Keywords: Geothermometry, advanced diagenesis, low grade metamorphism, carbonaceous materials (CM), Raman spectroscopy, pressure effect

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Raman Spectroscopy of Carbonaceous Material (RSCM)

geothermometery in rocks of advanced diagenesis processes and low-grade metamorphism : application to the Franciscan Complex, CA, to examine the pressure effect

Abdeltif Lahfid, Brice Lacroix, Sylvain


Anne Héron

David Dubayle

A focus on mast cells and pain

Keywords:

Mast cells (MCs) are immunocytes with secretory functions that act locally in peripheral tissues to modulate local hemodynamics, nociceptor activation and pain. They are also able to infiltrate the central nervous system (CNS), especially the spinal cord and the thalamus, but their cerebral function remains an enigma. A role in regulating the opening of the blood-brain barrier has been proposed. Paracrine-like action of MCs on synaptic transmission might also signal a modulation of the nervous system by the immune system. In this review, we examine the link between MCs and nociceptive process, at the periphery as well as in the CNS.

Introduction

Mast cells (MCs) are immune cells produced by the bone marrow [START_REF] Gurish | Mast cell growth, differentiation, and death[END_REF]. These cells pass the blood wall and quickly infiltrate most tissues, such as skin, mucous membranes, respiratory and gastrointestinal tracts, peritoneal cavity and meninges [START_REF] Metcalfe | Mast cells[END_REF]. MCs act by degranulation [START_REF] Florenzano | Degranulation, density, and distribution of mast cells in the rat thalamus: a light and electron microscopic study in basal conditions and after intracerebroventricular administration of nerve growth factor[END_REF] and produce a plethora of mediators such as biogenic amines (histamine and serotonin), enzymes (acid hydrolases, phospholipases, chymase, tryptase and other proteases), cytokines (interleukin-1 to interleukin-6, interferon, transforming growth factor TGF, granulocyte-microphage colony-stimulating factor, leukemia inhibitory factor, tumor necrosis factor TNF), lipid metabolites (leukotrienes, prostaglandins, platelet-activating factor), ATP (adenosine triphosphate), neuropeptides (vasoactive intestinal peptide), growth factors (nerve growth factor, NGF) and nitric oxide [START_REF] Schwartz | Enzymes of the mast cell granule[END_REF][START_REF] Johnson | Interactions of mast cells with the nervous system-recent advances[END_REF]. MCs are also the only cells containing intra-cytoplasmic granules of proteoglycans, mainly heparin. Indeed, the principle of specific staining of MCs on histological tissues is based on a metachromatic reaction of these proteoglycans with acidified toluidine blue (pH 2.3), which results in a shift of the natural color blue dye in characteristic red purple [START_REF] Humason | Animal tissue techniques[END_REF]. MCs adapt and release mediators according to local tissue conditions [START_REF] Lowman | Human mast cell heterogeneity: histamine release from mast cells dispersed from skin, lung, adenoids, tonsils, and colon in response to IgE-dependent and nonimmunologic stimuli[END_REF].

Peripheral and central mast cells

In the peripheral tissues, MCs are involved in the inflammatory reaction in response to exogenous pathogens and pro-inflammatory bioactive substances, such as cytokines and prostaglandins. They are also considered to be major effectors in IgE-associated hypersensitivity and in allergic responses such as asthma. More recently, the pathophysiological role of MCs have been recognized in various diseases affecting the periphery and/or the brain, such as atherosclerosis, pulmonary hypertension, autoimmune disorders, visceral diseases, cancer, ischemia-reperfusion injury, anxiety, Alzheimer's disease, migraine… (for review see [START_REF] Anand | Mast cells: an expanding pathophysiological role from allergy to other disorders[END_REF]. In addition to the periphery, numerous data indicate that MCs are also resident in the central nervous system (CNS) of many animal species, including humans [START_REF] Ibrahim | The mast cells of the mammalian central nervous system. Part 1: morphology, distribution and histochemistry[END_REF][START_REF] Dropp | Mast cells in mammalian brain[END_REF][START_REF] Michaloudi | Mast cells in the sheep, hedgehog and rat forebrain[END_REF][START_REF] Michaloudi | Parallel development of blood vessels and mast cells in the lateral geniculate nuclei[END_REF]. The exact function of MCs in the central nervous system is, however, much less understood.

During development MCs enter the brain by penetrating blood vessels with which they remain associated [START_REF] Lambracht-Hall | Migration of mast cells in the developing rat brain[END_REF]. The number of mast cells progressively decreases until the adulthood, even if they are still able to migrate from blood to brain. Almost 97% of brain MCs lie on the vessel wall (Fig. 1). They are especially found not only in the thalamus, but also in the hypothalamus, choroid plexus, olfactory bulb and pineal gland [START_REF] Krüger | Demonstration of mast cells in the albino rat brain[END_REF][START_REF] Dropp | Mast cells in mammalian brain[END_REF][START_REF] Persinger | Mast cells in the brain: possibilities for physiological psychology[END_REF][START_REF] Zhuang | Distribution and local differentiation of mast cells in the parenchyma of the forebrain[END_REF][START_REF] Khalil | Mast cells in the rat brain synthesize gonadotropinreleasing hormone[END_REF][START_REF] Kriegsfeld | Brain mast cells are influenced by chemosensory cues associated with estrus induction in female prairie voles (Microtus ochrogaster)[END_REF][START_REF] Michaloudi | Parallel development of blood vessels and mast cells in the lateral geniculate nuclei[END_REF]. In the thalamus, MC number can be regulated by environmental conditions or hormonal factors, such as hibernation, parturition, stress and aging [START_REF] Dropp | Mast cells in mammalian brain[END_REF][START_REF] Aydin | Ovarian, uterine and brain mast cells in female rats: cyclic changes and contribution to tissue histamine[END_REF]. They are more numerous in females than in males [START_REF] Goldschmidt | Mast cells in rat thalamus: nuclear location, sex difference and left-right asymmetry[END_REF]. Unlike peripheral tissues, brain MCs do not express the c-kit receptor, which binds to stem cell factor (SCF) [START_REF] Shanas | Brain mast cells lack the c-kit receptor: immunocytochemical evidence[END_REF]. In accordance with these results, centrally injected SCF was not able to increase the population of MC in the thalamus [START_REF] Taiwo | Chronic daily intrathecal injections of a large volume of fluid increase mast cells in the thalamus of mice[END_REF]. Within the CNS, MC proliferation is not possible. In this case, MC infiltration would damage neuronal tissue [START_REF] Galli | The kit ligand, stem cell factor[END_REF]. Cerebral MC number and degranulation are regulated, not only in physiological, but also in pathological conditions. In physiological conditions, MCs are attracted by chemotaxis [START_REF] Frei | Astrocytes of the brain synthesize interleukin 3-like factors[END_REF][START_REF] Da Cunha | Transforming growth factor-beta 1 (TGF-beta 1) expression and regulation in rat cortical astrocytes[END_REF][START_REF] Metcalfe | Mast cells[END_REF][START_REF] Esposito | Acute stress increases permeability of the blood-brain-barrier through activation of brain mast cells[END_REF]. This phenomenon involves many molecules produced by the brain, such as NGF, TGF-β1, chemokines (fractalkine), CRF (corticotropin releasing factor), neuropeptides (substance P and somatostatin) and interleukin-3. Blood MCs cling on the laminin wall of endothelium and slip between endothelial cells by diapedesis [START_REF] Flood | Fine structure of mast cells in the central nervous system of the hedgehog[END_REF][START_REF] Silverman | Mast cells migrate from blood to brain[END_REF]. The degranulation of the first MCs penetrating the brain parenchyma promotes the entry of others by releasing histamine, which acts as a vasodilator molecule increasing blood-brain barrier (BBB) permeability [START_REF] Esposito | Acute stress increases permeability of the blood-brain-barrier through activation of brain mast cells[END_REF][START_REF] Lindsberg | Mast cells as early responders in the regulation of acute blood-brain barrier changes after cerebral ischemia and hemorrhage[END_REF].

The reason why MCs are prevalently located within the CNS, and more particularly in the thalamus, remains to be elucidated. This raises the question of their potential roles in brain function. Considering that peripheral MCs are implicated in pain processes and that thalamus is the essential brain structure that relies on the integration of sensory messages to the cerebral cortex for conscious perception, we postulate that thalamic MCs could be implicated in sensory processing including nociception.

Role of peripheral mast cells in pain transmission

Pain information begins at the nerve endings called nociceptors, which form a functional pain unit with the nearby tissue capillaries. Peripheral MCs are often found in proximity to sensory nerve endings and vasculature (Fig. 2). Following injury or inflammatory stimuli, mediators such as bradykinin, prostaglandins and histamine are released and stimulate nociceptive afferents. They are produced by damaged tissues, platelets, granulocytes, macrophages and MCs. Nociceptive fibers, themselves, release neuromodulators such as substance P, calcitonin gene-related peptide (CGRP), the vasoactive intestinal protein (VIP), and CRH (Corticotropin Releasing Hormone), which, in turn, can stimulate activation of MCs [START_REF] Matsuda | Substance P induces granulocyte infiltration through degranulation of mast cells[END_REF]. Subsequently, MCs release algogenic molecules which amplify vasodilation and sensitize nociceptors [START_REF] Koda | Sensitization to mechanical stimulation by inflammatory mediators and by mild burn in canine visceral nociceptors in vitro[END_REF]. This positive feedback loop causes neurogenic inflammation [START_REF] Kowalski | Neurogenic inflammation, vascular permeability, and mast cells[END_REF][START_REF] Ansel | Cytokine modulation of keratinocyte cytokines[END_REF]. So, MC stabilizers such as cromolyn, are able to inhibit nociception and neurogenic inflammation [START_REF] Le Filliatre | Cyclooxygenase and lipoxygenase pathways in mast cell dependent-neurogenic inflammation induced by electrical stimulation of the rat saphenous nerve[END_REF][START_REF] Parada | The major role of peripheral release of histamine and 5-hydroxytryptamine in formalin-induced nociception[END_REF]. Fig. 2. Nociception is generated in the periphery but is integrated in the CNS. Pain information begins at nociceptors (yellow flash), which form a functional pain unit with the nearby tissue capillaries and peripheral MCs. Following injury or chemical stimuli, mediators released by degranulating MCs act on nociceptors and can modulate their excitability. Stimulation of first-order neurons (Aδ or unmyelinated C fibers, in blue) spreads to dorsal horn of the spinal cord where axons connect synapses with second-order neurons (in green). MCs are found in the dura matter of the spinal cord and can modulate synaptic transmission and nociception at this level. After spinal decussation, axons reach contralateral supraspinal structures, including the lateral or the median thalamus. The thalamic relay discriminates nociceptive stimulations and transmits them from the spinal cord to the sensorimotor or frontal cortex, which elaborates sensation and conscious perception of pain. MCs are particularly concentrated in the thalamus and can release mediators such as histamine or serotonin in the proximity of third order neurons targeting to the cortex (in violet). (A and B) Peripheral MCs in epidermis: heparin histochemistry (HC) by toluidine blue staining in A, and in situ hybridization labeling of histidine decarboxylase (HDC), the histamine synthesis enzyme in B. (C and D) Serotonin immunohistochemistry (IHC) with toluidine blue counterstaining of a thalamic MC: bright field illumination in C, and at higher magnification with dark field illumination in D. (E and F) Histamine immunoperoxidase staining of MCs present in a vessel (V) of the thalamus (E) and penetrating nervous parenchyma (F). Note the release of histamine containing granules in F. Arrows indicate MC granules. Scale bars AB = 20 µm, CDEF = 10 µm.

In addition to mediator release, communication between MCs and neurons can occur via adhesion molecules such as Cell ADhesion Molecule-1 (CADM) and N-cadherin [START_REF] Suzuki | N-cadherin plays a role in the synapse-like structures between mast cells and neurites[END_REF][START_REF] Ito | Direct interaction between nerves and mast cells mediated by the SgIGSF/SynCAM adhesion molecule[END_REF][START_REF] Van Diest | Relevance of mast cell-nerve interactions in intestinal nociception[END_REF], and through a transgranulation process, i.e neuronal uptake of MC particles [START_REF] Wilhelm | Central nervous system neurons acquire mast cell products via transgranulation[END_REF]. The pro-inflammatory substances released by MCs can also be transported retrogradely to neuronal cell bodies of dorsal root ganglia to regulate gene expression [START_REF] Murphy | Nature of the retrograde signal from injured nerves that induces interleukin-6 mRNA in neurons[END_REF].

MCs also contribute to the recruitment of other immune cells such as neutrophils, macrophages and T cells, which release pro-nociceptive mediators and reinforce the maintenance of inflammatory reactions [START_REF] Zuo | Inflammation and hyperalgesia induced by nerve injury in the rat: a key role of mast cells[END_REF]. As a consequence, inflammation can affect not only injured zones, but also adjacent territories, creating a secondary, widespread hyperalgesia. Hyperalgesia is an excessive pain response. For example, in a mouse model of autoimmune prostatitis, the application of culture supernatant of activated MCs induced hyperalgesia, accompanied by a significant longterm potentiation of spinal C-fiber synapses [START_REF] Done | Role of mast cells in male chronic pelvic pain[END_REF]. Hyperalgesia is observed in cases of peripheral nerve damage and in pathology such as multiple sclerosis, accidental injury, limb amputation, diabetes or sciatica [START_REF] Xanthos | Central nervous system mast cells in peripheral inflammatory nociception[END_REF]. MCs could play a direct role and histamine would be the mediator responsible of this type of pain hypersensibility [START_REF] Smith | Role of histamine H3 and H4 receptors in mechanical hyperalgesia following peripheral nerve injury[END_REF].

Many experimental data show that MCs play a role in chronic pain, particularly at the visceral level. Indeed, peripheral MC degranulation increases excitability of vagal, splanchnic and mesenteric afferents, contributing to nociceptive processes associated with visceral pain. So, the degranulation of MCs, in close proximity to the nerves innervating the colonic mucosa, is correlated with abdominal pain in patients with Irritable Bowel Syndrome (IBS) [START_REF] Barbara | Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome[END_REF]. The administration of ketotifen, a MC stabilizer, is therefore able to reduce rectal sensitivity, abdominal pain and other IBS symptoms [START_REF] Klooker | The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irritable bowel syndrome[END_REF]. Furthermore, an increased number of MCs associated with an increased number of serotonin cells have been demonstrated in colonic biopsies of IBS patients, suggesting that release of serotonin directly or indirectly from the intestinal MC may be responsible for sensory neuron activation and abdominal pain in this pathology [START_REF] Cremon | Intestinal serotonin release, sensory neuron activation, and abdominal pain in irritable bowel syndrome[END_REF]. MC tryptase and histamine would also cause activation of enteric nerves, resulting in neuronal hyperexcitability [START_REF] Traver | Mucosal mast cells mediate motor response induced by chronic oral exposure to ovalbumin in the rat gastrointestinal tract[END_REF].

In esophagi, local MC activation plays an important role in inflammatory nociception [START_REF] Yu | Mast cell-mediated longlasting increases in excitability of vagal c-fibers in guinea pig esophagus[END_REF]. Esophageal MCs are mainly distributed along the lamina propria of the mucosal layer and release mediators such as histamine and tryptase. These MCs sensitize the nociceptive afferent nerve terminals located in their proximity, to produce pain and hyperalgesia. In guinea pigs, it has been reported that MC tryptase, via Protease-Activated Receptor 2 (PAR2) and Transient Receptor Potential A1 (TRPA1), induces mechanical hypersensitivity of vagal C-fibers [START_REF] Yu | TRPA1 in mast cell activation-induced longlasting mechanical hypersensitivity of vagal afferent C-fibers in guinea pig esophagus[END_REF]. Pretreatment with the MC stabilizer cromolyn decreases the esophageal distension-induced mechano-excitability of esophageal C-fibers [START_REF] Gao | ERK1/2 signaling pathway in mast cell activation-induced sensitization of esophageal nodose C-fiber neurons[END_REF].

The pathogenesis of bladder pain syndrome associated with interstitial cystitis is unknown. However, the accumulation of bladder MCs in the muscular layer, lamina propria and submucosa seems to play an important role, as well as localized allergic reaction and inflammation [START_REF] Theoharides | Mast cell involvement in interstitial cystitis: a review of human and experimental evidence[END_REF][START_REF] Sant | The mast cell in interstitial cystitis: role in pathophysiology and pathogenesis[END_REF]. Indeed, clinical studies have shown an increased level of MC mediators including histamine, tryptase and IL-6 in the urine of patients suffering from cystitis [START_REF] Theoharides | Mast cell involvement in interstitial cystitis: a review of human and experimental evidence[END_REF]. The critical role of neural-immune interactions in pathogenesis of interstitial cystitis has been well documented. It has been proposed that activation of urinary bladder-associated circuits in the CNS initiates substance P release by peripheral nerves in the bladder, which then promotes substance P-mediated MC activation. This MC activation, in turn, would induce bladder inflammation by action on the epithelium lining the bladder.

In skin, the role of MCs in chronic granulomatous inflammation-induced hyperalgesia has also been well documented. In rat, the presence of degranulated MCs was evidenced in the granuloma and nearby nerve fibers. Furthermore, palmitoylethanolamide reduced granuloma-induced hyperalgesia by modulation of MC activation [START_REF] De Filippis | Palmitoylethanolamide reduces granuloma-induced hyperalgesia by modulation of mast cell activation in rats[END_REF]. In the dermis of patients with Fibromyalgia Syndrome, a significantly increased number of MCs has also been described [START_REF] Blanco | Abnormal overexpression of mastocytes in skin biopsies of fibromyalgia patients[END_REF]. Thus, one might ask what is the role of MCs in the genesis of this pathology with painful and inflammatory components, as shown in rheumatoid arthritis. Indeed, in this autoimmune pathology, MCs have been shown to accumulate in arthritic lesions of patients [START_REF] Maruotti | Mast cells in rheumatoid arthritis[END_REF] and mediators released by MC degranulation (chymases, tryptases, IL-17) contribute to the severity of the disease [START_REF] Tchougounova | A key role for mast cell chymase in the activation of pro-matrix metalloprotease-9 and promatrix metalloprotease-2[END_REF][START_REF] Mcneil | The mouse mast cell-restricted tetramer-forming tryptases mouse mast cell protease 6 and mouse mast cell protease 7 are critical mediators in inflammatory arthritis[END_REF][START_REF] Suurmond | Mast cells are the main interleukin 17-positive cells in anticitrullinated protein antibody-positive and -negative rheumatoid arthritis and osteoarthritis synovium[END_REF].

Do mast cells have a role in central integration of pain?

While MCs are clearly involved in the genesis of pain during inflammatory processes at the peripheral level, they could also be implicated in central integration of nociception. Pain is generated in the periphery and is integrated in the CNS (Fig. 2). Depolarization induced by stimulation of primary fibers spreads to the dorsal horn of the spinal cord via two pathways. One, corresponding to fast pain, is mediated by A-delta fibers (Aδ) responsible for localized pain and able to discriminate the precise topography. It joins the lateral thalamus by the neo-spinothalamic tract, then the S1 and S2 areas of the sensory cortex (path of sensation). The second way of pain dissemination is conveyed by unmyelinated C fibers, responsible for slow, widespread pain. After passing through a relay in the brainstem, pain information is transmitted to the medial thalamus, the limbic structures, the insula, the cingulate cortex and the frontal cortex (path of emotion and behavior). The thalamus is thus an essential nociceptive relay. It discriminates nociceptive stimulations and transmits some of them from spinal cord to the cortex, which then elaborates the conscious perception of pain sensation. In turn, the thalamus can be influenced by the cortex as well as by the limbic system. Then, the painful process acquires psycho-affective coloration. Signals from the supraspinal centers are also integrated in the periaqueductal gray, which modulates descending facilitation and inhibition of nociceptive input via the rostral ventromedial medulla. Supraspinal afferents influence the activity of spinal interneurons releasing a variety of neurotransmitters to modulate nociception [START_REF] Mchugh | Pain: neuroanatomy, chemical mediators, and clinical implications[END_REF]. Spinal interneurons themselves exert inhibitory effects on the processing of pain signals. The dural MCs are found at a significant density at the cervical, thoracic, and lumbar regions of spinal cord [START_REF] Majeed | Mast cell distribution in rats[END_REF] and can modulate synaptic transmission and nociception at these levels [START_REF] Sandkühler | Models and mechanisms of hyperalgesia and allodynia[END_REF].

Resident MCs located in the cerebral dura mater promote neurogenic inflammation, activate meningeal nociceptors and contribute significantly to the pathophysiology of migraine [START_REF] Theoharides | The role of mast cells in migraine pathophysiology[END_REF][START_REF] Levy | Migraine pain, meningeal inflammation, and mast cells[END_REF]. Electrical stimulation of the trigeminal ganglion which activates meningeal nociceptors, promotes the degranulation of dural MCs [START_REF] Dimitriadou | Trigeminal sensory fiber stimulation induces morphological changes reflecting secretion in rat dura mater mast cells[END_REF]. The activation of meningeal nociceptors induces substance P and CGRP. This phenomenon accompanies migraine with aura [START_REF] Pietrobon | Neurobiology of migraine[END_REF]. The local release of inflammatory molecules by MCs during this neurogenic inflammation would prolong activation of the trigeminal pain pathway by stimulating further meningeal nociceptors, thus prolonging headache [START_REF] Levy | Mast cell degranulation activates a pain pathway underlying migraine headache[END_REF].

Experimental data show that nociceptive signals influence the distribution of MCs in the brain during the development of hyperalgesia. Indeed, MCs infiltrate the thalamus from blood to brain within a few hours in response to chemotactic molecules directly released by peripheral sensory afferents. In animal model of cystitis associated with a referred cutaneous hyperalgesia, left (or right) repetitive punctures of the abdominal wall generate an infiltration of MCs in some parts of the contralateral thalamus (paraventricular pars anterior and reuniens nucleus; [START_REF] Dubayle | The effects of viscero-somatic interactions on thalamic mast cell recruitment in cystitic rats[END_REF]. Because of the asymmetrical distribution of MCs, they might thus be involved in thalamic sensory processes, implicated in some aspect of visceral pain. In other studies, the number of MCs increased in contralateral thalamus (posterior and lateral geniculate nuclei) after a painful unilateral ligation of the spinal nerve lasting several days in female mice [START_REF] Taiwo | Chronic daily intrathecal injections of a large volume of fluid increase mast cells in the thalamus of mice[END_REF]. It is interesting to see that in rodents, thalamic MCs are more numerous in females than in males [START_REF] Goldschmidt | Mast cells in rat thalamus: nuclear location, sex difference and left-right asymmetry[END_REF], and that females are more sensitive to nociceptive stimuli in models of neuropathic and inflammatory pain [START_REF] Coyle | Female rats are more susceptible to the development of neuropathic pain using the partial sciatic nerve ligation (PSNL) model[END_REF][START_REF] Tall | Effects of gender and gonadal hormones on nociceptive responses to intraplantar carrageenan in the rat[END_REF]. Sex hormones and thalamic MCs could be modulators of the basic processes involved in nociception [START_REF] Kovács | Mast cells modulate maintained neuronal activity in the thalamus in vivo[END_REF].

MCs might also be implicated in psycho-affective integration of nociceptive processes. Cyclophosphamide is an antineoplastic drug that generates cystitis, nausea, headache, vomiting, asthenia, taste aversion, dizziness, photo and phonophobia in humans [START_REF] Cubeddu | Antagonism of serotonin S3 receptors with ondansetron prevents nausea and emesis induced by cyclophosphamidecontaining chemotherapy regimens[END_REF]. After intra-peritoneal cyclophosphamide administration in rats, a significant infiltration and degranulation of MCs appeared in the part of the thalamus localized at the border of the third ventricle: the medial habenular nucleus [START_REF] Servière | Increase of rat medial habenular mast cell numbers by systemic administration of cyclophosphamide[END_REF]. This nucleus belongs to the limbic system. The presence of MCs in the habenula suggests that they could be implicated in modulation of emotional reactions occurring in painful conditions.

Several pharmaceutical molecules known to act on nociception are able to modulate infiltration and degranulation of thalamic MCs. An intraperitoneal injection of sumatriptan (a 5-HT1B/D agonist, an anti-migraine agent with large antalgic effects) doubles the number of degranulated MCs and especially those containing serotonin [START_REF] Menétrey | A one-step dual-labeling method for antigen detection in mast cells[END_REF]Dubayle et al., 2005a). In less than 4 h, MCs cross the BBB to infiltrate the thalamus. Serotonin is known to modulate pain mechanisms with pro-nociceptive effect at the periphery and anti-nociceptive effect at the central level [START_REF] Viguier | Multiple roles of serotonin in pain control mechanisms -Implications of 5-HT7 and other 5-HT receptor types[END_REF]. Indeed, microinjection of serotonin into the submedius thalamic nucleus produced anti-nociception, in a rat model of algesia induced by peripheral electrical stimulation [START_REF] Xiao | GABAergic modulation mediates antinociception produced by serotonin applied into thalamic nucleus submedius of the rat[END_REF]. From these results, we postulate that the specific thalamic MC population which releases serotonin may exert an anti-nociceptive effect. In turn, considering the effect of two analgesic drugs, we observed that Morphine chlorhydrate, a mu opioid agonist, has no effect on thalamic MCs infiltration; only acetylsalicylic acid, a non-steroidal anti-inflammatory drug, decreased the number of thalamic MCs (Dubayle et al., 2005b). It should be noted that the effect of all these pharmaceutical drugs is not due to direct action on MCs, but rather derives from systemic vasoactive molecules which would be able to increase or decrease the infiltration of MCs.

MCs act as early responders in the regulation of the BBB in pathological conditions, such as ischemia, hemorrhage, multiple sclerosis, Alzheimer disease and contention stress [START_REF] Esposito | Acute stress increases permeability of the blood-brain-barrier through activation of brain mast cells[END_REF][START_REF] Graves | Inflammation in amyotrophic lateral sclerosis spinal cord and brain is mediated by activated macrophages, mast cells and T cells[END_REF][START_REF] Biran | Stroke induces histamine accumulation and mast cell degranulation in the neonatal rat brain[END_REF][START_REF] Fiala | IL-17A is increased in the serum and in spinal cord CD8 and mast cells of ALS patients[END_REF][START_REF] Lindsberg | Mast cells as early responders in the regulation of acute blood-brain barrier changes after cerebral ischemia and hemorrhage[END_REF]. Disruption of the BBB involves vasoactive components of MCs including histamine and proteases. These enzymes can degrade basal lamina and activate metalloproteinases localized in the neurovascular matrix [START_REF] Tchougounova | A key role for mast cell chymase in the activation of pro-matrix metalloprotease-9 and promatrix metalloprotease-2[END_REF][START_REF] Mattila | Cerebral mast cells mediate blood-brain barrier disruption in acute experimental ischemic stroke through perivascular gelatinase activation[END_REF]. In opening the BBB, we speculate that MCs could then permit access of circulating molecules such as pro-inflammatory mediators to CNS parenchyma, particularly in conditions where inflammation is important. Pro-inflammatory molecules could act on neurons and regulate nociceptive integration occurring at spinal and/or brain levels. The interplay between MCs, pro-inflammatory molecules and the vasculature could enhance the responses of neurons, as described during inflammation of meninges and visceral tissues [START_REF] Barbara | Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome[END_REF][START_REF] Coldwell | Increased responsiveness of rat colonic splanchnic afferents to 5-HT after inflammation and recovery[END_REF][START_REF] Yu | Mast cell-mediated longlasting increases in excitability of vagal c-fibers in guinea pig esophagus[END_REF][START_REF] Levy | Migraine pain, meningeal inflammation, and mast cells[END_REF]. In other cases such as weak inflammatory conditions, down regulation of MC degranulation would prevent the opening of BBB in detecting the early hallmarks of putative bacterial infection [START_REF] Dubayle | Decrease of cerebral mast cell degranulation after systemic administration of lipopolysaccharide[END_REF].

At the neuronal cell level (Fig. 3) within the thalamus, the presence of degranulated MCs exerts a paracrine-like action on synaptic transmission of thalamocortical tracts. These cells could be the mark of a modulation of the thalamic activity by the immune system [START_REF] Persinger | Mast cells in the brain: possibilities for physiological psychology[END_REF][START_REF] Hough | Cellular localization and possible functions for brain histamine: recent progress[END_REF][START_REF] Silver | Mast cells in the brain: evidence and functional significance[END_REF]. The thalamic micro-iontophoretic application of 48/80, a specific compound inducing MCs degranulation, causes serotonin and histamine release, with subsequent increase in the activity of thalamic neurons [START_REF] Kovács | Mast cells modulate maintained neuronal activity in the thalamus in vivo[END_REF]. MCs could then be implicated in immuno-neuromodulation processes and may be at the origin of a new form of synaptic plasticity. In other nervous structures, such as the superior cervical ganglion, MC degranulation increases the activity of postsynaptic neurons and promotes the efficiency of synaptic transmission, a mechanism of long-term potentiation [START_REF] Weinreich | Antigen-induced long-term potentiation of nicotinic synaptic transmission in the superior cervical ganglion of the guinea pig[END_REF]. Moreover, spinal application of supernatant from activated cultured MCs was also reported to induce long-term potentiation at the synapses of nociceptive C-fibers [START_REF] Xanthos | Central nervous system mast cells in peripheral inflammatory nociception[END_REF]. We suggest that the same mechanism of immuneneuromodulation could occur in the thalamus after MC infiltration. At the level of glial cells (Fig. 3), MCs could act on microglia to indirectly influence neuronal activity [START_REF] Skaper | Microglia and mast cells: two tracks on the road to neuroinflammation[END_REF]. Indeed, emerging evidence suggests a role of mast cell-glia communications in the control of pain transmission pathways. For example, co-culture of mouse cortical microglial cells and human MCs promotes brain-derived neurotrophic factor (BDNF) release and P2X4R (BDNF receptor) expression by microglial cells [START_REF] Yuan | Role of mast cell activation in inducing microglial cells to release neurotrophin[END_REF]. P2X4R maintains the capacity of microglial cells to release high levels of BDNF. In neuropathic pain hypersensitivity, ATP-activated microglia releases BDNF which induces a depolarizing shift in neuronal anion gradient [START_REF] Tsuda | P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury[END_REF][START_REF] Coull | BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain[END_REF]. MCs contain ATP, so this mechanism could be influenced by the release of ATP by MCs [START_REF] Johnson | Interactions of mast cells with the nervous system-recent advances[END_REF] and thus modulate nociception.

Conclusion

MCs are immune cells localized at the peripheral and central levels. In the periphery, they amplify nociception, particularly after injury or inflammatory stimuli. In the CNS, MCs could modulate painful sensation. Depending on the subtype of MCs that infiltrate the parenchyma, MCs could stimulate or inhibit neuronal activity. In most cases, they could increase the pain perception by histamine release, but in some rare cases they could infiltrate the thalamus and exert an antinociceptive effect via serotonin release. In conclusion, in addition to its peripheral function, MCs could also be considered as cerebral immuno-neuromodulators of pain perception.

Fig. 1 .

 1 Fig. 1. Photomicrograph of thalamic mast cells (MCs) in the rat brain. MCs were identified by specific metachromatic (red-purple) staining of heparin with toluidine blue. Many MCs clung to the wall of the vessel (V). One MC entered the nervous parenchyma (*) and showed degranulation (black arrow) evidenced by the presence of granules outside the cytoplasm (scale bar: 15 µm).

Fig. 3 .

 3 Fig. 3. Diagrammatic representation of the possible nociceptive role of MCs in CNS. (1) The nociceptive information (yellow flash) is transmitted from nociceptor to second-order afference. (2) Axon terminal releases chemotactic factors in the parenchyma, which attract blood MCs at the vessel wall level. (3a) MCs open the BBB by the release of histamine, a vasodilatator mediator, and protease which activates metalloprotease localized in neuronal matrix. (3b) This phenomenon induces the infiltration of MCs by diapedesis. (4) In the parenchyma, MCs activate neurons by releasing histamine or serotonin, which subsequently modulate central integration of pain in regulating synaptic plasticity and/or long term potentiation processes. (5) MCs also indirectly communicate with neurons via microglial cells. MCs release ATP, which activates and amplifies P2X4R receptor expression and BDNF release. This mechanism could influence activity of neurons implicated in nociception.

Acknowledgments

The authors would especially like to thank Daniel Menetrey for his valuable advices as well as Joe McIntyre and William Wood for reviewing the manuscript.


Li-Jun Wang
email: wljun1970@tom.com

The growth phases of information construction in Chinese rural area

Keywords: information construction in rural area, main bodies, growth phase

Information construction in rural area, which is crucial factor in pushing forward rural economy, even for agriculture, rural economy, and farmer in present China, consists of three phases: preliminary phase, development phase, and mature phase. To identify the growth phase of information construction in rural area is essential to assessment it. The paper analyzes the characteristics of each growth phases and market main bodies of information construction in rural area (the government, rural household, and market) which play role in the process of information construction in rural area,propose corresponding measures to safeguard sound development of information construction in rural area at the mean time.

Introduction

Information construction in rural area, which is regarded as the booming technology wave is irreversible trend in China. That is to say, China has been stepping into the information era in rural area. Information construction is the characteristics of modernization for social-economic development in countryside. From 2005 to 2008, the Central Document stressed the fourth consecutive year to promote information technology in rural areas, the Central Document No. 2009 is proposed "to encourage qualified local transformation of construction of rural multi-service centers", the use of information technology in building a more Good to promote peasant incomes. It is the key to solve agriculture, rural economy, and farmer. As a most populous developing country, the information construction in Chinese rural area must impact its social-economic development, even for the whole world.

Research on the field can promote the understanding the characteristics and trend of information construction in Chinese rural area. So far, a few researches have made progress in this field. Some researchers analyzed information construction in rural area present situation, proposed the countermeasures of further development [START_REF] Wang | Information construction in rural area in Zhangye City[END_REF], Zhang et., 2004). Others described the information infrastructure, service system, education system and so on in rural area [START_REF] Zhao | Study on the information construction in Chinese rural area[END_REF]. Additional researches paid attention to the relationship between "digital agriculture" and information construction in Chinese rural area, analyzed the probability and necessities of information construction in rural area in Shandong Province [START_REF] Cao | Developing digital agriculture to promote rural information[END_REF].

These researches above focus on the regional information construction in rural area and present situation analysis. But few paper focus on the history of information construction in Chinese rural area. The paper attempted to identify the process above, analyzed its characteristics, the relationship between the information construction and social-economic development level, divide the phase of information construction in Chinese rural area at last.

To define the main bodies of information construction in Chinese rural area

Rural household main body

The service target of information construction is rural area, and the service main body is rural household. Therefore, the rural household is the beneficiary and implementer, so the rural household involvement is the important indicator in the process of information construction in rural area.

Market main body

The extent market intervene is considered to judge its role information construction in rural area. Along with the marketization development in rural area, market is more inseparable part in the process. Therefore, market is the primary entity and significant phase indictor of information construction in rural area.

Government main body

Market economy development demonstrates: the all difficulties in economy don't overcome by market only. Given the fuller market positive role, government interference is essential, including industrial regulation, sector policy, financial subsidy and so on. The cooperation between market and government often guarantee the sound development of information construction in rural area.

In conclusion, rural household, market, and government are inseparable three parts, which are also the important indictors in dividing the phase of rural area information.

Development phases of information construction in Chinese rural area

In accordance with the development, characteristics, interference of rural area information construction main bodies, this paper divide the history of information construction in rural area into three phases: (1) preliminary phase; (2) development phase; (3) mature phase.

Preliminary phase

Like any other industry, information construction in Chinese rural area also underwent the preliminary stage. Information construction in rural area consists of two parts: hardware and software. The hardware includes database, information pool platform, information dissemination media, and terminal equipments and so on; the software includes information processing, information management, and staff training, etc. Because of the amount of rural area is enormous, it is inevitable to invest a huge sum capital to finish information construction in rural area, under the circumstance, any enterprise and individual doesn't assume this task solely. In the light of public good theory, the majority equipments of information construction in rural area pertain to quasi-public goods. Therefore, the government acts on investment main body in the preliminary phase in information construction. Because of absence of credible information, rural household rides the fence toward information construction in rural area process (Fig 1

Development phase

In the preliminary phase, government invests enormous capital to build hardware infrastructure in preparation to step into development phase. In the process, more and more rural household begin to be acquainted with the information construction in rural area, and benefit from it at the mean time.

On the basis of preliminary phase accumulation, the direction of information construction becomes cleaner than previous phase in the development stage. The commercial opportunities in information construction in rural area attract private capital to invest it. In this phase, the government continues to improve information construction in rural area infrastructure in a planned way, intensify the safeguard measures. For example, market accessible procedure, market operation for information construction in rural area, safeguard mechanism for rural household interest, etc. So market efficiency appeals to more capital, technology, and trained personnel to involve, accelerates information construction in rural area development, realizes the integration between market and area household. They actively participate in building to information construction in rural area to obtain more agriculture efficiency. At the moment, government, market, and rural household push forward information construction in rural area together, cooperation main body shifts from the cooperation among government, market, and rural household to diversified cooperation models (Fig 2).

Fig 2. Development phase of information construction in Chinese rural area

Mature phase of information construction in rural area

During the development of information construction in rural area, all the main bodies cooperation become coordinated, diversified, steady, smoothly. All the interest of aspects tend towards maximum, it is the mature characteristics of information Market (Attract more capital, technology, and trained personnel to involve)

Information construction in rural area

Rural household (Invest actively) Government (Invest and formulate safeguard measures) construction in rural area. In the course of this phase, rural area faces are remodeled completely, the farm's standards of living turn to better and better. At the moment, government withdraws from investment on hardware, put the emphasis on the necessary maintenance, strengthen safeguard measures for information construction in rural area, and recoup the investment in the previous two phases. Market and rural household play more important roles in information construction in rural area (Fig 3).

Fig 3. Mature phase of information construction in Chinese rural area

On the three phases of information construction in rural area above analysis, rural household is main body in the process. The farmers' production and living are improved gradually, by the economic benefit driving, information construction in rural area can accelerate to development, which is essential instrument to solve agriculture, rural area, and farmer. Only under the government leadership, can the information construction in rural area develop steadily and soundly. Government plays invigorative, catalytic, and supportive role in the process.

Development countermeasures of information construction in rural area

As far as the report from the Ministry of Agriculture of China (2009.7), all levels of agricultural sector have its own information construction department, possessing 200,000 stuffs. 31 provinces (autonomous regions and municipalities), 80% (city) and 60% of the county agricultural department have set up a special web site, initially forming a national agricultural information network group. Additionally, in accordance to the report from communications industry newspaper, 70 billion will be invested into information construction in rural area in the next 3 years, and strive to build 100,000 rural information service stations by 2011, the agricultural information communication machine customers exceeds 100 million, information machines distributes all administrative villages, realize the goal of "one town one station, one village, one machine". We can infer from the above report, information construction in rural area still remains in its preliminary phase in the next few years. Market and rural household interference seldom occur. We should put the emphasis on the aspects below:

4.1. To propaganda information construction in rural area so that farmer understands and accepts its importance

Information construction in rural area turns towards rural area, combines farmer, services agriculture. Farmer plays utmost role in this process. In order to set up information construction in rural area, the government should establish links with farmer so that they understand the importance of information construction in rural area.

To push forward marketization of rural area information

Besides increase financial support, government ought to emphasize market intervene so that accelerate the step towards information construction in rural area. At present, the obstacles of market intervene originate from two aspects: (1) information asymmetry occurs between governmental policies and market players;

(2) information asymmetry occurs between market players and policy makers.

To formulate policy in order to safeguard mechanism for information construction in rural area

As the infant industry, information construction in rural area possesses expansive development space and speed. Meanwhile, indispensable policy is its safeguard. All level government should optimize information construction in rural area environment.

For example: information sharing mechanisms, personnel training system, supervision and management mechanism.

To intensify rural area information management

Unlike the traditional industrial management, information management possesses its own feature. Aiming at service agriculture, rural area, and farmer, information management should primarily disclose he relevant information of behaviors of principal part through different media instruments, and then inspire the principal part to improve their production and living behaviors. At present, we should set up agricultural database, support agricultural research, production, operation and management, technology generalization.

Conclusion

Information construction in rural area is at preliminary stage. All level government play role of investment. Therefore, we should vigorously explore information construction in rural area, attract private capital to intervene, combine farmer and other social sectors to participate, coordinate the benefit of investment entities, et up agricultural database, support agricultural research, production, operation and management, technology generalization and so on. In accordance with effective demand, heavy service, wide coverage, multi-mode requirements, integration of resources and build a platform to improve the rural information service system.

Promote "three-in-one" model of rural information and rural business information services, construction, information services and actively explore ways and means of villages and peasant households. Improve the collection and dissemination of agricultural information system for farmers and enterprises to provide timely and effective information services.

Fig 1 .

 1 Fig 1. Preliminary phase of information construction in Chinese rural area

Acknowledgments

I am especially grateful to the reviewers to give many useful comments and advice. In the process of relevant study and paper writing, many workmate provide some beneficial helps. The responsibility for any errors rests solely with me.


Jianjun Ding

Xihua Wang

Chao Sun

The The The The Application Application Application Application of of of of CPLD CPLD CPLD CPLD And And And And ARM ARM ARM ARM I I I In n n n Food Food Food Food Safety Safety Safety Safety Testing Testing Testing Testing D D D Data ata ata ata F F F Fusion

Keywords: ARM, CPLD, Data fusion, Food safety testing

Analyzes the main features of CPLD, and describes the process that use ARM for data fusion after obtaining a large number of food safety testing signals, and gives principle of CPLD. This system has realized the data fusion processing, and has the performances that easy to operation, high sensitivity, strong data analysis capability, stable output and so on. Improving the performance of system data processing greatly and reducing the development costs effectively, provides an effective method of data processing for food safety testing.

Introduction Introduction Introduction Introduction

As food safety affecting people's health and safety directly, more and more attention has been paid to it. While food security becoming the focus of which the public concern about, administration departments have also taken various measures to enhance the work of food safety testing. With the development of safety detection, all kinds of test items and test equipments were available. After each test, there will be a large number of data. In this case, on one side, could improve the level of food security testing, and on the other hand, new requirements for data acquisition and processing technology would be proposed.

CPLD is short for Complex Programmable Logic Device. Comparing with previous data collector, it has a higher acquisition speed and more stable. In the previous case, after data collecting, single chip microcomputer was used as the main tool for data Analysis. But with the growing data flow and the requirements for realtime from modern testing technology, the single chip microcomputer can not meet these requirements [START_REF] Zong | The Design of Data Acquisition and Control System Based on CPLD[END_REF]. ARM embedded technology could be used to solve these problems wonderfully. It will meet the requirements of improving data collection speed and data processing speed effectively by combining CPLD technology with the ARM. There will be a variety of detection volume during food safety testing process and circuit designed are multi-sensor circuit. Basing on actual requirements we can increase or decrease sensors signals output channels. Signals from various channels enter into CPLD first. CPLD controls signals from the strobe. The sensors output signals are so weak that system will take on signal amplification and frequency processing after signals gating through the CPLD. After processing the signals, they will be sent into A/D. In this way , it will be easy for ARM to take on data fusion. In the ARM processor, the signals collected will be processed by many methods , including wavelet analysis, least-squares method, DS evidence theory ,fuzzy neural network and so on.Then calling for database to analyze and compare the signals. Food safety testing has so many detection items that a lot of types and a large number of sensors are involved. It is very important to judge the state of the sensors [START_REF] Fu | Mine Monitoring System Based on Network of ARM and Data Fusion[END_REF].

Through a preliminary analysis of sensors output signals, we can discover non-normal state sensors. When the sensors are not working properly that the system will send warning signals immediately. This will remind the inspectors not to analyze the wrong output. In this way, it will save the time of data acquisition and analysis.

What's more, it can also increase system efficiency and reliability. As the multiple sources put into the circuit nearly at the same time that it needs CPLD to control A / D conversion work. Through the CPLD module internal clock frequency, pulse signals are generated [START_REF] Fu | Mine Monitoring System Based on Network of ARM and Data Fusion[END_REF]. Once count time, A / D conversion start to work for one time.

Another pulse signal will be issued after A / D conversion completed. And then the data will be sent to the ARM for the next step processing. CPLD's work signal is empty at that time, indicating that the data has been removed by ARM processor [START_REF] Qing | High-speed Data Acquisition and Signal Processing[END_REF] and CPLD can select a new signal channel and receive the new sensors output signals.

Pic(2) CPLD Work Logic Flow Chart

ARM ARM ARM ARM D D D Data ata ata ata P P P Processing rocessing rocessing rocessing

the previous data fusion process, use single chip microcomputer for data processing when the amount of data is small. Data will be sent to the PC when there is a large amount of data. So there are some problems. For example: some data may lose during the process of transmission; A longer transmission time will be needed when there is enormous amount of data, and it is easy to be affected by the external environment. In the process of food testing, as the sensors signals have an important influence on test results, and many cases require to achieve the rapid detection, so the whole system have a higher demand with real-time data transmission and stability.

With the development of embedded technology, the system's data processing capabilities continue to increase, and can completed the work of data fusion in the field gradually [START_REF] Hu | Research on the Information Integration Model of Embedded Multi-sensor[END_REF].

In this system, ARM processor needs to monitor the working status of each sensor and use several fusion algorithms on the sensors output signals at the same time. There has been a simple comparative analysis to evaluate sensors working conditions when the data into the CPLD. But only a simple estimate is not enough. It still needs the ARM processor for further identification. System identification method is adaptive fusion algorithm in wavelet analysis. In the testing process, by calling the database, compare with the state of each sensor in sensor systems. Estimate the reliability of data [START_REF] Yuan | Adaptive Multi-sensor Fusion Algorithm Based on Wavelet Neural Network[END_REF] and accept the sensor data according to the reliability. Sensors data fusion use the least square method, DS evidence theory and fuzzy neural network technology. Least squares method is simple and easy to operate. In this way the system can reduce the computational burden. DS evidence theory has the advantage of a strong theoretical foundation. It can deal with the uncertainty caused by random and ambiguity [START_REF] Hua | Multi-sensor Data Fusion Technology and Its Research Progress[END_REF]. This has great significance. Because during the process of sampling, the sensor may be affected by sampling time, sampling frequency, a sudden change in environmental conditions and so on. System can not avoid to occur some errors and uncertainties. DS evidence theory can analyze and solve such problems effectively.

Fuzzy neural network has the function of learning algorithm and high convergence speed. It can get the required input-output relationship quickly [START_REF] Bai | Muti-sensor Information Fusion Technology and Its Application[END_REF]. So, in this way, by calling the database, system can analyze data by itself. This can reduce the pressure on the system operation and save the test time.

Conclusion Conclusion Conclusion Conclusion

Food safety testing technology plays a significant role in the process of protecting food safety. Detection system with the CPLD can be used to improve data acquisition speed and ensure the security of data acquisition and stability at the same time. That will display the multi-sensor group's function fully. Using of ARM technology and a variety of data fusion methods will help to achieve real-time data analysis and improve the the speed of system detection. It will also help to facilitate the system in the actual detection and promotion. The using of multi-sensor group will meet the requirement that the same or different materials can be tested at the same time. This can reduce test cost and improve the detection speed. This method can simplify the process of food safety testing operation and easy to handle. So it will reduce the work volume and improve the level of food safety testing to some extent.

2 2 2 2

 2 The The The The D D D Design esign esign esign of of of of S S S System ystem ystem ystem S S S Structure tructure tructure tructure This system use EPM7128S and ARM7. System flow chart is shown in picture(1).

Finally, the test

  results are sent to the monitors, printers, or saved by network. Test results are saved for the purpose of data analysis and archiving. Pic(1) System Flow Chart 3 3 3 3 Principle Principle Principle Principle of of of of CPLD CPLD CPLD CPLD CPLD work logic flow chart is shown in picture(2). The main functions of CPLD are controlling of data collection, determining sensors work state, controlling A/D change.