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Abstract 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.

Transcutaneous auricular vagus nerve stimulation (taVNS) could be a promising treatment for epilepsy, a neurological disorder primarily characterized by seizures. One of the primary causes of premature mortality in patients with epilepsy is sudden unexpected death in epilepsy (SUDEP). Considering that reduced heart rate variability (HRV) is strongly associated with SUDEP, whether taVNS can modify the autonomic nervous system while simultaneously suppressing seizures in a rat model of epilepsy should be investigated. In this study, epileptic seizures were induced in anesthetized rats by administering pentylenetetrazol (PTZ) and performing taVNS twice. After completing the experiments, changes in HRV measurements were analyzed to investigate the function of the autonomic nervous system. From a histological perspective, the Iba-1, c-Fos, and GAD65 expression levels were examined to evaluate the antiepileptic effects of taVNS. Our study results revealed that taVNS significantly improved the HRV, including root mean square of differences between N–N intervals, standard deviation of all N–N intervals, high-frequency power, and total power. However, no significant difference was observed in the low-frequency power. Histological analysis revealed a significant reduction in Iba-1 and c-Fos expressions following taVNS, with no statistically significant difference observed in GAD65 expression. This study suggests that (1) taVNS could enhance the parasympathetic activity by improving the HRV and (2) potentially exhibit antiepileptic effects by protecting cells from damage caused by epileptic seizures.

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.

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.

BackgroundThe 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.MethodsThe 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.ResultsThe 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.ConclusionIn 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.

Abstract 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.

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.

Abstract Background Long non-coding RNAs (lncRNAs) exhibit highly cell type-specific expression and function, making this class of transcript attractive for targeted cancer therapy. However, the vast majority of lncRNAs have not been tested as potential therapeutic targets, particularly in the context of currently used cancer treatments. Malignant glioma is rapidly fatal, and ionizing radiation is part of the current standard-of-care used to slow tumor growth in both adult and pediatric patients. Results We use CRISPR interference (CRISPRi) to screen 5689 lncRNA loci in human glioblastoma (GBM) cells, identifying 467 hits that modify cell growth in the presence of clinically relevant doses of fractionated radiation. Thirty-three of these lncRNA hits sensitize cells to radiation, and based on their expression in adult and pediatric gliomas, nine of these hits are prioritized as lncRNA Glioma Radiation Sensitizers (lncGRS). Knockdown of lncGRS-1, a primate-conserved, nuclear-enriched lncRNA, inhibits the growth and proliferation of primary adult and pediatric glioma cells, but not the viability of normal brain cells. Using human brain organoids comprised of mature neural cell types as a three-dimensional tissue substrate to model the invasive growth of glioma, we find that antisense oligonucleotides targeting lncGRS-1 selectively decrease tumor growth and sensitize glioma cells to radiation therapy. Conclusions These studies identify lncGRS-1 as a glioma-specific therapeutic target and establish a generalizable approach to rapidly identify novel therapeutic targets in the vast non-coding genome to enhance radiation therapy.

Internet gaming disorder (IGD) is characterized by a loss of control over gaming and a decline in psychosocial functioning derived from excessive gameplay. We hypothesized that individuals with IGD would show different autonomic nervous system (ANS) responses to the games than those without IGD. In this study, heart rate variability (HRV) was assessed in 21 young males with IGD and 27 healthy controls while playing their favorite Internet game. The subjects could examine the game logs to identify the most and least concentrated periods of the game. The changes in HRV during specific 5-min periods of the game (first, last, and high- and low-attention) were compared between groups via a repeated measures analysis of variance. Significant predictors of HRV patterns during gameplay were determined from stepwise multiple linear regression analyses. Subjects with IGD showed a significant difference from controls in the patterns of vagally mediated HRV, such that they showed significant reductions in high-frequency HRV, particularly during the periods of high attention and the last 5 min, compared with baseline values. A regression analysis showed that the IGD symptom scale score was a significant predictor of this reduction. These results suggest that an altered HRV response to specific gaming situations is related to addictive patterns of gaming and may reflect the diminished executive control of individuals with IGD while playing Internet games.

This study investigated the chemical characteristics and microbial population during incubation of four kinds of aerated compost teas based on oriental medicinal herbs compost, vermicompost, rice straw compost, and mixtures of three composts (MOVR). It aimed to determine the effects of the aerated compost tea (ACT) based on MOVR on the growth promotion of red leaf lettuce, soybean and sweet corn. Findings showed that the pH level and EC of the compost tea slightly increased based on the incubation time except for rice straw compost tea. All compost teas except for oriental medicinal herbs and rice straw compost tea contained more NO⁻₃-N than NH⁺₄-N. Plate counts of bacteria and fungi were significantly higher than the initial compost in ACT. Microbial communities of all ACT were predominantly bacteria. The dominant bacterial genera were analyzed as Bacillus (63.0%), Ochrobactrum (13.0%), Spingomonas (6.0%) and uncultured bacterium (4.0%) by 16S rDNA analysis. The effect of four concentrations, 0.1%, 0.2%, 0.4% and 0.8% MOVR on the growth of red leaf lettuce, soybean and sweet corn was also studied in the greenhouse. The red leaf lettuce with 0.4% MOVR had the most effective concentration on growth parameters in foliage part. However, 0.8% MOVR significantly promoted the growth of root and shoot of both soybean and sweet corn. The soybean treated with higher MOVR concentration was more effective in increasing the root nodule formation by 7.25 times than in the lower MOVR concentrations Results indicated that ACT could be used as liquid nutrient fertilizer with active microorganisms for culture of variable crops under organic farming condition.

The epigenetic mechanisms that enable lifelong neurogenesis from neural stem cells (NSCs) in the adult mammalian brain are poorly understood. Here, we show that JMJD3, a histone H3 lysine 27 (H3K27) demethylase, acts as a critical activator of neurogenesis from adult subventricular zone (SVZ) NSCs. JMJD3 is upregulated in neuroblasts, and Jmjd3 deletion targeted to SVZ NSCs in both developing and adult mice impairs neuronal differentiation. JMJD3 regulates neurogenic gene expression via interaction at not only promoter regions but also neurogenic enhancer elements. JMJD3 localizes at neural enhancers genome-wide in embryonic brain, and in SVZ NSCs, JMJD3 regulates the I12b enhancer of Dlx2. In Jmjd3-deleted SVZ cells, I12b remains enriched with H3K27me3 and Dlx2-dependent neurogenesis fails. These findings support a model in which JMJD3 and the poised state of key transcriptional regulatory elements comprise an epigenetic mechanism that enables the activation of neurogenic gene expression in adult NSCs throughout life.

BackgroundWe evaluated the effect and safety of the immediate postoperative continuous infusion of remifentanil at two doses in patients undergoing laparoscopic-assisted vaginal hysterectomy (LAVH) with alfentanil-based patient-controlled analgesia (PCA).MethodsThe study enrolled 50 ASA physical status 1 or 2 patients scheduled to undergo LAVH. Anesthesia was maintained with sevoflurane-remifentanil-air. At the last skin suture, the sevoflurane was discontinued, and patients were randomized to receive remifentanil 0.05 µg/kg/min (group I) or 0.1 µg/kg/min (group II). PCA was started at the time of eye opening and response to a verbal command. In the recovery room, we monitored the mean arterial blood pressure (MAP), heart rate (HR), respiratory rate (RR), SpO2, and bispectral index (BIS) at 5-minute intervals. Thirty minutes after starting PCA, the remifentanil was discontinued. Pain was assessed using a visual analog scale (0 = no pain; 100 = the worst possible pain) at 0, 5, 10, and 30 minutes after stopping the remifentanil infusion.ResultsThe eye opening time, BIS, MAP, and HR did not differ significantly between the two groups, and pain scores were similar between the two groups. Respiratory depression (SpO2 < 90% or RR < 8/min) did not occur in group I but did occur in three patients in group II.ConclusionsContinuous remifentanil infusion (0.05 µg/kg/min) immediately postoperatively with alfentanil-based PCA had a similar effect as a 0.1 µg/kg/min infusion with respect to pain control without side effects. However, special attention must be given to respiratory depression.

We recently showed that streptozotocin (STZ) injections in rats lead to the development of painful peripheral diabetic neuropathy (PDN) accompanied by enhancement of CaV3.2 T-type calcium currents (T-currents) and hyperexcitability in dorsal root ganglion (DRG) neurons. Here we used the classical peripherally acting T-channel blocker mibefradil to examine the role of CaV3.2 T-channels as pharmacological targets for treatment of painful PDN. When administered intraperitoneally (i.p.), at clinically relevant doses, mibefradil effectively alleviated heat, cold and mechanical hypersensitivities in STZ-treated diabetic rats in a dose-dependent manner. We also found that CaV3.2 antisense (AS)-treated diabetic rats exhibit a significant decrease in painful PDN compared with mismatch antisense (MIS)-treated diabetic rats. Co-treatment with mibefradil (9 mg/kg i.p.) resulted in reversal of heat, cold and mechanical hypersensitivity in MIS-treated but not in AS-treated diabetic rats, suggesting that mibefradil and CaV3.2 AS share the same cellular target. Using patch-clamp recordings from acutely dissociated DRG neurons, we demonstrated that mibefradil similarly blocked T-currents in diabetic and healthy rats in a voltage-dependent manner by stabilizing inactive states of T-channels. We conclude that antihyperalgesic and antiallodynic effects of mibefradil in PDN are at least partly mediated by inhibition of CaV3.2 channels in peripheral nociceptors. Hence, peripherally acting voltage-dependent T-channel blockers could be very useful in the treatment of painful symptoms of PDN.

Spinal myoclonus is an unusual, self-limiting, adverse event that may occur during spinal anesthesia. The exact cause and underlying biochemical mechanism of spinal myoclonus remain unclear. A few cases of spinal myoclonus have been reported after administration of intrathecal bupivacaine. We report a case in which spinal myoclonus recurred after two episodes of spinal anesthesia with bupivacaine at a 1-year interval in a 35-year-old woman. The myoclonus was acute and transient. The patient recovered completely, with no neurologic sequelae.