Time lag between the increase of IL-6 with fever and NF-kappaB activation in the peripheral blood in inflammatory myofibroblastic tumor

We describe a case of inflammatory myofibroblastic tumor (IMT) that occurred in the retroperitoneum. The patient manifested systemic symptoms, such as intermittent fever, anemia, thrombocytosis, and hypergammaglobulinemia. In order to elucidate the mechanism of intermittent fever in IMT, we analyzed nuclear factor-kappa B (NF-kappaB) activation in peripheral blood mononuclear cells (PBMCs) using flow cytometry, and serum cytokine levels. NF-kappaB activation was observed in the peripheral blood T cells and monocytes/macrophages. Among the measured cytokines, only interleukin (IL)-6 levels were elevated. IL-6 levels during pyrexia in the afternoon were higher than those during apyrexia in the morning. In contrast to IL-6, NF-kappaB activation in PBMCs was lower during pyrexia than during apyrexia; this is considered to be because the activation is subject to negative feedback. The time lag between the increase of IL-6 in the serum and NF-kappaB activation in the PBMCs at the onset of intermittent fever in IMT may provide further insight into the role of cytokines and NF-kappaB activation in febrile inflammatory diseases.     

Muscle architecture of the upper limb in the orangutan

We dissected the left upper limb of a female orangutan and systematically recorded muscle mass, fascicle length, and physiological cross-sectional area (PCSA), in order to quantitatively clarify the unique muscle architecture of the upper limb of the orangutan. Comparisons of the musculature of the dissected orangutan with corresponding published chimpanzee data demonstrated that in the orangutan, the elbow flexors, notably M. brachioradialis, tend to exhibit greater PCSAs. Moreover, the digital II-V flexors in the forearm, such as M. flexor digitorum superficialis and M. flexor digitorum profundus, tend to have smaller PCSA as a result of their relatively longer fascicles. Thus, in the orangutan, the elbow flexors demonstrate a higher potential for force production, whereas the forearm muscles allow a greater range of wrist joint mobility. The differences in the force-generating capacity in the upper limb muscles of the two species might reflect functional specialization of muscle architecture in the upper limb of the orangutan for living in arboreal environments.     

Particle inflow gun-mediated transformation of multiple-shoot clumps in rhodes grass (Chloris gayana)

Rhodes grass (Chloris gayana) is one of the most important warm-season forage grasses. It is cultivated in tropical and subtropical parts of the world and is mostly used for grazing and hay production. We have established a particle-bombardment transformation protocol for rhodes grass using multiple-shoot clumps (MSCs) as the target tissue. A vector pAHC25 containing a herbicide-resistance gene (bar) together with the beta-glucuronidase (GUS) gene was used in transformation experiments. The most efficient recovery of bialaphos-resistant tissue was achieved when the bombarded MSCs were first cultured for 15 d on bialaphos-free medium before being subjected to selection pressure. The resistant tissues regenerated transgenic plants that displayed GUS gene expression. Under optimized conditions, 251 target pieces yielded 46 transgenic plants from 4 independent transgenic lines.     

Cholestatic liver fibrosis and toxin-induced fibrosis are exacerbated in matrix metalloproteinase-2 deficient mice

Matrix metalloproteinase (MMP) plays an important role in homeostatic regulation of the extracellular environment and degradation of matrix. During liver fibrosis, several MMPs, including MMP-2, are up-regulated in activated hepatic stellate cells, which are responsible for exacerbation of liver cirrhosis. However, it remains unclear how loss of MMP-2 influences molecular dynamics associated with fibrogenesis in the liver. To explore the role of MMP-2 in hepatic fibrogenesis, we employed two fibrosis models in mice; toxin (carbon tetrachloride, CCl4)-induced and cholestasis-induced fibrosis. In the chronic CCl4 administration model, MMP-2 deficient mice exhibited extensive liver fibrosis as compared with wild-type mice. Several molecules related to activation of hepatic stellate cells were up-regulated in MMP-2 deficient liver, suggesting that myofibroblastic change of hepatic stellate cells was promoted in MMP-2 deficient liver. In the cholestasis model, fibrosis in MMP-2 deficient liver was also accelerated as compared with wild type liver. Production of tissue inhibitor of metalloproteinase 1 increased in MMP-2 deficient liver in both models, while transforming growth factor β, platelet-derived growth factor receptor and MMP-14 were up-regulated only in the CCl4 model. Our study demonstrated, using 2 experimental murine models, that loss of MMP-2 exacerbates liver fibrosis, and suggested that MMP-2 suppresses tissue inhibitor of metalloproteinase 1 up-regulation during liver fibrosis.     

Structural basis of species differences between human and experimental animal CYP1A1s in metabolism of 3,3',4,4',5-pentachlorobiphenyl

Coplanar polychlorinated biphenyls included in dioxin-like compounds are bio-accumulated and adversely affect wildlife and human health. Although many researchers have studied the metabolism of PCBs, there have been few reports of the in vitro metabolism of 3,3',4,4',5-pentachlorobiphenyl (PCB126), despite the fact that it has the highest toxicity among PCB congeners. Cytochrome P450 (CYP) 1A1 proteins can metabolize some dioxins and PCBs by hydroxylation, but the activities of human and rat CYP1A1 proteins are very different. The mechanism remains unclear. From our results, rat CYP1A1 metabolized PCB126 into 4-OH-3,3',4',5-tetrachlorobiphenyl and 4-OH-3,3',4',5,5'-pentachlorobiphenyl, but human CYP1A1 did not metabolize. Homology models of the two CYP proteins, and docking studies, showed that differences in the amino acid residues forming their substrate-binding cavities led to differences in the size and shape of the cavities; only the cavity of rat CYP1A1 allowed PCB126 close enough to the haem to be metabolized. Comparison of the amino acid residues of other mammalian CYP1A1 proteins suggested that rats have a unique metabolism of xenobiotics. Our results suggest that it is necessary to be careful in human extrapolation of toxicity data estimated by using the rat as an experimental animal, especially in the case of compounds metabolized by CYP1A1.     

From snoRNA to miRNA: Dual function regulatory non-coding RNAs

Small nucleolar RNAs (snoRNAs) are an ancient class of small non-coding RNAs present in all eukaryotes and a subset of archaea that carry out a fundamental role in the modification and processing of ribosomal RNA. In recent years, however, a large proportion of snoRNAs have been found to be further processed into smaller molecules, some of which display different functionality. In parallel, several studies have uncovered extensive similarities between snoRNAs and other types of small non-coding RNAs, and in particular microRNAs. Here, we explore the extent of the relationship between these types of non-coding RNA and the possible underlying evolutionary forces that shaped this subset of the current non-coding RNA landscape.     

Hypoxia-Inducible Factor 1 Regulation through Cross Talk between mTOR and MT1-MMP

Hypoxia-inducible factor 1 (HIF-1) plays a key role in the cellular adaptation to hypoxia. Although HIF-1 is usually strongly suppressed by posttranslational mechanisms during normoxia, HIF-1 is active and enhances tumorigenicity in malignant tumor cells that express the membrane protease MT1-MMP. The cytoplasmic tail of MT1-MMP, which can bind a HIF-1 suppressor protein called factor inhibiting HIF-1 (FIH-1), promotes inhibition of FIH-1 by Mint3 during normoxia. To explore possible links between HIF-1 activation by MT1-MMP/Mint3 and tumor growth signals, we surveyed a panel of 252 signaling inhibitors. The mTOR inhibitor rapamycin was identified as a possible modulator, and it inhibited the mTOR-dependent phosphorylation of Mint3 that is required for FIH-1 inhibition. A mutant Mint3 protein that cannot be phosphorylated exhibited a reduced ability to inhibit FIH-1 and promoted tumor formation in mice. These data suggest a novel molecular link between the important hub proteins MT1-MMP and mTOR that contributes to tumor malignancy.     

Neural correlates of body comparison and weight estimation in weight-recovered anorexia nervosa: a functional magnetic resonance imaging study

Background

The neural mechanisms underlying body dissatisfaction and emotional problems evoked by social comparisons in patients with anorexia nervosa (AN) are currently unclear. Here, we elucidate patterns of brain activation among recovered patients with AN (recAN) during body comparison and weight estimation with functional magnetic resonance imaging (fMRI).

Methods

We used fMRI to examine 12 patients with recAN and 13 healthy controls while they performed body comparison and weight estimation tasks with images of underweight, healthy weight, and overweight female bodies. In the body comparison task, participants rated their anxiety levels while comparing their own body with the presented image. In the weight estimation task, participants estimated the weight of the body in the presented image. We used between-group region of interest (ROI) analyses of the blood oxygen level dependent (BOLD) signal to analyze differences in brain activation patterns between the groups. In addition, to investigate activation outside predetermined ROIs, we performed an exploratory whole-brain analysis to identify group differences.

Results

We found that, compared to healthy controls, patients with recAN exhibited significantly greater activation in the pregenual anterior cingulate cortex (pgACC) when comparing their own bodies with images of underweight female bodies. In addition, we found that, compared with healthy controls, patients with recAN exhibited significantly smaller activation in the middle temporal gyrus corresponding to the extrastriate body area (EBA) when comparing their own bodies, irrespective of weight, during self-other comparisons of body shape.

Conclusions

Our findings from a group of patients with recAN suggest that the pathology of AN may lie in an inability to regulate negative affect in response to body images via pgACC activation during body comparisons. The findings also suggest that altered body image processing in the brain persists even after recovery from AN.

     

Neurotrophins and the primate central nervous system: A minireview

The central nervous system (CNS) of primates is more complex than the CNS of other mammals. Details of the development and aging of the primate CNS have recently been revealed by various neurobiological techniques. It has become clear that the primate CNS has unique characteristics, for example, the capacity for the overproduction and elimination of fibers and synapses. Some differences have also been found in the distribution of and changes with development in levels of various neuroactive substances. Recent discoveries of a variety of neurotrophins in the mammalian CNS have led to research on the neurobiology of these molecules in the primate CNS. The distribution of and changes with development in levels of nerve growth factor (NGF) in the primate CNS are closely correlated with the cholinergic system of the basal forebrain. The administration of NGF into the monkey brain prevents the degeneration of the cholinergic neurons of the basal forebrain after axotomy, a result that suggests that neurotrophins might be very valuable agents for the future treatment of neurological diseases, such as Alzheimer's and Parkinson's diseases. This review is dedicted to Dr. Hans Thoenen.     

Differentiation of rat adipose tissue-derived stem cells into neuron-like cells by valproic acid,a histone deacetylase inhibitor

Valproic acid (VPA) is a widely used antiepileptic drug, which has recently been reported to modulate the neuronal differentiation of adipose tissue-derived stem cells (ASCs) in humans and dogs. However, controversy exists as to whether VPA really acts as an inducer of neuronal differentiation of ASCs. The present study aimed to elucidate the effect of VPA in neuronal differentiation of rat ASCs. One or three days of pretreatment with VPA (2 mM) followed by neuronal induction enhanced the ratio of immature neuron marker βIII-tubulin-positive cells in a time-dependent manner, where the majority of cells also had a positive signal for neurofilament medium polypeptide (NEFM), a mature neuron marker. RT-PCR analysis revealed increases in the mRNA expression of microtubule-associated protein 2 (MAP2) and NEFM mature neuron markers, even without neuronal induction. Three-days pretreatment of VPA increased acetylation of histone H3 of ASCs as revealed by immunofluorescence staining. Chromatin immunoprecipitation assay also showed that the status of histone acetylation at H3K9 correlated with the gene expression of TUBB3 in ASCs by VPA. These results indicate that VPA significantly promotes the differentiation of rat ASCs into neuron-like cells through acetylation of histone H3, which suggests that VPA may serve as a useful tool for producing transplantable cells for future applications in clinical treatments.