RESUMEN
GPR20, an orphan G protein-coupled receptor (GPCR), shows significant expression in intestinal tissue and represents a potential therapeutic target to treat gastrointestinal stromal tumors. GPR20 performs high constitutive activity when coupling with Gi. Despite the pharmacological importance of GPCR constitutive activation, determining the mechanism has long remained unclear. In this study, we explored the constitutive activation mechanism of GPR20 through large-scale unbiased molecular dynamics simulations. Our results unveil the allosteric nature of constitutively activated GPCR signal transduction involving extracellular and intracellular domains. Moreover, the constitutively active state of the GPR20 requires both the N-terminal cap and Gi protein. The N-terminal cap of GPR20 functions like an agonist and mediates long-range activated conformational shift. Together with the previous study, this study enhances our knowledge of the self-activation mechanism of the orphan receptor, facilitates the drug discovery efforts that target GPR20.
RESUMEN
OBJECTIVE: To explore the genetic etiology of a Chinese pedigree affected with Branchio-oculo-facial syndrome (BOFS) and summarize the prenatal phenotype of BOFS patients. METHODS: A pedigree with BOFS which had presented at the Genetics and Prenatal Diagnosis Center of the First Affiliated Hospital of Zhengzhou University in December 2021 was selected as the study subject. Clinical data of the pedigree was collected. The fetus was subjected to routine prenatal ultrasound scan. Trio-whole exome sequencing (trio-WES) was carried out for the fetus and its parents, and candidate variant was verified by Sanger sequencing. Relevant literature was searched from the database to summarize the prenatal phenotype of BOFS patients. RESULTS: Ultrasound exam suggested the fetus had cleft lip and palate. Its father had presented with high palatal arch, prematurely grayed hair, occult cleft lip, congenital preauricular fistula, red-green color blindness and unilateral renal agenesis. Its grandfather also had high palatal arch, prematurely gray hair, protruding ears, congenital preauricular fistula and hearing disorders. Trio-WES revealed that the fetus and its father had both harbored a heterozygous c.890-1G>A variant of the TFAP2A gene. The same variant was not found in its mother. Sanger sequencing confirmed that its grandfather had also harbored the same variant. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was rated as likely pathogenic (PVS1+PM2_Supporting). Combined with 36 similar cases retrieved from the literature, the prenatal phenotypes of BOFS patients had included growth restriction (25/37), renal abnormalities (10/37), cleft lip and palate (5/37) and oligohydramnios (5/37). CONCLUSION: The c.890-1G>A variant of the TFAP2A gene probably underlay the pathogenesis of BOFS in this pedigree. Discovery of the novel variant has enriched the mutational spectrum of the TFAP2A gene. The common prenatal phenotypes of BOFS have included growth restriction, renal abnormalities, cleft lip and palate and oligohydramnios. Delineation of the intrauterine phenotype of BOFS may facilitate its prenatal diagnosis, clinical diagnosis, treatment and genetic counseling.
Asunto(s)
Síndrome Branquio Oto Renal , Factor de Transcripción AP-2 , Adulto , Femenino , Humanos , Masculino , Embarazo , Síndrome Branquio Oto Renal/genética , China , Pueblos del Este de Asia/genética , Secuenciación del Exoma , Pruebas Genéticas , Mutación , Linaje , Fenotipo , Diagnóstico Prenatal , Factor de Transcripción AP-2/genéticaRESUMEN
Drained wetlands are thought to be carbon (C) source hotspots, and rewetting is advocated to restore C storage in drained wetlands for climate change mitigation. However, current assessments of wetland C balance mainly focus on vertical fluxes between the land and atmosphere, frequently neglecting lateral carbon fluxes and land-use effects. Here, we conduct a global synthesis of 893 annual net ecosystem C balance (NECB) measures that include net ecosystem exchange of CO2, along with C input via manure fertilization, and C removal through biomass harvest or hydrological exports of dissolved organic and inorganic carbon, across wetlands of different status and land uses. We find that elevating water table substantially reduces net ecosystem C losses, with the annual NECB decreasing from 2579 (95% interval: 1976 to 3214) kg C ha-1 year-1 in drained wetlands to -422 (-658 to -176) kg C ha-1 year-1 in natural wetlands, and to -934 (-1532 to -399) kg C ha-1 year-1 in rewetted wetlands globally. Climate, land-use history, and time since water table changes introduce variabilities, with drainage for (sub)tropical agriculture or forestry uses showing high annual C losses, while the net C losses from drained wetlands can continue to affect soil C pools for several decades. Rewetting all types of drained wetlands is needed, particularly for those formerly agriculture-used (sub)tropical wetlands where net ecosystem C losses can be largely reduced. Our findings suggest that elevating water table is an important initiative to reduce C losses in degraded wetlands, which could contribute to policy decisions for managing wetlands to enhance their C sequestration.
Asunto(s)
Ciclo del Carbono , Cambio Climático , Humedales , Carbono/análisis , Carbono/metabolismo , Agua Subterránea/química , Agua Subterránea/análisis , Agricultura/métodos , Biomasa , Ecosistema , Secuestro de CarbonoRESUMEN
Traumatic brain injury (TBI), which is characterized by acute neurological dysfunction, is also one of the most widely recognized environmental risk factors for various neurological and psychiatric disorders. However, the role of TBI in neurological perturbation and the mechanisms underlying these disorders remain unknown. We evaluated transcriptional changes in cells of the frontal cortex after TBI by exploiting single-cell RNA sequencing (scRNA-Seq). We adopted the gene expression omnibus and scRNA-Seq to identify the mediation by secretogranin II (SCG2) of TBI-induced schizophrenia. Astrocytes are a principal source of SCG2 in the frontal cortex after TBI. Our analysis indicated that SCG2-triggered disruption of the blood-brain barrier (BBB) via the CypA-MMP-9 signaling pathway. Furthermore, astrocytic SCG2 knockout in the frontal cortex reduced BBB damage, mitigated inflammation, and inhibited schizophrenia after TBI. In conclusion, we identified the SCG2-CypA-MMP-9 signaling pathway in reactive astrocytes as a key switch in the protection of the BBB and provided a novel therapeutic avenue for treating psychiatric disorders after TBI.
Asunto(s)
Barrera Hematoencefálica , Lesiones Traumáticas del Encéfalo , Ratones Endogámicos C57BL , Esquizofrenia , Animales , Masculino , Ratones , Astrocitos/metabolismo , Barrera Hematoencefálica/metabolismo , Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/patología , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Ratones Noqueados , Esquizofrenia/metabolismo , Transducción de SeñalRESUMEN
In this study, PBMCs used in reprogramming were from a boy suffered from AUTS2 syndrome confirmed by clinical and genetic diagnosis. iPSCs were established by non-integrated method, which carried AUTS2 heterozygous mutation. The established iPSCs presented similar appearance and expressed pluripotent markers in mRNA and protein level. Additionally, the iPSCs possessed favorable differentiative capacity in vivo and normal karyotype. This is an effective potential model for the study about AUTS2 syndrome and the screen about drug therapy.
RESUMEN
Background: Definitive chemoradiotherapy (dCRT) is the cornerstone for locally advanced non-small cell lung cancer (LA-NSCLC). The study aimed to construct a multi-omics model integrating baseline clinical data, computed tomography (CT) images and genetic information to predict the prognosis of dCRT in LA-NSCLC patients. Methods: The study retrospectively enrolled 105 stage III LA-NSCLC patients who had undergone dCRT. The pre-treatment CT images were collected, and the primary tumor was delineated as a region of interest (ROI) on the image using 3D-Slicer, and the radiomics features were extracted. The least absolute shrinkage and selection operator (LASSO) was employed for dimensionality reduction and selection of features. Genomic information was obtained from the baseline tumor tissue samples. We then constructed a multi-omics model by combining baseline clinical data, radiomics and genomics features. The predictive performance of the model was evaluated by the area under the curve (AUC) of the receiver operating characteristic (ROC) and the concordance index (C-index). Results: The median follow-up time was 30.1 months, and the median progression-free survival (PFS) was 10.60 months. Four features were applied to construct the radiomics model. Multivariable analysis demonstrated the Rad-score, KEAP1 and MET mutations were independent prognostic factors for PFS. The C-index of radiomics model, genomics model and radiogenomics model all performed well in the training group (0.590 vs. 0.606 vs. 0.663) and the validation group (0.599 vs. 0.594 vs. 0.650). Conclusions: The radiomics model, genomics model and radiogenomics model can all predict the prognosis of dCRT for LA-NSCLC, and the radiogenomics model is superior to the single type model.
RESUMEN
Background: In the recent decade, there has been substantial progress in the technologies and philosophies associated with diagnosing and treating anterior cruciate ligament (ACL) injuries in China. The therapeutic efficacy of ACL reconstruction in re-establishing the stability of the knee joint has garnered widespread acknowledgment. However, the path toward standardizing diagnostic and treatment protocols remains to be further developed and refined. Objective: In this context, the Chinese Association of Orthopaedic Surgeons (CAOS) and the Chinese Society of Sports Medicine (CSSM) collaboratively developed an expert consensus on diagnosing and treating ACL injury, aiming to enhance medical quality through refining professional standards. Methods: The consensus drafting team invited experts across the Greater China region, including the mainland, Hong Kong, Macau, and Taiwan, to formulate and review the consensus using a modified Delphi method as a standardization approach. As members of the CSSM Lower Limb Study Group and the CAOS Arthroscopy and Sports Medicine Study Group, invited experts concentrated on two pivotal issues: "Graft Selection" and "Clinical Outcome Evaluation" during the second part of the consensus development. Results: This focused discussion ultimately led to a strong consensus on nine specific consensus terms. Conclusion: The consensus clearly states that ACL reconstruction has no definitive "gold standard" graft choice. Autografts have advantages in healing capability but are limited in availability and have potential donor site morbidities; allografts reduce surgical trauma but incur additional costs, and there are concerns about slow healing, quality control issues, and a higher failure rate in young athletes; synthetic ligaments allow for early rehabilitation and fast return to sport, but the surgery is technically demanding and incurs additional costs. When choosing a graft, one should comprehensively consider the graft's characteristics, the doctor's technical ability, and the patient's needs. When evaluating clinical outcomes, it is essential to ensure an adequate sample size and follow-up rate, and the research should include patient subjective scoring, joint function and stability, complications, surgical failure, and the return to sport results. Medium and long-term follow-ups should not overlook the assessment of knee osteoarthritis.
RESUMEN
Age-related osteoporosis manifests as a complex pathology that disrupts bone homeostasis and elevates fracture risk, yet the mechanisms facilitating age-related shifts in bone marrow macrophages/osteoclasts (BMMs/OCs) lineage are not fully understood. To decipher these mechanisms, we conducted an investigation into the determinants controlling BMMs/OCs differentiation. We performed single-cell multi-omics profiling on bone marrow samples from mice of different ages (1, 6, and 20 months) to gain a holistic understanding of cellular changes across time. Our analysis revealed that aging significantly instigates OC differentiation. Importantly, we identified Cebpd as a vital gene for osteoclastogenesis and bone resorption during the aging process. Counterbalancing the effects of Cebpd, we found Irf8, Sox4, and Klf4 to play crucial roles. By thoroughly examining the cellular dynamics underpinning bone aging, our study unveils novel insights into the mechanisms of age-related osteoporosis and presents potential therapeutic targets for future exploration.
RESUMEN
In a rigorous 40-month study, we evaluated the geroprotective effects of metformin on adult male cynomolgus monkeys, addressing a gap in primate aging research. The study encompassed a comprehensive suite of physiological, imaging, histological, and molecular evaluations, substantiating metformin's influence on delaying age-related phenotypes at the organismal level. Specifically, we leveraged pan-tissue transcriptomics, DNA methylomics, plasma proteomics, and metabolomics to develop innovative monkey aging clocks and applied these to gauge metformin's effects on aging. The results highlighted a significant slowing of aging indicators, notably a roughly 6-year regression in brain aging. Metformin exerts a substantial neuroprotective effect, preserving brain structure and enhancing cognitive ability. The geroprotective effects on primate neurons were partially mediated by the activation of Nrf2, a transcription factor with anti-oxidative capabilities. Our research pioneers the systemic reduction of multi-dimensional biological age in primates through metformin, paving the way for advancing pharmaceutical strategies against human aging.
RESUMEN
Chimeric antigen receptor T (CAR-T)-cell therapy targeting B-cell maturation antigen (BCMA) is currently one of the promising treatment methods for relapsed/refractory multiple myeloma (MM). Herein, this study is a case report on a 41-year-old male patient with MM. Unfortunately, he still developed multidrug-resistant, refractory, and bone marrow suppression after receiving multiline high-intensity chemotherapy. After a detailed evaluation, the physician recommended autologous hematopoietic stem cell transplantation (ASCT) support, followed by sequential immunotherapy with autologous anti- BCMA CAR-T cells. The CAR-T product is a novel anti-BCMA CAR-T based on Retrovirus vectors (RV). It was worth noting that the patient achieved VGPR (very good partial remission) one month after infusion of anti-BCMA CAR-T cells. Recent tests have found that the M protein was no longer detectable and the patient has achieved CR (complete response). Although grade 3 cytokine release syndrome (CRS) appeared, the symptom was well controlled and immune effector cell-associated neurotoxicity syndrome (ICANS) did not occur. This was the first case report of RV prepared anti-BCMA CAR-T cells combined with ASCT for the treatment of MM patient in clinical practice, indicating that the RV-based anti-BCMA-CAR-T cells with ASCT have excellent therapeutic efficacy and high safety in triple-refractory MM patients.
RESUMEN
Background: The remission rate of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) patients who received standard induction therapy is far from satisfactory. Improving the remission rate of MPO-AAV patients is essential. Hydroxychloroquine (HCQ), one of the classic antimalarial drugs, has been widely used in various autoimmune rheumatic diseases. This retrospective observational cohort study is aimed to evaluate the efficacy and safety of HCQ during induction treatment for MPO-AAV. Methods: The medical records of patients diagnosed with MPO-AAV at Xiangya Hospital, Central South University from January 2021 to September 2023 were collected. They were assigned to the HCQ group or control group according to whether they used HCQ. The patients included were screened by propensity score matching. To evaluate whether MPO-AAV patients benefited from HCQ, we compared the prognosis of the two groups. The adverse effects of HCQ during follow-up were recorded. Results: The composition ratio of complete remission, response and treatment resistance between HCQ group and control group were different statistically (P = .021). There was no significant difference between the two groups in 1-year renal survival (P = .789). The HCQ group had better 1-year patient survival than the control group (P = .049). No serious adverse effects were documented in the HCQ group. Conclusions: HCQ together with standard induction treatment may improve the remission rate of MPO-AAV patients, and HCQ had good safety in our study.
RESUMEN
The technique of antimicrobial therapy action is to stop or slow the growth of bacteria that can kill people, animals, and crops. The most widely used antibacterial agents are antibiotics. Even though these antimicrobial medications are quite effective, there are still certain barriers or challenges in using them effectively. To solve these issues, new antimicrobial drug molecules that don't have side effects or resistance are needed. These days, antimicrobial drugs placed in nanosized vehicles, or nanomedicine, made of different metal and metallic oxides as well as of polymer, carbon or lipid-based may be used to address these issues with conventional therapy and delivery techniques. This review focuses on the importance of nanotechnology in antimicrobial therapy, nanoparticles (NPs) used in this therapy, their mode of action, and the recent advancement in nanotechnology for antimicrobial therapy.
RESUMEN
BACKGROUND: Flaxseed lignans, types of polyphenolic compounds, primarily consist of secoisolariciresinol diglucoside (SDG). Natural plant extracts are becoming increasingly important as feed for ruminant animals. An underutilized plant bioactive component, SDG shows promising benefits for young ruminant production. The objective of this study was to assess the impact of SDG on rumen fermentation using an in vitro rumen simulation technology. Additionally, we tested the effects of SDG (0.20 g kg-1 body weight) on rumen development and production performance of lambs in a production setting. RESULTS: The in vitro addition of 100 mg L-1 SDG demonstrated significant regulatory effects, with a notable decrease in the acetate/propionate ratio (P < 0.05). Feeding trials revealed that SDG significantly increased average daily feed intake and average daily weight gain (P < 0.05), and reduced the acetate/propionate ratio (P < 0.05). This led to a significant increase in the relative abundance of Eubacterium ruminantium (P = 0.038) and Butyrivibrio (P = 0.002). Furthermore, it promoted rumen development and upregulated the relative expression of mRNA of Cyclin E1 and CDK2 in rumen epithelial cells (P < 0.05). CONCLUSION: The SDG extract optimizes the composition of rumen microbiota and the development of rumen epithelial cells, promoting the growth of pre-weaning lambs. The SDG additive exhibits potential as a novel growth promoter for ruminant animals, offering a promising solution for sustainable livestock production. © 2024 Society of Chemical Industry.
RESUMEN
While numerous studies have explored NeRF-based novel view synthesis for dynamic humans, they often require training that exceeds several hours, limiting their practicality. Efforts to improve training efficiency have also encountered challenges because it is hard to optimize non-rigid transformations, thus leading to coarse renderings. In this work, we introduce an innovative approach for efficiently learning and integrating neural human representations. To achieve this, we propose a comprehensive utilization of the features stored in both canonical and observational spaces, facilitated through a collaborative refinement process that integrates canonical representations with observational details. Specifically, we initially propose decomposing high-dimensional multi-space feature volume into several feature planes, subsequently utilizing matrix multiplication to explicitly establish the correlations between different planes. This enables the simultaneous optimization of their counterparts across all dimensions by optimizing interpolated features, efficiently integrating associated details, and accelerating the rate of convergence. Additionally, we use the proposed collaborative refinement process to iteratively enhance the canonical representation. By integrating multi-space representations, we further facilitate the co-optimization of multiple frames' time-dependent observations. Experiments demonstrate that our method can achieve high-quality free-viewpoint renderings within nearly 5 minutes of optimization. Compared to state-of-the-art approaches, our results show more realistic rendering details, marking a significant advancement in both performance and efficiency.
RESUMEN
ABSTRACT: Guidelines on antiplatelet recommendation for CYP2C19 intermediate metabolizer (IM) have not come to an agreement. This study aimed to evaluate the clinical benefit of ticagrelor when compared with high-dose clopidogrel in CYP2C19 IM after percutaneous coronary intervention for acute coronary syndromes. Patients were enrolled according to CYP2C19 genotype and individual antiplatelet therapy. Patient characteristics and clinical outcomes were collected through electronic medical record system. The primary outcome was major adverse cardiac and cerebrovascular event (MACCE), namely a composite of death from cardiovascular causes, myocardial infarction, stroke, and stent thrombosis within 12 months. The secondary outcome was Bleeding Academic Research Consortium scale bleeding events within 12 months. The Cox proportional hazards regression model was performed, with inverse probability treatment weighting (IPTW) adjusting for potential confounders. A total of 532 CYP2C19 IM were enrolled in this retrospective single-center study. No statistically significant difference in incidence rate of MACCE was found between patients receiving ticagrelor versus clopidogrel (7.01 vs. 9.52 per 100 patient-years; IPTW-adjusted hazard ratio 0.71; 95% confidence interval: 0.32-1.58; adjusted log-rank P = 0.396), but the incidence rate of Bleeding Academic Research Consortium type 2, 3, or 5 bleeding events was statistically higher in the loss of function-ticagrelor group than in the loss of function-clopidogrel group (13.53 vs. 6.16 per 100 patient-years; IPTW-adjusted hazard ratio: 2.29; 95% confidence interval: 1.10-4.78; adjusted log-rank P = 0.027). Ticagrelor treatment in CYP2C19 IM resulted in a statistically higher risk of bleeding compared with high-dose clopidogrel, whereas a clear association between treatments and MACCE warrants further investigations.
Asunto(s)
Síndrome Coronario Agudo , Clopidogrel , Citocromo P-450 CYP2C19 , Hemorragia , Intervención Coronaria Percutánea , Variantes Farmacogenómicas , Inhibidores de Agregación Plaquetaria , Ticagrelor , Humanos , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Ticagrelor/efectos adversos , Ticagrelor/administración & dosificación , Clopidogrel/efectos adversos , Clopidogrel/administración & dosificación , Síndrome Coronario Agudo/terapia , Síndrome Coronario Agudo/mortalidad , Síndrome Coronario Agudo/diagnóstico , Masculino , Intervención Coronaria Percutánea/efectos adversos , Intervención Coronaria Percutánea/mortalidad , Femenino , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/administración & dosificación , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Resultado del Tratamiento , Hemorragia/inducido químicamente , Factores de Riesgo , Factores de Tiempo , Medición de Riesgo , FenotipoRESUMEN
Following ischemic stroke, aquaporin 4 (AQP4) expression modifications have been associated with increased inflammation. However, the underlying mechanisms are not fully understood. This study aims to elucidate the mechanistic basis of post-cerebral ischemia-reperfusion (I/R) inflammation by employing the AQP4-specific inhibitor, AER-271. The middle cerebral artery occlusion (MCAO) model was used to induce ischemic stroke in mice. C57BL/6 mice were randomly allocated into four groups: sham operation, I/R, AER-271, and 2-(nicotinamide)-1,3,4-thiadiazole (TGN-020) treatment, with observations recorded at 1 day, 3 days, and 7 days post-tMCAO. Each group consisted of 15 mice. Procedures included histological examination through HE staining, neurological scoring, Western blot analysis, and immunofluorescence staining. AER-271 treatment yielded significant improvements in post-stroke weight recovery and neurological scores, accompanied by a reduction in cerebral infarction volume. Moreover, AER-271 exhibited a noticeable influence on autophagic and apoptotic pathways, affecting the activation of both pro-inflammatory and anti-inflammatory cytokines. Alterations in the levels of inflammatory biomarkers MCP-1, NLRP3, and caspase 1 were also detected. Finally, a comparative assessment of the effects of AER-271 and TGN-020 in mitigating apoptosis and microglial polarization in ischemic mice revealed neuroprotective effects with no significant difference in efficacy. This study provides essential insights into the neuroprotective mechanisms of AER-271 in cerebral ischemia-reperfusion injury, offering potential clinical applications in the treatment of ischemic cerebrovascular disorders.
RESUMEN
The prevalent π-π interactions in 2D covalent organic frameworks (COFs) impart a certain flexibility to the structures, making the stacking of COF layers susceptible to external stimuli and introducing some structural disorder. Recent research indicates that the flexibility between COF layers and the associated disorder significantly influence their selective adsorption performance toward gas molecules. However, the adsorption process in a solution environment is more complex compared to gas-phase adsorption, involving interactions between adsorbents and adsorbates, as well as the solvation effects of flexible 2D COFs. Therefore, the inherent flexibility and disorder in 2D COFs under solution conditions and their impact on the adsorption performance of metal ions have not been observed yet. Herein, the synthesis of a novel carboxyl-functionalized COF featuring stable ß-ketoenamine and benzimidazole linkages, named DMTP-COOH, is presented. DMTP-COOH exhibits excellent selective adsorption capability for uranium, with significantly different adsorption capacities observed after treatment with different solvents. This notable difference in adsorption capacity is observed under varying pH, concentration, time, and even in the presence of multiple competing ions. This work represents the first observation of the significant impact of solvent soaking treatment on the selective adsorption performance of COFs for uranium under liquid conditions.
RESUMEN
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder characterized by cognitive impairments. Despite the limited efficacy of current treatments for AD, the 1,2,4-oxadiazole structure has garnered significant attention in medicinal chemistry due to its potential impact on mGluR1 and its association with AD therapy. In this study, a series of novel 1,2,4-oxadiazole derivatives were designed, synthesized, and evaluated for the neuroprotective effects in human neuroblastoma (SH-SY5Y) cells. Among all the derivatives tested, FO-4-15 (5f) existed the lowest cytotoxicity and the highest protective effect against H2O2. Based on these in vitro results, FO-4-15 was administered to 3×Tg mice and significantly improved the cognitive impairments of the AD mice. Pathological analysis showed that FO-4-15 significantly reduced Aß accumulation, Tau hyper-phosphorylation, and synaptic impairments in the 3×Tg mice. Dysfunction of the CaMKIIα/Fos signaling pathway in 3×Tg mice was found to be restored by FO-4-15 and the necessity of the CaMKIIα/Fos for FO-4-15 was subsequently confirmed by the use of a CaMKIIα inhibitor in vitro. Beyond that, mGluR1 was identified to be a potential target of FO-4-15, and the interaction of FO-4-15 and mGluR1 was displayed by Ca2+ flow increase, molecular docking, and interaction energy analysis. The target of FO-4-15 was further confirmed in vitro by JNJ16259685, a nonselective inhibitor of mGluR1. These findings suggest that FO-4-15 may hold promise as a potential treatment for Alzheimer's disease.
RESUMEN
BACKGROUND: Few studies have characterized the burden of late effects among childhood ependymoma survivors. To address this gap, we examined these sequelae using real-world health services data in a population-based ependymoma survivor cohort. METHODS: All individuals younger than 18 years diagnosed with an ependymoma in Ontario, Canada between 1987 and 2015 who had survived at least 5 years from their latest pediatric cancer event (index date) were matched 1:5 with population controls. Following linkage with provincial health services data, the cumulative incidences of multiple medical and functional outcomes between survivors and controls were compared. RESULTS: Among 96 survivors, 77.1% had been irradiated and 9.4% had received cisplatin. At 10 years post-index, survivors were at significantly higher risk of all-cause mortality (7.1%, 95% confidence interval [CI]: 1.0-13.3 vs. 0.3%, 95% CI: 0.0-1.0; p = .0002), non-obstetric hospitalization (45.1%, 95% CI: 32.6-56.7 vs. 10.6%, 95% CI: 7.6-14.1; p < .0001), stroke (6.5%, 95% CI: 2.3-13.7 vs. 0%; p < .0001), severe hearing loss requiring an amplification device (7.5%, 95% CI: 2.7-15.7 vs. 0%; p < .0001), receiving homecare service (27.6%, 95% CI: 18.5-37.5 vs. 7.7%, 95% CI: 5.3-10.7; p < .0001), and submitting a disability support prescription claim (24.0%, 95% CI: 14.8-34.3 vs. 5.4%, 95% CI: 3.5-7.8; p < .0001) compared to controls. CONCLUSIONS: Pediatric ependymoma survivors are highly vulnerable to severe late sequelae, including death, stroke, severe hearing loss, and disability. Urgent efforts are needed to improve risk-stratification approaches that mitigate exposure to toxic therapies for children with lower risk disease. Interventions to prevent or decrease the risk of developing late sequelae are critical to optimizing survivor long-term health.
RESUMEN
The mechanistic target of rapamycin complex 1 (mTORC1) is indispensable for preserving cellular and organismal homeostasis by balancing the anabolic and catabolic processes in response to various environmental cues, such as nutrients, growth factors, energy status, oxygen levels, and stress. Dysregulation of mTORC1 signaling is associated with the progression of many types of human disorders including cancer, age-related diseases, neurodegenerative disorders, and metabolic diseases. The way mTORC1 senses various upstream signals and converts them into specific downstream responses remains a crucial question with significant impacts for our perception of the related physiological and pathological process. In this review, we discuss the recent molecular and functional insights into the nutrient sensing of the mTORC1 signaling pathway, along with the emerging role of deregulating nutrient-mTORC1 signaling in cancer and age-related disorders.