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Background: Neo-tetraploid rice lines exhibit high fertility and strong heterosis and harbor novel specific alleles, which are useful germplasm for polyploid rice breeding. However, the mechanism of the fertility associated with miRNAs remains unknown. In this study, a neo-tetraploid rice line, termed Huaduo21 (H21), was used. Cytological observation and RNA-sequencing were employed to identify the fertility-related miRNAs in neo-tetraploid rice. Results: H21 showed high pollen fertility (88.08%), a lower percentage of the pollen mother cell (PMC) abnormalities, and lower abnormalities during double fertilization and embryogenesis compared with autotetraploid rice. A total of 166 non-additive miRNAs and 3108 non-additive genes were detected between H21 and its parents. GO and KEGG analysis of non-additive genes revealed significant enrichments in the DNA replication, Chromosome and associated proteins, and Replication and repair pathways. Comprehensive multi-omics analysis identified 32 pairs of miRNA/target that were associated with the fertility in H21. Of these, osa-miR408-3p and osa-miR528-5p displayed high expression patterns, targeted the phytocyanin genes, and were associated with high pollen fertility. Suppression of osa-miR528-5p in Huaduo1 resulted in a low seed set and a decrease in the number of grains. Moreover, transgenic analysis implied that osa-MIR397b-p3, osa-miR5492, and osa-MIR5495-p5 might participate in the fertility of H21. Conclusion: Taken together, the regulation network of fertility-related miRNAs-targets pairs might contribute to the high seed setting in neo-tetraploid rice. These findings enhance our understanding of the regulatory mechanisms of pollen fertility associated with miRNAs in neo-tetraploid rice. [ABSTRACT FROM AUTHOR]

A recent study by Funahashi et al. explores the expression of miRNA in schizophrenia patients, providing valuable insights into potential biomarkers and treatment effects. The study suggests that miR-675-3p is upregulated in patients with treatment-resistant schizophrenia (TRS) who are treated with clozapine. However, caution is needed when interpreting these findings, as the upregulation of miR-675-3p may be a feature of TRS itself rather than a specific effect of clozapine. The study also compares miRNA expression in non-TRS patients treated with antipsychotics other than clozapine, but the lack of detailed information on specific antipsychotic regimens introduces a significant variable. Further research is needed to separate the effects of the disease from the effects of treatment and to better understand clozapine's specific influence on miRNA expression in TRS. [Extracted from the article]

Background: Autotetraploid Carassius auratus (4nRCC, 4n = 200, RRRR) was derived from the whole genome duplication of diploid red crucian carp (Carassius auratus red var.) (2nRCC, 2n = 100, RR). To investigate the genetic effects of tetraploidization, we analyzed DNA variation, epigenetic modification and gene expression changes in the Sox9a-Amh-Cyp19a1a regulatory cascade between 4nRCC and 2nRCC. Results: We found that the Sox9a gene contained two variants in 2nRCC and four variants in 4nRCC. Compared with that in 2nRCC, DNA methylation in the promoter regions of the Amh and Cyp19a1a genes in 4nRCC was altered by single nucleotide polymorphism (SNP) mutations, which resulted in the insertions and deletions of CpG sites, and the methylation levels of the Sox9a, Amh and Cyp19a1a genes increased after tetraploidization. The gene expression level of the Sox9a-Amh-Cyp19a1a regulatory cascade was downregulated in 4nRCC compared with that in 2nRCC. Conclusion: The above results demonstrate that tetraploidization leads to significant changes in the genome, epigenetic modification and gene expression in the Sox9a-Amh-Cyp19a1a regulatory cascade; these findings increase the extant knowledge regarding the effects of polyploidization. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor (VEGF) is pathognomonically elevated in patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) syndrome. However, its source of overproduction is unclear. As clinical improvement is almost always associated with VEGF reduction after anti-plasma cell therapy, its increase at diagnosis has been attributed to the underlying monoclonal gammopathy, although direct evidence is still lacking. In the current study, we systemically measured VEGF levels in POEMS patients, before and after treatment. Bone marrow plasma cells showed remarkable VEGF expression, in both mRNA and protein levels, which decreased gradually in response to therapy. Of note, statistically linear correlations were observed between serum and bone marrow plasma cell VEGF levels (mRNA vs . serum, rho 0.343, p = 0.003; protein vs . serum, rho 0.644, p < 0.0001), supporting bone marrow plasma cells as the main source of circulating VEGF. Intriguingly, immunophenotyping revealed that bone marrow plasma cells were polyclonal in most patients at diagnosis. A clear monoclonal population, coexistent with polytypic cells, was only detectable in 11 cases (18%), in which comparable intracellular VEGF expression was observed between these two plasma cell populations ( p = 0.594), while monoclonal cells showed higher intracellular interleukin-6 expression ( p = 0.006). These patients had more serum monoclonal protein, less post-therapeutic complete remission, and inferior overall ( p = 0.027) and progression-free survival ( p = 0.002). Collectively, bone marrow plasma cells, mainly polyclonal population, are the major source of VEGF overproduction in POEMS patients. [ABSTRACT FROM AUTHOR]

Background and Purpose Emerging evidence indicates that stimulating adult neurogenesis provides novel strategies for central nervous system diseases. Iptakalim ( Ipt), a novel ATP-sensitive potassium (K- ATP) channel opener, has been demonstrated to play multipotential neuroprotective effects in vivo and in vitro. However, it remains unknown whether Ipt could regulate the adult neurogenesis. Methods and Results Based on the finding that adult neural stem cells ( ANSCs) in hippocampus expressed Kir6.1/ SUR1-composed K- ATP channel, Kir6.1 heterozygotic ( Kir6.1+/−) mice were used to investigate whether and how Ipt regulates adult hippocampal neurogenesis. We showed that administration of Ipt (10 mg/kg) or fluoxetine ( Flx, 10 mg/kg) for 4 weeks significantly increased newborn ANSCs in subgranular zone ( SGZ) of Kir6.1+/+ mice but failed to affect those of Kir6.1+/− mice. Meanwhile, ANSCs in Kir6.1+/− mice exhibited decreased survival rate and impaired ability of differentiation into astrocytes. We further found that Kir6.1+/− mice showed lower level of brain-derived neurotrophic factor ( BDNF) in hippocampus compared with Kir6.1+/+ mice. Furthermore, Ipt increased the levels of BDNF and basic fibroblast growth factor ( FGF-2) throughout the hippocampus in Kir6.1+/+ mice but not in Kir6.1+/− mice. Moreover, Ipt and Flx enhanced the phosphorylation of Akt and CREB in the hippocampus of Kir6.1+/+ mice. Notably, these effects were completely abolished in Kir6.1+/− mice. Conclusions Our findings demonstrate that Ipt stimulates the adult hippocampal neurogenesis via activation of Akt and CREB signal following the opening of Kir6.1-composed K- ATP channels, which gives us an insight into the therapeutic implication of Ipt in the diseases with adult neurogenesis deficiency, such as major depression. [ABSTRACT FROM AUTHOR]

Summary: Using a mouse model of human MLL-AF9 leukemia, we identified the lysine-specific demethylase KDM1A (LSD1 or AOF2) as an essential regulator of leukemia stem cell (LSC) potential. KDM1A acts at genomic loci bound by MLL-AF9 to sustain expression of the associated oncogenic program, thus preventing differentiation and apoptosis. In vitro and in vivo pharmacologic targeting of KDM1A using tranylcypromine analogs active in the nanomolar range phenocopied Kdm1a knockdown in both murine and primary human AML cells exhibiting MLL translocations. By contrast, the clonogenic and repopulating potential of normal hematopoietic stem and progenitor cells was spared. Our data establish KDM1A as a key effector of the differentiation block in MLL leukemia, which may be selectively targeted to therapeutic effect. [Copyright &y& Elsevier]

Abstract: Evidence from genetic, transgenic and post-mortem studies has strongly supported the critical role that neuregulin 1 (NRG1) and its ErbB4 receptor plays in the pathophysiology of schizophrenia. This article aims to review current evidence regarding the effects of antipsychotic treatment on NRG1–ErbB4 signalling. NRG1 and ErbB4 knockout mice display abnormal behaviours relevant to certain features of schizophrenia, which could be improved by antipsychotic (clozapine/haloperidol) treatment. In contrast to most NRG1/ErbB4 knockout mice with a decreased NRG1–ErbB4 signalling, the majority post-mortem studies showed an increased NRG1–ErbB4 signalling in schizophrenic patients. These differences could be due to degrees of alteration in risk genes (subtle variations in patients vs pronounced alteration in mutant mice) or the duration of the modification on NRG1 signalling. Various antipsychotics have different effects on NRG1 and ErbB4 expression and signalling that are dependent on treatment duration. Current evidence suggests that a chronic (12weeks) antipsychotic treatment, at least in animal models, could downregulate NRG1–ErbB4 signalling, although an upregulation is seen for a short-term treatment. These effects may be due to multiple binding profiles with various G-coupled protein receptors (e.g. dopamine, and serotonin receptors) of antipsychotics. Studies are needed to investigate the interactions between NRG1–ErbB4 and the other signalling pathways (such as glutamatergic, GABAergic and dopaminergic). Furthermore, the interactions between NRG1/ErbB4 and other schizophrenia suspensibility genes under antipsychotic treatment also require investigation. [Copyright &y& Elsevier]

Abstract: This study examined regional changes of 5-HT2A and 2C receptor mRNA expression in the rat brain after chronic administration of clozapine (1.5mg/kg/day) and haloperidol (2.0mg/kg/day) for 36 days. 5-HT2A and 2C receptor mRNA expression and distributions were detected by in situ hybridization after rats were sacrificed either 2 or 48h after the last drug administration to examine both immediate and delayed effects following drug withdrawal. Following 2h of drug withdrawal, it showed that clozapine administration significantly decreased 5-HT2A receptor mRNA, predominantly in the nucleus accumbens (65%), hippocampus (80%), lasteral septal nucleus (61%) and striatum (68%) compared to controls, whilst rebound increases were observed in most of these regions 48h later. In contrast, no change in 5-HT2A receptor mRNA expression was found in the haloperidol treated groups either 2h or 48h after drug withdrawal. Clozapine also decreased 5-HT2C receptor mRNA expression in the posteromedial cortical amygdala (32%) and substantia nigra (35%) 2h after the last drug administration, while rebound effects were also observed 48h later. 5-HT2C receptor mRNA was only decreased in the substantia nigra at both 2h (42%) and 48h (54%) after the last haloperidol administration. Alterations in serotonin receptor expression in limbic system region such as the nucleus accumbens, hippocampus and lateral septal nucleus as well as the striatum may represent the specific regional targets that mediate the clinical effects of antipsychotics via the serotonin system. [Copyright &y& Elsevier]

Abstract: This study examined regional changes in rat brain mRNA levels encoding 5-HT2A and 5-HT2C receptors following chronic olanzapine treatment. The immediate effect (2h after the last treatment) was a down-regulation of 5-HT2A receptor mRNA expression, predominantly in the hypothalamus, limbic system and striatum, while a rebound effect was observed 48h later. 5-HT2C receptor mRNA expressions were decreased in the substantia nigra. Correlations between 5-HT2A receptor mRNA expression and total food intake, weight gain and energy efficiency were observed. [Copyright &y& Elsevier]

The hetN gene plays an important role in heterocyst differentiation and pattern formation. An immunoblotting study showed that the hetN gene in Anabaena sp. PCC 7120 was expressed in vegetative cells grown with combined nitrogen. After a switch to a medium without combined nitrogen, hetN expression first declined and was then followed by a rapid increase in its product, HetN, which was only present in mature heterocysts. HetN is located on both thylakoid membranes and plasma membranes as determined by immunoblotting using purified membranes. Overexpression of hetN completely prevented hetR up-regulation under nitrogen-deprivation conditions, suggesting that its role in pattern control may depend on its inhibition of hetR expression. [Copyright &y& Elsevier]

Our previous study indicated that streptozotocin (STZ)‐induced diabetes leads to colonic platelet‐derived growth factor receptor‐α‐positive (PDGFRα+) cell proliferation accompanied by slow colonic transit in mice; however, the mechanism of this effect is unclear. The present study used western blotting, immunohistochemistry, and quantitative PCR to investigate whether proteinase‐activated receptor 2 (PAR2) mediates PDGFRα+ cell proliferation. Our results showed that PDGFRα, PAR2, and Ki‐67 coexpression was increased in the diabetic colonic muscle layer. PDGFRα and PAR2 mRNA and protein expression levels were also markedly enhanced in the diabetic colonic muscle layer. Mice treated with 2‐furoyl‐LIGRLO‐amide (2‐F‐L‐a), a PAR2 agonist, exhibited significant colon elongation and increased smooth muscle weight. In the 2‐F‐L‐a‐treated mice, PDGFRα, PAR2, and Ki‐67 coexpression was increased and PDGFRα and PAR2 mRNA and protein expression was significantly enhanced in the colonic smooth muscle layer. 2‐F‐L‐a also increased proliferation and PDGFRα expression in NIH/3T3 cells cultured in high glucose, while LY294002, a PI3K antagonist, decreased cell proliferation and PDGFRα expression. PI3K and Akt protein and mRNA expression and p‐Akt protein expression in diabetic and 2‐F‐L‐a‐treated mice were markedly reduced in colonic smooth muscle. 2‐F‐L‐a also reduced PI3K, Akt, and p‐Akt protein expression in NIH/3T3 cells, while the PI3K antagonist LY294002 increased this expression. The results indicate that PAR2 is involved in the proliferation of PDGFRα+ cells through the PI3K/Akt signaling pathway in the colon of STZ‐induced diabetic mice, which may contribute to the slow transit and constipation that are associated with diabetes. [ABSTRACT FROM AUTHOR]

Rhizoctonia solani is a devastating soil-borne pathogen that seriously threatens the cultivation of economically important crops. Multiple strains with a very broad host range have been identified, but only 1 (AG1-IA, which causes rice sheath blight disease) has been examined in detail. Here, we analyzed AG4-HGI 3 originally isolated from Tartary buckwheat (Fagopyrum tataricum), but with a host range comparable to AG1-IA. Genome comparison reveals abundant pathogenicity genes in this strain. We used multiomic approaches to improve the efficiency of screening for disease resistance genes. Transcriptomes of the plant–fungi interaction identified differentially expressed genes associated with virulence in Rhizoctonia and resistance in Tartary buckwheat. Integration with jasmonate-mediated transcriptome and metabolome changes revealed a negative regulator of jasmonate signaling, cytochrome P450 (FtCYP94C1), as increasing disease resistance probably via accumulation of resistance-related flavonoids. The integration of resistance data for 320 Tartary buckwheat accessions identified a gene homolog to aspartic proteinase (FtASP), with peak expression following R. solani inoculation. FtASP exhibits no proteinase activity but functions as an antibacterial peptide that slows fungal growth. This work reveals a potential mechanism behind pathogen virulence and host resistance, which should accelerate the molecular breeding of resistant varieties in economically essential crops. Multiomic association analysis dissects the genetic basis of the virulence mechanism in Rhizoctonia solani and the jasmonic acid–mediated resistance against R. solani in Tartary buckwheat. [ABSTRACT FROM AUTHOR]

In flowering plants, floral induction signals intersect at the shoot apex to modulate meristem determinacy and growth form. Here, we report a single-nucleus RNA sequence analysis of litchi apical buds at different developmental stages. A total of 41 641 nuclei expressing 21 402 genes were analyzed, revealing 35 cell clusters corresponding to 12 broad populations. We identify genes associated with floral transition and propose a model that profiles the key events associated with litchi floral meristem identity by analyzing 567 identified floral meristem cells at single cell resolution. Interestingly, single-nucleus RNA-sequencing data indicated that all putative FT and TFL1 genes were not expressed in bud nuclei, but significant expression was detected in bud samples by RT–PCR. Based on the expression patterns and gene silencing results, we highlight the critical role of LcTFL1-2 in inhibiting flowering and propose that the LcFT1 / LcTFL1-2 expression ratio may determine the success of floral transition. In addition, the transport of LcFT1 and LcTFL1-2 mRNA from the leaf to the shoot apical meristem is proposed based on in situ and dot-blot hybridization results. These findings allow a more comprehensive understanding of the molecular events during the litchi floral transition, as well as the identification of new regulators. [ABSTRACT FROM AUTHOR]

The glutamatergic system may be central to the neurobiology and treatment of major depressive disorder (MDD) and psychosis. Despite the success of N-methyl-D-aspartate receptor (NMDAR) antagonists for the treatment of MDD, little is known regarding the expression of these glutamate receptors in MDD. In this study we measured gene expression, via qRT-PCR, of the major NMDAR subunits, in the anterior cingulate cortex (ACC) in MDD subjects with and without psychosis, and non-psychiatric controls. Overall, GRIN2B mRNA was increased in both MDD with (+32%) and without psychosis (+40%) compared to controls along with a trend increase in GRIN1 mRNA in MDD overall (+24%). Furthermore, in MDD with psychosis there was a significant decrease in the GRIN2A:GRIN2B mRNA ratio (−19%). Collectively these results suggest dysfunction of the glutamatergic system at the gene expression level in the ACC in MDD. Increased GRIN2B mRNA in MDD, along with an altered GRIN2A:GRIN2B ratio in psychotic depression, suggests a disruption to NMDAR composition could be present in the ACC in MDD; this could lead to enhanced signalling via GluN2B-containing NMDARs and greater potential for glutamate excitotoxicity in the ACC in MDD. These results support future research into GluN2B antagonist-based treatments for MDD. [ABSTRACT FROM AUTHOR]

Introduction: Chronic kidney disease (CKD) is a major public health issue worldwide, which is characterized by irreversible loss of nephron and renal function. However, the molecular mechanism of CKD remains underexplored. Methods: This study integrated three transcriptional profile datasets to investigate the molecular mechanism of CKD. The differentially expressed genes (DEGs) between Sham control (Con) and unilateral ureteral obstruction (UUO)-operated mice were analyzed by utilizing the limma package in R. The shared DEGs were analyzed by Gene Ontology and functional enrichment. Protein-protein interactions (PPIs) were constructed by utilizing the STRING database. Hub genes were analyzed by MCODE and Cytohubba. We further validated the gene expression by using the other dataset and mouse UUO model. Results: A total of 315 shared DEGs between Con and UUO samples were identified. Gene function and KEGG pathway enrichment revealed that DEGs were mainly enriched in inflammatory response, immune system process, and chemokine signaling pathway. Two modules were clustered based on PPI network analysis. Module 1 contained 13 genes related to macrophage activation, migration, and chemotaxis. Ten hub genes were identified by PPI network analysis. Subsequently, the expression levels of hub genes were validated with the other dataset. Finally, these four validated hub genes were further confirmed by our UUO mice. Three validated hub genes, Gng2, Pf4, and Ccl9, showed significant response to UUO. Conclusion: Our study reveals the coordination of genes during UUO and provides a promising gene panel for CKD treatment. GNG2 and PF4 were identified as potential targets for developing CKD drugs. [ABSTRACT FROM AUTHOR]

Background: The nucleus accumbens (NAcc) has been implicated in the pathology and treatment of schizophrenia. Recent postmortem evidence suggests a hyperglutamatergic state in the NAcc. With the present study we aimed to explore possible glutamatergic alterations in the NAcc of a large schizophrenia cohort. Methods: We performed immunoblots on postmortem NAcc samples from 30 individuals who had schizophrenia and 30 matched controls. We examined the protein expression of primary glutamatergic receptors, including the Nmethyldaspartate (NMDA) receptor (NR1, NR2A and NR2B subunits) and the group 1 metabotropic glutamate receptor (mGluR1 and mGluR5; dimeric and monomeric forms). In addition, we measured the group 1 mGluR endogenous regulators, neurochondrin and Homer1b/c, which have recently been implicated in the pathophysiology of schizophrenia. Results: Protein levels of glutamatergic receptors and endogenous regulators were not significantly different between the controls and individuals who had schizophrenia. Furthermore, mGluR5, but not mGluR1, showed a positive association with NMDA receptor subunits, suggesting differential interactions between these receptors in this brain region. Limitations: Investigation of these proteins in antipsychotic-naive individuals, in addition to the subregions of the NAcc and subcellular fractions, will strengthen future studies. Conclusion: The present study does not provide evidence for glutamatergic abnormalities within the NAcc of individuals with schizophrenia. Taken together with the results of previous studies, these findings suggest NMDA receptors and group 1 mGluRs are altered in a brain region--dependent manner in individuals with schizophrenia. The differential associations between mGluR1, mGluR5 and NMDA receptors observed in this study warrant further research into the interactions of these proteins and the implications for the therapeutic and adverse effect profile of glutamatergic-based novel therapeutics. [ABSTRACT FROM AUTHOR]

Our previous studies have shown that CNP-NPR-B/pGC-cGMP is upregulated in the diabetic rats. The present study was designed to determine whether the upregulation of CNP-NPR-B/pGC-cGMP signal pathway affects cGMP-PDE3-cAMP signal pathway in diabetic gastric smooth muscle. The gastric smooth muscle motility was observed by using isometric measurement. PDEs expressions in diabetic gastric smooth muscle tissue were observed by using immunohistochemistry, Western blotting, and RT-PCR methods. The results demonstrated that the inhibitory effect of CNP on the spontaneous contraction of gastric antral circular smooth muscle was potentiated in STZ-induced diabetic rat. CNP-induced increase of cGMP and cAMP was much higher in diabetic gastric smooth muscle tissue than in controls. The expression of PDE3 is downregulated while the levels of gene expression of PDE1, PDE2, PDE4, and PDE5 were not altered in the diabetic gastric smooth muscle tissue. The results suggest that the sensitivity of gastric smooth muscle to CNP is potentiated via activation of CNP-pGC-cGMP-PDE3-cAMP signal pathway in STZ-induced diabetic rats, which may be associated with diabetes-induced gastric motility disorder. [ABSTRACT FROM AUTHOR]

Abstract: Weight regain after weight loss is a major hurdle for combating obesity. The aim of this study is to examine orexigenic and anorectic neuropeptides of the hypothalamic arcuate nucleus (Arc) in response to weight loss after chronic energy intake restriction. Thirty mice were fed with a high-fat diet for 8 weeks and then classified as diet-induced obese (DIO; n =10) or diet-resistant (DR; n =10) mice according to the highest and lowest body weight gainers. Five mice from DIO and DR groups were placed on an energy restricted diet or continued on their high-fat diet ad libitum for 6 weeks. An additional five mice were on a LF diet throughout the course of this study as controls. Results showed that a six-week energy restricted diet completely reversed the increased body weight, fat mass and leptin in the DIO mice to the levels of the LF and DR mice. Arc neuropeptide Y (NPY) and agouti-related protein (AgRP) mRNA expression in DIO mice after obesity reversal were significantly higher than DIO mice without obesity reversal (17%, 47%, both p <0.05), while the Arc pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) mRNA showed no difference. Both NPY and AgRP expression in DIO mice were negatively correlated with plasma leptin (R =−0.78, p <0.05; R =−0.72, p <0.05). In conclusion, while chronic energy restriction will lead to weight loss, it can up-regulate hypothalamic orexigenic peptides, which may be an important contributing factor to weight regain after a weight loss program from an energy restricted diet. [Copyright &y& Elsevier]

• 3D solid-based numerical model of infilled RC frame specimen under progressive collapse scenario was established and validated. • Failure behaviours and load–deflection curves for models with varying reinforcement configurations were predicted by FEM. • Semi-analytical design models were proposed using gene expression programming approach based on the data from test and FEM. The effect of infill walls on the progressive collapse behaviour of reinforced concrete (RC) frames should be fully considered due to the formation of alternative load paths. To explore the configuration that could affect the progressive collapse resistance of infilled RC frames, parametric analyses are performed based on the validated simulation method. In the study, the impact introduced by the extra tie and integrity rebars in walls is emphasised. It is indicated that the variation in the reinforcement ratio of tie rebars leads to a limited change in structural progressive collapse resistance. In contrast, with the arrangement of the integrity reinforcement, the progressive collapse resistance of the infilled frames is enhanced and the propagation of the diagonal cracks in partial infill walls is suppressed. The notable re-ascending trend in the resistance curve for models with integrity rebars reveals the significant development of the catenary action in the integrity reinforcement. Then, with the help of linear regression and gene expression programming (GEP) techniques, a semi-analytical model is proposed for the prediction of the load-bearing capacity of infilled frames after column loss. In the prediction model, the linear effect of geometrical parameters and the non-linear effect of openings on the progressive collapse resistance are included by introducing three modification coefficients. Based on the statistical assessment, the capability of this explainable model is verified, and the appropriate amount of integrity reinforcement to mitigate the progressive collapse is discussed. [ABSTRACT FROM AUTHOR]

Summary Through in silico and other analyses, we identified FOXC1 as expressed in at least 20% of human AML cases, but not in normal hematopoietic populations. FOXC1 expression in AML was almost exclusively associated with expression of the HOXA/B locus. Functional experiments demonstrated that FOXC1 contributes to a block in monocyte/macrophage differentiation and enhances clonogenic potential. In in vivo analyses, FOXC1 collaborates with HOXA9 to accelerate significantly the onset of symptomatic leukemia. A FOXC1-repressed gene set identified in murine leukemia exhibited quantitative repression in human AML in accordance with FOXC1 expression, and FOXC1 high human AML cases exhibited reduced morphologic monocytic differentiation and inferior survival. Thus, FOXC1 is frequently derepressed to functional effect in human AML. [ABSTRACT FROM AUTHOR]

Neuregulin-1 (NRG1) and ErbB4 genes have been identified as candidate genes for schizophrenia. Post-mortem studies indicated that NRG1-ErbB4 signalling is impaired in schizophrenia subjects. This study investigated whether short- or long-term antipsychotic treatment has different effects on the expression of NRG1 and ErbB4 receptors. Female Sprague-Dawley rats were treated orally with either aripiprazole (0.75 mg/kg), haloperidol (0.1 mg/kg), olanzapine (0.5 mg/kg), or vehicle, 3 times/day for 1 or 12 weeks. Western blotting was performed to examine the expression of NRG1 isoforms (135 kDa, 70 kDa and 40 kDa) and ErbB4 receptors. Both 1-week haloperidol and olanzapine treatment increased NRG1-70 kDa expression in the hippocampus; haloperidol also up-regulated ErbB4 levels in the prefrontal cortex (PFC). In the 12-week group, aripiprazole decreased the expression of all three NRG1 isoforms and ErbB4 receptors in the PFC, NRG1-70 kDa and -40 kDa in the cingulate cortex (Cg), and NRG1-135 kDa, -70 kDa and ErbB4 receptors in the hippocampus; haloperidol reduced NRG1-135 kDa in the PFC, NRG1-40 kDa in all three brain regions, and ErbB4 receptor levels in the PFC and hippocampus; NRG1-40 kDa in the PFC and Cg was also down-regulated by olanzapine. These results suggest that the time-dependent and region-specific effects of antipsychotics on NRG1-ErbB4 signalling may contribute to the efficacy of antipsychotics to treat schizophrenia. [ABSTRACT FROM AUTHOR]

The metabolic side-effects of olanzapine have undermined drug compliance and increased concern for this otherwise-effective treatment for schizophrenia. As obesity and type 2 diabetes are associated with low-grade inflammation, and olanzapine-induced weight gain has three typical stages, the current study investigated the inflammatory effects of olanzapine in three treatment stages. Female Sprague-Dawley rats were treated orally with olanzapine (1 mg/kg three times daily) or vehicle for one week, two weeks, and five weeks. Olanzapine significantly increased body weight and white visceral fat deposition in all three treatment stages compared to control. Olanzapine enhanced average adipocyte size and level of macrophage infiltration in white adipose tissue (WAT) compared to control, with levels of macrophage infiltration increased over time. There was a high correlation between adipocyte size and macrophage infiltration rate. Olanzapine also caused increased macrophage infiltration in brown adipose tissue (BAT), but not liver. Additionally, pro-inflammatory cytokines tumor necrosis factor α (TNFα), interleukin (IL)-1β, and IL-6 were upregulated by olanzapine in the hypothalamus, WAT, and BAT compared to control, but not the liver. Finally, plasma triglycerides were elevated by olanzapine compared to control, but not total cholesterol, high density lipoprotein (HDL) or low density lipoprotein (LDL). These findings indicate that olanzapine-induced inflammation and adiposity are closely related, and that peripheral low-grade inflammation develops during olanzapine treatment. [ABSTRACT FROM PUBLISHER]

Abstract: Background: The present study aims to examine the expression patterns and roles of nucleolin during the recovery of heat-denatured human umbilical vein endothelial cells (HUVECs). Methods: Deep partial thickness burn model in Sprague–Dawley rats and the heat denatured cell model (52°C, 35s) were used. The expression of nucleolin was measured using Western blot analysis and real-time PCR. Angiogenesis was assessed using in vitro parameters including endothelial cell proliferation, transwell migration assay, and scratched wound healing. Gene transfection and RNA interference approaches were employed to investigate the roles of nucleolin. Results: Nucleolin mRNA and protein expression showed a time-dependent increase during the recovery of heat-denatured dermis and HUVECs. Heat-denaturation time-dependently promoted cell growth, adhesion, migration, scratched wound healing and formation of tube-like structures in HUVECs. These effects of heat denaturation on endothelial wound healing and formation of tube-like structures were prevented by knockdown of nucleolin, whereas over-expression of nucleolin increased cell growth, migration, and formation of tube-like structures in cultured HUVEC endothelial cells. In addition, we found that the expression of vascular endothelial growth factor (VEGF) increased during the recovery of heat-denatured dermis and HUVECs, and nucleolin up-regulated VEGF in HUVECs. Conclusions: The present study reveals that the expression of nucleolin is up-regulated, and plays a pro-angiogenic role during the recovery of heat-denatured dermis and its mechanism is probably dependent on production of VEGF. General significance: We find a novel and important pro-angiogenic role of nucleolin during the recovery of heat-denatured dermis. [Copyright &y& Elsevier]

Abstract: Tyrosine hydroxylase is the rate-limiting enzyme in the synthesis of dopamine, a key neurotransmitter in the regulation of food intake. This study examined tyrosine hydroxylase mRNA expression in obese mice fed a high-fat diet. After 8 week feeding of high-fat diet mice were classified as diet-induced obese and obese-resistant according to body weight gain. They were then placed on different dietary interventions including a high-fat diet, a low-fat diet and an energy-restricted high-fat diet for six weeks. The control group was fed a low-fat diet. The results revealed that tyrosine hydroxylase mRNA expression was significantly decreased in the ventral tegmental area (VTA), ventromedial hypothalamic nucleus (VMH), and substantia nigra (SN) of the high-fat diet-induced obese (−29%, −26% and −26%) and obese-resistant mice (−21%, −24% and −18%) compared to controls. After switching the diet from high to low-fat diet tyrosine hydroxylase mRNA was increased in the VTA, VMH, and SN of the diet-induced obese mice and in the VMH, and SN of the obese-resistant mice. Energy restriction, even with high-fat feeding, reduced tyrosine hydroxylase mRNA expression in the VTA, VMH, and SN compared to controls. In addition, tyrosine hydroxylase mRNA expression in the VTA, VMH, and SN showed a significant negative correlation with plasma leptin levels. This study suggests that the up- or down-regulation of tyrosine hydroxylase mRNA expression in the VTA, VMH, and SN is mainly due to the intake of macronutrient type rather than body weight. [Copyright &y& Elsevier]

This study examined how perinatal phencyclidine (PCP) treatment would affect dopamine D receptor and dopamine transporter (DAT) binding at different stages after treatment cessation. Female rat pups received injections of PCP (10 mg/kg, s.c.) or saline on postnatal day (PN)7, 9 and 11. D receptor and transporter binding was examined at four time-points (PN12, 18, 32 and 96) following injections. PCP treatment altered D receptor binding throughout development, with a final end-point of 22-33% decreased binding at adulthood in the nucleus accumbens and caudate putamen ( P < 0.01), accompanied by a small but significant increase in DAT binding in the caudate putamen. Tyrosine hydroxylase mRNA expression was also significantly increased by 25% ( P < 0.05) in the ventral tegmental area of adult rats, suggesting that this model may produce a long-term increase in dopamine output. This study demonstrates that early insult to the brain from NMDA receptor hypofunction alters the dopaminergic system at different stages of development. [ABSTRACT FROM AUTHOR]

Mesangioproliferative glomerulonephritis (MPGN) is a disease of high incidence in humans. Rat Thy-1 nephritis (Thy-1 N), namely, anti-thymocyte serum (ATS)-induced nephritis, is considered to be an animal model for studying MPGN. Although previous studies have demonstrated that glomerular mesangial cell (GMCs) injury might be a feature of Thy-1 N, the mechanism of the disease (i.e., GMC apoptosis) remains unclear. We have examined the pathologic changes of GMCs and the gene expression profile of renal tissues in Thy-1 N. The pathologic changes of Thy-1 N include three phages: GMC apoptosis (40 min), necrosis (2 h), and proliferation (5 days). Many TUNEL-positive cells are found 40 min after administration of ATS. Concomitantly, 341 genes are up-regulated, whereas 392 genes are down-regulated, as shown by microarrays analysis. The mRNA and protein of two of the up-regulated genes (nerve growth factor induced protein I-B, NGFI-B; growth arrest- and DNA-damage-inducible protein 45 gamma, Gadd 45 γ) in the GMC apoptotic phase of Thy-1 N are markedly elevated, as observed by real-time polymerase chain reaction and immunohistochemistry. Our data indicate that pathologic changes of Thy-1 N are involved in the abnormal gene profile. The overexpression of the NGFI-B and Gadd 45 γ genes may be associated with GMC apoptosis of Thy-1 N. [ABSTRACT FROM AUTHOR]

Summary The reduction in the red to far-red light ratio (R/FR) and photosynthetically active radiation caused by dense planting initiates shade avoidance responses (SARs) to help plants compete against their neighbors. However, deep shade attenuates shade-induced stem elongation to suppress excessive reversion toward skotomorphogenic development, in which photoreceptor phytochrome A (PHYA) has been known to play the major role. However, the molecular mechanism underlying PHYA function in deep shade is poorly understood. Here, we report that shade-accumulated PHYA can release auxin/indole-3-acetic acid (AUX/IAA), suppressors in the auxin signaling pathway, from SCF TIR1 , an auxin receptor, to weaken auxin signaling and negatively regulate shade response. Corroborating this, phyA mutants display an enhanced auxin response to deep shade and auxin treatment. Specifically, PHYA competes with TIR1 by directly binding and stabilizing AUX/IAA. Our findings illustrate a mechanistic model of how plants sense different shade levels to fine-tune auxin signaling and generate appropriate SAR. [ABSTRACT FROM AUTHOR]