ライフサイエンスコーパス: degranulation

1 selective secretion of mediators (piecemeal degranulation).

2 RPV4-mediated Ca(++)-influx evokes mast cell degranulation.

3 le-dependent movement of SGs required for MC degranulation.

4 but decreased NK cell cytolytic activity and degranulation.

5 he calcium response that is essential for MC degranulation.

6 xtracellular Mg(2+) sensitivity of mast cell degranulation.

7 ecreted factors on neutrophil activation and degranulation.

8 s study as a negative regulator of mast cell degranulation.

9 SpeB, can trigger neutrophil activation and degranulation.

10 vergence with either directed or nondirected degranulation.

11 nts to define the impact of the two modes of degranulation.

12 polymorphonuclear neutrophil activation and degranulation.

13 t cells to IgE-independent vibration-induced degranulation.

14 in, led to an important decrease of basophil degranulation.

15 acid residues were also able to trigger cell degranulation.

16 c granules and is released upon induction of degranulation.

17 nducing a robust eosinophilia accompanied by degranulation.

18 gamma production, granzyme B expression, and degranulation.

19 iltrate accompanied by significant levels of degranulation.

20 ization rescue mast cell FcepsilonRI-induced degranulation.

21 ction, regulate different steps in mast cell degranulation.

22 smooth muscle cell and effects on mast cell degranulation.

23 gical processes as Ag-induced chemotaxis and degranulation.

24 cell number, indicative of greater mast cell degranulation.

25 ysicochemical properties influence mast cell degranulation.

26 and ROCK2 insufficiency attenuated mast cell degranulation.

27 pholipase Cgamma1 signaling, associated with degranulation.

28 also exhibit defects in FcepsilonRI-mediated degranulation.

29 ific IgE, basophil activation, and mast cell degranulation.

30 or segment inflammation paralleled mast cell degranulation.

31 nd AYP caused a 2-fold increase in mast cell degranulation.

32 eature of CSU, which could enhance mast cell degranulation.

33 lasmic vesiculation as evidence of piecemeal degranulation.

34 ithin genes involved in cytotoxic lymphocyte degranulation.

35 nt NK cell activation highly correlated with degranulation.

36 rization toward neighboring NK cells without degranulation.

37 previously unappreciated intrinsic defect in degranulation.

38 leukin-2 production and CD107(a/b) cytotoxic degranulation.

39 tin reduction at the immune synapse precedes degranulation.

40 ctivation with IL-3 on IgG-driven eosinophil degranulation.

41 mast cells was not correlated with mast cell degranulation.

42 ular activation and natural killer (NK) cell degranulation.

43 TRPV4 loss of function attenuates mast cell degranulation.

44 tion and survival, and suppressing mast cell degranulation.

45 r of CD32- and alphaMss2-mediated eosinophil degranulation.

46 actin acts as a barrier preventing sustained degranulation.

47 eases associated with IgE-mediated mast cell degranulation.

48 s were also dysfunctional and showed reduced degranulation.

49 te early immune events that impact mast cell degranulation.

50 lator (ITN) on conjunctival goblet cell (GC) degranulation.

51 ng proteins involved in cytotoxic lymphocyte degranulation.

52 During activation, these cells undergo degranulation, a process by which various kinds of media

53 ed tissues by cellular stress signals, on MC degranulation, a process possibly driven by selective se

54 oduction and at least a transiently impaired degranulation ability.

55 sinophils (p < 0.0116, r = 0.5656) and their degranulation/activation products (major basic protein [

56 selectin expression, which reflects platelet degranulation/activation, was quantified by flow cytomet

57 ws a significant impairment of cytolytic and degranulation activities in patients with STAT1 GOF muta

58 early lytic responses were marked by strong degranulation after an encounter of unstimulated TECs, r

59 with lower NK cell IFN-gamma production and degranulation after in vitro restimulation with pertussi

60 epletion of MCs granules or prevention of MC degranulation also reduced DVT.

61 its eosinophil effector functions, including degranulation and Ag presentation.

62 at DENV infection of skin mast cells induces degranulation and alters cytokine and growth factor expr

63 he first demonstration of in vivo eosinophil degranulation and basophil activation during ACS and of

64 onditions demonstrated increased nondirected degranulation and bystander killing.

65 he presence of CCL7 synergistically enhanced degranulation and calcium influx.

66 sessed major neutrophil functions, including degranulation and cell migration, associated with the p3

67 t also the magnitude of individual mast cell degranulation and chemokine production.

68 BV(+) individuals triggered vigorous NK cell degranulation and cytokine production (i.e., TNF-alpha a

69 ggers multiple cellular responses, including degranulation and cytokine production.

70 d in well-known activating functions such as degranulation and cytoskeletal reorganization, but also

71 NK cells cocultured with M2 displayed lower degranulation and cytotoxic activity than NK cells cocul

72 sion in control CTLs and NK cells diminishes degranulation and cytotoxic activity.

73 poresponsive CD56(dim) NK cells with limited degranulation and cytotoxic capacity.

74 atory cytokine production, without effecting degranulation and cytotoxic function.

75 BL-SX38 cells significantly reduced basophil degranulation and de novo TH2 cytokine production.

76 NK cells from patients also had increased degranulation and decreased production of IFNgamma and t

77 polymerize actin and exhibit a block in both degranulation and DNA release.

78 sfully interferes with allergen-induced cell degranulation and efficiently inhibits systemic anaphyla

79 CD107a degranulation and europium release assay were performed

80 We found that degranulation and histamine release proceeded independen

81 estigated the function of TRPM7 on mast cell degranulation and histamine release using wild-type (TRP

82 determine the function of TRPM7 in mast cell degranulation and histamine release.

83 or effects on FcepsilonRI-mediated mast cell degranulation and identified 15 potential regulators.

84 rains IL-9 production by mast cells, whereas degranulation and IL-6 expression are both unaffected.

85 Decreased MC degranulation and increased graft Foxp3 Treg infiltratio

86 ect and redirected polyfunctionality assays (degranulation and intracellular production of TNF-alpha

87 vation, requires elevated ROS production and degranulation and involves EET formation.

88 pathways that modulate both immediate-phase degranulation and late-phase cytokine production downstr

89 gous and allogeneic natural killer (NK)-cell degranulation and NK-cell-mediated antibody-dependent ce

90 onal anti-DNP IgE also resulted in mast-cell degranulation and overflow of renin.

91 Neutrophils of Akita/Ncf1 mice had normal degranulation and phagocytic efficiency when compared wi

92 flammatory responses, specifically mast cell degranulation and plasma leakage.

93 ent BMMCs results in significantly increased degranulation and proinflammatory cytokine production co

94 We found that M. tuberculosis-specific degranulation and proliferative capacities were impaired

95 p HK-1 promoted TNF and IL-6 secretion by MC degranulation and protein synthesis, the latter through

96 nleash numerous attacks on pathogens through degranulation and reactive oxygen species (ROS) producti

97 mpaired ability to re-express perforin after degranulation and reduced cytotoxic immune function.

98 at TRPM7 kinase activity regulates mast cell degranulation and release of histamine independently of

99 allergic and inflammatory disorders by rapid degranulation and release of inflammatory mediators upon

100 lls initiates activation events that lead to degranulation and release of inflammatory mediators.

101 s aeruginosa, LPS, or PAM(3)Cys4 resulted in degranulation and release of TREM-1sv.

102 stander B cells trigger Ab-dependent NK cell degranulation and TNF-alpha but not cytotoxicity or IFN-

103 also promoted specific Ab-dependent NK cell degranulation and TNF-alpha production but induced minim

104 tokinergic activity as measured by mast cell degranulation and TNF-alpha release.

105 r cell engager (BiKE) significantly enhanced degranulation and tumor necrosis factor-alpha and interf

106 binding to Cyp c 1, Cyp c 1-induced basophil degranulation, and allergic symptoms caused by allergen

107 migratory responsiveness, respiratory burst, degranulation, and calcium mobilization were conducted i

108 ced eosinophil IL-1beta and IL-18 secretion, degranulation, and cell death.

109 nition of Cyp c 1, Cyp c 1-specific basophil degranulation, and Cyp c 1-induced allergic symptoms in

110 ed reactive oxygen species production, early degranulation, and granule fusion processes, leading to

111 KIR that could trigger NK cell cytotoxicity, degranulation, and IFN-gamma release.

112 each anti-SEE mediated SEE-induced basophil degranulation, and IgG1 or antigen-binding fragments of

113 ive capability in response to cytokines, low degranulation, and impaired cytokine production on inter

114 ed during polymorphonuclear neutrophil (PMN) degranulation, and mediates dysregulation of vascular to

115 ding adhesion, transmigration, phagocytosis, degranulation, and neutrophil extracellular trap formati

116 Reactive oxygen species (ROS) production, degranulation, and phagocytosis are normal in the absenc

117 cient in antigen-stimulated calcium release, degranulation, and production of some cytokines (TNF-a,

118 ns, we compared interferon gamma production, degranulation, and proliferation of CD8+ T cells in resp

119 anical skin injury, enhances IgE-mediated MC degranulation, and promotes oral anaphylaxis after epicu

120 ction and responded by activation, piecemeal degranulation, and upregulation of Ag presentation marke

121 at markers of activation, proliferation, and degranulation are upregulated on gammadelta T cells in P

122 of PLA2denat decreased IgE-mediated basophil degranulation as compared to the native form of the alle

123 s (associated with eosinophil activation and degranulation) as well as elevated levels of eosinophil-

124 aggregation, shape change, coagulation, and degranulation, as well as how lipids generated by platel

125 on, we developed a high-throughput mast cell degranulation assay suitable for RNA interference experi

126 molecules was assessed in different cellular degranulation assays ex vivo and in a mouse model of pas

127 of Der p 13 were examined by ELISA, basophil degranulation assays, and in vitro airway epithelial cel

128 IgE activities were tested in basophil degranulation assays.

129 nity anti-IgE mAbs that trigger anaphylactic degranulation at low concentration.

130 d with histological evidence of defective MC degranulation but not with changes in MC development, di

131 blocking antibody, and inhibiting mast cell degranulation, but a deleterious role in malignant melan

132 ophils does not affect granule morphology or degranulation, but it causes LAMP1(+) lysosomes to engor

133 stantial inhibition of HDP-induced mast cell degranulation, but PgLPS1435/1449 had no effect.

134 n, we found that production of IFN-gamma and degranulation by CD56(bright) and CD56(dim) NK cells fol

135 7 kinase activity regulates murine mast cell degranulation by changing its sensitivity to intracellul

136 We induced mast cell degranulation by local subconjunctival injection of comp

137 erential regulation of HDP-induced mast cell degranulation by PgLPS1690 and PgLPS1435/1449 may contri

138 We investigated whether attenuation of MC degranulation by sodium cromoglycate allowed CD200 to in

139 -binding fragments of each anti-SEE enhanced degranulation by the other anti-SEE.

140 mediated responses (TNF-alpha production and degranulation) by neonatal Vdelta2 cells and may thus he

141 urface markers) and functions (phagocytosis, degranulation, calcium release, chemotaxis, and reactive

142 Immunoglobulins (Ig)-binding and the degranulation capacities of native and aggregated ovalbu

143 cules (NKG2D, perforin, and granzyme B), and degranulation capacity of CD4(+)CD28(-) T cells.

144 human NK cell adhesion, NK cytotoxicity and degranulation (CD107 expression) against PAEC; however,

145 NK cell degranulation (CD107a expression), target cell conjugati

146 icantly up-regulated the marker of cytotoxic degranulation (CD107a) on CD8(+) T cells (P = 0.03) from

147 Interferon-gamma (IFN-gamma) secretion, degranulation (CD107a), and anti-HCV (= inhibition of HC

148 .62 [5.27-8.73], P=0.63), whereas eosinophil degranulation (CD69) and basophil activation (CD203c) we

149 the limited propensity to activate basophil degranulation classifies Der p 13 as a minor HDM allerge

150 on induced by HDP/MRGPRX2-mediated mast cell degranulation contributes to gingival homeostasis but th

151 r wound healing, and therapies inhibiting MC degranulation could improve wound healing in diabetes.

152 and their functional characterization using degranulation, cytokine production, and proliferation as

153 improved multiple CD56bright cell functions: degranulation, cytotoxicity, and cytokine production.

154 duction in an NFAT-dependent manner, NK cell degranulation/cytotoxicity and tumor rejection in vivo r

155 AP3 complex formation and the degranulation defect in patient T cells were restored by

156 Although degranulation depends crucially on microtubule dynamics,

157 hairs showed a similar abrupt transition of degranulation/depolarization near sites of keratin depos

158 , disodium cromoglycate attenuated mast cell degranulation, development of autoimmunity, and developm

159 We show that PC degranulation does not directly occur upon stimulation w

160 ce-bound IgE without triggering anaphylactic degranulation even at high concentration, albeit they wo

161 n basophils to measure the effect of TSLP on degranulation, expression of activation markers and TH2

162 tate acetate stimulation, decreased platelet degranulation following ADP stimulation, and a higher co

163 Despite notable reductions in MC degranulation following DS, the high-affinity IgE recept

164 e marrow-derived mast cells showed decreased degranulation following IgE and Ag treatment compared wi

165 ulation of heterozygous mutations in the two degranulation genes Rab27a and syntaxin-11, impaired the

166 Perforin expression and the extent of degranulation have been more useful for diagnosing FHL t

167 ency impaired FcepsilonRI-mediated mast cell degranulation; however, PLD2 deficiency enhanced it.

168 Specific Abs promoted the degranulation (i.e., CD107a expression) and the producti

169 , granzyme K, perforin, CD107(a/b) cytotoxic degranulation, IFN-gamma, and multiplex cytokines assays

170 WASp KO NK cells with IL-2 ex vivo restored degranulation, IFNgamma production, and killing of MHC c

171 Furthermore, HDPs stimulated degranulation in a human mast cell line (LAD2) and in RB

172 ta display increased cytokine production and degranulation in an ERK-dependent manner.

173 These mast cells undergo degranulation in an IgE-dependent and -independent manne

174 Increased eosinophils degranulation in duodenum play an important role in path

175 lucan (a DECTIN-1 agonist) induced mast cell degranulation in mesenteric windows and HMC-1 cells resp

176 he production of reactive oxygen species and degranulation in neutrophils.

177 Hyporesponsiveness to degranulation in NK cells was not restored at least for

178 , demonstrating the involvement of mast cell degranulation in posterior segment disorders.

179 We monitored mast cell degranulation in real time by exploiting the capacity of

180 ed CD8(+) T cell proliferation and cytotoxic degranulation in response to alloantigen late after LTx.

181 IL-33 itself does not trigger basophil degranulation in vitro and ex vivo, even in subjects wit

182 sputum immunoglobulins to induce eosinophil degranulation in vitro was assessed.

183 '-sialyllactose directly inhibited mast cell degranulation in vitro, at high concentrations.

184 sed autoantibody levels triggered eosinophil degranulation in vitro, with release of extensive histon

185 rrelating with decreased bone marrow NK cell degranulation in vivo.

186 iated anion secretion, increased spontaneous degranulation in WT goblet cells and improved exocytotic

187 r-alpha (TNFalpha) expression, and extent of degranulation, in NSCLC tumour stroma and islets.

188 eosinophils, shock (hypothermia), mast cell degranulation (increased serum mouse mast cell protease

189 of anaphylaxis was associated with mast cell degranulation, increased plasma heparin levels, the inte

190 Conversely, postwounding MC degranulation increases in nondiabetic mice, but not in

191 Consequently, MC degranulation increases surface delivery of HLA class II

192 e degranulated than in those with PS (median degranulation index = 2.24 versus 1.73 respectively) (p

193 , production of reactive oxygen species, and degranulation induced by immobilized immune complexes, w

194 egranulation pattern into one that resembled degranulation induced by substance P.

195 Pretreatment with the MC degranulation inhibitor disodium cromoglycate rescues di

196 Survival is increased, and MC degranulation is decreased, in CD200 mice but not in CD2

197 We report that degranulation is linked to the number of FcepsilonRI occ

198 ersely, NK cell cytotoxicity, as measured by degranulation, is maintained across the CD56(dim) subset

199 found that whereas C5a was unable to induce degranulation, it stimulated GM-CSF, TNF, CXCL10, and CC

200 that while ICH induced mast cell activation/degranulation, IVIG attenuated post-ICH mast cell activa

201 n this article, we show that IgE-mediated MC degranulation leads to a rapid release of high quantitie

202 neutrophils, we hypothesized that neutrophil degranulation leads to the release of LLO-neutralizing m

203 ture phenotype and impaired cytotoxicity and degranulation, levels of memory B cells were reduced, an

204 olysis was not required directly for NK cell degranulation, limiting the rate of glycolysis significa

205 ptor and inhibiting mast cell activation and degranulation, local masitinib penetration around the CG

206 2 T-cell frequency, cytokine production, and degranulation longitudinally in Ugandan children enrolle

207 tion of CD8(+) T cells expressing the CD107a degranulation marker in the absence of IFNgamma, TNFalph

208 The %IFNgamma+ and CD107a+ (degranulation marker) in CD56+ NK cells were enumerated

209 ature granulocytes expressing high levels of degranulation markers, were specifically responsible for

210 The pharmacologic inhibition of mast cell degranulation may be a potential target for intervention

211 and potently stimulates expression of CD69, degranulation, migration, and cytokine production in nat

212 ause a single CTL can kill multiple targets, degranulation must be tightly regulated.

213 nalization, little calcium flux or mast cell degranulation occurred.

214 While allergic mast cell (MC) degranulation occurs by FcepsilonRI aggregation and vari

215 For pistachio, the degranulation of basophils after challenge with the hars

216 tions as diverse as phagocytosis, triggering degranulation of basophils and mast cells, promoting imm

217 ies reveal that OVA binds IgE and stimulates degranulation of basophils, and that its uptake by monoc

218 IL-33 significantly enhanced IgE-mediated degranulation of BMMCs in vitro.

219 ased proliferation, cytokine production, and degranulation of both TA-specific CD8(+) T cells and CD8

220 aling significantly affected the kinetics of degranulation of CD16.NK-92 cells providing evidence tha

221 ch as SP, STAT5 phosphorylation, spontaneous degranulation of CD8(+) T cells, and the frequency of tr

222 In the present work, we found a rapid degranulation of cultured MCs through a pannexin1 hemich

223 continuing exposure to IL-3 further induced degranulation of eosinophils on aggregated IgG via incre

224 document that the Allergan ITN can stimulate degranulation of goblet cells in the conjunctiva, which

225 T3 is essential for immunologically mediated degranulation of human and mouse mast cells and RBL cell

226 We show that free Fel d 1 induces degranulation of IgE-sensitized mast cells whereas Fel d

227 vation, as well as IgE- and calcium-mediated degranulation of LAD-2 cells, in a dose-dependent manner

228 nisms are conventionally known to facilitate degranulation of mast cells and basophils and promote TH

229 Degranulation of mast cells and basophils, with release

230 esponse to dermal vibration, with coincident degranulation of mast cells and increased histamine leve

231 Initial degranulation of mast cells was observed in the choroid

232 is model, and direct effects on IgE-mediated degranulation of mast cells were assessed.

233 endothelial cells, and indirectly, inducing degranulation of mast cells with release of histamine, a

234 block IgE-mediated allergen presentation and degranulation of mast cells, key factors that influence

235 DH is essential for immunologically mediated degranulation of mast cells.

236 injury can initiate an immediate novel zonal degranulation of MCs throughout all skin layers and a di

237 eficient mice was accompanied by accelerated degranulation of mucosal mast cells and increased Ag-spe

238 ents or by genetic manipulation prevents the degranulation of neutrophils and mitochondrial DNA relea

239 ll defined role in innate immunity, aberrant degranulation of neutrophils in several inflammatory dis

240 gether, these results suggest that FN-driven degranulation of neutrophils induces the production of L

241 These findings suggest that the local degranulation of ocular mast cells provoked acute ocular

242 2 with decreasing of oxidative activity and degranulation of PMNs in human blood via A(2)a receptors

243 Ent also impaired the degranulation of primary granules and inhibited phagocyt

244 ll (MC) IgE receptors (FcepsilonRI) triggers degranulation of secretory granules (SGs) and the releas

245 lammation, but the consequences of mast cell degranulation on ocular pathology remain uncharacterized

246 not induce neutrophil apoptosis or necrosis, degranulation, or release of extracellular traps, and it

247 oxygen species (ROS) production (P = 0.002), degranulation (P < 0.0001) or eosinophil extracellular t

248 P23/STX4 complex formation, and switched the degranulation pattern into one that resembled degranulat

249 Significant higher eosinophil degranulation positive rate in D2 (P = 0.003) and a tren

250 Pharmacological block of mast cell degranulation potently inhibited histamine release by ma

251 The degranulation process is monitored by using either time-

252 During the degranulation process, the granule matrix is externalize

253 ither FcepsilonRI or other receptors for the degranulation process.

254 HIV peptide stimulation increased CD8 T cell degranulation, production of intracellular cytokines, an

255 tially process various stimuli into distinct degranulation programs.

256 de and colleagues show that the adhesion and degranulation promoter protein (ADAP) promotes alphaIIbb

257 gs lacking the adaptor proteins adhesion and degranulation promoting adapter protein or CT10 regulato

258 el negative regulatory role for adhesion and degranulation-promoting adapter protein (ADAP) in CD8 T

259 We investigated the role of adhesion- and degranulation-promoting adapter protein (ADAP) in promot

260 eosinophil apoptosis and inhibits mast cell degranulation, providing an endogenous mechanism to down

261 Consistent with the immaturity of GF MCs, degranulation-provoking compound 48/80 induced less edem

262 NP-dependent exocytosis, slowed the cellular degranulation rate, and diminished the sensitivity to in

263 denal eosinophil and evaluate the eosinophil degranulation rate, number of duodenal degranulated eosi

264 ctors JFC1 and Munc13-4 in the regulation of degranulation, reactive oxygen species and neutrophil ex

265 hereas the magnitude of individual mast cell degranulation remained unchanged, suggesting an all-or-n

266 n response was significantly reduced and CD8 degranulation response was even more enhanced (P<0.05).

267 necrosis factor-alpha-activated TECs, the NK degranulation response was significantly reduced and CD8

268 esults in modest defects in phagocytosis and degranulation responses but a profound block in superoxi

269 ism, dependent on FcgammaR-mediated enhanced degranulation responses by MCs.

270 ogether, these findings suggest that reduced degranulation responses in desensitized MCs arise from a

271 terized by increased neutrophil adhesion and degranulation responses to LTB4.

272 By comparison, robust NK cell degranulation responses were observed both before and af

273 mically distinct ENMs caused a range of mast degranulation responses, with smaller sized Ag NPs (5 nm

274 strong heterogeneity of individual mast cell degranulation responses.

275 The pharmacological inhibition of degranulation reverted this effect, abolishing LTB4 and

276 dium cromoglycate blocks injurious mast cell degranulation specifically without affecting the immunom

277 il CD63 induction indicative of anaphylactic degranulation; suppress peanut-, cat-, and dansyl-specif

278 d by using IgE-binding inhibition assays and degranulation tests of humanized rat basophilic leukemia

279 also induced different patterns of mouse MC degranulation that were associated with distinct local a

280 ndering IgE incapable of eliciting mast cell degranulation, thereby preventing anaphylaxis.

281 trigger Vgamma9Vdelta2 T-cell activation and degranulation through poorly understood mechanisms.

282 Conversely, degranulation triggered by compound 48/80 is highly corr

283 tor molecules granzyme B and perforin; their degranulation upon exposure to K562 cells, as indicated

284 d activate a basophilic cell line to undergo degranulation upon the stimulation with their respective

285 ulated MC constitutively released CD9(+) EV, degranulation was accompanied by the release of CD63(+)

286 NK-cell degranulation was also affected.

287 Bone marrow-derived mast cell (BMMC) degranulation was assessed by using flow cytometry.

288 Maximal degranulation was elicited when approximately 2700 IgE-F

289 The degranulation was equivalent for MCs in the dermis and h

290 Although mouse mast cell degranulation was minimally affected by STAT3 blockade,

291 However, FcepsilonRI-induced mast cell degranulation was unaffected.

292 proliferation assays and ELISA, and basophil degranulation were examined after PLA2denat -MB-based th

293 d mast cells, but there was no difference in degranulation when cells were activated via an IgE-indep

294 nic entities released on frequent eosinophil degranulation, which further contributes to disease seve

295 excellence potently inhibits pseudo-allergic degranulation, while it simultaneously promotes allergic

296 time in the gingival tissue, and subsequent degranulation will contribute to tissue damage.

297 This initiates signals that induce cellular degranulation with release and secretion of vasoactive m

298 Blocking neutrophil degranulation with TAT-SNAP23 fusion protein significant

299 odium cromoglycate would attenuate mast cell degranulation without affecting IL-10 production.

300 termed "cytokinergic", of inducing basophil degranulation without the intervention of an antigen.