Trimethyltin chloride induces apoptosis and DNA damage via ROS/NF-κB in grass carp liver cells causing immune dysfunction.

Trimethyltin chloride (TMT), a common component in fungicides and plastic stabilizers, presents environmental risks, particularly to fish farming. The precise toxicological mechanisms of TMT in L8824 grass carp liver cells remain undefined. Our study investigates TMT's effects on these cells, focusing on its potential to induce hepatotoxicity via oxidative stress and NF-κB pathway activation. First, we selected 0, 3, 6, and 12 µM as the challenge doses, according to the inhibitory concentration of 50% (IC50) of TMT. Our results demonstrate that TMT decreases cell viability dose-dependently and triggers oxidative stress, as evidenced by increased ROS staining and MDA content. Concurrently, it inhibited the antioxidant activities of T-AOC, T-SOD, CAT, and GSH. The activation of the NF-κB pathway was confirmed by gene expression changes. Furthermore, we observed an increase in cell apoptosis rate by AO/EB staining and cell flow cytometry, and the downregulation of Bcl-2 and the upregulation of Bax, Cytc, Caspase-9, and casp3 verified that TMT passed through the BCL2/BAX/casp3 pathway induces apoptosis. DNA damage was validated by the comet assay and γH2AX gene overexpression. Lastly, our data showed increased expression of TNF-α, IL-1ß, IL-6, and INF-γ and decreased antimicrobial peptides, validating immune dysfunction. In conclusion, our findings establish that TMT induces apoptosis and DNA damage via ROS/NF-κB in grass carp liver cells, causing immune dysfunction. This study provides novel insights into the toxicology research of TMT and sheds light on the immunological effects of TMT toxicity, enriching our understanding of the immunotoxicity of TMT on aquatic organisms and contributing to the protection of ecosystems.

Contributions of climate change and human activities to grassland degradation and improvement from 2001 to 2020 in Zhaosu County, China.

Grassland degradation poses a serious threat to biodiversity, ecosystem services, and human well-being. In this study, we investigated grassland degradation in Zhaosu County, China, between 2001 and 2020, and analyzed the impacts of climate change and human activities using the Miami model. The actual net primary productivity (ANPP) obtained with CASA (Carnegie-Ames-Stanford Approach) modeling, showed a decreasing trend, reflecting the significant degradation that the grasslands in Zhaosu County have experienced in the past 20 years. Grassland degradation was found to be highest in 2018, while the degraded area continuously decreased in the last 3 years (2018-2020). Climatic factors for found to be the dominant factor affecting grassland degradation, particularly the decrease in precipitation. On the other hand, human activities were found to be the main factor affecting improvement of grasslands, especially in recent years. This finding profoundly elucidates the underlying causes of grassland degradation and improvement and helps implement ecological conservation and restoration measures. From a practical perspective, the research results provide an important reference for the formulation of policies and management strategies for sustainable land use.

Hepatotoxic Components Effect of Chebulae Fructus and Associated Molecular Mechanism by Integrated Transcriptome and Molecular Docking.

Chebulae Fructus (CF) is a natural medicinal plant widely used for its various pharmacological properties. Natural products used to cure several diseases have been considered safe thanks to their little or no side effects. However, in recent years, a hepatotoxic effect has been found due to the abuse of herbal medicine. CF has been reported to have hepatotoxicity, but the mechanism is unclear. In this experiment, the toxic aspect and mechanism of CF action were evaluated by transcriptome analysis. Components of toxic CF fractions were identified by LC-MS, and hepatotoxic toxic components in toxic CF fractions were predicted by molecular docking. The results showed that the ethyl acetate part of CF was the main toxic fraction, and transcriptome analysis found that the toxic mechanism was highly related to lipid metabolism-related pathways, and CFEA could inhibit the PPAR signaling pathway. Molecular docking results showed that 3'-O-methyl-4-O-(n″-O-galloyl-ß-d-xylopyranosyl) ellagic acid (n = 2, 3 or 4) and 4-O-(3″,4″-O-digalloyl-α-l-rhamnosyl) ellagic acid have better docking energies with PPARα protein and FABP protein than other components. In summary, 3'-O-methyl-4-O-(n″-O-galloyl-ß-d-xylopyranosyl) ellagic acid (n = 2, 3 or 4) and 4-O-(3″,4″-O-digalloyl-α-l-rhamnosyl) ellagic acid were the main toxic components, which may play a toxic role by inhibiting the PPAR signaling pathway and affect lipid metabolism.

MicroRNA-155 expression is associated with pulpitis progression by targeting SHIP1.

BACKGROUND: Pulpitis is a commonly seen oral inflammation condition in clinical practice, it can cause much pain for the patient and may induce infections in other systems. Much is still unknown for the pathogenic mechanism of pulpitis. In this work, we discovered that the expression of miR-155 was associated with dental pulpal inflammation both in vivo and in vitro. METHODS AND RESULTS: Our experiments of LPS stimulated odontoblast cell line MDPC-23 showed miR-155 could act as a positive regulator by increasing the production of pro-inflammatory cytokines IL-1ß and IL-6 during inflammatory responses, whereas knockdown of miR-155 can reverse the effects. Bioinformatics analysis demonstrated that SHIP1 is a direct target of miR-155 in odontoblasts, this result was further verified at both mRNA and protein level. Inhibition of miR-155 resulted in the downregulation of inflammation factors, while co-transfection of si-SHIP1 and miR-155 inhibitor promoted the inflammatory responses. Treatment with miR-155 mimic or si-SHIP1 up-regulated the protein level of p-PI3K and p-AKT. By contrast, miR-155 inhibitor exerted the opposite effects. miR-155 mimics could upregulate the gene expression of IL-1ß and IL-6. Co-transfection of LY294002 and miR-155 mimic attenuated the inflammatory responses. Consistent with in vitro results, miR-155-/- mice could alleviate inflammatory response, as well as decrease the activation of p-PI3K and p-AKT, whereas increase the activation of SHIP1. CONCLUSIONS: Our data revealed a novel role for miR-155 in regulation of dental pulpal inflammatory response by targeting SHIP1 through PI3K/AKT signaling pathway.

Transplantation of microbiota from drug-free patients with schizophrenia causes schizophrenia-like abnormal behaviors and dysregulated kynurenine metabolism in mice.

Accumulating evidence suggests that gut microbiota plays a role in the pathogenesis of schizophrenia via the microbiota-gut-brain axis. This study sought to investigate whether transplantation of fecal microbiota from drug-free patients with schizophrenia into specific pathogen-free mice could cause schizophrenia-like behavioral abnormalities. The results revealed that transplantation of fecal microbiota from schizophrenic patients into antibiotic-treated mice caused behavioral abnormalities such as psychomotor hyperactivity, impaired learning and memory in the recipient animals. These mice also showed elevation of the kynurenine-kynurenic acid pathway of tryptophan degradation in both periphery and brain, as well as increased basal extracellular dopamine in prefrontal cortex and 5-hydroxytryptamine in hippocampus, compared with their counterparts receiving feces from healthy controls. Furthermore, colonic luminal filtrates from the mice transplanted with patients' fecal microbiota increased both kynurenic acid synthesis and kynurenine aminotransferase II activity in cultured hepatocytes and forebrain cortical slices. Sixty species of donor-derived bacteria showed significant difference between the mice colonized with the patients' and the controls' fecal microbiota, highlighting 78 differentially enriched functional modules including tryptophan biosynthesis function. In conclusion, our study suggests that the abnormalities in the composition of gut microbiota contribute to the pathogenesis of schizophrenia partially through the manipulation of tryptophan-kynurenine metabolism.

Effect of cyclic uniaxial compressive stress on human dental pulp cells in vitro.

PURPOSE: Teeth are exposed to various forces during functional and parafunctional movements. These processes inevitably affect the dental pulp, and the mechanism of these influences has been the subject of many previous studies using different apparatuses and obtaining different results. In this study, we aimed to investigate the effects of compressive stress on the proliferation and differentiation of human dental pulp cells (hDPCs). MATERIALS AND METHODS: A four-point bending strain system was adopted to apply low-density cyclic uniaxial compressive stress (2000 microstrain, 0.5 Hz) to hDPCs for 1.5, 3, 6, 12, and 24 h. The cell cycle progression and mRNA expression of differentiation-related genes (BMP2, ALP, DMP1, DSPP, COL I) were then examined to investigate the proliferation and differentiation of hDPCs. RESULTS: The results showed that cyclic compressive stress changed the morphology of hDPCs after 12 and 24 h of mechanical loading; cell cycle progression was promoted, especially in the 24-h group (p < 0.05). The expression of BMP2 was significantly upregulated after 3 and 6 h of mechanical loading but declined in the 12- and 24-h groups, whereas the expression levels of DMP1 and DSPP were significantly upregulated in the 12- and 24-h loading groups (p < 0.05). CONCLUSIONS: Dental pulp cells were sensitive to compressive stress, especially after 12 and 24 h of applied force. Proliferation and odontogenic differentiation were significantly promoted in this in vitro model.

Extreme weather raises the prices of regional emission allowances in China.

Extreme weather is an unexpected shock to the socioeconomic, which is likely to create climate risks in the process of global warming mitigation. The aim of this study is to investigate the impact of extreme weather on prices of China's regional emission allowances, by using the panel data of four representative pilots in China (Beijing, Guangdong, Hubei, and Shanghai) from April 2014 to December 2020. The overall findings reveal that extreme weather, especially extreme heat, has a short-term lagged positive impact on carbon prices. In particular, the specific performance of extreme weather under different conditions is as follows: (i) carbon prices in tertiary-dominated markets are more sensitive to extreme weather, (ii) extreme heat has a positive effect on carbon prices while extreme cold does not, and (iii) the positive impact of extreme weather on carbon market is significantly stronger during compliance periods. This study provides the decision-making basis for emission traders to avoid losses caused by market fluctuations.

Determination and Mechanism of Antidiarrheal Chemical Constituents of Paederia scandens Determined by HPLC-ESI-MS Integrated with Network Pharmacology.

Paederia scandens is a natural medicinal plant that is widely used for its various pharmacological effects including antiviral, antitumor, anti-inflammatory, and antibacterial activities. However, there is no scientific evidence to support its antidiarrheal effect. In this study, the antidiarrheal activity of P. scandens was evaluated using several validated models. By using HPLC-ESI-MS in conjunction with a network pharmacology approach, the possible antidiarrheal mechanisms of P. scandens active fragments were studied, and they were subsequently verified in a mouse model of diarrhea. Finally, utilizing molecular docking, active compounds that might have antidiarrheal properties were hypothesized. The results show that the main antidiarrheal part of P. scandens has 10 chemical components in the n-butanol fraction (PSNB). The key targets of PSNB and diarrhea, EGFR, AKT1, and PIK3CA, were screened by network pharmacology analysis. And the mechanism of PSNB in the treatment of diarrhea may be highly related to the EGFR tyrosine kinase inhibitor resistance and PI3K/AKT signaling pathway. Besides, through the qRT-PCR and western-blot experiments, it was found that PSNB could inhibit the gene expression of proinflammatory factors by reducing the protein expression of AKT1 and PI3K and regulating the NF-κB signaling pathway in mice. In addition, asperuloside, paederosidic acid, paederoside, paederosidic acid methyl ester, and 6'-O-E-feruloylmonotropein have better docking energies than other chemical components in PSNB with EGFR, AKT1, and PIK3CA. In conclusion, the main antidiarrheal active site of P. scandens is the n-butanol site. PSNB may exert an antidiarrheal effect by regulating the PI3K/Akt/NF-κB signaling pathway. Among them, asperuloside, paederosidic acid, paederoside, paederosidic acid methyl ester, and 6'-O-E-feruloylmonotropein may be the active ingredients that exert an antidiarrheal effect.

3D-printed gelatin/sodium alginate/58S bioactive glass scaffolds promote osteogenesis in vitro and in vivo.

Three-dimensional (3D)-printed scaffolds are a new strategy to fabricate biomaterials for treating bone defects. Here, using a 3D-printing technique, we fabricated scaffolds consisting of gelatin (Gel), sodium alginate (SA), and 58S bioactive glass (58S BG). To evaluate mechanical properties and biocompatibility of Gel/SA/58S BG scaffolds, the degradation test, compressive strength test, and cytotoxicity test were performed. The effect of the scaffolds on cell proliferation in vitro was determined by 4',6-diamidino-2-phenylindole (DAPI) staining. To evaluate osteoinductive properties, rBMSCs were cultured on the scaffolds for 7, 14, and 21 days and the expression of osteogenesis-related genes was analyzed using qRT-PCR. To examine the bone healing properties of Gel/SA/58S BG scaffolds in vivo, we used a rat mandibular critical-size defect bone model. The scaffolds were implanted into the defect area of rat mandible and bone regeneration and new tissue formation were assessed using microcomputed tomography (microCT) and hematoxylin and eosin (H&E) staining. The results showed that Gel/SA/58S BG scaffolds had appropriate mechanical strength as a filling material for bone defects. Furthermore, the scaffolds could be compressed within certain limits and then could recover their shape. The extract of the Gel/SA/58S BG scaffold showed no cytotoxicity. In vitro, the expression levels of Bmp2, Runx2, and OCN were increased in rBMSCs cultured on the scaffolds. In vivo, microCT and H&E staining demonstrated that scaffolds induced the formation of new bone at the mandibular defect area. These results indicated that Gel/SA/58S BG scaffolds have excellent mechanical characteristics, biocompatibility, and osteoinductive properties, suggesting that it could be a promising biomaterial for the repair of bone defects.

A comparison of melancholic and nonmelancholic recurrent major depression in Han Chinese women.

BACKGROUND: Although the diagnosis of melancholia has had a long history, the validity of the current DSM-IV definition remains contentious. We report here the first detailed comparison of melancholic and nonmelancholic major depression (MD) in a Chinese population examining in particular whether these two forms of MD differ quantitatively or qualitatively. METHODS: DSM-IV criteria for melancholia were applied to 1,970 Han Chinese women with recurrent MD recruited from 53 provincial mental health centers and psychiatric departments of general medical hospitals in 41 cities. Statistical analyses, utilizing Student's t-tests and Pearson's χ(2) , were calculated using SPSS 13.0. RESULTS: Melancholic patients with MD were distinguished from nonmelancholic by being older, having a later age at onset, more episodes of illness and meeting more A criteria. They also had higher levels of neuroticism and rates of lifetime generalized anxiety disorder, panic disorder, and social and agoraphobia. They had significantly lower rates of childhood sexual abuse but did not differ on other stressful life events or rates of MD in their families. DISCUSSION: Consistent with most prior findings in European and US populations, we find that melancholia is a more clinically severe syndrome than nonmelancholic depression with higher rates of comorbidity. The evidence that it is a more "biological" or qualitatively distinct syndrome, however, is mixed.

Measuring the Demand Connectedness among China's Regional Carbon Markets.

After years of emission trading in segmented pilots, China operates a unified market in the power system and plans to involve more industries in the coming future. The aim of this study is to detect the commonalities of transaction behaviors across China's regional carbon pilots, so as to provide an empirical basis for a future multi-sectoral expansion of national trading. Based on a dataset of daily trading volume in seven regional markets during 2014-2021, the empirical results from connectedness measures show that the total demand connectedness ranges from 10% to 24%, indicating the existence of interactions among China's regional markets. This not-so-wide range of fluctuation usually shows a trend of rising first and then falling within each year, during which the upward trend is basically related to the accounting, verification and compliance of allowances. After these time nodes, the total connectedness declines. In addition, the directional connectedness could help clarify the specific roles that regional markets play in the variations of total demand connectedness when facing the shocks of these time nodes. Meanwhile, the frequency decomposition reveals that a longer-term component of more than 10 days dominates the connectedness. Based on these findings, some policy implications are provided alongside.

Peaking Global and G20 Countries' CO2 Emissions under the Shared Socio-Economic Pathways.

Mitigating climate change requires long-term global efforts. The aim of this study is to simulate the possible paths of CO2 emissions in G20 countries and the world from 2020 to 2050, by using the STIRPAT model and SSP scenarios with different constraints (SSP baseline, SSP-3.4). The results show that: (1) the world's CO2 emissions cannot peak in the SSP baseline scenarios, but can peak in the SSP-3.4 scenarios through four paths other than the high fossil energy consumption path; (2) for G20 countries, in the SSP baseline scenarios, 13 countries such as China, the United States, and the United Kingdom can achieve the peak, while six countries such as Argentina, India, and Saudi Arabia cannot. In the SSP-3.4 scenarios, Saudi Arabia cannot achieve the peak, while other countries can achieve the peak, and most of them are likely to achieve significant CO2 emission reductions by 2050; (3) climate goals have a crowding-out effect on other sustainable development goals, with less impact on developed countries and a greater impact on developing countries; and (4) the optimization of the energy structure and a low energy intensity can greatly advance the peak time of CO2 emissions.

Research on the osteogenesis and biosafety of ECM-Loaded 3D-Printed Gel/SA/58sBG scaffolds.

Employing scaffolds containing cell-derived extracellular matrix (ECM) as an alternative strategy for the regeneration of bone defects has shown prominent advantages. Here, gelatin (Gel), sodium alginate (SA) and 58s bioactive glass (58sBG) were incorporated into deionized water to form ink, which was further fabricated into composite scaffolds by the 3D printing technique. Then, rat aortic endothelial cells (RAOECs) or rat bone mesenchymal stem cells (RBMSCs) were seeded on the scaffolds. After decellularization, two kinds of ECM-loaded scaffolds (RAOECs-ECM scaffold and RBMSCs-ECM scaffold) were obtained. The morphological characteristics of the scaffolds were assessed meticulously by scanning electron microscopy (SEM). In addition, the effects of scaffolds on the proliferation, adhesion, and osteogenic and angiogenic differentiation of RBMSCs were evaluated by Calcein AM staining and reverse transcription polymerase chain reaction (RT-PCR). In vivo, full-thickness bone defects with a diameter of 5 mm were made in the mandibles of Sprague-Dawley (SD) rats to assess the bone regeneration ability and biosafety of the scaffolds at 4, 8 and 16 weeks. The osteogenic and angiogenic potential of the scaffolds were investigated by microcomputed tomography (Micro-CT) and histological analysis. The biosafety of the scaffolds was evaluated by blood biochemical indices and histological staining of the liver, kidney and cerebrum. The results showed that the ECM-loaded scaffolds were successfully prepared, exhibiting interconnected pores and a gel-like ECM distributed on their surfaces. Consistently, in vitro experiments demonstrated that the scaffolds displayed favourable cytocompatibility. In vitro osteogenic differentiation studies showed that scaffolds coated with ECM could significantly increase the expression of osteogenic and angiogenic genes. In addition, the results from mandibular defect repair in vivo revealed that the ECM-loaded scaffolds effectively promoted the healing of bone defects when compared to the pure scaffold. Overall, these findings demonstrate that both RAOECs-ECM scaffold and RBMSCs-ECM scaffold can greatly enhance bone formation with good biocompatibility and thus have potential for clinical application in bone regeneration.

Sleep-Disturbance-Induced Microglial Activation Involves CRH-Mediated Galectin 3 and Autophagy Dysregulation.

Chronic sleep disturbances (CSDs) including insomnia, insufficient sleep time, and poor sleep quality are major public health concerns around the world, especially in developed countries. CSDs are major health risk factors linked to multiple neurodegenerative and neuropsychological diseases. It has been suggested that CSDs could activate microglia (Mg) leading to increased neuroinflammation levels, which ultimately lead to neuronal dysfunction. However, the detailed mechanisms underlying CSD-mediated microglial activation remain mostly unexplored. In this study, we used mice with three-weeks of sleep fragmentation (SF) to explore the underlying pathways responsible for Mg activation. Our results revealed that SF activates Mg in the hippocampus (HP) but not in the striatum and prefrontal cortex (PFc). SF increased the levels of corticotropin-releasing hormone (CRH) in the HP. In vitro mechanism studies revealed that CRH activation of Mg involves galectin 3 (Gal3) upregulation and autophagy dysregulation. CRH could disrupt lysosome membrane integrity resulting in lysosomal cathepsins leakage. CRHR2 blockage mitigated CRH-mediated effects on microglia in vitro. SF mice also show increased Gal3 levels and autophagy dysregulation in the HP compared to controls. Taken together, our results show that SF-mediated hippocampal Mg activation involves CRH mediated galectin 3 and autophagy dysregulation. These findings suggest that targeting the hippocampal CRH system might be a novel therapeutic approach to ameliorate CSD-mediated neuroinflammation and neurodegenerative diseases.

Potential Toxicity Evaluation of Protopine in Macleaya cordata (Willd.) R. Br.-A Bioactivity Guided Approach.

Macleaya cordata (Willd.) R. Br. (M. cordata) is a perennial herb known for its chemotherapeutic properties, strong feeding additive, and potential antidiarrheal drug. Despite its therapeutic potentials, its clinical applications are hindered by an apparent lack of toxicity data. In this study, the toxic ingredients of this plant were investigated using a bioactivity-guided approach. Two compounds, protopine and allocryptopine, were purified and elucidated by LC-MS, 1H-NMR, and 13C-NMR. Protopine, a primary component in M. cordata, had an LD50 of 313.10 mg/kg i.e., which was considered toxic. An autopsy was performed on protopine-administered mice, and the histopathology of the kidney, liver, brain, heart, lung, and spleen was determined. Autopsy findings included hemorrhage in the respiratory system, lung congestion, and hemorrhage and edema in the parenchymatous organs (heart, liver, kidney, and brain). Histopathology confirmed the pathological changes in the brain, liver, and kidney. Protopine is one of the principal bioactive constituents of many phytopreparations used in veterinary and human medicine, such as Sangrovit and Iberogast. Our findings indicated that phytopreparations containing protopine might pose a serious health threat to humans and animals.

Cocaine self-administration differentially activates microglia in the mouse brain.

The evidence showing the involvement of microglial activation in the development of drug addiction remain scarce as microglia have not been systematically investigated in self-administered mice, a gold standard rodent model for drug addiction. Here we established the stable cocaine self-administration mice to examine microglial activation levels in various brain regions related to reward circuitry. Immunostaining for Iba1 showed a significant upregulation of intensity in the striatum but not in the medial prefrontal cortex (mPFc), hippocampus or thalamus. Further validation experiments showed that cocaine self-administered mice had significantly increased mRNA expression of ccl2 and IL1ß in the striatum but not the mPFc compared to saline controls. Consistently, we found elevated protein levels of Iba1, CCL2, TLR4 and mature IL1ß in the striatum, not in the mPFc of cocaine-receiving mice. In addition, cocaine-stimulated microglia had modified morphology including a reduced number of intersections, a shortened length and number of processes in the NAc. In summary, our results demonstrated that cocaine mediated microglial activation in a region-specific manner in vivo. These findings indicate that microglia could be activated in the early stage of cocaine addiction directly supporting the rationale that dysregulation on neuroimmune signaling is inherently involved in the development of drug addiction.

LncRNA H19 promotes odontoblastic differentiation of human dental pulp stem cells by regulating miR-140-5p and BMP-2/FGF9.

BACKGROUND: Increasing evidence has revealed that long non-coding RNAs (lncRNAs) exert critical roles in biological mineralization. As a critical process for dentin formation, odontoblastic differentiation is regulated by complex signaling networks. The present study aimed to investigate the biological role and regulatory mechanisms of lncRNA-H19 (H19) in regulating the odontoblastic differentiation of human dental pulp stem cells (hDPSCs). METHODS: We performed lncRNA microarray assay to reveal the expression patterns of lncRNAs involved in odontoblastic differentiation. H19 was identified and verified as a critical factor by qRT-PCR. The gain- and loss-of-function studies were performed to investigate the biological role of H19 in regulating odontoblastic differentiation of hDPSCs in vitro and in vivo. Odontoblastic differentiation was evaluated through qRT-PCR, Western blot, and Alizarin Red S staining. Bioinformatics analysis identified that H19 could directly interact with miR-140-5p, which was further verified by luciferase reporter assay. After overexpression of miR-140-5p in hDPSCs, odontoblastic differentiation was determined. Moreover, the potential target genes of miR-140-5p were investigated and the biological functions of BMP-2 and FGF9 in hDPSCs were verified. Co-transfection experiments were conducted to validate miR-140-5p was involved in H19-mediated odontoblastic differentiation in hDPSCs. RESULTS: The expression of H19 was significantly upregulated in hDPSCs undergoing odontoblastic differentiation. Overexpression of H19 stimulated odontoblastic differentiation in vitro and in vivo, whereas downregulation of H19 revealed the opposite effect. H19 binds directly to miR-140-5p and overexpression of miR-140-5p inhibited odontoblastic differentiation of hDPSCs. H19 acted as a miR-140-5p sponge, resulting in regulated the expression of BMP-2 and FGF9. Overexpression of H19 abrogated the inhibitory effect of miR-140-5p on odontoblastic differentiation. CONCLUSION: Our data revealed that H19 plays a positive regulatory role in odontoblastic differentiation of hDPSCs through miR-140-5p/BMP-2/FGF9 axis, suggesting that H19 may be a stimulatory regulator of odontogenesis.

Trends in the incidence and DALYs of schizophrenia at the global, regional and national levels: results from the Global Burden of Disease Study 2017.

AIM: Schizophrenia is a serious health problem worldwide. This systematic analysis aims to quantify the burden of schizophrenia at the global, regional and national levels using the Global Burden of Disease Study 2017 (GBD 2017). METHODS: We collected detailed information on the number of incidence cases, disability-adjusted life years (DALYs) and age-standardised incidence rate (ASIR) and age-standardised rate of DALYs (ASDR) during 1990-2017 from GBD 2017. The estimated annual percentage changes (EAPCs) in the ASIR and in the ASDR were calculated to quantify the temporal trends in the ASIR and ASDR of schizophrenia. RESULTS: Globally there were 1.13 million (95% uncertainty interval [UI] = 1.00 to 1.28) incident schizophrenia cases and 12.66 million (95% UI = 9.48 to 15.56) DALYs due to schizophrenia in 2017. The global ASIR decreased slightly from 1990 to 2017 (EAPC = -0.124, 95% UI = -0.114 to -0.135), while the ASDR was stable. The number of incident cases, DALYs, ASIR and ASDR were higher for males than for females. The incident rate and DALYs rate were highest among those aged 20-29 and 30-54 years, respectively. ASIR and ASDR were highest in East Asia in 2017, at 19.66 (95% UI = 17.72 to 22.00) and 205.23 (95% UI = 153.13 to 253.34), respectively. In 2017, the ASIR was highest in countries with a high-moderate sociodemographic index (SDI) and the ASDR was highest in high-SDI countries. We also found that the EAPC in ASDR was negatively correlated with the ASDR in 1990 (P = 0.001, ρ = -0.23). CONCLUSION: The global burden of schizophrenia remains large and continues to increase, thereby increasing the burden on health-care systems. The reported findings should be useful for resource allocation and health services planning for the increasing numbers of patients with schizophrenia in ageing societies.

Metagenome-wide association of gut microbiome features for schizophrenia.

Evidence is mounting that the gut-brain axis plays an important role in mental diseases fueling mechanistic investigations to provide a basis for future targeted interventions. However, shotgun metagenomic data from treatment-naïve patients are scarce hampering comprehensive analyses of the complex interaction between the gut microbiota and the brain. Here we explore the fecal microbiome based on 90 medication-free schizophrenia patients and 81 controls and identify a microbial species classifier distinguishing patients from controls with an area under the receiver operating characteristic curve (AUC) of 0.896, and replicate the microbiome-based disease classifier in 45 patients and 45 controls (AUC = 0.765). Functional potentials associated with schizophrenia include differences in short-chain fatty acids synthesis, tryptophan metabolism, and synthesis/degradation of neurotransmitters. Transplantation of a schizophrenia-enriched bacterium, Streptococcus vestibularis, appear to induces deficits in social behaviors, and alters neurotransmitter levels in peripheral tissues in recipient mice. Our findings provide new leads for further investigations in cohort studies and animal models.

Efficacy and tolerability of different doses of three new antidepressants for treating major depressive disorder: A PRISMA-compliant meta-analysis.

In last decade, the US FDA has approved three new antidepressants: vortioxetine, levomilnacipran, and vilazodone. Many studies have researched the effects of these antidepressants on major depressive disorder (MDD), but they have not determined the optimum dosage. This meta-analysis investigated the efficacies of these three drugs at different dosages in the treatment of MDD. The PubMed, Embase, Cochrane Library, psycINFO, and ClinicalTrials.gov databases were searched to identify relevant literature. The primary outcomes were efficacy [quantified as the change from baseline in total score on the Montgomery-Asberg Depression Rating Scale (MADRS)] and tolerability (discontinuations due to adverse events). The effect size was quantified as the weighted mean difference for continuous data and the risk ratio (RR) for dichotomous data. Overall 22 studies were included. The changes in the MADRS total score were significantly higher for vortioxetine at 5, 10, 20, and 10-20 mg/day than for placebo. The tolerability was significantly worse for 20 mg/day vortioxetine than for placebo (RR = 1.84, 95% confidence interval = 1.13 to 3.02). In addition, increasing the dosage improved the efficacy of vortioxetine but worsened the tolerability. Levomilnacipran and vilazodone at any dosage produced a significantly higher mean change from baseline in the MADRS total score and a worse tolerability than for placebo. In conclusion, considering both efficacy and tolerability, 10 mg/day vortioxetine might be optimal for the treatment of MDD. The long-term efficacy and safety of vortioxetine needed to be investigated, and more studies of levomilnacipran and vilazodone are needed to define their optimal dosages.