Search

Stenus absconditus Hu & Tang, 2018 was published in our recent paper, and latter Dr. Alfred Francis Newton kindly informed us that the name was preoccupied by Stenus absconditus Puthz 2017. After confirming the information, we propose a new replacement name for this species.

Phosphatidylinositol-4,5-bisphosphate 3-kinases (PI3Ks) regulate several important cellular and subcellular processes including cell proliferation and differentiation. LY294002 was originally reported to be a selective inhibitor of PI3K-Akt. Later, it showed that this compound also inhibits several other molecules. In this study, we investigated the effect of LY294002 on the growth of suspension (MV4-11 and TF-1a) and tissue (Hep-G2) cells. In exponential phase, MV4-11 cells, but not TF-1a and Hep-G2 cells, expressed a low level of PI3Kp85 and addition of LY294002 inhibited the phosphorylation of PI3Kp85. LY294002 also significantly inhibited the proliferation of MV4-11, TF-1a and Hep-G2 cell and caused formation of cell clusters/aggregates measured by MTT and BrdU assays, and observed under an inverted microscope, respectively. Surprisingly, we found that LY294002 markedly repressed the activation of mitogen-activated protein kinase (MAPK) signal molecules, MEK and ERK, in all these cells. The inhibition of MEK and ERK was confirmed by using MEK stimulators, GM-CSF and phorbol 12-myristate 13-acetate, and MEK-specific inhibitor, PD98059. Although transforming growth factor beta (TGFβ) also inhibited the growth of Hep-G2 cells, it had no effect on the activity of MEK and ERK. The clusters/aggregates found in LY294002-treated cells were not detectable in TGFβ-treated cells. Our data suggest that LY294002 may directly inhibit the activation of MEK and ERK by its ability to bind to the ATP-binding site of the MAPK molecules.

Summary: Impaired interhemispheric connectivity is commonly found in various psychiatric disorders, although how interhemispheric connectivity regulates brain function remains elusive. Here, we use the mouse amygdala, a brain region that is critical for social interaction and fear memory, as a model to demonstrate that contralateral connectivity intensifies the synaptic response of basolateral amygdalae (BLA) and regulates amygdala-dependent behaviors. Retrograde tracing and c-FOS expression indicate that contralateral afferents widely innervate BLA non-randomly and that some BLA neurons innervate both contralateral BLA and the ipsilateral central amygdala (CeA). Our optogenetic and electrophysiological studies further suggest that contralateral BLA input results in the synaptic facilitation of BLA neurons, thereby intensifying the responses to cortical and thalamic stimulations. Finally, pharmacological inhibition and chemogenetic disconnection demonstrate that BLA contralateral facilitation is required for social interaction and memory. Our study suggests that interhemispheric connectivity potentiates the synaptic dynamics of BLA neurons and is critical for the full activation and functionality of amygdalae. : Huang et al. show that contralateral innervation between two basolateral amygdalae (BLA) in the two brain hemispheres evokes the synaptic activity of BLA and intensifies the BLA response to ipsilateral afferents, including cortical and thalamic inputs. BLA contralateral connectivity is required for amygdala-dependent behaviors, including social interaction and memory. Keywords: amygdala, anterior commissure, associative memory, contralateral innervation, social interaction, synaptic facilitation

Background Dendritic spines, the actin-rich protrusions emerging from dendrites, are the subcellular locations of excitatory synapses in the mammalian brain. Many actin-regulating molecules modulate dendritic spine morphology. Since dendritic spines are neuron-specific structures, it is reasonable to speculate that neuron-specific or -predominant factors are involved in dendritic spine formation. KLHL17 (Kelch-like 17, also known as Actinfilin), an actin-binding protein, is predominantly expressed in brain. Human genetic study has indicated an association of KLHL17/Actinfilin with infantile spasms, a rare form of childhood epilepsy also resulting in autism and mental retardation, indicating that KLHL17/Actinfilin plays a role in neuronal function. However, it remains elusive if and how KLHL17/Actinfilin regulates neuronal development and brain function. Methods Fluorescent immunostaining and electrophysiological recording were performed to evaluate dendritic spine formation and activity in cultured hippocampal neurons. Knockdown and knockout of KLHL17/Actinfilin and expression of truncated fragments of KLHL17/Actinfilin were conducted to investigate the function of KLHL17/Actinfilin in neurons. Mouse behavioral assays were used to evaluate the role of KLHL17/Actinfilin in brain function. Results We found that KLHL17/Actinfilin tends to form circular puncta in dendritic spines and are surrounded by or adjacent to F-actin. Klhl17 deficiency impairs F-actin enrichment at dendritic spines. Knockdown and knockout of KLHL17/Actinfilin specifically impair dendritic spine enlargement, but not the density or length of dendritic spines. Both N-terminal Broad-Complex, Tramtrack and Bric-a-brac (BTB) domain and C-terminal Kelch domains of KLHL17/Actinfilin are required for F-actin remodeling and enrichment at dendritic spines, as well as dendritic spine enlargement. A reduction of postsynaptic and presynsptic markers at dendritic spines and altered mEPSC profiles due to Klhl17 deficiency evidence impaired synaptic activity in Klhl17-deficient neurons. Our behavioral assays further indicate that Klhl17 deficiency results in hyperactivity and reduced social interaction, strengthening evidence for the physiological role of KLHL17/Actinfilin. Conclusion Our findings provide evidence that KLHL17/Actinfilin modulates F-actin remodeling and contributes to regulation of neuronal morphogenesis, maturation and activity, which is likely relevant to behavioral impairment in Klhl17-deficient mice. Trial registration Non-applicable.

Summary Neurofibromatosis type 1 (NF1) is a dominant genetic disorder manifesting, in part, as cognitive defects. Previous study indicated that neurofibromin (NF1 protein) interacts with valosin-containing protein (VCP)/P97 to control dendritic spine formation, but the mechanism is unknown. Here, using Nf1+/– mice and transgenic mice overexpressing wild-type Vcp/p97, we demonstrate that neurofibromin acts with VCP to control endoplasmic reticulum (ER) formation and consequent protein synthesis and regulates dendritic spine formation, thereby modulating contextual fear memory and social interaction. To validate the role of protein synthesis, we perform leucine supplementation in vitro and in vivo. Our results suggest that leucine can effectively enter the brain and increase protein synthesis and dendritic spine density of Nf1+/– neurons. Contextual memory and social behavior of Nf1+/– mice are also restored by leucine supplementation. Our study suggests that the “ER-protein synthesis” pathway downstream of neurofibromin and VCP is a critical regulator of dendritic spinogenesis and brain function.

Functional synapse formation requires tight coordination between pre- and post-synaptic termini. Previous studies have shown that postsynaptic expression of heparan sulfate proteoglycan syndecan-2 (SDC2) induces dendritic spinogenesis. Those SDC2-induced dendritic spines are frequently associated with presynaptic termini. However, how postsynaptic SDC2 accelerates maturation of corresponding presynaptic termini is unknown. Because fibroblast growth factor 22 (FGF22), a heparan sulfate binding growth factor, has been shown to act as a presynaptic organizer released from the postsynaptic site, it seems possible that postsynaptic SDC2 presents FGF22 to the presynaptic FGF receptor to promote presynaptic differentiation. Here, we show that postsynaptic SDC2 uses its ectodomain to interact with and facilitate dendritic filopodial targeting of FGF22, triggering presynaptic maturation. Since SDC2 also enhances filopodial targeting of NMDAR via interaction with the CASK-mLIN7-MINT1 adaptor complex, presynaptic maturation promoted by FGF22 further feeds back to activate NMDAR at corresponding postsynaptic sites through increased neurotransmitter release and, consequently, promotes the dendritic filopodia-spines (F-S) transition. Meanwhile, via regulation of the KIF17 motor, CaMKII (activated by the NMDAR pathway) may further facilitate FGF22 targeting to dendritic filopodia that receive presynaptic stimulation. Our study suggests a positive feedback that promotes the coordination of postsynaptic and presynaptic differentiation.

Tie2 is an endothelial receptor tyrosine kinase. An amino-acid substitution of tryptophan for arginine at residue 849 (Tie2-R849W) leads to a ligand-independent activation of its kinase activity. This mutation has been associated with familial venous malformations (VMs), manifested by variable thickness or lack of smooth-muscle cells in the veins of patient lesions. The underlying mechanism for Tie2-R849W action in endothelial cells remains elusive. In this study, we used adenoviral infection to differentiate the effects of ectopic Tie2 (wild type, kinase-dead K855A, or constitutively active R849W) expression on endothelial cellular behaviors and Tie2-mediated downstream targets. Ectopic Tie2 reduced endothelial cell proliferation and serum withdrawal-induced apoptosis, while stimulating migration. When comparing R849W with K855A and its wild-type counterpart, a functional tyrosine kinase activity was required only for migration, and constitutively active Tie2-R849W conferred highest resistance to serum-induced apoptosis, but lowest ability to maintain tube-like structures formed on Matrigel. We further demonstrated that Tie2-R849W chronically induced STAT1 tyrosine phosphorylation and the promoter activity of STAT1-responsive IFN-regulatory factor 1 (IRF1). Although STAT1 phosphorylation required JNK and p38MAPK activation, only JNK activation was essential for IRF1 promoter activation by Tie2-R849W. Additional studies are needed to study the role of STAT1 activation in VMs.

TGFbeta is well known for its inhibitory effect on cell cycle G1 checkpoint kinases. However, its role in the control of pRb-E2F complexes is not well established. TGFbeta inhibits phosphorylation of pRb at several serine and threonine residues and regulates the association of E2F transcription factors with pRb family proteins. Recent studies found that predominantly E2F-4, p130, and histone deacetylase (HDAC) are found to bind to corresponding E2F-responsive promoters in G0/G1 phase. As cells progress through mid-G1, p130-E2F4 complex are replaced by p107-E2F4 followed by activators E2F1, 2, and 3. pRb was not detectable in the promoters containing the E2F-responsive site in cycling cells but was associated with E2F4-p130 complexes or E2F4-p107 complexes during G0/G1 phase. In human myeloid leukemia cell line, MV4-11, TGFbeta upregulated pRb-E2F-4 and p130-E2F-4, and downregulated p107-E2F-4 complexes. However, pRB-E2F1 and pRb-E2F3 complexes were found in proliferating cells but not in TGFbeta arrested G1 cells. In addition, electrophoretic gel mobility shift assay (EMSA) could not detect pRb-E2F DNA-binding activities either in S or G1 phase but exhibited the existence of p107-E2F4 in proliferating cells and p130-E2F4 complexes in TGFbeta-arrested G1 cells, respectively. Our data suggest that p107 and p130, but not pRb, and the repressor E2F, but not activator E2Fs, play a critical role in regulating E2F-responsive gene expression in TGFbeta-mediated cell cycle control in human myeloid leukemia cells.

Innate immune responses have been shown to influence brain development and function. Dysregulation of innate immunity is significantly associated with psychiatric disorders such as autism spectrum disorders and schizophrenia, which are well-known neurodevelopmental disorders. Recent studies have revealed that critical players of the innate immune response are expressed in neuronal tissues and regulate neuronal function and activity. For example, Sarm1, a negative regulator that acts downstream of Toll-like receptor (TLR) 3 and 4, is predominantly expressed in neurons. We have previously shown that Sarm1 regulates neuronal morphogenesis and the expression of inflammatory cytokines in the brain, which then affects learning ability, cognitive flexibility, and social interaction. Because impaired neuronal morphogenesis and dysregulation of cytokine expression may disrupt neuronal activity, we investigated whether Sarm1 knockdown affects the synaptic responses of neurons. We here show that reduced Sarm1 expression impairs metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) formation but enhances N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation production in hippocampal CA1 neurons. The expression levels of post-synaptic proteins, including NR2a, NR1, Shank1 and Shank3, are also altered in Sarm1 knockdown mice, suggesting a role for Sarm1 in the maintenance of synaptic homeostasis. The addition of a positive allosteric modulator of mGluR5, CDPPB, ameliorates the LTD defects in slice recording and the behavioral deficits in social interaction and associative memory. These results suggest an important role for mGluR5 signaling in the function of Sarm1. In conclusion, our study demonstrates a role for Sarm1 in the regulation of synaptic plasticity. Through these mechanisms, Sarm1 knockdown results in the impairment of associative memory and social interactions in mice.

Hematopoiesis is the formation and development of blood cells. In a healthy adult person, approximately 1011–1012 new blood cells are produced daily in order to maintain steady state levels in the peripheral circulation. Disruption of the steady state may cause the development of hematological diseases, such as acute (AML) or chronic myelogenous leukemia (CML). All mature blood cells ultimately originate from a rare population of primitive pluripotent (multipotential) stem cells. The pluripotent stem cells possess selfrenewal and multi-lineage differentiation potential. The latter process leads to two major multipotent progenitors: myeloid progenitors and lymphoid progenitors. The myeloid progenitors have the ability to differentiate into mature white cells, erythrocytes, megakaryocytes/platelets and mast cells; whereas the lymphoid progenitors cells mainly produce mature T, NK, and B lymphocytes. Production of myeloid lineage cells is a highly complex process involving the balance between cell proliferation and differentiation, which is regulated by growth stimulating or inhibiting signals. Transforming Growth Factor-beta (TGF┚) is a pleiotropic growth factor and is one of the major regulators of hematopoiesis (Fortunel NO et al. 2000). A major effect of TGF┚ on hematopoietic cells is inhibitory (Hu X et al 1999, Batard P et al. 2000, Ducos K et al. 2000, Fortunel NO 2000) although its stimulatory effect has also been observed in some types of blood cells (Keller JR 1990, 1992). Due to its importance in the understanding human diseases including leukemia, over past 20 years, the mechanisms responsible for TGF┚-induced growth inhibition or stimulation have been a major area of investigation and considerable insights into its action mechanisms have been learned. This review highlights recent progress in understanding regulatory role of TGF┚ and its signaling pathways in various types of cells with a focus on human myeloid leukemia cells.

The purpose of the study was to assess the impact of CYP2C19 genotypes, CYP3A phenotypes and gender-related difference on the pharmacokinetics of new proton pump inhibitor ilaprazole. Twenty-four healthy Chinese volunteers (age 24.0  1.9 years) were enrolled in an open-label study stratified for gender (12 males and 12 females) and their CYP2C19 genotype (12 of CYP2C19*1/*1 and 12 of CYP2C19*1/*2 or *1/*3). After a single 10-mg dose of ilaprazole was administrated, blood samples were collected at time 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36h from all subjects. Ilaprazole and its metabolite sulfone-ilaprazole plasma concentrations were measured using the well-validated HPLC/MS/MS method. CYP3A phenotype was determined by the classic CYP3A probe drug midazolam one week after the clinical trial. The kinetics characteristics of ilaprazole and sulfone-ilaprazole were significantly influenced by gender. The clearance/systemic bioavailability (CL/F) of ilaprazole was much lower in female than in male (2.5  1.0 versus 3.7  1.6 h-1, P = 0.029), difference became more significant even after corrected by body weight (P = 0.008). However, the differences on half-life, AUC0-36 and AUC0→∞ of ilaprazole between genders were not significantly after normalized by body weight. As for sulfone ilaprazole, larger AUC0→36 and AUC0→∞ were detected in female when compared with male (406.8  126.3 vs. 246.7  70.0 ng • h/ml, P = 0.007, and 606.7  224.5 vs. 332.0  117.1 ng • h/ml, P = 0.001), discrepancies were still significant after corrected by total body weight, P value were 0.017 and 0.010 respectively. The pharmacokinetics parameters of ilaprazole and ilaprazole sulfone were neither different across CYP2C19 genotype groups nor related to CYP3A phenotype. CL/F of ilaprazole were much smaller in women than in men even after adjusted by body weight, indicating great effect of gender on the pharmacokinetics of ilaprazole. CYP2C19 genotypes and CYP3A phenotypes did not affect the pharmacokinetics of ilaprazole or sulfone-ilaprazole.

Machado–Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant spinocerebellar degeneration characterized by a wide range of clinical manifestations. The molecular mechanisms underlying the selective neuronal death typical of MJD/SCA3 are unknown. In this study, human SK-N-SH neuroblastoma cells stably transfected with full-length MJD with 78 CAG repeats were assayed for the dynamic expression of Hsp27, known as a suppressor of poly-Q mediated cell death, in the presence of mutant ataxin-3 in different passages of cultured cells. A dramatic decrease of Hsp27 expression was observed in the earlier passage of cultured SK-N-SH-MJD78 cells, however, the later passage of cells showed a significant increase of Hsp27 to almost the same level of the parental cells. Furthermore, immunohistochemical analysis of MJD transgenic mice and post-mortem human brain tissues showed increased expression of Hsp27 compared to normal control brain, suggesting an up-regulation of Hsp27 in the end stage of MJD. However, mutant cells of earlier passages were more susceptible to serum deprivation than mutant cells of later passages, indicating weak tolerance toward stress in cells with reduced Hsp27. While heat shock was used to assess the stress response, cells expressing mutant ataxin-3 displayed normal response upon heat shock stimuli when compared to the parental cells. Taken together, we proposed that during the early disease stage, the reduction of Hsp27 synthesis mitigated the ability of neuron cells to cope with cytotoxicity induced by mutant ataxin-3, triggering the cell death process during the disease progress. In the late stage of disease, after prolonged stressful conditions of polyglutamine cytotoxicity, the increased level of Hsp27 may reflect a dynamic process of the survived cells to unfold and remove mutant ataxin-3. However, this increased Hsp27 still cannot reverse the global dysfunction of cellular proteins due to accumulation of cytotoxic effects.

In the present study, the combined effect of organic materials and lime on cadmium uptake by ryegrass (Lolium multiflorum Lam.) was investigated in three cadmium polluted acid soils with different cadmium concentrations. Two sources of organic materials, peat and compost, with three levels (0, 2.5 and 5%) and four levels (0, 2, 4 and 6g CaCO3 kg-1 soil) of lime were designed. The cadmium content in the shoot of ryegrass decreased with increasing level of lime or organic materials in each treatment. Compost had a better effect on reducing cadmium uptake than did peat, partially resulting from higher pH of the former (7.47) than the latter (5.03). At the same lime level, Cd content in the shoot was reduced more by joint application with compost or peat compared to lime alone. These results suggest that application of organic materials combined with higher rate of lime is more effective in decreasing Cd uptake.

Globally, hepatocellular carcinoma (HCC) accounts for 70-85% of primary liver cancers and ranks second in the leading cause of male cancer death. Serum alpha-fetoprotein (AFP), normally highly expressed in the liver only during fetal development, is reactivated in 60% of HCC tumors and associated with poor patient outcome. We hypothesize that AFP+ and AFP- tumors differ biologically. Using microarray-based global microRNA profiling in 223 HCC patients, we found that members of the miR-29 family were the most significantly (p Citation Format: Sonya T. Parpart, Stephanie Roessler, Fei Dong, Vinay Rao, Junfang Ji, Lun–Xiu Qin, Qing–Hai Ye, Zhao–You Tang, Hu–Liang Jia, Xin Wei Wang. Modulation of miR-29 expression by alpha-fetoprotein is linked to the hepatocellular carcinoma epigenome. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5183. doi:10.1158/1538-7445.AM2014-5183