Sleep shapes the associative structure underlying pattern completion in multielement event memory.

Sleep supports the consolidation of episodic memory. It is, however, a matter of ongoing debate how this effect is established, because, so far, it has been demonstrated almost exclusively for simple associations, which lack the complex associative structure of real-life events, typically comprising multiple elements with different association strengths. Because of this associative structure interlinking the individual elements, a partial cue (e.g., a single element) can recover an entire multielement event. This process, referred to as pattern completion, is a fundamental property of episodic memory. Yet, it is currently unknown how sleep affects the associative structure within multielement events and subsequent processes of pattern completion. Here, we investigated the effects of post-encoding sleep, compared with a period of nocturnal wakefulness (followed by a recovery night), on multielement associative structures in healthy humans using a verbal associative learning task including strongly, weakly, and not directly encoded associations. We demonstrate that sleep selectively benefits memory for weakly associated elements as well as for associations that were not directly encoded but not for strongly associated elements within a multielement event structure. Crucially, these effects were accompanied by a beneficial effect of sleep on the ability to recall multiple elements of an event based on a single common cue. In addition, retrieval performance was predicted by sleep spindle activity during post-encoding sleep. Together, these results indicate that sleep plays a fundamental role in shaping associative structures, thereby supporting pattern completion in complex multielement events.

Antibody-peptide conjugates deliver covalent inhibitors blocking oncogenic cathepsins.

Cysteine cathepsins are a family of proteases that are relevant therapeutic targets for the treatment of different cancers and other diseases. However, no clinically approved drugs for these proteins exist, as their systemic inhibition can induce deleterious side effects. To address this problem, we developed a modular antibody-based platform for targeted drug delivery by conjugating non-natural peptide inhibitors (NNPIs) to antibodies. NNPIs were functionalized with reactive warheads for covalent inhibition, optimized with deep saturation mutagenesis and conjugated to antibodies to enable cell-type-specific delivery. Our antibody-peptide inhibitor conjugates specifically blocked the activity of cathepsins in different cancer cells, as well as osteoclasts, and showed therapeutic efficacy in vitro and in vivo. Overall, our approach allows for the rapid design of selective cathepsin inhibitors and can be generalized to inhibit a broad class of proteases in cancer and other diseases.

Sleep promotes T-cell migration towards CCL19 via growth hormone and prolactin signaling in humans.

Sleep strongly supports the formation of adaptive immunity, e.g., after vaccination. However, the underlying mechanisms remain largely obscure. Here we show in healthy humans that sleep compared to nocturnal wakefulness specifically promotes the migration of various T-cell subsets towards the chemokine CCL19, which is essential for lymph-node homing and, thus, for the initiation and maintenance of adaptive immune responses. Migration towards the inflammatory chemokine CCL5 remained unaffected. Incubating the cells with plasma from sleeping participants likewise increased CCL19-directed migration, an effect that was dependent on growth hormone and prolactin signaling. These findings show that sleep selectively promotes the lymph node homing potential of T cells by increasing hormonal release, and thus reveal a causal mechanism underlying the supporting effect of sleep on adaptive immunity in humans.

Identification of the GlialCAM interactome: the G protein-coupled receptors GPRC5B and GPR37L1 modulate megalencephalic leukoencephalopathy proteins.

Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC) is a type of vacuolating leukodystrophy, which is mainly caused by mutations in MLC1 or GLIALCAM. The two MLC-causing genes encode for membrane proteins of yet unknown function that have been linked to the regulation of different chloride channels such as the ClC-2 and VRAC. To gain insight into the role of MLC proteins, we have determined the brain GlialCAM interacting proteome. The proteome includes different transporters and ion channels known to be involved in the regulation of brain homeostasis, proteins related to adhesion or signaling as several G protein-coupled receptors (GPCRs), including the orphan GPRC5B and the proposed prosaposin receptor GPR37L1. Focusing on these two GPCRs, we could validate that they interact directly with MLC proteins. The inactivation of Gpr37l1 in mice upregulated MLC proteins without altering their localization. Conversely, a reduction of GPRC5B levels in primary astrocytes downregulated MLC proteins, leading to an impaired activation of ClC-2 and VRAC. The interaction between the GPCRs and MLC1 was dynamically regulated upon changes in the osmolarity or potassium concentration. We propose that GlialCAM and MLC1 associate with different integral membrane proteins modulating their functions and acting as a recruitment site for various signaling components as the GPCRs identified here. We hypothesized that the GlialCAM/MLC1 complex is working as an adhesion molecule coupled to a tetraspanin-like molecule performing regulatory effects through direct binding or influencing signal transduction events.

Meibomian glands visibility assessment through a new quantitative method.

PURPOSE: The aim of this study is to develop a new objective semiautomatic method for analysing Meibomian glands visibility quantitatively. METHODS: One hundred twelve healthy volunteers aged between 18 and 90 years (48.29 ± 27.46 years) participated in this study. Infrared meibography was obtained from the right upper eyelid through Oculus Keratograph 5 M. Meibographies were classified into 3 groups: Group 1 = patients with good subjective glands visibility and a gland dropout percentage < 1/3 of the total Meibomian gland area; Group 2 = patients with low subjective glands visibility and a gland dropout < 1/3; and Group 3 = patients with low subjective glands visibility and a gland dropout > 1/3. New metrics based on the visibility of the Meibomian glands were calculated and later compared between groups. Rho Spearman test was used to assess the correlation between each metric, and Meibomian gland dropout percentage with the entire sample and after excluding Group 2. A p value less than 0.05 was defined as statistically significant. RESULTS: Fifty-six subjects were classified in Group 1 (24.48 ± 9.62 years), 19 in Group 2 (69.16 ± 21.30 years) and 37 in Group 3 (73.59 ± 13.70 years). No statistically significant differences were found between Groups 1 and 2 in dropout percentage. All metrics, with the exception of entropy, showed a higher Meibomian gland visibility in Group 1 than in the other two groups. Moderate correlations were statistically significant for all metrics with the exception of entropy. Correlations were higher after excluding Group 2. CONCLUSION: The proposed method is able to assess Meibomian gland visibility in an objective and repeatable way, which might help clinicians enhance Meibomian gland dysfunction diagnosis and follow-up treatment.

Diagnostic Capability of a New Objective Method to Assess Meibomian Gland Visibility.

SIGNIFICANCE: The diagnosis of dry eye disease and meibomian gland dysfunction (MGD) is challenging. Measuring meibomian gland visibility may provide an additional objective method to diagnose MGD. PURPOSE: This study aimed to evaluate the ability of new metrics to better diagnose MGD, based on measuring meibomian gland visibility. METHODS: One hundred twelve healthy volunteers (age, 48.3 ± 27.5 years) were enrolled in this study. Ocular surface parameters were measured using the Oculus Keratograph 5M (Oculus GmbH, Wetzlar). Subjects were classified according to the presence or absence of MGD. New metrics based on the visibility of the meibomian glands were calculated and later compared between groups. The diagnostic ability of ocular surface parameters and gland visibility metrics was studied through receiver operating characteristic curves. Logistic regression was used to obtain the combined receiver operating characteristic curve of the metrics with the best diagnostic ability. RESULTS: Statistically significant differences were found between groups for all ocular surface parameters and new gland visibility metrics, except for the first noninvasive keratograph breakup time and gland expressibility. New gland visibility metrics showed higher sensitivity and specificity than did current single metrics when their diagnostic ability was assessed without any combination. The diagnostic capability increased when gland visibility metrics were incorporated into the logistic regression analysis together with gland dropout percentage, tear meniscus height, dry eye symptoms, and lid margin abnormality score (P < .001). The combination of median pixel intensity of meibography gray values and the aforementioned ocular surface metrics achieved the highest area under the curve (0.99), along with excellent sensitivity (1.00) and specificity (0.93). CONCLUSIONS: New meibomian gland visibility metrics are more powerful to diagnose MGD than current single metrics and can serve as a complementary tool for supporting the diagnosis of MGD.

Repeatability of Non-invasive Keratograph Break-Up Time measurements obtained using Oculus Keratograph 5M.

PURPOSE: The aim of this study is to assess the intraexaminer repeatability of Non-invasive Keratograph Break-Up Time (NIKBUT) obtained using the Oculus Keratograph 5M (K5M), given its relevance as a homeostasis marker in Dry Eye Disease (DED). METHODS: In total, 80 healthy volunteers aged between 30 and 89 years participated. Measurements were classified according to age, sex and the presence or not of DED. Repeatability was evaluated by the calculation of within-subject standard deviation (Sw), coefficient of repeatability (CoR) and coefficient of variation (CoV). Moreover, the Passing-Bablok regression method was applied. RESULTS: Sw, CoR and CoV coefficients showed low repeatability in all groups with values between 3.57 and 7.14; 9.90 and 19.79; and 51.90 and 65.49, for each coefficient, respectively. No statistically significant differences were found in the NIKBUT measurements between healthy and DED patients (p = 0.188). Groups with more DED risk had better repeatability. Passing-Bablok regression also confirmed a lack of agreement between the maximum and minimum NIKBUT measurement. CONCLUSION: NIKBUT measurement has low intraexaminer repeatability even when considering sex, age and DED diagnosis. Nevertheless, not only is this low repeatability due to the device, but also it is largely due to the intrinsic variability of the tear film.

Response of the Aging Eye to First Day of Modern Material Contact Lens Wear.

OBJECTIVES: To investigate the ocular surface of an aged population wearing a daily disposable contact lens (CL) over their 1st day of wear. METHODS: Forty eyes from 40 presbyopic subjects were fitted a daily CL (Delefilcon A). Tear osmolarity, tear meniscus area (TMA), and ocular surface aberrations (total higher-order root mean square [RMS]) were assessed at baseline (t0), at 20 min (t1) and after 8 hr (t2) of wear. Fluorescein corneal and conjunctival staining and tear breakup time (TBUT) were performed at t0 and t2. RESULTS: No statistically significant changes were found between t0, t1, and t2 for TMA and between t0 and t2 for fluorescein corneal and conjunctival staining. Tear breakup time worsened by the end of the day from 10.4±0.4 sec t0 to 9.0±0.3 sec t2 (P<0.05). Osmolarity showed significant changes between t0 306.9±2.3 mOsm/L and t1 312.4±2.4 mOsmol/L (P=0.02) but returned to baseline values at 8 hr (310.40±2.26 mOsm/L; P=0.09). Total higher-order RMS showed significant changes between t0 0.38±0.02 µm and t1 0.61±0.04 µm (P≤0.001) and between t0 and t2 0.64±0.41 µm (P≤0.001). CONCLUSIONS: Delefilcon A may induce measures changes (osmolarity and TBUT values) in a presbyopic population; however, TMA and vital staining were maintained at the baseline level over the day.

Obesity promotes the expansion of metastasis-initiating cells in breast cancer.

BACKGROUND: Obesity is a strong predictor of poor prognosis in breast cancer, especially in postmenopausal women. In particular, tumors in obese patients tend to seed more distant metastases, although the biology behind this observation remains poorly understood. METHODS: To elucidate the effects of the obese microenvironment on metastatic spread, we ovariectomized C57BL/6 J female mice and fed them either a regular diet (RD) or a high-fat diet (HFD) to generate a postmenopausal diet-induced obesity model. We then studied tumor progression to metastasis of Py230 and EO771 grafts. We analyzed and phenotyped the RD and HFD tumors and the surrounding adipose tissue by flow cytometry, qPCR, immunohistochemistry (IHC) and western blot. The influence of the microenvironment on tumor cells was assessed by performing cross-transplantation of RD and HFD tumor cells into other RD and HFD mice. The results were analyzed using the unpaired Student t test when comparing two variables, otherwise we used one-way or two-way analysis of variance. The relationship between two variables was calculated using correlation coefficients. RESULTS: Our results show that tumors in obese mice grow faster, are also less vascularized, more hypoxic, of higher grade and enriched in CD11b+Ly6G+ neutrophils. Collectively, this favors induction of the epithelial-to-mesenchymal transition and progression to claudin-low breast cancer, a subtype of triple-negative breast cancer that is enriched in cancer stem cells. Interestingly, transplanting HFD-derived tumor cells in RD mice transfers enhanced tumor growth and lung metastasis formation. CONCLUSIONS: These data indicate that a pro-metastatic effect of obesity is acquired by the tumor cells in the primary tumor independently of the microenvironment of the secondary site. Effects of postmenopausal obesity on primary breast cancer tumoursᅟ.

Repeatability assessment of anterior segment biometric measurements under accommodative and nonaccommodative conditions using an anterior segment OCT.

PURPOSE: As accommodation is a dynamic process changing anterior ocular structures, we aim to compare the repeatability between the biometric measurements taken with and without accommodation. METHODS: Thirty healthy right eyes were measured in a baseline and an accommodative state using Visante-OCT. Three repeated measurements were taken to obtain central corneal thickness (CCT), anterior chamber depth (ACD), angle-to-angle distance (ATA), iridocorneal angles (IA), and crystalline lens thickness (LT). Repeatability was evaluated by the calculation of coefficient of repeatability (CoR), coefficient of variation (CoV), and intraclass correlation coefficient (ICC). In addition, the Passing-Bablok regression method was applied. RESULTS: For the nonaccommodative state, the CoR for CCT, ACD, ATA, and LT was 20.02 µm, 0.09 mm, 0.25 mm, and 0.12 mm respectively. The CoR for CCT, ACD, ATA, and LT in the 6D-accommodative state was 20.85 µm, 0.08 mm, 0.26 mm, and 0.14 mm respectively. IA had similar results for both states; the CoR ranged between 3 and 4°, CoV was less than 4%, and the ICC was between 0.984-0.988. There were no significant differences between the three repeated measurements for any measurement. CONCLUSIONS: Visante-OCT provides good repeatability for anterior segment measurements for both accommodative and nonaccommodative states.

Interactions between cancer stem cells and their niche govern metastatic colonization.

Metastatic growth in distant organs is the major cause of cancer mortality. The development of metastasis is a multistage process with several rate-limiting steps. Although dissemination of tumour cells seems to be an early and frequent event, the successful initiation of metastatic growth, a process termed 'metastatic colonization', is inefficient for many cancer types and is accomplished only by a minority of cancer cells that reach distant sites. Prevalent target sites are characteristic of many tumour entities, suggesting that inadequate support by distant tissues contributes to the inefficiency of the metastatic process. Here we show that a small population of cancer stem cells is critical for metastatic colonization, that is, the initial expansion of cancer cells at the secondary site, and that stromal niche signals are crucial to this expansion process. We find that periostin (POSTN), a component of the extracellular matrix, is expressed by fibroblasts in the normal tissue and in the stroma of the primary tumour. Infiltrating tumour cells need to induce stromal POSTN expression in the secondary target organ (in this case lung) to initiate colonization. POSTN is required to allow cancer stem cell maintenance, and blocking its function prevents metastasis. POSTN recruits Wnt ligands and thereby increases Wnt signalling in cancer stem cells. We suggest that the education of stromal cells by infiltrating tumour cells is an important step in metastatic colonization and that preventing de novo niche formation may be a novel strategy for the treatment of metastatic disease.

Reelin Regulates the Maturation of Dendritic Spines, Synaptogenesis and Glial Ensheathment of Newborn Granule Cells.

Significance Statement: The extracellular protein Reelin has an important role in neurological diseases, including epilepsy, Alzheimer's disease and psychiatric diseases, targeting hippocampal circuits. Here we address the role of Reelin in the development of synaptic contacts in adult-generated granule cells (GCs), a neuronal population that is crucial for learning and memory and implicated in neurological and psychiatric diseases. We found that the Reelin pathway controls the shapes, sizes, and types of dendritic spines, the complexity of multisynaptic innervations and the degree of the perisynaptic astroglial ensheathment that controls synaptic homeostasis. These findings show a pivotal role of Reelin in GC synaptogenesis and provide a foundation for structural circuit alterations caused by Reelin deregulation that may occur in neurological and psychiatric disorders.

Megalencephalic leukoencephalopathy with subcortical cysts protein 1 regulates glial surface localization of GLIALCAM from fish to humans.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a leukodystrophy characterized by myelin vacuolization and caused by mutations in MLC1 or GLIALCAM. Patients with recessive mutations in either MLC1 or GLIALCAM show the same clinical phenotype. It has been shown that GLIALCAM is necessary for the correct targeting of MLC1 to the membrane at cell junctions, but its own localization was independent of MLC1 in vitro. However, recent studies in Mlc1(-/-) mice have shown that GlialCAM is mislocalized in glial cells. In order to investigate whether the relationship between Mlc1 and GlialCAM is species-specific, we first identified MLC-related genes in zebrafish and generated an mlc1(-/-) zebrafish. We have characterized mlc1(-/-) zebrafish both functionally and histologically and compared the phenotype with that of the Mlc1(-/-) mice. In mlc1(-/-) zebrafish, as in Mlc1(-/-) mice, Glialcam is mislocalized. Re-examination of a brain biopsy from an MLC patient indicates that GLIALCAM is also mislocalized in Bergmann glia in the cerebellum. In vitro, impaired localization of GlialCAM was observed in astrocyte cultures from Mlc1(-/-) mouse only in the presence of elevated potassium levels, which mimics neuronal activity. In summary, here we demonstrate an evolutionary conserved role for MLC1 in regulating glial surface levels of GLIALCAM, and this interrelationship explains why patients with mutations in either gene (MLC1 or GLIALCAM) share the same clinical phenotype.

Mutant GlialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a leukodystrophy characterized by early-onset macrocephaly and delayed-onset neurological deterioration. Recessive MLC1 mutations are observed in 75% of patients with MLC. Genetic-linkage studies failed to identify another gene. We recently showed that some patients without MLC1 mutations display the classical phenotype; others improve or become normal but retain macrocephaly. To find another MLC-related gene, we used quantitative proteomic analysis of affinity-purified MLC1 as an alternative approach and found that GlialCAM, an IgG-like cell adhesion molecule that is also called HepaCAM and is encoded by HEPACAM, is a direct MLC1-binding partner. Analysis of 40 MLC patients without MLC1 mutations revealed multiple different HEPACAM mutations. Ten patients with the classical, deteriorating phenotype had two mutations, and 18 patients with the improving phenotype had one mutation. Most parents with a single mutation had macrocephaly, indicating dominant inheritance. In some families with dominant HEPACAM mutations, the clinical picture and magnetic resonance imaging normalized, indicating that HEPACAM mutations can cause benign familial macrocephaly. In other families with dominant HEPACAM mutations, patients had macrocephaly and mental retardation with or without autism. Further experiments demonstrated that GlialCAM and MLC1 both localize in axons and colocalize in junctions between astrocytes. GlialCAM is additionally located in myelin. Mutant GlialCAM disrupts the localization of MLC1-GlialCAM complexes in astrocytic junctions in a manner reflecting the mode of inheritance. In conclusion, GlialCAM is required for proper localization of MLC1. HEPACAM is the second gene found to be mutated in MLC. Dominant HEPACAM mutations can cause either macrocephaly and mental retardation with or without autism or benign familial macrocephaly.

Are rescue workers still at risk? A meta-regression analysis of the worldwide prevalence of post-traumatic stress disorder and risk factors.

Rescue workers (policemen, firefighters, emergency medical staff, etc.) experience intense stress due to rescuing and helping victims of accidents, terrorist attacks, violent crimes, and natural disasters. Overexposure and ineffective coping with such stressful events may lead to developing Post-Traumatic Stress Disorder (PTSD). Meta-regression procedures were applied to examine moderators such as the sample sex composition, age, working experience, occupation, country, or type of PTSD evaluation. The 9.8% PTSD prevalence found here was virtually the same compared with earlier findings from 10 years ago. There was a large heterogeneity, however, associated with geographical location and the instrument used to evaluate PTSD. The main findings revealed that rescue workers are a high-risk group with increased levels of Post-traumatic Stress Disorder (PTSD). Moreover, PTSD prevalence could depend on a great extent on geographical and cultural factors, and on the type of PTSD evaluation.

CellCharter reveals spatial cell niches associated with tissue remodeling and cell plasticity.

Tissues are organized in cellular niches, the composition and interactions of which can be investigated using spatial omics technologies. However, systematic analyses of tissue composition are challenged by the scale and diversity of the data. Here we present CellCharter, an algorithmic framework to identify, characterize, and compare cellular niches in spatially resolved datasets. CellCharter outperformed existing approaches and effectively identified cellular niches across datasets generated using different technologies, and comprising hundreds of samples and millions of cells. In multiple human lung cancer cohorts, CellCharter uncovered a cellular niche composed of tumor-associated neutrophil and cancer cells expressing markers of hypoxia and cell migration. This cancer cell state was spatially segregated from more proliferative tumor cell clusters and was associated with tumor-associated neutrophil infiltration and poor prognosis in independent patient cohorts. Overall, CellCharter enables systematic analyses across data types and technologies to decode the link between spatial tissue architectures and cell plasticity.

Cell-autonomous inactivation of the reelin pathway impairs adult neurogenesis in the hippocampus.

Adult hippocampal neurogenesis is thought to be essential for learning and memory, and has been implicated in the pathogenesis of several disorders. Although recent studies have identified key factors regulating neuroprogenitor proliferation in the adult hippocampus, the mechanisms that control the migration and integration of adult-born neurons into circuits are largely unknown. Reelin is an extracellular matrix protein that is vital for neuronal development. Activation of the Reelin cascade leads to phosphorylation of Disabled-1, an adaptor protein required for Reelin signaling. Here we used transgenic mouse and retroviral reporters along with Reelin signaling gain-of-function and loss-of-function studies to show that the Reelin pathway regulates migration and dendritic development of adult-generated hippocampal neurons. Whereas overexpression of Reelin accelerated dendritic maturation, inactivation of the Reelin signaling pathway specifically in adult neuroprogenitor cells resulted in aberrant migration, decreased dendrite development, formation of ectopic dendrites in the hilus, and the establishment of aberrant circuits. Our findings support a cell-autonomous and critical role for the Reelin pathway in regulating dendritic development and the integration of adult-generated granule cells and point to this pathway as a key regulator of adult neurogenesis. Moreover, our data reveal a novel role of the Reelin cascade in adult brain function with potential implications for the pathogenesis of several neurological and psychiatric disorders.

Accelerated aging of the GABAergic septohippocampal pathway and decreased hippocampal rhythms in a mouse model of Alzheimer's disease.

Patients with Alzheimer's disease (AD) display altered functioning of cortical networks, including altered patterns of synchronous activity and a serious deficit in cholinergic septohippocampal (SH) innervation. However, the mechanisms underlying these alterations and the implication of the GABAergic SH component in AD are largely unknown. In addition, the GABAergic septohippocampal pathway (SHP) is believed to regulate synchronous hippocampal activity by controlling the activity of interneurons. Here we show, using well-characterized pathway tracing experiments, that innervation of the GABAergic SHP decreases during normal aging. Furthermore, in an AD mouse model (hAPP(Sw,Ind); J20 mice), the GABAergic SHP shows a dramatic and early onset of this decrease in 8-mo-old mice. This decline is not caused by neuronal loss, but by the reduced number and complexity of GABAergic SH axon terminals. Finally, we demonstrate that hippocampal θ and γ rhythm power spectra are markedly diminished in 8-mo-old behaving mice expressing mutated hAPP. In addition to the well-known loss of cholinergic input to the hippocampus in AD, these data suggest that the altered patterns of synchronous activity seen in patients with AD could be caused by the loss of GABAergic SH axons, which modulate hippocampal network activities.

Expression of Semaphorin 4F in neurons and brain oligodendrocytes and the regulation of oligodendrocyte precursor migration in the optic nerve.

Semaphorins are secreted or membrane-anchored proteins that play critical roles in neural development and adult brain plasticity. Sema4F is a transmembrane semaphorin found on glutamatergic synapses, in which it is attached to the PSD-95-scaffolding protein. Here we further examined the expression of Sema4F by raising specific antibodies. We show that Sema4F protein is widely expressed by neurons during neural development and in the adult brain. We also demonstrate a preferential localization of this protein in postsynaptic dendrites. Moreover, Sema4F is expressed not only by neurons but also by oligodendrocyte precursors in the optic nerve and along the migratory pathways of oligodendroglial cells, and also by subsets of postnatal oligodendroglial cells in the brain. Finally, in vitro experiments demonstrate that endogenous Sema4F expressed by brain cells of oligodendroglial lineage regulates the outgrowth migration of oligodendrocyte precursors and promotes their differentiation. The present data extend our knowledge about the expression of Sema4F and uncover a novel function in the control of oligodendrocyte precursor migration in the developing brain.

Risk Factors for Myopia: A Review.

Due to the myopia prevalence increase worldwide, this study aims to establish the most relevant risk factors associated with its development and progression. A review search was carried out using PubMed, Web of Science, and Scopus databases to identify the main myopia risk factors. The inclusion criteria for the articles were those related to the topic, carried out in subjects from 5 to 30 years, published between January 2000 and May 2023, in English, and with the full text available. Myopia etiology has proven to be associated with both genetic and environmental factors as well as with gene-environment interaction. The risk of developing myopia increases in children with myopic parents (one parent ×2 times, two parents ×5 times). Regarding environmental factors, education is the main risk factor correlated with myopia prevalence increase. Further, several studies found that shorter distance (<30 cm) and longer time spent (>30 min) for near work increase the risk of myopia. Meanwhile, increased outdoor activity (>40 min/day) has been shown to be a key factor in reducing myopia incidence. In conclusion, the interventional strategy suggested so far to reduce myopia incidence is an increase in time outdoors and a reduction in the time spent performing near-work tasks.