Explore the vast range of titles available.

The N -methyl- d -aspartate receptor (NMDAR) antagonist ketamine has attracted enormous interest in mental health research owing to its rapid antidepressant actions, but its mechanism of action has remained elusive. Here we show that blockade of NMDAR-dependent bursting activity in the ‘anti-reward center’, the lateral habenula (LHb), mediates the rapid antidepressant actions of ketamine in rat and mouse models of depression. LHb neurons show a significant increase in burst activity and theta-band synchronization in depressive-like animals, which is reversed by ketamine. Burst-evoking photostimulation of LHb drives behavioural despair and anhedonia. Pharmacology and modelling experiments reveal that LHb bursting requires both NMDARs and low-voltage-sensitive T-type calcium channels (T-VSCCs). Furthermore, local blockade of NMDAR or T-VSCCs in the LHb is sufficient to induce rapid antidepressant effects. Our results suggest a simple model whereby ketamine quickly elevates mood by blocking NMDAR-dependent bursting activity of LHb neurons to disinhibit downstream monoaminergic reward centres, and provide a framework for developing new rapid-acting antidepressants. The rapid antidepressant activity of ketamine results from reversal of increased burst firing and synchronization in the lateral habenula in rat and mouse models of depression. A burst of activity for antidepressants The lateral habenula (LHb) is a region of the brain that is associated with aversion and other negative emotions. Hailan Hu and colleagues present a pair of papers in this week's issue on the role of burst firing in LHb neurons in depression in rats. First, they show that ketamine, a drug that can be used as an antidepressant, blocks LHb neuron bursting activity, and that both NMDAR and low-voltage-sensitive T-type calcium channels (T-VSCCs) are required for the drug to be effective. In the second study, the authors identify a potential mechanism for regulating this bursting behaviour that could represent a new therapeutic target. Levels of an astroglial potassium channel, Kir4.1, covary with the degree of membrane hyperpolarization and bursting activity of LHb neurons, as well as depression-related behaviours in various rodent models. The team suggest that blocking LHb neuron bursting activity could revive reward centres in the brain and elevate mood, and provide a model framework for developing rapid-acting antidepressants.

Salmonella Typhimurium establishes systemic infection by replicating in host macrophages. Here we show that macrophages infected with S . Typhimurium exhibit upregulated glycolysis and decreased serine synthesis, leading to accumulation of glycolytic intermediates. The effects on serine synthesis are mediated by bacterial protein SopE2, a type III secretion system (T3SS) effector encoded in pathogenicity island SPI-1. The changes in host metabolism promote intracellular replication of S . Typhimurium via two mechanisms: decreased glucose levels lead to upregulated bacterial uptake of 2- and 3-phosphoglycerate and phosphoenolpyruvate (carbon sources), while increased pyruvate and lactate levels induce upregulation of another pathogenicity island, SPI-2, known to encode virulence factors. Pharmacological or genetic inhibition of host glycolysis, activation of host serine synthesis, or deletion of either the bacterial transport or signal sensor systems for those host glycolytic intermediates impairs S . Typhimurium replication or virulence. Salmonella Typhimurium establishes systemic infection by replicating in host macrophages. Here, Jiang et al. show that infected macrophages exhibit upregulated glycolysis and decreased serine synthesis, leading to accumulation of glycolytic intermediates that promote intracellular replication and virulence of S . Typhimurium.

Ketamine, an N -methyl- d -aspartate receptor (NMDAR) antagonist 1 , has revolutionized the treatment of depression because of its potent, rapid and sustained antidepressant effects 2 – 4 . Although the elimination half-life of ketamine is only 13 min in mice 5 , its antidepressant activities can last for at least 24 h 6 – 9 . This large discrepancy poses an interesting basic biological question and has strong clinical implications. Here we demonstrate that after a single systemic injection, ketamine continues to suppress burst firing and block NMDARs in the lateral habenula (LHb) for up to 24 h. This long inhibition of NMDARs is not due to endocytosis but depends on the use-dependent trapping of ketamine in NMDARs. The rate of untrapping is regulated by neural activity. Harnessing the dynamic equilibrium of ketamine–NMDAR interactions by activating the LHb and opening local NMDARs at different plasma ketamine concentrations, we were able to either shorten or prolong the antidepressant effects of ketamine in vivo. These results provide new insights into the causal mechanisms of the sustained antidepressant effects of ketamine. The ability to modulate the duration of ketamine action based on the biophysical properties of ketamine–NMDAR interactions opens up new opportunities for the therapeutic use of ketamine. The discrepancy between the short half-life of ketamine and its long-lasting effects is due to ketamine being trapped in NMDA receptors, and its release depends on neural activity in the lateral habenula.

Increased expression of the potassium channel Kir4.1 on astrocytes in the lateral habenula drives neuronal bursting in rodent models of depression. A burst of activity for antidepressants The lateral habenula (LHb) is a region of the brain that is associated with aversion and other negative emotions. Hailan Hu and colleagues present a pair of papers in this week's issue on the role of burst firing in LHb neurons in depression in rats. First, they show that ketamine, a drug that can be used as an antidepressant, blocks LHb neuron bursting activity, and that both NMDAR and low-voltage-sensitive T-type calcium channels (T-VSCCs) are required for the drug to be effective. In the second study, the authors identify a potential mechanism for regulating this bursting behaviour that could represent a new therapeutic target. Levels of an astroglial potassium channel, Kir4.1, covary with the degree of membrane hyperpolarization and bursting activity of LHb neurons, as well as depression-related behaviours in various rodent models. The team suggest that blocking LHb neuron bursting activity could revive reward centres in the brain and elevate mood, and provide a model framework for developing rapid-acting antidepressants. Enhanced bursting activity of neurons in the lateral habenula (LHb) is essential in driving depression-like behaviours, but the cause of this increase has been unknown. Here, using a high-throughput quantitative proteomic screen, we show that an astroglial potassium channel (Kir4.1) is upregulated in the LHb in rat models of depression. Kir4.1 in the LHb shows a distinct pattern of expression on astrocytic membrane processes that wrap tightly around the neuronal soma. Electrophysiology and modelling data show that the level of Kir4.1 on astrocytes tightly regulates the degree of membrane hyperpolarization and the amount of bursting activity of LHb neurons. Astrocyte-specific gain and loss of Kir4.1 in the LHb bidirectionally regulates neuronal bursting and depression-like symptoms. Together, these results show that a glia–neuron interaction at the perisomatic space of LHb is involved in setting the neuronal firing mode in models of a major psychiatric disease. Kir4.1 in the LHb might have potential as a target for treating clinical depression.

Background: Acute hepatitis E (AHE) poses escalating risks to older adults (>=65 years), compounded by immunosenescence and comorbidities. Using Global Burden of Disease (GBD) 2021 data, this study analyzes global AHE burden, trends, and projections in aging populations. Methods: Age-standardized rates (ASIR, ASMR, ASDR) for AHE in adults >=65 years were extracted from GBD 2021 across 204 countries (1990-2021). Frontier analysis assessed gaps between observed burdens and sociodemographic index (SDI)-based theoretical minima. Age-period-cohort (APC) modeling evaluated age/period/cohort effects. Bayesian (BAPC), NORDPRED, and ARIMA models projected trends to 2050. Results: Global ASIR increased by 1.5% annually (1990-2021), with ASMR and DALYs declining significantly. Middle SDI regions showed the steepest ASIR rise (net drift: 0.064%/year), while high SDI areas had volatile trends. Age effects peaked in >=95-year-olds. Frontier analysis revealed persistent ASIR-SDI gaps, particularly in low-middle SDI regions. Projections indicate a ASIR rise by 2050 (113.04/100,000), contrasting with declining ASMR (0.056/100,000) and ASDR (1.31/100,000) and the NORDPRED, ARIMA, and EAPC models exhibit analogous global predictive trends. Conclusions: Diverging trends of rising incidence and falling mortality highlight unmet prevention needs. High-burden regions require SDI-stratified strategies, prioritizing vaccination programs (e.g., HEV 239), zoonotic transmission control, and enhanced surveillance. The Sustainable Development Goals (SDGs) envision hepatitis elimination by 2030 (Target 3.3). However, our analysis projects ongoing AHE burden in aging populations through 2050, indicating the need for post-2030 policy adaptations.

TikTok is an important channel for consumers to obtain and adopt health information. However, misinformation on TikTok could potentially impact public health. Currently, the quality of content related to GDM on TikTok has not been thoroughly reviewed. This study aims to explore the information quality of GDM videos on TikTok. A comprehensive cross-sectional study was conducted on TikTok videos related to GDM. The quality of the videos was assessed using three standardized evaluation tools: DISCERN, the Journal of the American Medical Association (JAMA) benchmarks, and the Global Quality Scale (GQS). The comprehensiveness of the content was evaluated through six questions covering definitions, signs/symptoms, risk factors, evaluation, management, and outcomes. Additionally, a correlational analysis was conducted between video quality and the characteristics of the uploaders and the videos themselves. A total of 216 videos were included in the final analysis, with 162 uploaded by health professionals, 40 by general users, and the remaining videos contributed by individual science communicators, for-profit organizations, and news agencies. The average DISCERN, JAMA, and GQS scores for all videos were 48.87, 1.86, and 2.06, respectively. The videos uploaded by health professionals scored the highest in DISCERN, while the videos uploaded by individual science communicators scored significantly higher in JAMA and GQS than those from other sources. Correlation analysis between video quality and video features showed DISCERN scores, JAMA scores and GQS scores were positively correlated with video duration (P<0.001). Content scores were positively correlated with the number of comments (P<0.05), the number of shares (P<0.001), and video duration (P<0.001). We found that the quality of GDM video on TikTok is poor and lack of relevant information, highlighting the potential risks of using TikTok as a source of health information. Patients should pay attention to identifying health-related information on TikTok.

Background Mood disorders are strongly associated with melatonin disturbances. However, it is unclear whether there is a difference in melatonin concentrations and melatonin circadian rhythm profiles between depression and bipolar disorder. In addition, the relationship between anhedonia, a common symptom of affective disorders, and its melatonin circadian rhythm remains under-investigated. Methods Thirty-four patients with depression disorder, 20 patients diagnosed with bipolar disorder and 21 healthy controls participated in this study. The Revised Physical Anhedonia Scale (RPAS) was performed to assess anhedonia. Saliva samples were collected from all subjects at fixed time points (a total of 14 points) in two consecutive days for measuring the melatonin concentrations to fit circadian rhythms of subjects. Melatonin circadian rhythms were compared between the three groups using ANOVA. Partial correlation analysis and linear regression analysis were used to explore the correlation between melatonin rhythm variables and anhedonia. Results We found that the peak phase of melatonin in the depression group was significantly advanced compared to the control group ( P  < 0.001) and the bipolar disorder group ( P  = 0.004). The peak phase of melatonin and RPAS showed a negative correlation ( P  = 0.003) in depression patients, which was also demonstrated in the multiple linear regression model (B=-2.47, P  = 0.006). Conclusions These results suggest that circadian rhythms of melatonin are differentiated in depression and bipolar disorder and correlate with anhedonia in depression. Future research needs to explore the neurobiological mechanisms linking anhedonia and melatonin circadian rhythms in depressed patients.

Abstract Maternal prenatal depression is associated with child sleep. We investigated whether maternal depression comorbid with anxiety worsens toddler’s sleep problems in a prospective cohort study. A total of 1583 mother-infant pairs from the China-Anhui Birth Cohort study were examined. The participants completed the Center for Epidemiologic Studies Depression Scale (CES-D) and Self-Rating Anxiety Scale (SAS) at 30–34 weeks of gestation, and the Edinburgh Postnatal Depression Scale (EPDS) at 3-month postpartum. Toddler’s sleep was assessed by the Brief Infant Sleep Questionnaire (BISQ) at 30 months old. Logistic regression models were used to investigate the associations between prenatal depression and anxiety and toddler’s sleep, while adjusting for maternal gestational age, education, family income, alcohol use, premature birth, fetal growth restriction, mode of delivery, postnatal depression, and 3-month breastfeeding. In total, 9.0% of participants reported prenatal depression comorbid with anxiety symptoms, and the prevalence of depression, anxiety was 6.7% and 7.3%, respectively. Compared with mothers without depression and anxiety, maternal depression combined with anxiety were significantly associated with shorter total sleep duration (11.16 ± 1.06 h), longer settling time (29.25 ± 23.57 min), and higher risk of toddlers’ sleep problems assessed by BISQ (OR = 2.09, 95% CI: 1.22–3.57) or parental report (OR = 1.84, 95% CI: 1.22–2.77). However, there was no significant association between maternal postnatal depression and toddler sleep behaviors. Maternal prenatal depression comorbid with anxiety significantly associated with poorer toddler’s sleep. Strategies to regulate prenatal mood status should be considered during prenatal health care to improve children’s sleep development.

Circadian clocks generate endogenous rhythms in most organisms from cyanobacteria to humans and facilitate entrainment to environmental diurnal cycles, thus conferring a fitness advantage. Both transcriptional and posttranslational mechanisms are prominent in the basic network architecture of circadian systems. Posttranscriptional regulation, including mRNA processing, is emerging as a critical step for clock function. However, little is known about the molecular mechanisms linking RNA metabolism to the circadian clock network. Here, we report that a conserved SNW/Ski-interacting protein (SKIP) domain protein, SKIP, a splicing factor and component of the spliceosome, is involved in posttranscriptional regulation of circadian clock genes in Arabidopsis thaliana. Mutation in SKIP lengthens the circadian period in a temperature-sensitive manner and affects light input and the sensitivity of the clock to light resetting. SKIP physically interacts with the spliceosomal splicing factor Ser/Arg-rich protein45 and associates with the pre-mRNA of clock genes, such as PSEUDORESPONSE REGULATOR7 (PRR7) and PRR9, and is necessary for the regulation of their alternative splicing and mRNA maturation. Genome-wide investigations reveal that SKIP functions in regulating alternative splicing of many genes, presumably through modulating recognition or cleavage of 5' and 3' splice donor and acceptor sites. Our study addresses a fundamental question on how the mRNA splicing machinery contributes to circadian clock function at a posttranscriptional level.

Background Inflammation and dysregulated immunity play vital roles in idiopathic pulmonary arterial hypertension (IPAH), while the mechanisms that initiate and promote these processes are unclear. Methods Transcriptomic data of lung tissues from IPAH patients and controls were obtained from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA), differential expression analysis, protein-protein interaction (PPI) and functional enrichment analysis were combined with a hemodynamically-related histopathological score to identify inflammation-associated hub genes in IPAH. The monocrotaline-induced rat model of pulmonary hypertension was utilized to confirm the expression pattern of these hub genes. Single-cell RNA-sequencing (scRNA-seq) data were used to identify the hub gene-expressing cell types and their intercellular interactions. Results Through an extensive bioinformatics analysis, CXCL9, CCL5, GZMA and GZMK were identified as hub genes that distinguished IPAH patients from controls. Among these genes, pulmonary expression levels of Cxcl9, Ccl5 and Gzma were elevated in monocrotaline-exposed rats. Further investigation revealed that only CCL5 and GZMA were highly expressed in T and NK cells, where CCL5 mediated T and NK cell interaction with endothelial cells, smooth muscle cells, and fibroblasts through multiple receptors. Conclusions Our study identified a new inflammatory pathway in IPAH, where T and NK cells drove heightened inflammation predominantly via the upregulation of CCL5, providing groundwork for the development of targeted therapeutics.