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Damage to the central nervous system (CNS) often leads to irreversible neurological deficits, and there are currently few effective treatments available. However, recent advancements in regenerative medicine have identified CNS organoids as promising therapeutic options for addressing CNS injuries. These organoids, composed of various neurons and supporting cells, have shown potential for direct repair at injury sites. CNS organoids resemble the structure and function of actual brain tissue, which allows them to adapt and function well within the physiological environment when transplanted into injury sites. Research findings suggest that CNS organoids can replace damaged neurons, form new neural connections, and promote neural recovery. This review highlights the emerging benefits, evaluates preclinical transplantation outcomes, and explores future strategies for optimizing neuroregeneration using CNS organoids. With continued research and technological advancements, these organoids could provide new hope for patients suffering from neurological deficits.
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Sistema Nervoso Central , Organoides , Humanos , Organoides/citologia , Organoides/transplante , Regeneração Nervosa , Animais , Neurônios/citologia , Neurônios/fisiologia , Medicina Regenerativa/métodosRESUMO
The aberrant expression of specific long noncoding RNAs (lncRNAs) has been associated with cognitive and psychiatric disorders. Although a growing number of lncRNAs are now known to regulate neural cell development and function, relatively few lncRNAs have been shown to underlie animal behavior. Pnky is an evolutionarily conserved, neural lncRNA that regulates brain development. Using mouse genetic strategies, we show that Pnky has sex-specific roles in mouse behavior and that this lncRNA can underlie specific behavior by functioning in trans. Male Pnky-knockout mice have decreased context generalization in a paradigm of associative fear learning and memory. In female Pnky-knockout mice, there is an increase in the acoustic startle response, a behavior that is altered in affective disorders. Remarkably, expression of Pnky from a bacterial artificial chromosome transgene decreases the acoustic startle response in female Pnky-knockout mice, demonstrating that Pnky can modulate specific animal behavior by functioning in trans. More broadly, these studies illustrate how specific lncRNAs can underlie cognitive and mood disorders.
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Comportamento Animal , Medo , Camundongos Knockout , RNA Longo não Codificante , Reflexo de Sobressalto , Animais , Feminino , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Masculino , Comportamento Animal/fisiologia , Camundongos , Reflexo de Sobressalto/fisiologia , Medo/fisiologia , Memória/fisiologia , Camundongos Endogâmicos C57BL , Fatores SexuaisRESUMO
Since the emergence of the first cerebral organoid (CO) in 2013, advancements have transformed central nervous system (CNS) research. Initial efforts focused on studying the morphogenesis of COs and creating reproducible models. Numerous methodologies have been proposed, enabling the design of the brain organoid to represent specific regions and spinal cord structures. CNS organoids now facilitate the study of a wide range of CNS diseases, from infections to tumors, which were previously difficult to investigate. We summarize the major advancements in CNS organoids, concerning morphogenetic designs and disease models. We examine the development of fabrication procedures and how these advancements have enabled the generation of region-specific brain organoids and spinal cord models. We highlight the application of these organoids in studying various CNS diseases, demonstrating the versatility and potential of organoid models in advancing our understanding of complex conditions. We discuss the current challenges in the field, including issues related to reproducibility, scalability, and the accurate recapitulation of the in vivo environment. We provide an outlook on prospective studies and future directions. This review aims to provide a comprehensive overview of the state-of-the-art CNS organoid research, highlighting key developments, current challenges, and prospects in the field.
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Sistema Nervoso Central , Organoides , Humanos , Animais , Doenças do Sistema Nervoso Central/patologia , Morfogênese , Modelos BiológicosRESUMO
Composites of reduced graphene oxides (rGOs) with transition metal dichalcogenides have garnered considerable attention as promising anode materials for sodium-ion batteries (SIBs) because of their superior theoretical capacity and long-term stability compared with pure graphene. However, the underlying mechanism of how the oxygen functional groups improve the functionality of rGO remains unclear. In this study, we investigated the roles of functional groups in rGO-based heterogeneous bilayers using first-principles density functional theory calculations. The thermodynamic affinities to Na atoms, kinetic diffusion, and working potential behaviors of the Na atoms in various models, such as MoS2/graphene (Gr), MoS2/Gr-O, MoS2/Gr-OH, and MoS2/Gr-COOH, were accurately evaluated. It is clearly demonstrated that the noncovalent bonding nature is a predominant descriptor of Na affinity rather than the charge distribution around the intercalated Na atom. The activation barriers for Na atomic diffusion in the MoS2/Gr, MoS2/Gr-O, MoS2/Gr-OH, and MoS2/Gr-COOH models were estimated to be 0.24, 0.27, 0.35, and 0.31 eV, respectively. This indicated that the functional groups slightly delayed the Na motion. Notably, the obtained results demonstrated that the -COOH group not only enhanced the affinity towards Na intercalation but also induced a low working voltage at approximately 1 V. Therefore, the carboxyl functional group exhibits high material stability, making rGO a promising candidate for SIB anode materials.
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The human brain expresses thousands of different long noncoding RNAs (lncRNAs), and aberrant expression of specific lncRNAs has been associated with cognitive and psychiatric disorders. While a growing number of lncRNAs are now known to regulate neural cell development and function, relatively few have been shown to underlie animal behavior, particularly with genetic strategies that establish lncRNA function in trans. Pnky is an evolutionarily conserved, neural lncRNA that regulates brain development. Using mouse genetic strategies, we show that Pnky has sex-specific roles in mouse behavior and that this lncRNA underlies specific behavior by functioning in trans. Male Pnky-knockout (KO) mice have deficits in cued fear recall, a type of Pavlovian associative memory. In female Pnky-KO mice, the acoustic startle response (ASR) is increased and accompanied by a decrease in prepulse inhibition (PPI), both of which are behaviors altered in affective disorders. Remarkably, expression of Pnky from a bacterial artificial chromosome (BAC) transgene reverses the ASR phenotype of female Pnky-KO mice, demonstrating that Pnky underlies specific animal behavior by functioning in trans. More broadly, these data provide genetic evidence that a lncRNA gene and its function in trans can play a key role in the behavior of adult mammals, contributing fundamental knowledge to our growing understanding of the association between specific lncRNAs and disorders of cognition and mood.
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Background: The diminished executive control along with cue-reactivity has been suggested to play an important role in addiction. Hear rate variability (HRV), which is related to the autonomic nervous system, is a useful biomarker that can reflect cognitive-emotional responses to stimuli. In this study, Internet gaming disorder (IGD) subjects' autonomic response to gaming-related cues was evaluated by measuring HRV changes in exposure to gaming situation. We investigated whether this HRV reactivity can significantly classify the categorical classification according to the severity of IGD. Methods: The present study included 70 subjects and classified them into 4 classes (normal, mild, moderate and severe) according to their IGD severity. We measured HRV for 5 min after the start of their preferred Internet game to reflect the autonomic response upon exposure to gaming. The neural parameters of deep learning model were trained using time-frequency parameters of HRV. Using the Class Activation Mapping (CAM) algorithm, we analyzed whether the deep learning model could predict the severity classification of IGD and which areas of the time-frequency series were mainly involved. Results: The trained deep learning model showed an accuracy of 95.10% and F-1 scores of 0.995 (normal), 0.994 (mild), 0.995 (moderate), and 0.999 (severe) for the four classes of IGD severity classification. As a result of checking the input of the deep learning model using the CAM algorithm, the high frequency (HF)-HRV was related to the severity classification of IGD. In the case of severe IGD, low frequency (LF)-HRV as well as HF-HRV were identified as regions of interest in the deep learning model. Conclusion: In a deep learning model using the time-frequency HRV data, a significant predictor of IGD severity classification was parasympathetic tone reactivity when exposed to gaming situations. The reactivity of the sympathetic tone for the gaming situation could predict only the severe group of IGD. This study suggests that the autonomic response to the game-related cues can reflect the addiction status to the game.
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Bacterial leaf blight of carrots caused by Xanthomonas hortorum pv. carotae (Xhc) is an important worldwide seed-borne disease. In 2012 and 2013, symptoms similar to bacterial leaf blight were found in carrot farms in Jeju Island, Korea. The phenotypic characteristics of the Korean isolation strains were similar to the type strain of Xhc. Pathogenicity showed symptoms on the 14th day after inoculation on carrot plants. Identification by genetic method was multi-position sequencing of the isolated strain JJ2001 was performed using four genes (danK, gyrB, fyuA, and rpoD). The isolated strain was confirmed to be most similar to Xhc M081. Furthermore, in order to analyze the genetic characteristics of the isolated strain, whole genome analysis was performed through the next-generation sequencing method. The draft genome size of JJ2001 is 5,443,372 bp, which contains 63.57% of G + C and has 4,547 open reading frames. Specifically, the classification of pathovar can be confirmed to be similar to that of the host lineage. Plant pathogenic factors and determinants of the majority of the secretion system are conserved in strain JJ2001. This genetic information enables detailed comparative analysis in the pathovar stage of pathogenic bacteria. Furthermore, these findings provide basic data for the distribution and diagnosis of Xanthomonas hortorum pv. carotae, a major plant pathogen that infects carrots in Korea.
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Background: Use of opioids for chronic intractable pain is increasing globally, and their proper use can improve patients' quality of life. In contrast, opioid use disorders, such as abuse or addiction, caused by prescribing opioids, are a worldwide issue. This study aimed to understand current opioid prescribing patterns and pain physicians' experiences with opioid use in South Korea. Methods: Pain physicians in 42 university hospitals in South Korea were asked to complete anonymous questionnaires regarding opioid prescriptions. Results: A total of 69 surveys were completed. Most pain physicians started prescribing opioids at a pain score of 7/10 and aimed to reduce pain by 50%. Most physicians (73.1%) actively explained the prescribed medications and possible side effects, and 61.2% of physicians preferred the prescription interval of 4 weeks. Immediate-release opioids were the most popular treatment for breakthrough pain (92.6%). The most common side effect encountered by physicians was constipation (43.3%), followed by nausea/vomiting (34.3%). Of the physicians, 56.5% replied that addiction and misuse prevalences were less than 5%. However, the most concerning side effect was addiction (33.0%). Conclusions: The survey results showed that the prescribing patterns of pain physicians generally followed Korean guidelines. Physicians were most interested in the safety and effectiveness of opioid prescriptions. They were most concerned about respiratory depression and abuse or addiction. A significant number of physicians agreed that the NHIS regulations needed improvement for patient convenience and safe and effective treatment, though there were pros and cons of the NHIS restrictions on prescription conditions.
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The modulating of the geometric and electronic structures of metal-N-C atomic catalysts for improving their performance in catalyzing oxygen reduction reactions (ORRs) is highly desirable yet challenging. We herein report a delicate "encapsulation-substitution" strategy for the synthesis of paired metal sites in N-doped carbon. With the regulation of the d-orbital energy level, a significant increment in oxygen electroreduction activity was demonstrated in Ru-Co diatomic catalyst (DAC) compared with other diatomic (Ru-Fe and Ru-Ni) and single-atomic counterparts. The Ru-Co DAC efficiently reduces oxygen with a halfwave potential of 0.895 V vs RHE and a turnover frequency of 2.424 s-1 at 0.7 V, establishing optimal thermodynamic and kinetic behaviors in the triple-phase reaction under practical conditions. Moreover, the Ru-Co DAC electrode displays bifunctional activity in a gas diffusion Zn-air battery with a small voltage gap of 0.603 V, outperforming the commercial Pt/C|RuO2 catalyst. Our findings provide a clear understanding of site-to-site interaction on ORR and a benchmark evaluation of atomic catalysts with correlations of diatomic structure, energy level, and overall catalytic performance at the subnanometer level.
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Environmental damage from serious nuclear accidents should be urgently restored, which needs the removal of radioactive species. Radioactive iodine isotopes are particularly problematic for human health because they are released in large amounts and retain radioactivity for a substantial time. Herein, we prepare platinum-coated iron nanoparticles (Fe@Pt) as a highly selective and reusable adsorbent for iodine species, i.e., iodide (I-), iodine (I2), and methyl iodide (CH3I). Fe@Pt selectively separates iodine species from seawater and groundwater with a removal efficiency ≥ 99.8%. The maximum adsorption capacity for the iodine atom of all three iodine species was determined to be 25 mg/g. The magnetic properties of Fe@Pt allow for the facile recovery and reuse of Fe@Pt, which remains stable with high efficiency (97.5%) over 100 uses without structural and functional degradation in liquid media. Practical application to the removal of radioactive 129I and feasibility for scale-up using a 20 L system demonstrate that Fe@Pt can function as a reusable adsorbent for the selective removal of iodine species. This systematic procedure is a standard protocol for designing highly active adsorbents for the clean separation and removal of various chemical species dissolved in wastewater.
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Iodo , Neoplasias da Glândula Tireoide , Poluentes Químicos da Água , Adsorção , Humanos , Iodetos , Radioisótopos do Iodo/química , Água/química , Poluentes Químicos da Água/químicaRESUMO
Herpes zoster (HZ) is caused by reactivation of latent varicella-zoster virus (VZV) when VZV-specific cellular immunity is insufficient to control reactivation. Currently, Shingrix, which contains the VZV gE protein and GSK's AS01B adjuvant composed of liposomes formulated with cholesterol, monophosphoryl lipid A (MPL) and QS21, is used for prevention of HZ. However, reactogenicity to Shingrix is common leading to poor patient compliance in receiving one or both shots. Here, we evaluated the immunogenicity of a newly formulated gE protein-based HZ vaccine containing Second-generation Lipid Adjuvant (SLA), a synthetic TLR4 ligand, formulated in an oil-in-water emulsion (SLA-SE) without QS21 (gE/SLA-SE). In VZV-primed mouse models, gE/SLA-SE-induced gE-specific humoral and cellular immune responses at comparable levels to those elicited by Shingrix in young mice, as both gE/SLA-SE and Shingrix induce polyfunctional CD4+ T-cell responses. In aged mice, gE/SLA-SE elicited more robust gE-specific T-cell responses than Shingrix. Furthermore, gE/SLA-SE-induced T-cell responses were sustained until 5 months after immunization. Thus, QS21-free, gE/SLA-SE is a promising candidate for development of gE-based HZ vaccines with high immunogenicity-particularly when targeting an older population.
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Background: The coronavirus disease 2019 (COVID-19) pandemic has caused significant changes. This study aimed to investigate the impact of COVID-19 on patients with chronic pain. Methods: Patients with chronic pain from 23 university hospitals in South Korea participated in this study. The anonymous survey questionnaire consisted of 25 questions regarding the following: demographic data, diagnosis, hospital visit frequency, exercise duration, time outside, sleep duration, weight change, nervousness and anxiety, depression, interest or pleasure, fatigue, daily life difficulties, and self-harm thoughts. Depression severity was evaluated using the Patient Health Questionnaire-9 (PHQ-9). Logistic regression analysis was used to investigate the relationship between increased pain and patient factors. Results: A total of 914 patients completed the survey, 35.9% of whom had decreased their number of visits to the hospital, mostly due to COVID-19. The pain level of 200 patients has worsened since the COVID-19 outbreak, which was more prominent in complex regional pain syndrome (CRPS). Noticeable post-COVID-19 changes such as exercise duration, time spent outside, sleep patterns, mood, and weight affected patients with chronic pain. Depression severity was more significant in patients with CRPS. The total PHQ-9 average score of patients with CRPS was 15.5, corresponding to major depressive orders. The patients' decreased exercise duration, decreased sleep duration, and increased depression were significantly associated with increased pain. Conclusions: COVID-19 has caused several changes in patients with chronic pain. During the pandemic, decreased exercise and sleep duration and increased depression were associated with patients' increasing pain.
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Metastable phases-kinetically favoured structures-are ubiquitous in nature1,2. Rather than forming thermodynamically stable ground-state structures, crystals grown from high-energy precursors often initially adopt metastable structures depending on the initial conditions, such as temperature, pressure or crystal size1,3,4. As the crystals grow further, they typically undergo a series of transformations from metastable phases to lower-energy and ultimately energetically stable phases1,3,4. Metastable phases sometimes exhibit superior physicochemical properties and, hence, the discovery and synthesis of new metastable phases are promising avenues for innovations in materials science1,5. However, the search for metastable materials has mainly been heuristic, performed on the basis of experiences, intuition or even speculative predictions, namely 'rules of thumb'. This limitation necessitates the advent of a new paradigm to discover new metastable phases based on rational design. Such a design rule is embodied in the discovery of a metastable hexagonal close-packed (hcp) palladium hydride (PdHx) synthesized in a liquid cell transmission electron microscope. The metastable hcp structure is stabilized through a unique interplay between the precursor concentrations in the solution: a sufficient supply of hydrogen (H) favours the hcp structure on the subnanometre scale, and an insufficient supply of Pd inhibits further growth and subsequent transition towards the thermodynamically stable face-centred cubic structure. These findings provide thermodynamic insights into metastability engineering strategies that can be deployed to discover new metastable phases.
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Nuclear compartments are thought to play a role in three-dimensional genome organization and gene expression. In mammalian brain, the architecture and dynamics of nuclear compartment-associated genome organization is not known. In this study, we developed Genome Organization using CUT and RUN Technology (GO-CaRT) to map genomic interactions with two nuclear compartments-the nuclear lamina and nuclear speckles-from different regions of the developing mouse, macaque and human brain. Lamina-associated domain (LAD) architecture in cells in vivo is distinct from that of cultured cells, including major differences in LADs previously considered to be cell type invariant. In the mouse and human forebrain, dorsal and ventral neural precursor cells have differences in LAD architecture that correspond to their regional identity. LADs in the human and mouse cortex contain transcriptionally highly active sub-domains characterized by broad depletion of histone-3-lysine-9 dimethylation. Evolutionarily conserved LADs in human, macaque and mouse brain are enriched for transcriptionally active neural genes associated with synapse function. By integrating GO-CaRT maps with genome-wide association study data, we found speckle-associated domains to be enriched for schizophrenia risk loci, indicating a physical relationship between these disease-associated genetic variants and a specific nuclear structure. Our work provides a framework for understanding the relationship between distinct nuclear compartments and genome function in brain development and disease.
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Encéfalo/fisiologia , Núcleo Celular/fisiologia , Expressão Gênica/genética , Genoma/genética , Neurogênese/fisiologia , Animais , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Macaca , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/fisiologia , Esquizofrenia/genéticaRESUMO
BACKGROUND: Complex regional pain syndrome (CRPS) is an intractable pain disease with various symptoms. Here, we investigated the disease status, work life, sleep problems, medical insurance, economic status, psychological problems, and quality of life (QOL) of CRPS patients. METHODS: CRPS patients from 37 university hospitals in South Korea were surveyed. The survey questionnaire consisted of 24 questions on the following aspects of CRPS patients: sex, age, occupation, cause of injury, activities of daily living (ADL), pain severity, sleep disturbance, level of education, economic status, therapeutic effect, and suicidal ideation. Additionally, the abbreviated World Health Organization Quality of Life (WHOQOL-BREF) questionnaire, consisting of 26 questions, was used to identify the status of QOL. RESULTS: A total of 251 patients completed the questionnaire. According to the survey, 54.2% patients could not perform ADL on their own. Over the previous week, the mean pain score was 7.15 ± 1.78 (out of a total of 10 points); 92.1% of patients had sleep disorders and 80.5% had suicidal ideation, with most patients suffering from psychological problems. The average for each domain of WHOQOL-BREF was as follows: 21.74 ± 14.77 for physical, 25.22 ± 17.66 for psychological, 32.02 ± 22.36 for social relationship, and 30.69 ± 15.83 for environmental (out of a total of 100 points each). Occupation, ADL, sleep time, therapeutic effect, and suicidal ideation were statistically correlated with multiple domains. CONCLUSIONS: Most patients had moderate to severe pain, economic problems, limitations of their ADL, sleep problems, psychological problems, and a low QOL score.
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Morphine is widely used in pain management although the risk of side effects is significant. The use of biased agonists to the G protein of µ-opioid receptors has been suggested as a potential solution, although oliceridine and PZM21 have previously failed to demonstrate benefits in clinical studies. An amplification-induced confusion in the process of comparing G protein and beta-arrestin pathways may account for previously biased agonist misidentification. Here, we have devised a strategy to discover biased agonists with intrinsic efficacy. We computationally simulated 430â¯000 molecular dockings to the µ-opioid receptor to construct a compound library. Hits were then verified experimentally. Using the verified compounds, we performed simulations to build a second library with a common scaffold and selected compounds that showed a bias to µ- and δ-opioid receptors in a cell-based assay. Three compounds (ID110460001, ID110460002, and ID110460003) with a dual-biased agonistic effect for µ- and δ-opioid receptors were identified. These candidates are full agonists for the µ-opioid receptor and show specific binding modes. On the basis of our findings, we expect our novel compounds to act as more biased agonists compared to existing drugs, including oliceridine.
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Machine-learning (ML) techniques have drawn an ever-increasing focus as they enable high-throughput screening and multiscale prediction of material properties. Especially, ML force fields (FFs) of quantum mechanical accuracy are expected to play a central role for the purpose. The construction of ML-FFs for polymers is, however, still in its infancy due to the formidable configurational space of its composing atoms. Here, we demonstrate the effective development of ML-FFs using kernel functions and a Gaussian process for an organic polymer, polytetrafluoroethylene (PTFE), with a data set acquired by first-principles calculations and ab initio molecular dynamics (AIMD) simulations. Even though the training data set is sampled only with short PTFE chains, structures of longer chains optimized by our ML-FF show an excellent consistency with density functional theory calculations. Furthermore, when integrated with molecular dynamics simulations, the ML-FF successfully describes various physical properties of a PTFE bundle, such as a density, melting temperature, coefficient of thermal expansion, and Young's modulus.
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BACKGROUND: Spinal epidural hematoma is rare condition that can rapidly develop into severe neurologic deficits. The pathophysiology of this development remains unclear. There are several case reports of emergency hematoma evacuations after epidural steroid injection. CASE: We report on two patients who developed acute, large amounts of epidural hematoma without neurological deficits after transforaminal epidural steroid injection. After fluoroscopy guided aspiration for epidural hematoma was performed, neurological defects did not progress and the hematoma was shown to be absorbed on magnetic resonance imaging. CONCLUSIONS: These reports are believed to be the first of treating epidural hematoma occurring after transforaminal epidural steroid injection through non-surgical hematoma aspiration. If large amounts of epidural hematoma are not causing neurological issues, it can be aspirated until it is absorbed.
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Among the large, diverse set of mammalian long noncoding RNAs (lncRNAs), long noncoding primary microRNAs (lnc-pri-miRNAs) are those that host miRNAs. Whether lnc-pri-miRNA loci have important biological function independent of their cognate miRNAs is poorly understood. From a genome-scale lncRNA screen, lnc-pri-miRNA loci were enriched for function in cell proliferation, and in glioblastoma (i.e., GBM) cells with DGCR8 or DROSHA knockdown, lnc-pri-miRNA screen hits still regulated cell growth. To molecularly dissect the function of a lnc-pri-miRNA locus, we studied LOC646329 (also known as MIR29HG), which hosts the miR-29a/b1 cluster. In GBM cells, LOC646329 knockdown reduced miR-29a/b1 levels, and these cells exhibited decreased growth. However, genetic deletion of the miR-29a/b1 cluster (LOC646329-miR29Δ) did not decrease cell growth, while knockdown of LOC646329-miR29Δ transcripts reduced cell proliferation. The miR-29a/b1-independent activity of LOC646329 corresponded to enhancer-like activation of a neighboring oncogene (MKLN1), regulating cell propagation. The LOC646329 locus interacts with the MKLN1 promoter, and antisense oligonucleotide knockdown of the lncRNA disrupts these interactions and reduces the enhancer-like activity. More broadly, analysis of genome-wide data from multiple human cell types showed that lnc-pri-miRNA loci are significantly enriched for DNA looping interactions with gene promoters as well as genomic and epigenetic characteristics of transcriptional enhancers. Functional studies of additional lnc-pri-miRNA loci demonstrated cognate miRNA-independent enhancer-like activity. Together, these data demonstrate that lnc-pri-miRNA loci can regulate cell biology via both miRNA-dependent and miRNA-independent mechanisms.