Programmed cell death factor 4-mediated hippocampal synaptic plasticity is involved in early life stress and susceptibility to depression.

Early life stress (ELS) increases the risk of depression later in life. Programmed cell death factor 4 (PDCD4), an apoptosis-related molecule, extensively participates in tumorigenesis and inflammatory diseases. However, its involvement in a person's susceptibility to ELS-related depression is unknown. To examine the effects and underlying mechanisms of PDCD4 on ELS vulnerability, we used a "two-hit" stress mouse model: an intraperitoneal injection of lipopolysaccharide (LPS) into neonatal mice was performed on postnatal days 7-9 (P7-P9) and inescapable foot shock (IFS) administration in adolescent was used as a later-life challenge. Our study shows that compared with mice that were only exposed to the LPS or IFS, the "two-hit" stress mice developed more severe depression/anxiety-like behaviors and social disability. We detected the levels of PDCD4 in the hippocampus of adolescent mice and found that they were significantly increased in "two-hit" stress mice. The results of immunohistochemical staining and Sholl analysis showed that the number of microglia in the hippocampus of "two-hit" stress mice significantly increased, with morphological changes, shortened branches, and decreased numbers. However, knocking down PDCD4 can prevent the number and morphological changes of microglia induced by ELS. In addition, we confirmed through the Golgi staining and immunohistochemical staining results that knocking down PDCD4 can ameliorate ELS-induced synaptic plasticity damage. Mechanically, the knockdown of PDCD4 exerts neuroprotective effects, possibly via the mediation of BDNF/AKT/CREB signaling. Combined, these results suggest that PDCD4 may play an important role in the ELS-induced susceptibility to depression and, thus, may become a therapeutic target for depressive disorders.

Early life stress enhances the susceptibility to depression and interferes with neuroplasticity in the hippocampus of adolescent mice via regulating miR-34c-5p/SYT1 axis.

Early life events are major risk factors for the onset of depression and have long-term effects on the neurobiological changes and behavioral development of rodents. However, little is known about the specific mechanisms of early life adversity in the susceptibility to subsequent stress exposure in adolescence. This study characterized the effect of maternal separation (MS), an animal model of early life adversity, on the behavioral responses to restraint stress in mice during adolescence and investigated the molecular mechanism underlying behavioral vulnerability to chronic stress induced by MS. Our results showed that MS exposure could further reinforce the depressive vulnerability to restraint stress in adolescent mice. In addition, miR-34c-5p expression was obviously up-regulated in the hippocampi of MS mice at postnatal day (P) 14 and P42. Further, synaptotagmin-1 (SYT1) was deemed as a target gene candidate of miR-34c-5p on the basis of dual luciferase assay. It was found that the downregulation of miR-34c-5p expression in the hippocampi of MS mice could ameliorate dysfunction of synaptic plasticity by targeting molecule SYT1, effects which were accompanied by alleviation of depressive and anxious behaviors in these mice. The results demonstrated that the miR-34c-5p/SYT1 pathway was involved in the susceptibility to depression induced by MS via regulating neuroplasticity in the hippocampi of mice.

The miR-9-5p/CXCL11 pathway is a key target of hydrogen sulfide-mediated inhibition of neuroinflammation in hypoxic ischemic brain injury.

We previously showed that hydrogen sulfide (H2S) has a neuroprotective effect in the context of hypoxic ischemic brain injury in neonatal mice. However, the precise mechanism underlying the role of H2S in this situation remains unclear. In this study, we used a neonatal mouse model of hypoxic ischemic brain injury and a lipopolysaccharide-stimulated BV2 cell model and found that treatment with L-cysteine, a H2S precursor, attenuated the cerebral infarction and cerebral atrophy induced by hypoxia and ischemia and increased the expression of miR-9-5p and cystathionine ß synthase (a major H2S synthetase in the brain) in the prefrontal cortex. We also found that an miR-9-5p inhibitor blocked the expression of cystathionine ß synthase in the prefrontal cortex in mice with brain injury caused by hypoxia and ischemia. Furthermore, miR-9-5p overexpression increased cystathionine-ß-synthase and H2S expression in the injured prefrontal cortex of mice with hypoxic ischemic brain injury. L-cysteine decreased the expression of CXCL11, an miR-9-5p target gene, in the prefrontal cortex of the mouse model and in lipopolysaccharide-stimulated BV-2 cells and increased the levels of proinflammatory cytokines BNIP3, FSTL1, SOCS2 and SOCS5, while treatment with an miR-9-5p inhibitor reversed these changes. These findings suggest that H2S can reduce neuroinflammation in a neonatal mouse model of hypoxic ischemic brain injury through regulating the miR-9-5p/CXCL11 axis and restoring ß-synthase expression, thereby playing a role in reducing neuroinflammation in hypoxic ischemic brain injury.

Mitochondria-targeted cerium vanadate nanozyme suppressed hypoxia-ischemia injury in neonatal mice via intranasal administration.

Oxidative stress is a major obstacle for neurological functional recovery after hypoxia-ischemia (HI) brain damage. Nanozymes with robust anti-oxidative stress properties offer a therapeutic option for HI injury. However, insufficiency of nanozyme accumulation in the HI brain by noninvasive administration hinders their application. Herein, we reported a cerium vanadate (CeVO4) nanozyme to realize a noninvasive therapy for HI brain in neonatal mice by targeting brain neuron mitochondria. CeVO4 nanozyme with superoxide dismutase activity mainly co-located with neuronal mitochondria 1 h after administration. Pre- and post-HI administrations of CeVO4 nanozyme were able to attenuate acute brain injury, by inhibiting caspase-3 activation, microglia activation, and proinflammation cytokine production in the lesioned cortex 2 d after HI injury. Moreover, CeVO4 nanozyme administration led to short- and long-term functional recovery following HI insult without any potential toxicities in peripheral organs of mice even after prolonged delivery for 4 weeks. These beneficial effects of CeVO4 nanozyme were associated with suppressed oxidative stress and up-regulated nuclear factor erythroid-2-related factor 2 (Nrf2) expression. Finally, we found that Nrf2 inhibition with ML385 abolished the protective effects of CeVO4 nanozyme on HI injury. Collectively, this strategy may provide an applicative perspective for CeVO4 nanozyme therapy in HI brain damage via noninvasive delivery.

Identification of the SNARE complex that mediates the fusion of multivesicular bodies with the plasma membrane in exosome secretion.

Exosomes play crucial roles in local and distant cellular communication and are involved in various physiological and pathological processes. Tumour-derived exosomes are pivotal to tumorigenesis, but the precise mechanisms underlying their secretion remain elusive. In particular, the SNARE proteins that mediate the fusion of multivesicular bodies (MVBs) with the plasma membrane (PM) in tumour cells are subject to debate. In this study, we identified syntaxin-4, SNAP-23, and VAMP-7 as the SNAREs responsible for exosome secretion in MCF-7 breast cancer cells and found that a SNARE complex consisting of these SNAREs can drive membrane fusion in vitro. Deletion of any of these SNAREs in MCF-7 cells did not affect MVB biogenesis and transportation, indicating their specific involvement in MVB-PM fusion. In addition, syntaxin-4, SNAP-23, and VAMP-7 play equivalent roles in exosome secretion in both HeLa cervical cancer cells and A375 melanoma cells, suggesting their conserved function in exosome secretion. Furthermore, deletion of VAMP-7 in 4T1 mammary carcinoma cells efficiently inhibited exosome secretion and led to significant attenuation of tumour growth and lung metastasis in mouse models, implying that VAMP-7 may hold promise as a novel therapeutic target for breast cancer.

Dual-energy micro-focus computed tomography based on the energy-angle correlation of inverse Compton scattering source.

BACKGROUND: Inverse Compton scattering (ICS) source can produce quasi-monoenergetic micro-focus X-rays ranging from keV to MeV level, with potential applications in the field of high-resolution computed tomography (CT) imaging. ICS source has an energy-angle correlated feature that lower photon energy is obtained at larger emission angle, thus different photon energies are inherently contained in each ICS pulse, which is especially advantageous for dual- or multi-energy CT imaging. OBJECTIVE: This study proposes a dual-energy micro-focus CT scheme based on the energy-angle correlation of ICS source and tests its function using numerical simulations. METHODS: In this scheme, high- and low-energy regions are chosen over the angular direction of each ICS pulse, and dual-energy projections of the object are obtained by an angularly-splicing scanning method. The field-of-view (FOV) of ICS source is extended simultaneously through this scanning method, thus the scale of the imaging system can be efficiently reduced. A dedicated dual-energy CT algorithm is developed to reconstruct the monoenergetic attenuation coefficients, electron density, and effective atomic number distributions of the object. RESULTS: A test object composed of different materials (carbon, aluminium, titanium, iron and copper) and line pairs with different widths (15/24/39/60 µm) is imaged by the proposed dual-energy CT scheme using numerical simulations, and high-fidelity monoenergetic attenuation coefficient, electron density, and effective atomic number distributions are obtained. All the line pairs are well identified, and the contrast ratio of the 15 µm lines is 22%, showing good accordance with the theoretical predictions. CONCLUSIONS: The proposed dual-energy CT scheme can reconstruct fine inner structures and material compositions of the object simultaneously, opening a new possibility for the application of ICS source in the field of non-destructive testing.

Multiple brain regions are involved in reaction to acute restraint stress in CYLD-knockout mice.

The lysine 63 deubiquitinase cylindromatosis (CYLD) is expressed at high levels in the brain and is considered to be involved in anxious and depressive behavior, cognitive inflexibility, and autism disorders. Previous research was limited in some brain regions, including the hippocampus, striatum, and amygdala. To better understand whether CYLD plays a role in adaptation to stress and which brain regions are involved, we analyzed the behavior of CYLD-knockout mice in the elevated plus maze (EPM) and light-dark box test (LDT) after acute restraint stress (ARS) and mapped their c-Fos immunoreactivity in brain sections. Here we report that CYLD deficiency leads to an unexpected reaction to ARS in mice, and is accompanied by significant neuronal activation of brain regions including the medial prefrontal cortex (mPFC), dorsal striatum (DS), nucleus accumbens (NAc), and basal lateral amygdala (BLA), but not ventral hippocampus (vHPC). Our findings show that CYLD participates in ARS-induced anxious behavior and that this involves multiple brain regions.

Mechanistic Insights into the Role of OPN in Mediating Brain Damage via Triggering Lysosomal Damage in Microglia/Macrophage.

We previously found that osteopontin (OPN) played a role in hypoxia-ischemia (HI) brain damage. However, its underlying mechanism is still unknown. Bioinformatics analysis revealed that the OPN protein was linked to the lysosomal cathepsin B (CTSB) and galectin-3 (GAL-3) proteins after HI exposure. In the present study, we tested the hypothesis that OPN was able to play a critical role in the lysosomal damage of microglia/macrophages following HI insult in neonatal mice. The results showed that OPN expression was enhanced, especially in microglia/macrophages, and colocalized with lysosomal-associated membrane protein 1 (LAMP1) and GAL-3; this was accompanied by increased LAMP1 and GAL-3 expression, CTSB leakage, as well as impairment of autophagic flux in the early stage of the HI process. In addition, the knockdown of OPN expression markedly restored lysosomal function with significant improvements in the autophagic flux after HI insult. Interestingly, cleavage of OPN was observed in the ipsilateral cortex following HI. The wild-type OPN and C-terminal OPN (Leu152-Asn294), rather than N-terminal OPN (Met1-Gly151), interacted with GAL-3 to induce lysosomal damage. Furthermore, the secreted OPN stimulated lysosomal damage by binding to CD44 in microglia in vitro. Collectively, this study demonstrated that upregulated OPN in microglia/macrophages and its cleavage product was able to interact with GAL-3, and secreted OPN combined with CD44, leading to lysosomal damage and exacerbating autophagosome accumulation after HI exposure.

Inhibition of mGluR5 alters BDNF/TrkB and GLT-1 expression in the prefrontal cortex and hippocampus and ameliorates PTSD-like behavior in rats.

RATIONALE AND OBJECTIVE: Post-traumatic stress disorder (PTSD) is a prevalent and debilitating psychiatric disorder. However, its specific etiological mechanism remains unclear. Previous studies have shown that traumatic stress changes metabotropic glutamate receptor 5 (mGluR5) expression in the hippocampus (HIP) and prefrontal cortex (PFC). More importantly, mGluR5 expression is often accompanied by alterations in brain-derived neurotrophic factor (BDNF). Furthermore, BDNF/tropomyosin-associated kinase B (TrkB) signaling plays multiple roles, including roles in neuroplasticity and antidepressant activity, by regulating glutamate transporter-1 (GLT-1) expression. This study aims to explore the effects of inhibiting mGluR5 on PTSD-like behaviors and BDNF, TrkB, and GLT-1 expression in the HIP and PFC of inevitable foot shock (IFS)-treated rats. METHODS: Seven-day IFS was used to establish a PTSD rat model, and 2-methyl-6-(phenylethynyl)-pyridine (MPEP) (10 mg/kg, intraperitoneal injection) was used to inhibit the activity of mGluR5 during IFS in rats. After modeling, behavioral changes and mGluR5, BDNF, TrkB, and GLT-1 expression in the PFC and HIP were examined. RESULTS: First, the IFS procedure induced PTSD-like behavior. Second, IFS increased the expression of mGluR5 and decreased BDNF, TrkB, and GLT-1 expression in the PFC and HIP. Third, the mGluR5 antagonist blocked the above behavioral and molecular alterations. CONCLUSIONS: mGluR5 was involved in IFS-induced PTSD-like behavior by changing BDNF, TrkB, and GLT-1 expression.

Rifaximin ameliorates depression-like behaviour in chronic unpredictable mild stress rats by regulating intestinal microbiota and hippocampal tryptophan metabolism.

BACKGROUND: Chronic unpredictable mild stress (CUMS) can induce depressive behaviours and alter the composition of the gut microbiome. Although modulating gut microbiota can improve depression-like behaviour in rats, the mechanism of action is unclear. Additionally, gut microbiota can affect brain function through the neuroendocrine pathway. This pathway may function by regulating the secretion of neurotransmitters such as tryptophan (TRP). Metabolites of TRP, such as 5-hydroxytryptamine (5-HT) and kynurenine (KYN), are related to the pathophysiological process of depression. Indoleamine-2, 3-dioxygenase-1 (IDO1) and Tryptophan hydroxylase 2 (TPH2) are the key rate-limiting enzymes in TRP metabolism and play an important role in KYN and 5-HT metabolism. METHODS: Rats were subjected to four weeks of CUMS and given rifaximin150 mg/kg by oral gavage daily. After modelling, we investigated the rat's behaviours, composition of the faecal microbiome, neurotransmitter metabolism and key metabolic enzymes of the TRP pathway in the hippocampus (HIP). RESULTS: Rifaximin administration improved depressive behaviour in rats, corrected intestinal microbiota disorders and HIP TRP metabolism and regulated the expression of IDO1 and TPH2 in the HIP. CONCLUSIONS: Rifaximin improves depression-like behaviour in CUMS rats by influencing the gut microbiota and tryptophan metabolism.

Blocking osteopontin expression attenuates neuroinflammation and mitigates LPS-induced depressive-like behavior in mice.

INTRODUCTION: Neuroinflammation plays an important role in the development of major depressive disorder (MDD). Osteopontin (OPN) is one of the key molecules involved in neuroinflammation. We demonstrate here for the first time a key role of OPN in lipopolysaccharide (LPS)-induced depressive-like behavioral syndrome. METHODS: Systemic administration of LPS (5 mg/kg) mimics distinct depressive-like behavior, which could significantly upregulate OPN expression in microglia/macrophage in the hippocampus. The neurobehavioral assessments, quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), Western blot, immunofluorescent staining, flow cytometry cell staining and Golgi staining were performed. RESULTS: Similar to fluoxetine treatment (the positive control), OPN knockdown with shRNA lentivirus markedly reversed LPS-induced depressive-like behavior. Moreover, knockdown of OPN suppressed LPS-induced proinflammatory cytokine expression, microglial activation, dendritic spines loss, as well as unregulated PSD-95 and BDNF in the hippocampus. CONCLUSION: We demonstrated that targeting OPN expression in microglia/macrophage might help to rescue LPS-induced depressive-like behavior. The underlying mechanism may relate to the modulation of neuroinflammation, BDNF signaling and synaptic structural complexity.

Involvement of brain-derived neurotrophic factor methylation in the prefrontal cortex and hippocampus induced by chronic unpredictable mild stress in male mice.

Early life stress alters brain-derived neurotrophic factor (BDNF) promoter IV methylation and BDNF expression, which is closely related to the pathophysiological process of depression. However, the role of abnormal methylation of BDNF induced by stress during adolescence due to depression has not yet been clarified. In this study, adolescent mice were exposed to chronic unpredictable mild stress (CUMS). Depression-like behaviors, BDNF promoter IV methylation, expression of DNA methyltransferases (DNMTs), demethylation machinery enzymes, BDNF protein levels, and neuronal development in the prefrontal cortex (PFC) and hippocampus (HIP) were assessed in adolescent and adult mice. The DNMT inhibitor, 5-Aza-2-deoxycytidine (5-AzaD), was used as an intervention. Stress in adolescence induces behavioral dysfunction, elevated methylation levels of BDNF promoter IV, changes in the expression of DNMT, and demethylation machinery enzymes in adolescent and adult mice. Additionally, the stress in adolescence induced lower levels of BDNF and abnormal hippocampal doublecortin (DCX) expression in adolescent and adult mice. However, DNMT inhibitor treatment in adolescent-stressed mice relieved the abnormal behaviors, normalized the methylation level of BDNF promoter IV, BDNF protein expression, expression of DNMTs, and demethylation machinery enzymes, and improved the neuronal development of adult mice. These results suggest that stress in adolescence induces short- and long-term hypermethylation of BDNF promoter IV, which is regulated by DNMTs, and leads to the development of depression.

The delivery of miR-21a-5p by extracellular vesicles induces microglial polarization via the STAT3 pathway following hypoxia-ischemia in neonatal mice.

Extracellular vesicles (EVs) from mesenchymal stromal cells (MSCs) have previously been shown to protect against brain injury caused by hypoxia-ischemia (HI). The neuroprotective effects have been found to relate to the anti-inflammatory effects of EVs. However, the underlying mechanisms have not previously been determined. In this study, we induced oxygen-glucose deprivation in BV-2 cells (a microglia cell line), which mimics HI in vitro, and found that treatment with MSCs-EVs increased the cell viability. The treatment was also found to reduce the expression of pro-inflammatory cytokines, induce the polarization of microglia towards the M2 phenotype, and suppress the phosphorylation of selective signal transducer and activator of transcription 3 (STAT3) in the microglia. These results were also obtained in vivo using neonatal mice with induced HI. We investigated the potential role of miR-21a-5p in mediating these effects, as it is the most highly expressed miRNA in MSCs-EVs and interacts with the STAT3 pathway. We found that treatment with MSCs-EVs increased the levels of miR-21a-5p in BV-2 cells, which had been lowered following oxygen-glucose deprivation. When the level of miR-21a-5p in the MSCs-EVs was reduced, the effects on microglial polarization and STAT3 phosphorylation were reduced, for both the in vitro and in vivo HI models. These results indicate that MSCs-EVs attenuate HI brain injury in neonatal mice by shuttling miR-21a-5p, which induces microglial M2 polarization by targeting STAT3.

L-Cysteine attenuates osteopontin-mediated neuroinflammation following hypoxia-ischemia insult in neonatal mice by inducing S-sulfhydration of Stat3.

We previously show that L-Cysteine administration significantly suppresses hypoxia-ischemia (HI)-induced neuroinflammation in neonatal mice through releasing H2S. In this study we conducted proteomics analysis to explore the potential biomarkers or molecular therapeutic targets associated with anti-inflammatory effect of L-Cysteine in neonatal mice following HI insult. HI brain injury was induced in postnatal day 7 (P7) neonatal mice. The pups were administered L-Cysteine (5 mg/kg) at 24, 48, and 72 h post-HI. By conducting TMT-based proteomics analysis, we confirmed that osteopontin (OPN) was the most upregulated protein in ipsilateral cortex 72 h following HI insult. Moreover, OPN was expressed in CD11b+/CD45low cells and infiltrating CD11b+/CD45high cells after HI exposure. Intracerebroventricular injection of OPN antibody blocked OPN expression, significantly attenuated brain damage, reduced pro-inflammatory cytokine levels and suppressed cerebral recruitment of CD11b+/CD45high immune cells following HI insult. L-Cysteine administration reduced OPN expression in CD11b+/CD45high immune cells, concomitant with improving the behavior in Y-maze test and suppressing cerebral recruitment of CD11b+/CD45high immune cells post-HI insult. Moreover, L-Cysteine administration suppressed the Stat3 activation by inducing S-sulfhydration of Stat3. Intracerebroventricular injection of Stat3 siRNA not only decreased OPN expression, but also reversed HI brain damage. Our data demonstrate that L-Cysteine administration effectively attenuates the OPN-mediated neuroinflammation by inducing S-sulfhydration of Stat3, which contributes to its anti-inflammatory effect following HI insult in neonatal mice. Blocking OPN expression may serve as a new target for therapeutic intervention for perinatal HI brain injury.

Effects of traumatic stress in adolescence on PTSD-like behaviors, dendrite development, and H3K9me2/BDNF expression in the amygdala of male rats.

Early detrimental experiences increase the risk of psychiatric disorders, including posttraumatic stress disorder (PTSD). In a previous experiment, we demonstrated that traumatic stress in adolescence triggers changes in the expression of the epigenetic marker H3K9me2 in the hippocampus and prefrontal cortex of adolescent and adult rats, which suppresses transcription of the brain-derived neurotrophic factor (Bdnf) gene that promotes dendrite development and synaptic growth. However, corresponding changes in the amygdala in response to traumatic stress in early life have not yet been fully elucidated. In the current study, we used the inescapable foot shock (IFS) procedure to establish a PTSD model. Half an hour after the end of electric shocks, intraperitoneal injection of the G9a enzyme inhibitor Unc0642, a small molecule inhibitor of EHMT2 that can decrease H3K9me2 expression, was applied to reverse the corresponding epigenetic changes. Exploratory behaviors, anxiety-like behavior, social communication ability, spatial exploration and memory were determined using the open field test (OFT), elevated plus maze (EPM) test, three-chamber sociability test (SIT), Morris water maze (MWM) test, and Y maze test (YMZ), respectively. Additionally, the levels of H3K9me2 and BDNF were measured by quantitative reverse transcription-polymerase chain reaction (qPCR) and Western blotting. Furthermore, neuronal development was examined using Golgi staining. The results showed that the IFS procedure induced anxiety-like and depression-like behaviors, social skills dysfunction, and spatial exploration and memory disorders. It also decreased the mRNA expression of BDNF and BDNF and increased the expression of H3K9me2 in the amygdala. More importantly, compared to unstressed animals, traumatic stress during adolescence induced dendrite maldevelopment in adolescent and adult rats. In summary, the present study indicates that early-life stress alters the epigenetic marker expression of H3K9me2 and decreases levels of BDNF in the amygdala, resulting in dendrite maldevelopment and a higher risk of mental disorders.

Rifaximin-mediated gut microbiota regulation modulates the function of microglia and protects against CUMS-induced depression-like behaviors in adolescent rat.

BACKGROUND: Chronic unpredictable mild stress (CUMS) can not only lead to depression-like behavior but also change the composition of the gut microbiome. Regulating the gut microbiome can have an antidepressant effect, but the mechanism by which it improves depressive symptoms is not clear. Short-chain fatty acids (SCFAs) are small molecular compounds produced by the fermentation of non-digestible carbohydrates. SFCAs are ubiquitous in intestinal endocrine and immune cells, making them important mediators of gut microbiome-regulated body functions. The balance between the pro- and anti-inflammatory microglia plays an important role in the occurrence and treatment of depression caused by chronic stress. Non-absorbable antibiotic rifaximin can regulate the structure of the gut microbiome. We hypothesized that rifaximin protects against stress-induced inflammation and depression-like behaviors by regulating the abundance of fecal microbial metabolites and the microglial functions. METHODS: We administered 150 mg/kg rifaximin intragastrically to rats exposed to CUMS for 4 weeks and investigated the composition of the fecal microbiome, the content of short-chain fatty acids in the serum and brain, the functional profiles of microglia and hippocampal neurogenesis. RESULTS: Our results show that rifaximin ameliorated depressive-like behavior induced by CUMS, as reflected by sucrose preference, the open field test and the Morris water maze. Rifaximin increased the relative abundance of Ruminococcaceae and Lachnospiraceae, which were significantly positively correlated with the high level of butyrate in the brain. Rifaximin increased the content of anti-inflammatory factors released by microglia, and prevented the neurogenic abnormalities caused by CUMS. CONCLUSIONS: These results suggest that rifaximin can regulate the inflammatory function of microglia and play a protective role in pubertal neurodevelopment during CUMS by regulating the gut microbiome and short-chain fatty acids.

What Factors Are Most Closely Associated With Mood Disorders in Adolescents During the COVID-19 Pandemic? A Cross-Sectional Study Based on 1,771 Adolescents in Shandong Province, China.

Background and Aims: COVID-19 has been proven to harm adolescents' mental health, and several psychological influence factors have been proposed. However, the importance of these factors in the development of mood disorders in adolescents during the pandemic still eludes researchers, and practical strategies for mental health education are limited. Methods: We constructed a sample of 1,771 adolescents from three junior high middle schools, three senior high middle schools, and three independent universities in Shandong province, China. The sample stratification was set as 5:4:3 for adolescent aged from 12 - 15, 15 - 18, 18 - 19. We examined the subjects' anxiety, depression, psychological resilience, perceived social support, coping strategies, subjective social/school status, screen time, and sleep quality with suitable psychological scales. We chose four widely used classification models-k-nearest neighbors, logistic regression, gradient-boosted decision tree (GBDT), and a combination of the GBDT and LR (GBDT + LR)-to construct machine learning models, and we utilized the Shapley additive explanations value (SHAP) to measure how the features affected the dependent variables. The area under the curve (AUC) of the receiver operating characteristic (ROC) curves was used to evaluate the performance of the models. Results: The current rates of occurrence of symptoms of anxiety and depression were 28.3 and 30.8% among the participants. The descriptive and univariate analyses showed that all of the factors included were statistically related to mood disorders. Among the four machine learning algorithms, the GBDT+LR algorithm achieved the best performance for anxiety and depression with average AUC values of 0.819 and 0.857. We found that the poor sleep quality was the most significant risk factor for mood disorders among Chinese adolescents. In addition, according to the feature importance (SHAP) of the psychological factors, we proposed a five-step mental health education strategy to be used during the COVID-19 pandemic (sleep quality-resilience-coping strategy-social support-perceived social status). Conclusion: In this study, we performed a cross-sectional investigation to examine the psychological impact of COVID-19 on adolescents. We applied machine learning algorithms to quantify the importance of each factor. In addition, we proposed a five-step mental health education strategy for school psychologists.

Efficacy of small-dose ganciclovir on cytomegalovirus infections in children and its effects on liver function and miR-UL112-3p expression.

The aim of the study was to explore the efficacy of small-dose ganciclovir on cytomegalovirus infections as well as its effects on the liver function and miR-UL112-3p of children. A total of 141 children infected with cytomegalovirus admitted to the Affiliated Hospital of Weifang Medical University from May 2015 to August 2017 were enrolled, of which 74 children were treated with small-dose ganciclovir as an observation group (Obs group), and the rest were treated with conventional-dose ganciclovir as a control group (Con group). The two groups were compared in efficacy after treatment, changes of liver function indexes [total bilirubin (TB), alanine aminotransferase (ALT), and aspartate aminotransferase (AST)] and miR-UL112-3p before and after treatment, and adverse reactions after treatment. A receiver operating characteristic (ROC) curve was drawn to analyze the value of miR-UL112-3p in predicating efficacy on cytomegalovirus infections in children, and Pearson's correlation analysis was carried out to analyze the correlation between miR-UL112-3p expression and TB, ALT and AST. The MV-DNA level between the two groups after treatment was compared. The two groups showed no significant difference in efficacy and adverse reactions (both P>0.05), and before treatment, there was also no significant difference between the two groups in miR-UL112-3p, TB, ALT, and AST, while after treatment, both groups showed lower levels of miR-UL112-3p, TB, ALT, and AST, and the Obs group showed significantly lower levels thereof than the Con group (all P<0.05). In addition, the area under the curve (AUC), specificity, and sensitivity of miR-UL112-3p in the ROC curve of the Obs group were 0.866, 73.77 and 84.62%, respectively, while the AUC, specificity, and sensitivity of the ROC of the Con group were 0.837, 75.44, and 90.00%, respectively. Furthermore, miR-UL112-3p was positively correlated with TB, ALT, and AST, respectively. The CMV-DNA level in the Obs group was lower than that in the Con group, but the difference was not significant, and the level of CMV-DNA was positively correlated with that of miR-UL112-3p. In conclusion, small-dose ganciclovir can better improve the liver function of the children, and downregulate miR-UL112-3p in them. The AUC, specificity, and sensitivity of miR-UL112-3p for predicting the efficacy of small-dose ganciclovir were 0.866, 73.77 and 84.62%, respectively, and the AUC, specificity, and sensitivityfor predicting the efficacy of conventional-dose ganciclovir were 0.837, 75.44 and 90.00%, respectively.

H3K9me2 regulation of BDNF expression in the hippocampus and medial prefrontal cortex is involved in the depressive-like phenotype induced by maternal separation in male rats.

BACKGROUND: Early life stress (ELS) induces a depressive-like phenotype and increases the risk of depression. Brain-derived neurotrophic factor (BDNF) has been confirmed to be involved in the pathophysiology of depression. However, the mechanism by which ELS alters the epigenetic regulation of BDNF and changes susceptibility to depression has not been fully clarified. METHODS: The present study used maternal separation (MS) and chronic unpredicted mild stress (CUMS) to establish an MS animal model and a depressive animal model. We assessed depressive-like behaviours, including anhedonia, locomotor activity, anxiety-like behaviour, and spatial memory, using the sucrose preference test, the open field test, the elevated plus maze test, and the Morris water maze test. We also investigated BDNF and H3K9me2 expression in the hippocampus and medial prefrontal cortex (mPFC) by immunohistochemistry, western blotting, and qPCR analysis. Additionally, we used Unc0642, a small molecule inhibitor of histone methyltransferase (G9a), as an intervention. RESULTS: The results showed that CUMS induced depressive-like behaviours in rats and resulted in increased H3K9me2 expression and decreased BDNF expression in the hippocampus and mPFC. More importantly, adult MS rats experiencing CUMS had more severe depressive behaviours, had higher expression of H3K9me2 in the hippocampus and mPFC, and had lower expression of BDNF in the hippocampus and mPFC. In addition, administration of the G9a inhibitor reversed most of the changes. CONCLUSIONS: Our study suggests that ELS changed BDNF and H3K9me2 expression in the rat brain, resulting in a depressive-like phenotype.