaluate 19 potential mediators of association and determine the proportions of these mediators. RESULTS: The combined effect of inverse variance weighted revealed that a one standard deviation (SD) increase in genetically predicted Leisure screen time (LST) was associated with a 27.7% increase (95% CI: 1.14-1.44) in migraine risk, while Moderate or/and vigorous physical activity (MVPA) was associated with a 26.9% decrease (95% CI: 0.61-0.87) in migraine risk. The results of the mediation analysis indicated that out of the 19 modifiable metabolic risk factors examined, hypertension explains 24.81% of the relationship between LST and the risk of experiencing migraine. Furthermore, hypertension and diastolic blood pressure (DBP) partially weaken the association between MVPA and migraines, mediating 4.86% and 4.66% respectively. CONCLUSION: Our research findings indicated that both LST and MVPA in lifestyle have independent causal effects on migraine. Additionally, we have identified that hypertension and DBP play a mediating role in the causal pathway between these two factors and migraine.
Subject(s)
Exercise , Genome-Wide Association Study , Hypertension , Mendelian Randomization Analysis , Migraine Disorders , Screen Time , Humans , Migraine Disorders/genetics , Migraine Disorders/epidemiology , Migraine Disorders/physiopathology , Exercise/physiology , Hypertension/genetics , Hypertension/epidemiology , Leisure ActivitiesABSTRACT
Objective: To explore the effect of traditional Chinese medicine (TCM) nursing under the integrated management mode during anesthesia recovery. Methods: The researchers' hospital admitted 114 patients who underwent general anesthesia between August 2022 and April 2023. Based on the admission order, these patients were divided into a control group (N=57) and an observation group (N=57). The control group received routine nursing intervention, while the observation group received comprehensive TCM nursing management, which included therapies such as cupping, acupressure, massage, herbal decoction, and mirabilite application. The study evaluated the psychological status, recovery indexes after anesthesia, comfort level, incidence of complications, and patient satisfaction with nursing care. Results: Compared to the control group, the observation group showed significant improvement in their psychological well-being (P < .05) and better recovery outcomes after anesthesia (P < .05). Additionally, the observation group reported higher levels of comfort (P < .05), a lower incidence of complications (8.77% vs 29.82%, P < .05), and greater satisfaction with nursing care (98.25% vs 84.21%, P < .05) compared to the control group. Conclusion: Integrated management of traditional Chinese medicine effectively reduces postoperative adverse events, improves treatment outcomes, and facilitates patient recovery. Its benefits are evident, and its feasibility is well-established.
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Pancreatic ß cells actively respond to glucose fluctuations through regulating insulin processing and secretion. However, how this process is elaborately tuned in circumstance of variable microenvironments as well as ß cell-intrinsic states and whether its dysfunction links to metabolic diseases remain largely elusive. Here, we show that the cytosolic pH (pHc) in ß cells is increased upon glucose challenge, which can be sensed by Smad5 via its nucleocytoplasmic shuttling. Lesion of Smad5 in ß cells results in hyperglycemia and glucose intolerance due to insulin processing and secretion deficiency. The role of Smad5 in regulating insulin processing and secretion attributes to its non-canonical function by regulating V-ATPase activity for granule acidification. Genetic mutation of Smad5 or administration of alkaline water to mirror cytosolic alkalization ameliorated glucose intolerance in high-fat diet (HFD)-treated mice. Collectively, our findings suggest that pHc is a direct nexus in linking environmental cues with insulin processing and secretion in ß cells.
Subject(s)
Cytosol , Insulin Secretion , Insulin-Secreting Cells , Insulin , Mice, Inbred C57BL , Animals , Insulin-Secreting Cells/metabolism , Hydrogen-Ion Concentration , Cytosol/metabolism , Mice , Insulin/metabolism , Male , Diet, High-Fat , Glucose Intolerance/metabolism , Glucose/metabolism , HumansABSTRACT
Vitreous replacement is a commonly employed method for treating a range of ocular diseases, including posterior vitreous detachment, complex retinal detachment, diabetic retinopathy, macular hole, and ocular trauma. Various clinical substitutes for vitreous include air, expandable gas, silicone oil, heavy silicone oil, and balanced salt solution. However, these substitutes have drawbacks such as short retention time, cytotoxicity, high intraocular pressure, and the formation of cataracts, rendering them unsuitable for long-term treatment. Polymeric hydrogels possess the potential to serve as ideal vitreous substitutes due to their structure-mimicking to natural vitreous and adjustable mechanical properties. Replacement with hydrogels as the tamponade can help maintain the shape of the eyeball, apply pressure to the detached retina, and ensure the metabolic transport of substances without impairing vision. This literature review examines the required properties of artificial vitreous, including the optical properties, rheological properties, expansive force action, and physiological and biochemical functions of chemically and physically crosslinked hydrogels. The strategies for enhancing the biocompatibility and injectability of hydrogels are also summarized and discussed. From a clinical ophthalmology perspective, this paper presents the latest developments in vitreous replacement, providing clinicians with a comprehensive understanding of hydrogel clinical applications, which offers guidance for future design directions and methodologies for hydrogel development.
Subject(s)
Cataract , Diabetic Retinopathy , Ophthalmology , Humans , Hydrogels , Eye , PolymersABSTRACT
AIM: The nocebo effect, such as nausea and vomiting, is one of the major reasons patients discontinue therapy. The underlying mechanisms remain unknown due to a lack of reliable experimental models. The goal of this study was to develop a new animal model of nocebo-related nausea by combining observational learning and Pavlovian conditioning paradigms. METHODS: Male Sprague-Dawley rats with nitroglycerin-induced migraine were given 0.9% saline (a placebo) or LiCl (a nausea inducer) following headache relief, according to different paradigms. RESULTS: Both strategies provoked nocebo nausea responses, with the conditioning paradigm having a greater induction impact. The superposition of two mechanisms led to a further increase in nausea responses. A preliminary investigation of the underlying mechanism revealed clearly raised peripheral and central cholecystokinin (CCK) levels, as well as specific changes in the 5-hydroxytryptamine and cannabinoid systems. Brain networks related to emotion, cognition, and visceral sense expressed higher c-Fos-positive neurons, including the anterior cingulate cortex (ACC), insula, basolateral amygdala (BLA), thalamic paraventricular nucleus (PVT), hypothalamic paraventricular nucleus (PVN), nucleus tractus solitarius (NTS), periaqueductal gray (PAG), and dorsal raphe nucleus-dorsal part (DRD). We also found that nausea expectances in the model could last for at least 12 days. CONCLUSION: The present study provides a useful experimental model of nocebo nausea that might be used to develop potential molecular pathways and therapeutic strategies for nocebo.
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Nocebo Effect , Solitary Nucleus , Humans , Rats , Male , Animals , Rats, Sprague-Dawley , Solitary Nucleus/metabolism , Cholecystokinin/metabolism , Cholecystokinin/pharmacology , Nausea/chemically induced , Nausea/metabolism , Proto-Oncogene Proteins c-fos/metabolismABSTRACT
Primary headache disorder is the main cause of headache attacks, leading to significant disability and impaired quality of life. This disorder is increasingly recognized as a heterogeneous condition with a complex network of genetic, environmental, and lifestyle factors. However, the timely diagnosis and effective treatment of these headaches remain challenging. Precision medicine is a potential strategy based on P4 (predictive, preventive, personalized, and participatory) medicine that may bring new insights for headache care. Recent machine learning advances and widely available molecular biology and imaging data have increased the usefulness of this medical strategy. Precision medicine emphasizes classifying headaches according to their risk factors, clinical presentation, and therapy responsiveness to provide individualized headache management. Furthermore, early preventive strategies, mainly utilizing predictive tools, are critical in reducing headache attacks and improving the quality of life of individuals with headaches. The current review comprehensively discusses the potential application value of P4 medicine in headache management.
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Intrinsic biological clocks drive the circadian rhythm, which coordinates the physiological and pathophysiological processes in the body. Recently, a bidirectional relationship between circadian rhythms and several neurological diseases has been reported. Neurological diseases can lead to the disruption of circadian homeostasis, thereby increasing disease severity. Therefore, optimizing the current treatments through circadian-based approaches, including adjusted dosing, changing lifestyle, and targeted interventions, offer a promising opportunity for better clinical outcomes and precision medicine. In this review, we provide detailed implications of the circadian rhythm in neurological diseases through bench-to-bedside approaches. Furthermore, based on the unsatisfactory clinical outcomes, we critically discuss the potential of circadian-based interventions, which may encourage more studies in this discipline, with the hope of improving treatment efficacy in neurological diseases.
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OBJECTIVE: To investigate the effect of the aryl hydrocarbon receptor (AHR)/regulatory T cell (Treg)/T-helper 17 (Th17) cell pathway on the pathogenesis of migraine. BACKGROUND: Migraine is a disabling neurovascular disease that imposes an enormous burden on both individuals and society. The pathophysiological mechanisms of migraine remain controversial. Recent studies have suggested that immune dysfunction may be involved in the pathogenesis of migraine. The AHR, a receptor expressed on most immune cells, has been implicated in the occurrence of many autoimmune diseases; however, whether it is involved in the pathogenesis of migraine is unclear. METHODS: A chronic migraine rat model was established through repeated intraperitoneal injection of nitroglycerin (NTG). The mechanical and thermal pain thresholds were assessed using von Frey filaments and radiant heat. Next, the protein expression levels of AHR in the trigeminal nucleus caudalis (TNC) region of chronic migraine (CM)-like rats were quantified and the changes in Treg/Th17-related transcription factors and inflammatory factors in the TNC were explored. To determine the role of AHR in CM, we examined the effects of the AHR agonist 2-(1'-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), and AHR antagonist CH-223191 on pain behavior, c-Fos, calcitonin gene-related peptide (CGRP), AHR, and Treg/Th17-related factor expression in CM-like rats. RESULTS: Repeated administration of NTG significantly enhanced nociceptive hypersensitivity and increased expression of c-Fos and CGRP in rats, while AHR was significantly decreased in the TNC. In addition, the expression of the transcription factor forkhead box protein P3 and the signal transducer and activator of transcription 5 decreased significantly. In contrast, the expression of the transcription factor retinoic acid receptor-related orphan receptor γ t and signal transducer and activator of transcription 3 were significantly increased. Moreover, the mRNA level of transforming growth factor beta-1 was decreased, while that of interleukin (IL)-10 and IL-22 was increased in the TNC. The AHR agonist ITE alleviated migraine-like pain behaviors in rats, activated the AHR signaling pathway, and improved the imbalance of Treg/Th17-related transcription factors and inflammatory factors. Conversely, the AHR antagonist CH-223191 did not alleviate migraine-like pain behaviors in rats; and even exacerbated them. CONCLUSIONS: The AHR participates in the development of CM by regulating Treg/Th17-related homeostasis. Therefore, treatments targeting the AHR/Treg/Th17 signaling pathway could be new effective interventions for CM treatment.
Subject(s)
Calcitonin Gene-Related Peptide , Migraine Disorders , Rats , Animals , Calcitonin Gene-Related Peptide/metabolism , Receptors, Aryl Hydrocarbon , T-Lymphocytes, Regulatory/metabolism , Pain Threshold , Nitroglycerin/pharmacology , Migraine Disorders/metabolism , HomeostasisABSTRACT
Extracting invariant representations in unlabeled electrocardiogram (ECG) signals is a challenge for deep neural networks (DNNs). Contrastive learning is a promising method for unsupervised learning. However, it should improve its robustness to noise and learn the spatiotemporal and semantic representations of categories, just like cardiologists. This article proposes a patient-level adversarial spatiotemporal contrastive learning (ASTCL) framework, which includes ECG augmentations, an adversarial module, and a spatiotemporal contrastive module. Based on the ECG noise attributes, two distinct but effective ECG augmentations, ECG noise enhancement, and ECG noise denoising, are introduced. These methods are beneficial for ASTCL to enhance the robustness of the DNN to noise. This article proposes a self-supervised task to increase the antiperturbation ability. This task is represented as a game between the discriminator and encoder in the adversarial module, which pulls the extracted representations into the shared distribution between the positive pairs to discard the perturbation representations and learn the invariant representations. The spatiotemporal contrastive module combines spatiotemporal prediction and patient discrimination to learn the spatiotemporal and semantic representations of categories. To learn category representations effectively, this article only uses patient-level positive pairs and alternately uses the predictor and the stop-gradient to avoid model collapse. To verify the effectiveness of the proposed method, various groups of experiments are conducted on four ECG benchmark datasets and one clinical dataset compared with the state-of-the-art methods. Experimental results showed that the proposed method outperforms the state-of-the-art methods.
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The glymphatic system is important for waste removal in the central nervous system. It removes soluble proteins and metabolic waste under the action of aquaporin-4 (AQP4) at the end of astrocytes. The glymphatic system plays a role in numerous neurological diseases; however, the relationship between migraine and the glymphatic system remains unclear. In this study, we explored the relationship between the glymphatic system and migraine using the nitroglycerin migraine model in C57/BL6mice. The glymphatic influx of cerebrospinal fluid tracer was reduced in mice in the migraine model, accompanied by decreased expression and impaired polarization of AQP4, thereby suggesting glymphatic dysfunction in migraine mice model. Then, further suppression of glymphatic function by TGN-020 (an AQP4 blocker) aggravated the migraine pathological changes in mice. The results indicated that glymphatic dysfunction may aggravate migraine pathology. Therefore, our findings revealed the potential role of the glymphatic system in migraine, providing possible targets for migraine prevention and treatment.
Subject(s)
Glymphatic System , Migraine Disorders , Nervous System Diseases , Mice , Animals , Brain/metabolism , Glymphatic System/metabolism , Migraine Disorders/metabolism , Nervous System Diseases/metabolism , Astrocytes/metabolism , Disease Models, Animal , Aquaporin 4/metabolismABSTRACT
Migraine is the second highest cause of disability worldwide, bringing a huge socioeconomic burden. Improving mitochondrial function has promise as an effective treatment strategy for migraine. Szeto-Schiller peptide (SS-31) is a new mitochondria-targeted tetrapeptide molecule that has been shown to suppress the progression of diseases by restoring mitochondrial function, including renal disease, cardiac disease, and neurodegenerative disease. However, whether SS-31 has a therapeutic effect on migraine remains unclear. The aim of this study is to clarify the treatment of SS-31 for headache and its potential mechanisms. Here we used a mouse model induced by repeated dural infusion of inflammatory soup (IS), and examined roles of Sirt3/Pgc-1α positive feedback loop in headache pathogenesis and mitochondrial function. Our results showed that repeated IS infusion impaired mitochondrial function, mitochondrial ultrastructure and mitochondrial homeostasis in the trigeminal nucleus caudalis (TNC). These IS-induced damages in TNC were reversed by SS-31. In addition, IS-induced nociceptive responses were simultaneously alleviated. The effects of SS-31 on mitochondrial function and mitochondrial homeostasis (mainly mitochondrial biogenesis) were attenuated partially by the inhibitor of Sirt3/Pgc-1α. Overexpression of Sirt3/Pgc-1α increased the protein level of each other. These results indicated that SS-31 alleviated nociceptive responses and restored mitochondrial function in an IS-induced headache mouse model via Sirt3/Pgc-1α positive feedback loop. SS-31 has the potential to be an effective drug candidate for headache treatment.
Subject(s)
Migraine Disorders , Neurodegenerative Diseases , Sirtuin 3 , Mice , Animals , Sirtuin 3/metabolism , Sirtuin 3/pharmacology , Feedback , Neurodegenerative Diseases/metabolism , Nociception , Mitochondria/metabolism , Disease Models, Animal , Headache/metabolism , Migraine Disorders/metabolismABSTRACT
AIMS: Chronic migraine (CM) is a common neurological disorder with complex pathogenesis. Evidence suggests that pituitary adenylate cyclase-activating peptide (PACAP) induces migraine-like attacks and may be potential a new target for migraine treatment, but the therapeutic results of targeting PACAP and its receptors are not uniform. Therefore, the aim of this study was to investigate the regulatory effect of PACAP type I receptor (PAC1R) antagonist, PACAP6-38, on nitroglycerin (NTG)-induced central sensitization in a CM model. METHODS: Sprague-Dawley (SD) rats received repeated injections of NTG to construct a CM model. Mechanical and thermal thresholds were measured using Von Frey filaments and hot plate tests. C-Fos expression was measured by western blotting and immunofluorescence staining to assess the central sensitization. PACAP6-38 was intracerebrally injected into the trigeminal nucleus caudalis (TNC), and then the changes in c-Fos, the synaptic-associated proteins, phospho-ERK1/2 (p-ERK1/2), phosphorylation of cyclic adenosine monophosphate response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) were detected. Transmission electron microscopy (TEM) and Golgi-Cox staining were used to observe the ultrastructure of synapses and dendritic structures of TNC neurons. RESULTS: The results showed that PACAP and PAC1R expression were significantly raised in the TNC after repeated NTG injections. Additionally, PACAP6-38 treatment alleviated nociceptive sensitization, inhibited NTG-induced overexpression of c-Fos and synaptic-associated proteins in the TNC of CM rat, restored aberrant synaptic structures. Furthermore, the expression of ERK/CREB/BDNF pathway was depressed by PACAP6-38. CONCLUSIONS: Our results demonstrated that abnormal synaptic structure in the TNC of CM, which could be reversed by inhibition of PAC1R via down-regulating the ERK/CREB/BDNF signaling pathway. PACAP6-38 improves NTG-induced central sensitization by regulating synaptic plasticity in the TNC of CM rat, which may provide new insights into the treatments targeting PACAP/PAC1R in migraine.
Subject(s)
Migraine Disorders , Nitroglycerin , Rats , Male , Animals , Nitroglycerin/toxicity , Brain-Derived Neurotrophic Factor/metabolism , Rats, Sprague-Dawley , Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism , Central Nervous System Sensitization/physiology , Migraine Disorders/chemically induced , Migraine Disorders/drug therapy , Migraine Disorders/metabolism , Trigeminal Nuclei , Neuronal Plasticity/physiologyABSTRACT
Background: Targeting metabolic pathways has emerged as a new migraine treatment strategy as researchers realize the critical role metabolism plays in migraine. Activated inflammatory cells undergo metabolic reprogramming and rely on glycolysis to function. The objective of this study was to investigate the glycolysis changes in the experimental model of migraine and the effect of glycolysis inhibitor 2-Deoxy-D-glucose (2-DG) in the pathophysiology of migraine. Methods: We used a rat model of migraine that triggered migraine attacks by applying inflammatory soup (IS) to the dura and examined changes in glycolysis. 2-DG was used to inhibit glycolysis, and the effects of 2-DG on mechanical ectopic pain, microglial cell activation, calcitonin gene-related peptides (CGRP), c-Fos, and inflammatory factors induced by inflammatory soup were observed. LPS stimulated BV2 cells to establish a model in vitro to observe the effects of 2-DG on brain-derived neurotrophic factor (BDNF) after microglia activation. Results: In the experimental model of migraine, key enzymes involved in glycolysis such as phosphofructokinase platelet (PFKP), hexokinase (HK2), hypoxia inducible factor-1α (HIF-1α), lactate dehydrogenase (LDH) and pyruvate kinase (PKM2) were expressed in the medullary dorsal horn. While the expression of electronic respiratory transport chain complex IV (COXIV) decreased. There were no significant changes in glucose 6-phosphate dehydrogenase (G6PD), a key enzyme in the pentose phosphate pathway. The glycolysis inhibitor 2-DG alleviated migraine-like symptoms in an experimental model of migraine, reduced the release of proinflammatory cytokines caused by microglia activation, and decreased the expression of CGRP and c-Fos. Further experiments in vitro demonstrated that glycolysis inhibition can reduce the release of Iba-1/proBDNF/BDNF and inhibit the activation of microglia. Conclusion: The migraine rat model showed enhanced glycolysis. This study suggests that glycolytic inhibitor 2-DG is an effective strategy for alleviating migraine-like symptoms. Glycolysis inhibition may be a new target for migraine treatment.
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BACKGROUND AND OBJECTIVES: Based on the Global Burden of Diseases, Injuries, and Risk Factors (GBD) study, neurologic disorders are a major cause of morbidity and mortality worldwide. However, there has been no comprehensive assessment of neurologic disorders in Asia. Data from the GBD 1990-2019 study were investigated to provide new details for neurologic disorders in Asia. METHODS: The burden of common neurologic disorders in Asia was calculated for 1990 and 2019 as incidence, prevalence, deaths, and disability-adjusted life-years (DALYs). Thirteen common neurologic disorders were analyzed. Data are presented as totals and by sex, age, year, location, risk factors, and sociodemographic index (SDI) and shown as counts and rates. RESULTS: In 2019, the most burdensome neurologic disorders in Asia for the absolute number of DALYs were stroke (98.8 million, 95% uncertainty interval [UI] 91.0-107.0), migraine (24.6 million, 95% UI 3.4-56.4), and Alzheimer disease (AD) and other dementias (13.5 million, 95% UI 5.9-29.8). From 1990 to 2019, the absolute number of DALYs and deaths caused by combined neurologic disorders (deaths by 60.7% and DALYs by 17.6%) increased, but the age-standardized rates (deaths by 34.1% and DALYs by 36.3%) decreased. The burden of neurologic disorders peaked among individuals aged 65-74 years and was higher among male than among female individuals; moreover, this burden varied considerably across Asian subregions and countries. Risk-attributable DALYs accounted for 86.9%, 28.5%, and 11.1% of DALYs for stroke, AD and other dementias, and multiple sclerosis, respectively. SDI was associated with both stroke and communicable neurological disorders. In terms of crude rate, the higher the SDI value, the higher the prevalence of stroke, and the lower all metrics of communicable neurological disorders. DISCUSSION: Neurologic disorders were the leading cause of DALYs and the second leading cause of deaths in Asia in 2019, and the burden may likely increase with the growth and aging of the Asian population. Urgent measures are needed for prevention, treatment, rehabilitation, and support services for common neurologic disorders regionally and nationally.
Subject(s)
Alzheimer Disease , Nervous System Diseases , Stroke , Humans , Male , Female , Global Burden of Disease , Quality-Adjusted Life Years , Risk Factors , Nervous System Diseases/epidemiology , Prevalence , Global HealthABSTRACT
BACKGROUND: Pituitary adenylate cyclase-activating polypeptide (PACAP) is a multipotent neuropeptide widely distributed in the trigeminovascular system (TVS) and higher brain regions. At present, the underlying mechanism of PACAP/PACAP type1 (PAC1) receptor in migraine generation remains unclear. METHODS: The rat model of chronic migraine (CM) was established by repeated intraperitoneal injection of nitroglycerin (NTG). Von Frey filaments and hot plate tests were used to measure the mechanical and thermal thresholds. The expression levels of c-Fos, calcitonin gene-related peptide (CGRP), PACAP, PAC1, protein kinase A (PKA) and phosphorylated extracellular signal-regulated kinase (ERK) were assessed by western blotting or immunofluorescence staining. The internalization of PAC1 receptor was visualized by fluorescence microscope and laser scanning confocal microscope. RESULTS: The results showed that c-Fos and CGRP expression significantly increased after repeated administrations of NTG or PACAP. Pitstop2 notably improved hyperalgesia in CM rats, while PACAP6-38 offered no benefit. In addition, PACAP-induced PAC1 receptor internalization, PKA and ERK pathways activation were blocked by Pitstop2 instead of PACAP6-38. CONCLUSIONS: Our results demonstrate that inhibition of PAC1 receptor internalization could effectively improve allodynia in CM rats by restraining ERK signaling pathway activation in a chronic migraine rat model. Modulation of receptor internalization may be a novel perspective to explore specific mechanisms of PACAP signaling activation in the trigeminal vascular system.
Subject(s)
Migraine Disorders , Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide , Rats , Animals , Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism , Extracellular Signal-Regulated MAP Kinases , Pituitary Adenylate Cyclase-Activating Polypeptide/pharmacology , Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism , Hyperalgesia , MAP Kinase Signaling System , Calcitonin Gene-Related Peptide/metabolismABSTRACT
Previous clinical and basic studies have shown that migraine is associated with cognitive impairment, anxiety, and depression. It severely affects the quality of life. In this study, C57BL/6 mice were randomly divided into four groups: IS group, IS+M group, and IS+S group with repeated application of dural inflammatory soup (IS) stimulation to establish a migraine model, followed by PBS, memantine, and sumatriptan interventions, respectively; the blank control group underwent the same treatment procedure but with PBS instead of IS and intervention drugs. The cognitive function of the mice was used as the main outcome indicator. After application of the IS, mice showed reduced pain threshold for mechanical stimulation, decreased learning memory capacity, attention deficit, a reduced number of dendritic spines in hippocampal neurons, and altered synaptic ultrastructure. The cognitive function indexes of mice in the IS+M group recovered with changes in Arc protein expression to a level not statistically different from that of the Control group, while the IS and IS+S groups remained at lower levels. The present results suggest that Arc-mediated synaptic plasticity may be an essential mechanism of cognitive dysfunction in migraine.
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Hypoimmunogenic human pluripotent stem cells (hPSCs) are expected to serve as an unlimited cell source for generating universally compatible "off-the-shelf" cell grafts. However, whether the engineered hypoimmunogenic hPSCs still preserve their advantages of unlimited self-renewal and multilineage differentiation to yield functional tissue cells remains unclear. Here, we systematically studied the self-renewal and differentiation potency of three types of hypoimmunogenic hPSCs, established through the biallelic lesion of B2M gene to remove all surface expression of classical and nonclassical HLA class I molecules (B2Mnull), biallelic homologous recombination of nonclassical HLA-G1 to the B2M loci to knockout B2M while expressing membrane-bound ß2m-HLA-G1 fusion proteins (B2MmHLAG), and ectopic expression of soluble and secreted ß2m-HLA-G5 fusion proteins in B2MmHLAG hPSCs (B2Mm/sHLAG) in the most widely used WA09 human embryonic stem cells. Our results showed that hypoimmunogenic hPSCs with variable expression patterns of HLA molecules and immune compromising spectrums retained their normal self-renewal capacity and three-germ-layer differentiation potency. More importantly, as exemplified by neurons, cardiomyocytes and hepatocytes, hypoimmunogenic hPSC-derived tissue cells were fully functional as of their morphology, electrophysiological properties, macromolecule transportation and metabolic regulation. Our findings thus indicate that engineered hypoimmunogenic hPSCs hold great promise of serving as an unlimited universal cell source for cell therapeutics.
Subject(s)
Human Embryonic Stem Cells , Pluripotent Stem Cells , Humans , HLA-G Antigens/metabolism , Pluripotent Stem Cells/metabolism , Cell Differentiation/physiologyABSTRACT
Percutaneous coronary intervention (PCI) has increasingly become the main treatment for coronary artery disease. The procedure requires high experienced skills and dexterous manipulations. However, there are few techniques to model PCI skill so far. In this study, a learning framework with local and ensemble learning is proposed to learn skill characteristics of different skill-level subjects from their PCI manipulations. Ten interventional cardiologists (four experts and six novices) were recruited to deliver a medical guidewire to two target arteries on a porcine model for in vivo studies. Simultaneously, translation and twist manipulations of thumb, forefinger, and wrist are acquired with electromagnetic (EM) and fiber-optic bend (FOB) sensors, respectively. These behavior data are then processed with wavelet packet decomposition (WPD) under 1-10 levels for feature extraction. The feature vectors are further fed into three candidate individual classifiers in the local learning layer. Furthermore, the local learning results from different manipulation behaviors are fused in the ensemble learning layer with three rule-based ensemble learning algorithms. In subject-dependent skill characteristics learning, the ensemble learning can achieve 100% accuracy, significantly outperforming the best local result (90%). Furthermore, ensemble learning can also maintain 73% accuracy in subject-independent schemes. These promising results demonstrate the great potential of the proposed method to facilitate skill learning in surgical robotics and skill assessment in clinical practice.
Subject(s)
Percutaneous Coronary Intervention , Robotics , Humans , Animals , Swine , Neural Networks, Computer , Algorithms , LearningABSTRACT
Endometrial cancer (EC) is a kind of gynecologic malignancy with a rising incidence rate. This study aimed to explore the role of VPS9D1 antisense RNA1 (VPS9D1-AS1) in EC. The expression of VPS9D1-AS1, microRNA (miR)-377-3p, and serum and glucocorticoid-regulated kinase 1 (SGK1) was detected by Quantitative Real-Time PCR (qRT-PCR). Cell proliferation, invasion and epithelial-mesenchymal transition (EMT) were determined by cell counting kit-8 (CCK-8), 5-Ethynyl-2'-Deoxyuridine (EdU) transwell, and western bolt. VPS9D1-AS1 was predicted to sponge miR-377-3p via Starbase, and verified by luciferase reporter, RNA binding protein immunoprecipitation (RIP), and RNA pull-down experiments. The clinical characteristics of VPS9D1-AS1, miR-377-3p, and SGK1 were analyzed. The role of VPS9D1-AS1 on EC tumorigenesis was assessed in xenografted nude mice. VPS9D1-AS1 was upregulated in EC cells and tissues. Interference of VPS9D1-AS1 inhibited growth, invasion, and EMT of EC cells. Mechanically, VPS9D1-AS1 was a molecular sponge of miR-377-3p, and overexpression of miR-377-3p reversed VPS9D1-AS1-induced EC cells proliferation, invasion, and EMT. Moreover, SGK1 was confirmed to bind with miR-377-3p. Furthermore, overexpression of SGK1 alleviated sh-VPS9D1-AS1-caused effects on EC cells. High level of VPS9D1-AS1 and SGK1, or low miR-377-3p expression predicted a poor prognosis. The expression of the three genes was correlated with lymph node metastasis, pathological stage, and International Federation of Gynecology and Obstetrics (FIGO) stage, but not associated with age, ER, and PR expression. Interestingly, knockdown of VPS9D1-AS1 suppressed EC tumor growth in mice. VPS9D1-AS1 promoted cell invasion, proliferation, and EMT via modulating miR-377-3p/SGK1 axis, which provided new options for therapeutic strategies of EC.