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Recently, along with the era of the 4th Industrial Revolution, education trends are rapidly changing. Education focused on the role of first movers based on creative ideas and on how to respond in new environment changes is necessary. This study examines the role of instructors in the field of education and identifies the direction of training for teachers that is fit for the changing times. This is done by empirically grasping the effect of the role of instructors on educational service quality, recommendation, and course repetition through the implementation of the development of faculty member competency. As a result of this study, it is found that the role of the instructor, seen from the perspective of a user, has a close direct and indirect effect on the education service quality, recommendation, and intention for course repetition. The obtained result was that the quality of education for learners should improve through the individual competency improvement of the instructors and that resources should be devoted to improving competency in order to cultivate talented students that match the flow of the times. It is hoped that this could be an opportunity to realize once again that education and its results can be different depending on the efforts of the instructor.

We study the Birkhoff-James orthogonality on operator spaces in terms of the Bhatia-Semrl property. We first prove that every functional on a Banach space X has the Bhatia-Semrl property if and only if X is reflexive. We also find some geometric conditions of Banach space which ensure the denseness of operators with Bhatia-Semrl property. Finally, we investigate operators with the Bhatia-Semrl property when a domain space is L 1 [ 0 , 1 ] or C [ 0 , 1 ] .

In pathological brain conditions, glial cells become reactive and show a variety of responses. We examined Ca2+ signals in pathological brains and found that reactive astrocytes share abnormal Ca2+ signals, even in different types of diseases. In a neuropathic pain model, astrocytes in the primary sensory cortex became reactive and showed frequent Ca2+ signals, resulting in the production of synaptogenic molecules, which led to misconnections of tactile and pain networks in the sensory cortex, thus causing neuropathic pain. In an epileptogenic model, hippocampal astrocytes also became reactive and showed frequent Ca2+ signals. In an Alexander disease (AxD) model, hGFAP-R239H knock-in mice showed accumulation of Rosenthal fibers, a typical pathological marker of AxD, and excessively large Ca2+ signals. Because the abnormal astrocytic Ca2+ signals observed in the above three disease models are dependent on type II inositol 1,4,5-trisphosphate receptors (IP3RII), we reanalyzed these pathological events using IP3RII-deficient mice and found that all abnormal Ca2+ signals and pathologies were markedly reduced. These findings indicate that abnormal Ca2+ signaling is not only a consequence but may also be greatly involved in the cause of these diseases. Abnormal Ca2+ signals in reactive astrocytes may represent an underlying pathology common to multiple diseases.

Chemotherapy-induced peripheral neuropathy (CIPN) often develops in patients with cancer treated with commonly used anti-cancer drugs. The symptoms of CIPN can occur acutely during chemotherapy or emerge after cessation, and often accompany long-lasting intractable pain. This adverse side effect not only affects the quality of life but also limits the use of chemotherapy, leading to a reduction in the survival rate of patients with cancer. Currently, effective treatments for CIPN are limited, and various interventions are being applied by clinicians and patients because of the unmet clinical need. Potential approaches to ameliorate CIPN include traditional Eastern medicine-based methods. Medicinal substances from traditional Eastern medicine have well-established analgesic effects and are generally safe. Furthermore, many substances can also improve other comorbid symptoms in patients. This article aims to provide information regarding traditional Eastern medicine-based plant extracts and natural compounds for CIPN. In this regard, we briefly summarized the development, mechanisms, and changes in the nervous system related to CIPN, and reviewed the substances of traditional Eastern medicine that have been exploited to treat CIPN in preclinical and clinical settings.

Activation of astrocytes has a profound effect on brain plasticity and is critical for the pathophysiology of several neurological disorders including neuropathic pain. Here, we show that metabotropic glutamate receptor 5 (mGluR5), which reemerges in astrocytes in a restricted time frame, is essential for these functions. Although mGluR5 is absent in healthy adult astrocytes, it transiently reemerges in astrocytes of the somatosensory cortex (S1). During a limited spatiotemporal time frame, astrocytic mGluR5 drives Ca2+ signals; upregulates multiple synaptogenic molecules such as Thrombospondin-1, Glypican-4, and Hevin; causes excess excitatory synaptogenesis; and produces persistent alteration of S1 neuronal activity, leading to mechanical allodynia. All of these events were abolished by the astrocyte-specific deletion of mGluR5. Astrocytes dynamically control synaptic plasticity by turning on and off a single molecule, mGluR5, which defines subsequent persistent brain functions, especially under pathological conditions.

Neuropathic pain is an intractable chronic pain, caused by damage to the somatosensory nervous system. To date, treatment for neuropathic pain has limited effects. For the development of efficient therapeutic methods, it is essential to fully understand the pathological mechanisms of neuropathic pain. Besides abnormal sensitization in the periphery and spinal cord, accumulating evidence suggests that neural plasticity in the brain is also critical for the development and maintenance of this pain. Recent technological advances in the measurement and manipulation of neuronal activity allow us to understand maladaptive plastic changes in the brain during neuropathic pain more precisely and modulate brain activity to reverse pain states at the preclinical and clinical levels. In this review paper, we discuss the current understanding of pathological neural plasticity in the four pain-related brain areas: the primary somatosensory cortex, the anterior cingulate cortex, the periaqueductal gray, and the basal ganglia. We also discuss potential treatments for neuropathic pain based on the modulation of neural plasticity in these brain areas.

Oxaliplatin, a third-generation platinum derivative, is the mainstay of current antineoplastic medications for advanced colorectal cancer therapy. However, peripheral neuropathic complications, especially cold allodynia, undermine the life-prolonging outcome of this anti-cancer agent. Rosavin, a phenylpropanoid derived originally from Rhodiola rosea, exhibits a wide range of therapeutic properties. The present study explored whether and how rosavin alleviates oxaliplatin-induced cold hypersensitivity in mice. In the acetone drop test, cold allodynia behavior was observed from days 3 to 5 after a single injection of oxaliplatin (6 mg/kg, i.p.). Cold allodynia was significantly attenuated following rosavin treatment (10 mg/kg, i.p.). Specific endogenous 5-HT depletion by three consecutive pretreatments with para-chlorophenylalanine (150 mg/kg/day, i.p.) abolished the analgesic action of rosavin; this effect was not observed following pretreatment with naloxone (opioid receptor antagonist, 10 mg/kg, i.p.). Furthermore, 5-HT1A receptor antagonist WAY-100635 (0.16 mg/kg, i.p.), but not 5-HT3 receptor antagonist MDL-72222 (1 mg/kg, i.p.), blocked rosavin-induced analgesia. These results suggest that rosavin may provide a novel approach to alleviate oxaliplatin-induced cold allodynia by recruiting the activity of 5-HT1A receptors.

Chemotherapy‐induced peripheral neuropathy (CIPN) frequently occurs in cancer patients. This side effect lowers the quality of life of patients and may cause the patients to abandon chemotherapy. Several medications (e.g., duloxetine and gabapentin) are recommended as remedies to treat CIPN; however, usage of these drugs is limited because of low efficacy or side effects such as dizziness, nausea, somnolence, and vomiting. From ancient East Asia, the decoction of medicinal herbal formulas or single herbs have been used to treat pain and could serve as alternative therapeutic option. Recently, the analgesic potency of medicinal plants and their phytochemicals on CIPN has been reported, and a majority of their effects have been shown to be mediated by glial modulation. In this review, we summarize the analgesic efficacy of medicinal plants and their phytochemicals, and discuss their possible mechanisms focusing on glial modulation in animal studies., Medicinal plants and phytochemicals alleviate CIPN by modulating spinal glial activity.

We study approximation of operators between Banach spaces $X$ and $Y$ that nearly attain their norms in a given point by operators that attain their norms at the same point. When such approximations exist, we say that the pair $(X, Y)$ has the pointwise Bishop-Phelps-Bollob\'as property (pointwise BPB property for short). In this paper we mostly concentrate on those $X$, called universal pointwise BPB domain spaces, such that $(X, Y)$ possesses pointwise BPB property for every $Y$, and on those $Y$, called universal pointwise BPB range spaces, such that $(X, Y)$ enjoys pointwise BPB property for every uniformly smooth $X$. We show that every universal pointwise BPB domain space is uniformly convex and that $L_p(\mu)$ spaces fail to have this property when $p>2$. For universal pointwise BPB range space, we show that every simultaneously uniformly convex and uniformly smooth Banach space fails it if its dimension is greater than one. We also discuss a version of the pointwise BPB property for compact operators., Comment: 19 pages, to appear in the Canadian J. Math. In this version, section 6 and the appendix of the previous version have been removed

Metabotropic glutamate receptor 5 (mGluR5) in astrocytes is a key molecule for controlling synapse remodeling. Although mGluR5 is abundant in neonatal astrocytes, its level is gradually down-regulated during development and is almost absent in the adult. However, in several pathological conditions, mGluR5 re-emerges in adult astrocytes and contributes to disease pathogenesis by forming uncontrolled synapses. Thus, controlling mGluR5 expression in astrocyte is critical for several diseases, but the mechanism that regulates mGluR5 expression remains unknown. Here, we show that adenosine triphosphate (ATP)/adenosine-mediated signals down-regulate mGluR5 in astrocytes. First, in situ Ca

Cachexia causes high mortality, low quality of life, and rapid weight loss in cancer patients. Sarcopenia, a condition characterized by the loss of muscle, is generally present in cachexia and is associated with inflammation. M2 macrophages, also known as an anti-inflammatory or alternatively activated macrophages, have been shown to play a role in muscle repair. Magnoliae Cortex (M.C) is a widely used medicinal herb in East Asia reported to have a broad range of anti-inflammatory activities, however, the effects of M.C on sarcopenia and on M2 macrophage polarization have to date not been studied. This study was designed to investigate whether the oral administration of M.C could decrease cisplatin-induced sarcopenia by modulating M2 macrophage polarization in mice. C57BL/6 mice were injected intraperitoneally with cisplatin (2.5 mg/kg) to mimic chemotherapy-induced sarcopenia. M.C extract (50, 100, and 200 mg/kg) was administered orally every 3 days (for a total of 12 times). M.C (100 and 200 mg/kg) significantly alleviated the cisplatin-induced loss of body mass, skeletal muscle weight, and grip strength. In addition, M.C increased the expression of M2 macrophage markers, such as MRC1, CD163, TGF-β, and Arg-1, and decreased the expression of M1-specific markers, including NOS2 and TNF-α, in skeletal muscle. Furthermore, the levels of like growth factor-1(IGF-1), as well as the number of M2a and M2c macrophages, significantly increased in skeletal muscle after M.C administration. M.C did not interfere with the anticancer effect of cisplatin in colon cancer. Our results demonstrated that M.C can alleviate cisplatin-induced sarcopenia by increasing the number of M2 macrophages. Therefore, our findings suggest that M.C could be used as an effective therapeutic agent to reverse or prevent cisplatin-induced sarcopenia.

Very recently, motivated by the result of Bhatia and \v{S}emrl which characterizes the Birkhoff-James orthogonality of operators on a finite dimensional Hilbert space in terms of norm attaining points, the Bhatia-\v{S}emrl property was introduced. The main purpose of this article is to study the denseness of the set of multilinear maps with the Bhatia-\v{S}emrl property which is contained in the set of norm attaining ones. Contrary to the most of previous results which were shown for operators on real Banach spaces, we prove the denseness for multilinear maps on some complex Banach spaces. We also show that the denseness of operators does not hold when the domain space is $c_0$ for arbitrary range. Moreover, we find plenty of Banach spaces $Y$ such that only the zero operator has the Bhatia-\v{S}emrl property in the space of operators from $c_0$ to $Y$., Comment: 13 pages

Vincristine is a vinca alkaloid anti-mitotic drug with a broad spectrum of effects on solid and hematologic cancers. The major dose-limiting factor of this anti-cancer regimen is painful peripheral neuropathy. However, no gold-standard analgesic option has been used clinically. In this study, we investigated the effects and mechanism of bee venom acupuncture (BVA) to alleviate peripheral neuropathic pain induced by repeated intraperitoneal infusions of vincristine (1 mg/kg/day, days 1&ndash, 5 and 8&ndash, 12) in rats. Subcutaneous injection with bee venom (BV, 1.0 mg/kg) at the ST36 acupoint ameliorated cold and mechanical hypersensitivity (i.e., aberrant withdrawal responses in acetone drop and von Frey hair tests, respectively). In vivo extracellular recording demonstrated that BVA inhibited cutaneous cold (acetone) and mechanical (brush, press, and pinch) stimuli-elicited abnormal hyperexcitation of the spinal wide dynamic range (WDR) neurons in vincristine-treated rats. In addition, the microinjection of lidocaine into the ipsilateral locus coeruleus or the antagonism of the spinal &alpha, 2-adrenergic receptors clearly reversed the effects of BVA on cold and mechanical hypersensitivity, indicating a vital role of the descending noradrenergic modulation in analgesia. These findings suggest that BVA could be a potential therapeutic option for vincristine-induced peripheral neuropathy.

Climbing fibers (CFs) generate complex spikes (CS) and Ca2+ transients in cerebellar Purkinje cells (PCs), serving as instructive signals. The so-called 'all-or-none' character of CSs has been questioned since the CF burst was described. Although recent studies have indicated a sensory-driven enhancement of PC Ca2+ signals, how CF responds to sensory events and contributes to PC dendritic Ca2+ and CS remains unexplored. Here, single or simultaneous Ca2+ imaging of CFs and PCs in awake mice revealed the presynaptic CF Ca2+ amplitude encoded the sensory input’s strength and directly influenced post-synaptic PC dendritic Ca2+ amplitude. The sensory-driven variability in CF Ca2+ amplitude depended on the number of spikes in the CF burst. Finally, the spike number of the CF burst determined the PC Ca2+ influx and CS properties. These results reveal the direct translation of sensory information-coding CF inputs into PC Ca2+, suggesting the sophisticated role of CFs as error signals.

Paclitaxel, a primary chemotherapeutic agent used to treat numerous solid malignancies, is commonly associated with debilitating peripheral neuropathy. However, a satisfactory gold-standard monotherapy for this neuropathic pain is not currently available. A combination strategy of two or more medications with different properties may achieve more beneficial effects than monotherapy. Thus, we investigated the analgesic efficacies and spinal mechanisms of the combination strategy, including bee venom acupuncture (BVA) and venlafaxine (VLX) against paclitaxel-induced allodynia in mice. Four intraperitoneal infusions of paclitaxel on alternating days (2 mg/kg/day) induced cold and mechanical allodynia for at least 1 week as assessed using acetone and the von Frey hair test, respectively. Co-treatment of BVA (1.0 mg/kg, s.c., ST36) with VLX (40 mg/kg, i.p.) at the medium dose produced a longer-lasting and additive effect than each monotherapy at the highest dose (BVA, 2.5 mg/kg, VLX, 60 mg/kg). Spinal pre-administration of idazoxan (&alpha, 2-adrenergic receptor antagonist, 10 &mu, g), methysergide (mixed 5-HT1/5-HT2 receptor antagonist, 10 &mu, g), or MDL-72222 (5-HT3 receptor antagonist, 10 &mu, g) abolished this analgesia. These results suggest that the combination therapy with BVA and VLX produces long-lasting and additive analgesic effects on paclitaxel-induced allodynia, via the spinal noradrenergic and serotonergic mechanism, providing a promising clinical strategy.

The primary somatosensory (S1) cortex plays a key role in distinguishing different sensory stimuli. Vibrotactile touch information is conveyed from the periphery to the S1 cortex through three major classes of mechanoreceptors: slowly adapting type 1 (SA1), rapidly adapting (RA), and Pacinian (PC) afferents. It has been a long-standing question whether specific populations in the S1 cortex preserve the peripheral segregation by the afferent submodalities. Here, we investigated whether S1 neurons exhibit specific responses to two distinct vibrotactile stimuli, which excite different types of mechanoreceptors (e.g., SA1 and PC afferents). Using in vivo two-photon microscopy and genetically encoded calcium indicator, GCaMP6s, we recorded calcium activities of S1 L2/3 neurons. At the same time, static (

We introduce and investigate the mth polarization constant of a Banach space X for the numerical radius. We first show the difference between this constant and the original mth polarization constant associated with the norm by proving that the new constant is minimal if and only if X is strictly convex, and that there exists a Banach space which does not have an almost isometric copy of $$\ell _1^2$$ , such that the second polarization constant for the numerical radius is maximal. We also give a negative answer for complex Banach spaces to the question of Choi and Kim (J Lond Math Soc (2) 54(1):135–147, 1996) whether $$\frac{\sum _{k=1}^m k^m ~\left( {\begin{array}{c}m\\ k\end{array}}\right) }{m!}$$ is the optimal upper bound for the mth polarization constant for arbitrary $$m\in \mathbb {N}$$ . Finally, we generalize the result of Garcia et al. (Proc Am Math Soc 142(4):1229–1235, 2014) that, for 2-homogeneous polynomials, the numerical index of a complex lush space is greater or equal than 1/3.

We developed AI-bRNN (Average training, Individual test-bidirectional Recurrent Neural Network) to decipher spontaneous pain information from brain cellular calcium signals recorded by two-photon imaging in awake, head-fixed mice. The AI-bRNN determines the intensity and time point of spontaneous pain even during the chronic pain period and evaluates the efficacy of analgesics. Furthermore, it could be applied to different cell types and brain areas, and it distinguished between itch and pain, proving its versatility.

In this paper, we are interested in studying two properties related to the denseness of the operators which attain their numerical radius: the Bishop-Phelps-Bollob\'as point and operator properties for numerical radius (BPBpp-nu and BPBop-nu, respectively). We prove that every Banach space with micro-transitive norm and second numerical index strictly positive satisfy the BPBpp-nu and that, if the numerical index of $X$ is 1, only one-dimensional spaces enjoy it. On the other hand, we show that the BPBop-nu is a very restrictive property: under some general assumptions, it holds only for one-dimensional spaces. We also consider two weaker properties, the local versions of BPBpp-nu and BPBop-nu, where the $\eta$ which appears in their definition does not depend just on $\epsilon > 0$ but also on a state $(x, x^*)$ or on a numerical radius one operator $T$. We address the relation between the local BPBpp-nu and the strong subdifferentiability of the norm of the space $X$. We show that finite dimensional spaces and $c_0$ are examples of Banach spaces satisfying the local BPBpp-nu, and we exhibit an example of a Banach space with strongly subdifferentiable norm failing it. We finish the paper by showing that finite dimensional spaces satisfy the local BPBop-nu and that, if $X$ has strictly positive numerical index and has the approximation property, this property is equivalent to finite dimensionality.

We study the Bhatia–Semrl property which is related to Birkhoff–James orthogonality on operator spaces. Recently, many authors obtained some conditions for operators to have Bhatia–Semrl property. Using them, we explore the denseness of operators with Bhatia–Semrl property or without Bhatia–Semrl property on some classes of Banach spaces.

We study the Bishop–Phelps–Bollobas property and the Bishop–Phelps–Bollobas property for numerical radius. Our main aim is to extend some known results about norm or numerical radius attaining operators to multilinear and polynomial cases. We characterize the pair ( l 1 ( X ) , Y ) to have the BPBp for bilinear forms and prove that on L 1 ( μ ) the numerical radius and the norm of a multilinear mapping are the same. We also show that L 1 ( μ ) fails the BPBp-nu for multilinear mappings although L 1 ( μ ) satisfies it in the operator case for every measure μ.

Astrocytes, a major type of glia, reciprocally influence synaptic transmission and connectivity, forming the "tripartite synapses". Astrocytic metabotropic glutamate receptor (mGluR)-mediated Ca2+ waves and release of gliotransmitters or synaptogenic molecules mediate this neuron-glia interaction in the developing brain, but this signaling has been challenged for adult brain. However, cumulative evidence has suggested that mature astrocytes exhibit re-awakening of such immature phenotype in the pathological adult brain. This phenotypic change in astrocytes in response to injury may induce neural circuit and synapse plasticity. In this review article, we summarize astrocyte-mediated synapse remodeling during physiological development, discuss re-emergence of immature astrocytic signaling in adult pathological brain, and finally highlight its contribution to significant modification of synaptic connections correlating with functional progress of brain pathology.

Tissue or nerve injury induces widespread plastic changes from the periphery and spinal cord up to the cortex, resulting in chronic pain. Although many clinicians and researchers have extensively studied altered nociceptive signaling and neural circuit plasticity at the spinal cord level, effective treatments to ameliorate chronic pain are still insufficient. For about the last two decades, the rapid development in macroscopic brain imaging studies on humans and animal models have revealed maladaptive plastic changes in the 'pain matrix' brain regions, which may subsequently contribute to chronic pain. Among these brain regions, our group has concentrated for many years on the primary somatosensory (S1) cortex with a help of advanced imaging techniques and has found the functional and structural changes in neurons/glia as well as individual synapses in the S1 cortex during chronic pain. Taken together, it is now believed that such S1 plasticity is one of the causes for chronic pain, not a simple and passive epiphenomenon following tissue/nerve injury as previously thought. In this small review, we discuss the relation of plasticity in the S1 cortex with chronic pain, based on clinical trials and experimental studies conducted on this field. This article is part of the special article series "Pain".

We exhibit a new class of Banach spaces Y such that the pair ( c 0 , Y ) has the Bishop–Phelps–Bollobas property for operators. This class contains uniformly convex Banach spaces and spaces with the property β of Lindenstrauss. We also provide new examples of spaces in this class.

In this article, we study a version of the Bishop–Phelps–Bollobas property. We investigate a pair of Banach spaces ( X , Y ) such that every operator from X into Y is approximated by operators which attain their norm at the same point where the original operator almost attains its norm. In this case, we say that such a pair has the Bishop–Phelps–Bollobas point property (BPBpp). We characterize uniform smoothness in terms of BPBpp and we give some examples of pairs ( X , Y ) which have and fail this property. Some stability results are obtained about l 1 and l ∞ sums of Banach spaces and we also study this property for bilinear mappings.

Oxaliplatin is a chemotherapeutic agent used for metastatic colon and other advanced cancers. Most common side effect of oxaliplatin is peripheral neuropathy, manifested in mechanical and cold allodynia. Although the analgesic effect of bee venom has been proven to be effective against oxaliplatin-induced peripheral neuropathy, the effect of its major component, melittin has not been studied yet. Thus, in this study, we investigated whether melittin has an analgesic effect on oxaliplatin-induced allodynia. Intraperitoneal single injection of oxaliplatin (6 mg/kg) induced mechanical and cold allodynia, resulting in increased withdrawal behavior in response to von Frey filaments and acetone drop on hind paw. Subcutaneous melittin injection on acupoint ST36 (0.5 mg/kg) alleviated oxaliplatin-induced mechanical and cold allodynia. In electrophysiological study, using spinal in vivo extracellular recording, it was shown that oxaliplatin-induced hyperexcitation of spinal wide dynamic range neurons in response to peripheral stimuli, and melittin administration inhibited this neuronal activity. In behavioral assessment, analgesic effect of melittin was blocked by intrathecal &alpha, 1- and &alpha, 2- adrenergic receptor antagonists administration. Based on these results, we suggest that melittin could be used as an analgesic on oxaliplatin-induced peripheral neuropathy, and that its effect is mediated by activating the spinal &alpha, 2-adrenergic receptors.

Some local versions of the Bishop–Phelps–Bollobás property for operators have been recently presented in Dantas et al. (J Math Anal Appl 468(1):304–323, 2018). In the present article, we continue studying these properties for multilinear mappings. We show some differences between the local and uniform versions of these and also provide some interesting examples which show that this study is not just a mere generalization of the linear case. As a consequence of our results, we get that, for 2 < p, q< ∞, the norm of the projective tensor product ℓp⊗ ^ πℓq is strongly subdifferentiable. Moreover, we present necessary and sufficient conditions for the norm of a Banach space Y to be strongly subdifferentiable through the study of these properties for bilinear mappings on ℓ1N×Y. Fil: Dantas, Sheldon. Czech Technical University in Prague; República Checa Fil: Kim, Sun Kwang. Chungbuk National University; Corea del Sur Fil: Lee, Han Ju. Dongguk University, Seoul; Corea del Sur Fil: Mazzitelli, Martin Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; Argentina. Universidad Nacional de Cuyo; Argentina. Comisión Nacional de Energía Atómica. Fundación José A. Balseiro; Argentina

The analgesic effect of venlafaxine (VLX), which is a selective serotonin and noradrenaline reuptake inhibitor (SNRI), has been observed on oxaliplatin-induced neuropathic pain in mice. Significant allodynia was shown after oxaliplatin treatment (6 mg/kg, i.p.), acetone and von Frey hair tests were used to assess cold and mechanical allodynia, respectively. Intraperitoneal administration of VLX at 40 and 60 mg/kg, but not 10 mg/kg, significantly alleviated these allodynia. Noradrenaline depletion by pretreatment of N-(2-Chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, 50 mg/kg, i.p.) blocked the relieving effect of VLX (40 mg/kg, i.p.) on cold and mechanical allodynia. However, serotonin depletion by three consecutive pretreatments of para-chlorophenylalanine (PCPA, 150 mg/kg/day, i.p.) only blocked the effect of VLX on mechanical allodynia. In cold allodynia, the &alpha, 2-adrenergic antagonist idazoxan (10 &mu, g, i.t.), but not the &alpha, 1-adrenergic antagonist prazosin (10 &mu, g, i.t.), abolished VLX-induced analgesia. Furthermore, idazoxan and 5-HT3 receptor antagonist bemesetron (MDL-72222, 15 &mu, g, i.t.), but not prazosin or mixed 5-HT1, 2 receptor antagonist methysergide (10 &mu, g, i.t.), abolished VLX-induced analgesia in mechanical allodynia. In conclusion, 40 mg/kg of VLX treatment has a potent relieving effect against oxaliplatin-induced neuropathic pain, and &alpha, 2-adrenergic receptor, and both &alpha, 2-adrenergic and 5-HT3 receptors are involved in this effect of VLX on cold and mechanical allodynia, respectively.

A chemotherapy drug, oxaliplatin, induces cold and mechanical hypersensitivity, but effective treatments for this neuropathic pain without side effects are still lacking. We previously showed that Cinnamomi Cortex suppresses oxaliplatin-induced pain behaviors in rats. However, it remains unknown which phytochemical of Cinnamomi Cortex plays a key role in that analgesic action. Thus, here we investigated whether and how cinnamic acid or cinnamaldehyde, major components of Cinnamomi Cortex, alleviates cold and mechanical allodynia induced by a single oxaliplatin injection (6 mg/kg, i.p.) in rats. Using an acetone test and the von Frey test for measuring cold and mechanical allodynia, respectively, we found that administration of cinnamic acid, but not cinnamaldehyde, at doses of 10, 20 and 40 mg/kg (i.p.) significantly attenuates the allodynic behaviors in oxaliplatin-injected rats with the strongest effect being observed at 20 mg/kg. Our in vivo extracellular recordings also showed that cinnamic acid (20 mg/kg, i.p.) inhibits the increased activities of spinal wide dynamic range neurons in response to cutaneous mechanical and cold stimuli following the oxaliplatin injection. These results indicate that cinnamic acid has an effective analgesic action against oxaliplatin-induced neuropathic pain through inhibiting spinal pain transmission, suggesting its crucial role in mediating the effect of Cinnamomi Cortex.

Given two real Banach spaces $X$ and $Y$ with dimensions greater than one, it is shown that there is a sequence $\{T_n\}_{n\in \mathbb{N}}$ of norm attaining norm-one operators from $X$ to $Y$ and a point $x_0\in X$ with $\|x_0\|=1$, such that $\|T_n(x_0)\|\longrightarrow 1$ but $\inf_{n \in \mathbb{N}} \{\mbox{dist} (x_0,\,\{x\in X: \|T_n(x)\|=\|x\|=1\})\} >0.$ This shows that a version of the Bishop-Phelps-Bollob\'as property in which the operator is not changed is possible only if one of the involved Banach spaces is one-dimensional., Comment: The content of this paper overlaps with the old version of arXiv:1709.00032 (arXiv:1709.00032v1, submitted on 31 Aug 2017). Nevertheless, there is no intersection between the present version and the updated one of arXiv:1709.00032 (arXiv:1709.00032v2, submitted on 26 Sep 2018)

Summary Pain sensation is powerfully modulated by signal processing in the brain, and pain becomes chronic with the dysfunction of the pain modulatory system; however, the underlying mechanisms are unclear. We found that the metabotropic glutamate receptor 5 (mGluR5) in the periaqueductal gray (PAG), the key area of endogenous pain modulation, is persistently active in normal conditions to maintain an appropriate sensory perception. In the neuropathic pain condition, Homer1a, an activity-dependent immediate early gene product, disrupted the persistent mGluR5 activity resulting in chronic pain. Remarkably a single-time blockage of the mGluR5 resulted in chronic neuropathic pain-like symptoms even in the absence of nerve injury. The decline of mGluR5 activity induced the pain modulatory dysfunction with a profound reduction of excitability of PAG neurons. These findings uncover the role of the persistent mGluR5 activity in vivo and provide new insight into how pain becomes chronic with the maladaptive coping of the PAG to pain sensation.

This study was performed to investigate whether the spinal cholinergic and serotonergic analgesic systems mediate the relieving effect of electroacupuncture (EA) on oxaliplatin-induced neuropathic cold allodynia in rats. The cold allodynia induced by an oxaliplatin injection (6 mg/kg, i.p.) was evaluated by immersing the rat's tail into cold water (4℃) and measuring the withdrawal latency. EA stimulation (2 Hz, 0.3-ms pulse duration, 0.2~0.3 mA) at the acupoint ST36, GV3, or LI11 all showed a significant anti-allodynic effect, which was stronger at ST36. The analgesic effect of EA at ST36 was blocked by intraperitoneal injection of muscarinic acetylcholine receptor antagonist (atropine, 1 mg/kg), but not by nicotinic (mecamylamine, 2 mg/kg) receptor antagonist. Furthermore, intrathecal administration of M2 (methoctramine, 10 µg) and M3 (4-DAMP, 10 µg) receptor antagonist, but not M1 (pirenzepine, 10 µg) receptor antagonist, blocked the effect. Also, spinal administration of 5-HT3 (MDL-72222, 12 µg) receptor antagonist, but not 5-HT1A (NAN-190, 15 µg) or 5-HT2A (ketanserin, 30 µg) receptor antagonist, prevented the anti-allodynic effect of EA. These results suggest that EA may have a signifi cant analgesic action against oxaliplatin-induced neuropathic pain, which is mediated by spinal cholinergic (M2, M3) and serotonergic (5-HT3) receptors.

In this paper, we study both the numerical index and the polynomial numerical index. First, we give a sufficient condition for a Banach space X to have lushness. Second, we study the relation between the renormings of a Banach space and the k-order polynomial numerical index. This shows that every real Banach spaces of dimension greater that 1 can be renormed to have 2-order polynomial numerical index for any .

We study the Bishop–Phelps–Bollobas property for numerical radius (for short, BPBp-nu) of operators on `1-sums and `∞-sums of Banach spaces. More precisely, we introduce a property of Banach spaces, which we call strongly lush. We find that if X is strongly lush and X ⊕1 Y has the weak BPBp-nu, then (X,Y ) has the Bishop–Phelps– Bollobas property (BPBp). On the other hand, if Y is strongly lush and X ⊕∞ Y has the weak BPBp-nu, then (X,Y ) has the BPBp. Examples of strongly lush spaces are C(K) spaces, L1(μ) spaces, and finite-codimensional subspaces of C[0, 1].

It is shown that the Bishop–Phelps–Bollobas theorem holds for bilinear forms on the complex \(C_0(L_1)\times C_0(L_2)\) for arbitrary locally compact topological Hausdorff spaces \(L_1\) and \(L_2\).

The effect of the iron nitride phases, &epsilon, Fe2-3N and &gamma, &prime, Fe4N, on the fatigue strength was investigated. Pure iron was used to observe only the effect of nitride, excluding the effects of factors, such as residual stress, depending on the alloy composition and microstructural change according to working on the fatigue strength. In this work, &epsilon, and &gamma, phases were respectively grown at a time on the surface of the pure iron specimens using the appropriate nitriding potential KN, the mixture rates of ammonia and hydrogen gases, at same temperature of 570 &deg, C according to the Fe-N Lehrer diagram. Another &gamma, phase was prepared by first growing the &epsilon, phase and then transformed from &epsilon, phase into &gamma, phase by changing the KN at the same temperature of 570 &deg, C in the 2-stage gas nitriding. The fatigue strengths of the iron nitride consisted of &epsilon, phases, &gamma, phase, and &gamma, phase grown by the 2-stage gas nitriding were evaluated, respectively. As a result, first, it can be seen that the diffusion layer of &epsilon, phase was deeper than &gamma, phase, but fatigue strength was lower. On the other hand, fatigue strength of both the &gamma, phases are higher than that of the &epsilon, and the fatigue strength of &gamma, phase nitride grown by 2-stage gas nitriding was almost similar to that of &gamma, phase nitride grown at a time, i.e., fatigue strength was not significantly related to diffusion depth and depended on nitride phases in this study. Secondly, we cannot clearly conclude that there was the difference in fatigue strength according to the thickness of nitride layer consisted of &gamma, phase. However, it is clear that when &epsilon, phase was transformed to &gamma, phase, fatigue strength had the same level as &gamma, phase formed at one time.

A Urysohn-type theorem is introduced for a subalgebra of the algebra C b ( Ω ) of all bounded complex-valued continuous functions on a Hausdorff topological space Ω. With use of this theorem, it is shown that a type of the Bishop-Phelps-Bollobas theorem holds for certain classes of holomorphic functions on the unit ball of a complex Banach space X if X is either a locally uniformly convex space or a locally c-uniformly convex, order-continuous sequence space.

In this paper we introduce some local versions of Bishop–Phelps–Bollobás type property for operators. That is, the function η which appears in their definitions depends not only on a given ε > 0, but also on either a fixed norm-one operator T or a fixed norm-one vector x. We investigate those properties and show differences between local and uniform versions. Fil: Dantas, Sheldon. Pohang University Of Science And Technology; Corea del Sur Fil: Kim, Sun Kwang. Chungbuk National University; Corea del Sur Fil: Lee, Han Ju. Dongguk University; Corea del Sur Fil: Mazzitelli, Martin Diego. Universidad Nacional del Comahue. Facultad de Economía y Administración; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Peripheral nerve injury causes maladaptive plasticity in the central nervous system and induces chronic pain. In addition to the injured limb, abnormal pain sensation can appear in the limb contralateral to the injury, called mirror image pain. Because synaptic remodeling in the primary somatosensory cortex (S1) has critical roles in the induction of chronic pain, cortical reorganization in the S1 ipsilateral to the injured limb may also accompany mirror image pain. To elucidate this, we conducted in vivo 2-photon calcium imaging of neuron and astrocyte activity in the ipsilateral S1 after a peripheral nerve injury. We found that cross-callosal inputs enhanced the activity of both S1 astrocytes and inhibitory neurons, whereas activity of excitatory neurons decreased. When local inhibitory circuits were blocked, astrocyte-dependent spine plasticity and allodynia were revealed. Thus, we propose that cortical astrocytes prime the induction of spine plasticity and mirror image pain after peripheral nerve injury. Moreover, this result suggests that cortical synaptic rewiring could be sufficient to cause allodynia on the uninjured periphery.

Oxaliplatin is a widely used chemotherapy agent, but induces serious peripheral neuropathy. Duloxetine is a dual reuptake inhibitor of serotonin and norepinephrine, and is shown to be effective against pain. However, whether and how duloxetine can attenuate oxaliplatin-induced allodynia in rodents is not clearly understood. A single injection of oxaliplatin (6 mg/kg, intraperitoneal; i.p.) induced a cold and mechanical allodynia, which was assessed by acetone and von Frey filament tests, respectively. When significant allodynic signs were observed, three different doses of duloxetine (10, 30, and 60 mg/kg, i.p.) were injected. Administration of 30 and 60 mg/kg of duloxetine significantly reduced the allodynia, whereas 10 mg/kg did not. By using an in vivo extracellular recording method, we further confirmed that 30 mg/kg of duloxetine could significantly inhibit the hyperexcitability of spinal wide dynamic range (WDR) cells. The anti-allodynic effect of duloxetine was completely blocked by an intrathecal injection of phentolamine (non-selective α-adrenergic receptor antagonist, 20 μg), or prazosin (α₁-adrenergic receptor antagonists, 10 μg); however, idazoxan (α₂-adrenergic receptor antagonist, 10 μg) did not block it. In conclusion, we suggest that duloxetine may have an effective protective action against oxaliplatin-induced neuropathic pain and spinal hyperexcitability, which is mediated by spinal α₁-adrenergic receptors.

Previously, we found that Foxp3-expressing CD4(+) regulatory T (Treg) cells attenuate cisplatin-induced acute kidney injury in mice and that bee venom and its constituent phospholipase A2 (PLA2) are capable of modulating Treg cells. Here we tested whether PLA2 could inhibit cisplatin-induced acute kidney injury. As a result of treatment with PLA2, the population of Treg cells was significantly increased, both in vivo and in vitro. PLA2-injected mice showed reduced levels of serum creatinine, blood urea nitrogen, renal tissue damage, and pro-inflammatory cytokine production upon cisplatin administration. These renoprotective effects were abolished by depletion of Treg cells. Furthermore, PLA2 bound to CD206 mannose receptors on dendritic cells, essential for the PLA2-mediated protective effects on renal dysfunction. Interestingly, PLA2 treatment increased the secretion of IL-10 in the kidney from normal mice. Foxp3(+)IL-10(+) cells and CD11c(+)IL-10(+) cells were increased by PLA2 treatment. The anticancer effects of repeated administrations of a low dose of cisplatin were not affected by PLA2 treatment in a tumor-bearing model. Thus, PLA2 may prevent inflammatory responses in cisplatin-induced acute kidney injury by modulating Treg cells and IL-10 through the CD206 mannose receptor.

We introduce a generalized approximate hyperplane series property for a pair ( X , Y ) of Banach spaces to characterize when ( l 1 ( X ) , Y ) has the Bishop–Phelps–Bollobas property. In particular, we show that ( X , Y ) has this property if X, Y are finite-dimensional, if X is a C ( K ) space and Y is a Hilbert space, or if X is Asplund and Y = C 0 ( L ) , where K is a compact Hausdorff space and L is a locally compact Hausdorff space.

A single infusion of oxaliplatin, which is widely used to treat metastatic colorectal cancer, induces specific sensory neurotoxicity signs that are triggered or aggravated when exposed to cold or mechanical stimuli. Bee Venom (BV) has been traditionally used in Korea to treat various pain symptoms. Our recent study demonstrated that BV alleviates oxaliplatin-induced cold allodynia in rats, via noradrenergic and serotonergic analgesic pathways. In this study, we have further investigated whether BV derived phospholipase A(2) (bvPLA(2)) attenuates oxaliplatin-induced cold and mechanical allodynia in mice and its mechanism. The behavioral signs of cold and mechanical allodynia were evaluated by acetone and a von Frey hair test on the hind paw, respectively. The significant allodynia signs were observed from one day after an oxaliplatin injection (6 mg/kg, i.p.). Daily administration of bvPLA(2) (0.2 mg/kg, i.p.) for five consecutive days markedly attenuated cold and mechanical allodynia, which was more potent than the effect of BV (1 mg/kg, i.p.). The depletion of noradrenaline by an injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4, 50 mg/kg, i.p.) blocked the analgesic effect of bvPLA(2), whereas the depletion of serotonin by injecting DL-p-chlorophenylalanine (PCPA, 150 mg/kg, i.p.) for three successive days did not. Furthermore, idazoxan (2-adrenegic receptor antagonist, 1 mg/kg, i.p.) completely blocked bvPLA(2)-induced anti-allodynic action, whereas prazosin (1-adrenegic antagonist, 10 mg/kg, i.p.) did not. These results suggest that bvPLA(2) treatment strongly alleviates oxaliplatin-induced acute cold and mechanical allodynia in mice through the activation of the noradrenergic system, via 2-adrenegic receptors, but not via the serotonergic system.

We show that the pair ( C ( K ) , X ) has the Bishop–Phelps–Bollobas property for operators if K is a compact Hausdorff space and X is a uniformly convex space.