Activation Of Beta Research Articles

Contact allergen (PPD and DNCB)-induced keratinocyte sensitization is partly mediated through a low molecular weight hyaluronan (LMWHA)/TLR4/NF-κB signaling axis

Allergic contact dermatitis (ACD) is caused by topical exposure to chemical allergens. Keratinocytes play a key role in innate immunity, as well as in ACD progression. The transmembrane Toll-like receptor 4 (TLR4), strongly implicated in skin inflammation, has the ability to bind Damage Associated Molecular Patterns (DAMPs), like Low Molecular Weight Hyaluronan (LMWHA). Previously, we had determined that p-phenylenediamine (PPD) and 2,4-dinitrochlorobenzene (DNCB) modulate keratinocyte HA deposition in a manner correlated to their sensitization. In the present study, we aimed to investigate putative co-operation of HA and TLR4 in the process of PPD and DNCB-induced keratinocyte activation. Contact sensitizers were shown to significantly increase the expression of Hyaluronan Synthases (HAS) and TLR4 in NCTC2544 human keratinocytes, as demonstrated by western blot and Real-Time PCR. These data, in correlation to earlier shown enhanced HA degradation suggest that the contact sensitizers facilitate HA turnover of keratinocytes and increase the release of pro-inflammatory, LMWHA fragments. Treatment with exogenous LMWHA enhanced TLR4, HAS levels and Nuclear factor-kappa beta (NF-κΒ) activation. PPD, DNCB and LMWHA-effects were shown to be partly executed through TLR4 downstream signaling as shown by Real-Time, western blot, siRNA and confocal microscopy approaches. Specifically, PPD and DNCB stimulated the activation of the TLR4 downstream mediator NF-κB. Therefore, the shown upregulation of TLR4 expression is suggested to further facilitate the release of endogenous, bioactive HA fragments and sustain keratinocyte activation. In conclusion, keratinocyte contact allergen-dependent sensitization is partly mediated through a LMWHA/TLR4/ NF-κB signaling axis.

Structural consequences of transforming growth factor beta-1 activation from near-therapeutic X-ray doses.

Dissociation of transforming growth factor beta-1 (TGFβ-1) from the inhibitory protein latency-associated peptide (LAP) can occur from low doses of X-ray irradiation of the LAP-TGFβ-1 complex, resulting in the activation of TGFβ-1, and can have health-related consequences. Using the tools and knowledge developed in the study of radiation damage in the crystallographic setting, small-angle X-ray scattering (SAXS) and complementary techniques suggest an activation process that is initiated but not driven by the initial X-ray exposure. LAP is revealed to be extended when not bound to TGFβ-1 and has a different structural conformation compared to the bound state. These studies pave the way for the structural understanding of systems impacted at therapeutic X-ray doses and show the potential impact of radiation damage studies beyond their original intent.

Primary central nervous system lymphoma: A curable disease.

Primary central nervous system lymphoma is a rare subtype of non-Hodgkin lymphoma that is confined to the brain, leptomeninges, or the eye and is associated with a relatively poor prognosis compared to other extranodal diffuse large B-cell lymphomas. However, methotrexate-based induction chemotherapy followed by consolidative chemotherapy or high-dose therapy and autologous stem cell transplantation is associated with improved survival and reduced neurotoxicity. Aberrant activation of B-cell receptor signaling and activation of nuclear factor kappa beta is a frequent genetic alteration and offers opportunities for targeted therapies in this lymphoma subtype.

1970-P: Epinephrine and Insulin Stimulates White Adipocyte Secretion of Diverse Adiponectin Forms

The white adipocyte hormone adiponectin is released in different molecular forms and a reduction of high-molecular weight (HMW) adiponectin has specifically been associated with the development of metabolic disease. We have recently shown that adiponectin is released via cAMP/epinephrine-stimulated exocytosis, involving activation of beta 3 adrenergic receptors (beta3ARs). However, a number of studies have, seemingly incompatible with the catecholamine-triggered release, reported that insulin (lowers cAMP) increases adiponectin secretion. Here we have pinpointed the differences between insulin- and catecholamine-stimulated short-term adiponectin secretion. Using a combination of biophysical and biochemical techniques applied to mouse and human adipocytes as well as whole animal studies, we show that catecholamines specifically stimulate the rapid exocytosis of high-molecular weight (HMW) adiponectin. In contrast, insulin induces secretion of smaller adiponectin forms only, with slower time kinetics. The catecholamine-stimulated secretion of HMW adiponectin is blunted in adipocytes isolated from obese and diabetic mice (8 weeks high-fat diet) and this secretory defect is paralleled by a ∼50% reduction of serum HMW adiponectin. The insulin-induced release of smaller adiponectin forms is also abrogated i adipocytes from obese/diabetic mice. However, the total serum adiponectin level remains unaltered, likely due to enhanced basal (unstimulated) release of smaller adiponectin forms. Our findings suggest that insulin and catecholamines have entirely different roles in the regulation of adiponectin secretion and demonstrate a previously unknown role of beta3ARs for human white adipocyte physiology. We propose that the reduced levels of HMW adiponectin observed in diabetic individuals, and that have been linked to the development of metabolic disease, is a result of a secretory disturbance largely depending on disrupted adrenergic signaling. Disclosure S. Musovic: None. A.M. Komai: None. E. Banke Nordbeck: None. U.A. Noor: None. I. Wernstedt Asterholm: None. C.S. Olofsson: None. Funding Swedish Diabetes Foundation; Knut and Alice Wallenberg Foundation; Swedish Medical Research Council

Reliability based assessment of remote maintenance system for CFETR divertor

China Fusion Engineering Testing Reactor (CFETR) will be built to test and verify the feasibility of engineering and technology in practice for the future fusion reactor. Long pulse and steady-state operation will be demonstrated with duty cycle time not less than 30˜50%. Because of the beta and gamma activation of the component bulk and surface dust, special remote handling techniques will be required during machine maintenance periods. The divertor cassettes remote replacement is one of the key maintenance operations for the CFETR to meet the duty cycle time requirements. RH maintenance strategies will have a significant impact on the layout of the machine and design of components. Overview of the different CFETR divertor components remote maintenance strategies as well as to describe the maintenance process of the in vessel components will be discussed. Preliminary reliability assessment of the divertor maintenance system was done in order to carry out RH maintenance tasks safely and efficiently.

Thrombospondin 1 and Its Diverse Roles as a Regulator of Extracellular Matrix in Fibrotic Disease.

Thrombospondin 1 (TSP1) is a matricellular extracellular matrix protein that has diverse roles in regulating cellular processes important for the pathogenesis of fibrotic diseases. We will present evidence for the importance of TSP1 control of latent transforming growth factor beta activation in renal fibrosis with an emphasis on diabetic nephropathy. Other functions of TSP1 that affect renal fibrosis, including regulation of inflammation and capillary density, will be addressed. Emerging roles for TSP1 N-terminal domain regulation of collagen matrix assembly, direct effects of TSP1-collagen binding, and intracellular functions of TSP1 in mediating endoplasmic reticulum stress responses in extracellular matrix remodeling and fibrosis, which could potentially affect renal fibrogenesis, will also be discussed. Finally, we will address possible strategies for targeting TSP1 functions to treat fibrotic renal disease.

Activation of Interleukin-1 Beta in Arterialized Vein Grafts and the Influence of the -511C/T IL-1β Gene Polymorphism.

The interleukin-1 family is associated with innate immunity and inflammation. The latter has been linked to the genesis of cardiovascular diseases. We, therefore, investigated whether interleukin-1 beta (IL-1β) is activated during arterialization of vein grafts. First, we examined the activation of IL-1β using the rat arterialized jugular vein serially sampled for up to 90 days. IL-1β expression increased 18 times on day 1 in the arterialized rat jugular vein and remained five times above nonarterialized vein levels for up to 90 days. Similarly, IL-1β expression increased early (1–5 days) in human vein graft autopsy samples compared with late phases (1–4 years). Activation was also detected in ex vivo arterialized human saphenous veins. Upon stratification of the results, we uncovered a T allele promoter attenuating effect in IL-1β activation in response to hemodynamic stress. Altogether, the results show that IL-1β is activated during arterialization of vein grafts in rats and humans, and this response is modulated by -511C/T IL-1β gene polymorphism. It is tempting to speculate that the activation of IL-1β, and consequently local inflammation, modulates early vascular remodeling and that the gene polymorphism may be useful in predicting outcomes or assisting in interventions.

Drug-induced activation of integrin alpha IIb beta 3 leads to minor localized structural changes.

Integrins are transmembrane proteins involved in hemostasis, wound healing, immunity and cancer. In response to intracellular signals and ligand binding, integrins adopt different conformations: the bent (resting) form; the intermediate extended form; and the ligand-occupied active form. An integrin undergoing such conformational dynamics is the heterodimeric platelet receptor αIIbβ3. Although the dramatic rearrangement of the overall structure of αIIbβ3 during the activation process is potentially related to changes in the protein secondary structure, this has not been investigated so far in a membrane environment. Here we examine the Mn2+- and drug-induced activation of αIIbβ3 and the impact on the structure of this protein reconstituted into liposomes. By quartz crystal microbalance with dissipation monitoring and activation assays we show that Mn2+ induces binding of the conformation-specific antibody PAC-1, which only recognizes the extended, active integrin. Circular dichroism spectroscopy reveals, however, that Mn2+-treatment does not induce major secondary structural changes of αIIbβ3. Similarly, we found that treatment with clinically relevant drugs (e.g. quinine) led to the activation of αIIbβ3 without significant changes in protein secondary structure. Molecular dynamics simulation studies revealed minor local changes in the beta-sheet probability of several extracellular domains of the integrin. Our experimental setup represents a new approach to study transmembrane proteins, especially integrins, in a membrane environment and opens a new way for testing drug binding to integrins under clinically relevant conditions.

(239) Tissue Inhibitor of Matrix Metalloproteinase-1 Attenuates the Onset of Hypersensitivity Using a Model of Cutaneous Inflammation

Tissue damage results in the release of molecules that aid in tissue repair and produce hypersensitivity. Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), a protease inhibitor involved in extracellular matrix remodeling, contributes to neuropathic pain, but its role in modulating hypersensitivity during inflammatory conditions remains to be elucidated. To determine how inflammation regulates TIMP-1 expression in the skin we injected complete Freund's adjuvant (CFA) subcutaneously (s.c.) into the dorsal hindpaw of WT mice and found that TIMP-1 protein was significantly increased 1- and 3-dayspost-injection, a time when behavioral hypersensitivity is not observed. Therefore, we hypothesized that the release of TIMP-1 following inflammation attenuates the onset of hypersensitivity. To test this, we used global TIMP-1 knockout (T1KO) mice to examine the development of inflammatory hypersensitivity in the absence of TIMP-1. We found that T1KO mice developed hypersensitivity within 24 hours of inflammation and remained sensitive for 7 days, while WT controls developed hypersensitivity 3 days following inflammation that resolved by day 7. Ex vivo electrophysiological recordings of cutaneous sensory neurons demonstrated that T1KO afferents exhibited greater sensitivity that WT afferents. Analysis of WT and T1KO skin did not detect any genotype-specific differences in MMP-9 activity or inflammatory cytokine expression. Given that the C terminal region of TIMP-1 binds to the CD63/beta 1 Integrin receptor complex, our results suggest that TIMP-1 may attenuate hypersensitivity through a receptor-mediated signaling pathway. To explore this possibility, we injected T1KO mice with a beta 1 integrin inhibitor (Ha2/5) at the time of inflammation. We found that antagonizing beta 1 integrin reversed inflammatory hypersensitivity. Thus, our data suggest that in the absence of TIMP-1 activation of beta 1 integrin contributes to inflammatory hypersensitivity.

Lateral Inhibition Organizes Beta Attentional Modulation in the Primary Visual Cortex.

We have previously shown that during top-down attentional modulation (stimulus expectation) correlations of the beta signals across the primary visual cortex were uniform, while during bottom-up attentional processing (visual stimulation) their values were heterogeneous. These different patterns of attentional beta modulation may be caused by feed-forward lateral inhibitory interactions in the visual cortex, activated solely during stimulus processing. To test this hypothesis, we developed a large-scale computational model of the cortical network. We first identified the parameter range needed to support beta rhythm generation, and next, simulated the different activity states corresponding to experimental paradigms. The model matched our experimental data in terms of spatial organization of beta correlations during different attentional states and provided a computational confirmation of the hypothesis that the paradigm-specific beta activation spatial maps depend on the lateral inhibitory mechanism. The model also generated testable predictions that cross-correlation values depend on the distance between the activated columns and on their spatial position with respect to the location of the sensory inputs from the thalamus.

A Macrophage-Pericyte Axis Directs Tissue Restoration via Amphiregulin-Induced Transforming Growth Factor Beta Activation

SummaryThe epidermal growth factor receptor ligand Amphiregulin has a well-documented role in the restoration of tissue homeostasis after injury; however, the mechanism by which Amphiregulin contributes to wound repair remains unknown. Here we show that Amphiregulin functioned by releasing bioactive transforming growth factor beta (TGF-β) from latent complexes via integrin-αV activation. Using acute injury models in two different tissues, we found that by inducing TGF-β activation on mesenchymal stromal cells (pericytes), Amphiregulin induced their differentiation into myofibroblasts, thereby selectively contributing to the restoration of vascular barrier function within injured tissue. Furthermore, we identified macrophages as a critical source of Amphiregulin, revealing a direct effector mechanism by which these cells contribute to tissue restoration after acute injury. Combined, these observations expose a so far under-appreciated mechanism of how cells of the immune system selectively control the differentiation of tissue progenitor cells during tissue repair and inflammation.

Estradiol and progesterone regulate proliferation and apoptosis in colon cancer.

Epidemiological studies describe estrogens as protectors in the development of colon cancer in postmenopausal women treated with hormone replacement therapy. However, the role of progesterone in colon cancer has been minimally studied and the results are controversial. For the above, the objective of this work was to determine the hormonal regulation exerted by natural ovarian steroids on proliferation and apoptosis in an experimental model of colon cancer in ovariectomized rats treated with 17-beta estradiol and progesterone. Sprague–Dawley rats were exposed to the carcinogen 1,2-dimethylhydrazine to induce colon tumors. Thirty days later, the rats were ovariectomized and treated with estradiol (60 μg/kg), progesterone (10 mg/kg), estradiol plus progesterone (60 μg/kg and 10 mg/kg) or vehicle. We observed no significant differences in colon cancer incidence and tumor multiplicity between the groups. Nevertheless, we observed a decrease in PCNA expression and a greater number of apoptotic index, higher expression of caspase 3, cleaved PARP and cleaved caspase 8 in tumors, confirming the activation of the extrinsic pathway of apoptosis by the combined treatment. In addition, we observed a higher expression of estrogen receptor beta in these tumors. We conclude that the action of both hormones, estradiol and progesterone, is necessary to reduce proliferation and increase apoptosis in colon tumors, probably through estrogen receptor beta activation.

Orally administered gold nanoparticles protect against colitis by attenuating Toll-like receptor 4- and reactive oxygen/nitrogen species-mediated inflammatory responses but could induce gut dysbiosis in mice

BackgroundGold nanoparticles (AuNPs) are attracting interest as potential therapeutic agents to treat inflammatory diseases, but their anti-inflammatory mechanism of action is not clear yet. In addition, the effect of orally administered AuNPs on gut microbiota has been overlooked so far. Here, we evaluated the therapeutic and gut microbiota-modulating effects, as well as the anti-inflammatory paradigm, of AuNPs with three different coatings and five difference sizes in experimental mouse colitis and RAW264.7 macrophages.ResultsCitrate- and polyvinylpyrrolidone (PVP)-stabilized 5-nm AuNPs (Au-5 nm/Citrate and Au-5 nm/PVP) and tannic acid (TA)-stabilized 5-, 10-, 15-, 30- and 60-nm AuNPs were intragastrically administered to C57BL/6 mice daily for 8 days during and after 5-day dextran sodium sulfate exposure. Clinical signs and colon histopathology revealed more marked anti-colitis effects by oral administration of Au-5 nm/Citrate and Au-5 nm/PVP, when compared to TA-stabilized AuNPs. Based on colonic myeloperoxidase activity, colonic and peripheral levels of interleukin-6 and tumor necrosis factor-α, and peripheral counts of leukocyte and lymphocyte, Au-5 nm/Citrate and Au-5 nm/PVP attenuated colonic and systemic inflammation more effectively than TA-stabilized AuNPs. High-throughput sequencing of fecal 16S rRNA indicated that AuNPs could induce gut dysbiosis in mice by decreasing the α-diversity, the Firmicutes/Bacteroidetes ratio, certain short-chain fatty acid-producing bacteria and Lactobacillus. Based on in vitro studies using RAW264.7 cells and electron spin resonance oximetry, AuNPs inhibited lipopolysaccharide (LPS)-triggered inducible nitric oxide (NO) synthase expression and NO production via reduction of Toll-like receptor 4 (TLR4), and attenuated LPS-induced nuclear factor kappa beta activation and proinflammatory cytokine production via both TLR4 reduction and catalytic detoxification of peroxynitrite and hydrogen peroxide.ConclusionsAuNPs have promising potential as anti-inflammatory agents; however, their therapeutic applications via the oral route may have a negative impact on the gut microbiota.

PO-095 Effects of dynamic foot stimulation on GSK-3 beta signaling pathway in rat soleus muscle under hindlimb unloading

Objective It is known that under simulated microgravity GSK-3 beta phosphorylation (Ser 9) is decreased [Mirzoev et al., 2016] which is associated with the activation of its kinase activity. GSK-3 beta activation may lead to NFATc1 export from myonuclei resulting in a slow-to-fast myosin shift in soleus muscle and may cause a decrease in muscle oxidative capacity and protein synthesis [Glass, 2003, Theeuwes et al, 2017].
 It was demonstrated that GSK-3 beta Ser 9 phosphorylation is decreased in response to nitric oxide synthase inhibition [Martins et al., 2011]. Under unloading conditions, the content of NO as well as nitric oxide synthase is attenuated in rat soleus muscle [Tidball et al., 1998; Lomonosova et al, 2011]. Dynamic foot stimulation (DFS) of the soles of the feet results in an increase of neuromuscular activation [Muller et al., 2005] of the lower limb muscles and prevents nitric synthase content decrease during 7-day exposure to dry immersion [Moukhina et al, 2004; Shenkman et al., 2004]. The aim of our study was to analyze the effect of rat dynamic foot stimulation during early unloading on GSK-3 beta phosphorylation and some of its downstream targets.
 Methods Male Wistar rats were randomly assigned to vivarium control, 1-day unloading and 1-day
 unloading with DFS. The pressure stimulation protocol mimicked the normal animal walking (104 mm Hg pressure, 4 Hz frequency and 250 ms signal duration) for a total of 20 min followed by a 10-min rest interval for 4 hours.
 Results We found that 1-day unloading caused a significant decrease (p˂ 0.025) in NFATc1 nuclear content as well as slow myosin (MHC I (beta) isoform) mRNA expression. In the 1-day unloading group, the level of glycogen synthase 1 phosphorylation (Ser 641), which is a direct GSK-3 beta target, was significantly higher than that in the control group, although a decrease in GSK-3 beta Ser 9 phosphorylation in the 1-day unloaded group was not statistically significant compared to the control group. However, in the DFS-treated unloaded rats the level of GSK-3 beta phosphorylation was significantly higher than in the untreated unloaded rats. NFATc1 nuclear content, slow myosin mRNA expression and glycogen synthase 1 phosphorylation (Ser 641) did not differ from the control group. The glycogen content in soleus muscles of both unloaded groups was higher than in the control group, which is in accordance with previous studies [Henriksen and Tischler, 1988], but in DFS subjected unloaded group the glycogen content was higher compared to the untreated unloaded group.
 Conclusions Thus, we found that dynamic foot stimulation during 1-day hindlimb unloading leads to GSK-3 beta inactivation and prevention of both NFATc1 myonuclei export and the decrease in MyHC I beta expression.
 The study was supported by the Russian Foundation for Basic Research grant #17-29-1029 and Basic Research Program of the IBMP, RAS. The authors express their deep gratitude to Prof. Inessa B. Kozlovskaya for useful recommendations concerning the design of the study.

Innate immunity in the postmortem brain of depressed and suicide subjects: Role of Toll-like receptors

Abnormalities of Toll-like receptors (TLRs) have been implicated in the pathophysiology of depression and suicide. Interactions of TLRs with pathogen-associated molecular patterns (PAMP) and damage-associated molecular patterns (DAMP) initiate signaling through myeloid differentiation primary response-88 (MyD88) and produce cytokines through the activation of the transcription factor nuclear factor kappa beta (NF-kB). We have earlier shown an increase in the protein and mRNA expression of TLR3 and TLR4 in the prefrontal cortex (PFC) of depressed suicide (DS) subjects compared with normal control (NC) subjects. To examine if other TLRs are altered in postmortem brain, we have now determined the protein and mRNA expression of other TLRs (TLR1, TLR2, TLR5, TLR6, TLR7, TLR8, TLR9 and TLR10) in the PFC of DS, depressed non-suicide (DNS), non-depressed suicide (NDS) and NC subjects. We determined the protein expression by Western blot and mRNA expression levels by real-time PCR (qPCR) in the PFC of 24 NC, 24 DS, 12 DNS and 11 NDS subjects. Combined with our previous study of TLR3 and TLR4, we found that the protein expression of TLR2, TLR3, TLR4, TLR6 and TLR10, and mRNA expression of TLR2 and TLR3 was significantly increased in the DS group compared with NC group. This study demonstrated that certain specific TLRs are altered in DS subjects, and hence those TLRs may be appropriate targets for the development of therapeutic agents for the treatment of suicidal behavior.

172. Vitamin D decreases gene and protein expression of NLRP3 inflammasome in placental explants cultured with hydrogen peroxide from women with preeclampsia

Introduction Pregnancies complicated by preeclampsia (PE) are associated with placental oxidative stress and related to the activation of NLRP3 inflammasome, an important complex for activation of caspase-1, interleukin-1 beta (IL-1β) and high-mobility group box-1 (HMGB1). The hyperactivation of NLRP3 inflammasome in placental tissues may be involved in the huge systemic inflammatory state in PE, which could be modulate by administration of substances with anti-inflammatory properties such as vitamin D (VD). Objectives This study aimed to evaluate vitamin D immunomodulatory effect on the NLRP3 inflammassome in placental explants from normotensive (NT) and preeclamptic women cultured with hydrogen peroxide. Methods Placental explants from 7 PE and 7 NT women in the third trimester of pregnancy were obtained from women undergoing elective cesarean section. Explants were cultured with or without H2O2 and H2O2 plus VD. NLRP3, HMGB1, caspase-1 and IL-1β gene expression were analysed by qPCR. Protein expression were determined by western blotting or ELISA. Results Endogenous gene expression of NLRP3 and HMGB1 were significantly higher in PE than in NT explants. NLRP3, caspase-1, IL-1β and HMGB1 gene expression were higher in cultures treated with H2O2 compared to control cultures, while explants treated with H2O2 plus VD led to lower gene expression in NT and PE groups. High protein expression of NLRP3, caspase-1, IL-1β and HMGB1 was detected in explants cultured with H2O2 compared to controls whereas cultures treated with H2O2 plus VD decreased these protein expression compared to H2O2 stimuli. Conclusion Vitamin D was able to decrease the gene and protein expression of NLRP3 inflammasome and HMGB1 production in placental explants cultured with H2O2 in PE and NT groups. These results suggest that vitamin D may play an immunomodulatory role in the systemic inflammatory response present in preeclampsia. Financial support FAPESP 2016/18155-9 and 2016/23452-2.

Nerve growth factor prevents arsenic-induced toxicity in PC12 cells through the AKT/GSK-3β/NFAT pathway.

The potential risk of arsenic-related neurodegeneration has been a growing concern. Arsenic exposure has been reported to disrupt neurite growth and neuron body integrity in vitro; however, its underlying mechanism remains unclear. Previously, we showed that arsenic sulfide (AS) exerted cytotoxicity in gastric and colon cancer cells through regulating nuclear factor of the activated T cells (NFAT) pathway. The NFAT pathway regulates axon path finding and neural development. Using neural crest cell line PC12 cells as a model, here we show that AS caused mitochondrial membrane potential collapse, reactive oxygen species production, and cytochrome c release, leading to mitochondria-mediated apoptosis via the AKT/GSK-3β/NFAT pathway. Increased glycogen synthase kinase-3 beta (GSK-3β) activation leads to the inactivation of NFAT and its antiapoptotic effects. Through inhibiting GSK-3β activity, both nerve growth factor (NGF) and Tideglusib, a GSK-3β inhibitor partially rescued the PC12 cells from the AS-induced cytotoxicity and restored the expression of NFATc3. In addition, overexpression of NFATc3 stimulated neurite outgrowth and potentiated the effect of NGF on promoting the neurite outgrowth. Collectively, our results show that NFATc3 serves as the downstream target of NGF and plays a key role in preventing AS-induced neurotoxicity through regulating the AKT/GSK-3β/NFAT pathway in PC12 cells.

From the Editor’s desk....: July 2018

From the Editor’s desk....: July 2018

Mice deficient in AKAP13 (BRX) develop compulsive-like behavior and increased body weight

ObjectiveHormonal contributions to the sex-dependent development of both obsessive-compulsive disorder (OCD) and obesity have been described, but the underlying mechanisms are incompletely understood. A-kinase anchoring protein 13 (AKAP13) significantly augments ligand-dependent activation of estrogen receptors alpha and beta. The hypothalamus and pituitary gland are implicated in the development and exacerbation of OCD and obesity and have strong AKAP13 expression. The AKAP13 localization pattern observed in these key brain regions together with its effects on sex steroid action suggest a potential role for AKAP13 in compulsive-like behaviors. Here we tested the role of AKAP13 in compulsive-like behavior and body weight using an Akap13 haploinsufficient murine model. Materials and methodsTargeted deletion of the Akap13 gene generated haploinsufficient (Akap13+/−) mice in a C57BL6/J genetic background. Established behavioral assays were conducted, video recorded, and scored blindly to assess compulsive-like behavior based on genotype and gender. Tests included: marble-burying, grooming, open- field and elevated plus-maze. Brain and body weights were also obtained. Mean levels of test outcomes were compared using multi-way ANOVA to test for genotype, sex, genotype*sex, and genotype*sex*age interaction effects with Bonferroni adjustment for multiple comparisons, to further explain any significant interactions. ResultsThe marble-burying and grooming assays revealed significant sex-dependent increases in perseverative, compulsive-like behaviors in female Akap13 haploinsufficient mice compared to female wild type (WT) mice by demonstrating increased marble-burying activity (p = .0025) and a trend towards increased grooming behavior (p = .06). Male Akap13 haploinsufficient mice exhibited no behavioral changes (p > 0.05). Elevated plus-maze and open-field test results showed no overt anxiety-like behavior in Akap13 haploinsufficient mice irrespective of sex (p > 0.05, both). No differences in brain weight were found in Akap13 haploinsufficient mice compared to WT mice (p > 0.05). However, female Akap13 haploinsufficient mice weighed more than female WT mice in the 4 to <7 months age range (p = .0051). Male Akap13 haploinsufficient mice showed no differences in weight compared to male WT mice (p = >0.05) at any age range examined. ConclusionAkap13 haploinsufficiency led to sex-dependent, compulsive-like behavioral changes in a murine model. Interestingly, Akap13 haploinsufficiency also led to a sex-dependent increase in body weight. These results revealed a requirement for AKAP13 in murine behavior, particularly in female mice, and is the first report of AKAP13 involvement in murine behavior. Future studies may examine the involvement of AKAP13 in the pathophysiology of OCD in female humans and may contribute to a better understanding of the role of AKAP13 and sex hormones in the development and exacerbation of OCD.

Mobile Phone Chips Reduce Increases in EEG Brain Activity Induced by Mobile Phone-Emitted Electromagnetic Fields.

Recent neurophysiological studies indicate that exposure to electromagnetic fields (EMFs) generated by mobile phone radiation can exert effects on brain activity. One technical solution to reduce effects of EMFs in mobile phone use is provided in mobile phone chips that are applied to mobile phones or attached to their surfaces. To date, there are no systematical studies on the effects of mobile phone chip application on brain activity and the underlying neural mechanisms. The present study investigated whether mobile phone chips that are applied to mobile phones reduce effects of EMFs emitted by mobile phone radiation on electroencephalographic (EEG) brain activity in a laboratory study. Thirty participants volunteered in the present study. Experimental conditions (mobile phone chip, placebo chip, no chip) were set up in a randomized within-subjects design. Spontaneous EEG was recorded before and after mobile phone exposure for two 2-min sequences at resting conditions. During mobile phone exposure, spontaneous EEG was recorded for 30 min during resting conditions, and 5 min during performance of an attention test (d2-R). Results showed increased activity in the theta, alpha, beta and gamma bands during EMF exposure in the placebo and no chip conditions. Application of the mobile phone chip reduced effects of EMFs on EEG brain activity and attentional performance significantly. Attentional performance level was maintained regarding number of edited characters. Further, a dipole analysis revealed different underlying activation patterns in the chip condition compared to the placebo chip and no chip conditions. Finally, a correlational analysis for the EEG frequency bands and electromagnetic high-frequency (HF) emission showed significant correlations in the placebo chip and no chip condition for the theta, alpha, beta, and gamma bands. In the chip condition, a significant correlation of HF with the theta and alpha bands, but not with the beta and gamma bands was shown. We hypothesize that a reduction of EEG beta and gamma activation constitutes the key neural mechanism in mobile phone chip use that supports the brain to a degree in maintaining its natural activity and performance level during mobile phone use.