Chemical Probes and Activity-Based Protein Profiling for Cancer Research.

Chemical probes can be used to understand the complex biological nature of diseases. Due to the diversity of cancer types and dynamic regulatory pathways involved in the disease, there is a need to identify signaling pathways and associated proteins or enzymes that are traceable or detectable in tests for cancer diagnosis and treatment. Currently, fluorogenic chemical probes are widely used to detect cancer-associated proteins and their binding partners. These probes are also applicable in photodynamic therapy to determine drug efficacy and monitor regulating factors. In this review, we discuss the synthesis of chemical probes for different cancer types from 2016 to the present time and their application in monitoring the activity of transferases, hydrolases, deacetylases, oxidoreductases, and immune cells. Moreover, we elaborate on their potential roles in photodynamic therapy.

Role of nociceptin/orphanin FQ and nociceptin opioid peptide receptor in depression and antidepressant effects of nociceptin opioid peptide receptor antagonists.

Nociceptin/orphanin FQ (N/OFQ) and its receptor, nociceptin opioid peptide (NOP) receptor, are localized in brain areas implicated in depression including the amygdala, bed nucleus of the stria terminalis, habenula, and monoaminergic nuclei in the brain stem. N/OFQ inhibits neuronal excitability of monoaminergic neurons and monoamine release from their terminals by activation of G protein-coupled inwardly rectifying K+ channels and inhibition of voltage sensitive calcium channels, respectively. Therefore, NOP receptor antagonists have been proposed as a potential antidepressant. Indeed, mounting evidence shows that NOP receptor antagonists have antidepressant-like effects in various preclinical animal models of depression, and recent clinical studies again confirmed the idea that blockade of NOP receptor signaling could provide a novel strategy for the treatment of depression. In this review, we describe the pharmacological effects of N/OFQ in relation to depression and explore the possible mechanism of NOP receptor antagonists as potential antidepressants.

Depot-specific differences in angiogenic capacity of adipose tissue in differential susceptibility to diet-induced obesity.

OBJECTIVE: Adipose tissue (AT) expansion requires AT remodeling, which depends on AT angiogenesis. Modulation of AT angiogenesis could have therapeutic promise for the treatment of obesity. However, it is unclear how the capacity of angiogenesis in each adipose depot is affected by over-nutrition. Therefore, we investigated the angiogenic capacity (AC) of subcutaneous and visceral fats in lean and obese mice. METHODS: We compared the AC of epididymal fat (EF) and inguinal fat (IF) using an angiogenesis assay in diet-induced obese (DIO) mice and diet-resistant (DR) mice fed a high-fat diet (HFD). Furthermore, we compared the expression levels of genes related to angiogenesis, macrophage recruitment, and inflammation using RT-qPCR in the EF and IF of lean mice fed a low-fat diet (LFD), DIO mice, and DR mice fed a HFD. RESULTS: DIO mice showed a significant increase in the AC of EF only at 22 weeks of age compared to DR mice. The expression levels of genes related to angiogenesis, macrophage recruitment, and inflammation were significantly higher in the EF of DIO mice than in those of LFD mice and DR mice, while expression levels of genes related to macrophages and their recruitment were higher in the IF of DIO mice than in those of LFD and DR mice. Expression of genes related to angiogenesis (including Hif1a, Vegfa, Fgf1, Kdr, and Pecam1), macrophage recruitment, and inflammation (including Emr1, Ccr2, Itgax, Ccl2, Tnf, and Il1b) correlated more strongly with body weight in the EF of HFD-fed obese mice compared to that of IF. CONCLUSIONS: These results suggest depot-specific differences in AT angiogenesis and a potential role in the susceptibility to diet-induced obesity.

The effect of metformin on neuronal activity in the appetite-regulating brain regions of mice fed a high-fat diet during an anorectic period.

Metformin reduces body weight by decreasing food intake in humans and animals. However, the brain regions involved in metformin-induced anorexia remain unclear. Therefore, we investigated c-Fos expression (FOS), a marker of neuronal activity, in the appetite-regulating brain regions after oral administration of metformin (PO, 300mg/kg daily for 1 or 3days) or vehicle. The body weight and food intake decreased in mice treated with metformin for 3days (RM group) and mice that had the same amount of food as the RM group (Pair-fed group; PF) compared to the control group. FOS expression levels increased in the paraventricular nucleus, area postrema, and central amygdala of mice administered an acute single dose of metformin (SM group) compared to the control mice. In the nucleus tractus solitarius, the FOS expression levels increased in both the SM and RM groups compared to the control group. The FOS expression levels also increased in the nucleus accumbens of the RM group compared to other groups. The FOS expression levels decreased in the ventromedial hypothalamic nucleus in the PF group, but not the RM group, compared to the control group, suggesting a potential hypothalamic area involvement for metformin-induced anorexia. These results suggest that both the hypothalamic and extra-hypothalamic regions are associated with metformin-induced anorexia, which is dependent on metformin treatment duration.

Increase in cocaine- and amphetamine-regulated transcript (CART) in specific areas of the mouse brain by acute caffeine administration.

Caffeine produces a variety of behavioral effects including increased alertness, reduced food intake, anxiogenic effects, and dependence upon repeated exposure. Although many of the effects of caffeine are mediated by its ability to block adenosine receptors, it is possible that other neural substrates, such as cocaine- and amphetamine-regulated transcript (CART), may be involved in the effects of caffeine. Indeed, a recent study demonstrated that repeated caffeine administration increases CART in the mouse striatum. However, it is not clear whether acute caffeine administration alters CART in other areas of the brain. To explore this possibility, we investigated the dose- and time-dependent changes in CART immunoreactivity (CART-IR) after a single dose of caffeine in mice. We found that a high dose of caffeine (100 mg/kg) significantly increased CART-IR 2 h after administration in the nucleus accumbens shell (AcbSh), dorsal bed nucleus of the stria terminalis (dBNST), central nucleus of the amygdala (CeA), paraventricular hypothalamic nucleus (PVN), arcuate hypothalamic nucleus (Arc), and locus coeruleus (LC), and returned to control levels after 8 h. But this increase was not observed in other brain areas. In addition, caffeine administration at doses of 25 and 50 mg/kg appears to produce dose-dependent increases in CART-IR in these brain areas; however, the magnitude of increase in CART-IR observed at a dose of 50 mg/kg was similar or greater than that observed at a dose of 100 mg/kg. This result suggests that CART-IR in AcbSh, dBNST, CeA, PVN, Arc, and LC is selectively affected by caffeine administration.

Effect of acute and chronic electroconvulsive shock on 5-hydroxytrypamine 6 receptor immunoreactivity in rat hippocampus.

Electroconvulsive shock (ECS) induces not only an antidepressant effect but also adverse effects such as amnesia. One potential mechanism underlying both the antidepressant and amnesia effect of ECS may involve the regulation of serotonin (5-hydroxytryptamine) 6 (5-HT6) receptor, but less is known about the effects of acute ECS on the changes in 5-HT6 receptor expression in the hippocampus. In addition, as regulation of 5-HT receptor expression is influenced by the number of ECS treatment and by interval between ECS treatment and sacrifice, it is probable that magnitude and time-dependent changes in 5-HT6 receptor expression could be influenced by repeated ECS exposure. To explore this possibility, we observed and compared the changes of 5-HT6 receptor immunoreactivity (5-HT6 IR) in rat hippocampus at 1, 8, 24, or 72 h after the treatment with either a single ECS (acute ECS) or daily ECS for 10 days (chronic ECS). We found that acute ECS increased 5-HT6 IR in the CA1, CA3, and granule cell layer of hippocampus, reaching peak levels at 8 h and returning to basal levels 72 h later. The magnitude and time-dependent changes in 5-HT6 IR observed after acute ECS were not affected by chronic ECS. These results demonstrate that both acute and chronic ECS transiently increase the 5-HT6 IR in rat hippocampus, and suggest that the magnitude and time-dependent changes in 5-HT6 IR in the hippocampus appear not to be influenced by repeated ECS treatment.

Comparison of aqueous levels of inflammatory mediators between toxic anterior segment syndrome and endotoxin-induced uveitis animal models.

PURPOSE: To compare clinical findings and the aqueous levels of inflammatory mediators between toxic anterior segment syndrome (TASS) and endotoxin-induced uveitis (EIU) animal models and to evaluate the efficacy of systemic steroid pretreatment in both animal models. METHODS: Rats were used in this study. Ortho-phthalaldehyde solution was injected into the anterior chamber to produce TASS (n=30), and lipopolysaccharide was injected into one hind footpad to produce EIU (n=30). Clinical findings were evaluated under slit-lamp examination, and the aqueous levels of prostaglandin E2 (PGE2) and tumor necrosis factor-α (TNF-α) were measured 24 hours after these procedures. Twelve of the rats in each animal model were pretreated with intraperitoneal injection of dexamethasone for 4 days before the development of TASS and EIU. RESULTS: Corneal haze scores were significantly higher for TASS than EIU, but clinical scores for anterior uveitis were not different between the two animal models. Although aqueous levels of PGE2 were markedly increased in both animal models, PGE2 levels were significantly higher for TASS than for EIU. However, an increase in aqueous levels of TNF-α was observed only in EIU. Dexamethasone pretreatment reduced the corneal haze score and clinical score for anterior uveitis in both animal models and inhibited the increase in aqueous levels of PGE2 and TNF-α. CONCLUSIONS: Prostaglandin E2 and TNF-α in aqueous humor seem to be regulated differently in animal models of TASS and EIU. However, dexamethasone pretreatment improved the clinical findings and inhibited the increases in PGE2 and TNF-α in both animal models.

Desipramine and citalopram attenuate pretest swim-induced increases in prodynorphin immunoreactivity in the dorsal bed nucleus of the stria terminalis and the lateral division of the central nucleus of the amygdala in the forced swimming test.

Dynorphin in the nucleus accumbens shell plays an important role in antidepressant-like effect in the forced swimming test (FST), but it is unclear whether desipramine and citalopram treatments alter prodynorphin levels in other brain areas. To explore this possibility, we injected mice with desipramine and citalopram 0.5, 19, and 23 h after a 15-min pretest swim and observed changes in prodynorphin expression before the test swim, which was conducted 24 h after the pretest swim. The pretest swim increased prodynorphin immunoreactivity in the dorsal bed nucleus of the stria terminalis (dBNST) and lateral division of the central nucleus of the amygdala (CeL). This increase in prodynorphin immunoreactivity in the dBNST and CeL was blocked by desipramine and citalopram treatments. Similar changes in prodynorphin mRNA levels were observed in the dBNST and CeL, but these changes did not reach significance. To understand the underlying mechanism, we assessed changes in phosphorylated CREB at Ser(133) (pCREB) immunoreactivity in the dBNST and central nucleus of the amygdala (CeA). Treatment with citalopram but not desipramine after the pretest swim significantly increased pCREB immunoreactivity only in the dBNST. These results suggest that regulation of prodynorphin in the dBNST and CeL before the test swim may be involved in the antidepressant-like effect of desipramine and citalopram in the FST and suggest that changes in pCREB immunoreactivity in these areas may not play an important role in the regulation of prodynorphin in the dBNST and CeA.

Effect of desipramine and citalopram treatment on forced swimming test-induced changes in cocaine- and amphetamine-regulated transcript (CART) immunoreactivity in mice.

Recent study demonstrates antidepressant-like effect of cocaine- and amphetamine-regulated transcript (CART) in the forced swimming test (FST), but less is known about whether antidepressant treatments alter levels of CART immunoreactivity (CART-IR) in the FST. To explore this possibility, we assessed the treatment effects of desipramine and citalopram, which inhibit the reuptake of norepinephrine and serotonin into the presynaptic terminals, respectively, on changes in levels of CART-IR before and after the test swim in mouse brain. Levels of CART-IR in the nucleus accumbens shell (AcbSh), dorsal bed nucleus of the stria terminalis (dBNST), and hypothalamic paraventricular nucleus (PVN) were significantly increased before the test swim by desipramine and citalopram treatments. This increase in CART-IR in the AcbSh, dBNST, and PVN before the test swim remained elevated by desipramine treatment after the test swim, but this increase in these brain areas returned to near control levels after test swim by citalopram treatment. Citalopram, but not desipramine, treatment increased levels of CART-IR in the central nucleus of the amygdala (CeA) and the locus ceruleus (LC) before the test swim, and this increase was returned to control levels after the test swim in the CeA, but not in the LC. These results suggest common and distinct regulation of CART by desipramine and citalopram treatments in the FST and raise the possibility that CART in the AcbSh, dBNST, and CeA may be involved in antidepressant-like effect in the FST.

Sex Differences in Hippocampal Neuronal Sensitization by Nicotine in M. gerbils.

We studied the sex different nicotine effect on evoked population spike amplitudes (ePSA) and connexin (Cx) expression in the hippocampus CA1 area of gerbils. Acute doses of nicotine bitartrate (0.5 mg/kg: NT-0.5) slightly reduced ePSA in males but markedly augmented that in females. Acute NT (5.0 mg/kg) markedly increased the ePSA in all gerbils. Unlike acute NT-0.5, repeated NT-0.5 injection (twice a day for 7 days) significantly increased the ePSA in males and slightly affected the NT-0.5 effect in females. The Cx36 and Cx43 expression levels as well as Cx expressing neuronal populations were significantly increased by repeated NT-0.5 in in both male and female gerbils, and particularly, Cx43 expression was somewhat prominent in females. These results demonstrated a sex difference with respect to the nicotine effect on hippocampal bisynaptic excitability, irrelevant to connexin expression.

Fabrication of nano-sized magnetic tunnel junctions using lift-off process assisted by atomic force probe tip.

We present a fabrication method for nano-scale magnetic tunnel junctions (MTJs), employing e-beam lithography and lift-off process assisted by the probe tip of atomic force microscope (AFM). It is challenging to fabricate nano-sized MTJs on small substrates because it is difficult to use chemical mechanical planarization (CMP) process. The AFM-assisted lift-off process enables us to fabricate nano-sized MTJs on small substrates (12.5 mm x 12.5 mm) without CMP process. The e-beam patterning has been done using bi-layer resist, the poly methyl methacrylate (PMMA)/ hydrogen silsesquioxane (HSQ). The PMMA/HSQ resist patterns are used for both the etch mask for ion milling and the self-aligned mask for top contact formation after passivation. The self-aligned mask buried inside a passivation oxide layer, is readily lifted-off by the force exerted by the probe tip. The nano-MTJs (160 nm x 90 nm) fabricated by this method show clear current-induced magnetization switching with a reasonable TMR and critical switching current density.

Changes in c-Fos Expression in the Forced Swimming Test: Common and Distinct Modulation in Rat Brain by Desipramine and Citalopram.

Rodents exposed to a 15-min pretest swim in the forced swimming test (FST) exhibit prolonged immobility in a subsequent 5-min test swim, and antidepressant treatment before the test swim reduces immobility. At present, neuronal circuits recruited by antidepressant before the test swim remain unclear, and also less is known about whether antidepressants with different mechanisms of action could influence neural circuits differentially. To reveal the neural circuits associated with antidepressant effect in the FST, we injected desipramine or citalopram 0.5 h, 19 h, and 23 h after the pretest swim and observed changes in c-Fos expression in rats before the test swim, namely 24 h after the pretest swim. Desipramine treatment alone in the absence of pretest swim was without effect, whereas citalopram treatment alone significantly increased the number of c-Fos-like immunoreactive cells in the central nucleus of the amygdala and bed nucleus of the stria terminalis, where this pattern of increase appears to be maintained after the pretest swim. Both desipramine and citalopram treatment after the pretest swim significantly increased the number of c-Fos-like immunoreactive cells in the ventral lateral septum and ventrolateral periaqueductal gray before the test swim. These results suggest that citalopram may affect c-Fos expression in the central nucleus of the amygdala and bed nucleus of the stria terminalis distinctively and raise the possibility that upregulation of c-Fos in the ventral lateral septum and ventrolateral periaqueductal gray before the test swim may be one of the probable common mechanisms underlying antidepressant effect in the FST.

Central administration of metformin into the third ventricle of C57BL/6 mice decreases meal size and number and activates hypothalamic S6 kinase.

Administration of metformin is known to reduce both body weight and food intake. Although the hypothalamus is recognized as a critical regulator of energy balance and body weight, there is currently no evidence for an effect of metformin in the hypothalamus. Therefore, we sought to determine the central action of metformin on energy balance and body weight, as well as its potential involvement with key hypothalamic energy sensors, including adenosine monophosphate-activated protein kinase (AMPK) and S6 kinase (S6K). We used meal pattern analysis and a conditioned taste aversion (CTA) test and measured energy expenditure in C56BL/6 mice administered metformin (0, 7.5, 15, or 30 µg) into the third ventricle (I3V). Furthermore, we I3V-administered either control or metformin (30 µg) and compared the phosphorylation of AMPK and S6K in the mouse mediobasal hypothalamus. Compared with the control, I3V administration of metformin decreased body weight and food intake in a dose-dependent manner and did not result in CTA. Furthermore, the reduction in food intake induced by I3V administration of metformin was accomplished by decreases in both nocturnal meal size and number. Compared with the control, I3V administration of metformin significantly increased phosphorylation of S6K at Thr(389) and AMPK at Ser(485/491) in the mediobasal hypothalamus, while AMPK phosphorylation at Thr(172) was not significantly altered. Moreover, I3V rapamycin pretreatment restored the metformin-induced anorexia and weight loss. These results suggest that the reduction in food intake induced by the central administration of metformin in the mice may be mediated by activation of S6K pathway.

Distinct universality classes of domain wall roughness in two-dimensional Pt/Co/Pt films.

We demonstrate here that the current-driven domain wall (DW) in two dimensions forms a "facet" roughness, distinctive to the conventional self-affine roughness induced by a magnetic field. Despite the different universality classes of these roughnesses, both the current- and field-driven DW speed follow the same creep law only with opposite angular dependences. Such angular dependences result in a stable facet angle, from which a single DW image can unambiguously quantify the spin-transfer torque efficiency, an essential parameter in DW-mediated nanodevices.

Electroconvulsive shock increases SIRT1 immunoreactivity in the mouse hippocampus and hypothalamus.

OBJECTIVES: Recent study shows that silent mating-type information regulation 2 homolog 1 (SIRT1) regulation may be involved with depression. Electroconvulsive shock (ECS) has been used for the treatment of depression, but little is known about the effect of ECS on the changes in SIRT1 levels in the brain. The present study was designed to observe whether ECS dynamically regulates SIRT1 levels in the hippocampus and hypothalamus; both of these regions have been implicated in the pathophysiology of depression. METHODS: Male imprinting control region mice were given a single ECS via ear clip electrodes, and then killed 0.5, 2, 8, 24, or 48 hours after ECS. Changes in SIRT1 were observed by Immunohistochemistry, and obtained results were compared with sham controls that did not receive ECS. RESULTS: Silent mating-type information regulation 2 homolog 1 immunoreactivity levels in the CA1 and CA3 subfields of the hippocampus peaked 2 hours after ECS and then returned to control levels by 24 hours after ECS. Silent mating-type information regulation 2 homolog 1 immunoreactivity levels in the dentate gyrus of hippocampus, hypothalamic paraventricular, dorsomedial, arcuate, and suprachiasmatic nuclei peaked 8 hours after ECS but had not completely returned to baseline levels 48 hours after ECS, except for the dentate gyrus. Electroconvulsive shock resulted in a gradual increase of SIRT1 immunoreactivity in the hypothalamic ventromedial nucleus and lateral hypothalamic area, which appeared to be still rising or peaking at the 48-hour post-ECS time point. CONCLUSIONS: The present results demonstrate that a single ECS increases SIRT1 in the mouse hippocampus and hypothalamus differentially in a region-specific time-dependent manner.

Metformin decreases meal size and number and increases c-Fos expression in the nucleus tractus solitarius of obese mice.

Metformin is widely used to treat obese diabetics because of its beneficial effects on body weight, energy intake, and glucose regulation. However, it has not been investigated how oral metformin affects meal patterns, or whether the reduced food intake is associated with neuronal activation in the hindbrain. Accordingly, we investigated how orally administered metformin (150 or 300 mg/kg daily for 4 or 7 days) reduces body weight in obese mice on a high-fat diet by continuously measuring meal patterns, energy expenditure, and locomotor activity, and whether oral metformin (300 mg/kg daily for 3 days) increases c-Fos expression in the nucleus tractus solitarius (NTS) and area postrema. Furthermore, we determined whether oral metformin produces a conditioned taste aversion (CTA) in obese mice administered a single dose of metformin (75, 150, or 300 mg/kg, p.o.). Metformin (300 mg/kg daily for 7 days) reduced body weight and adiposity by decreasing nocturnal energy intake but did not significantly change energy expenditure or locomotor activity relative to vehicle, and it transiently decreased nocturnal meal size and reduced meal number throughout the experiments. Furthermore, metformin significantly increased c-Fos immunoreactivity within the NTS of obese mice compared to that in controls and pair-fed group, and induced a CTA at doses of 150 or 300 mg/kg. These results indicate that metformin-induced weight loss is associated with a sustained reduction in energy intake maintained by a reduction in meal size and number, and that oral administration of metformin causes visceral illness and neuronal activation in the NTS.

Magnetic-field-controlled reconfigurable semiconductor logic.

Logic devices based on magnetism show promise for increasing computational efficiency while decreasing consumed power. They offer zero quiescent power and yet combine novel functions such as programmable logic operation and non-volatile built-in memory. However, practical efforts to adapt a magnetic device to logic suffer from a low signal-to-noise ratio and other performance attributes that are not adequate for logic gates. Rather than exploiting magnetoresistive effects that result from spin-dependent transport of carriers, we have approached the development of a magnetic logic device in a different way: we use the phenomenon of large magnetoresistance found in non-magnetic semiconductors in high electric fields. Here we report a device showing a strong diode characteristic that is highly sensitive to both the sign and the magnitude of an external magnetic field, offering a reversible change between two different characteristic states by the application of a magnetic field. This feature results from magnetic control of carrier generation and recombination in an InSb p-n bilayer channel. Simple circuits combining such elementary devices are fabricated and tested, and Boolean logic functions including AND, OR, NAND and NOR are performed. They are programmed dynamically by external electric or magnetic signals, demonstrating magnetic-field-controlled semiconductor reconfigurable logic at room temperature. This magnetic technology permits a new kind of spintronic device, characterized as a current switch rather than a voltage switch, and provides a simple and compact platform for non-volatile reconfigurable logic devices.

Comparison of inflammatory markers between diabetic and nondiabetic ST segment elevation myocardial infarction.

BACKGROUND: Inflammation plays a significant role in acute coronary syndrome (ACS) and type 2 diabetes mellitus (DM). There may be similar inflammatory changes in non-DM patients with ST elevation myocardial infarction (STEMI) and DM patients with stable angina (SA), and DM patients with STEMI may have more severe changes than the former two groups. The objectives of this study were to investigate whether the level of inflammation was similar in patients with non-DM STEMI and DM SA, and to evaluate whether the changes in the level of inflammation were more severe in patients with DM STEMI compared to the other two groups. METHODS AND RESULTS: A variety of inflammatory markers including: highly sensitive C-reactive protein (hsCRP), erythrocyte sedimentation rate (ESR), interleukin-6 (IL-6), IL-18, vascular cell adhesion molecule-1 (VCAM-1), and matrix metallopeptidase-9 (MMP-9) as well as insulin resistance were compared among the three groups: DM STEMI (90 patients), DM SA (91 patients), and non-DM STEMI (76 patients). Inflammatory marker levels were not significantly different between the DM SA and non-DM STEMI groups. However, hsCRP and IL-6 were increased in the DM STEMI compared to the DM SA patients (p=0.005 and p=0.004, respectively). In addition, hsCRP, ESR, and IL-18 were increased in the DM STEMI compared to the non-DM STEMI patients (p=0.017, p=0.020, and p=0.033, respectively). Furthermore, the fasting insulin and the homeostasis model assessment were significantly increased in the DM STEMI compared to the DM SA patients (p=0.04 and p=0.004, respectively). CONCLUSIONS: DM SA and non-DM STEMI may have similar inflammatory changes. DM STEMI may be a more severe inflammatory condition compared to patients with DM SA or non-DM STEMI.

Zaprinast activates MAPKs, NFκB, and Akt and induces the expressions of inflammatory genes in microglia.

Previously, the authors reported that zaprinast, an inhibitor of cGMP-selective phosphodiesterases, induced the secretions of TNF-α and IL-1ß by microglia and enhanced the induction of iNOS by lipopolysaccharide (LPS). In this study, the signaling mechanism responsible for microglial activation by zaprinast was investigated and the effects of zaprinast and LPS on microglial activation were compared. Zaprinast was found to activate ERK1/2, p38 MAPK, JNK, NFκB, and PI3K/Akt, and subsequently, induce the mRNA expressions of IL-1α, IL-1ß, TNF-α, CCL2, CCL4, CXCL1, CXCL2, and CD14. Associations between signaling pathways and gene expressions were examined by treating microglia with signal inhibitors. PDTC inhibited the induction of all the above genes by zaprinast, and SB203580 inhibited all genes except CXCL1. SP600125, PD98059, and LY294002 inhibited the induction of at least CCL2. Microglial activation by zaprinast was then compared with full-blown activation by LPS. The zaprinast-induced phosphorylations of MAPKs and IκB were less prompt than LPS-induced phosphorylations. IκB degradation by LPS was significant at 10min and did not return to normal, whereas zaprinast induced a later, transient degradation. LPS induced the mRNA expressions of IL-1ß, TNF-α, IL-6, CCL2, iNOS, and COX-2, and although zaprinast significantly induced the expressions of all except IL-6 and iNOS, these inductions were far less than those induced by LPS. Collectively, zaprinast was found to upregulate microglial activity mainly via NFκB and p38 MAPK signaling and the subsequent expressions of inflammatory genes. Although, zaprinast was found to have obvious effects on microglia, these were weaker than the effects of LPS.

Electric current effect on the energy barrier of magnetic domain wall depinning: origin of the quadratic contribution.

The energy barrier of a magnetic domain wall trapped at a defect is measured experimentally. When the domain wall is pushed by an electric current and/or a magnetic field, the depinning time from the barrier exhibits perfect exponential distribution, indicating that a single energy barrier governs the depinning. The electric current is found to generate linear and quadratic contributions to the energy barrier, which are attributed to the nonadiabatic and adiabatic spin-transfer torques, respectively. The adiabatic spin-transfer torque reduces the energy barrier and, consequently, causes depinning at lower current densities, promising a way toward low-power current-controlled magnetic applications.