ライフサイエンスコーパス: VSG

1 VSG causes sustained reduction in body weight, which res

2 VSG did not affect fasting secretion of triglyceride, li

3 VSG did not alter total intestinal triglyceride levels o

4 VSG ES activation in African trypanosomes therefore appe

5 VSG expression is monoallelic such that only one of appr

6 VSG internalization results in decreased expression of a

7 VSG rats maintained their reduced body weights.

8 VSG reduced postprandial levels of plasma lipid, indepen

9 VSG switches involve the activation of VSG genes, from a

10 VSG switching is spontaneous and occurs at a rate of abo

11 VSG switching is thought to occur predominantly through

12 VSG switching occurs by frequent homologous recombinatio

13 VSG was performed in Long-Evans rats with diet-induced o

14 VSG was performed on Long-Evans rats with diet-induced o

15 VSGs are expressed exclusively from subtelomeric loci, a

16 VSGs are monoallelically expressed from subtelomeric exp

17 osoma brucei genome contains more than 1,000 VSG genes.

18 T. brucei has >1000 VSG genes and pseudogenes, of which one is transcribed a

19 f the VSG family, no complete structure of a VSG has been reported.

20 the promoter region of silent but not active VSG ESs in bloodstream form T. brucei.

21 VEX1 was sequestered by the active VSG and silencing of other VSGs failed when VEX1 was eit

22 SG alone is sufficient to silence the active VSG gene and directionally attenuate the ES by disruptor

23 The active VSG gene is in a Pol I-transcribed telomeric expression

24 The active VSG is transcribed by RNA polymerase I in one of approxi

25 The active VSG is transcribed from one of about 15 telomeric VSG ex

26 Consistent with lower adiposity, VSG decreased plasma leptin levels.

27 ereas negative regulation primarily affected VSGs.

28 Positive regulation affected VSGs and nontelomeric pol-I-transcribed genes, whereas n

29 ayed decreased chromatin accessibility after VSG.

30 he improvements in glucose homeostasis after VSG.

31 re was no hyperplasia of the intestine after VSG, but the intestinal absorption of alimentary glucose

32 sm, are up-regulated in livers of mice after VSG while genes in inflammatory pathways are down-regula

33 ng total bile acids are known to occur after VSG.

34 t and body fat in male and female rats after VSG.

35 t blood levels of ghrelin were reduced after VSG, but not after Roux-en-Y gastric bypass, based on en

36 flammatory pathways are down-regulated after VSG.

37 ockdown of tbRAP1 led to derepression of all VSGs in silent ESs, but not VSGs located elsewhere, and

38 xceptionally high efficiency of mono-allelic VSG expression is essential to bloodstream trypanosomes

39 Although VSG slightly improved leptin's anorectic action, the res

40 ant antigens derived from multiple ancestral VSG lineages, whereas in Trypanosoma brucei VSG have rec

41 expenditure was similar between control and VSG rats.

42 GB increases intestinal glucose disposal and VSG delays glucose absorption; both contribute to observ

43 DNA hybrids, telomeric/subtelomeric DSBs and VSG switching frequency back to WT levels.

44 controls transcription of telomeric ESs and VSG antigenic switching in Trypanosoma brucei.

45 rom subtelomeric expression sites (ESs), and VSG switching exploits subtelomere plasticity.

46 o control telomere-linked VSG expression and VSG switching.

47 e dimensions of Trypanosoma brucei HpHbR and VSG have been determined by small-angle X-ray scattering

48 gression, reduced the abundances of rRNA and VSG mRNA, and resulted in rapid cell death.

49 cifically affected the abundance of rRNA and VSG mRNA.

50 bly increased in rats that received RYGB and VSG compared with those that were pair-fed or fed ad lib

51 n DA D2 receptor availability after RYGB and VSG most likely reflect increases in extracellular dopam

52 a key role in tbRAP1-dependent silencing and VSG regulation.

53 P1 play important roles in VSG switching and VSG silencing regulation, respectively.

54 nked to mutually exclusive transcription and VSG recombination, and how these act in the control of t

55 egularly switches its major surface antigen, VSG, in the bloodstream of its mammalian host to evade t

56 egularly switches its major surface antigen, VSG, thereby evading the host's immune response.

57 gularly switching its major surface antigen, VSG, which is expressed exclusively from subtelomeric lo

58 C3 is specifically required for silencing at VSG ES promoters in both bloodstream and insect-stage ce

59 Specific association between VSG transcription and replication timing reveals a model

60 Sequence diversity between VSGs facilitates escape of a subpopulation of trypanosom

61 Blocking VSG synthesis normally triggers a precise precytokinesis

62 VSG lineages, whereas in Trypanosoma brucei VSG have recent origins, and ancestral gene lineages hav

63 the C-terminal domain of Trypanosoma brucei VSG plays a crucial role in facilitating exchange, we re

64 ry for the metabolic improvements induced by VSG surgery.

65 the beneficial metabolic effects induced by VSG.

66 ntly low enough to trigger a characteristic 'VSG synthesis block' cell-cycle checkpoint, as some cell

67 a critical density threshold of its cognate VSGs on the parasite surface.

68 attering to elucidate the first two complete VSG structures.

69 a Pol I-transcribed ES, as well as conserved VSG 3'UTR 16-mer sequences for the generation of functio

70 y switching to the expression of a different VSG gene.

71 ace VSG using a repertoire of ~2500 distinct VSG genes.

72 Mutational analysis of the ectopic VSG 3'UTR demonstrated the essentiality of a conserved 1

73 echanism for diversifying the genome-encoded VSG repertoire.

74 atively examining the diversity of expressed VSGs in any population of trypanosomes and monitored VSG

75 In fact, VSG normalized the impairment in glucose tolerance and c

76 TbSpt16 knock-down results in 16- to 25-fold VSG ES derepression.

77 hat TbRAP1, a telomere protein essential for VSG silencing, suppresses VSG gene conversion-mediated s

78 by recombination, arguing against models for VSG switch initiation through direct generation of a DNA

79 ent genomic locations showed that functional VSG levels could be produced from a gene 60 kb upstream

80 the effects of vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass surgeries for obesity.

81 cial effects of vertical sleeve gastrectomy (VSG) on plasma lipid levels are weight independent.

82 Vertical sleeve gastrectomy (VSG) produces dramatic, sustained weight loss; we invest

83 Vertical sleeve gastrectomy (VSG) produces sustainable weight loss, remission of type

84 pass (RYGB) and vertical sleeve gastrectomy (VSG) reduce weight and improve glucose metabolism in obe

85 pass (RYGB) and Vertical Sleeve Gastrectomy (VSG) surgery and that these changes would influence eati

86 s, we performed vertical sleeve gastrectomy (VSG), a surgery with clinical efficacy very similar to t

87 ures, including vertical sleeve gastrectomy (VSG), and has been widely hypothesized to contribute to

88 edures, such as vertical sleeve gastrectomy (VSG), are at present the most effective therapy for the

89 ypass (RYGB) or vertical sleeve gastrectomy (VSG), are the most effective approaches to resolve type

90 the trypanosome surface following a genetic VSG switch, and show that full coat replacement requires

91 ycoprotein (VSG) coat from its large genomic VSG repertoire.

92 To be expressed, a given VSG gene must be located in one of 15 telomeric regions

93 e proteins-the variant surface glycoprotein (VSG) and procyclin.

94 its protective Variant Surface Glycoprotein (VSG) coat by antigenic variation.

95 ons within the variant surface glycoprotein (VSG) coat displayed by African trypanosomes are predicte

96 cing its dense variant surface glycoprotein (VSG) coat from its large genomic VSG repertoire.

97 nges its dense variant surface glycoprotein (VSG) coat to avoid elimination by the immune system of i

98 itching of its variant surface glycoprotein (VSG) coat.

99 changes in its variant surface glycoprotein (VSG) coat.

100 placement of a variant surface glycoprotein (VSG) coat.

101 changing their variant surface glycoprotein (VSG) coat.

102 ential coat of Variant Surface Glycoprotein (VSG) comprising approximately 10% total protein.

103 oodstream form Variant Surface Glycoprotein (VSG) expression sites (BESs), of which one is expressed

104 I transcribed variant surface glycoprotein (VSG) expression sites (ESs) of Trypanosoma brucei.

105 omere-proximal variant surface glycoprotein (VSG) expression sites (ESs), suggesting a role in contro

106 ximal silenced variant surface glycoprotein (VSG) expression sites and procyclin loci, indicating a d

107 eam, expresses variant surface glycoprotein (VSG) from 1 of 15 bloodstream expression sites (BESs) by

108 one telomeric variant surface glycoprotein (VSG) gene at a time, producing superabundant and switcha

109 ranscribes its variant surface glycoprotein (VSG) gene expression sites (ESs) in a monoallelic fashio

110 I)-transcribed variant surface glycoprotein (VSG) gene expression sites (ESs), which are monoallelica

111 t subtelomeric variant surface glycoprotein (VSG) gene expression sites, but not in the active expres

112 sses involving Variant Surface Glycoprotein (VSG) gene rearrangements at subtelomeres.

113 t 20 telomeric variant surface glycoprotein (VSG) gene-expression sites (ESs) while multiplying in th

114 e silencing of variant surface glycoprotein (VSG) genes found adjacent to telomeres in polycistronic

115 ucei expresses variant surface glycoprotein (VSG) genes in a strictly monoallelic fashion in its mamm

116 sed for moving variant surface glycoprotein (VSG) genes into expression sites during immune evasion b

117 f subtelomeric variant surface glycoprotein (VSG) genes to achieve antigenic variation.

118 oximately 1500 variant surface glycoprotein (VSG) genes while multiplying in the mammalian bloodstrea

119 ss hundreds of variant surface glycoprotein (VSG) genes, but only one is expressed from a telomeric e

120 hive of silent Variant Surface Glycoprotein (VSG) genes, which are activated by recombination into sp

121 more than 1000 Variant Surface Glycoprotein (VSG) genes.

122 omere-adjacent variant surface glycoprotein (VSG) genes.

123 sponses to the variant surface glycoprotein (VSG) of African trypanosomes play a critical role in con

124 The variant surface glycoprotein (VSG) of African trypanosomes, for example, is sized for

125 The variant surface glycoprotein (VSG) of bloodstream form Trypanosoma brucei (Tb) is a cr

126 lion copies of variant surface glycoprotein (VSG) that is expressed from a single VSG gene, drawn fro

127 urface antigen variant surface glycoprotein (VSG) to evade mammalian host immune responses at the blo

128 e antigen, the Variant Surface Glycoprotein (VSG), in a monoallelic manner.

129 expressing the variant surface glycoprotein (VSG), the key protein in antigenic variation, we investi

130 c coat made of variant surface glycoprotein (VSG).

131 e monolayer of variant surface glycoprotein (VSG).

132 at comprises a variant surface glycoprotein (VSG).

133 ective coat of Variant Surface Glycoprotein (VSG).

134 ly immunogenic Variant Surface Glycoprotein (VSG).

135 ombination of Variant Surface Glycoproteins (VSG) genes, most of which reside in a subtelomeric repos

136 iation of the Variant Surface Glycoproteins (VSG) that coat parasites while they reside within mammal

137 monolayer of variant surface glycoproteins (VSG) that covers its cell surface.

138 n of distinct variant surface glycoproteins (VSGs) at extremely high density on the cell surface.

139 ing different variant surface glycoproteins (VSGs).

140 ed that as parasites enter the tsetse's gut, VSG molecules released from trypanosomes are internalize

141 However, VSG levels were not consistently low enough to trigger a

142 propose that BRCA2 acts to maintain the huge VSG repository of T. brucei, and this function has neces

143 e RAD51 paralogue gene significantly impedes VSG switching.

144 ed to an internal amphipathic alpha helix in VSG monomers and may have evolved due to selective press

145 Epigenetic regulation is involved in VSG control but our understanding of the mechanisms invo

146 y confirmed and its potential involvement in VSG repression or switching has not been thoroughly inve

147 of TDP1 results in up to 40-90% reduction in VSG and rRNA transcripts and a concomitant increase in h

148 has been proposed to play a critical role in VSG regulation, yet no telomeric protein has been identi

149 factor, TbTRF, also plays a critical role in VSG switching regulation, as a transient depletion of Tb

150 ing activity is critical for TbTRF's role in VSG switching regulation.

151 Using this approach, we demonstrate roles in VSG ES silencing for two histone chaperones.

152 ns TbTIF2 and TbRAP1 play important roles in VSG switching and VSG silencing regulation, respectively

153 ssion of VSG is controlled, and how inactive VSG ESs are silenced.

154 repression of transcription in the inactive VSG Basic Copy arrays, minichromosomes and procyclin loc

155 , although NUP-2 silencing does not increase VSG switching.

156 silent VSGs in both BF and PF, and increased VSG switching particularly through the in situ transcrip

157 ir antigenic variation, but causes increased VSG switching by recombination, arguing against models f

158 affinity also led to significantly increased VSG switching frequencies, indicating that the telomere

159 Further, NUP-1 depletion leads to increased VSG switching and therefore appears to have a role in co

160 of high-resolution structures of individual VSG domains, we employed small-angle X-ray scattering to

161 ification of the range of pathways involving VSG recombination in the context of mono-telomeric VSG t

162 The strength of TbRAP1-mediated BES-linked VSG silencing is stronger in the PF cells than that in B

163 is also required to control telomere-linked VSG expression and VSG switching.

164 xpression of BF Expression Site (BES)-linked VSGs and silencing of metacyclic VSGs (mVSGs) in BF cell

165 e previously shown that silencing BES-linked VSGs in BF cells depends on TbRAP1.

166 a central role for chromatin in maintaining VSG ES silencing.

167 BES)-linked VSGs and silencing of metacyclic VSGs (mVSGs) in BF cells are essential for antigenic var

168 any population of trypanosomes and monitored VSG population dynamics in vivo.

169 Monoallelic VSG transcription resumes after reexpression of TbPIP5K;

170 pletion of TbTRF leads to significantly more VSG switching events.

171 rimary cell responsible for activating naive VSG-specific Th cell responses in resistant responder an

172 ewly encountered exogenous Ag, including new VSG molecules, during high parasitemia.

173 epression of all VSGs in silent ESs, but not VSGs located elsewhere, and resulted in stronger derepre

174 eover, in the absence of FXR, the ability of VSG to reduce body weight and improve glucose tolerance

175 VSG switches involve the activation of VSG genes, from an enormous silent archive, by recombina

176 rtunities, as well as considering aspects of VSG biology that remain to be fully explored.

177 hanisms underlying the metabolic benefits of VSG have remained elusive.

178 tributed throughout the N-terminal domain of VSG but are not clustered exclusively within HV-1 or oth

179 he relatively conserved C-terminal domain of VSG.

180 e been examined extensively, the dynamics of VSG coat replacement at the protein level, and the impac

181 However, the dynamics of VSG expression in T. brucei during an infection are poor

182 We compared the effects of VSG in ghrelin-deficient mice and wild-type mice on food

183 t appear to be required for these effects of VSG.

184 rchitecture probably maximizes efficiency of VSG transport and fidelity in organellar segregation dur

185 It is unclear how monoallelic expression of VSG is controlled, and how inactive VSG ESs are silenced

186 ting that a DSB is a natural intermediate of VSG gene conversion and that VSG switching is the result

187 ors mediating these extremely high levels of VSG expression by inserting ectopic VSG117 into VSG221 e

188 s for the generation of functional levels of VSG expression in bloodstream form T. brucei.

189 itro, and presented relatively low levels of VSG peptides to T cells in vivo.

190 Single-molecule diffusion measurements of VSG in supported lipid bilayers substantiate this possib

191 tial species differences in the mechanism of VSG diversification.

192 le is known about the molecular mechanism of VSG switching in T. brucei.

193 n but suggest a telomere-independent mode of VSG-silencing.

194 les, secretion of IL-12, and presentation of VSG peptides to T cells in vivo.

195 Here we evaluate the rate of VSG replacement at the trypanosome surface following a g

196 We therefore examined the results of VSG surgery applied to mice with diet-induced obesity an

197 A breaks, including in the telomeric site of VSG expression.

198 Thus, we examined the fine specificity of VSG-specific T-cell lines, T-cell hybridomas, and Th cel

199 e biosynthesis, trafficking, and turnover of VSG, emphasising those unusual mechanisms that act to ma

200 Thus, initial uptake of VSG (or other trypanosome factors) may interfere with Ag

201 we demonstrate that the therapeutic value of VSG does not result from mechanical restriction imposed

202 loped a method, based on de novo assembly of VSGs, for quantitatively examining the diversity of expr

203 urprising insight that a broad repertoire of VSGs is rapidly expressed.

204 ontributes to its strong silencing effect on VSGs.

205 They transcribe only one VSG gene at a time from 1 of about 20 telomeric expressi

206 Each cell expresses only one VSG gene at a time from a telomeric expression site (ES)

207 ne ES is fully active at a time, so only one VSG gene is transcribed per cell.

208 Rats underwent RYGB or VSG and were compared to sham-operated rats fed ad lib o

209 icantly better in rats that received RYGB or VSG compared with rats fed ad lib or pair-fed, whereas g

210 y and at approximately 7 weeks after RYGB or VSG surgery.

211 Following RYGB or VSG, glucose tolerance and insulin sensitivity improved

212 fter a meal among rats that received RYGB or VSG.

213 glucose metabolism in rats following RYGB or VSG.

214 red by the active VSG and silencing of other VSGs failed when VEX1 was either ectopically expressed o

215 Our results demonstrate how past VSG evolution indirectly determines the ability of conte

216 resulted in prerestriction, rather than pre-VSG, body weights.

217 Rather, VSG is associated with increased circulating bile acids,

218 In obese rats, VSG is as effective as RYGB for increasing secretion of

219 Rats that received VSG and high-fat diets had markedly lower fasting levels

220 Rats that received VSG had a marked, weight-independent reduction in secret

221 We reconstruct VSG diversification showing that Trypanosoma congolense

222 proteins play important roles in regulating VSG silencing and switching.

223 While the mechanisms regulating VSG gene expression and diversification have been examin

224 role of the telomere adjacent to a repressed VSG.

225 G mRNA appears to have a role in restricting VSG expression to a single gene.

226 The mechanism(s) restricting VSG expression to a single BES are not well understood.

227 Obese male rats underwent RYGB, VSG, or sham (control) operations.

228 We found that the expression of a second VSG alone is sufficient to silence the active VSG gene a

229 ity of these animals to elicit a significant VSG-specific T cell response.

230 complex and a major regulator for silencing VSG expression sites (ESs).

231 nce of repressed chromatin present at silent VSG ES promoters, but is also essential for chromosome s

232 lts in 20- to 23-fold derepression of silent VSG ES promoters in bloodstream form T. brucei, with der

233 is of TbISWI leads to derepression of silent VSG ES promoters, this does not lead to fully processive

234 enriched at the active compared with silent VSG ES and immediately downstream of ribosomal DNA promo

235 ed in derepression of telomere-linked silent VSGs in both BF and PF, and increased VSG switching part

236 rotein (VSG) that is expressed from a single VSG gene, drawn from a large repertoire and located near

237 terminant of the activation of at least some VSG genes.

238 incomplete, however, allowing G2/M-specific VSG ES derepression following knockdown of histone H3.

239 ut has the opposite effect at a subtelomeric VSG.

240 al recombination, it suppressed subtelomeric VSG recombination, and these locus-specific effects were

241 s significantly stronger at the subtelomeric VSG loci than at chromosome internal loci.

242 Such VSG switching can occur at rates substantially higher th

243 A major route for such VSG switching is gene conversion reactions in which RAD5

244 tein essential for VSG silencing, suppresses VSG gene conversion-mediated switching.

245 asite varies this highly immunogenic surface VSG using a repertoire of ~2500 distinct VSG genes.

246 hly flexible overall topology of the surface VSG coat, which displays both lateral movement in the pl

247 time, producing superabundant and switchable VSG coats.

248 repression is lost along with the telomere, VSG-silencing is preserved.

249 that only one of approximately 15 telomeric VSG expression sites (ESs) is transcribed at a time.

250 s transcribed from one of about 15 telomeric VSG expression sites (ESs).

251 erase I in one of approximately 15 telomeric VSG expression sites (ESs).

252 combination in the context of mono-telomeric VSG transcription.

253 bed at a time from one of multiple telomeric VSG expression sites.

254 some depletion and derepression of telomeric VSG ESs.

255 d genes (ESAGs) in addition to the telomeric VSG.

256 cated in one of 15 telomeric regions termed "VSG expression sites" (ESs), each of which contains a po

257 ression site-associated genes and a terminal VSG gene.

258 ufficient to maintain secondary and tertiary VSG structure, prompted us to test the hypothesis that T

259 aling the receptor to be more elongated than VSG.

260 intermediate of VSG gene conversion and that VSG switching is the result of the resolution of this DS

261 We found that VSG produced comparable outcomes in each strain.

262 We found that VSG reduced body mass and improved both glucose and lipi

263 We found that VSG-operated GLP-1 receptor-deficient mice responded sim

264 We demonstrate here that VSG in C57BL/6J wild-type male mice can reverse these ch

265 Our results indicate that VSG induces global regulatory changes that impact hepati

266 ingestion of a lipid meal and indicates that VSG has important effects on metabolism.

267 teins is a novel function and indicates that VSG serves a dual role in trypanosome biology-that of fa

268 Here, the authors show that VSG replacement takes several days to complete, and the

269 ibility between domains, which suggests that VSGs can adopt two main conformations to respond to obst

270 The VSG glycosylphosphatidylinositol (GPI)-anchor strongly i

271 likely that the receptor protrudes above the VSG layer and unlikely that the VSG coat can prevent imm

272 ted where it is readily accessible above the VSG layer.

273 Bs inefficiently direct recombination in the VSG expression site.

274 lian bloodstream, antigenic variation of the VSG coat is the parasite's means to evade the immune res

275 nderpinning synthesis and maintenance of the VSG coat.

276 Despite the importance of the VSG family, no complete structure of a VSG has been repo

277 een telomeric ESs or by recombination of the VSG gene expressed.

278 ter that is located 45-60 kb upstream of the VSG gene.

279 nderstand the receptor in the context of the VSG layer, the dimensions of Trypanosoma brucei HpHbR an

280 elatively invariant C-terminal region of the VSG molecule during infection, suggesting that it could

281 ption initiation and that, surprisingly, the VSG mRNA appears to have a role in restricting VSG expre

282 er, most of the resultant cells switched the VSG gene expressed.

283 es above the VSG layer and unlikely that the VSG coat can prevent immunoglobulin binding to the recep

284 virulence of African trypanosomes, where the VSG coat is used to evade the host immune system.

285 , fed either ad libitum or pair-fed with the VSG group, were used as controls.

286 obin-hemoglobin receptor (HpHbR) within this VSG coat mediates heme acquisition.

287 Thus, VSG-specific Th1 cell responses may be determined by tis

288 rapid internalization of antibodies bound to VSG on the surface of the trypanosome is blocked.

289 has been identified whose disruption led to VSG derepression.

290 the first readily druggable target linked to VSG ES control in the African trypanosome.

291 repeats upstream of the actively transcribed VSG gene, indicating that a DSB is a natural intermediat

292 ion dynamics, we reveal that the transcribed VSG expression site is the only telomeric site that is e

293 air (bp) repeats upstream of the transcribed VSG gene increases switching in vitro approximately 250-

294 We identified trypanosome VSG exclusion-1 (VEX1) using a genetic screen for defect

295 icity of T-cell responses to the trypanosome VSG and suggests that evolution of a conserved HV-1 regi

296 lelic expression of the antigenically varied VSG is disrupted.

297 enic variation and the evolution of the vast VSG gene family.

298 ndividuals or animals that underwent RYGB vs VSG.

299 The intestine adapts differently to RYGB vs VSG.

300 ry for the metabolic improvements shown with VSG, but also suggest an interesting role for apoA-IV in

301 cycle-specific chromatin remodelling within VSG ESs.