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The N6-methyladenosine (m6A) RNA modification is used widely to alter the fate of mRNAs. Here we demonstrate that the C. elegans writer METT-10 (the ortholog of mouse METTL16) deposits an m6A mark on the 3' splice site (AG) of the S-adenosylmethionine (SAM) synthetase pre-mRNA, which inhibits its proper splicing and protein production. The mechanism is triggered by a rich diet and acts as an m6A-mediated switch to stop SAM production and regulate its homeostasis. Although the mammalian SAM synthetase pre-mRNA is not regulated via this mechanism, we show that splicing inhibition by 3' splice site m6A is conserved in mammals. The modification functions by physically preventing the essential splicing factor U2AF35 from recognizing the 3' splice site. We propose that use of splice-site m6A is an ancient mechanism for splicing regulation.
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Adenosina/análogos & derivados , Sitios de Empalme de ARN/genética , Empalme del ARN/genética , Factor de Empalme U2AF/metabolismo , Adenosina/metabolismo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Caenorhabditis elegans/genética , Secuencia Conservada/genética , Dieta , Células HeLa , Humanos , Intrones/genética , Metionina Adenosiltransferasa , Metilación , Metiltransferasas/química , Ratones , Mutación/genética , Conformación de Ácido Nucleico , Unión Proteica , Precursores del ARN/química , Precursores del ARN/genética , Precursores del ARN/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Nuclear Pequeño , S-Adenosilmetionina , Transcriptoma/genéticaRESUMEN
Neurogenesis is initiated by basic helix-loop-helix proneural proteins. Here, we show that Actin-related protein 6 (Arp6), a core component of the H2A.Z exchange complex SWR1, interacts with proneural proteins and is crucial for efficient onset of proneural protein target gene expression. Arp6 mutants exhibit reduced transcription in sensory organ precursors (SOPs) downstream of the proneural protein patterning event. This leads to retarded differentiation and division of SOPs and smaller sensory organs. These phenotypes are also observed in proneural gene hypomorphic mutants. Proneural protein expression is not reduced in Arp6 mutants. Enhanced proneural gene expression fails to rescue retarded differentiation in Arp6 mutants, suggesting that Arp6 acts downstream of or in parallel with proneural proteins. H2A.Z mutants display Arp6-like retardation in SOPs. Transcriptomic analyses demonstrate that loss of Arp6 and H2A.Z preferentially decreases expression of proneural protein-activated genes. H2A.Z enrichment in nucleosomes around the transcription start site before neurogenesis correlates highly with greater activation of proneural protein target genes by H2A.Z. We propose that upon proneural protein binding to E-box sites, H2A.Z incorporation around the transcription start site allows rapid and efficient activation of target genes, promoting rapid neural differentiation.
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Proteínas de Arabidopsis , Arabidopsis , Activación Transcripcional , Actinas/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Histonas/metabolismo , Nucleosomas/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismoRESUMEN
Severe respiratory infections can result in acute respiratory distress syndrome (ARDS)1. There are no effective pharmacological therapies that have been shown to improve outcomes for patients with ARDS. Although the host inflammatory response limits spread of and eventually clears the pathogen, immunopathology is a major contributor to tissue damage and ARDS1,2. Here we demonstrate that respiratory viral infection induces distinct fibroblast activation states, which we term extracellular matrix (ECM)-synthesizing, damage-responsive and interferon-responsive states. We provide evidence that excess activity of damage-responsive lung fibroblasts drives lethal immunopathology during severe influenza virus infection. By producing ECM-remodelling enzymes-in particular the ECM protease ADAMTS4-and inflammatory cytokines, damage-responsive fibroblasts modify the lung microenvironment to promote robust immune cell infiltration at the expense of lung function. In three cohorts of human participants, the levels of ADAMTS4 in the lower respiratory tract were associated with the severity of infection with seasonal or avian influenza virus. A therapeutic agent that targets the ECM protease activity of damage-responsive lung fibroblasts could provide a promising approach to preserving lung function and improving clinical outcomes following severe respiratory infections.
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Proteína ADAMTS4/metabolismo , Fibroblastos/enzimología , Fibroblastos/patología , Virus de la Influenza A/patogenicidad , Pulmón/patología , Pulmón/fisiopatología , Proteína ADAMTS4/antagonistas & inhibidores , Animales , Aves/virología , Matriz Extracelular/enzimología , Perfilación de la Expresión Génica , Humanos , Gripe Aviar/virología , Gripe Humana/patología , Gripe Humana/terapia , Gripe Humana/virología , Interferones/inmunología , Interferones/metabolismo , Antígenos Comunes de Leucocito/metabolismo , Pulmón/enzimología , Pulmón/virología , Ratones , Síndrome de Dificultad Respiratoria/enzimología , Síndrome de Dificultad Respiratoria/fisiopatología , Síndrome de Dificultad Respiratoria/terapia , Síndrome de Dificultad Respiratoria/virología , Estaciones del Año , Análisis de la Célula Individual , Células del Estroma/metabolismoRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Internal modification of RNAs with N6-methyladenosine (m6A) is a highly conserved means of gene expression control. While the METTL3/METTL14 heterodimer adds this mark on thousands of transcripts in a single-stranded context, the substrate requirements and physiological roles of the second m6A writer METTL16 remain unknown. Here we describe the crystal structure of human METTL16 to reveal a methyltransferase domain furnished with an extra N-terminal module, which together form a deep-cut groove that is essential for RNA binding. When presented with a random pool of RNAs, METTL16 selects for methylation-structured RNAs where the critical adenosine is present in a bulge. Mouse 16-cell embryos lacking Mettl16 display reduced mRNA levels of its methylation target, the SAM synthetase Mat2a. The consequence is massive transcriptome dysregulation in â¼64-cell blastocysts that are unfit for further development. This highlights the role of an m6A RNA methyltransferase in facilitating early development via regulation of SAM availability.
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Adenosina/análogos & derivados , Metiltransferasas/metabolismo , Metiltransferasas/ultraestructura , Adenosina/metabolismo , Animales , Desmetilación , Desarrollo Embrionario/genética , Desarrollo Embrionario/fisiología , Expresión Génica/genética , Células HEK293 , Humanos , Metionina Adenosiltransferasa , Metilación , Metiltransferasas/fisiología , Ratones/embriología , Ratones Noqueados , ARN , Procesamiento Postranscripcional del ARN/fisiología , ARN Mensajero/metabolismo , ARN Nuclear Pequeño/metabolismoRESUMEN
Because the mechanotransduction by stromal stiffness stimulates the rupture and repair of the nuclear envelope in pancreatic progenitor cells, accumulated genomic aberrations are under selection in the tumor microenvironment. Analysis of cell growth, micronuclei, and phosphorylated Ser-139 residue of the histone variant H2AX (γH2AX) foci linked to mechanotransduction pressure in vivo during serial orthotopic passages of mouse KrasLSL-G12D/+;Trp53flox/flox;Pdx1-Cre (KPC) cancer cells in the tumor and in migrating through the size-restricted 3-µm micropores. To search for pancreatic cancer cell-of-origin, analysis of single-cell data sets revealed that the extracellular matrix shaped an alternate route of acinar-ductal transdifferentiation of acinar cells into topoisomerase II α (TOP2A)-overexpressing cancer cells and derived subclusters with copy number amplifications in MYC-PTK2 (protein tyrosine kinase 2) locus and PIK3CA. High-PTK2 expression is associated with 171 differentially methylated CpG loci, 319 differentially expressed genes, and poor overall survival in The Cancer Genome Atlas-Pancreatic Adenocarcinoma cohort. Abolished RGD-integrin signaling by disintegrin KG blocked the PTK2 phosphorylation, increased cancer apoptosis, decreased vav guanine nucleotide exchange factor 1 (VAV1) expression, and prolonged overall survival in the KPC mice. Reduction of α-smooth muscle actin deposition in the CD248 knockout KPC mice remodeled the tissue stroma and down-regulated TOP2A expression in the epithelium. In summary, stromal stiffness induced the onset of cancer cells-of-origin by ectopic TOP2A expression, and the genomic amplification of MYC-PTK2 locus via alternative transdifferentiation of pancreatic progenitor cells is the vulnerability useful for disintegrin KG treatment.
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Inestabilidad Cromosómica , Progresión de la Enfermedad , Neoplasias Pancreáticas , Animales , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Ratones , Humanos , Carcinoma in Situ/patología , Carcinoma in Situ/genética , Carcinoma in Situ/metabolismo , Células del Estroma/metabolismo , Células del Estroma/patología , Microambiente Tumoral , Mecanotransducción Celular , Quinasa 1 de Adhesión FocalRESUMEN
Present-day islet culture methods provide short-term maintenance of cell viability and function, limiting access to islet transplantation. Attempts to lengthen culture intervals remain unsuccessful. A new method was developed to permit the long-term culture of islets. Human islets were embedded in polysaccharide 3D-hydrogel in cell culture inserts or gas-permeable chambers with serum-free CMRL 1066 supplemented media for up to 8 weeks. The long-term cultured islets maintained better morphology, cell mass, and viability at 4 weeks than islets in conventional suspension culture. In fact, islets cultured in the 3D-hydrogel retained ß cell mass and function on par with freshly isolated islets in vitro and, when transplanted into diabetic mice, restored glucose balance similar to fresh islets. Using gas-permeable chambers, the 3D-hydrogel culture method was scaled up over 10-fold and maintained islet viability and function, although the cell mass recovery rate was 50%. Additional optimization of scale-up methods continues. If successful, this technology could afford flexibility and expand access to islet transplantation, especially single-donor islet-after-kidney transplantation.
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Diabetes Mellitus Experimental , Trasplante de Islotes Pancreáticos , Islotes Pancreáticos , Humanos , Ratones , Animales , Técnicas de Cultivo de Célula , Hidrogeles , Insulina , Supervivencia CelularRESUMEN
AMP-activated protein kinase (AMPK) is a crucial cellular nutrient and energy sensor that maintains energy homeostasis. AMPK also governs cancer cell invasion and migration by regulating gene expression and activating multiple cellular signaling pathways. ADP-ribosylation factor 6 (Arf6) can be activated via nucleotide exchange by guanine-nucleotide-exchange factors (GEFs), and its activation also regulates tumor invasion and migration. By studying GEF-mediated Arf6 activation, we have elucidated that AMPK functions as a noncanonical GEF for Arf6 in a kinase-independent manner. Moreover, by examining the physiological role of the AMPK-Arf6 axis, we have determined that AMPK activates Arf6 upon glucose starvation and 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside (AICAR) treatment. We have further identified the binding motif in the C-terminal regulatory domain of AMPK that is responsible for promoting Arf6 activation and, thus, inducing cell migration and invasion. These findings reveal a noncanonical role of AMPK in which its C-terminal regulatory domain serves as a GEF for Arf6 during glucose deprivation.
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Factor 6 de Ribosilación del ADP , Glucosa , Factores de Ribosilacion-ADP/genética , Factores de Ribosilacion-ADP/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismoRESUMEN
INTRODUCTION: In real-world practice, most non-small cell lung cancer (NSCLC) patients receiving combined immunochemotherapy are exposed to short-course corticosteroids following immune checkpoint inhibitor (ICI) infusion to prevent chemotherapy-related adverse events. However, whether this early short-course corticosteroid use prevents immune-related adverse events (irAEs) remains unknown. METHODS: Between January 1st, 2015, and December 31st, 2020, NSCLC patients who received at least one cycle of ICI with or without chemotherapy were enrolled. Early short-course corticosteroids were defined as corticosteroids administered following ICI injection and before chemotherapy on the same day and no longer than 3 days afterward. The patients were categorized as either "corticosteroid group" or "non-corticosteroid group" depending on their exposure to early short-course corticosteroid. The frequencies of irAEs requiring systemic corticosteroid use and irAEs leading to ICI discontinuation were compared between the two groups, and exploratory survival analyses were performed. RESULTS: Among 252 eligible patients, 137 patients were categorized as "corticosteroid group" and 115 patients as "non-corticosteroid group." The corticosteroid group enriched patients in the first-line setting (n = 75, 54.7%), compared to the non-corticosteroid group (n = 28, 24.3%). Thirty patients (21.9%) in the corticosteroid group and 35 patients (30.4%) in the non-corticosteroid group developed irAEs requiring systemic corticosteroid use (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.35-1.18; p = 0.15). Eight patients (5.8%) in the corticosteroid group, as compared with 18 patients (15.7%) in the non-corticosteroid group, permanently discontinued ICI due to irAEs (OR, 0.34; 95% CI, 0.12-0.85; p = 0.013). CONCLUSION: Early short-course corticosteroids following each ICI injection may reduce the rate of irAEs that lead to ICIs discontinuation, warranting further investigation of its prophylactic use to mitigate clinically significant irAEs.
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Antineoplásicos Inmunológicos , Carcinoma de Pulmón de Células no Pequeñas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias Pulmonares/tratamiento farmacológico , Antineoplásicos Inmunológicos/efectos adversos , Estudios Retrospectivos , Corticoesteroides/efectos adversosRESUMEN
AIMS: Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are proposed to alleviate the development of inflammatory eye diseases. However, the association between SGLT2i and retinal vascular occlusion remains unclear. Therefore, this study aims to explore the effects of SGLT2i on the incidence of retinal vascular occlusion. MATERIALS AND METHODS: This retrospective cohort study analysed electronic medical records data from the largest multi-institutional database in Taiwan. Individuals who initiated SGLT2is and dipeptidyl peptidase 4 inhibitors (DPP4is) between 2016 and 2019 were included in our analysis. To conduct a homogenous comparison, inverse probability of treatment weighting with propensity scoring was employed. The primary outcome was retinal vascular occlusion, and the secondary outcomes were retinal vascular occlusion-related complications (macular oedema, vitreous haemorrhage, and tractional retinal detachment) and conditions requiring vitreoretinal intervention (intravitreal injection, retinal laser therapy, and vitrectomy). RESULTS: In total, 12,074 SGLT2i users and 39,318 DPP4i users were included. The incidence rate of retinal vascular occlusion in the SGLT2i and DPP4i groups was 1.2 (95% confidence interval [CI], 0.9-1.4) and 1.6 (95% CI, 1.3-1.8) events per 1000 person-years, respectively, which yielded a subdistribution hazard ratio (SHR) of 0.74 (95% CI, 0.55-0.99). Similar risk reductions were observed in the retinal vascular occlusion-related complications (SHR, 0.76; 95% CI, 0.69-0.84) and conditions requiring vitreoretinal intervention (SHR, 0.84; 95% CI, 0.77-0.94). CONCLUSIONS: In this multi-institutional study in Taiwan, SGLT2i use was associated with a reduced risk of retinal vascular occlusion. Further prospective studies are required to ascertain this association.
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Inhibidores de la Dipeptidil-Peptidasa IV , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Estudios Retrospectivos , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Taiwán/epidemiologíaRESUMEN
Visible-light active heterogeneous organophotocatalysts have recently gained considerable interest in organic synthetic community. Ordered mesoporous polymers (OMPs) are highly promising as heterogeneous alternative to traditional precious metal/organic dyes-based photocatalysts. Herein, we report the preparation of a benzothiadiazole functionalized OMPs (BT-MPs) through a "bottom-up" strategy. High ordered periodic porosity, large surface area, excellent stability and rational energy-band structures guarantee the high catalytic activity of BT-MPs. As a result, at least six conversions, e.g., the [3+2] cycloaddition of phenols with olefins, the selective oxidation of sulfides, the C-3 thiocyanation of indole and the aminothiocyanation of ß-keto ester, could be promoted smoothly by BT-MPs. In addition, BT-MPs was readily recovered with well maintaining its photocatalytic activity and could be reused for at least eight times. This study highlights the potential of exploiting photoactive OMPs as recyclable, robust and metal-free heterogeneous photocatalysts.
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BACKGROUND: The delineation of brain arteriovenous malformations (bAVMs) is crucial for subsequent treatment planning. Manual segmentation is time-consuming and labor-intensive. Applying deep learning to automatically detect and segment bAVM might help to improve clinical practice efficiency. PURPOSE: To develop an approach for detecting bAVM and segmenting its nidus on Time-of-flight magnetic resonance angiography using deep learning methods. STUDY TYPE: Retrospective. SUBJECTS: 221 bAVM patients aged 7-79 underwent radiosurgery from 2003 to 2020. They were split into 177 training, 22 validation, and 22 test data. FIELD STRENGTH/SEQUENCE: 1.5 T, Time-of-flight magnetic resonance angiography based on 3D gradient echo. ASSESSMENT: The YOLOv5 and YOLOv8 algorithms were utilized to detect bAVM lesions and the U-Net and U-Net++ models to segment the nidus from the bounding boxes. The mean average precision, F1, precision, and recall were used to assess the model performance on the bAVM detection. To evaluate the model's performance on nidus segmentation, the Dice coefficient and balanced average Hausdorff distance (rbAHD) were employed. STATISTICAL TESTS: The Student's t-test was used to test the cross-validation results (P < 0.05). The Wilcoxon rank test was applied to compare the median for the reference values and the model inference results (P < 0.05). RESULTS: The detection results demonstrated that the model with pretraining and augmentation performed optimally. The U-Net++ with random dilation mechanism resulted in higher Dice and lower rbAHD, compared to that without that mechanism, across varying dilated bounding box conditions (P < 0.05). When combining detection and segmentation, the Dice and rbAHD were statistically different from the references calculated using the detected bounding boxes (P < 0.05). For the detected lesions in the test dataset, it showed the highest Dice of 0.82 and the lowest rbAHD of 5.3%. DATA CONCLUSION: This study showed that pretraining and data augmentation improved YOLO detection performance. Properly limiting lesion ranges allows for adequate bAVM segmentation. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 1.
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Aprendizaje Profundo , Malformaciones Arteriovenosas Intracraneales , Humanos , Encéfalo/diagnóstico por imagen , Procesamiento de Imagen Asistido por Computador/métodos , Malformaciones Arteriovenosas Intracraneales/diagnóstico por imagen , Malformaciones Arteriovenosas Intracraneales/cirugía , Angiografía por Resonancia Magnética , Imagen por Resonancia Magnética , Estudios Retrospectivos , Niño , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , AncianoRESUMEN
Manipulating the motion of water droplets on surfaces, which is crucial for various applications, such as microfluidics and heat transfer, presents considerable challenges, primarily due to the significant influence of capillary forces. This effect becomes more pronounced when droplets are in close proximity, often resulting in undesired coalescence. Triboelectrification, which involves charging pure water droplets, is a promising approach to enhance the ability to manipulate water droplets. For effective triboelectrification, charges must accumulate within the droplets; this ensures efficient and sustained droplet manipulation while minimizing dissipation. Low-friction, superhydrophobic, insulating surfaces are ideal for this purpose. However, few studies have explored the application of insulating superhydrophobic surfaces to manipulate droplet motion. In this study, we investigated the behavior of water droplets on insulating superhydrophobic quartz surfaces after triboelectrification. The droplets acquired significant charge when dripped onto a superhydrophobic glass surface. Consequently, these charged droplets exhibited behaviors such as repulsion and acceleration from one another, uphill movement, and rapid long-distance transport to specific positions. These advancements in droplet manipulation techniques hold promise for diverse fields such as microfluidics and heat exchangers.
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Organocatalytic asymmetric Mannich reactions and kinetic resolutions of the products via retro-Mannich reactions that afford enantiomerically enriched tetrasubstituted α-amino acid derivatives (α,α-disubstituted-α-amino acid derivatives) were developed. Furthermore, the combination of the Mannich reaction and the retro-Mannich reaction allowed access to products with almost perfect enantiopurities.
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The Childhood Autism Rating Scale™, Second Edition (CARS™-2) and Social Responsiveness Scale™, Second Edition (SRS™-2) are two measures for identifying autism symptoms. The CARS™-2 has two versions: Standard (CARS-ST) and High-Functioning (CARS-HF). To better understand their properties, this study aimed to investigate: (1) the associations among the CARS-ST, CARS-HF and the SRS™-2, and (2) the severity consistency between the CARS-ST and the CARS-HF. A sample of 125 children with autism spectrum disorder was recruited (mean age: 80.98 months, SD = 16.08). Based on Verbal Comprehension Index (VCI), children were divided into two groups: low severity level of autism spectrum disorder (LSL-ASD: VCI ≥ 80) and high severity level of autism spectrum disorder (HSL-ASD: VCI < 80). All children were evaluated with the CARS-ST and the SRS™-2, and the HF group, with the CARS-HF as well. In the LSL group, the CARS-ST and the CARS-HF had high correlation (r = 0.852, p < .001). Both versions had small to moderate correlations with the SRS™-2 (r = 0.130-0.491). In the HSL group, no significant correlations were found between the CARS-ST and SRS™-2 (p > .05). The CARS-HF and the CARS-ST had low severity consistency (Kappa = 0.376, p < .01). The CARS-ST and the CARS-HF had high correlations but low severity consistency. Different correlation patterns were found between the CARS™-2 and the SRS™-2 in the LSL and HSL groups. The results should help clinicians better understand the properties of the measures and choose appropriate measures when assessing autism symptoms.
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Trastorno del Espectro Autista , Trastorno Autístico , Niño , Humanos , Trastorno del Espectro Autista/diagnóstico , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Tumor staging plays a pivotal role in melanoma management, where the depth of tumor invasion has been traditionally used as the cornerstone of staging. Paradoxically, the tumor diameter has not been integrated into the staging system. The aim of this study is to elucidate the clinical implications and prognostic value of tumor diameter in cutaneous melanoma, with a particular emphasis on the acral-melanoma predominant East Asian population, thus potentially enriching the clinical evaluation and treatment strategies for cutaneous melanoma. METHODS: From January 1st, 2006 to December 31st, 2022, a total of 352 patients were diagnosed with melanoma in our center. Among them, there were 135 patients diagnosed as cutaneous melanoma who received complete surgical wide excision and regional lymph nodes assessment. The diameter of the tumor, the depth of tumor invasion, lymph node status and patient survival were all collected and analyzed. RESULTS: The diameter of cutaneous melanoma had a weak positive correlation with tumor thickness (r = 0.26), however, it still had a significant predictive value for patients' overall survival (p = 0.005) and disease free survival (p = 0.023). As for lymph node metastasis prediction, the Breslow thickness had a better predictive value than tumor diameter (p = 0.002 vs. p = 0.565). CONCLUSIONS: In this study, though with only weak positive correlation to tumor thickness, the tumor diameter of melanoma showed a statistically significant correlation with the patients' overall survival and disease free survival. However, the larger tumor diameter cannot be used as an indicator of high risk of lymph node metastasis.
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Melanoma , Estadificación de Neoplasias , Neoplasias Cutáneas , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Asia Oriental , Pueblos del Este de Asia , Metástasis Linfática/patología , Melanoma/mortalidad , Melanoma/patología , Melanoma/cirugía , Melanoma Cutáneo Maligno , Invasividad Neoplásica/patología , Pronóstico , Estudios Retrospectivos , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/cirugía , Tasa de SupervivenciaRESUMEN
PIWI-interacting RNAs (piRNAs) guide PIWI proteins to suppress transposons in the cytoplasm and nucleus of animal germ cells, but how silencing in the two compartments is coordinated is not known. Here we demonstrate that endonucleolytic slicing of a transcript by the cytosolic mouse PIWI protein MILI acts as a trigger to initiate its further 5'â3' processing into non-overlapping fragments. These fragments accumulate as new piRNAs within both cytosolic MILI and the nuclear MIWI2. We also identify Exonuclease domain-containing 1 (EXD1) as a partner of the MIWI2 piRNA biogenesis factor TDRD12. EXD1 homodimers are inactive as a nuclease but function as an RNA adaptor within a PET (PIWI-EXD1-Tdrd12) complex. Loss of Exd1 reduces sequences generated by MILI slicing, impacts biogenesis of MIWI2 piRNAs, and de-represses LINE1 retrotransposons. Thus, piRNA biogenesis triggered by PIWI slicing, and promoted by EXD1, ensures that the same guides instruct PIWI proteins in the nucleus and cytoplasm.
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Proteínas Argonautas/metabolismo , Núcleo Celular/enzimología , Citosol/enzimología , Exonucleasas/metabolismo , Procesamiento Postranscripcional del ARN , ARN Interferente Pequeño/metabolismo , Proteínas de Unión al ARN/metabolismo , Secuencia de Aminoácidos , Animales , Proteínas Argonautas/química , Proteínas Argonautas/genética , Proteínas Portadoras/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Exonucleasas/química , Exonucleasas/genética , Femenino , Regulación de la Expresión Génica , Masculino , Ratones Transgénicos , Modelos Moleculares , Datos de Secuencia Molecular , Complejos Multiproteicos , Dominios y Motivos de Interacción de Proteínas , Interferencia de ARN , ARN Interferente Pequeño/genética , Proteínas de Unión al ARN/química , Proteínas de Unión al ARN/genéticaRESUMEN
It remains unclear whether non-vitamin K antagonist oral anticoagulants (NOACs) are more effective and safer than warfarin in low-weight patients with atrial fibrillation (AF). Here, we retrospectively compared the effectiveness and safety of NOACs with those of warfarin in low-weight patients with AF. We extracted the July 2011-September 2022 data of patients with AF treated with a NOAC (dabigatran, rivaroxaban, apixaban, or edoxaban) or warfarin at a tertiary hospital. The patients were divided into low-weight (body weight ≤ 60 kg) and non-low-weight (body weight = 60-100 kg) groups. The primary outcomes were hospitalization for ischemic stroke (IS) or systemic embolism (SE) and major bleeding, whereas the secondary outcomes were any ischemic and bleeding events. We used the inverse probability of treatment weighting to balance the baseline characteristics between the groups. In total, 5,044 patients (mean age = 73.7 years, mean CHA2DS2-VASc score = 3.0, mean HAS-BLED score = 2.3) were enrolled and divided into low-weight and non-low-weight groups-containing 1,666 (1,406 NOAC users, 260 warfarin users) and 3,378 (2,978 NOAC users, 400 warfarin users) patients, respectively. NOACs were associated with a lower risk of any bleeding event in the low-weight group (adjusted hazard ratio = 0.61, 95% confidence interval = 0.51-0.73). The between-group differences in the risks of IS/SE, any ischemic event, major bleeding, and any bleeding event were nonsignificant. Thus, the use of NOACs (specifically dabigatran or edoxaban) is associated with a lower risk of any bleeding event than warfarin use in low-weight patients with AF.
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PURPOSE: To evaluate stereopsis in term-born, preterm, and preterm children with and without retinopathy of prematurity (ROP) and its treatment. METHODS: The cross-sectional study included 322 children between 3 and 11 years of age born term or preterm, with or without ROP, and with or without treatment for ROP. The ROP treatments were laser therapy, intravitreal injection (IVI) of anti-vascular endothelial growth factor, or their combination. Stereoacuity was measured using the Titmus Stereo Test, and the results among various age groups were analyzed. RESULTS: Stereopsis was found to improve with increasing age at testing (P < 0.001) across the entire study population. The term group exhibited significantly better stereoacuity than the preterm group (P < 0.001). At 3-5 years and 6-8 years, the preterm children without ROP exhibited significantly better stereoacuity than did those with ROP (P < 0.001 and P = 0.02, respectively); however, at 9-11 years, both groups exhibited similar stereoacuity (P = 0.34). The stereoacuity in the children with untreated ROP was similar to that of the children with treated ROP in all age groups (P > 0.05). No significant differences in stereopsis were identified between children with ROP treated with laser versus with IVI (P > 0.05). From multivariate analysis, younger age at testing (P = 0.001) and younger gestational age (P < 0.001) were associated with poorer stereopsis. CONCLUSIONS: Stereopsis development gradually improved with age in all groups. The children born preterm exhibited poorer stereoacuity than those born term. Children with ROP treated with laser photocoagulation versus IVI may exhibit similar levels of stereoacuity. Younger age at testing and gestational age were independent risk factors for poorer stereoacuity.
Asunto(s)
Percepción de Profundidad , Edad Gestacional , Recien Nacido Prematuro , Retinopatía de la Prematuridad , Agudeza Visual , Humanos , Retinopatía de la Prematuridad/fisiopatología , Retinopatía de la Prematuridad/diagnóstico , Retinopatía de la Prematuridad/cirugía , Percepción de Profundidad/fisiología , Masculino , Femenino , Estudios Transversales , Preescolar , Niño , Agudeza Visual/fisiología , Estudios de Seguimiento , Recién Nacido , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/uso terapéutico , Visión Binocular/fisiología , Inyecciones Intravítreas , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Coagulación con Láser/métodosRESUMEN
PURPOSE: To evaluate choroidal changes over time in school-age children with a history of prematurity. METHODS: A study of 416 eyes of 208 eligible participants, including 88, 190, 36, 56, and 46 eyes in the full-term control, preterm, spontaneously regressed retinopathy of prematurity, intravitreal bevacizumab (injection of bevacizumab)-treated retinopathy of prematurity, and laser-treated retinopathy of prematurity groups, respectively, were enrolled in this study. The choroidal thickness was measured 4 times at 6-month intervals using optical coherence tomography. RESULTS: Of all the groups, the laser-treated children had the thinnest choroid compared with full-term children (-52.3 µ m, P = 0.04). Preterm children exhibited greater attenuation in choroidal thickness over time than did full-term children (-6.3 ± 26.9 and -1.1 ± 12.8 µ m/year, P = 0.03), whereas no difference was observed between injection of bevacizumab and laser treatments (-4.6 ± 18.9 and -2.0 ± 15.7 µ m/year, P = 0.46). In all groups, the changes in axial length were negatively associated with the changes in choroidal thickness (all P < 0.05). CONCLUSION: A greater attenuation in choroid thickness over time was observed in preterm children than in full-term children, but this attenuation did not differ between injection of bevacizumab and laser treatments. Axial elongation was associated with choroidal thinning in school-age children.