A common cardiac sodium channel variant associated with sudden infant death in African Americans, SCN5A S1103Y.

Thousands die each year from sudden infant death syndrome (SIDS). Neither the cause nor basis for varied prevalence in different populations is understood. While 2 cases have been associated with mutations in type Valpha, cardiac voltage-gated sodium channels (SCN5A), the "Back to Sleep" campaign has decreased SIDS prevalence, consistent with a role for environmental influences in disease pathogenesis. Here we studied SCN5A in African Americans. Three of 133 SIDS cases were homozygous for the variant S1103Y. Among controls, 120 of 1,056 were carriers of the heterozygous genotype, which was previously associated with increased risk for arrhythmia in adults. This suggests that infants with 2 copies of S1103Y have a 24-fold increased risk for SIDS. Variant Y1103 channels were found to operate normally under baseline conditions in vitro. As risk factors for SIDS include apnea and respiratory acidosis, Y1103 and wild-type channels were subjected to lowered intracellular pH. Only Y1103 channels gained abnormal function, demonstrating late reopenings suppressible by the drug mexiletine. The variant appeared to confer susceptibility to acidosis-induced arrhythmia, a gene-environment interaction. Overall, homozygous and rare heterozygous SCN5A missense variants were found in approximately 5% of cases. If our findings are replicated, prospective genetic testing of SIDS cases and screening with counseling for at-risk families warrant consideration

The incidence of liver injury in Uyghur patients treated for TB in Xinjiang Uyghur autonomous region, China, and its association with hepatic enzyme polymorphisms nat2, cyp2e1, gstm1 and gstt1.

BACKGROUND AND OBJECTIVE: Of three first-line anti-tuberculosis (anti-TB) drugs, isoniazid is most commonly associated with hepatotoxicity. Differences in INH-induced toxicity have been attributed to genetic variability at several loci, NAT2, CYP2E1, GSTM1and GSTT1, that code for drug-metabolizing enzymes. This study evaluated whether the polymorphisms in these enzymes were associated with an increased risk of anti-TB drug-induced hepatitis in patients and could potentially be used to identify patients at risk of liver injury. METHODS AND DESIGN: In a cross-sectional study, 2244 tuberculosis patients were assessed two months after the start of treatment. Anti-TB drug-induced liver injury (ATLI) was defined as an ALT, AST or bilirubin value more than twice the upper limit of normal. NAT2, CYP2E1, GSTM1 and GSTT1 genotypes were determined using the PCR/ligase detection reaction assays. RESULTS: 2244 patients were evaluated, there were 89 cases of ATLI, a prevalence of 4% 9 patients (0.4%) had ALT levels more than 5 times the upper limit of normal. The prevalence of ATLI was greater among men than women, and there was a weak association with NAT2*5 genotypes, with ATLI more common among patients with the NAT2*5*CT genotype. The sensitivity of the CT genotype for identifying patients with ATLI was 42% and the positive predictive value 5.9%. CT ATLI was more common among slow acetylators (prevalence ratio 2.0 (95% CI 0.95,4.20) )compared to rapid acetylators. There was no evidence that ATLI was associated with CYP2E1 RsaIc1/c1genotype, CYP2E1 RsaIc1/c2 or c2/c2 genotypes, or GSTM1/GSTT1 null genotypes. CONCLUSIONS: In Xinjiang Uyghur TB patients, liver injury was associated with the genetic variant NAT2*5, however the genetic markers studied are unlikely to be useful for screening patients due to the low sensitivity and low positive predictive values for identifying persons at risk of liver injury

A Short Review for Ontology Learning: Stride to Large Language Models Trend

Ontologies provide formal representation of knowledge shared within Semantic Web applications. Ontology learning involves the construction of ontologies from a given corpus. In the past years, ontology learning has traversed through shallow learning and deep learning methodologies, each offering distinct advantages and limitations in the quest for knowledge extraction and representation. A new trend of these approaches is relying on large language models (LLMs) to enhance ontology learning. This paper gives a review in approaches and challenges of ontology learning. It analyzes the methodologies and limitations of shallow-learning-based and deep-learning-based techniques for ontology learning, and provides comprehensive knowledge for the frontier work of using LLMs to enhance ontology learning. In addition, it proposes several noteworthy future directions for further exploration into the integration of LLMs with ontology learning tasks

Pharmacokinetics, tissue distribution, excretion, and metabolism of a novel antitumor agent, gambogenic acid, in rats

The plasma pharmacokinetics, tissue distribution, excretion, and metabolism of gambogenic acid (GNA), potential antitumor candidate, were investigated in rats. GNA showed linear pharmacokinetic characteristics in rats within the test dose (1, 2, and 4 mg/kg). The t1/2β was 40.38-41.16 min. GNA showed an extensive distribution into multiple tissues, and the bile excretion is the major pathway of excretion, accounting for 52.12 %. About 40 % of GNA might undergo metabolism in vivo and the main phase I metabolites of GNA may be 10-hydroxygambogenic acid and 9,10-epoxygambogenic acid.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Pharmacokinetics, tissue distribution, excretion, and metabolism of a novel antitumor agent, gambogenic acid, in rats

The plasma pharmacokinetics, tissue distribution, excretion, and metabolism of gambogenic acid (GNA), potential antitumor candidate, were investigated in rats. GNA showed linear pharmacokinetic characteristics in rats within the test dose (1, 2, and 4 mg/kg). The t1/2β was 40.38-41.16 min. GNA showed an extensive distribution into multiple tissues, and the bile excretion is the major pathway of excretion, accounting for 52.12 %. About 40 % of GNA might undergo metabolism in vivo and the main phase I metabolites of GNA may be 10-hydroxygambogenic acid and 9,10-epoxygambogenic acid.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Highly Efficient and Unsupervised Framework for Moving Object Detection in Satellite Videos

Abstract Moving object detection in satellite videos (SVMOD) is a challenging task due to the extremely dim and small target characteristics. Current learning-based methods extract spatio-temporal information from multi-frame dense representation with labor-intensive manual labels to tackle SVMOD, which needs high annotation costs and contains tremendous computational redundancy due to the severe imbalance between foreground and background regions. In this paper, we propose a highly efficient unsupervised framework for SVMOD. Specifically, we propose a generic unsupervised framework for SVMOD, in which pseudo labels generated by a traditional method can evolve with the training process to promote detection performance. Furthermore, we propose a highly efficient and effective sparse convolutional anchor-free detection network by sampling the dense multi-frame image form into a sparse spatio-temporal point cloud representation and skipping the redundant computation on background regions. Coping these two designs, we can achieve both high efficiency (label and computation efficiency) and effectiveness. Extensive experiments demonstrate that our method can not only process 98.8 frames per second on 1024×1024 images but also achieve state-of-the-art performance.Abstract Moving object detection in satellite videos (SVMOD) is a challenging task due to the extremely dim and small target characteristics. Current learning-based methods extract spatio-temporal information from multi-frame dense representation with labor-intensive manual labels to tackle SVMOD, which needs high annotation costs and contains tremendous computational redundancy due to the severe imbalance between foreground and background regions. In this paper, we propose a highly efficient unsupervised framework for SVMOD. Specifically, we propose a generic unsupervised framework for SVMOD, in which pseudo labels generated by a traditional method can evolve with the training process to promote detection performance. Furthermore, we propose a highly efficient and effective sparse convolutional anchor-free detection network by sampling the dense multi-frame image form into a sparse spatio-temporal point cloud representation and skipping the redundant computation on background regions. Coping these two designs, we can achieve both high efficiency (label and computation efficiency) and effectiveness. Extensive experiments demonstrate that our method can not only process 98.8 frames per second on 1024×1024 images but also achieve state-of-the-art performance

Role of a Genetic Variant on the 15q25.1 Lung Cancer Susceptibility Locus in Smoking-Associated Nasopharyngeal Carcinoma

Background: The 15q25.1 lung cancer susceptibility locus, containing CHRNA5, could modify lung cancer susceptibility and multiple smoking related phenotypes. However, no studies have investigated the association between CHRNA5 rs3841324, which has been proven to have the highest association with CHRNA5 mRNA expression, and the risk of other smoking-associated cancers, except lung cancer. In the current study we examined the association between rs3841324 and susceptibility to smoking-associated nasopharyngeal carcinoma (NPC). Methods: In this case-control study we genotyped the CHRNA5 rs3841324 polymorphism with 400 NPC cases and 491 healthy controls who were Han Chinese and frequency-matched by age (±5 years), gender, and alcohol consumption. Univariate and multivariate logistic regression analyses were used to calculate the odds ratio (OR) and 95% confidence intervals (95% CI)

Dysregulated CREB3 cleavage at the nuclear membrane induces karyoptosis-mediated cell death

Cancer cells often exhibit resistance to apoptotic cell death, but they may be vulnerable to other types of cell death. Elucidating additional mechanisms that govern cancer cell death is crucial for developing new therapies. Our research identified cyclic AMP-responsive element-binding protein 3 (CREB3) as a crucial regulator and initiator of a unique cell death mechanism known as karyoptosis. This process is characterized by nuclear shrinkage, deformation, and the loss of nuclear components following nuclear membrane rupture. We found that the N-terminal domain (aa 1-230) of full-length CREB3 (CREB3-FL), which is anchored to the nuclear inner membrane (INM), interacts with lamins and chromatin DNA. This interaction maintains a balance between the outward force exerted by tightly packed DNA and the inward constraining force, thereby preserving INM integrity. Under endoplasmic reticulum (ER) stress, aberrant cleavage of CREB3-FL at the INM leads to abnormal accumulation of the cleaved form of CREB3 (CREB3-CF). This accumulation disrupts the attachment of CREB3-FL to the INM, resulting in sudden rupture of the nuclear membrane and the onset of karyoptosis. Proteomic studies revealed that CREB3-CF overexpression induces a DNA damage response akin to that caused by UVB irradiation, which is associated with cellular senescence in cancer cells. These findings demonstrated that the dysregulation of CREB3-FL cleavage is a key factor in karyoptotic cell death. Consequently, these findings suggest new therapeutic strategies in cancer treatment that exploit the process of karyoptosis

Pharmacokinetics, tissue distribution, excretion, and metabolism of a novel antitumor agent, gambogenic acid, in rats

The plasma pharmacokinetics, tissue distribution, excretion, and metabolism of gambogenic acid (GNA), potential antitumor candidate, were investigated in rats. GNA showed linear pharmacokinetic characteristics in rats within the test dose (1, 2, and 4 mg/kg). The t1/2β was 40.38-41.16 min. GNA showed an extensive distribution into multiple tissues, and the bile excretion is the major pathway of excretion, accounting for 52.12 %. About 40 % of GNA might undergo metabolism in vivo and the main phase I metabolites of GNA may be 10-hydroxygambogenic acid and 9,10-epoxygambogenic acid.Colegio de Farmacéuticos de la Provincia de Buenos Aire