Search Results (258)

Serotonin reuptake inhibitors (SSRIs) are commonly prescribed to pregnant women experiencing depression. Such drugs, however, might adversely affect placenta and fetal brain development. Parietal trophoblast giant cells (pTGCs) in the mouse placenta are postulated to internalize maternal serotonin (5-HT) via transport through SERT, encoded by Slc6a4, and to provide the initial source of 5-HT to the emerging brain via the placental–brain axis. Genetic deletion of Slc6a4 in pTGCs has been hypothesized to impact placental and fetal brain development. A transgenic mouse line with high-affinity SERT, encoded by Slc6a4, was selectively deleted by pairing mice with Cre recombinase linked to Prl2c2, with LoxP sites flanking the Slc6a4 gene. PRL2C2 is solely expressed by pTGCs and other giant cells of the placenta. To compare placental and fetal brain development in selective Slc6a4 KO and WT mice, 5-HT content in the placenta and fetal brains of conceptuses was measured. No significant differences in 5-HT content were evident between knockout (KO) and wild-type (WT) placentas or fetal brains. However, there were significantly fewer pTGCs in KO placentas compared to WT (p ≤ 0.05). Sexually dimorphic differences in gene expression were evident in the placenta and fetal brain between KO and WT counterparts, with female conceptuses showing the most dramatic responses, including decrease in Prl7a2, Prl5a1, Prl3a1, Slc28a3, and Ceacam 15 in female placental samples. These findings suggest that ablation of Slc6a4 in pTGC disrupts the placenta–brain axis in a sex-dependent manner. The results might have important clinical ramifications for pregnant women being treated with SSRIs. Full article

One controversial issue in pituitary pathology is the simultaneous proliferation of PitNETs and endothelial cells. No previous studies have compared the MIB1 Labeling Index (MIB1 LI) of PitNETs and stromal endothelial compartments and its connection with VEGF protein and gene expression. Simultaneous PitNETs proliferation index assessment in tumor and endothelial cells is related to VEGF protein and gene expression, and by using the automated QuPath platform for digital image analysis (DIA), it can be determined whether this dual proliferation specifically characterizes certain PitNETs subtypes. A total of 109 PitNETs were immunostained for endothelial cells (CD34) and proliferation (MIB1). VEGF was assessed by using IHC and RNA scopes. QuPath_DIA measured hormone-dependent MIB1 nuclear expression in tumor and stromal endothelial cells. MIB1 LI correlated with VEGF_mRNA and protein expression. PRL-secreting and non-functioning PitNETs had a high MIB1 LI in stromal endothelial cells. MIB1-positive tumor cell (%MIB1 LI.T) and endothelial cell (%MIB1 LI.E) percentages were substantially correlated (p = 0.01). The profiles of VEGF and hormones significantly and heterogeneously impact the MIB1-LI of tumor and endothelial cells. Tumor–endothelial cell proliferative interaction is specific to PRL-secreting and non-functioning PitNETs. These findings suggest that digital analysis of MIB1 and VEGF expression may serve as a valuable tool for risk stratification in PitNETs. Full article

Mutations in the POU1F1 gene cause defects in the expression of the genes encoding thyroid-stimulating hormone (TSH)-β subunit, growth hormone (GH), and prolactin (PRL). Here, we characterized 15 missense and nonsense mutations. Protein stability was reduced in the P14L, P24L, F135C, K145X, F233S and E250X mutants. Transactivation by 15 mutants in the TSHβ promoter was moderately correlated with that of the PRL promoter. Based on their transcriptional activity, we classified them into three groups: group I, equivalent to the wild type; group II, partial; and group III, substantially lost. A review of case reports on four patients with group II mutations revealed that TSH deficiency manifested after recombinant GH therapy. A transcription factor, GATA2, is the main activator in the TSHβ gene, while POU1F1 protects its function from inhibition by the suppressor region (SR). We found that the SR is critical for the pathogenesis of TSH deficiency. The transactivation of the TSHβ promoter by the K216E mutant was equivalent to that of wild-type POU1F1; however, that of the PRL promoter was low, while the opposite was found in the R271W mutant. The functional property of K216E suggests that the interaction of POU1F1 with GATA2 may not always be necessary for the activation of the TSHβ promoter. Full article

Background: Endometriosis is a chronic inflammatory disorder that affects approximately 10% of women of reproductive age and exhibits tumor-like characteristics such as invasion, recurrence, and hormone-dependent proliferation despite its benign nature. Its pathogenesis is thought to involve hormonal imbalance, oxidative stress, hypoxia, immune dysregulation, and epigenetic alterations. This review summarizes how these factors contribute to lesion formation through intracellular signaling pathways, with a particular focus on the role of the stress-responsive transcription factor Forkhead box O (FOXO1). Methods: A comprehensive literature search was conducted using PubMed and Google Scholar without temporal restriction. Results: FOXO1 is a transcription factor that integratively regulates decidualization, cellular senescence, autophagy, and apoptosis. In the normal endometrium, under mild stress or hormonal stimulation, FOXO1 induces decidualization-associated genes (PRL, IGFBP1) and antioxidant enzymes, thereby promoting differentiation and survival. In contrast, in endometriosis, activation of the PI3K/AKT signaling pathway and an estrogen-dominant environment suppress the nuclear activity of FOXO1, leading to apoptosis resistance, accumulation of senescent cells, and chronic inflammation through the senescence-associated secretory phenotype (SASP). Moreover, depending on the intensity and duration of oxidative, metabolic, and environmental stress, FOXO1 drives distinct cellular fates—including decidualization, senescence, and apoptosis—thus contributing to the persistence and progression of endometriotic lesions. Conclusion: Dysregulation of the FOXO1-dependent cellular fate–control network plays a central role in the development of endometriosis. Elucidating the molecular mechanisms governing FOXO1 activity and its nuclear dynamics will be crucial for a comprehensive understanding of disease progression and for the development of novel therapeutic strategies. Full article

Background and Objective: Changes in female sex hormone levels are closely linked to the development and progression of uterine fibroids (UFs). Clinical approaches to fibroid management vary according to guidelines and depend on patient symptoms, fibroid size, and clinician judgment. Despite available diagnostic tools, surgical decisions remain largely subjective. With the advancement of artificial intelligence (AI) and clinical decision support technologies, clinical experience can now be transferred into data-driven computational models trained with hormone-based parameters. To develop a clinical decision support algorithm that predicts surgical necessity for uterine fibroids by integrating fibroid characteristics and female sex hormone levels. Methods: This multicenter study included 618 women with UFs who presented to three hospitals; 238 underwent surgery. Statistical analyses and artificial intelligence-based modeling were performed to compare surgical and non-surgical groups. Training was conducted with each hormone—follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen (E2), prolactin (PRL), and anti-Müllerian hormone (AMH)—and with 126 input combinations including hormonal and morphological variables. Five supervised learning algorithms—support vector machine, decision tree, random forest, and k-nearest neighbors—were applied, resulting in 630 trained models. In addition to this retrospective development phase, a prospective validation was conducted in which 20 independent clinical cases were evaluated in real time by a gynecologist blinded to both the model predictions and the surgical outcomes. Agreement between the clinician’s assessments and the model outputs was measured. Results: FSH, LH, and PRL levels were significantly lower in the surgery group (p < 0.001, 0.009, and <0.001, respectively), while E2 and AMH were higher (p = 0.012 and 0.001). Fibroid volume was also greater among surgical cases (90.8 cc vs. 73.1 cc, p < 0.001). The random forest model using LH, FSH, E2, and AMH achieved the highest accuracy of 91 percent. In the external validation phase, the model’s predictions matched the blinded gynecologist’s decisions in 18 of 20 cases, corresponding to a 90% concordance rate. The two discordant cases were later identified as borderline scenarios with clinically ambiguous surgical indications. Conclusions: The decision support algorithm integrating hormonal and fibroid parameters offers an objective and data-driven approach to predicting surgical necessity in women with UFs. Beyond its strong internal performance metrics, the model demonstrated a high level of clinical concordance during external validation, achieving a 90% agreement rate with an independent, blinded gynecologist. This alignment underscores the model’s practical reliability and its potential to reduce subjective variability in surgical decision-making. By providing a reproducible and clinically consistent framework, the proposed AI-based system represents a meaningful advancement toward the validated integration of computational decision tools into routine gynecological practice. Full article

Siniperca chuatsi, commonly known as mandarin fish, is one of the most economically valuable freshwater species in China. In 2022, the national aquaculture production of mandarin fish reached approximately 401,000 tons, accounting for a significant share of freshwater aquaculture in China and nearly dominating the global commercial farming landscape. With the rapid development of recirculating aquaculture systems (RASs), higher requirements have been raised for feeding efficiency and fish health monitoring. Traditional on-site visual observation methods are highly subjective, inefficient, difficult to quantify, and prone to misjudgment under conditions such as insufficient illumination, turbid water, or high stocking density. To address these challenges, this study proposes FishSegNet-PRL, an instance segmentation-based model designed to quantify the feeding intensity of mandarin fish. The model is built upon the YOLOv11-seg framework, enhanced with a P2 detection layer (P), a residual cross-stage spatial–channel attention module (RCSOSA, R), and a lightweight semantic-detail-enhanced cascaded decoder (LSDECD, L). These improvements collectively enhance small-target detection capability, boundary segmentation accuracy, and real-time inference performance. Experimental results demonstrate that FishSegNet-PRL achieves superior performance in mandarin fish instance segmentation, with a Box mAP50 of 85.7% and a Mask mAP50 of 79.4%, representing improvements of approximately 4.6% and 13.2%, respectively, compared with the baseline YOLOv11-seg model. At the application level, multiple feeding intensity quantification indices were constructed based on the segmentation results and evaluated, achieving a temporal intersection-over-union (IoU_time) of 95.9%. Overall, this approach enables objective and fine-grained assessment of mandarin fish feeding behavior, striking an effective balance between accuracy and real-time performance. It provides a feasible and efficient technical solution for intelligent feeding and behavioral monitoring in aquaculture. Full article

Standard operating procedures (SOPs) serve as critical control mechanisms in manufacturing systems, yet systematic approaches for quantifying procedural inefficiencies remain theoretically underdeveloped. Unlike traditional qualitative SOP analysis methods that rely on expert intuition and subjective assessment, current procedural optimization approaches lack the systematic rigor applied to physical process improvement. While lean manufacturing principles have demonstrated effectiveness in physical process optimization, their systematic application to procedural analysis represents an unexplored theoretical domain with significant potential for manufacturing systems improvement. This research addresses this gap by developing the Procedural Waste Index (PWI) framework, which establishes the first systematic theoretical integration of lean waste identification principles with procedural analysis. The framework extends the seven wastes of lean manufacturing to procedural analysis through systematic mapping to procedural elements identified via the extended Procedure Representation Language (e-PRL), creating a quantitative approach that enables the objective measurement of procedural efficiency where only subjective assessment methods previously existed. The PWI framework provides the following three key advantages over existing approaches: (1) systematic waste identification using proven lean principles rather than ad hoc improvement methods, (2) quantitative measurement capability enabling objective assessment and statistical process control, and (3) multi-perspective analytical framework through three complementary calculation methodologies (weighted aggregation, maximum constraint identification, and root mean square analysis) providing comprehensive analytical perspectives on procedural waste across discrete manufacturing contexts. The theoretical framework demonstrates practical applicability through a systematic analysis of a respirator fit testing procedure, revealing inventory waste as the primary inefficiency (70.0% waste score). This represents the first quantitative procedural waste assessment in the manufacturing literature, contributing to the foundational theory for systematic procedural optimization while establishing a methodology for future empirical validation studies. Full article

The Loess Plateau is one of the most landslide-prone regions in China, where rainfall-induced shallow loess landslides severely constrain regional economic and social development. Therefore, investigating the stability of shallow loess slopes under rainfall conditions is of great significance. Taking Yuzhong County in Gansu Province as an example, this study uses the SINMAP model (Version 2.0) to assess slope stability. The areas of unstable zones under different rainfall intensities were identified, and the spatial distribution of hazard sites was analyzed to evaluate the applicability of this deterministic physical model in the study area. Furthermore, a Personnel Risk Level (PRL) determined by combining population density with the Stability Index (SI, defined as the probability that the factor of safety exceeds 1: SI = Prob (FS > 1)) was proposed and applied to assess the potential impact of landslides on local residents. The novelty of this study lies in three aspects: (1) targeting Yuzhong County (a loess region with scarce comprehensive landslide risk assessments) to fill the regional research gap, (2) quantifying PRL through a modified hazard index (HI = population density × (1/SI)) to achieve spatialized risk mapping for vulnerable populations, and (3) systematically analyzing the dynamic response of slope stability to five gradient rainfall intensities (from light rain to severe rainstorm) and verifying model sensitivity to key parameters. The results show that as rainfall intensity increases, stable areas gradually decrease while unstable areas expand, with stable zones progressively transforming into unstable ones. Greater rainfall intensity also leads to an increase in the number of landslides within unstable zones. The proposed PRL helps delineate the severity of hazards in different townships, providing new references for mitigating casualties and property losses caused by landslides. Full article

Nutritional and cooling strategies to abate the negative effects of heat stress during the dry period have been used to improve the performance of dairy cattle. The objective of this study was to evaluate the effects of feeding an immunomodulatory supplement (OmniGen-AF^®, OMN) before, during, and after exposure to either heat stress or active cooling during the dry period on immune function and mammary development in dairy cows. During late lactation (at least 60 d before dry off), cows were provided with evaporative cooling systems (shade, fans, and soakers) and assigned to two groups: placebo (56 g/d of AB20^® top-dressed; CON) or OmniGen-AF^® (OMN, 56 g/d top-dressed). Cows were dried off ~46 d before the expected calving date and further split into evaporative cooling (shade, fans, and soakers; CL) or heat stress (only shade; HT) pens. Thus, after dry off, there were four treatment groups: heat stress with placebo (HT, n = 17), HT with OMN supplementation (HT + OMN, n = 19), CL with placebo (CL, n = 16), and CL with OMN supplementation (CL + OMN, n = 11). From a subset of cows (n = 6–8 per group), four blood samples were collected during the dry period (−43, −39, −32, and −21 d relative to calving) to evaluate neutrophil function and blood hematology. In addition, mammary biopsies (4–6 cows/treatment) were collected at −43, −39, −32, and −21 d relative to calving to evaluate mammary gland gene expression and histology, i.e., Tdt dUTP nick-end labeling (TUNEL) and Ki67. Genes related to autophagy, apoptosis, and cell proliferation were analyzed by qRT-PCR. Relative to CL, HT downregulated the expression of beclin-2 (BECN2) but upregulated the expression of beclin-1 (BECN1) on days −43 and −39 relative to calving, respectively. Also, relative to CL, HT upregulated the expression of BAX and FAS on day −39 relative to calving. These differences in gene expression were followed by HT cows having a lower total cell apoptosis rate during involution relative to CL cows. Further to these effects, HT leads to a lower alveoli number relative to CL cows. As in the CL treatment, OMN cows have a higher total cell apoptosis rate and alveoli number relative to CON cows. In addition, OMN cows have higher total cell proliferation relative to CON. Prolactin (PRL) and cortisol concentrations were evaluated during the dry period at days −45, −26, −3, and −1 relative to calving. Relative to CL, HT cows had higher PRL at day −45 but lower PRL on day −1 relative to calving, and a similar trend was observed for cortisol concentrations. In summary, HT impacts mammary gland gene expression, compromises mammary involution, reduces alveoli number, and alters hormone dynamics throughout the dry period. Following the same trends as the CL treatment, OMN increases mammary gland turnover by having a higher cell apoptosis and cell proliferation rate and lower connective tissue relative to CON cows. Full article

Prolactin (PRL) and growth hormone (GH) originate from somatomammotropic cells and share regulatory mechanisms. Alpha₂-adrenergic receptor stimulation with clonidine is routinely used in diagnosing GH deficiency (GHD), yet its effect on PRL secretion remains unclear. This study aimed to assess the impact of clonidine-induced α₂-adrenergic receptor stimulation on PRL secretion and compare PRL dynamics between children with idiopathic short stature (ISS) and GHD. Forty-nine children with height < −2.0 SD (29 ISS, 20 GHD) underwent clonidine stimulation (0.15 mg/m² administered orally). Serum GH and PRL were measured at 0, 30, 60, 90, and 120 min. Groups did not differ in chronological age, bone age, height SDS, or BMI SDS. Both groups exhibited a significant decrease in PRL at 30, 60, and 90 min compared to baseline. In ISS, PRL concentrations increased from 60 min onward, returning near baseline at 120 min. In GHD, PRL remained suppressed throughout the test. GH and PRL concentrations correlated positively at 90 (r = 0.35, p < 0.05) and 120 min (r = 0.35, p < 0.05). Clonidine-induced alpha2-adrenergic stimulation suppresses PRL in both ISS and GHD, but recovery is observed only in ISS, suggesting a potential involvement of GH signaling in PRL regulation. Full article

Banana (Musa cavendish) peel, usually discarded as waste, is a polyphenol-rich source with antioxidant and chelating properties. This study evaluated its ability to mitigate ovarian toxicity induced by a heavy metal mixture (HMM) consisting of Hg, Mn, Pb, and Al in female rats. Animals received the HMM with or without banana peel extract at 200, 400, and 800 mg/kg dosages for 60 days. Co-treatment dose-dependently reduced ovarian metal accumulation, attenuated oxidative and nitrosative stress (MDA, NO), restored antioxidant enzyme activities (SOD, CAT, GSH, GPx), and modulated pro-inflammatory (IL-6, TNF-α), apoptotic (Caspase-3), and transcriptional factors (NF-κB, Nrf2). The gonadal endocrine profile also improved gonadotropins (FSH, LH), prolactin (PRL), and progesterone (P), which were normalized at the medium dose (400 mg/kg), and demonstrated a clear dose-related effect. Histological examination further revealed that this dose most effectively improved ovarian tissue. GC–MS analysis identified bioactive compounds including resveratrol, proanthocyanidins, and anthocyanidins, supporting both antioxidant and chelating actions. These findings demonstrate that banana peel extract exerts a dual, dose-dependent protective role in the gonad, limiting metal burden while enhancing redox defenses, and highlight its translational potential as a sustainable agro-food waste product in reproductive toxicology. Full article

Maternal behavior encompasses a range of biologically driven responses whose expression and duration vary across species. Maternal responses rely on robust adaptive changes in the female brain, enabling mothers to engage in caregiving, nourishing, and offspring protection. Morphological and functional changes in the maternal brain enhance sensitivity to offspring cues, eliciting maternal behaviors, rewarding responses, and social processing stimuli essential for parenting. Maternal behavior comprises a range of biological responses that extend beyond basic actions, reflecting a complex, evolutionarily shaped neurobiological adaptation. These behaviors can be broadly categorized into direct behaviors, which are explicitly aimed at the care of the offspring, and indirect behaviors that, overall, ensure the protection, nourishment, and survival of the newborn. The secretion of main neuropeptide hormones, such as oxytocin (OT), prolactin (PRL), and placental lactogens (PLs), during the peripartum period, is relevant for inducing and regulating maternal responses to offspring cues, including suckling behavior. Although PRL is primarily associated with reproductive and parental functions in vertebrates, it also modulates distinct neural functions during pregnancy that extend from lactogenesis to adult neurogenesis, neuroprotection, and neuroplasticity, all of which contribute to preparing the maternal brain for motherhood and parenting interactions. Parvocellular OT-containing neurons in the paraventricular nucleus (PVN) and in the anterior hypothalamic nucleus (AHN) project axon collaterals to the medial preoptic area, which, in turn, projects to the nucleus accumbens (NACC) and lateral habenula (lHb) via the retrorubral field (RRF) and the ventral tegmental area (VTA), which mediate the motivational aspects of maternal responses to offspring cues. The reshaping process of the brain and neural networks implicated in motherhood depends on several factors, such as up- and downregulation of neuronal gene expression of bioactive peptide hormones (i.e., OT, PRL, TIP-39, galanin, spexin, pituitary adenylate cyclase-activating polypeptide (PACAP), corticotropin-releasing hormone (CRH), peptide receptors, and transcription factors (i.e., c-fos and pSTAT)) in target neurons in hypothalamic nuclei, mesolimbic areas, the hippocampus, and the brainstem, which, overall, regulate the expression of maternal behavior to offspring cues, as shown in postpartum female rodents. In this review, we describe the modulatory neuropeptides, the neural networks underlying peptide transmission systems, and cell signaling involved in parenthood. We highlight the dysregulation of neuropeptide hormones and their receptors in the central nervous system in relation to psychiatric disorders. Full article

Background/Objectives: Gestational diabetes mellitus (GDM) prevalence in Australia has increased from 5.6% (2010) to 19.3% (2022), coinciding with the introduction of mandatory folic acid (FA) food fortification and increased supplementation. Animal studies show that high FA intake in pregnancy impairs maternal glucose regulation, but the underlying mechanisms are unknown. We investigated whether fortification has altered maternal folate status to increase GDM risk, and whether key hormones that regulate maternal glucose homeostasis are affected following FA fortification. Methods: Serum folate, red cell folate (RCF), prolactin (PRL), human placental lactogen (hPL) and placental growth hormone (GH2) were measured in early pregnancy samples from women enrolled in prospective cohorts: SCOPE (N = 1164; pre-fortification) and STOP (N = 1300; post-fortification). Associations with GDM were assessed. Results: Compared to pre-fortification, women post-fortification had a higher GDM incidence (5.0% vs. 15.2%), serum folate (↑ 18%), RCF (↑ 259%), hPL (↑ 29%), and GH2 (↑ 13%) concentrations. RCF concentrations above the clinical reference range were found in 57.6% of women post-fortification. Causal mediation analysis suggests that higher RCF contributed to increased GDM risk. Women with RCF excess had 48% more GDM cases, and higher PRL (↑ 24.2%) and hPL (↑ 12.7%) levels compared to those within the reference range. Conclusions: Maternal folate excess is likely contributing to the rising prevalence of GDM in Australia. These findings highlight the need to evaluate excess FA/folate safety in pregnancy, particularly in countries with mandatory fortification. Placental hormones may represent a mechanistic link between excess folate and GDM, warranting further investigation. Full article

This study investigates reading performances and eye movements in individuals with eccentric fixation due to age-related macular degeneration (AMD). Overall, 17 individuals with bilateral AMD (7 males; mean age 77.47 ± 5.96 years) and 17 controls (10 males; mean age 72.18 ± 5.98 years) were assessed for reading visual acuity (VA), reading speed (Minnesota low vision reading chart in Slovene, MNREAD-SI), and near contrast sensitivity (Pelli-Robson). Microperimetry (NIDEK MP-3) was used to evaluate preferential retinal locus (PRL) location and fixation stability. Eye movements were recorded with Tobii Pro-glasses 2 and analyzed for reading duration, saccade amplitude, peak velocity, number of saccades, saccade duration, and fixation duration. Individuals with AMD exhibited significantly reduced reading indices (worse reading VA (p < 0.001), slower reading (p < 0.001), and lower near contrast sensitivity (p < 0.001)). Eye movement analysis revealed prolonged reading duration, longer fixation duration, and an increased number of saccades in individuals with AMD per paragraph. The number of saccades per paragraph was significantly correlated with all measured reading indices. These findings provide insights into reading adaptations in AMD. Simultaneously, the proposed approach in analyzing eye movements puts forward eye trackers as a prospective diagnostic tool in ophthalmology. Full article

Background: Cigarette smoking is one of the most common lifestyle and environmental risk factors for male infertility. Although smoking has been implicated in male fertility decline, the association between endocrine disruption and semen quality reduction remains underexplored in smokers. This study demonstrates the impact of reproductive hormones on the modulation of semen quality in infertile men. Methods: Eighty infertile men participated in this observational study. They were interviewed for environment and lifestyle factors, following which their semen and four reproductive hormones, viz, follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), and testosterone, were analyzed. A comparative analysis between non-smokers and smokers highlighted notable differences in hormone levels and semen quality. To explore the relationships between reproductive hormones and semen quality parameters, correlation and multiple linear regression analyses were conducted. Results: Smokers exhibited a lower percentage of live sperm (p = 0.0000) and a reduction in normal morphology. Furthermore, elevated levels of FSH, LH, and PRL were found among smokers (p = 0.0000). Notably, heightened levels of LH and PRL were linked to a decreased percentage of live sperm cells, while increased LH alone significantly impacted sperm concentration. FSH showed a negative correlation with both live sperm cells (r = −0.50) and total sperm count (r = −0.46). In contrast, testosterone levels demonstrated a positive association with normal sperm morphology (r = 0.47). Conclusion: Cigarette smoking disrupts the regulation of reproductive hormones, which further impacts semen quality. This study provides insights into the potential impact of smoking on semen quality through hormonal mechanisms. Full article