RESUMEN
Synucleinopathies are characterized by the accumulation of α-synuclein (α-Syn) aggregates in the brain. Positron emission tomography (PET) imaging of synucleinopathies requires radiopharmaceuticals that selectively bind α-Syn deposits. We report the identification of a brain permeable and rapid washout PET tracer [18F]-F0502B, which shows high binding affinity for α-Syn, but not for Aß or Tau fibrils, and preferential binding to α-Syn aggregates in the brain sections. Employing several cycles of counter screenings with in vitro fibrils, intraneuronal aggregates, and neurodegenerative disease brain sections from several mice models and human subjects, [18F]-F0502B images α-Syn deposits in the brains of mouse and non-human primate PD models. We further determined the atomic structure of the α-Syn fibril-F0502B complex by cryo-EM and revealed parallel diagonal stacking of F0502B on the fibril surface through an intense noncovalent bonding network via inter-ligand interactions. Therefore, [18F]-F0502B is a promising lead compound for imaging aggregated α-Syn in synucleinopathies.
Asunto(s)
Enfermedades Neurodegenerativas , Sinucleinopatías , Animales , Humanos , alfa-Sinucleína/metabolismo , Sinucleinopatías/diagnóstico por imagen , Sinucleinopatías/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Tomografía de Emisión de Positrones , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismoRESUMEN
Activation of RIPK1 controls TNF-mediated apoptosis, necroptosis and inflammatory pathways1. Cleavage of human and mouse RIPK1 after residues D324 and D325, respectively, by caspase-8 separates the RIPK1 kinase domain from the intermediate and death domains. The D325A mutation in mouse RIPK1 leads to embryonic lethality during mouse development2,3. However, the functional importance of blocking caspase-8-mediated cleavage of RIPK1 on RIPK1 activation in humans is unknown. Here we identify two families with variants in RIPK1 (D324V and D324H) that lead to distinct symptoms of recurrent fevers and lymphadenopathy in an autosomal-dominant manner. Impaired cleavage of RIPK1 D324 variants by caspase-8 sensitized patients' peripheral blood mononuclear cells to RIPK1 activation, apoptosis and necroptosis induced by TNF. The patients showed strong RIPK1-dependent activation of inflammatory signalling pathways and overproduction of inflammatory cytokines and chemokines compared with unaffected controls. Furthermore, we show that expression of the RIPK1 mutants D325V or D325H in mouse embryonic fibroblasts confers not only increased sensitivity to RIPK1 activation-mediated apoptosis and necroptosis, but also induction of pro-inflammatory cytokines such as IL-6 and TNF. By contrast, patient-derived fibroblasts showed reduced expression of RIPK1 and downregulated production of reactive oxygen species, resulting in resistance to necroptosis and ferroptosis. Together, these data suggest that human non-cleavable RIPK1 variants promote activation of RIPK1, and lead to an autoinflammatory disease characterized by hypersensitivity to apoptosis and necroptosis and increased inflammatory response in peripheral blood mononuclear cells, as well as a compensatory mechanism to protect against several pro-death stimuli in fibroblasts.
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Caspasa 8/metabolismo , Enfermedades Autoinflamatorias Hereditarias/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Adolescente , Adulto , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Niño , Preescolar , Femenino , Células HEK293 , Enfermedades Autoinflamatorias Hereditarias/genética , Enfermedades Autoinflamatorias Hereditarias/patología , Humanos , Masculino , Ratones , Ratones Noqueados , Proteína Serina-Treonina Quinasas de Interacción con Receptores/deficiencia , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Alineación de Secuencia , Homología de Secuencia de AminoácidoRESUMEN
The effects of hypoxia on brain function remain largely unknown. This study aimed to clarify this issue by visual-stimulated functional magnetic resonance imaging design. Twenty-three college students with a 30-d high-altitude exposure were tested before, 1 week and 3 months after returning to sea level. Brain functional magnetic resonance imaging and retinal electroretinogram were acquired. One week after returning to sea level, decreased blood oxygenation level dependent in the right lingual gyrus accompanied with increased blood oxygenation level dependent in the frontal cortex and insular cortex, and decreased amplitude of electroretinogram a-wave in right eye; moreover, the bilateral lingual gyri showed increased functional connectivity within the dorsal visual stream pathway, and the blood oxygenation level dependent signals in the right lingual gyrus showed positive correlation with right retinal electroretinogram a-wave. Three months after returning to sea level, the blood oxygenation level dependent signals recovered to normal level, while intensively increased blood oxygenation level dependent signals in a broad of brain regions and decreased retinal electroretinogram were also existed. In conclusion, hypoxic exposure has long-term effects on visual cortex, and the impaired retinal electroretinogram may contribute to it. The increased functional connectivity of dorsal stream may compensate for the decreased function of retinal photoreceptor cells to maintain normal visual function.
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Electrorretinografía , Imagen por Resonancia Magnética , Plasticidad Neuronal , Vías Visuales , Humanos , Masculino , Adulto Joven , Femenino , Plasticidad Neuronal/fisiología , Vías Visuales/fisiología , Vías Visuales/diagnóstico por imagen , Hipoxia/fisiopatología , Adulto , Oxígeno/sangre , Corteza Visual/diagnóstico por imagen , Corteza Visual/fisiología , Encéfalo/fisiología , Encéfalo/diagnóstico por imagen , Estimulación Luminosa/métodos , Retina/fisiología , Retina/diagnóstico por imagen , Mapeo Encefálico/métodosRESUMEN
The accumulation of abnormal Tau protein is a common feature of various neurodegenerative diseases. Truncated Tau, resulting from cleavage by asparaginyl endopeptidase (AEP, δ-secretase), promotes its own phosphorylation and aggregation. Our study focused on understanding the regulatory mechanisms of AEP activation and its interaction with other proteins. We discovered that c-Src plays a critical role in mediating the activation and polyubiquitination of AEP in response to epidermal growth factor stimulation. In addition, we investigated the involvement of tumor necrosis factor receptor-associated factor 6 (Traf6), an E3 ligase, in the regulation of AEP levels and its interaction with c-Src. Knockdown of Traf6 effectively inhibited c-Src-induced AEP activation. To gain further insights into the molecular mechanisms, we employed mass spectrometry to identify the specific tyrosine residues of Traf6 that are phosphorylated by c-Src. By mutating these phosphorylation sites to phenylalanine, we disrupted Traf6-mediated polyubiquitination and subsequently observed the inactivation of AEP. This finding suggests that the phosphorylation of Traf6 by c-Src is crucial for AEP activation. Pharmacological inhibition of c-Src reduced the phosphorylation of Traf6 and inhibited AEP activation in neurons derived from human-induced pluripotent stem cells. Conditional knockout of Traf6 in neurons prevented c-Src-induced AEP activation and subsequent Tau truncation in vivo. Moreover, phosphorylation of Traf6 is highly correlated with AEP activation, Tau368 and pathological Tau (AT8) in Alzheimer's disease brain. Overall, our study elucidates the role of c-Src in regulating AEP-cleaved Tau through phosphorylating Traf6. Targeting the c-Src-Traf6 pathway may hold potential for the treatment of Alzheimer's disease and other tauopathies.
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Cisteína Endopeptidasas , Factor 6 Asociado a Receptor de TNF , Ubiquitina-Proteína Ligasas , Familia-src Quinasas , Proteínas tau , Animales , Humanos , Ratones , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Cisteína Endopeptidasas/metabolismo , Fosforilación , Familia-src Quinasas/antagonistas & inhibidores , Familia-src Quinasas/metabolismo , Proteínas tau/metabolismo , Factor 6 Asociado a Receptor de TNF/química , Factor 6 Asociado a Receptor de TNF/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Activación Enzimática , Fenilalanina , UbiquitinaciónRESUMEN
PURPOSE: Autoimmunity is a significant feature of APDS1 patients. We aimed to explore the pathogenic immune phenotype and possible mechanisms of autoimmunity in APDS1 patients. METHODS: The clinical records and laboratory data of 42 APDS1 patients were reviewed. Immunophenotypes were evaluated by multiparametric flow cytometry. Autoantibodies were detected via antigen microarray analysis. RESULTS: A total of 42 children with PIK3CD gene mutations were enrolled. Immunological tests revealed increased proportions of effector memory cells (86%) and central memory cells (59%) among CD4+ T cells; increased proportions of effector memory cells (83%) and terminally differentiated effector memory T cells (38%) among CD8+ T cells. Fewer CD3+ T cells and B cells and higher IgG levels were reported in patients with autoimmunity. The proportion of Tregs was decreased, and the proportions of Th9, Tfh, and Tfr cells were increased in APDS1 patients. Among APDS1 patients, higher proportion of Th2 and Tfr cells were found in those with autoimmunity. The proportions of CD11c+ B and CD21lo B cells in patients with autoimmunity were significantly increased. Antigen microarray analysis revealed a wide range of IgG/IgM autoantibodies in patients with APDS1. In patients with autoimmunity, the proportion of Tfr might be positively correlated with autoantibodies. CONCLUSIONS: The pathogenic immune phenotype of APDS1 patients included (1) deceased CD3+ T-cell and B-cell counts and increased IgG levels in patients with autoimmunity, (2) an imbalanced T helper cell subset, (3) increased proportions of autoreactive B cells, and (4) distinct autoantibody reactivities in patients with autoimmunity.
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Autoanticuerpos , Autoinmunidad , Niño , Humanos , Linfocitos B , Fenotipo , Síndrome , Inmunoglobulina GRESUMEN
The clinical penetrance of infectious diseases varies considerably among patients with inborn errors of immunity (IEI), even for identical genetic defects. This variability is influenced by pathogen exposure, healthcare access and host-environment interactions. We describe here a patient in his thirties who presented with epidermodysplasia verruciformis (EV) due to infection with a weakly virulent beta-papillomavirus (HPV38) and CD4+ T-cell lymphopenia. The patient was born to consanguineous parents living in the United States. Exome sequencing identified a previously unknown biallelic STK4 stop-gain mutation (p.Trp425X). The patient had no relevant history of infectious disease during childhood other than mild wart-like lesion on the skin, but he developed diffuse large B-cell lymphoma (DLBCL) and EBV viremia with a low viral load in his thirties. Despite his low CD4+ T-cell count, the patient had normal counts of CD3+ cells, predominantly double-negative T cells (67.4%), which turned out to be Vδ2+ γδ T cells. γδ T-cell expansion has frequently been observed in the 33 reported cases with STK4 deficiency. The Vδ2 γδ T cells of this STK4-deficient patient are mostly CD45RA-CD27+CCR7+ central memory γδT cells, and their ability to proliferate in response to T-cell activation was impaired, as was that of CD4+ T cells. In conclusion, γδ T-cell expansion may act as a compensatory mechanism to combat viral infection, providing immune protection in immunocompromised individuals.
Asunto(s)
Epidermodisplasia Verruciforme , Proteínas Serina-Treonina Quinasas , Humanos , Epidermodisplasia Verruciforme/genética , Epidermodisplasia Verruciforme/diagnóstico , Masculino , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/deficiencia , Adulto , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/deficiencia , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/etiología , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/diagnóstico , Mutación/genética , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/complicaciones , Linfocitos Intraepiteliales/inmunología , ConsanguinidadRESUMEN
PURPOSE: Moesin (MSN) deficiency is a recently reported combined immunodeficiency, and few cases have been reported to date. We describe a Chinese patient with a novel mutation causing MSN deficiency and a novel phenotype. METHODS: Clinical and immunological data were collected. Whole-exome sequencing was performed to identify gene mutations. MSN protein expression and T cell proliferation and activation were determined by flow cytometry. Cell migration was confirmed with a Transwell assay. Autoantibody levels were analyzed using antigen microarrays. RESULTS: The patient was a 10-year-old boy who presented with recurrent fever, oral ulcers and dermatomyositis-like symptoms, such as periorbital edema, facial swelling, elevated creatine kinase levels, and abnormal electromyography and muscle biopsy results. Epstein-Barr virus (EBV) DNA was detected in the serum, cells and tissues of this patient. He further developed nasal-type NK/T-cell lymphoma. A novel hemizygous mutation (c.68 A > G, p.N23S) in the MSN gene was found. The immunological phenotype of this patient included persistent decreases in T and B lymphocyte counts but normal immunoglobulin IgG levels. The patient had attenuated MSN protein expression and impaired T-cell proliferation and migration. The proportions of Tfh cells and CD21low B cells in the patient were higher than those in the controls. Moreover, 82 IgG and 102 IgM autoantibodies were more abundant in the patient than in the healthy controls. CONCLUSIONS: The novel mutation N23S is pathogenic and leads to a severe clinical phenotype. EBV infection, tumor, and dermatomyositis-like autoimmune symptoms may be associated with MSN deficiency, further expanding the understanding of the disease.
Asunto(s)
Dermatomiositis , Infecciones por Virus de Epstein-Barr , Proteínas de Microfilamentos , Mutación , Humanos , Masculino , Infecciones por Virus de Epstein-Barr/diagnóstico , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/inmunología , Dermatomiositis/genética , Dermatomiositis/diagnóstico , Dermatomiositis/inmunología , Niño , Proteínas de Microfilamentos/genética , Mutación/genética , Herpesvirus Humano 4 , Secuenciación del Exoma , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/diagnóstico , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Fenotipo , Linfocitos T/inmunologíaRESUMEN
Major depressive disorder (MDD) is a severe mental illness. Decreased brain plasticity and dendritic fields have been consistently found in MDD patients and animal models; however, the underlying molecular mechanisms remain to be clarified. Here, we demonstrate that the deletion of cancerous inhibitor of PP2A (CIP2A), an endogenous inhibitor of protein phosphatase 2A (PP2A), leads to depression-like behaviors in mice. Hippocampal RNA sequencing analysis of CIP2A knockout mice shows alterations in the PI3K-AKT pathway and central nervous system development. In primary neurons, CIP2A stimulates AKT activity and promotes dendritic development. Further analysis reveals that the effect of CIP2A in promoting dendritic development is dependent on PP2A-AKT signaling. In vivo, CIP2A deficiency-induced depression-like behaviors and impaired dendritic arborization are rescued by AKT activation. Decreased CIP2A expression and impaired dendrite branching are observed in a mouse model of chronic unpredictable mild stress (CUMS). Indicative of clinical relevance to humans, CIP2A expression is found decreased in transcriptomes from MDD patients. In conclusion, we discover a novel mechanism that CIP2A deficiency promotes depression through the regulation of PP2A-AKT signaling and dendritic arborization.
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Trastorno Depresivo Mayor , Humanos , Ratones , Animales , Trastorno Depresivo Mayor/genética , Fosfatidilinositol 3-Quinasas , Neuronas , Plasticidad NeuronalRESUMEN
BACKGROUND: Vitiligo is a common autoimmune skin disease. Capsaicin has been found to exert a positive effect on vitiligo treatment, and mesenchymal stem cells (MSCs) are also confirmed to be an ideal cell type. This study aimed to explore the influence of capsaicin combined with stem cells on the treatment of vitiligo and to confirm the molecular mechanism of capsaicin combined with stem cells in treating vitiligo. METHODS AND RESULTS: PIG3V cell proliferation and apoptosis were detected using CCK-8 and TUNEL assays, MitoSOX Red fluorescence staining was used to measure the mitochondrial ROS level, and JC-1 staining was used to detect the mitochondrial membrane potential. The expression of related genes and proteins was detected using RTâqPCR and Western blotting. Coimmunoprecipitation was used to analyze the protein interactions between HSP70 and TLR4 or between TLR4 and mTOR. The results showed higher expression of HSP70 in PIG3V cells than in PIG1 cells. The overexpression of HSP70 reduced the proliferation of PIG3V cells, promoted apoptosis, and aggravated mitochondrial dysfunction and autophagy abnormalities. The expression of HSP70 could be inhibited by capsaicin combined with MSCs, which increased the levels of Tyr, Tyrp1 and DCT, promoted the proliferation of PIG3V cells, inhibited apoptosis, activated autophagy, and improved mitochondrial dysfunction. In addition, capsaicin combined with MSCs regulated the expression of TLR4 through HSP70 and subsequently affected the mTOR/FAK signaling pathway CONCLUSIONS: Capsaicin combined with MSCs inhibits TLR4 through HSP70, and the mTOR/FAK signaling pathway is inhibited to alleviate mitochondrial dysfunction and autophagy abnormalities in PIG3V cells.
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Apoptosis , Capsaicina , Proliferación Celular , Proteínas HSP70 de Choque Térmico , Melanocitos , Mitocondrias , Transducción de Señal , Serina-Treonina Quinasas TOR , Receptor Toll-Like 4 , Vitíligo , Humanos , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Capsaicina/farmacología , Línea Celular , Proliferación Celular/efectos de los fármacos , Proteínas HSP70 de Choque Térmico/efectos de los fármacos , Proteínas HSP70 de Choque Térmico/metabolismo , Melanocitos/metabolismo , Melanocitos/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Serina-Treonina Quinasas TOR/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Vitíligo/metabolismo , Vitíligo/tratamiento farmacológico , Quinasa 1 de Adhesión Focal/efectos de los fármacos , Quinasa 1 de Adhesión Focal/metabolismoRESUMEN
Abnormal accumulation of hyperphosphorylated tau protein plays a pivotal role in a collection of neurodegenerative diseases named tauopathies, including Alzheimer's disease (AD). We have recently conceptualized the design of hetero-bifunctional chimeras for selectively promoting the proximity between tau and phosphatase, thus specifically facilitating tau dephosphorylation and removal. Here, we sought to optimize the construction of tau dephosphorylating-targeting chimera (DEPTAC) and obtained a new chimera D14, which had high efficiency in reducing tau phosphorylation both in cell and tauopathy mouse models, while showing limited cytotoxicity. Moreover, D14 ameliorated neurodegeneration in primary cultured hippocampal neurons treated with toxic tau-K18 fragments, and improved cognitive functions of tauopathy mice. These results suggested D14 as a cost-effective drug candidate for the treatment of tauopathies.
RESUMEN
Astrocyte-microglial interaction plays a crucial role in brain injury-associated neuroinflammation. Our previous data illustrated that astrocytes secrete microRNA, leading to anti-inflammatory effects on microglia. Long non-coding RNAs participate in neuroinflammation regulation after traumatic brain injury. However, the effect of astrocytes on microglial phenotype via long non-coding RNAs and the underlying molecular mechanisms remain elusive. We used long non-coding RNA sequencing on murine astrocytes and found that exosomal long non-coding RNA 4933431K23Rik attenuated traumatic brain injury-induced microglial activation in vitro and in vivo and ameliorated cognitive function deficiency. Furthermore, microRNA and messenger RNA sequencing together with binding prediction illustrated that exosomal long non-coding RNA 4933431K23Rik up-regulates E2F7 and TFAP2C expression by sponging miR-10a-5p. Additionally, E2F7 and TFAP2C, as transcription factors, regulated microglial Smad7 expression. Using Cx3cr1-Smad7 overexpression of adeno-associated virus, microglia specifically overexpressed Smad7 in the attenuation of neuroinflammation, resulting in less cognitive deficiency after traumatic brain injury. Mechanically, overexpressed Smad7 physically binds to IκBα and inhibits its ubiquitination, preventing NF-κB signaling activation. The Smad7 activator asiaticoside alleviates neuroinflammation and protects neuronal function in traumatic brain injury mice. This study revealed that an exosomal long non-coding RNA from astrocytes attenuates microglial activation after traumatic brain injury by up-regulating Smad7, providing a potential therapeutic target.
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Lesiones Traumáticas del Encéfalo , MicroARNs , ARN Largo no Codificante , Ratones , Animales , Microglía/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Astrocitos/metabolismo , Enfermedades Neuroinflamatorias , MicroARNs/metabolismo , Lesiones Traumáticas del Encéfalo/genética , Lesiones Traumáticas del Encéfalo/metabolismo , Fenotipo , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Antepartum depression has been reported to be associated with the intensity of maternal prenatal noise exposure; however, the association between noise exposure duration and the development of antepartum depression has not been established. This study aimed to determine the total and trimester-specific association of prenatal noise exposure duration with the development of antepartum depression. METHODS: From May 2018 to June 2021, we recruited 2,166 pregnant women from Shengjing Hospital, northeast China. We used a standardized questionnaire to assess women's prenatal noise exposure and used the Edinburgh Postnatal Depression Scale to assess pregnant women's antepartum depression during the 1st -, 2nd -, and 3rd - trimesters. We calculated a cumulative noise exposure score ranging from 0 to 3, with a higher score reflecting higher frequency and longer duration of noise exposure during pregnancy. RESULTS: Women who were exposed to noise for ≥ 15 min per day had an increased risk of antepartum depression compared with women who were not exposed to noise during pregnancy [odds ratio (OR) = 1.83, 95%CI:1.18, 2.83]. Noise exposure in a specific trimester was associated with higher risk of depression in the same trimester and subsequent trimesters. We observed increases in antepartum depression risk with increasing cumulative noise exposure scores (P for trend < 0.05 for all). Pregnant women with the highest scores had the highest risk of antepartum depression during the first (OR = 1.30, 95%CI:1.02, 1.65), second (OR = 1.75, 95%CI:1.23, 2.50) trimesters. Women with a cumulative noise exposure score of 2 had the highest risk of antepartum depression during the third trimester (OR = 1.79, 95%CI:1.14, 2.80), as well as during the whole pregnancy (OR = 1.94, 95%CI:1.14, 3.30). CONCLUSIONS: Maternal prenatal noise exposure duration was positively associated with antepartum depression risk in a dose-response manner. It is necessary to develop strategies by which pregnant women can avoid excessive exposure to noise to prevent antepartum depression.
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Depresión Posparto , Depresión , Ruido , Femenino , Humanos , Embarazo , Depresión/etiología , Depresión/complicaciones , Depresión Posparto/epidemiología , Depresión Posparto/etiología , Exposición Materna , Tercer Trimestre del Embarazo , Trimestres del Embarazo , Mujeres Embarazadas , Ruido/efectos adversosRESUMEN
BACKGROUND: The forgotten ureteral stents (FUS) is one of the late complications of stent placement. This systematic review summarized different aspects of FUS and focused on the problems and solutions related to FUS. METHODS: This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. PubMed® and Embase® were searched from inception until October 1st, 2022. Eligible studies were those defining FUS as a stent unintentionally left in situ longer than at least 2 months. RESULTS: Total 147 studies with 1292 patients were finally included. The mean indwelling time of FUS was 33.5 months (range from 3 months to 32 years). The most common initial cause for stent placement was adjunct treatment to urolithiasis (79.2%). The major forgetting reasons were patient-related (83.9%), which included poor compliance, lapse in memory, and misconceptions about the necessity of timely removal. Primary presenting complaints were flank pain (37.3%), lower urinary tract symptoms (33.3%), and hematuria (22.8%). Encrustation (80.8%) and urinary tract infections (40.2%) were the most common complications detected in patients with FUS. Computed tomography evolving as a preferred imaging test (76.1%) was indispensable for evaluating encrustation, migration, fracture and other complicated situations in patients with FUS. Besides, evaluation of kidney function and infection status was also of great importance. Multiple and multimodal procedures (59.0%) were often necessitated to achieve the stent-free status, and were mostly endoscopic procedures. Cystoscope was most commonly used (64.8%). Retrograde ureteroscopy (43.4%) and antegrade stent removal (31.6%) were often used when dealing with more complicated situations. Extracorporeal shockwave lithotripsy (30.4%) was often used as adjunctive to other endoscopic procedures, but it sometimes failed. The decision regarding the choice of treatment is based on the volume and site of encrustation, the direction of migration, the site of fracture, kidney function and other urinary comorbidities. CONCLUSIONS: FUS not only pose hazard to patients' health, but also impose a huge economic burden on medical care. Thorough preoperative evaluation is fundamental to developing the treatment strategy. The management of FUS should be individualized using different treatment modalities with their advantages to minimize patients' morbidities. Prevention is better than cure. Strengthening health education and setting a tracking program are of great importance to the prevention of FUS.
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Cuerpos Extraños , Fracturas Óseas , Litotricia , Stents , Urolitiasis , Humanos , Cistoscopios , Hematuria , Ureteroscopía , Stents/efectos adversosRESUMEN
OBJECTIVE: Both piperine and a 308-nm excimer laser have significant curative effects on vitiligo. This study mainly explored the molecular mechanism of a 308-nm excimer combined with piperine in regulating melanocyte proliferation. METHODS: Epidermal melanocytes were cultured in piperine solution, and the cells were irradiated by an XTRAC excimer laser treatment system at 308-nm output monochromatic light. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were for detecting the expression levels of genes or proteins. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and Transwell method was for assessing cell viability and migration capacity. The content of melanin was also detected. RESULTS: The combination of the 308-nm excimer laser and piperine enhanced the cell proliferation, migration, and melanin production of melanocytes and upregulated the level of miR-328, and restraint of miR-328 reversed the influence of the 308-nm excimer laser and piperine. Secreted frizzled-related protein 1 (SFRP1) is a direct target gene of miR-328, and miR-328 can inhibit the expression of SFRP1 and elevate the protein level of the Wnt/ß-catenin signaling pathway. CONCLUSION: The 308-nm excimer laser combined with piperine may be more efficient than piperine alone in the remedy of vitiligo, and the miR-328/SFRP1 and Wnt/ß-catenin pathways are participated in the proliferation, migration, and melanin synthesis of melanocytes.
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Benzodioxoles , Movimiento Celular , Proliferación Celular , Melaninas , Piperidinas , Humanos , Alcaloides/farmacología , Benzodioxoles/farmacología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Melaninas/biosíntesis , Melanocitos/metabolismo , Melanocitos/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , MicroARNs/genética , MicroARNs/metabolismo , Piperidinas/farmacología , Alcamidas Poliinsaturadas/farmacología , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Rayos Láser , Vitíligo/tratamiento farmacológico , Vitíligo/terapiaRESUMEN
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection has many neurological manifestations, and its effects on the nervous system are increasingly recognized. There has been no systematic analysis of electroencephalography (EEG) characteristics in children exhibiting neurological symptoms of Coronavirus disease 2019 (COVID-19). The primary aim of this study was to describe the EEG characteristics caused by COVID-19 infection in children who were showing neurological symptoms and to assess the relationship between COVID-19-related EEG changes and clinical features in these children. METHOD: This study included 125 pediatric patients infected with SARS-CoV2 and showing neurological symptoms, and their continuous EEG was recorded. In addition, the demographic and clinical characteristics of these patients were analyzed and the correlation between the two was investigated. RESULTS: Abnormal EEG findings were detected in 31.20% (N = 39) of the patients. Abnormal discharges (43.59%) were the most common EEG abnormalities, followed by background abnormalities (41.03%). The proportion of patients diagnosed with febrile seizure was higher in the normal EEG group than in the abnormal EEG group (P = 0.002), while the opposite was true for epilepsy and encephalitis/encephalopathy (P = 0.016 and P = 0.003, respectively). The independent associated factors of abnormal EEG were age and total length of stay (P < 0.001 and P = 0.003, respectively). Non-specific EEG abnormalities were found in COVID-19-related encephalitis/encephalopathy. CONCLUSION: Our study corroborated that a small group of pediatric patients infected by COVID-19 and showing neurological symptoms may exhibit abnormal EEG. This study could help improve the understanding of clinical and EEG characteristics in children with COVID-19 and inform triage policies in other hospitals during the COVID-19 pandemic.
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Encefalopatías , COVID-19 , Encefalitis , Humanos , Niño , SARS-CoV-2 , Pandemias , ARN Viral , ElectroencefalografíaRESUMEN
C9orf72-derived dipeptide repeats (DPRs) proteins have been regarded as the pathogenic cause of neurodegeneration in amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). As the most toxic DPRs in C9-ALS/FTD, poly-proline-arginine (poly-PR) is associated with the stability and accumulation of p53, which consequently induces neurodegeneration. However, the exact molecular mechanism via which C9orf72 poly-PR stabilizes p53 remains unclear. In this study, we showed that C9orf72 poly-PR induces not only neuronal damage but also p53 accumulation and p53 downstream gene activation in primary neurons. C9orf72 (PR)50 also slows down p53 protein turnover without affecting the p53 transcription level and thus promotes its stability in N2a cells. Interestingly, the ubiquitin-proteasome system but not the autophagy function was impaired in (PR)50 transfected N2a cells, resulting in defective p53 degradation. Moreover, we found that (PR)50 induces mdm2 mistranslocation from the nucleus to the cytoplasm and competitively binds to p53, reducing mdm2-p53 interactions in the nucleus in two different (PR)50 transfected cells. Our data strongly indicate that (PR)50 reduces mdm2-p53 interactions and causes p53 to escape from the ubiquitin-proteasome system, promoting its stability and accumulation. Inhibiting or at least downregulating (PR)50 binding with p53 may be therapeutically exploited for the treatment of C9-ALS/FTD.
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Esclerosis Amiotrófica Lateral , Demencia Frontotemporal , Humanos , Esclerosis Amiotrófica Lateral/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Demencia Frontotemporal/genética , Demencia Frontotemporal/metabolismo , Ubiquitina/metabolismo , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Citoplasma/metabolismo , Dipéptidos/genética , Expansión de las Repeticiones de ADNRESUMEN
BACE1 is essential for the generation of amyloid-ß (Aß) that likely initiates the toxicity in Alzheimer's disease (AD). BACE1 activity is mainly regulated by post-translational modifications, but the relationship between these modifications is not fully characterized. Here, we studied the effects of BACE1 SUMOylation on its phosphorylation and ubiquitination. We demonstrate that SUMOylation of BACE1 inhibits its phosphorylation at S498 and its ubiquitination in vitro. Conversely, BACE1 phosphorylation at S498 suppresses its SUMOylation, which results in promoting BACE1 degradation in vitro. Furthermore, an increase in BACE1 SUMOylation is associated with the progression of AD pathology, while its phosphorylation and ubiquitination are decreased in an AD mouse model. Our findings suggest that BACE1 SUMOylation reciprocally influences its phosphorylation and competes against its ubiquitination, which might provide a new insight into the regulations of BACE1 activity and Aß accumulation.
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Enfermedad de Alzheimer , Secretasas de la Proteína Precursora del Amiloide , Animales , Ratones , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Fosforilación , Sumoilación , Ubiquitinación , HumanosRESUMEN
PURPOSE: Summarize the characteristics of a large cohort of BCG disease and compare differences in clinical characteristics and outcomes among different genotypes and between primary immunodeficiency disease (PID) and patients without identified genetic etiology. METHODS: We collected information on patients with BCG disease in our center from January 2015 to December 2020 and divided them into four groups: chronic granulomatous disease (CGD), Mendelian susceptibility to mycobacterial disease (MSMD), severe combined immunodeficiency disease (SCID), and gene negative group. RESULTS: A total of 134 patients were reviewed, and most of them had PID. A total of 111 (82.8%) patients had 18 different types of pathogenic gene mutations, most of whom (91.0%) were classified with CGD, MSMD, and SCID. CYBB was the most common gene mutation (52/111). BCG disease behaves differently in individuals with different PIDs. Significant differences in sex (P < 0.001), age at diagnosis (P = 0.013), frequency of recurrent fever (P = 0.007), and vaccination-homolateral axillary lymph node enlargement (P = 0.039) and infection severity (P = 0.006) were noted among the four groups. The CGD group had the highest rate of males and the oldest age at diagnosis. The MSMD group had the highest probability of disseminated infection (48.3%). The course of anti-tuberculosis treatment and the survival time between patients with PID and without identified genetic etiology were similar. CONCLUSION: Greater than 80% of BCG patients have PID; accordingly, gene sequencing should be performed in patients with BCG disease for early diagnosis. BCG disease behaves differently in patients with different types of PID. Patients without identified genetic etiology had similar outcomes to PID patients, which hints that they may have pathogenic gene mutations that need to be discovered.
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Enfermedad Granulomatosa Crónica , Infecciones por Mycobacterium , Inmunodeficiencia Combinada Grave , Niño , Humanos , Masculino , Pueblos del Este de Asia , Enfermedad Granulomatosa Crónica/diagnóstico , Enfermedad Granulomatosa Crónica/epidemiología , Enfermedad Granulomatosa Crónica/genética , Infecciones por Mycobacterium/diagnóstico , Infecciones por Mycobacterium/epidemiología , Infecciones por Mycobacterium/genética , Estudios Retrospectivos , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/epidemiología , Inmunodeficiencia Combinada Grave/genética , FemeninoRESUMEN
PURPOSE: Pediatric patients with inborn errors of immunity (IEI) undergoing umbilical cord blood transplantation (UCBT) are at risk of early mortality. Our aim was to develop and validate a prediction model for early mortality after UCBT in pediatric IEI patients based on pretransplant factors. METHODS: Data from 230 pediatric IEI patients who received their first UCBT between 2014 and 2021 at a single center were analyzed retrospectively. Data from 2014-2019 and 2020-2021 were used as training and validation sets, respectively. The primary outcome of interest was early mortality. Machine learning algorithms were used to identify risk factors associated with early mortality and to build predictive models. The model with the best performance was visualized using a nomogram. Discriminative ability was measured using the area under the curve (AUC) and decision curve analysis. RESULTS: Fifty days was determined as the cutoff for distinguishing early mortality in pediatric IEI patients undergoing UCBT. Of the 230 patients, 43 (18.7%) suffered early mortality. Multivariate logistic regression with pretransplant albumin, CD4 (absolute count), elevated C-reactive protein, and medical history of sepsis showed good discriminant AUC values of 0.7385 (95% CI, 0.5824-0.8945) and 0.827 (95% CI, 0.7409-0.9132) in predicting early mortality in the validation and training sets, respectively. The sensitivity and specificity were 0.5385 and 0.8154 for validation and 0.7667 and 0.7705 for training, respectively. The final model yielded net benefits across a reasonable range of risk thresholds. CONCLUSION: The developed nomogram can predict early mortality in pediatric IEI patients undergoing UCBT.
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Trasplante de Células Madre de Sangre del Cordón Umbilical , Trasplante de Células Madre Hematopoyéticas , Sepsis , Humanos , Niño , Nomogramas , Estudios Retrospectivos , Trasplante de Células Madre de Sangre del Cordón Umbilical/efectos adversosRESUMEN
Resting-state functional magnetic resonance imaging (rs-fMRI) helps characterize regional interactions that occur in the human brain at a resting state. Existing research often attempts to explore fMRI biomarkers that best predict brain disease progression using machine/deep learning techniques. Previous fMRI studies have shown that learning-based methods usually require a large amount of labeled training data, limiting their utility in clinical practice where annotating data is often time-consuming and labor-intensive. To this end, we propose an unsupervised contrastive graph learning (UCGL) framework for fMRI-based brain disease analysis, in which a pretext model is designed to generate informative fMRI representations using unlabeled training data, followed by model fine-tuning to perform downstream disease identification tasks. Specifically, in the pretext model, we first design a bi-level fMRI augmentation strategy to increase the sample size by augmenting blood-oxygen-level-dependent (BOLD) signals, and then employ two parallel graph convolutional networks for fMRI feature extraction in an unsupervised contrastive learning manner. This pretext model can be optimized on large-scale fMRI datasets, without requiring labeled training data. This model is further fine-tuned on to-be-analyzed fMRI data for downstream disease detection in a task-oriented learning manner. We evaluate the proposed method on three rs-fMRI datasets for cross-site and cross-dataset learning tasks. Experimental results suggest that the UCGL outperforms several state-of-the-art approaches in automated diagnosis of three brain diseases (i.e., major depressive disorder, autism spectrum disorder, and Alzheimer's disease) with rs-fMRI data.