Genetic deletion of zinc transporter ZnT3 induces progressive cognitive deficits in mice by impairing dendritic spine plasticity and glucose metabolism.

Zinc transporter 3 (ZnT3) is abundantly expressed in the brain, residing in synaptic vesicles, where it plays important roles in controlling the luminal zinc levels. In this study, we found that ZnT3 knockout in mice decreased zinc levels in the hippocampus and cortex, and was associated with progressive cognitive impairments, assessed at 2, 6, and 9-month of age. The results of Golgi-Cox staining demonstrated that ZnT3 deficiency was associated with an increase in dendritic complexity and a decrease in the density of mature dendritic spines, indicating potential synaptic plasticity deficit. Since ZnT3 deficiency was previously linked to glucose metabolism abnormalities, we tested the expression levels of genes related to insulin signaling pathway in the hippocampus and cortex. We found that the Expression of glucose transporters, GLUT3, GLUT4, and the insulin receptor in the whole tissue and synaptosome fraction of the hippocampus of the ZnT3 knockout mice were significantly reduced, as compared to wild-type controls. Expression of AKT (A serine/threonine protein kinase) and insulin-induced AKT phosphorylation was also reduced in the hippocampus of ZnT3 knockout mice. We hypothesize that the ZnT3 deficiency and reduced brain zinc levels may cause cognitive impairment by negatively affecting glycose metabolism via decreased expression of key components of insulin signaling, as well as via changes in synaptic plasticity. These finding may provide new therapeutic target for treatments of neurodegenerative disorders.

Robust photogalvanic effect, full spin polarization and pure spin current in the BiC photodetector by vacancy- and substitution-doping.

The photogalvanic effects (PGEs) in low-dimensional devices have attracted great interests recently. Herein, based on non-equilibrium Green's function combined with density functional theory, we investigated spin-dependent PGE phenomena in the BiC photodetector for the case of linearly polarized light and zero bias. Due to the presence of strong spin-orbital interaction (SOI) and C3v symmetry for the BiC monolayer, the armchair and zigzag BiC photodetectors produce robust spin-dependent PGEs which possess the cos(2θ) and sin(2θ) relations on the photon energies. Especially, the armchair and Bi-vacancy armchair BiC photodetector can produce fully spin polarization, and pure spin current was found in the armchair and zigzag BiC photodetector. Furthermore, after introducing the Bi-vacancy, C-vacancy, Bi-doping and C-doping respectively, corresponding armchair and zigzag BiC photodetector can produce higher spin-dependent PGEs for their Cs symmetry. Moreover, the behaviors of spin-dependent photoresponse are highly anisotropic and can be tuned by the photon energy. This work suggested great potential applications of the BiC monolayer on PGE-driven photodetectors in low energy-consumption optoelectronics and spintronic devices. .

Role of Native Defects in Fe-Doped ß-Ga2O3.

Iron impurities are believed to act as deep acceptors that can compensate for the n-type conductivity in as-grown Ga2O3, but several scientific issues, such as the site occupation of the Fe heteroatom and the complexes of Fe-doped ß-Ga2O3 with native defects, are still lacking. In this paper, based on first-principle density functional theory calculations with the generalized gradient approximation approach, the controversy regarding the preferential Fe incorporation on the Ga site in the ß-Ga2O3 crystal has been addressed, and our result demonstrates that Fe dopant is energetically favored on the octahedrally coordinated Ga site. The structural stabilities are confirmed by the formation energy calculations, the phonon dispersion relationships, and the strain-dependent analyses. The thermodynamic transition level Fe3+/Fe2+ is located at 0.52 eV below the conduction band minimum, which is consistent with Ingebrigtsen's theoretical conclusion, but slightly smaller than some experimental values between 0.78 eV and 1.2 eV. In order to provide direct guidance for material synthesis and property design in Fe-doped ß-Ga2O3, the defect formation energies, charge transitional levels, and optical properties of the defective complexes with different kinds of native defects are investigated. Our results show that VGa and Oi can be easily formed for the Fe-doped ß-Ga2O3 crystals under O-rich conditions, where the +3 charge state FeGaGai and -2 charge state FeGaOi are energetically favorable when the Fermi level approaches the valence and conduction band edges, respectively. Optical absorption shows that the complexes of FeGaGai and FeGaVGa can significantly enhance the optical absorption in the visible-infrared region, while the energy-loss function in the ß-Ga2O3 material is almost negligible after the extra introduction of various intrinsic defects.

Effect of combined procedural pain interventions during neonatal intensive care on sleep, cognitive development, and internalizing behavior: a follow-up analysis of a randomized controlled trial.

ABSTRACT: Repeated procedural pain can cause preterm infants to spend excessive time awake at the cost of sleep and can have a detrimental impact on later cognitive and behavioral development. What's more, poor sleep may be correlated with worse cognitive development and more internalizing behaviors in infants and toddlers. In a randomized controlled trial (RCT), we found that combined procedural pain interventions (sucrose, massage, music, nonnutritive sucking, and gentle human touch) during neonatal intensive care could improve preterm infants' early neurobehavioral development. Here, we followed up the participants who were enrolled in the RCT to evaluate the effect of combined pain interventions on later sleep, cognitive development, and internalizing behavior and to determine whether sleep may moderate the effect of combined pain interventions on the cognitive development and internalizing behavior. Total sleep time and night awakenings at 3, 6, and 12 months old; the cognitive development (adaptability, gross motor, fine motor, language, and personal-social domains) at 12 and 24 months old measured by the Chinese version of Gesell Development Scale; and the internalizing behavior at 24 months old measured by the Chinese version of Child Behavior Checklist were assessed. Our findings showed the potential benefits of combined pain interventions during neonatal intensive care for preterm infant's later sleep, motor and language development, and internalizing behavior, and the effect of combined pain interventions on motor development and internalizing behavior might be moderated by the mean total sleep duration and night awakenings at 3, 6, and 12 months old.

Intracellular zinc protects Kv7 K+ channels from Ca2+/calmodulin-mediated inhibition.

Zinc (Zn) is an essential trace element; it serves as a cofactor for a great number of enzymes, transcription factors, receptors, and other proteins. Zinc is also an important signaling molecule, which can be released from intracellular stores into the cytosol or extracellular space, for example, during synaptic transmission. Amongst cellular effects of zinc is activation of Kv7 (KCNQ, M-type) voltage-gated potassium channels. Here, we investigated relationships between Kv7 channel inhibition by Ca2+/calmodulin (CaM) and zinc-mediated potentiation. We show that Zn2+ ionophore, zinc pyrithione (ZnPy), can prevent or reverse Ca2+/CaM-mediated inhibition of Kv7.2. In the presence of both Ca2+ and Zn2+, the Kv7.2 channels lose most of their voltage dependence and lock in an open state. In addition, we demonstrate that mutations that interfere with CaM binding to Kv7.2 and Kv7.3 reduced channel membrane abundance and activity, but these mutants retained zinc sensitivity. Moreover, the relative efficacy of ZnPy to activate these mutants was generally greater, compared with the WT channels. Finally, we show that zinc sensitivity was retained in Kv7.2 channels assembled with mutant CaM with all four EF hands disabled, suggesting that it is unlikely to be mediated by CaM. Taken together, our findings indicate that zinc is a potent Kv7 stabilizer, which may protect these channels from physiological inhibitory effects of neurotransmitters and neuromodulators, protecting neurons from overactivity.

Up-regulation of miR-133a-3p promotes ovary insulin resistance on granulosa cells of obese PCOS patients via inhibiting PI3K/AKT signaling.

BACKGROUND: MicroRNAs are a type of non-coding single-stranded RNA, which is involved in the regulation of ovary insulin resistance (IR). This study aims to explore the underlying mechanisms of miR-133a-3p regulating ovary IR in obese polycystic ovary syndrome (PCOS). METHODS: Granulosa cells (GCs) were extracted from follicular fluids of PCOS patients (obese PCOS group and non-obese PCOS group) and healthy women (control group). The expression of miR-133a-3p in GCs was detected by qRT-PCR. The targets and pathways of miR-133a-3p were predicted by bioinformatics analyses. The protein levels of PI3K, p-AKT, GLUT4, p-GSK-3ß, and p-FOXO1 were measured by Western blotting. RESULTS: MiR-133a-3p was highly expressed in GCs from PCOS patients, especially in obese PCOS patients. The protein levels of PI3K and p-AKT was downregulated in GCs from PCOS patients. There were 11 target genes of miR-133a-3p enriching in PI3K/AKT signaling pathway. miR-133a-3p mimic downregulated the expression of PI3K, p-AKT, and GLUT4, and upregulated the protein levels of p-GSK-3ß and p-FOXO1. miR-133a-3p inhibitor presented the opposite effect of miR-133a-3p mimic. CONCLUSION: MiR-133a-3p promotes ovary IR on GCs of obese PCOS patients via inhibiting PI3K/AKT signaling pathway. This study lays a foundation for further research on the mechanism of ovary IR in obese PCOS patients.

Gut microbial dysbiosis in rheumatoid arthritis: a systematic review protocol of case-control studies.

INTRODUCTION: Rheumatoid arthritis (RA) has a huge societal impact due to the high prevalence, irreversible joint damage and systemic complications. Gut microbiota plays an important role in the pathogenesis and progression of RA by regulating the host immune system. Restoring intestinal homeostasis by altering the microbiota could be an attractive strategy for the prevention and treatment of RA. However, the signature features of microbial dysbiosis in RA are still controversial. Therefore, we aim to elucidate the characteristic change in the diversity and composition of gut microbiota in RA. METHODS AND ANALYSIS: We will systematically search through PubMed, EMBASE, Web of Science and Cochrane Library, as well as dissertations and conference proceedings. The reference lists of all included studies will be also reviewed to retrieve additional relevant studies. The case-control studies that reported either the relative abundance of bacteria at the phylum or genus level or at least one of the alpha-diversity, beta-diversity indexes in both RA and healthy controls will be included. Eligible studies will be screened independently by two reviewers according to the inclusion criteria. The Newcastle-Ottawa Quality Assessment Scale will be used to assess the quality of the included studies. Data extraction, qualitative and quantitative analysis will be performed within the gut microbial dysbiosis in RA. The expected outcomes will be the identification of the specific changes in composition and diversity of the gut microbiota in patients with RA. The quality of evidence will be assessed by the Grading of Recommendations Assessment, Development and Evaluation framework. ETHICS AND DISSEMINATION: Ethical approval is unnecessary as this review does not address the data and privacy of patients. The results will be published in a peer-reviewed scientific journal and conference presentations. PROSPERO REGISTRATION NUMBER: CRD42021225229.

Exogenous sucrose influences KEA1 and KEA2 to regulate abscisic acid-mediated primary root growth in Arabidopsis.

Arabidopsis K+-efflux antiporter (KEA)1 and KEA2 are chloroplast inner envelope membrane K+/H+ antiporters that play an important role in plastid development and seedling growth. However, the function of KEA1 and KEA2 during early seedling development is poorly understood. In this work, we found that in Arabidopsis, KEA1 and KEA2 mediated primary root growth by regulating photosynthesis and the ABA signaling pathway. Phenotypic analyses revealed that in the absence of sucrose, the primary root length of the kea1kea2 mutant was significantly shorter than that of the wild-type Columbia-0 (Col-0) plant. However, this phenotype could be remedied by the external application of sucrose. Meanwhile, HPLC-MS/MS results showed that in sucrose-free medium, ABA accumulation in the kea1kea2 mutant was considerably lower than that in Col-0. Transcriptome analysis revealed that many key genes involved in ABA signals were repressed in the kea1kea2 mutant. We concluded that KEA1 and KEA2 deficiency not only affected photosynthesis but was also involved in primary root growth likely through an ABA-dependent manner. This study confirmed the new function of KEA1 and KEA2 in affecting primary root growth.

The active ingredient (DSH-20) of Salvia miltiorrhiza flower reduces oxidative damage and apoptosis in cardiomyocytes by regulating miR-1.

BACKGROUND: DSH-20, the active ingredient of Salvia miltiorrhiza flower extract, is used to treat cardiovascular diseases. However, its mechanism of action remains unclear. Herein, we investigated the intervention of DSH-20 in H2O2-induced oxidative damage and apoptosis in cardiomyocytes. METHODS AND RESULTS: H2O2 was used to induce oxidative damage and apoptosis in H9c2 cardiomyocytes. Based on concentration gradient studies, we found that 62.5 µg/mL DSH-20 significantly reduced reactive oxygen species and lactate dehydrogenase levels and increased superoxide dismutase levels. DSH-20 also alleviated the apoptosis rate, the changes in mRNA of apoptosis-related genes (Bcl-2, BAX, and Caspase-3) and miR-1 expression. Moreover, transfection of miR-1 mimics aggravated oxidative damage and apoptosis, whereas DSH-20 alleviated these effects. CONCLUSIONS: DSH-20 reduced H2O2-induced oxidative damage and apoptosis in H9c2 cardiomyocytes likely by downregulating miR-1 expression.

miR-126 regulates angiogenesis in myocardial ischemia by targeting HIF-1α.

Promoting angiogenesis by targeting various angiogenic regulators has emerged as a new treatment strategy for myocardial ischemia (MI). MicroRNA-126 (miR-126) has been identified as the main regulator of compensatory angiogenesis; however, its role in MI is unclear. A rat MI model and an EA. hy926 endothelial cell hypoxia model were constructed and it was found that miR-126 was highly expressed in both models. The knockdown of HIF-1α expression in EA. hy926 cells in turn downregulated VEGF and CD34 expression and consequently inhibited angiogenesis. MiR-126 inhibitor inhibited EA. hy926 cell migration and tube formation as well as downregulated VEGF and CD34 expression, and these were reversed by transfection of miR-126 mimics. Rescue tests using miR-126 and HIF-1α demonstrated that miR-126-mediated regulation of angiogenesis was dependent on HIF-1α. In summary, miR-126 regulates the occurrence and progression of angiogenesis during MI via HIF-1α and may be a potential new therapeutic target.

Screening and identification of differentially expressed microRNAs in diffuse large B-cell lymphoma based on microRNA microarray.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of B-cell non-Hodgkin lymphoma in adults and the pathogenesis of DLBCL is multifactorial and complex. Understanding the molecular mechanisms involved in DLBCL is important to identify new therapeutic targets. The present study aimed to screen and identify differentially expressed microRNAs (miRNAs/miRs) between diffuse large B-cell lymphoma (DLBCL) and control [lymph node reactive hyperplasia (LRH)] groups, and to investigate whether miRNAs associated with DLBCL could serve as potential therapeutic targets. In total, 5 DLBCL experimental samples and 5 control samples were obtained from fresh patient tissues. Firstly, the fresh samples were analyzed using miRNA microarray to identify differentially expressed miRNAs. Next, three databases (TargetScan, microRNA.org and PITA) were used to predict by intersection the potential target genes of the 204 differential miRNAs identified, and a Venn diagram of the results was performed. Subsequently, the target genes of differential miRNAs were analyzed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis. Finally, to validate the miRNA microarray data, reverse transcription-quantitative PCR (RT-qPCR) was performed for 8 differentially expressed miRNAs (miR-193a-3p, miR-19a-3p, miR-19b-3p, miR-370-3p, miR-1275, miR-490-5p, miR-630 and miR-665) using DLBCL and LRH fresh samples. In total, 204 miRNAs exhibited differential expression, including 105 downregulated and 54 upregulated miRNAs. The cut-off criteria were set as P≤0.05 and fold-change ≥2. A total of 7,522 potential target genes for the 204 miRNAs were predicted. Potential target genes were enriched in the following pathways: 'Cancer', 'MAPK signaling pathway', 'regulation of actin cytoskeleton', 'focal adhesion', 'endocytosis', 'Wnt signaling pathway', 'axon guidance', 'calcium signaling pathway' and 'PI3K/AKT signaling pathway'. A total of 8 miRNAs were validated by RT-qPCR, and 4 miRNAs (miR-19b-3p, miR-193a-3p, miR-370-3p and miR-490-5p) exhibited low expression levels in DLBCL (P<0.05), while miR-630 was highly expressed in DLBCL (P<0.05). Overall, the present study screened 204 differentially expressed miRNAs and analyzed the expression levels of 8 differentially expressed miRNAs in DLBCL. These differentially expressed miRNAs may serve as therapeutic targets for improvement of therapeutic efficacy in DLBCL in the future.

Yiqi-Huoxue granule promotes angiogenesis of ischemic myocardium through miR-126/PI3K/Akt axis in endothelial cells.

BACKGROUND: Yiqi-Huoxue granule (YQHX), consisting of four kinds of traditional Chinese medicine, is an empirical prescription for the treatment of coronary heart disease. It is known to promote angiogenesis, but the mechanism is unknown. PURPOSE: This article investigates the possible mechanism of YQHX inducing angiogenesis in the ischemic myocardium. METHODS: EAhy.926 cells were treated with YQHX hypoxic cardiomyocyte-conditioned medium (YHMCM) and the levels of VEGF, CD34, and phosphorylation of PI3K/Akt were detected by western blotting. Also, the effects on endothelial tube formation and migration were observed. The level of miR-126 was detected by qRT-PCR. RESULTS: YQHX promoted tube formation and migration of EAhy.926 cells and upregulated VEGF, CD34, and the phosphorylation of PI3K/AKT via regulating miR-126 levels. However, these effects were inhibited by a miR-126 inhibitor. CONCLUSION: In summary, YQHX improves angiogenesis by regulating the miR-126/PI3K/Akt signaling pathway, which indicates that YQHX could be a promising therapeutic strategy for ischemic myocardium.

Effect of Yiqi Huoxue Granules on Platelet Activation Induced by Thrombin.

OBJECTIVE: To study the effects of Yiqi Huoxue (YQHX) granules on platelet activation and aggregation induced by thrombin. METHODS: The effect of YQHX on platelet aggregation rate was detected by platelet aggregation instrument; the effect of YQHX on thrombosis time was observed by the mouse mesentery thrombosis model. DAMI cells were induced to transform into platelet-like granules using PMA, and the effects of SCH (PAR-1 inhibitor) on thrombin-induced changes in platelet intracellular calcium concentration, PAR-1 protein expression, and phosphorylation of MAPK were examined. RESULTS: Compared with the control group, the platelet aggregation rate, PAR-1 protein expression, phosphorylation of ERK1/2, and p38 protein in the YQHX group decreased (P < 0.05), and there was no significant difference between the YQHX + SCH group and YQHX group (P > 0.05). CONCLUSION: YQHX suppresses the platelet activation induced by thrombin by inhibiting PAR-1 expression.

Mechanisms of polymyxin resistance induced by Salmonella typhimurium in vitro.

The increase incidence of multi-drug resistant (MDR) Salmonella has become a major global health concern. Polymyxin, an ancient polypeptide antibiotic, has been given renewed attention over recent years, resulting in resistance of Gram-negative bacteria to polymyxin, but its resistance mechanism is not completely clear. Thus, it is important to study its resistance mechanisms. In this study, an in vitro induced polymyxin-resistant strain of Salmonella typhimurium in the laboratory were constructed to investigate the mechanism of resistance of Salmonella to polymyxin. Gradual induction of Salmonella typhimurium ATCC13311 (AT) by concentration increment was used to screen for a highly polymyxin-resistant strain AT-P128. The broth dilution technique was used to compare the sensitivity of the two strains to different antimicrobial drugs. Single nucleotide polymorphisms (SNPs) were then identified by whole genome sequencing, and differences in gene expression between the two strains were compared by transcriptome sequencing and reverse transcription-quantitative PCR (RT-qPCR). Finally, for the first time, the CRISPR/Cas9 gene-editing system was used to construct gene deletion mutants in Salmonella to knock out the phoP gene of AT-P128. The results showed that strain AT-P128 was significantly more resistant to amoxicillin, ceftiofur, ampicillin, fluphenazine, and chloramphenicol and significantly less resistant to sulfamethoxazole than the parental strain AT. The growth curve results showed no significant change in the growth rate between AT-P128 and AT. Motility and biofilm formation assays showed a significant decrease in AT-P128. Additionally, the WGS results showed that AT-P128 had mutations in 9 genes involving 14 SNPs. RNA-seq and RT-qPCR results showed increased expression of phoPQ. The loss of the phoP gene decreased AT-P128ΔphoP resistance to polymyxin by 32-fold. These results suggested that polymyxin resistance affected the biology, genome components, and gene expression levels of Salmonella and that the PhoPQ two-component system played a key role in polymyxin resistance in Salmonella, providing insights into the diversity and complexity of polymyxin resistance in Salmonella.

Kv7 Channels and Excitability Disorders.

Kv7.1-Kv7.5 (KCNQ1-5) K+ channels are voltage-gated K+ channels with major roles in neurons, muscle cells and epithelia where they underlie physiologically important K+ currents, such as neuronal M current and cardiac IKs. Specific biophysical properties of Kv7 channels make them particularly well placed to control the activity of excitable cells. Indeed, these channels often work as 'excitability breaks' and are targeted by various hormones and modulators to regulate cellular activity outputs. Genetic deficiencies in all five KCNQ genes result in human excitability disorders, including epilepsy, arrhythmias, deafness and some others. Not surprisingly, this channel family attracts considerable attention as potential drug targets. Here we will review biophysical properties and tissue expression profile of Kv7 channels, discuss recent advances in the understanding of their structure as well as their role in various neurological, cardiovascular and other diseases and pathologies. We will also consider a scope for therapeutic targeting of Kv7 channels for treatment of the above health conditions.

Evaluation of Nonviral piggyBac and lentiviral Vector in Functions of CD19chimeric Antigen Receptor T Cells and Their Antitumor Activity for CD19+ Tumor Cells.

Nonviral transposon piggyBac (PB) and lentiviral (LV) vectors have been used to deliver chimeric antigen receptor (CAR) to T cells. To understand the differences in the effects of PB and LV on CAR T-cell functions, a CAR targeting CD19 was cloned into PB and LV vectors, and the resulting pbCAR and lvCAR were delivered to T cells to generate CD19pbCAR and CD19lvCAR T cells. Both CD19CAR T-cell types were strongly cytotoxic and secreted high IFN-γ levels when incubated with Raji cells. TNF-α increased in CD19pbCAR T cells, whereas IL-10 increased in CD19lvCAR T cells. CD19pbCAR and CD19lvCAR T cells showed similar strong anti-tumor activity in Raji cell-induced mouse models, slightly reducing mouse weight while enhancing mouse survival. High, but not low or moderate, concentrations of CD19pbCAR T cells significantly inhibited Raji cell-induced tumor growth in vivo. These CD19pbCAR T cells were distributed mostly in mesenteric lymph nodes, bone marrow of the femur, spleen, kidneys, and lungs, specifically accumulating at CD19-rich sites and CD19-positive tumors, with CAR copy number being increased on day 7. These results indicate that pbCAR has its specific activities and functions in pbCAR T cells, making it a valuable tool for CAR T-cell immunotherapy.

Effect of combined pharmacological, behavioral, and physical interventions for procedural pain on salivary cortisol and neurobehavioral development in preterm infants: a randomized controlled trial.

Repeated procedural pain may lead to increased secretion of cortisol and future neurobehavioral development disorders in preterm infants. Changes in the cortisol level may mediate the effect of neonatal repetitive procedural pain on altered childhood neurobehavioral development in preterm infants. However, few studies have investigated the effect of combined pharmacological, behavioral, and physical interventions over repeated painful procedures on pain response, cortisol level, and neurobehavioral development. This study examined (1) the efficacy and safety of sucrose combined with massage, music, non-nutritive sucking, and gentle human touch to treat preterm infants with repeated procedural pain; (2) the cortisol level at discharge from the neonatal intensive care unit (NICU); (3) neurobehavioral development at 40 weeks' corrected gestational age; and (4) the potential mediating effect of the cortisol level in the combined interventions on neurobehavioral development. Stable preterm infants (n = 76) were randomized to receive routine care or combined interventions across repeated painful procedures throughout their NICU stay. The Premature Infant Pain Profile scores in the early, middle, and late periods of the NICU stay were measured, as were the basal salivary cortisol level at admission and discharge, the Neonatal Behavioral Neurological Assessment score at 40 weeks' corrected gestational age, and the incidence of adverse effects during the study period. Our findings indicated that the combined interventions remained efficacious and safe for reducing repeated procedural pain, decreased the cortisol level at discharge, and promoted early neurobehavioral development in preterm infants. This effect may have been mediated through decreased cortisol levels and reduced repeated procedural pain.

Morphine use in the neonatal period and later neuropsychological development: a systematic review.

AIM: To identify and evaluate the evidence documenting the association between neonatal morphine and later childhood neuropsychological development. METHOD: We conducted a systematic literature search of eight electronic databases from inception until June 2019. We included all randomized controlled trials (RCTs) and cohort studies recruiting neonates who received morphine treatment, and measuring neuropsychological development outcomes with a minimum follow-up of 6 months. RESULTS: Twelve separate reports from three RCTs and five cohort studies met our inclusion criteria. Owing to the small number of the included trials and the variable study designs, a meta-analysis was not performed. The findings from this review indicated that neonatal morphine use had no adverse effects on behaviour, cognition, motor, and executive function development at 8 to 9 years and earlier; except for the inconsistent conclusions on internalizing behavioural problems at 5 to 7 years and cognitive and motor developments at 18 months. INTERPRETATION: Why a child needs morphine may have a more profound impact on later neuropsychological development than morphine itself. The small number, high heterogeneity, and limitations of the included studies limit confidence in the result of this systematic review.

Expression of YAP1 and pSTAT3-S727 and their prognostic value in glioma.

AIMS: A growing research demonstrated that YAP1 played important roles in gliomagenesis. We explored the expression of YAP1 and STAT3, the relationship between them and the effect of YAP1, STAT3 on prognosis in glioma. METHODS: Expression of YAP1, p-YAP1, STAT3, pSTAT3-S727 and pSTAT3-Y705 in 141 cases of low-grade gliomas (LGG) and 74 cases of high-grade gliomas (HGG) of surgical specimens were measured by immunohistochemistry. Pearson's X2 test was used to determine the correlation between immunohistochemical expressions and clinicopathological parameters. Pearson's or Spearman correlation test was used to determine the association between these proteins expression. Survival analysis was used to investigate the effect of these proteins on prognosis. RESULTS: High expressions of YAP1, STAT3, pSTAT3-S727 and pSTAT3-Y705 were found in HGG compared with LGG (p=0.000). High expressions of YAP1, STAT3, pSTAT3-S727 and pSTAT3-Y705 were found in 63.5%, 59.5%, 66.2% and 31.1% cases of HGG, respectively. YAP1 expression was associated to tumour location, Ki-67 and P53, STAT3 expression was related with Ki-67 and P53, and the expression of pSTAT3-S727 was associated with Ki-67. There was a significantly positive correlation between YAP1 and pSTAT3-S727 (p<0.0001; r=0.5663). Survival analysis revealed that patients with YAP1 and pSTAT3-S727 coexpression had worse overall survival (OS) and progression-free survival (PFS) (p<0.0001). Tumour grade, age, Ki-67 and YAP1 expression were independent prognostic factors for OS. In LGG group, both YAP1 and pSTAT3-S727 expressions were negative correlation with IDH1 mutation, YAP1 and pSTAT3-S727 coexpression showed worse OS and PFS of glioma patients. CONCLUSION: Our research showed that YAP1 and STAT3 were significantly activated in HGG compared with LGG. YAP1 significantly correlated with pSTAT3-S727 in glioma, YAP1 and pSTAT3-S727 coexpression may serve as a reliable prognostic biomarker and therapeutic target for glioma.