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Congenital scoliosis (CS), affecting approximately 0.5 to 1 in 1,000 live births, is commonly caused by congenital vertebral malformations (CVMs) arising from aberrant somitogenesis or somite differentiation. While Wnt/ß-catenin signaling has been implicated in somite development, the function of Wnt/planar cell polarity (Wnt/PCP) signaling in this process remains unclear. Here, we investigated the role of Vangl1 and Vangl2 in vertebral development and found that their deletion causes vertebral anomalies resembling human CVMs. Analysis of exome sequencing data from multiethnic CS patients revealed a number of rare and deleterious variants in VANGL1 and VANGL2, many of which exhibited loss-of-function and dominant-negative effects. Zebrafish models confirmed the pathogenicity of these variants. Furthermore, we found that Vangl1 knock-in (p.R258H) mice exhibited vertebral malformations in a Vangl gene dose- and environment-dependent manner. Our findings highlight critical roles for PCP signaling in vertebral development and predisposition to CVMs in CS patients, providing insights into the molecular mechanisms underlying this disorder.
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Proteínas Portadoras , Polaridad Celular , Proteínas de la Membrana , Columna Vertebral , Pez Cebra , Animales , Pez Cebra/genética , Pez Cebra/embriología , Humanos , Ratones , Polaridad Celular/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Columna Vertebral/anomalías , Columna Vertebral/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Escoliosis/genética , Escoliosis/congénito , Escoliosis/metabolismo , Vía de Señalización Wnt/genética , Predisposición Genética a la Enfermedad , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , FemeninoRESUMEN
USP25 encodes ubiquitin-specific proteases 25, a key member of deubiquitinating enzyme family and is involved in neural fate determination. Although abnormal expression in Down's syndrome was reported previously, the specific role of USP25 in human diseases has not been defined. In this study, we performed trio-based whole exome sequencing in a cohort of 319 cases (families) with generalized epilepsy of unknown etiology. Five heterozygous USP25 variants including two de novo and three co-segregated variants were determined in eight individuals affected by generalized seizures and/or febrile seizures from five unrelated families. The frequency of USP25 variants showed a significantly high aggregation in this cohort compared to the East Asian population and all populations in the gnomAD database. The mean onset ages of febrile and afebrile seizures were 10 months (infancy) and 11.8 years (juvenile), respectively. The patients achieved seizure freedom except one had occasional nocturnal seizures at the last follow-up. Two patients exhibited intellectual disability. Usp25 was ubiquitously expressed in mouse brain with two peaks on embryonic days (E14âE16) and postnatal day 21, respectively. Similarly, USP25 expressed in fetus/early childhood stage with a second peak at approximately 12â20 years old in human brain, consistent with the seizure onset age at infancy and juvenile in the patients. To investigate the functional impact of USP25 deficiency in vivo, we established Usp25 knock-out mice, which showed increased seizure susceptibility compared to wild-type mice in pentylenetetrazol-induced seizure test. To explore the impact of USP25 variants, we employed multiple functional detections. In HEK293T cells, the severe phenotype associated variant (p.Gln889Ter) led to a significant reduction of mRNA and protein expressions but formed a stable truncated dimers with increment of deubiquitinating enzyme activities and abnormal cellular aggregations, indicating a gain-of-function effect. The p.Gln889Ter and p.Leu1045del increased neuronal excitability in mice brain, with a higher firing ability in p.Gln889Ter. These functional impairments align with the severity of the observed phenotypes, suggesting a genotype-phenotype correlation. Hence, a moderate association between USP25 and epilepsy was noted, indicating USP25 is potentially a predisposing gene for epilepsy. Our results from Usp25 null mice and the patient-derived variants indicated that USP25 would play epileptogenic role via loss-of-function or gain-of-function effects. The truncated variant p.Gln889Ter would have profoundly different effect on epilepsy. Together, our results underscore the significance of USP25 heterozygous variants in epilepsy, thereby highlighting the critical role of USP25 in the brain.
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Background: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease globally, with the potential to progress to non-alcoholic steatohepatitis (NASH), cirrhosis, and even hepatocellular carcinoma. Given the absence of effective treatments to halt its progression, novel molecular approaches to the NAFLD diagnosis and treatment are of paramount importance. Methods: Firstly, we downloaded oxidative stress-related genes from the GeneCards database and retrieved NAFLD-related datasets from the GEO database. Using the Limma R package and WGCNA, we identified differentially expressed genes closely associated with NAFLD. In our study, we identified 31 intersection genes by analyzing the intersection among oxidative stress-related genes, NAFLD-related genes, and genes closely associated with NAFLD as identified through Weighted Gene Co-expression Network Analysis (WGCNA). In a study of 31 intersection genes between NAFLD and Oxidative Stress (OS), we identified three hub genes using three machine learning algorithms: Least Absolute Shrinkage and Selection Operator (LASSO) regression, Support Vector Machine - Recursive Feature Elimination (SVM-RFE), and RandomForest. Subsequently, a nomogram was utilized to predict the incidence of NAFLD. The CIBERSORT algorithm was employed for immune infiltration analysis, single sample Gene Set Enrichment Analysis (ssGSEA) for functional enrichment analysis, and Protein-Protein Interaction (PPI) networks to explore the relationships between the three hub genes and other intersecting genes of NAFLD and OS. The distribution of these three hub genes across six cell clusters was determined using single-cell RNA sequencing. Finally, utilizing relevant data from the Attie Lab Diabetes Database, and liver tissues from NASH mouse model, Western Blot (WB) and Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR) assays were conducted, this further validated the significant roles of CDKN1B and TFAM in NAFLD. Results: In the course of this research, we identified 31 genes with a strong association with oxidative stress in NAFLD. Subsequent machine learning analysis and external validation pinpointed two genes: CDKN1B and TFAM, as demonstrating the closest correlation to oxidative stress in NAFLD. Conclusion: This investigation found two hub genes that hold potential as novel targets for the diagnosis and treatment of NAFLD, thereby offering innovative perspectives for its clinical management.
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Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Animales , Ratones , Genes cdc , Perfilación de la Expresión Génica , BiomarcadoresRESUMEN
OBJECTIVE: To explore the potential value of three-dimensional fast spin echoï¼3D-SPACEï¼ combined with multilayer spiral CT ï¼MSCTï¼ in the diagnosis of knee cruciate ligament injury, to provide a new direction for the optimization of subsequent clinical diagnosis. METHODS: A total of 120 patients with knee cruciate ligament injury were treated from April 2020 to April 2021, aged from 21 to 68 with an average ofï¼41.52±4.13ï¼ years old. For all patients, separate MSCT scanner scans, 3D-SPACE sequence scans alone and 3D-SPACE sequence combined with MSCT scans were used. The injury and classification of the anterior and posterior cruciate ligament of the knee were compared, the length of the anterior-medial bundle and posterolateral bundle and its angle of the knee with the horizontal plane were observed, the diagnostic value of 3 diagnostic methods in knee cruciate ligament injury were determined. RESULTS: There was no significant difference between the 3D-SPACE sequence scan alone and the MSCT test alone on the total diagnostic rate and grading total diagnostic rateï¼P>0.05ï¼. The total diagnostic rate and grading total diagnostic rate of 3D-SPACE scan combined with MSCT were significantly higher than those of 3D-SPACE scan or MSCT aloneï¼P<0.05ï¼. The 3D-SPACE sequence scan alone and the MSCT detection alone had no significant difference in the measurement values related to the anterior and posterior cruciate ligaments of the knee jointï¼P>0.05ï¼. 3D-SPACE sequence scanning combined with MSCT detection on the knee joint anterior and posterior cruciate ligament related measurements were significantly higher than the 3D-SPACE sequence scan or MSCT detection aloneï¼P<0.05ï¼. The area under the ROC curve estimated by 3D-SPACE sequence scanning combined with MSCT was 0.960, which was significantly higher than that of 3D-SPACE sequence scanning and MSCT alone evaluating the area under the ROC curve line of 0.756 and 0.795. The combined 3D-SPACE sequence scanning and 3D-SPACE sequence scanning MSCT analysis and prediction models were statistically differentï¼Z=2.236, P<0.05ï¼, and MSCT alone and 3D-SPACE sequence scanning combined with MSCT analysis and prediction models were statistically differentï¼Z=2.653, P<0.05ï¼. CONCLUSION: The application of 3D-SPACE sequence combined with MSCT scanning for knee cruciate ligament injury can improve the diagnosis rate of patients with knee cruciate ligament injury.It can be used as a diagnostic tool for patients with knee cruciate ligament injury and is worthy of clinical application.
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Lesiones del Ligamento Cruzado Anterior , Traumatismos de la Rodilla , Ligamento Cruzado Posterior , Traumatismos de los Tejidos Blandos , Humanos , Adulto , Persona de Mediana Edad , Imagen por Resonancia Magnética/métodos , Artroscopía , Traumatismos de la Rodilla/diagnóstico por imagen , Articulación de la Rodilla/diagnóstico por imagen , Ligamento Cruzado Posterior/lesiones , Tomografía Computarizada Espiral , Lesiones del Ligamento Cruzado Anterior/diagnóstico por imagenRESUMEN
Lenvatinib is a multitargeted tyrosine kinase inhibitor capable of promoting apoptosis, suppressing angiogenesis, inhibiting tumor cell proliferation, and modulating the immune response. In multiple cancer types, lenvatinib has presented manageable safety and is currently approved as an effective first-line therapy. However, with the gradual increase in lenvatinib application, the inevitable progression of resistance to lenvatinib is becoming more prevalent. A series of recent researches have reported the mechanisms underlying the development of lenvatinib resistance in tumor therapy, which are related to the regulation of cell death or proliferation, histological transformation, metabolism, transport processes, and epigenetics. In this review, we aim to outline recent discoveries achieved in terms of the mechanisms and potential predictive biomarkers of lenvatinib resistance as well as to summarize untapped approaches available for improving the therapeutic efficacy of lenvatinib in patients with various types of cancers.
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Apoptosis , Epigénesis Genética , Compuestos de Fenilurea , Quinolinas , Humanos , Biomarcadores , Proliferación CelularRESUMEN
The cytoplasmic pattern recognition receptor, absent in melanoma 2 (AIM2), detects cytosolic DNA, activating the inflammasome and resulting in pro-inflammatory cytokine production and pyroptotic cell death. Recent research has illuminated AIM2's contributions to PANoptosis and host defense. However, the role of AIM2 in acetaminophen (APAP)-induced hepatoxicity remains enigmatic. In this study, we unveil AIM2's novel function as a negative regulator in the pathogenesis of APAP-induced liver damage in aged mice, independently of inflammasome activation. AIM2-deficient aged mice exhibited heightened lipid accumulation and hepatic triglycerides in comparison to their wild-type counterparts. Strikingly, AIM2 knockout mice subjected to APAP overdose demonstrated intensified liver injury, compromised mitochondrial stability, exacerbated glutathione depletion, diminished autophagy, and elevated levels of phosphorylated c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). Furthermore, our investigation revealed AIM2's mitochondrial localization; its overexpression in mouse hepatocytes amplified autophagy while dampening JNK phosphorylation. Notably, induction of autophagy through rapamycin administration mitigated serum alanine aminotransferase levels and reduced the necrotic liver area in AIM2-deficient aged mice following APAP overdose. Mechanistically, AIM2 deficiency exacerbated APAP-induced acute liver damage and inflammation in aged mice by intensifying oxidative stress and augmenting the phosphorylation of JNK and ERK. Given its regulatory role in autophagy and lipid peroxidation, AIM2 emerges as a promising therapeutic target for age-related acute liver damage treatment.
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BACKGROUND: Human patients often experience an episode of serious seizure activity, such as status epilepticus (SE), prior to the onset of temporal lobe epilepsy (TLE), suggesting that SE can trigger the development of epilepsy. Yet, the underlying mechanisms are not fully understood. The low-density lipoprotein receptor related protein (Lrp4), a receptor for proteoglycan-agrin, has been indicated to modulate seizure susceptibility. However, whether agrin-Lrp4 pathway also plays a role in the development of SE-induced TLE is not clear. METHODS: Lrp4f/f mice were crossed with hGFAP-Cre and Nex-Cre mice to generate brain conditional Lrp4 knockout mice (hGFAP-Lrp4-/-) and pyramidal neuron specific knockout mice (Nex-Lrp4-/-). Lrp4 was specifically knocked down in hippocampal astrocytes by injecting AAV virus carrying hGFAP-Cre into the hippocampus. The effects of agrin-Lrp4 pathway on the development of SE-induced TLE were evaluated on the chronic seizure model generated by injecting kainic acid (KA) into the amygdala. The spontaneous recurrent seizures (SRS) in mice were video monitored. RESULTS: We found that Lrp4 deletion from the brain but not from the pyramidal neurons elevated the seizure threshold and reduced SRS numbers, with no change in the stage or duration of SRS. More importantly, knockdown of Lrp4 in the hippocampal astrocytes after SE induction decreased SRS numbers. In accord, direct injection of agrin into the lateral ventricle of control mice but not mice with Lrp4 deletion in hippocampal astrocytes also increased the SRS numbers. These results indicate a promoting effect of agrin-Lrp4 signaling in hippocampal astrocytes on the development of SE-induced TLE. Last, we observed that knockdown of Lrp4 in hippocampal astrocytes increased the extracellular adenosine levels in the hippocampus 2 weeks after SE induction. Blockade of adenosine A1 receptor in the hippocampus by DPCPX after SE induction diminished the effects of Lrp4 on the development of SE-induced TLE. CONCLUSION: These results demonstrate a promoting role of agrin-Lrp4 signaling in hippocampal astrocytes in the development of SE-induced development of epilepsy through elevating adenosine levels. Targeting agrin-Lrp4 signaling may serve as a potential therapeutic intervention strategy to treat TLE.
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Lung adenocarcinoma (LUAD) is highly lethal tumor; understanding immune response is crucial for current effective treatment. Research investigated immunogenic cell death (ICD) impact on LUAD through 75 ICD-related genes which encompass cell damage, endoplasmic reticulum stress, microenvironment, and immunity. Transcriptome data and clinical info were analyzed, revealing two ICD-related clusters: B, an immune osmotic subgroup, had better prognosis, stronger immune signaling, and higher infiltration, while A represented an immune-deficient subgroup. Univariate Cox analysis identified six prognostic genes (AGER, CD69, CD83, CLEC9A, CTLA4, and NT5E), forming a validated risk score model. It was validated across datasets, showing predictive performance. High-risk group had unfavorable prognosis, lower immune infiltration, and higher chemotherapy sensitivity. Conversely, low-risk group had better prognosis, higher immune infiltration, and favorable immunotherapy response. The key gene NT5E was examined via immunohistochemistry, with higher expression linked to poorer prognosis. NT5E was predominantly expressed in B cells, fibroblasts, and endothelial cells, correlated with immune checkpoints. These outcomes suggest that NT5E can serve as a LUAD therapeutic target. The study highlights gene predictive value, offers an efficient tumor assessment tool, guides clinical treatment strategies, and identifies NT5E as therapeutic target for LUAD.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Humanos , Células Endoteliales , Muerte Celular Inmunogénica , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Inmunoterapia , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Microambiente TumoralRESUMEN
Plants convert solar energy and carbon dioxide into organic compounds through photosynthesis. Sucrose is the primary carbonate produced during photosynthesis. Sucrose phosphate synthase (SPS) is the key enzyme controlling sucrose biosynthesis in plants. There are at least three SPS gene families in higher plants, named A, B, and C. However, in monocotyledonous plants from Poaceae, there are at least five SPS gene families, named A, B, C, DIII, and DIV. Each family of SPS genes in different plants shows a divergent expression pattern. So different families of SPS genes participate in diverse biological functions, including sucrose accumulation, plant growth and production, and abiotic stress tolerance. SPS activity in plants is regulated by exogenous factors through gene expression and reversible protein phosphorylation. It is a practicable way to improve crop traits through SPS gene transformation. This work analyzes the cloning, phylogeny, and regulatory mechanism of the SPS gene in plants, reviews its biological function as well as its role in crop improvement, and discusses the challenges and future perspectives. This paper can serve as a reference for further study on plant SPS genes and eventually for crop improvement.
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Productos Agrícolas , Regulación de la Expresión Génica de las Plantas , Glucosiltransferasas , Proteínas de Plantas , Glucosiltransferasas/genética , Glucosiltransferasas/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Productos Agrícolas/genética , Productos Agrícolas/metabolismo , Productos Agrícolas/crecimiento & desarrollo , Productos Agrícolas/enzimología , Sacarosa/metabolismo , Filogenia , Plantas/genética , Plantas/enzimología , Plantas/metabolismoRESUMEN
Motivation-driven mating is a basic affair for the maintenance of species. However, the underlying molecular mechanisms that control mating motivation are not fully understood. Here, we report that NRG1-ErbB4 signaling in the medial amygdala (MeA) is pivotal in regulating mating motivation. NRG1 expression in the MeA negatively correlates with the mating motivation levels in adult male mice. Local injection and knockdown of MeA NRG1 reduce and promote mating motivation, respectively. Consistently, knockdown of MeA ErbB4, a major receptor for NRG1, and genetic inactivation of its kinase both promote mating motivation. ErbB4 deletion decreases neuronal excitability, whereas chemogenetic manipulations of ErbB4-positive neuronal activities bidirectionally modulate mating motivation. We also identify that the effects of NRG1-ErbB4 signaling on neuronal excitability and mating motivation rely on hyperpolarization-activated cyclic nucleotide-gated channel 3. This study reveals a critical molecular mechanism for regulating mating motivation in adult male mice.
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Motivación , Transducción de Señal , Ratones , Masculino , Animales , Neuronas/metabolismo , Receptor ErbB-4/metabolismo , Amígdala del Cerebelo/metabolismo , Neurregulina-1/metabolismoRESUMEN
Hepatic ischemia-reperfusion injury (HIRI) is a prevalent issue during liver resection and transplantation, with currently no cure or FDA-approved therapy. A promising drug, Cyclosporin A (CsA), ameliorates HIRI by maintaining mitochondrial homeostasis but has systemic side effects due to its low bioavailability and high dosage requirements. This study introduces a biomimetic CsA delivery system that directly targets hepatic lesions using mesenchymal stem cell (MSC) membrane-camouflaged liposomes. These hybrid nanovesicles (NVs), leveraging MSC-derived proteins, demonstrate efficient inflammatory chemotaxis, transendothelial migration, and drug-loading capacity. In a HIRI mouse model, the biomimetic NVs accumulated at liver injury sites entered hepatocytes, and significantly reduced liver damage and restore function using only one-tenth of the CsA dose typically required. Proteomic analysis verifies the protection mechanism, which includes reactive oxygen species inhibition, preservation of mitochondrial integrity, and reduced cellular apoptosis, suggesting potential for this biomimetic strategy in HIRI intervention.
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Tissue engineering for penile corpora cavernosa defects requires microvascular system reconstruction.GelMA hydrogels show promise for tissue regeneration. However, using stem cells faces challenges such as immune rejection, limited proliferation and differentiation, and biosafety concerns. Therefore, acellular tissue regeneration may avoid these issues. Exosomes are used from muscle-derived stem cells (MDSCs) to modify 3D-printed hydrogel scaffolds for acellular tissue regeneration. Hypoxia-preconditioned MDSC-derived exosomes are obtained to enhance the therapeutic effect. In contrast to normoxic exosomes (N-Exos), hypoxic exosomes (H-Exos) are found to markedly enhance the proliferation, migration, and capillary-like tube formation of human umbilical vein endothelial cells (HUVECs). High-throughput sequencing analysis of miRNAs isolated from both N-Exos and H-Exos revealed a significant upregulation of miR-21-5p in H-Exos following hypoxic preconditioning. Further validation demonstrated that the miR-21-5p/PDCD4 pathway promoted the proliferation of HUVECs. Epigallocatechin gallate (EGCG) is introduced to improve the mechanical properties and biocompatibility of GelMA hydrogels. EGCG-GelMA scaffolds loaded with different types of Exos are transplanted to repair rabbit penile corpora cavernosa defects, observed the blood flow and repair status of the defect site through color Doppler ultrasound and magnetic resonance imaging, and ultimately restored the rabbit penile erection function and successfully bred offspring. Thus, acellular hydrogel scaffolds offer an effective treatment for penile corpora cavernosa defects.
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Designing and developing cost-effective, high-performance catalysts for hydrogen evolution reaction (HER) is crucial for advancing hydrogen production technology. Tungsten-based sulfides (WSx) exhibit great potential as efficient HER catalysts, however, the activity is limited by the larger energy required for water dissociation under alkaline conditions. Herein, we adopt a top-down strategy to construct heterostructure Co-WS2 nanofiber catalysts. The experimental results and theoretical simulations unveil that the work functions-induced built-in electric field at the interface of Co-WS2 catalysts facilitates the electron transfer from Co to WS2, significantly reducing water dissociation energy and optimizing the Gibbs free energy of the entire reaction step for HER. Besides, the self-supported catalysts of Co-WS2 nanoparticles confining 1D nanofibers exhibit an increased number of active sites. As expected, the heterostructure Co-WS2 catalysts exhibit remarkable HER activity with an overpotential of 113 mV to reach 10 mA cm-2 and stability with 30 h catalyzing at 23 mA cm-2. This work can provide an avenue for designing highly efficient catalysts applicable to the field of energy storage and conversion.
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Adolescent idiopathic scoliosis (AIS) is a common and progressive spinal deformity in children that exhibits striking sexual dimorphism, with girls at more than fivefold greater risk of severe disease compared to boys. Despite its medical impact, the molecular mechanisms that drive AIS are largely unknown. We previously defined a female-specific AIS genetic risk locus in an enhancer near the PAX1 gene. Here, we sought to define the roles of PAX1 and newly identified AIS-associated genes in the developmental mechanism of AIS. In a genetic study of 10,519 individuals with AIS and 93,238 unaffected controls, significant association was identified with a variant in COL11A1 encoding collagen (α1) XI (rs3753841; NM_080629.2_c.4004C>T; p.(Pro1335Leu); p=7.07E-11, OR = 1.118). Using CRISPR mutagenesis we generated Pax1 knockout mice (Pax1-/-). In postnatal spines we found that PAX1 and collagen (α1) XI protein both localize within the intervertebral disc-vertebral junction region encompassing the growth plate, with less collagen (α1) XI detected in Pax1-/- spines compared to wild-type. By genetic targeting we found that wild-type Col11a1 expression in costal chondrocytes suppresses expression of Pax1 and of Mmp3, encoding the matrix metalloproteinase 3 enzyme implicated in matrix remodeling. However, the latter suppression was abrogated in the presence of the AIS-associated COL11A1P1335L mutant. Further, we found that either knockdown of the estrogen receptor gene Esr2 or tamoxifen treatment significantly altered Col11a1 and Mmp3 expression in chondrocytes. We propose a new molecular model of AIS pathogenesis wherein genetic variation and estrogen signaling increase disease susceptibility by altering a PAX1-COL11a1-MMP3 signaling axis in spinal chondrocytes.
Adolescent idiopathic scoliosis (AIS) is a twisting deformity of the spine that occurs during periods of rapid growth in children worldwide. Children with severe cases of AIS require surgery to stop it from getting worse, presenting a significant financial burden to health systems and families. Although AIS is known to cluster in families, its genetic causes and its inheritance pattern have remained elusive. Additionally, AIS is known to be more prevalent in females, a bias that has not been explained. Advances in techniques to study the genetics underlying diseases have revealed that certain variations that increase the risk of AIS affect cartilage and connective tissue. In humans, one such variation is near a gene called Pax1, and it is female-specific. The extracellular matrix is a network of proteins and other molecules in the space between cells that help connect tissues together, and it is particularly important in cartilage and other connective tissues. One of the main components of the extracellular matrix is collagen. Yu, Kanshour, Ushiki et al. hypothesized that changes in the extracellular matrix could affect the cartilage and connective tissues of the spine, leading to AIS. To show this, the scientists screened over 100,000 individuals and found that AIS is associated with variants in two genes coding for extracellular matrix proteins. One of these variants was found in a gene called Col11a1, which codes for one of the proteins that makes up collagen. To understand the relationship between Pax1 and Col11a1, Yu, Kanshour, Ushiki et al. genetically modified mice so that they would lack the Pax1 gene. In these mice, the activation of Col11a1 was reduced in the mouse spine. They also found that the form of Col11a1 associated with AIS could not suppress the activation of a gene called Mmp3 in mouse cartilage cells as effectively as unmutated Col11a1. Going one step further, the researchers found that lowering the levels of an estrogen receptor altered the activation patterns of Pax1, Col11a1, and Mmp3 in mouse cartilage cells. These findings suggest a possible mechanism for AIS, particularly in females. The findings of Yu, Kanshour, Ushiki et al. highlight that cartilage cells in the spine are particularly relevant in AIS. The results also point to specific molecules within the extracellular matrix as important for maintaining proper alignment in the spine when children are growing rapidly. This information may guide future therapies aimed at maintaining healthy spinal cells in adolescent children, particularly girls.
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Escoliosis , Masculino , Animales , Niño , Ratones , Humanos , Femenino , Adolescente , Escoliosis/genética , Metaloproteinasa 3 de la Matriz/genética , Columna Vertebral , Factores de Transcripción/genética , Colágeno/genética , Variación Genética , Colágeno Tipo XI/genéticaAsunto(s)
Biomarcadores , Lupus Eritematoso Sistémico , Valor Predictivo de las Pruebas , Humanos , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Femenino , Biomarcadores/sangre , Adulto , Masculino , Persona de Mediana EdadRESUMEN
PURPOSE: To compare the curative effects of ureteroscopic lithotripsy and laparoscopic ureterolithotomy for unilateral upper ureteral stones, and to explore optimal surgical indications and skills. METHODS: Fifty cases of unilateral upper ureteral stones were randomly divided into two groups: one group underwent ureteroscopic holmium laser lithotripsy under epidural or lumbar anesthesia (n=25), and another group underwent laparoscopic ureterolithotomy under general anesthesia (n=25). Double-J stent was routinely indwelled in both groups. Operating time, postoperative hospitalization time, stone clearance rate and perioperative complications were compared. RESULTS: Operation was successfully performed in all 50 cases, and no open surgery was converted in any case. In the ureteroscopy and laparoscopy groups, the mean operating time was 49.0±10.7 min and 41.8±8.0 min (t=2.68, P=0.00999), respectively, their hospitalization time was 2.8±1.3 days vs. 2.9±0.8 days (t =-0.40, P=0.69413), and stone clearance rate was 88.0 percent (22/25) vs. 100 percent (25/25). Stone moved to the renal pelvis in three cases in the ureteroscopy group, and residual stones were removed by extracorporeal shock-wave lithotripsy (ESWL). All patients were followed up for more than three months, and no serious complications such as ureterostenosis occurred. CONCLUSIONS: Laparoscopic ureterolithotomy has a higher stone clearance rate and shorter operation time compared with ureteroscopic lithotripsy. Laparoscopic ureterolithotomy is one safe and effective treatment on unilateral upper ureteral stones.
OBJETIVO: Comparar os efeitos curativos da litotripsia ureteroscópica e a ureterolitotomia laparoscópica para cálculos unilaterais altos e pesquisar as indicações e resultados. MÉTODOS: Cinquenta casos de cálculos unilaterais altos foram distribuídos aleatoriamente em dois grupos: um grupo submetido a litotripsia ureteroscópica com laser holmium sob anestesia epidural ou lombar (n=25) e outro grupo submetido a ureterolitotomia laparoscópica sob anestesia geral (n=25). Duplo-J stent foi rotineiramente instalado em ambos os grupos. Comparou-se o tempo operatório, tempo de hospitalização pós-operatória, nível de desaparecimento dos cálculos e complicações pós-operatórias. RESULTADOS: Atos operatórios nos 50 casos sem ocorrências e nenhum ato convertido. Nos grupos por ureteroscopia e laparoscopia, o tempo operatório médio foi 49,0±10,7 minutos e 41,8±8,0 minutos (t=2,68, P=0,00999) respectivamente, tempo de hospitalização foi 2,8±1,3 dias vs. 2,9±0,8 dias (t=0,40, P=0,69413) e o nível de desaparecimento dos cálculos foi 88.0 por cento (22/25) vs. 100 por cento (25/25). Cálculo deslocado para pelve renal em três casos no grupo ureteroscópico e cálculos residuais foram removidos por litotripsia por onda de choque extracorpóreo (ESWL). Todos pacientes foram seguidos por mais de três meses e não ocorreram complicações sérias como estenoses ureterais. CONCLUSÕES: A ureterolitotomia laparoscópica teve maior nível desaparecimento dos cálculos e tempo operatório menor comparado à litotripsia ureteroscópica A ureterolitotomia laparoscópica é um tratamento seguro e efetivo para cálculos ureterais unilaterais altos.