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BACKGROUND: Neutrophilic inflammation, characterized by dysregulated neutrophil activation, triggers a variety of inflammatory responses such as chemotactic infiltration, oxidative bursts, degranulation, neutrophil extracellular traps (NETs) formation, and delayed turnover. This type of inflammation is pivotal in the pathogenesis of acute respiratory distress syndrome (ARDS) and psoriasis. Despite current treatments, managing neutrophil-associated inflammatory symptoms remains a significant challenge. AIM OF REVIEW: This review emphasizes the role of cyclin-dependent kinases (CDKs) in neutrophil activation and inflammation. It aims to highlight the therapeutic potential of repurposing CDK inhibitors to manage neutrophilic inflammation, particularly in ARDS and psoriasis. Additionally, it discusses the necessary precautions for the clinical application of these inhibitors due to potential off-target effects and the need for dose optimization. KEY SCIENTIFIC CONCEPTS OF REVIEW: CDKs regulate key neutrophilic functions, including chemotactic responses, degranulation, NET formation, and apoptosis. Repurposing CDK inhibitors, originally developed for cancer treatment, shows promise in controlling neutrophilic inflammation. Clinical anticancer drugs, palbociclib and ribociclib, have demonstrated efficacy in treating neutrophilic ARDS and psoriasis by targeting off-label pathways, phosphoinositide 3-kinase (PI3K) and phosphodiesterase 4 (PDE4), respectively. While CDK inhibitors offer promising therapeutic benefits, their clinical repurposing requires careful consideration of off-target effects and dose optimization. Further exploration and clinical trials are necessary to ensure their safety and efficacy in treating inflammatory conditions.
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PURPOSE: PCDH19 gene variants, termed PCDH19 clustering epilepsy, represent a distinct etiology of epilepsy. This study aimed to elucidate the clinical manifestations and explore the genotypes and phenotypes of children affected by PCDH19 clustering epilepsy. METHODS: This retrospective study included medical history, magnetic resonance imaging, video-electroencephalography, and genetic analysis of patients diagnosed with PCDH19 Clustering Epilepsy at the Neurology Department of Beijing Children's Hospital from 2015 to 2023. Chi-square tests and logistic regression analyses were conducted to study the factors associated with developmental delay in patients. RESULTS: The age at seizure onset ranged from 5 to 61 months among all 30 patients (median 14 months; IQR 9.25-22.5 months). Among the 30 patients, 29 were female and 1 was male. Clusters of seizures and fever-triggered seizures were observed, with the most prevalent seizure types being focal to bilateral tonic-clonic seizures (FBTCS). Seizures were successfully controlled in 15 patients. Unfortunately, one patient experienced a sudden unexpected death in epilepsy (SUDEP). Additionally, 14 patients had hereditary mutations, 14 had de novo mutations, 1 had both hereditary and de novo mutations, and 1 male patient had a mosaic component mutation of 0.64 due to a somatic mutation. Developmental delays were identified in 17 patients (56.7 %), and 6 patients (20 %) were diagnosed with autism spectrum disorder (ASD). Among the 17 patients, 9 experienced developmental delays before the onset of epilepsy, while 8 were initially normal but later developed developmental delays during disease progression. Statistical analysis revealed that the presence of drug-resistant epilepsy was an independent risk factor for the occurrence of developmental delays (P = 0.020, OR = 9.758, 95 % CI (1.440-66.111)). CONCLUSION: In this study, 13 new potential rare pathogenic variations in PCDH19 clustering epilepsy were identified. The clinical features observed in patients are consistent with known phenotypic features, and we found that patients with drug-resistant epilepsy are more likely to have developmental delays. The severity of the phenotype in patients with PCDH19 variants ranged from drug-responsive seizures to refractory epilepsy.
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Colistin is commonly regarded as the "last-resort" antibiotic for combating life-threatening infections caused by multidrug-resistant (MDR) gram-negative bacteria. Neurotoxicity is a potential adverse event associated with colistin application in clinical settings, yet the exact molecular mechanisms remain unclear. This study examined the detrimental impact of colistin exposure on PC12 cells and the associated molecular mechanisms. Colistin treatment at concentrations of 0-400 µM decreased cell viability and induced apoptotic cell death in both time- and concentration-dependent manners. Exposure to colistin triggered the production of reactive oxygen species (ROS) and caused oxidative stress damage in PC12 cells. N-acetylcysteine (NAC) supplementation partially mitigated the cytotoxic and apoptotic outcomes of colistin. Evidence of mitochondrial dysfunction was observed through the dissipation of membrane potential. Additionally, colistin treatment upregulated the expression of AhR and CYP1A1 mRNAs in PC12 cells. Pharmacological inhibition of AhR (e.g., using α-naphthoflavone) or intervention with the CYP1A1 gene significantly decreased the production of ROS induced by colistin, subsequently lowering caspase activation and cell apoptosis. In conclusion, our findings demonstrate, for the first time, that the activation of the AhR/CYP1A1 pathway contributes partially to colistin-induced oxidative stress and apoptosis, offering insights into the cytotoxic effects of colistin.
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The mosquito Aedes aegypti is a prominent vector for arboviruses, but the breadth of mosquito viruses that infects this specie is not fully understood. In the broadest global survey to date of over 200 Ae. aegypti small RNA samples, we detected viral small interfering RNAs (siRNAs) and Piwi interacting RNAs (piRNAs) arising from mosquito viruses. We confirmed that most academic laboratory colonies of Ae. aegypti lack persisting viruses, yet two commercial strains were infected by a novel tombus-like virus. Ae. aegypti from North to South American locations were also teeming with multiple insect viruses, with Anphevirus and a bunyavirus displaying geographical boundaries from the viral small RNA patterns. Asian Ae. aegypti small RNA patterns indicate infections by similar mosquito viruses from the Americas and reveal the first wild example of dengue virus infection generating viral small RNAs. African Ae. aegypti also contained various viral small RNAs including novel viruses only found in these African substrains. Intriguingly, viral long RNA patterns can differ from small RNA patterns, indicative of viral transcripts evading the mosquitoes' RNA interference (RNAi) machinery. To determine whether the viruses we discovered via small RNA sequencing were replicating and transmissible, we infected C6/36 and Aag2 cells with Ae. aegypti homogenates. Through blind passaging, we generated cell lines stably infected by these mosquito viruses which then generated abundant viral siRNAs and piRNAs that resemble the native mosquito viral small RNA patterns. This mosquito small RNA genomics approach augments surveillance approaches for emerging infectious diseases.
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Vector competence defines the ability of a vector to acquire, host, and transmit a pathogen. Understanding the molecular determinants of the mosquitos' competence to host dengue virus (DENV) holds promise to prevent its transmission. To this end, we employed RNA-seq to profile mRNA transcripts of the female Aedes aegypti mosquitos feeding on naïve vs viremic mouse. While most transcripts (12,634) did not change their abundances, 360 transcripts showed decreases. Biological pathway analysis revealed representatives of the decreased transcripts involved in the wnt signaling pathway and hippo signaling pathway. One thousand three hundred fourteen transcripts showed increases in abundance and participate in 21 biological pathways including amino acid metabolism, carbon metabolism, fatty acid metabolism, and oxidative phosphorylation. Inhibition of oxidative phosphorylation with antimycin A reduced oxidative phosphorylation activity and ATP concentration associated with reduced DENV replication in the Aedes aegypti cells. Antimycin A did not affect the amounts of the non-structural proteins 3 and 5, two major components of the replication complex. Ribavirin, an agent that reduces GTP concentration, recapitulated the effects of reduced ATP concentration on DENV replication. Knocking down one of the oxidative phosphorylation components, ATP synthase subunit ß, reduced DENV replication in the mosquitos. In summary, our results suggest that DENV enhances metabolic pathways in the female Aedes aegypti mosquitos to supply nutrients and energy for virus replication. ATP synthase subunit ß knockdown might be exploited to reduce the mosquitos' competence to host and transmit DENV. IMPORTANCE: Through evolution, the mosquito-borne viruses have adapted to the blood-feeding behaviors of their opportunist hosts to fulfill a complete lifecycle in humans and mosquitos. Disruption in the mosquitos' ability to host these viruses offers strategies to prevent diseases caused by them. With the advent of genomic tools, we discovered that dengue virus (DENV) benefited from the female mosquitos' bloodmeals for metabolic and energetic supplies for replication. Chemical or genetic disruption in these supplies reduced DENV replication in the female mosquitos. Our discovery can be exploited to produce genetically modified mosquitos, in which DENV infection leads to disruption in the supplies and thereby reduces replication and transmission. Our discovery might be extrapolated to prevent mosquito-borne virus transmission and the diseases they cause.
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Aedes , Virus del Dengue , Dengue , Replicación Viral , Aedes/virología , Animales , Femenino , Virus del Dengue/fisiología , Dengue/transmisión , Dengue/virología , Dengue/metabolismo , Fosforilación Oxidativa , Ratones , Mosquitos Vectores/virología , Adenosina Trifosfato/metabolismoRESUMEN
Constructing carbonaceous materials with versatile surface structures still remains a great challenge due to limited self-assembly methods, especially at high temperatures. This study presents an innovative template evolution induced relay self-assembly (TEIRSA) for the fabrication of large polyoxometalate (POM)-mixed carbonaceous nanosheets featuring surface mesoporous structures through hydrothermal carbonization (HTC). The method employs POM and acetone as additives, cleverly modulating the Ostwald ripening-like process of P123-based micelles, effectively addressing the instability challenges inherent in traditional soft-template methods, especially within the demanding carbohydrate HTC process. Additionally, this method allows for the independent regulation of surface architectures through the selection of organic additives. The resulting nanosheets exhibit diverse surface morphologies, including surface spherical mesopores, 1D open channels, and smooth surfaces. Their unexpectedly versatile properties have swiftly garnered recognition, showing potential in the application of lithium-sulfur batteries.
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Geopolymer concrete (GPC) represents an innovative green and low-carbon construction material, offering a viable alternative to ordinary Portland cement concrete (OPC) in building applications. However, existing studies tend to overlook the recyclability aspect of GPC for future use. Various structural applications necessitate the use of concrete with distinct strength characteristics. The recyclability of the parent concrete is influenced by these varying strengths. This study examined the recycling potential of GPC across a spectrum of strength grades (40, 60, 80, and 100 MPa, marked as C40, C60, C80, and C100) when subjected to freeze-thaw conditions. Recycling 5-16 mm recycled geopolymer coarse aggregate (RGAs) from GPC prepared from 5 to 16 mm natural coarse aggregates (NAs). The cementitious material comprised 60% metakaolin and 40% slag, with natural gravel serving as the NAs, and the alkali activator consisting of sodium hydroxide solution and sodium silicate solution. The strength of the GPC was modulated by altering the Na/Al ratio. After 350 freeze-thaw cycles, the GPC specimens underwent crushing, washing, and sieving to produce RGAs. Subsequently, their physical properties (apparent density, water absorption, crushing index, and attached mortar content and microstructure (microhardness, SEM, and XRD) were thoroughly examined. The findings indicated that GPC with strength grades of C100, C80, and C60 were capable of enduring 350 freeze-thaw cycles, in contrast to C40, which did not withstand these conditions. RGAs derived from GPC of strength grades C100 and C80 complied with the criteria for Class II recycled aggregates, whereas RGAs produced from GPC of strength grade C60 aligned with the Class III level. A higher-strength grade in the parent concrete correlated with enhanced performance characteristics in the resulting recycled aggregates.
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In this paper, four water-binder ratios (w/b) of 0.29, 0.33, 0.39, and 0.46 were designed. A variable test temperature was implemented in the drying-wetting cycle test according to the temperature fluctuations in the actual service environment, and the constant temperature test was established as the control group. The mechanical properties and chloride corrosion resistance of concrete with different w/b ratios under variable temperature drying-wetting cycles, as well as the microstructure changes, phase composition, and damage mechanism inside the concrete, were investigated. The results showed that the mechanical properties of concrete increased first and then decreased with drying-wetting cycles increasing, whereas the chloride corrosion resistance continued to decline. A higher w/b exacerbated the deterioration of the concrete performance. A higher w/b increased the porosity, chloride diffusion depth, and chloride content, thus reducing the resistance of chloride corrosion. Compared with w/b = 0.29, the compressive strength, splitting tensile strength, mass, and relative dynamic elasticity modulus of w/b = 0.46 exposed to 60 drying-wetting cycles decreased by 54.50%, 52.44%, 0.96%, and 6.50%, respectively, while the porosity, peak chloride content, and erosion depth increased by 45.12%, 70.45%, and 45.00%. Compared with the drying-wetting cycle with a constant temperature, the cumulative damage caused by the drying-wetting cycle with a variable temperature was greater, resulting in more severe deterioration of concrete performance. The increase in the test temperature significantly accelerated the diffusion rate, penetration depth, and chemical binding capacity of chloride ions. After 60 drying-wetting cycles, the peak chlorine content and erosion depth of w/b = 0.46 under variable temperature cycles were 15.38% and 10.32% higher than those under a constant temperature, while the compressive strength, splitting tensile strength, mass, and relative dynamic elastic modulus were reduced by 7.76%, 14.81%, 0.33%, and 2.40%, respectively. Microscopic analysis confirmed that higher w/b and variable temperature cycles accelerated the decay of mechanical properties and the decline of chloride corrosion resistance. According to the numerical fitting analysis, the w/b should be 0.29~0.39 under the condition that the mechanical properties and chloride corrosion resistance of concrete are met.
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This study focused on miR-486-5p in atrial fibrillation (AF) evaluating its clinical significance and revealing its regulatory mechanism in cardiac fibroblasts, aiming to explore a novel biomarker for AF. The study enrolled 131 AF patients and 77 non-AF individuals. With the help of polymerase chain reaction (PCR), the expression of miR-486-5p was evaluated. The significance of miR-486-5p in the diagnosis of AF and the occurrence of left atrial fibrosis (LAF) was assessed by receiver operating curve (ROC) and logistic analyses. The regulatory effect and mechanism of miR-486-5p on cardiac fibrosis were investigated in human cardiac fibroblasts treated with angiotensin II. miR-486-5p was significantly upregulated in AF patients and discriminated AF patients from non-AF individuals. Increasing miR-486-5p showed a significant association with decreasing left ventricular ejection fraction (LVEF), increasing left atrial diameter (LAD) and left ventricular end-diastolic diameter (LVEDd), and the high incidence of LAF in AF patients. Moreover, miR-486-5p was identified as a risk factor for LAF and could distinguish AF patients with LAF and without LAF. In cardiac fibroblasts, angiotensin II induced the upregulation of miR-486-5p and promoted cell proliferation, migration, and collagen synthesis. miR-486-5p negatively regulated forkhead box O1 (FOXO1) and its knockdown could reverse the promoted effect of angiotensin II. FOXO1 alleviated the effect of miR-486-5p, and the miR-486-5p/FOXO1 could activate PI3K/Akt signaling. The activation of PI3K/Akt signaling alleviated the enhanced proliferation, migration, and collagen synthesis of cardiac fibroblasts induced by angiotensin II, and its inhibition showed opposite effects. Increased miR-486-5p served as a biomarker for the diagnosis and development prediction of AF. miR-486-5p regulated cardiac fibroblast viability and collagen synthesis via modulating the PI3K/Akt signaling through targeting FOXO1.
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C-type lectins (CTLs) are a family of carbohydrate-binding proteins and an important component of mosquito saliva. Although CTLs play key roles in immune activation and viral pathogenesis, little is known about their role in regulating dengue virus (DENV) infection and transmission. In this study, we established a homozygous CTL16 knockout Aedes aegypti mutant line using CRISPR/Cas9 to study the interaction between CTL16 and viruses in mosquito vectors. Furthermore, mouse experiments were conducted to confirm the transmission of DENV by CTL16-/- A. aegypti mutants. We found that CTL16 was mainly expressed in the medial lobe of the salivary glands (SGs) in female A. aegypti. CTL16 knockout increased DENV replication and accumulation in the SGs of female A. aegypti, suggesting that CTL16 plays an important role in DENV transmission. We also found a reduced expression of immunodeficiency and Janus kinase/signal transducer and activator of transcription pathway components correlated with increased DENV viral titer, infection rate, and transmission efficiency in the CTL16 mutant strain. The findings of this study provide insights not only for guiding future investigations on the influence of CTLs on immune responses in mosquitoes but also for developing novel mutants that can be used as vector control tools.
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BACKGROUND: Autoimmune hepatitis (AIH) is an immune-mediated hepatic disease associated with intense complications. AIH is more common in females and needs effective drugs to treat. Guizhi Fuling Wan (GZFLW) is a traditional Chinese herbal formula used to treat various gynecologic diseases. In this study, we aim to extend the new use of GZFLW for AIH. METHODS: The tandem MS-based analysis was used to identify secondary metabolites in GZFLW. Therapeutic effects of GZFLW were tested in a concanavalin A (Con A)-induced AIH model in mice. Ethnopharmacological mechanisms underlying the antiapoptotic, antioxidant, and immunomodulatory protective effects were determined. RESULTS: Oral administration of GZFLW attenuates AIH in a Con A-induced hepatotoxic model in vivo. The tandem MS-based analysis identified 15 secondary metabolites in GZFLW. The Con A-induced AIH syndromes, including hepatic apoptosis, inflammation, reactive oxygen species accumulation, function failure, and mortality, were significantly alleviated by GZFLW in mice. Mechanistically, GZFLW restrained the caspase-dependent apoptosis, restored the antioxidant system, and decreased pro-inflammatory cytokine production in the livers of Con A-treated mice. Besides, GZFLW repressed the Con A-induced hepatic infiltration of inflammatory cells, splenic T cell activation, and splenomegaly in mice. CONCLUSIONS: Our findings demonstrate the applicable potential of GZFLW in treating AIH. It prompts further investigation of GZFLW as a treatment option for AIH and possibly other hepatic diseases.
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INTRODUCTION: Overwhelming neutrophil activation and oxidative stress significantly contribute to acute respiratory distress syndrome (ARDS) pathogenesis. However, the potential of repurposing ribociclib, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor used clinically in cancer treatment, for treating neutrophilic ARDS remains uncertain. This study illustrated the ability and underlying mechanism of ribociclib for treating ARDS and neutrophilic inflammation. METHODS: Primary human neutrophils were used to determine the therapeutic effects of ribociclib on respiratory bursts, chemotactic responses, and inflammatory signaling. In vitro and silico analyses were performed to determine the underlying molecular mechanisms. The potential of ribociclib repurposing was evaluated using an in vivo ARDS model in lipopolysaccharide (LPS)-primed mice. RESULTS: We found that treatment using ribociclib markedly limited overabundant oxidative stress (reactive oxygen species [ROS]) production and chemotactic responses (integrin levels and adhesion) in activated human neutrophils. Ribociclib was also shown to act as a selective inhibitor of phosphodiesterase 4 (PDE4), thereby promoting the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway, leading to the inhibition of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) phosphorylation, and calcium influx. Notably, prophylactic administration and post-treatment with ribociclib ameliorated neutrophil infiltration, lung inflammation, accumulation of oxidative stress, pulmonary destruction, and mortality in mice with LPS-induced ARDS. CONCLUSION: We demonstrated for the first time that ribociclib serves as a novel PDE4 inhibitor for treating neutrophilic inflammation and ARDS. The repurposing ribociclib and targeting neutrophilic PDE4 offer a potential off-label alternative for treating lung lesions and other inflammatory conditions.
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Aminopiridinas , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Inflamación , Lipopolisacáridos , Neutrófilos , Inhibidores de Fosfodiesterasa 4 , Purinas , Síndrome de Dificultad Respiratoria , Aminopiridinas/farmacología , Purinas/farmacología , Animales , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Inhibidores de Fosfodiesterasa 4/farmacología , Humanos , Ratones , Inflamación/tratamiento farmacológico , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Estrés Oxidativo/efectos de los fármacos , Modelos Animales de Enfermedad , Especies Reactivas de Oxígeno/metabolismo , Masculino , AMP Cíclico/metabolismo , Transducción de Señal/efectos de los fármacos , Activación Neutrófila/efectos de los fármacosAsunto(s)
Marcapaso Artificial , Escoliosis , Humanos , Escoliosis/terapia , Escoliosis/complicaciones , Femenino , Resultado del Tratamiento , MasculinoRESUMEN
BACKGROUND: Although whole-genome sequencing (WGS) is the preferred genotyping method for most genomic analyses, limitations are often experienced when studying genomes characterized by a high percentage of repetitive elements, high linkage, and recombination deserts. The Asian tiger mosquito (Aedes albopictus), for example, has a genome comprising up to 72% repetitive elements, and therefore we set out to develop a single-nucleotide polymorphism (SNP) chip to be more cost-effective. Aedes albopictus is an invasive species originating from Southeast Asia that has recently spread around the world and is a vector for many human diseases. Developing an accessible genotyping platform is essential in advancing biological control methods and understanding the population dynamics of this pest species, with significant implications for public health. METHODS: We designed a SNP chip for Ae. albopictus (Aealbo chip) based on approximately 2.7 million SNPs identified using WGS data from 819 worldwide samples. We validated the chip using laboratory single-pair crosses, comparing technical replicates, and comparing genotypes of samples genotyped by WGS and the SNP chip. We then used the chip for a population genomic analysis of 237 samples from 28 sites in the native range to evaluate its usefulness in describing patterns of genomic variation and tracing the origins of invasions. RESULTS: Probes on the Aealbo chip targeted 175,396 SNPs in coding and non-coding regions across all three chromosomes, with a density of 102 SNPs per 1 Mb window, and at least one SNP in each of the 17,461 protein-coding genes. Overall, 70% of the probes captured the genetic variation. Segregation analysis found that 98% of the SNPs followed expectations of single-copy Mendelian genes. Comparisons with WGS indicated that sites with genotype disagreements were mostly heterozygotes at loci with WGS read depth < 20, while there was near complete agreement with WGS read depths > 20, indicating that the chip more accurately detects heterozygotes than low-coverage WGS. Sample sizes did not affect the accuracy of the SNP chip genotype calls. Ancestry analyses identified four to five genetic clusters in the native range with various levels of admixture. CONCLUSIONS: The Aealbo chip is highly accurate, is concordant with genotypes from WGS with high sequence coverage, and may be more accurate than low-coverage WGS.
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Aedes , Mosquitos Vectores , Humanos , Animales , Genotipo , Mosquitos Vectores/genética , Heterocigoto , Aedes/genéticaAsunto(s)
Ablación por Catéter , Embolia Aérea , Infarto del Miocardio , Taquicardia Ventricular , Humanos , Enfermedad Aguda , Ablación por Catéter/métodos , Ablación por Catéter/efectos adversos , Embolia Aérea/etiología , Complicaciones Intraoperatorias/etiología , Infarto del Miocardio/complicaciones , Infarto del Miocardio/cirugía , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/cirugía , Taquicardia Ventricular/cirugía , Taquicardia Ventricular/etiologíaRESUMEN
PURPOSE: PAFAH1B1, also known as LIS1, is associated with type I lissencephaly in humans, which is a severe developmental brain disorder believed to result from abnormal neuronal migration. Our objective was to characterize the genotypes and phenotypes of PAFAH1B1-related epilepsy. METHODS: We conducted a comprehensive analysis of the medical histories, magnetic resonance imaging findings, and video-electroencephalogram recordings of 11 patients with PAFAH1B1 variants at the Neurology Department of Beijing Children's Hospital from June 2017 to November 2022. RESULTS: The age of onset of epilepsy ranged from 2 months to 4 years, with a median onset age of 5 months. Among these 11 patients (comprising 6 boys and 5 girls), all were diagnosed with lissencephaly type 1. Predominantly, generalized tonic-clonic and spasm seizures characterized PAFAH1B1-related epilepsy. Additionally, 10 out of the 11 patients exhibited severe developmental disorders. All patients exhibited de novo variants, with three individuals displaying 17p13.3 deletions linked to haploinsufficiency of PAFAH1B1. Four variants were previously unreported. Notably, three patients with 17p13.3 deletions displayed developmental delay and drug resistant epilepsy, whereas the single patient with mild developmental delay, Intelligence Quotient (IQ) 57 and well-controlled seizures had a splicing-site variant. CONCLUSION: The severity of the phenotype in patients with PAFAH1B1 variants ranged from drug-responsive seizures to severe epileptic encephalopathy. These observations underscore the clinical heterogeneity of PAFAH1B1-related disorders, with most patients exhibiting developmental disorders. Moreover, the severity of epilepsy appears to be linked to genetic variations.
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1-Alquil-2-acetilglicerofosfocolina Esterasa , Epilepsia , Proteínas Asociadas a Microtúbulos , Humanos , Masculino , Femenino , 1-Alquil-2-acetilglicerofosfocolina Esterasa/genética , Preescolar , Lactante , Epilepsia/genética , Epilepsia/fisiopatología , Electroencefalografía , Fenotipo , Imagen por Resonancia Magnética , Discapacidades del Desarrollo/genética , NiñoRESUMEN
PURPOSE: This study used optical coherence tomography scanning and 3D reconstruction of the macular region in high myopia to examine more thoroughly and carefully the differences between high myopia-related macular complications with and without dome-shape macula (DSM) and to determine whether the DSM's fine structure has an effect on them. METHODS: Retrospective analysis of the medical records of 345 eyes with high myopia who underwent an optical coherence tomography (OCT) examination. They were divided into the DSM group (69 eyes) and the group without DSM (276 eyes). Macular complications between the two groups were compared. The height of the DSM and the diameter of the dome base were measured. And then the association between DSM type, protrusion height and macular problems were analyzed. RESULTS: Epiretinal membrane (ERM) and extrafoveal schisis occurred more frequently in the DSM group, but the was no statistically significant difference in the frequency of foveal schisis between the two groups. The majority of eyes in the DSM categorization had a horizontal oval-shaped domain. In the DSM group, there was no evident difference in the percentage of eyes with macular complications in the groups below 150â um and above 150â um. CONCLUSIONS: OCT examination-based fine macular structure analysis reveals that DSM affects various macular problems in distinct ways. DSM could increase the risk of extrafoveal schisis and ERM while decreasing the risk of foveal schisis. The height of the DSM had no obvious impact on the prevalence of macular complications.
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BACKGROUND: Mitochondrial dysfunction and toxic protein aggregates have been shown to be key features in the pathogenesis of neurodegenerative diseases, such as Parkinson's disease (PD). Functional analysis of genes linked to PD have revealed that the E3 ligase Parkin and the mitochondrial kinase PINK1 are important factors for mitochondrial quality control. PINK1 phosphorylates and activates Parkin, which in turn ubiquitinates mitochondrial proteins priming them and the mitochondrion itself for degradation. However, it is unclear whether dysregulated mitochondrial degradation or the toxic build-up of certain Parkin ubiquitin substrates is the driving pathophysiological mechanism leading to PD. The iron-sulphur cluster containing proteins CISD1 and CISD2 have been identified as major targets of Parkin in various proteomic studies. METHODS: We employed in vivo Drosophila and human cell culture models to study the role of CISD proteins in cell and tissue viability as well as aged-related neurodegeneration, specifically analysing aspects of mitophagy and autophagy using orthogonal assays. RESULTS: We show that the Drosophila homolog Cisd accumulates in Pink1 and parkin mutant flies, as well as during ageing. We observed that build-up of Cisd is particularly toxic in neurons, resulting in mitochondrial defects and Ser65-phospho-Ubiquitin accumulation. Age-related increase of Cisd blocks mitophagy and impairs autophagy flux. Importantly, reduction of Cisd levels upregulates mitophagy in vitro and in vivo, and ameliorates pathological phenotypes in locomotion, lifespan and neurodegeneration in Pink1/parkin mutant flies. In addition, we show that pharmacological inhibition of CISD1/2 by rosiglitazone and NL-1 induces mitophagy in human cells and ameliorates the defective phenotypes of Pink1/parkin mutants. CONCLUSION: Altogether, our studies indicate that Cisd accumulation during ageing and in Pink1/parkin mutants is a key driver of pathology by blocking mitophagy, and genetically and pharmacologically inhibiting CISD proteins may offer a potential target for therapeutic intervention.