Search Results (120)

Background: While a few studies suggest that depigmentation tends to develop more frequently in patients with malignant melanoma (MM), the association between vitiligo and MM has been sparsely investigated in the setting of controlled studies. Methods: A population-based case–control study compared 14,632 patients with vitiligo with 71,580 control subjects matched by age, sex, and ethnicity regarding the prevalence of preexisting MM. Logistic regression was used to calculate the odds ratio (OR) and 95% confidence intervals (CIs) of developing vitiligo both in univariate and multivariate models, adjusting for demographic variables and comorbidities. The OR was also stratified by age, sex, ethnicity, and ultraorthodox status. Results: The prevalence of preexisting MM was statistically comparable between individuals with vitiligo and controls (0.30% vs. 0.35%, respectively). In the general study population, a history of MM was not significantly associated with an elevated likelihood of developing vitiligo (multivariate OR, 1.03; CI 95%, 0.76–1.40). Among the Arab population, however, preexisting MM was associated with a sixfold-increased likelihood of subsequent vitiligo (univariate OR, 6.55; 95% CI, 1.46–29.27). Patients with vitiligo and comorbid MM were older at the onset of vitiligo, had a higher burden of comorbid conditions, and showed an overrepresentation of Jewish ancestry. Conclusions: A history of MM does not increase the probability of vitiligo in the general Israeli population, except among the Arab minority, who show a sixfold-elevated odds of vitiligo after MM. Further investigation is essential to gain deeper insights into this relationship. Full article

Background: The Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) was a 3-year, multicenter, randomized controlled trial to test the effects of the MIND diet on cognitive decline in 604 individuals at risk for Alzheimer’s dementia. Here, we describe the genotyping, imputation, and quality control (QC) procedures for the genetic data of trial participants. Methods: DNA was extracted from either whole blood or serum, and genotyping was performed using the Infinium Global Diversity Array. Established sample and SNP QC procedures were applied to the genotyping data, followed by imputation using the 1000 Genomes Phase 3 v5 reference panel. Results: Significant study-site, specimen type, and batch effects were observed. A total of 494 individuals of inferred European ancestry and 58 individuals of inferred African ancestry were included in the final imputed dataset. Evaluation of the imputed APOE genotype against gold-standard sequencing data showed high concordance (98.2%). We replicated several known genetic associations identified from previous genome-wide association studies, including SNPs previously linked to adiponectin (rs16861209, p = 1.5 × 10⁻⁵), alpha-linolenic acid (rs174547, p = 1.3 × 10⁻⁷), and alpha-tocopherol (rs964184, p = 0.003). Conclusions: This dataset represents the first genetic resource derived from a dietary intervention trial focused on cognitive outcomes. It enables investigation of genetic contributions to variability in cognitive response to the MIND diet and supports integrative analyses with other omics data types to elucidate the biological mechanisms underlying cognitive decline. These efforts may ultimately inform precision nutrition strategies to promote cognitive health. Full article

Background/Objectives: Latinos, particularly those of Mexican ancestry, experience high rates of type 2 diabetes and sleep disturbances, exacerbating adverse health outcomes. This study aimed to examine the prevalence of excessive daytime sleepiness and its associations with diet, cardiometabolic risk factors, and glycemic control in this population. Methods: This cross-sectional study utilized data from the El Banco por Salud biobank, including 1685 participants (aged 52.6 ± 14.5 years, BMI: 32.4 ± 7.0 kg/m²) recruited from Federally Qualified Community Health Centers. Excessive daytime sleepiness was assessed using the Epworth Sleepiness Scale, while dietary information was obtained via the Brief Dietary Assessment Tool for Hispanics. Primary outcomes included cardiometabolic risk factors and glycated hemoglobin (HbA1c) levels. Results: Excessive daytime sleepiness (Epworth Sleepiness Scale > 10) was present in 22.0% of participants and was associated with higher BMI (p < 0.001), larger waist circumference (p = 0.002), poorer diet quality, increased dyslipidemia (p = 0.036), and elevated HbA1c (p = 0.007). Linear regression analyses confirmed that excessive daytime sleepiness was significantly associated with higher HbA1c levels, both in unadjusted (R² = 0.011; p < 0.001) and adjusted for demographic, anthropometric, and socioeconomic factors (R² = 0.107; p = 0.004) models. Conclusions: Excessive daytime sleepiness among Latinos of Mexican ancestry is associated with unhealthy dietary patterns and poor glycemic control, highlighting the need for targeted interventions addressing sleep and dietary habits in this vulnerable population. Full article

Background/Objectives: The RTK-RAS signaling cascade is a central axis in colorectal cancer (CRC) pathogenesis, governing cellular proliferation, survival, and therapeutic resistance. Somatic alterations in key pathway genes—including KRAS, NRAS, BRAF, and EGFR—are pivotal to clinical decision-making in precision oncology. However, the integration of these genomic events with clinical and demographic data remains hindered by fragmented resources and a lack of accessible analytical frameworks. To address this challenge, we developed AI-HOPE-RTK-RAS, a domain-specialized conversational artificial intelligence (AI) system designed to enable natural language-based, integrative analysis of RTK-RAS pathway alterations in CRC. Methods: AI-HOPE-RTK-RAS employs a modular architecture combining large language models (LLMs), a natural language-to-code translation engine, and a backend analytics pipeline operating on harmonized multi-dimensional datasets from cBioPortal. Unlike general-purpose AI platforms, this system is purpose-built for real-time exploration of RTK-RAS biology within CRC cohorts. The platform supports mutation frequency profiling, odds ratio testing, survival modeling, and stratified analyses across clinical, genomic, and demographic parameters. Validation included reproduction of known mutation trends and exploratory evaluation of co-alterations, therapy response, and ancestry-specific mutation patterns. Results: AI-HOPE-RTK-RAS enabled rapid, dialogue-driven interrogation of CRC datasets, confirming established patterns and revealing novel associations with translational relevance. Among early-onset CRC (EOCRC) patients, the prevalence of RTK-RAS alterations was significantly lower compared to late-onset disease (67.97% vs. 79.9%; OR = 0.534, p = 0.014), suggesting the involvement of alternative oncogenic drivers. In KRAS-mutant patients receiving Bevacizumab, early-stage disease (Stages I–III) was associated with superior overall survival relative to Stage IV (p = 0.0004). In contrast, BRAF-mutant tumors with microsatellite-stable (MSS) status displayed poorer prognosis despite higher chemotherapy exposure (OR = 7.226, p < 0.001; p = 0.0000). Among EOCRC patients treated with FOLFOX, RTK-RAS alterations were linked to worse outcomes (p = 0.0262). The system also identified ancestry-enriched noncanonical mutations—including CBL, MAPK3, and NF1—with NF1 mutations significantly associated with improved prognosis (p = 1 × 10⁻⁵). Conclusions: AI-HOPE-RTK-RAS exemplifies a new class of conversational AI platforms tailored to precision oncology, enabling integrative, real-time analysis of clinically and biologically complex questions. Its ability to uncover both canonical and ancestry-specific patterns in RTK-RAS dysregulation—especially in EOCRC and populations with disproportionate health burdens—underscores its utility in advancing equitable, personalized cancer care. This work demonstrates the translational potential of domain-optimized AI tools to accelerate biomarker discovery, support therapeutic stratification, and democratize access to multi-omic analysis. Full article

Background: Second-generation androgen receptor signaling inhibitors are one of the main treatment options in metastatic castration-resistant prostate cancer (mCRPC). Nonetheless, a considerable proportion show limited response to treatment, which indicates the need for convenient, easily accessible predictor biomarkers, a role suited for liquid biopsy. Methods: We conducted a PRISMA-compliant systematic review of four databases (Embase, Medline, Scopus, Web of Science) to identify all studies (observational studies and clinical trials) investigating cell-free DNA, circulating tumor cells, exosomes, and circulating RNAs as prognostic markers in metastatic castration-resistant patients starting androgen receptor signaling inhibitors. We excluded studies that evaluated combination therapies, rare histological subtypes or included nonmetastatic or castrate-sensitive disease. We also evaluated whether published papers followed reporting guidelines (REMARK, STROBE, or CONSORT for abstracts). Results: We identified a total of 123 reports, from which we identified only a few well-studied and consistent biomarkers: androgen receptor overexpression/copy number gain and splice variant 7, as well as disease burden markers (circulating tumor DNA fraction and circulating tumor cell concentration). Alterations or copy number loss in tumor suppressors PTEN, RB1, and TP53 were second in terms of quantity and consistency of evidence. However, a large majority of identified biomarkers were relatively understudied or inconsistent. We identified two potential vulnerabilities: inconsistent adherence to reporting guidelines and the under-inclusion of patients of non-Western European ancestry. Conclusions: A large number of biomarkers were linked to worse outcomes in prostate cancer; nonetheless, in most cases, the evidence is limited or inconsistent, or even contradictory. The main exceptions pertain to androgen receptor signaling and disease burden, and, to a smaller extent, to certain tumor suppressor genes. Further studies are needed to confirm their clinical utility, using clear and consistent methodologies and including patients from currently understudied populations. Full article

Background/Objectives: The implementation of polygenic scores (PGSs) and multifactorial risk assessments (MFRAs) has the potential to enhance breast cancer risk stratification, particularly in carriers of moderate-penetrance pathogenic variants (PVs), whose risk profiles often remain unclear if testing is limited to monogenic risk factors. Methods: To enhance breast cancer risk stratification, we included the BCAC313 polygenic score, together with MFRA, for carriers of moderate-penetrance pathogenic variants (PVs) during routine diagnostics and assessed its effect on the classification of patients’ risk categories in a real-world cohort at our center in its first year of implementation. Seventeen carriers with PVs in moderate-risk breast cancer genes were included in this study. Thirteen of them qualified for analysis for a full MFRA, including PGS, according to ancestry estimation and clinical criteria. The MFRA was performed using the CanRisk tool, which incorporates clinical, lifestyle, familial, and genetic data, including the BCAC313 score. Results: PGS z-scores were significantly higher in breast cancer patients compared to the unaffected control cohort (p = 0.016). The MFRA, including PGS, increased risk estimates for contralateral breast cancer in seven of eight patients with breast cancer and for primary breast cancer in three of five healthy carriers, compared to the risk conferred by the MFRA and moderate-penetrance pathogenic variant alone. Risk estimates varied widely, demonstrating the value of MFRA in personalized care. In five cases, one with a CHEK2-PV and four with an ATM-PV, the modified risk assessment contributed to the surgical decision for a prophylactic mastectomy. Conclusions: The MFRA, including PGS, provides the clinically meaningful refinement of breast cancer risk estimates in individuals with moderate-risk PVs. Personalized risk predictions can inform clinical management and support decision-making, which highlights the utility of this approach in clinical practice. Full article

Background/Objectives: Cardiovascular diseases are a global health issue with an increasing burden and are exacerbated by hypertension. High blood pressure is partly attributed to genetic variants that are generally not well understood or extensively studied in sub-Saharan African populations. Variants linked to blood pressure have been found through genome-wide association studies (GWASs), which were mostly conducted among European ancestry populations; however, limited research has been undertaken in Africa. The current study evaluated single-nucleotide polymorphisms (SNPs) of PCSK9, ABCA1, LPL, and PON1 in relation to blood pressure measurements of 1839 Ghanaian adults. Methods: Genotypes were extracted from data generated by the H3Africa SNP array. After adjusting for sex, age, smoking, and body mass index (BMI), inferential statistics were used to investigate the relationships between SNPs and blood pressure (BP) indices. Additionally, Bonferroni correction was used to adjust for multiple testing. Results: Diastolic blood pressure (DBP) and the minor allele T of the PCSK9 variant (rs17111557) were positively associated at p = 0.006 after covariate adjustments. Although this novel DBP-associated variant is located in the 3′ untranslated region (3′ UTR) of the PCSK9 gene, in silico functional prediction suggests it is an expression quantitative trait locus (eQTL) that may change the binding site of transcription factors, potentially altering the rate of transcription and impacting DBP in this Ghanaian population. Conclusions: Our findings highlight the role of genetics in hypertension risk and the potential of discovering new therapies targeting isolated diastolic blood pressure in this rural African population. Full article

Background/Objectives: Epilepsy and sleep disturbances frequently co-occur, yet the causal nature of this relationship remains uncertain, particularly in relation to epilepsy subtypes and status epilepticus. We investigated potential bidirectional causal associations between sleep-related traits and epilepsy, including subtypes and status epilepticus, using Mendelian randomization (MR). Methods: We conducted two-sample MR using genome-wide association study (GWAS) summary statistics from European ancestry cohorts. Epilepsy, its subtypes, and status epilepticus were analyzed using data from the International League Against Epilepsy Consortium on Complex Epilepsies (ILAE) and the FinnGen study. Nine self-reported sleep-related traits were derived from the UK Biobank-based GWAS. Causal estimates were primarily obtained using inverse variance weighted models with additional MR analysis methods. Pleiotropy and heterogeneity were assessed to enhance the robustness of the finding. Results: Several subtype-specific associations were identified, with direction and statistical significance varying across cohorts and subtypes. After correction for multiple testing and filtering for tests with ≥10 instrumental variables to ensure robust and reliable MR estimates, several consistent and potentially mutually reinforcing associations emerged. In the ILAE cohort, focal epilepsy with hippocampal sclerosis was associated with an increased risk of insomnia, and juvenile myoclonic epilepsy with reduced sleep duration. In the FinnGen cohort, overall epilepsy was associated with increased risk of both insomnia and daytime sleepiness. In reverse MR, daytime sleepiness and napping were associated with increased risk of epilepsy, while daytime napping and frequent insomnia symptoms were linked to elevated risk of status epilepticus. Conclusions: Our findings reveal subtype-specific and bidirectional causal links between epilepsy and sleep-related traits. These results highlight the biological interplay between epileptic networks and sleep regulation and underscore the need for further clinical and mechanistic studies. Full article

Background/Objectives: Endocrine hormones play critical roles in regulating physiological processes, and previous studies have reported their associations with psychiatric disorders. Levels of endocrine hormones and the risk of developing psychiatric disorders are influenced by both genetic and non-genetic factors. However, the shared genetic basis underlying these associations remains largely unexplored. This study aims to dually evaluate the genetic correlations among endocrine hormones, including thyroid and sex hormones, as well as between endocrine hormone metrics and psychiatric disorders to identify potential shared genetic architectures. Methods: We obtained genome-wide association study summary statistics for six thyroid hormone metrics, three sex hormone metrics, and ten psychiatric disorders from predominantly European-ancestry populations. Genetic correlations were computed using linkage disequilibrium score regression after harmonizing variant data to ensure consistency across studies. Results: Significant genetic correlations were observed among thyroid and sex hormone metrics, indicating a strong shared genetic basis. Sex hormones exhibited multiple genetic correlations with psychiatric disorders, including negative correlations between sex hormone-binding globulin and attention-deficit hyperactivity disorder (ADHD) (p = 3.95 × 10⁻¹²) and major depressive disorder (p = 4.67 × 10⁻⁵), and positive genetic correlations with anorexia nervosa (p = 2.86 × 10⁻¹²) and schizophrenia (p = 2.00 × 10⁻⁴). Testosterone and estradiol had negative genetic correlations with ADHD and major depressive disorder, while testosterone had positive genetic correlations with anorexia nervosa and schizophrenia. Although thyroid hormone metrics did not exhibit Bonferroni-significant genetic correlations, nominal associations were observed, such as a negative genetic correlation between thyroid-stimulating hormone and major depressive disorder (p = 2.33 × 10⁻²). Conclusions: These findings suggest a shared genetic basis between endocrine hormones and psychiatric disorders, particularly for sex hormones. Future studies leveraging larger, more diverse populations are warranted to validate and extend the genetic correlations observed in this study. Full article

Background/Objectives: The anti-Müllerian hormone (AMH) is a key biomarker of the ovarian reserve, correlating with ovarian follicle count, fertility outcomes, and menopause timing. Understanding its genetic determinants has broad implications for female reproductive health. However, prior genome-wide association studies (GWASs) have focused exclusively on women of European ancestry, limiting insights into diverse populations. Methods: We conducted a GWAS to identify genetic loci associated with circulating AMH levels in a sample of 1185 Samoan women from two independently recruited samples. Using a Cox mixed-effects model we accounted for AMH levels below detectable limits and meta-analysed the summary statistics using a fixed-effect model. To prioritize variants and genes, we used FUMA and performed colocalization and transcriptome-wide association analysis (TWAS). We also assessed whether any previously reported loci were replicated in our GWAS. Results: We identified eleven genome-wide suggestive loci, with the strongest signal at ARID3A (19-946163-G-C; p = 2.32 × 10⁻⁷) and replicated rs10093345 near EIF4EBP1. The gene-based testing revealed ARID3A and R3HDM4 as significant genes. Integrating GWAS results with expression quantitative trait loci via TWAS, we detected seven transcriptome-wide significant genes. The lead variant in ARID3A is in high linkage disequilibrium (r² = 0.79) with the known age-at-menopause variant 19-950694-G-A. Nearby KISS1R is a biologically plausible candidate gene that encodes the kisspeptin receptor, a regulator of ovarian follicle development linked to AMH levels. Conclusions: This study expands our understandings of AMH genetics by focusing on Samoan women. While these findings may be particularly relevant to Pacific Islanders, they hold broader implications for reproductive phenotypes such as the ovarian reserve, menopause timing, and polycystic ovary syndrome. Full article

Background/Objectives: The prevalence of dementia among South Asians across India is high among those who are 65 years and older, yet little is known about genetic risk factors for dementia in this population. Methods: Using whole-genome sequence data from 2680 participants from the Diagnostic Assessment of Dementia for the Longitudinal Aging Study of India (LASI-DAD), we performed a gene-based analysis on the missense/loss-of-function (LoF) and brain-specific promoter/enhancer variants of 84 genes, previously associated with AD in European Ancestry (EA). These analyses were performed separately, both with and without incorporating additional annotation weights (e.g., deleteriousness, conservation scores), using the variant-Set Test for Association using Annotation infoRmation (STAAR). We investigated associations with the Hindi Mental State Examination (HMSE) score and factor scores for general cognitive function and five cognitive domains. Results: In the missense/LoF analysis, without annotation weights and controlling for age, sex, state/territory, and genetic ancestry, three genes were associated with at least one measure of cognitive function (FDR q < 0.1). APOE was associated with four measures of cognitive function, PICALM was associated with HMSE score, and TSPOAP1 was associated with executive function. The most strongly associated variants in each gene were rs429358 (APOE ε4), rs779406084 (PICALM), and rs9913145 (TSPOAP1). Rs779406084 is a rare missense mutation that is enriched in LASI-DAD compared to EA (minor allele frequency = 0.075% vs. 0.0015%). Conclusions: Missense/LoF variants in some genes previously associated with AD in EA are associated with measures of cognitive function in South Asians from India. Analyzing genome sequence data allows the identification of potential novel causal variants enriched in South Asians. Full article

Background. The coevolution of nuclear and mitochondrial genomes has guaranteed mitochondrial function for millions of years. The introduction of European (EUR) and African (AFR) genomes into the Ameridian continent during the Columbus exchange in Latin America created an opportunity to naturally test different combinations of nuclear and mitochondrial genomes. However, the impact of potential “mitonuclear discordance” (MND, differences in ancestries) has not been evaluated in Latin American admixed individuals (AMR) affected with developmental disorders, even though MND alters mitochondrial function and reduces viability in other organisms. Methods. To characterize MND in healthy and affected AMR individuals, we used AMR genotype data from the 1000 Genomes Project (n = 385), two cohorts of 22q.11 deletion syndrome patients 22qDS-ARG (n = 26) and 22qDS-CHL (n = 58), and a cohort of patients with multiple congenital anomalies and/or neurodevelopmental disorders (DECIPHERD, n = 170). Based on their importance to mitochondrial function, genes were divided into all mitonuclear genes (n = 1035), high-mt (n = 167), low-mt (n = 793), or OXPHOS (n = 169). We calculated local ancestry using FLARE and estimated MND as the fraction of nuclear mitochondrial genes ancestry not matching the mtDNA ancestry and ∆MND as (MNDoffspring—MNDmother)/MNDmother. Results. Generally, MND showed distinctive population and haplogroup distributions (ANOVA p < 0.05), with haplogroup D showing the lowest MND of 0.49 ± 0.17 (mean ± s.d.). MND was significantly lower in 22qDS-ARG patients at 0.43 ± 0.24 and DECIPHERD patients at 0.56 ± 0.12 compared to healthy individuals at 0.60 ± 0.09 (ANOVA p < 0.05). OXPHOS and high-mt showed the same trend, but with greater differences between healthy and affected individuals. Conclusions. MND seems to inform population history and constraint among affected individuals, especially for OXPHOS and high-mt genes. Full article

Lung cancer remains as the leading cause of cancer mortality worldwide. However, while current evidence suggests the existence of genomic differences between populations, indicating different risk factors associated with population-level genetic backgrounds, most studies have concentrated on populations of European ancestry, and more research is needed on non-European populations. We analyzed whole-exome sequencing data from 25 Mexican lung adenocarcinoma patients and compared them with a TCGA-PanCancer cohort enriched with patients of European ancestry as reference. Clinically relevant germline variants in cancer susceptibility genes are more frequent in our cohort (32% vs. 6.4%) than in the reference. Several mutational signatures (SBS32, SBS85, SBS12, SBS19) occurred at significantly higher frequencies in the Mexican cohort compared to the reference (p < 0.0001). Interestingly, the smoking-associated signature SBS4, present in 67.6% of smokers in the reference cohort, was absent in smoking Mexican patients (p < 0.01656). Somatic variant frequencies in SLC36A4 (20%; p < 0.00002), AP1S1 (8%; p < 0.00002), and TP53 (16%; p = 0.00005) showed significant differences from the European reference cohort. We demonstrate that all these observed biases were independent of the sample size. This study uncovers distinct genomic biases in lung cancer carcinogenesis in this population, compared to a European ancestry reference population, suggesting implications for precision medicine strategies in Latin American populations. Full article

Background: Primary congenital glaucoma (PCG) is a rare disease with an incidence of 1 in 12,000 to 18,000 in Europeans. The scarcity of the disease and limited access to genetic testing have hindered research, particularly within the Latvian population. Objectives: This study aims to present the preliminary results of a molecular genetic investigation into PCG in a Latvian cohort and to compare the prevalence of gene CYP1B1 variants with other European studies as well as to the general population in Latvia. Methods: Twenty probands with clinically diagnosed PCG and 36 family members enrolled in the study. Genetic testing was conducted using genomic DNA from peripheral blood using next generation sequencing (NGS) of seven selected genes: CYP1B1, FOXC1, FOXE3, PXDN, PITX2, PITX3, PAX6, and CPAMD8. Four probands had whole-genome sequencing (WGS). Results: All participants were of European ancestry, with no family history of PCG. Most probands were diagnosed in their first year of life, with a female to male ratio of 1:1.2 and with 80.0% of cases being unilateral. No CYP1B1 pathogenic variants were identified in the screened subjects. However, a heterozygous missense variant c.4357C>A (p.Pro4357Thr) in the PXDN gene was found in one proband and one of her parents that was classified as a variant of uncertain significance. Conclusions: This study represents the first genetic characterization of PCG in the Latvian population. Using NGS, we identified no pathogenic variants in the CYP1B1 gene among affected individuals. Preliminary evidence from this cohort does not support CYP1B1 variants as a predominant cause of PCG, though larger studies are needed to confirm this observation. Comprehensive genetic screening using whole-exome or whole-genome sequencing will be essential to identify the underlying genetic etiology of PCG in Latvia. Full article

Background: Bighead carp (Hypophthalmichthys nobilis), a vital species in China’s freshwater ecosystems and aquaculture, has experienced significant population declines due to habitat degradation and intensive farming. Methods: In this study, eight polymorphic microsatellite markers were utilized to examine the genotypes and genetic diversity of 320 individuals of bighead carp populations located in the middle Yangtze River. This included four wild populations (ZX, DTH, SS, WH) and six cultured populations (HH, XZ, CH, QC, CD, HG). Results: Wild populations exhibited significantly higher genetic diversity (mean Na = 12.25 ± 0.63, Ho = 0.802 ± 0.063) than cultured groups (mean Na = 8.85 ± 1.21, He = 0.779 ± 0.032). Low differentiation (Fst < 0.05) among wild populations indicated high connectivity with low genetic structure, whereas cultured populations CH and HG showed moderate-to-high differentiation (Fst = 0.156–0.293). Bayesian analysis (K = 7) revealed a distinct clustering of wild populations, while cultured stocks exhibited admixed genetic ancestries. Bottleneck tests confirmed recent genetic bottlenecks in three cultured populations. Conclusions: Wild bighead carp populations retain a critical genetic diversity, serving as reservoirs for conservation, while intensive aquaculture practices threaten genetic integrity through allele loss and inbreeding. Full article