Search Results (426)

Forty per cent of major depression patients are resistant to antidepressant medication. Thus, it is necessary to search for alternative treatments. Melatonin (N-acetyl-5-hydroxytryptamine) enhances neurogenesis and neuronal survival in the adult mouse hippocampal dentate gyrus. Additionally, melatonin stimulates the activity of Ca²⁺/Calmodulin-dependent Kinase II (CaMKII), promoting dendrite formation and neurogenic processes in human olfactory neuronal precursors and rat organotypic cultures. Similarly, ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, modulates CaMKII activity. Importantly, co-treatment of low doses of ketamine (10⁻⁷ M) in combination with melatonin (10⁻⁷ M) produces additive effects on neurogenic responses in olfactory neuronal precursors. Importantly, enhanced neurogenic responses are produced by conventional antidepressants like ISSRs. The goal of this study was to investigate whether hippocampal CaMKII participates in the signaling pathway elicited by combining doses of melatonin with ketamine acutely administered to mice, 30 min before being subjected to the forced swimming test. The results showed that melatonin, in conjunction with ketamine, significantly enhances CaMKII activation and changes its subcellular distribution in the dentate gyrus of the hippocampus. Remarkably, melatonin causes nuclear translocation of the active form of CaMKII. Luzindole, a non-selective MT₁ and MT₂ receptor antagonist, abolished these effects, suggesting that CaMKII is downstream of the melatonin receptor pathway that causes the antidepressant-like effects. These findings provide molecular insights into the combined effects of melatonin and ketamine on neuronal plasticity-related signaling pathways and pave the way for combating depression using combination therapy. Full article

Hypoxia can adversely affect multiple organ systems. This study investigated the impact of intermittent hypoxia on serotonin levels and depression-like behaviors across distinct neuroanatomical regions. Sixteen adult female Wistar albino rats were divided into two groups: control (n = 8) and hypoxia (n = 8). The hypoxia group was exposed to a simulated altitude of 3000 for 5 h daily over 14 days. Behavioral assessments included locomotor activity (open field test) and depression-like behaviors (forced swimming test). Serotonin levels were quantified via ELISA in the prefrontal cortex, striatum, thalamus, hypothalamus, hippocampus, and serum. Intermittent hypoxia did not alter locomotor activity (p > 0.05) but significantly increased depression-like behavior (p < 0.05), accompanied by a pronounced reduction in swimming behavior (p < 0.0001), a marker associated with serotonergic function. Serotonin levels were significantly reduced in the prefrontal cortex (p < 0.005) and striatum (p < 0.05), while no changes were observed in other regions or serum (p > 0.05). These findings demonstrate that intermittent hypoxia induces depression-like behaviors and region-specific serotonin depletion, particularly in the prefrontal cortex and striatum. This underscores the need to evaluate hypoxia-related brain health implications in conditions such as sleep apnea and acute mountain sickness. Full article

Background and Objectives: Alzheimer’s disease (AD) has become a serious health problem. Agomelatine (Ago) is a neuroprotective antidepressant. This study aimed to assess how Ago influences behavioral outcomes in AD-like rat model. Materials and Methods: Forty-eight Wistar albino rats were allocated into four groups: Control (C), Alzheimer’s disease-like model (AD), Alzheimer’s disease-like model treated with Ago (ADAgo), and Ago alone (Ago). Physiological saline was injected intrahippocampally in C and Ago animals, whereas Aβ peptide was delivered similarly in AD and ADAgo rats. On day 15, 0.9% NaCl was administered to the C and AD groups, and Agomelatine (1 mg/kg/day) was infused into ADAgo and Ago rats via osmotic pumps for 30 days. Behavioral functions were evaluated using Open Field (OF), Forced Swim (FST), and Morris Water Maze (MWM) tests. Brain tissues were examined histopathologically. Neuritin, Nestin, DCX, NeuN, BDNF, MASH1, MT1, and MT2 transcripts were quantified by real-time PCR. Statistical analyses were performed in R 4.3.1, with p < 0.05 deemed significant. Results: In the FST, swimming, climbing, immobility time, and mobility percentage differed significantly among groups (p < 0.05). In the MWM, AD rats exhibited impaired learning and memory that was ameliorated by Ago treatment (p < 0.05). DCX expression decreased in AD rats but was elevated by Ago (p < 0.05). Nestin levels differed significantly between control and AD animals; MT1 expression varied between control and AD cohorts; and MT2 transcript levels were significantly lower in AD, ADAgo, and Ago groups compared to C (all p < 0.05). Conclusions: Ago exhibits antidepressant-like activity in this experimental AD model and may enhance cognitive function via mechanisms beyond synaptic plasticity and neurogenesis. Full article

Objectives: The aim of this study was to indicate which variables are the most important determinants of swimming results in the 50 m front crawl among non-elite pre-pubertal female swimmers. Methods: The study group consisted of 14 female swimmers (at the time of the research commencement—biological age: 10.52 ± 0.37 years; body mass: 34.99 ± 2.77 kg; height: 146.00 ± 3.05 cm). The study was conducted over three years. The swimmers performed capacity training recommended by the British Swimming Federation. Every 6 months, in the participants the following parameters were measured: percentage of body fat; anthropometric measurements; aerobic and anaerobic capacity; and respiratory parameters: vital capacity—VC, forced expiratory volume—FEV1, and forced vital capacity—FVC. Additionally, a 50 m front crawl swim test was performed. Results: After adjusting for multicollinearity, the most influential determinants of swimming performance were anthropometric measures: shoulder width was the most influential predictor, with a regression coefficient of −0.66, followed by foot length (with a beta of −0.15) and chest depth (with a beta of 0.008). The remaining anthropometric and physical predictors did not contribute to the prediction of 50 m freestyle performance. Conclusions: These research results suggest to coaches and trainers that sports performance in sprint distances in pre-pubertal girls is not determined by aerobic and anaerobic capacity or body fat but is based on the somatic build of the swimmer. Full article

Background/Objectives: Urolithin A (UA), a gut-derived metabolite of ellagitannins or ellagic acid, has recently gained attention for its potential benefits to brain health. The present research aimed to assess the antidepressant-like properties of UA in both in vitro and in vivo models and explored the molecular mechanisms underlying these effects. Methods: We investigated the antidepressant effects and mechanisms of UA in a model of corticosterone-induced damage to PC12 cells and in a model of chronic socially frustrating stress. Results: Our results demonstrate that UA treatment (5 and 10 μM) significantly alleviated cellular damage and inflammation in corticosterone (CORT)-treated PC12 cells. Furthermore, UA administration (50 and 100 mg/kg) significantly reduced immobility time in the mouse tail suspension test (TST) and forced swim test (FST), indicating its antidepressant-like activity. Additionally, treatment with UA led to the activation of the cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling cascade and triggered the activation of adenosine monophosphate-activated protein kinase (AMPK) during these processes. Importantly, pretreatment with AMPK-specific inhibitor Compound C abolished UA’s cytoprotective effects in PC12 cells, as well as its behavioral efficacy in the FST and TST, and its neurotrophic effects, highlighting the critical role of AMPK activation in mediating these effects. Furthermore, in the chronic social defeat stress (CSDS) mouse model, UA treatment (50 and 100 mg/kg) significantly alleviated depression-like behaviors, including reduced sucrose preference in the sucrose preference test, increased social avoidance behavior in the social interaction test, and anxiety-like behaviors, including diminished exploration, in the elevated plus maze test, suggesting the antidepressant-like and anxiolytic-like activities of UA. Moreover, UA treatment reversed elevated serum stress hormone levels, hippocampal inflammation, and the decreased AMPK/CREB/BDNF signaling pathway in the hippocampus of CSDS mice. Conclusions: Together, these results provide compelling evidence for UA as a viable dietary supplement or therapeutic option for managing depression. Full article

Sceletium tortuosum (ST) induces antidepressant and anxiolytic effects, purportedly by monoamine regulation, anti-inflammatory and antioxidant properties, and phosphodiesterase 4 (PDE4) inhibition. These multimodal actions have not been demonstrated in an animal model of major depressive disorder. Wistar rats (both sexes) were subjected to 8-week unpredictable chronic mild stress, subsequently receiving saline, a standardized ST extract, Zembrin^® 25 and 12.5 mg/kg (ZEM25 and ZEM12.5), its primary alkaloid mesembrine (MES), or escitalopram (20 mg/kg) for 36 days. Sucrose preference, open field, Barnes maze, and forced swim tests were performed, with cortico-hippocampal monoamines, inflammatory and oxidative stress markers analyzed post-mortem. Male, but not female rats, presented with increased anhedonia and anxiety but not despair. Males presented with increased hippocampal PDE4B expression, increased dopamine metabolites, and decreased cortical serotonin. In males, ZEM12.5 decreased anhedonia- and anxiety-like behavior, decreased cortical and hippocampal PDE4B, and increased plasma interleukin-10. MES induced a transient decrease in anhedonia-like behavior and increased hippocampal serotonergic and cortical dopaminergic activity, whilst decreasing hippocampal PDE4B. ZEM25 increased plasma interleukin-10 but decreased cortical glutathione, indicating paradoxical anti-inflammatory and prooxidant effects. ZEM12.5 and MES more effectively addressed anxious–depressive-like behavior and stress-induced inflammation and monoaminergic alterations, respectively. Multitargeted actions on monoamines, redox-inflammation, and PDE4 may provide ST with antidepressant effects across multiple symptom domains, although mutually synergistic/antagonistic effects of constituent alkaloids should be considered. Full article

Background: Shirakiopsis indica (Willd.) (Family: Euphorbiaceae), a mangrove species found in the Asian region, is a popular folkloric plant. Locally, the plant is traditionally used to treat various types of ailments, especially for pain relief. Therefore, the current study investigates the neuropharmacological, antipyretic, thrombolytic, and anthelmintic properties of the S. indica fruit methanolic extract (SIF-ME). Methods: The neuropharmacological activity was evaluated using several bioactive assays, and the antipyretic effect was investigated using the yeast-induced pyrexia method, both in Swiss albino mice models. Human blood clot lysis was employed to assess thrombolytic activity, while in vitro anthelmintic characteristics were tested on Tubifex tubifex. Insights into phytochemicals from SIF-ME have also been reported from a literature review, which were further subjected to molecular docking, pass prediction, and ADME/T analysis and validated the wet-lab outcomes. Results: In the elevated plus maze test, SIF-ME at 400 mg/kg demonstrated significant anxiolytic effects (200.16 ± 1.76 s in the open arms, p < 0.001). SIF-ME-treated mice exhibited increased head dipping behavior and spent a longer time in the light box, confirming strong anxiolytic activity in the hole board and light–dark box tests, respectively. It (400 mg/kg) also significantly reduced depressive behavior during forced swimming and tail suspension tests (98.2 ± 3.83 s and 126.33 ± 1.20 s, respectively). The extract induced strong locomotor activity, causing mice’s mobility to gradually decrease over time in the open field and hole cross tests. The antipyretic effect of SIF-ME (400 mg/kg) was minimal using the yeast-induced pyrexia method, while it (100 μg/mL) killed T. tubifex in 69.33 ± 2.51 min, indicating a substantial anthelmintic action. SIF-ME significantly reduced blood clots by 67.74% (p < 0.001), compared to the control group’s 5.56%. The above findings have also been predicted by in silico molecular docking studies. According to the molecular docking studies, the extract’s constituents have binding affinities ranging from 0 to −10.2 kcal/mol for a variety of human target receptors, indicating possible pharmacological activity. Conclusions: These findings indicate that SIF-ME could serve as a promising natural source of compounds with neuropharmacological, anthelmintic, thrombolytic, and antipyretic properties. Full article

Background/Objectives: Major depressive disorder (MDD) is a debilitating illness, and chronic stress is a contributing factor for depressive symptoms. However, despite intense research, the mechanisms of MDD remain substantially unidentified. Quercetin is a powerful flavonoid and could be used as a possible therapeutic strategy for depression. Acknowledging the potential benefits of quercetin, this study investigated its effect alone or in association with the standard drug tranylcypromine (TCP) in a rodent model of chronic restraint stress (CRS). Methods: Adult male rats were subjected to a CRS model consisting of an immobilization session of 4 h daily during 14 consecutive days. Quercetin (50 mg/kg, gavage) was administered for 45 days. TCP (10 mg/kg, gavage) was administered for 14 days. Behavioral tasks were conducted to assess locomotor functions, memory, anhedonia, depression-like behaviors, and anxiety-like behaviors. The activity, gene expression, and protein density of acetylcholinesterase (AChE) were investigated. Results: Behavioral tasks showed that the CRS model effectively induced stable behavioral changes. CRS did not alter locomotor function assessed by the open field test (OFT) or anhedonia behavior assessed by the sucrose preference test (SPT). CRS increased total fecal count, which was prevented by quercetin administration in rats. TCP and the association of quercetin and TCP increased the recognition index in comparison with the CRS group in the novel object recognition (NOR) test and improved the swimming and immobility times in comparison to stressed animals in the forced swim test (FST). All treatments were able to decrease the anxiety index assessed by the elevated plus maze (EPM) test. The activity, gene expression, and protein density of AChE were increased in the CRS model compared to control males. Overall, quercetin and TCP proved to reverse CRS-induced alterations in these parameters. Conclusions: Quercetin mitigated cognitive deficits, behavioral impairments, and neurochemical alterations induced by the CRS model, especially in association with TCP, supporting its potential as a promising therapeutic agent for depression. Full article

Cognitive problems are associated with impaired learning ability and memory dysfunction. Neuroinflammation has been identified as an important factor in the progression of anxiety and depressive disorders. Zingerone is a phenolic alkanone derived from ginger (Zingiber officinale Roscoe), which is known for its antioxidant and anti-inflammatory properties. A number of studies have investigated the effect of zingerone on neuroinflammation and cognitive impairment. However, this evidence has not been systematically reviewed. This study sought to systematically review the effect of zingerone on neuroinflammation and neurobehavioural changes associated with memory and learning impairment and anxiety-like and depressive-like behaviours. A systematic review was conducted using pre-defined search criteria on Google Scholar, Scopus and Web of Science. The records obtained were screened based on inclusion criteria, and data was extracted from the included studies. Out of the 482 studies that were identified, only 9 studies met the inclusion criteria. Neuroinflammatory markers such as interleukin 1β (IL-1β), interleukin 6 (IL-6), tumour necrosis factor-alpha (TNF-α) and ionized calcium binding adaptor molecule (IBA-1), as well as behavioural parameters including Morris water maze, Y-Maze, recognition test, passive avoidance test, elevated plus maze, sucrose preference test and forced swimming test were measured. Zingerone exhibited anti-neuroinflammatory effects by improving IL-1β, IL-6 and TNF-α levels. However, zingerone did not show any significant changes on activated microglia. The anti-neuroinflammatory mechanisms of zingerone were linked to the inhibition of nuclear factor kappa B (NF-kB) activation and the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome, as well as the reduction in neuronal nitric oxide synthase (nNOS). The anxiolytic and anti-depressive effects of zingerone were also associated with an improvement in cortical cholinergic transmission, the mitigation of oxidative stress and the upregulation of neurotransmitters such as serotonin and dopamine. This review provides scientific evidence on the cognitive enhancing and neuroprotective mechanisms of zingerone, which may be beneficial for future experimental investigations. Full article

In West Africa, Paullinia pinnata (P. pinnata) alcohol leaf extracts are used to treat disorders such as depression and anxiety with no documented scientific justification. We have therefore evaluated the potential anxiolytic and antidepressant effects of Paullinia pinnata methanol leaf extract (PPME) in mice, along with probable underlying mechanisms. Adult Swiss albino mice were administered 100, 200, and 400 mg/kg of PPME orally before subjecting them through elevated plus maze (EPM) and hole-board tests to assess the anxiolytic effect. The tail suspension test (TST) and the forced swim test (FST) were used to assess the antidepressant-like effects. Reserpine, labetalol, and risperidone were used to investigate probable mechanisms of action. In both FST and TST, the duration of immobility was considerably reduced by PPME. Conversely, PPME had no significant effect on the number of mice who dipped their heads into the hole-board or entered the EPM’s open arm. Mechanistic analysis revealed that in mice given labetalol or risperidone beforehand, PPME dramatically reduced the length of immobility and reversed ptosis and akinesia caused by reserpine. Our findings suggest that PPME possesses antidepressant-like, but not anxiolytic-like, effects in mice, and antidepressant action may involve enhancing noradrenergic and serotonergic mechanisms. Full article

Background/Objectives: Dimethyl trisulfide (DMTS) is a naturally occurring polysulfide with known antioxidant and neuroprotective properties. DMTS is a lipophilic transient receptor potential ankyrin 1 (TRPA1) ligand that reaches the central nervous system (CNS). Its role in the CNS, particularly regarding depression-like behaviour, has yet to be explored. This study investigates the influence of DMTS on stress responses and whether this effect is mediated through the TRPA1 ion channel, known for its role in stress adaptation. Using a mouse model involving three-week exposure, we examined the impact of DMTS on depression-like behaviour and anxiety and identified the involved brain regions. Methods: Our methods involved testing both Trpa1-wild-type and gene-knockout mice under CUMS conditions and DMTS treatment. DMTS was administered intraperitoneally at a dose of 30 mg/kg on days 16 and 20 of the 21-day CUMS protocol—in hourly injections seven times to ensure sustained exposure. Various behavioural assessments—including the open field, marble burying, tail suspension, forced swim, and sucrose preference tests—were performed to evaluate anxiety and depression-like behaviour. Additionally, we measured body weight changes and the relative weights of the thymus and adrenal glands, while serum levels of corticosterone and adrenocorticotropic hormone were quantified via ELISA. FOSB (FBJ murine osteosarcoma viral oncogene homolog B) immunohistochemistry was utilised to assess chronic neuronal activation in stress-relevant brain areas. Results: Results showed that CUMS induces depression-like behaviour, with the response being modulated by the TRPA1 status and that DMTS treatment significantly reduced these effects when TRPA1 channels were functional. DMTS also mitigated thymus involution due to hypothalamic–pituitary–adrenal (HPA) axis dysregulation. Conclusions: Overall, DMTS appears to relieve depressive and anxiety symptoms through TRPA1-mediated pathways, suggesting its potential as a dietary supplement or adjunct therapy for depression and anxiety. Full article

Current treatments fail to prevent long-term consequences induced by a severe traumatic brain injury (TBI). This study aimed to evaluate the efficacy of repetitive intranasal administration of NeuroEPO (a derivative of erythropoietin) on long-term alterations after a severe TBI induced by the application of a lateral fluid percussion in male rats. A otal of 30–31 days after the trauma, TBI+vehicle group showed sensorimotor dysfunction (Neuroscore, p < 0.0009; beam walking test, p < 0.0001 vs. Sham+vehicle group) and depressive-like behavior suggested by increased immobility (p = 0.0009 vs. baseline) during the forced swim test. Rats also showed increased production of malondialdehyde (a marker of oxidative damage), increased catalase activity (an antioxidant enzyme), and atrophy of brain areas evaluated with Magnetic Resonance Imaging 31 days after the trauma. TBI+NeuroEPO group received intranasal administration of NeuroEPO (0.136 mg/kg) starting 3 h post-TBI and continued every 8 h for four days. This group showed less sensorimotor dysfunction (Neuroscore, p = 0.020; beam walking test, p = 0.001, vs. TBI+vehicle group) and normal immobility behavior (p = 0.998 vs. Sham+vehicle group). Levels of malondialdehyde and catalase as well as the volume of brain structures of this group were like the Sham+vehicle group. These findings support the potential of NeuroEPO as a therapeutic agent to reduce long-term consequences of TBI. Full article

Biological systems can adaptively navigate multi-terrain environments via morphological and behavioral flexibility. While robotic systems increasingly achieve locomotion versatility in one or two domains, integrating terrestrial, aquatic, and aerial mobility into a single platform remains an engineering challenge. This work tackles this by introducing a bipedal robot equipped with a reconfigurable locomotion framework, enabling seven adaptive policies: (1) thrust-assisted jumping, (2) legged crawling, (3) balanced wheeling, (4) tricycle wheeling, (5) paddling-based swimming, (6) air-propelled drifting, and (7) quadcopter flight. Field experiments and indoor statistical tests validated these capabilities. The robot achieved a 3.7-m vertical jump via thrust forces counteracting gravitational forces. A unified paddling mechanism enabled seamless transitions between crawling and swimming modes, allowing amphibious mobility in transitional environments such as riverbanks. The crawling mode demonstrated the traversal on uneven substrates (e.g., medium-density grassland, soft sand, and cobblestones) while generating sufficient push forces for object transport. In contrast, wheeling modes prioritize speed and efficiency on flat terrain. The aquatic locomotion was validated through trials in static water, an open river, and a narrow stream. The flight mode was investigated with the assistance of the jumping mechanism. By bridging terrestrial, aquatic, and aerial locomotion, this platform may have the potential for search-and-rescue and environmental monitoring applications. Full article

Prolonged sleep deprivation impairs brain function and increases the risk of mental health disorders. Cichorium intybus L. Oligo-polysaccharides (JSO), bioactive compounds derived from chicory, belong to the category of food-medicine homologous substances, possess gut microbiota-modulating and anti-inflammatory properties, and serve as a natural prebiotic, having significant research value in food science. This research examined the anxiolytic properties of JSO in a murine model subjected to chronic sleep deprivation (CSD) stress and explored the mechanisms behind this effect, providing experimental evidence for the development of Cichorium intybus L. as a functional food. Specific pathogen-free (SPF) KM male mice were allocated at random into six experimental groups: the control group, the CSD model group, the diazepam (10 mg/kg) group, and the JSO treatment groups at low (50 mg/kg), medium (100 mg/kg), and high (200 mg/kg) doses. Following 3 weeks of CSD, anxiety-like behaviors were assessed using the open field test, elevated plus maze test, light–dark box test, forced swim test, and marble-burying test. To analyze the composition of gut microbiota, 16S rRNA sequencing was employed, while protein expression in the BDNF, PI3K/AKT/mTOR, and NLRP3 inflammasome pathways was detected by Western blot. Behavioral analysis indicated that JSO (at doses of 100 and 200 mg/kg) markedly enhanced both the time allocated to open arms and the number of entries into open arms in the elevated plus maze test (p < 0.05). JSO (at doses of 50 and 200 mg/kg) significantly elevated transitions in the light–dark box test (p < 0.05), all JSO doses drastically cut down marble-burying behavior (p < 0.001, p < 0.01, p < 0.01). The 16S rRNA sequencing indicated that JSO intervention increased Bacteroidetes abundance while reducing Actinobacteria. Western blot analysis demonstrated that JSO significantly downregulated the ratios of p-mTOR/mTOR, p-PI3K/PI3K, p-AKT/AKT, BAX/BCL-2, as well as the expression levels of NLRP3, ASC, Caspase-1, and IL-6 proteins (p < 0.05), while upregulating hippocampal BDNF (p < 0.05). These results indicate that JSO ameliorates CSD-induced anxiety-like behaviors by restoring gut microbiota homeostasis, regulating the BDNF-PI3K/AKT/mTOR and BAX/BCL-2 apoptosis pathways, and suppressing NLRP3 inflammasome-mediated neuroinflammation. Full article

Background: This study aimed to develop a model for understanding stress-induced sleep disturbances and to explore the potential interactions between sleep disturbances and mood disturbances. Methods: The chronic unpredictable mild stress (CUMS) group was established using the CUMS method, while the CUMS+Noise group was subjected to an additional 8-h exposure to noise in conjunction with the CUMS protocol. Each group was tested for anxiety and depressive-like behavior using the open-field, elevated plus maze, tail suspension, and forced swimming tests in male C57BL/6J mice. Subsequently, we assessed sleep status using sleep recordings and a standardized scoring system alongside the pentobarbital sodium-induced sleep test. Results: The mice in both model groups exhibited anxiety-like behavior. Sleep disturbances observed in the CUMS+Noise group were characterized by disruptions in sleep duration and circadian rhythm. This observation was supported by a marked reduction in multiple sleep time intervals and single sleep duration, as well as a significant increase in sleep duration at the final time interval of ZT23-24. To further investigate the potential mechanisms of interaction, we conducted an analysis of hub genes present in the hippocampal sequencing data utilizing weighted gene co-expression network analysis (WGCNA). Pearson correlation analysis revealed a significant association between the hub genes Alb, P2rx1, and Npsr1 and key phenotypic traits. However, PCR experiments indicated that only Alb showed a significant difference, which aligns with the sequencing results. Conclusions: Albumin is a crucial transporter protein for thyroid hormones and plays a vital role in their metabolism. The interaction between sleep disorders and anxiety-like behavior may be closely linked to the dysfunctional transportation of thyroid hormones by albumin. Full article