Search Results (69)

The transition from high school to university is a critical developmental period marked by substantial academic, social, and lifestyle changes that may increase vulnerability to academic difficulties, disengagement, and dropout. Given the importance of academic achievement for student retention and long-term success and the growing recognition of sleep as a modifiable determinant of academic performance, this scoping review examined how the relationship between sleep and academic achievement has been investigated among first-year university students. Following PRISMA guidelines, a systematic search identified 20 records representing 21 studies published between 2013 and 2026. Sleep duration and sleep quality were the most frequently examined domains, although findings were heterogeneous. Nevertheless, shorter sleep duration, particularly below 6–7 h per night, was generally associated with poorer academic achievement. Poor sleep quality was also linked to lower academic performance in some studies, with affective factors influencing this relationship. Sleep problems, including chronic sleep deprivation and risk of sleep disorders, showed consistent associations with poorer academic outcomes. Similarly, an evening chronotype was generally associated with poorer academic performance and adjustment. These findings emphasize sleep as an essential target for future research and initiatives aimed at promoting academic success and student retention during the transition to higher education. Full article

Background/Objectives: Tinnitus is a significant global health concern with substantial geographic variation in prevalence. However, data on tinnitus epidemiology in southern Saudi Arabia remain limited, despite emerging evidence suggesting a relatively high regional burden. Therefore, this study aimed to estimate the prevalence of tinnitus and identify its epidemiological determinants among adults in southern Saudi Arabia. Methods: A community-based cross-sectional study was conducted among 501 adults from four regions in southern Saudi Arabia (Jazan, Aseer, Najran, and Al-Baha). Data were collected on sociodemographic characteristics, chronic medical conditions, noise exposure patterns, and clinical features of tinnitus. Multivariable logistic regression analysis was used to identify factors independently associated with tinnitus. Results: The overall tinnitus prevalence was 31.1% (156/501). The mean age of participants was 30 ± 11 years, and 61.7% were female. Bilateral tinnitus was the most common (47.4%). Symptom duration was reported as <3 months in 31.4% of cases and between 3 months and 1 year in another 31.4%. The mean severity score was 3.7 ± 1.9. Most affected individuals (76.9%) did not seek medical care. Primary exacerbating factors included sleep deprivation (41.7%), noise exposure (41.0%), and stress (39.1%). Multivariable analysis identified two significant independent predictors: weekly noise exposure exceeding 5 h (odds ratio [OR] = 2.14; 95% confidence interval [CI]: 1.34–3.42; p = 0.001) and higher body mass index (BMI) (OR = 1.06; 95% CI: 1.02–1.10; p = 0.005). The most commonly associated underlying conditions were ear infections (25.6%) and hearing loss (24.4%). Conclusions: Tinnitus prevalence in southern Saudi Arabia (31.1%) substantially exceeds global estimates. Noise exposure and elevated BMI are key modifiable factors associated with tinnitus. The substantial healthcare gap, with most affected individuals not seeking treatment, represents a critical public health challenge requiring targeted prevention programs, provider education, and improved access to evidence-based care. Full article

Brain-derived neurotrophic factor (BDNF) is one of the most pleiotropic signaling molecules in mammalian biology, regulating processes ranging from neuronal survival and synaptic plasticity to metabolic homeostasis. Under physiological conditions, BDNF expression is tightly regulated; however, it may be disrupted by a variety of adverse factors, including chronic psychological stress, sleep deprivation, oxidative stress, inflammation, aging, and metabolic imbalance. Prolonged exposure to any of these factors can chronically reduce BDNF levels, contributing to numerous disorders whose systemic consequences remain difficult to define conclusively. This uncertainty arises because the available evidence is drawn from heterogeneous sources including many species, wild-type and various gene-knockout models, and pharmacological studies of differing specificity—yielding findings that are often inconsistent and difficult to compare. Consequently, the full spectrum of multisystemic effects resulting from long-term partial BDNF deficiency remains incompletely characterized. The SD-BDNFtm1sage rat line, developed by SAGE/Envigo/Inotiv using zinc finger nuclease technology, was created to fill this gap. Sprague–Dawley rats with a heterozygous genotype retain one functional allele of the Bdnf gene, resulting in a partial, permanent reduction in BDNF expression that persists throughout life. This chronic and moderate BDNF deficiency allows the animal to survive but is insufficient to maintain normal homeostasis, disrupting many physiological systems and behavioral responses. This review summarizes findings from studies using the SD-BDNFtm1sage rat line and shows that its phenotypic spectrum—susceptibility to mental disorders, sleep disturbances, metabolic abnormalities, altered nociception, and impaired neuromuscular adaptation—closely reflects the multisystemic consequences of chronic BDNF deficiency. This broad relevance makes the model particularly useful for research with potential medical applications. Full article

Chronic sleep deprivation (SD) disrupts gut–brain axis (GBA) homeostasis and is closely associated with gut microbiota dysbiosis, neuroinflammation, and depression-like behaviors. This study investigated whether fermentation enhances the antidepressant-like effects of Dendrobium officinale by comparing fermented Dendrobium officinale (FDO) with unfermented Dendrobium officinale (DO) in a chronic SD mouse model. FDO significantly ameliorated anxiety and depressive-like behaviors in SD mice. It reshaped gut microbial structures, enriched beneficial bacteria taxa such as Dubosiella, [Eubacterium]_coprostanoligenes_group, and Allobaculum, and increased SCFA levels. FDO also enhanced colonic ZO-1 and Occludin expression and reduced serum levels of LPS and the pro-inflammatory cytokines. At the central nervous system level, FDO inhibited the activation of hippocampal microglia and astrocytes; alleviated neuroinflammation; restored hippocampal TPH2, 5-hydroxytryptamine (5-HT), and 5-HIAA levels; and modulated the 5-HT_1A/5-HT_2A receptor balance. In addition, FDO upregulated BDNF, PSD-95, and SYN expression and reduced corticosterone (CORT) levels. Compared with DO, FDO showed more pronounced regulatory effects. Correlation analysis suggested that 5-HT may link gut microbial metabolites, inflammation, and synaptic plasticity. In summary, these findings support FDO as a potential GBA-targeted functional food for SD-related depressive-like behaviors. Full article

Not all sleep loss is equal, and overlooking this limits progress in sleep and neurological disease research. We compared nine rodent sleep deprivation paradigms, gentle handling, multiple platform variants, disk-over-water, the Unpredictable Chronic Sleep Deprivation (UCSD) paradigm, novel object introduction, curling prevention by water, automated systems, and head-lifting, evaluating stress confounds, sleep stage specificity, chronicity, and neurobiological outcomes. Effects included hippocampal plasticity, prefrontal chemistry, glymphatic clearance, neuroinflammation, oxidative stress, neurogenesis, and circadian regulation, linked to Alzheimer’s, Parkinson’s, and psychiatric comorbidities. UCSD with caffeine produced antioxidant depletion, serotonin reduction, acetylcholinesterase upregulation, and synaptophysin loss, early neurodegeneration markers. We propose a disease-targeted framework with six translational priorities and reporting standards. Full article

Working conditions in the offshore oil and gas industry can expose workers to fatigue and sleep deprivation due to extended working hours, irregular shift schedules, and highly complex operational environments. This study aimed to conduct a systematic review of scientific literature on fatigue and sleep deprivation in the offshore oil and gas sector and their implications for health, performance, and safety. The systematic review was conducted in accordance with the PRISMA 2020 guidelines and included primary studies published between 2015 and 2025, retrieved from the Scopus, Web of Science, ScienceDirect, PubMed, and Embase databases. Following the eligibility assessment, fifty studies were included in the final analysis. The selected studies were classified according to their level of direct relevance to offshore oil and gas operations, distinguishing evidence derived from offshore platforms from that obtained in analogous operational settings. The findings demonstrate consistent associations between fatigue and chronic sleep deprivation and adverse occupational health outcomes. Regulatory gaps were also identified when comparing different international approaches to fatigue risk management in the offshore sector. Overall, the results underscore the need for integrated fatigue management strategies aligned with best international practices to enhance health and safety in offshore operations. Full article

This study aimed to assess the relative impact of the Osijek multidisciplinary biopsychosocial program for chronic low back pain (CLBP) compared with standard multimodal care with respect to pain intensity, disability, health-related quality of life, anxiety, depression, stress, and sleep quality using standardized self-assessment questionnaires and a smartwatch. A total of 128 patients treated at the Department of Pain Management, University Hospital Osijek, were randomly allocated to two groups. The multidisciplinary biopsychosocial group participated in a structured four-week program combining education, exercise, and individualized multidisciplinary care, while the multimodal group received conventional conservative treatment including pharmacotherapy and selected physical therapy modalities. The four-week intervention included standardized self-report questionnaires, a sociodemographic data form, and a Fitbit Charge 3 smartwatch for objective monitoring of sleep and physical activity. A significant reduction in pain intensity was observed across numerical scales and most questionnaire measures (Wilcoxon test, p < 0.01), except for the subscale assessing difficulties in performing daily activities due to sleep deprivation. Participants who underwent the multidisciplinary biopsychosocial treatment exhibited significant improvements (p < 0.03) in pain intensity, disability, health-related quality of life, stress, anxiety, and sleep quality compared with those receiving multimodal treatment. In both groups, a weak negative correlation was found between sleep quality and daily step count (Spearman’s rho = −0.234, p = 0.04). A multidisciplinary biopsychosocial program was associated with greater improvements in health-related quality of life, psychological well-being, and sleep quality in patients with chronic low back pain compared with a multimodal conservative approach. Increased daily physical activity was linked to improvements in anxiety and sleep. Although this study was designed as a randomized controlled trial, certain baseline differences between groups should be considered when interpreting the findings. Full article

Background/Objectives: Baichuan Baile (BCBL), a novel functional dietary formula, has been shown to exert antidepressant-like effects through modulation of the 5-HT system in our prior studies. Given the close neurobiological connections between depression and insomnia, along with its pharmacodynamic profile guided by TCM theory and nutritional assessments, BCBL is likely to possess beneficial effects against insomnia. However, this hypothesis and its underlying mechanisms require further validation. Methods: The chemical constituents of BCBL were analyzed by UPLC-Q-TOF-MS, and network pharmacology was applied to predict potential sleep-relevant targets and pathways. Subsequently, BCBL was evaluated for sedative-hypnotic effects using pentobarbital-induced hypnosis, locomotor activity, and polysomnography (EEG/EMG). Its therapeutic efficacy was further assessed in insomnia models induced by environmental stress, serotonin depletion, and rotarod-based sleep deprivation. The rotarod-induced chronic model was selected for mechanistic studies due to its sustained insomnia-like phenotype. Finally, key network-predicted targets were validated in this model through histopathology, Western blotting, and ELISA. Results: Pharmacological evaluation confirmed that BCBL significantly promoted sleep at both behavioral and EEG levels, confirming its sedative-hypnotic properties. BCBL mitigated environmental stress-triggered impairments in NREM sleep continuity and duration, and exerted protective effects against body weight loss and sleep disturbances in a serotonin depletion-induced insomnia model. In the rotarod sleep deprivation model, BCBL treatment increased spontaneous alternation rates and recognition indices, ameliorated hippocampal pathological alterations, and reduced hippocampal levels of HIF-1α, TNF-α, and IL-1β. Furthermore, BCBL elevated the p-GSK3β/GSK3β ratio and enhanced SIRT₁ expression in the hypothalamus. It also modulated the activity of key sleep–wake neurotransmitters/neuromodulators (serotonin, dopamine, adenosine, and glutamate) and key circadian rhythm regulators (BMAL₁, PER₂, and CLOCK) in this region. Conclusions: BCBL exhibits significant therapeutic efficacy against insomnia, indicating its potential as a dietary supplement for managing insomnia. Its mechanisms appear to involve anti-inflammatory effects, rebalancing of neurotransmitters/neuromodulators, and stabilization of circadian rhythm gene expression. Full article

Purpose of Review—sleep disturbance is the main complaint associated with patients who suffer acute postoperative pain. Sleep disturbance may also increase the pain sensitivity and contribute to the development and maintenance of chronic pain. The pathophysiology of pain is complex; management of perioperative pain and preventing chronic pain are challenges in clinical. Use of opioids for pain management are still a therapeutic mainstay and generally safe when taken, in a short time, for severe postoperative pain relief. For long-term use tolerance may be developed, and for their euphoric property, addiction, overdose incidents, and even death may be the social problems. Therefore, the opioid-sparing multimodal analgesia (MMA) for pain management is recommended in current postoperative pain management. The successful MMA for pain management will enhance patient recovery after surgery with less chronic CPSP and long-term opioid use disorder (OUD). The present review discusses all currently used analgesics actions and interactions, and opioid-sparing or opioid-free analgesia in perioperative pain management. Acute pain following major trauma or surgery may originate from both nociceptive and neuropathic mechanisms. Approximately 10–50% of surgical patients develop chronic postoperative pain, which not only causes persistent discomfort but also leads to functional limitations and psychological distress. Growing evidence highlights a close and bidirectional relationship between sleep and pain: pain disrupts sleep architecture, while sleep deprivation intensifies pain sensitivity and impairs recovery. This reciprocal interaction forms a vicious cycle that poses challenges for effective pain management. Melatonin—a neurohormone secreted by the pineal gland—plays a crucial role in regulating circadian rhythm and sleep–wake cycles. Beyond its chronobiotic action, melatonin exhibits anti-nociceptive, anti-inflammatory, and opioid-sparing properties. Recent preclinical studies have demonstrated that exogenous melatonin can attenuate nociceptive responses to noxious stimuli and enhance morphine analgesia while attenuating morphine tolerance. Moreover, environmental light manipulation preserving the circadian rhythm has been shown to synergistically maintain melatonin secretion, improve sleep quality, and modulate neuroimmune responses involved in pain regulation. Together, these findings suggest that circadian alignment and melatonin supplementation may represent a promising integrative approach for improving both pain control and sleep health in perioperative and chronic pain conditions. Chronic pain patients frequently experience opioid tolerance during long-term therapy, resulting in diminished analgesic efficacy and a need for escalating doses. Our recent work revealed that constant light exposure suppresses endogenous melatonin, heightens pro-inflammatory cytokines (TNF-α, IL-1β), reduces IL-10, and accelerates morphine tolerance in a neuropathic pain model. In contrast, maintaining circadian light–dark cycles or supplementing melatonin preserves melatonin rhythm, reduces glial activation, and sustains morphine antinociception. Melatonin’s co-administration not only attenuates morphine tolerance but also enhances morphine efficacy through the modulation of inflammatory and glial pathways. These findings underscore melatonin’s multifaceted role as both a chronotherapeutic and neuroprotective agent, integrating circadian regulation with pain modulation. Clinically, the application of melatonin or circadian-aligned strategies could guide personalized pain and sleep management, offering safer and more effective multimodal analgesic protocols with reduced opioid dependence and improved quality of life. Full article

Oxidative alcohol metabolism in the liver relies on sequential enzymatic reactions involving alcohol dehydrogenase (ADH), cytochrome P450 2E1 (CYP2E1), and aldehyde dehydrogenase (ALDH) isozymes. However, the circadian regulation of these enzymes, their susceptibility to genetic, environmental, and metabolic disruption, and their functional implications toward alcohol-mediated tissue injury remain incompletely defined. To address this gap, we performed a comprehensive integrative analysis of the publicly available circadian transcriptome datasets spanning genetic clock disruption, acute sleep deprivation, chronic high-fat diet feeding, and occupational shift work to systematically characterize the temporal regulation and disruption vulnerability of the major alcohol-metabolizing enzymes. Mouse tissue-cycling analyses revealed pronounced gene- and tissue-specific diurnal regulation, with Adh1 oscillating primarily in adipose tissues; Cyp2e1 and mitochondrial Aldh2 cycling broadly across kidney, aorta, lung, adrenal gland, and liver; and cytosolic Aldh1b1 being uniformly arrhythmic. In the liver, Cyp2e1 and Aldh2 exhibited robust ~24 h oscillations that peaked during the light/resting phase, while Adh1 showed inconsistent rhythmicity and Aldh1b1 remained arrhythmic. Notably, Cyp2e1 and Aldh2 rhythms persisted in Bmal1 knockout and Clock mutant livers under light–dark conditions, despite complete loss of core clock gene oscillations, yet were abolished in constant darkness, revealing that systemic zeitgeber cues can mask the loss of intrinsic clock function to maintain apparent rhythmicity in these metabolic genes. Systematic cross-paradigm comparison established a novel gene-specific vulnerability hierarchy. Aldh2 was found to be most disrupted by environmental and metabolic perturbations, with acute sleep deprivation eliminating its rhythmicity and temporal expression pattern and a Western-style high-fat diet inducing pronounced phase delays and rhythm loss relative to low-fat diet controls. Both disruptions paralleled alterations in hepatocyte nuclear factor 4α (Hnf4a), newly implicating HNF4α as a potential mediator of ALDH2 circadian instability. In humans, ALDH2 and CYP2E1 exhibited conserved but phase-inverted circadian rhythms across multiple tissues relative to mice, and, importantly, night-shift workers showed markedly dampened and phase-shifted ALDH2 rhythms in peripheral blood mononuclear cells, providing the molecular link between occupational circadian misalignment and impaired acetaldehyde detoxification. Collectively, our detailed and innovative analytical approach reveals gene- and tissue-specific circadian regulation of alcohol-metabolizing enzymes, identifies ALDH2 as uniquely vulnerable to circadian misalignment, underscores the importance of circadian timing for optimal hepatic detoxification and resistance to tissue injury, and suggests that monitoring circadian rhythms could help tailor individualized advice on alcohol consumption for shift workers and populations with irregular sleep schedules, informing precision medicine approaches for alcohol-related disorders. Full article

Chronic sleep deprivation (CSD) disrupts redox homeostasis and enhances neuroinflammatory activation, contributing to progressive cognitive impairment. Propyl gallate (PG), a lipophilic ester of gallic acid with established antioxidant activity, has not been investigated in the context of prolonged sleep deprivation. The current study examined whether PG alleviates CSD-induced oxidative imbalance, inflammatory activation, and associated behavioral deficits. Male ICR mice were subjected to 14 days of CSD using a rolling-drum apparatus and received oral PG (50, 100, or 200 mg/kg) or Ginkgo biloba extract (GBE, 40 mg/kg). Behavioral outcomes were assessed through a battery of tests, including the open-field, novel-object recognition, step-through, and Morris water maze paradigms. Oxidative and inflammatory biomarkers were assessed in serum and hippocampus, and Western blotting quantified the expression of nuclear factor erythroid 2–related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), nuclear factor-κB (NF-κB), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX2). PG improved CSD-induced impairments in exploration, recognition memory, and spatial learning; restored antioxidant capacity; reduced lipid peroxidation; enhanced Nrf2-associated antioxidant signaling; and suppressed NF-κB-mediated inflammatory activation. These findings indicate that PG alleviates cognitive deficits induced by CSD through the modulation of redox homeostasis and neuroinflammatory responses, supporting its potential as an antioxidant derivative under chronic sleep-deprivation conditions. Full article

High-density micro-electrocorticography (μECoG) arrays offer precise spatial resolution with minimal invasiveness. This study employed a custom ultra-thin 64-channel μECoG array to investigate cortical activity in mice under chronic caffeine exposure. While caffeine is known to enhance short-term alertness, its long-term impact on sleep microarchitecture and brain connectivity is unclear. Continuous recordings from adult mice during baseline and recovery revealed that prolonged caffeine intake significantly reduced broadband power spectral density (PSD) and spindle power but increased interregional coherence and altered spindle duration and density. In contrast, six hours of sleep deprivation elevated PSD and coherence, mainly affecting sensorimotor and retrosplenial cortices. These findings validate the μECoG array’s functionality and demonstrate that post-chronic caffeine withdrawal lowers cortical oscillatory power yet enhances network connectivity, whereas acute sleep loss boosts global synchrony. This work clarifies how sustained caffeine use and sleep deprivation distinctly disrupt sleep homeostasis through different neural mechanisms. Full article

Urban environmental noise represents a major public health issue contributing to chronic sleep disturbances, mainly from road, aircraft, and railway traffic. Night-time recreational noise from cafés, bars, and restaurants has emerged as a frequent source of sleep complaints but remains poorly understood, along with the influence of sociodemographic and economic factors. We addressed this gap by conducting a large-scale ecological study across the Paris Metropolitan Area (~10.5 million inhabitants) examining associations between the Average Energetic Index of night-time noise (AEI L_n) from road, aircraft, railway, and recreational sources and the prevalence of adults aged 18–79 reimbursed for hypnotic psychotropic drugs prescribed for chronic insomnia between 2017 and 2019, stratified by sex, age, and socioeconomic status. The AEI L_n represents the population-weighted average energy noise level within each territory at night (22:00–06:00 in France), calculated at the IRIS level (~2487 inhabitants per IRIS). The dispensing of hypnotic psychotropic drugs concerned 513,276 inhabitants (65.4 per 1000 inhabitants [‰]) on average per year. About 8 million inhabitants (75.7%) are exposed to night-time road traffic noise exceeding WHO health guidelines, followed by railway (~1.2 million, 11.6%), recreational (~1.2 million, 11.5%), and aircraft noise (~1.0 million, 9.8%). Each 5 dB(A) increase in AEI L_n was significantly associated (p < 0.001) with higher dispensing of hypnotic psychotropic drugs, strongest for road noise (+1.0‰), followed by recreational (+0.8‰), aircraft (+0.5‰), and railway noise (+0.3‰). Effects were significantly greater among individuals aged >50 (+8.3‰), women (+2.0‰), and those in the most socioeconomically deprived areas (+2.5‰). These results support proactive public policies aimed at reducing noise from transportation and recreational activities in densely urban areas to mitigate chronic insomnia. Full article

Background: Gallic acid (GA) is a dietary polyphenol widely found in walnuts, tea leaves, and grapes, and it is recognized for its potent antioxidant and anti-inflammatory properties. Chronic sleep deprivation (CSD) is known to disrupt redox balance, promote neuroinflammation, and impair cognition, while effective nutritional strategies to mitigate these effects remain scarce. This study was designed to evaluate the protective potential of GA against CSD-induced cognitive deficits in mice and to elucidate the underlying mechanisms. Methods: Seventy-two male ICR mice were randomly allocated to six groups, including control, CSD model, Ginkgo biloba extract, and GA at three doses (50, 100, and 200 mg/kg). After 28 days of treatment, cognitive performance was assessed using the open field test (OFT), novel object recognition (NOR), step-through passive avoidance (ST), and Morris water maze (MWM). Redox status and inflammatory mediators were determined by ELISA, while the hippocampal expression of proteins related to antioxidant defense and NF-κB signaling was analyzed by Western blotting. Results: GA supplementation improved exploratory activity, recognition memory, and spatial learning in the CSD mice. Biochemical evaluation revealed that total antioxidant capacity (T-AOC) and superoxide dismutase (SOD) activity were restored, while malondialdehyde (MDA) levels, an indicator of lipid peroxidation, were reduced. These changes were accompanied by decreased circulating concentrations of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). At the molecular level, GA enhanced the expression of Nrf2, HO-1, and NQO1, while inhibiting p-p65, iNOS, and COX2 in the hippocampus. Conclusions: These findings demonstrate that GA alleviates CSD-induced cognitive deficits through the activation of the Nrf2/HO-1 antioxidant pathway and inhibition of NF-κB–mediated inflammatory responses. Thus, GA may represent a promising nutraceutical candidate for maintaining cognitive health under chronic sleep loss. Full article

Background/Objectives: Adequate sleep has a fundamental role in human health, mainly in cognitive and physiological functions. However, the daily demands of modern society have led to a constant pursuit of better living conditions, requiring more active hours at the expense of sleeping hours. This sleep deprivation has been associated with human health deterioration, namely an increase in Diabetes Mellitus incidence. This metabolic disease is a chronic pathology that imposes a big burden on health systems and is associated with the rise in insulin resistance. In this sense, the aim of this review is to analyze the relation between sleep deprivation and insulin resistance, emphasizing the metabolic parameters and hormones that may be involved in the subjacent mechanism. Methods: A literature review of the last 10 years was performed with specific terms related to “sleep deprivation” and “insulin resistance”. Results: Overall, the studies analyzed showed a decrease in insulin sensitivity in cases of sleep deprivation, even with different study protocols. In addition, an association between sleep deprivation and increased non-esterified fatty acids was also noticeable; however, other parameters such as cortisol, metanephrines, and normetanephrines showed no consistent results among the studies. Conclusions: This review allowed us to confirm the relationship between sleep deprivation and insulin resistance; however, despite the difficulties to monitor sleep, more research is needed to understand the related mechanisms that have not yet been clarified. Full article