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.

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.

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.

Interdimensional universality of dynamic interfaces.

Despite the complexity and diversity of nature, there exists universality in the form of critical scaling laws among various dissimilar systems and processes such as stock markets, earthquakes, crackling noise, lung inflation and vortices in superconductors. This universality is mainly independent of the microscopic details, depending only on the symmetry and dimension of the system. Exploring how universality is affected by the system dimensions is an important unresolved problem. Here we demonstrate experimentally that universality persists even at a dimensionality crossover in ferromagnetic nanowires. As the wire width decreases, the magnetic domain wall dynamics changes from elastic creep in two dimensions to a particle-like stochastic behaviour in one dimension. Applying finite-size scaling, we find that all our experimental data in one and two dimensions (including the crossover regime) collapse onto a single curve, signalling universality at the criticality transition. The crossover to the one-dimensional regime occurs at a few hundred nanometres, corresponding to the integration scale for modern nanodevices.

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.

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.

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.

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.

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.

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.

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.

Universality classes of magnetic domain wall motion.

We examine magnetic domain wall motion in metallic nanowires Pt-Co-Pt. Regardless of whether the motion is driven by either magnetic fields or current, all experimental data fall onto a single universal curve in the creep regime, implying that both the motions belong to the same universality class. This result is in contrast to the report on magnetic semiconductor (Ga,Mn)As exhibiting two different universality classes. Our finding signals the possible existence of yet other universality classes which go beyond the present understanding of the statistical mechanics of driven interfaces.

A single administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin that produces reduced food and water intake induces long-lasting expression of corticotropin-releasing factor, arginine vasopressin, and proopiomelanocortin in rat brain.

The mechanism by which a single administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) reduces food and water intake is unclear. We examined whether such a food and water intake-reducing single administration of TCDD induced changes in corticotropin-releasing factor (CRF), arginine vasopressin (AVP), and proopiomelanocortin (POMC) expression in rat brain. To observe time-dependent changes in these neuropeptides, male Sprague-Dawley rats were given TCDD (50 microg/kg) and terminated 1, 2, 4, or 7 days later. In addition, to observe dose-dependent changes in feeding and neuropeptides, rats were also given a range of TCDD doses (12.5, 25, or 50 microg/kg) and terminated 14 days later. TCDD suppressed food and water intake over 14 days in a dose-dependent manner. TCDD treatment also increased CRF and POMC mRNA levels in the hypothalamic paraventricular nucleus (PVN) and arcuate nucleus, respectively, in a dose- and time-dependent manner. These increases were related to decreased food intake following TCDD administration. TCDD treatment increased AVP and CRF mRNA levels in the PVN, and these increases were related to decreased water intake. Interestingly, the increases in CRF, AVP and POMC expression were observed 7 to 14 days after TCDD administration. These results suggest that a single administration of TCDD induced long-lasting increases in CRF, AVP, and POMC mRNA levels in the hypothalamus and that these changes are related to reduced food and water intake 7 to 14 days after TCDD administration.

Lamotrigine prevents MK801-induced alterations in early growth response factor-1 mRNA levels and immunoreactivity in the rat brain.

MK801 (dizocilpine) induces selective neurotoxic effects in the retrosplenial cortex, ranging from neuronal vacuolization to irreversible neurodegeneration depending on the dose administered. Although lamotrigine prevents MK801-induced neuronal vacuolization in the retrosplenial cortex 4 h after injection, it is not clear whether lamotrigine attenuates the subsequent neurodegeneration that occurs 3-4 days later. Because early growth response factor-1 (egr-1) plays a key role in neurodegeneration and its expression is induced in the retrosplenial cortex following MK801 treatment, it is possible that lamotrigine may attenuate MK801-induced neurodegeneration via inhibition of egr-1 expression in the retrosplenial cortex. To address this issue, we treated rats with lamotrigine (10 or 20 mg/kg) followed by MK801 (2 mg/kg) and measured changes in the levels of egr-1 mRNA and immunoreactivity in the retrosplenial cortex and other brain regions 3 h later. We also evaluated the effects of these treatments on neurodegeneration 4 days following treatment using Fluoro-Jade B staining. MK801 treatment increased egr-1 mRNA and immunoreactivity in the restrosplenial, cingulate, entorhinal and piriform cortices, but decreased levels in hippocampal subfields. These MK801-induced changes in egr-1 expression were significantly inhibited by lamotrigine pretreatment. In addition, MK801-induced neurodegeneration in the retrosplenial cortex was partially blocked by lamotrigine pretreatment in a dose dependent manner. These results demonstrate that lamotrigine pretreatment prevents the MK801-induced upregulation of egr-1 expression in a region-selective manner, and suggest that this effect may contribute, in part, to the attenuation of MK801-induced neurodegeneration in the retrosplenial cortex.

Cytokine imbalance in the pathophysiology of major depressive disorder.

OBJECTIVE: A substantial body of evidence indicates that dysregulation of the immune system is associated with Major Depressive Disorder (MDD). Because most cytokines have pleiotropic effects, we measured various subsets of cytokines to examine the association between immune response and MDD. METHODS: Forty-eight hospitalized MDD patients and 63 normal controls were recruited. We measured in vitro monocytic (IL-6 and tumor necrosis factor (TNF)-alpha), Th1 (interferon (IFN)-gamma and interleukin (IL)-2), Th2 (IL-4), and Treg (transforming growth factor (TGF)-beta1) cytokine production as well as IL-2/IL-4 and IFN-gamma/IL-4 ratios for both groups. Depressive symptoms were assessed by Hamilton Depression Rating Scale. Patients were evaluated before and after 6 weeks of antidepressant treatment. RESULTS: At admission, IL-6, TNF-alpha, TGF-beta1 production, and IFN-gamma/IL-4 ratio were significantly higher, whereas IFN-gamma, IL-2, and IL-4 were significantly lower in MDD patients. After treatment, IL-6 and TGF-beta1 production were significantly lower than before treatment. CONCLUSION: We suggest that activation of monocytic proinflammatory cytokines, and inhibition of both Th1 and Th2 cytokines may be associated with immunological dysregulation in MDD. TGF-beta1 may be associated with the regulation of monocytic cytokines as well as Th1 and Th2 cytokines in MDD.

Field dependence of switching currents in an exchange biased spin valve.

Current induced magnetic reversal due to spin transfer torque is a promising candidate in advanced information storage technology. It has been intensively studied. This work reports the field-dependence of switching-currents for current induced magnetization switching in a uncoupled nano-sized cobalt-based spin valve of exchange biased type. The dependency is investigated in hysteretic regime at room temperature, in comparison with that of a trilayer simple spin valve. In the simple spin valve, the switching currents behave to the positive and the negative applied magnetic field symmetrically. In the exchange biased type, in contrast, the switching currents respond to the negative field in a quite unusual and different manner than to the positive field. A negative magnetic field then can shift the switching-currents into either negative or positive current range, dependently on whether a parallel or an antiparallel state of the spin valve was produced by that field. This different character of switching currents in the negative field range can be explained by the effect of the exchange bias pinning field on the spin-polarizer (the fixed Co layer) of the exchange biased spin valve. That unidirectional pinning filed could suppress the thermal magnetization fluctuation in the spin-polarizer, leading to a higher spin polarization of the current, and hence a lower switching current density than in the simple spin valve.

Effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of amlodipine in healthy Korean subjects.

BACKGROUND AND OBJECTIVE: 1,4-Dihydropyridine calcium channel blockers, including amlodipine, are mainly metabolized by cytochrome P450 (CYP) 3A. We investigated the effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of amlodipine in healthy Korean male subjects. METHODS: Forty healthy male participants were enrolled and genotyped for the CYP3A5*3 gene. Each subject ingested a 5-mg dose of amlodipine, and plasma amlodipine concentrations were measured for 144 hours after dosing. Blood pressure and pulse rate were also measured for pharmacodynamic analysis. RESULTS: Among the 40 volunteers, 24 were CYP3A5*3/*3 carriers and 16 were CYP3A5*1 carriers (CYP3A5*1/*1 in 2 and CYP3A5*1/*3 in 14). The difference in the oral clearance of amlodipine approached statistical significance between the 2 major genotype groups, with CYP3A5*1 carriers (27.0 +/- 8.2 L/h) showing 20% lower clearance than CYP3A5*3/*3 carriers (32.4 +/- 10.2 L/h) (P = .063). However, the mean area under the plasma concentration-time curve of amlodipine was 200.9 +/- 61.9 ng . h/mL for CYP3A5*1 carriers and 167.6 +/- 45.0 ng . h/mL for CYP3A5*3/*3 carriers (P = .029). Moreover, the peak plasma concentration was significantly higher in CYP3A5*1 carriers (3.8 +/- 1.1 ng/mL) than in CYP3A5*3/*3 carriers (3.1 +/- 0.8 ng/mL) (P = .037). Pharmacodynamically, blood pressure and pulse rate were not significantly different between the 2 groups. CONCLUSIONS: CYP3A5*3/*3 carriers exhibited lower plasma amlodipine concentrations than CYP3A5*1 carriers. These findings suggest that the polymorphic CYP3A5 gene affects the disposition of amlodipine and provides a plausible explanation for interindividual variability in amlodipine disposition.

Effects of repeated tianeptine treatment on CRF mRNA expression in non-stressed and chronic mild stress-exposed rats.

Accumulating evidence suggests that dysregulation of corticotropin-releasing factor (CRF) may play a role in depression and that this dysregulation may be corrected by antidepressant drug treatment. Here, we examined whether chronic mild stress (CMS) alters CRF mRNA levels in stress-related brain areas including the bed nucleus of the stria terminalis (BNST) and the central nucleus of amygdala (CeA), and whether repeated tianeptine treatment can attenuate CMS-induced changes in CRF mRNA levels. Male rats were exposed to CMS for 19 days, and control animals were subjected to brief handling. Both groups were injected daily with tianeptine or saline. CMS significantly increased CRF mRNA levels in the dorsal BNST (dBNST), but not in other areas. Repeated tianeptine treatment prevented the CMS-induced increase in CRF mRNA levels in the dBNST, and reduced CRF mRNA levels in dBNST in non-stressed controls. Moreover, repeated tianeptine treatment significantly decreased CRF mRNA levels in the ventral BNST and CeA of non-stressed controls as well as CMS-exposed rats. These results show that CMS induces a rather selective increase of CRF mRNA in the dBNST. In addition, these results suggest that repeated tianeptine treatment diminishes the basal activity of CRF neurons and reduces their sensitivity to stress.

Chronic mild stress decreases survival, but not proliferation, of new-born cells in adult rat hippocampus.

New-born cells continue to proliferate and survive to become mature granule cells in adult rat hippocampus. Although this process, known as neurogenesis, is inhibited by acute stress, it is not clear whether chronic stress affects neurogenesis. To determine whether chronic mild stress (CMS) influences neurogenesis in the adult rat hippocampus, male Sprague-Dawley rats were exposed to CMS and administered bromodeoxyuridine (BrdU) before or after CMS to observe the survival/differentiation or proliferation of new-born cells, respectively. In addition, we measured brain-derived neurotrophic factor (BDNF) mRNA in the granule cell layer (GCL) of the hippocampus, because BDNF is known to play an important role in the survival of new-born cells. CMS significantly decreased the survival of new-born cells in the GCL, but did not influence the proliferation or differentiation of new-born cells. CMS did not affect the proliferation and survival of new-born cells in the hilus. In addition, CMS did not change BDNF mRNA levels in the GCL. These results demonstrate that CMS reduces the survival of new-born cells but not of their proliferation, suggesting that repeated mild stress could influence a part of neurogenesis, but not the whole part of neurogenesis. These results raise the possibility that the survival of new-born cells may be suppressed in the presence of normal BDNF mRNA levels in GCL.