ライフサイエンスコーパス: CDG

1 CDG-3 can detect 10 colony-forming units of the attenuat

2 CDGs effectively reduced islet loss by minimizing islet

3 se human homologs are associated with Type 1 CDG, including PGM1, which encodes the minor isoform of

4 y of this variant in 301 controls and in 101 CDG patients who carry known mutations in other genes in

5 ongenital disorder of glycosylation type 1a (CDG-1a) is a congenital disease characterized by severe

6 N-acetylgalactosaminyltransferase 3 (GALNT)3-CDG, is caused by mutations in GALNT3, resulting in hype

7 ortantly, the F304S genotype frequency in 55 CDG-Ia patients classified as mild/moderate (n = 28), or

8 A CDG with high sensitivity was derived and validated.

9 hemical profiling was conducted to confirm a CDG type I defect.

10 Although most patients receive a CDG diagnosis based on abnormal glycosylation of transfe

11 have previously been described to lead to a CDG.

12 First, intranasally administered CDG greatly enhances Ag uptake, including pinocytosis an

13 cal outcome, especially in severely affected CDG patients.

14 12-CDG), DPAGT1 (DPAGT1-CDG), and ALG1 (ALG1-CDG) also identified multiple genotypes including wild-t

15 MPI (MPI-CDG), ALG3 (ALG3-CDG), ALG12 (ALG12-CDG), DPAGT1 (DPAGT1-CDG), and ALG1 (ALG1-CDG) also iden

16 ALG3-CDG is a rare autosomal recessive disease.

17 f PMM2 (PMM2-CDG), MPI (MPI-CDG), ALG3 (ALG3-CDG), ALG12 (ALG12-CDG), DPAGT1 (DPAGT1-CDG), and ALG1 (

18 review shows that visual impairment in ALG3-CDG is most commonly linked to optic nerve hypoplasia.

19 irty-three variants in 43 subjects with ALG3-CDG have been reported.

20 The patients with subtypes CDG-Ia and CDG-Ib have mutations in the genes encoding phosphomanno

21 similar clinical and microscopic findings as CDG but DIF staining is negative.

22 ified in individuals with TMEM165-associated CDG.

23 n-6-P for glycosylation and possibly benefit CDG-Ia patients with residual PMM2 activity.

24 ariant allele frequency is identical in both CDG patients (0.30) and controls (0.28).

25 CAMLG-CDG is the third disorder, after GET4 and GET3 deficienc

26 ely shared among cancer types than canonical CDGs, mainly because of the higher resolution at the nuc

27 Besides causing CDG, recent investigations have demonstrated the functio

28 ic nutritional treatment options for certain CDG types include oral supplementation of monosaccharide

29 ic acid containing 7-carboxy-7-deazaguanine (CDG) into its corresponding nitrile, 7-cyano-7-deazaguan

30 7-Carboxy-7-deazaguanine (CDG) synthase (QueE) catalyzes a key step in the biosynt

31 7-Carboxy-7-deazaguanine (CDG) synthase (QueE) catalyzes the complex heterocyclic

32 ovel intermediate, 7-carboxy-7-deazaguanine (CDG), by an unusual transformation catalyzed by Bacillus

33 pterin (CPH(4)) to 7-carboxy-7-deazaguanine (CDG).

34 G and PMM2 (phosphomannomutase 2)-deficiency CDG, and 23 first- and second-degree relatives with a he

35 e-linked glycosylation protein 6)-deficiency CDG and PMM2 (phosphomannomutase 2)-deficiency CDG, and

36 tation of phosphomannose isomerase-deficient CDG-Ib (MPI-CDG) cells and complementation with PMM2 in

37 rom exogenous mannose, whereas MPI-deficient CDG fibroblasts with reduced glucose flux secure 80% of

38 everse most of the symptoms of MPI-deficient CDG-Ib patients.

39 complementation with PMM2 in PMM2-deficient CDG-Ia (PMM2-CDG) cells partially corrected hypoglycosyl

40 The derived CDG included new or increased cough (2 points), headache

41 The derived CDG was then validated.

42 We propose to call this new disorder CDG-IIh or CDG-II/COG8.

43 in DPM1 define a new glycosylation disorder, CDG-Ie.

44 hnic backgrounds as a cause of a distinctive CDG of variable severity.

45 s in STT3A, leading to an autosomal-dominant CDG.

46 ALG3-CDG), ALG12 (ALG12-CDG), DPAGT1 (DPAGT1-CDG), and ALG1 (ALG1-CDG) also identified multiple genot

47 s of DPM: DPM1, DPM2, and DPM3, whereby DPM2-CDG links the congenital disorders of glycosylation to t

48 impaired, consistent with a role in driving CDG in those patients.

49 pecific Abs or Th1/Th2/Th17 cytokines during CDG/Ag immunization.

50 We propose to call this deficiency EDEM3-CDG.

51 y contrast, GCS1 cDNA with an R486T or F652L CDG IIb mutation gave substantial rescue of the Lec23 ph

52 Twenty-two of 23 female CDG cases were positive for ER, although the degree of s

53 ate that TNF-alpha signaling is critical for CDG-induced Ag-specific Ab and Th1/Th2 cytokine producti

54 tablish a mannose-responsive mouse model for CDG-Ib, we ablated Mpi and provided dams with mannose to

55 ), is shown to be an alternate substrate for CDG synthase.

56 n profiles are reliable diagnostic tools for CDGs.

57 The most common form, CDG type Ia (CDG-Ia), results from a deficiency of the e

58 lycoproteins (detected with antibodies) from CDG-Ia fibroblasts being fully glycosylated.

59 arious cell lines including fibroblasts from CDG-Ia patients and improves N-glycosylation.

60 congenital disorder of glycosylation (GALNT2-CDG), an O-linked glycosylation disorder.

61 Rodent (mouse and rat) models of GALNT2-CDG recapitulated much of the human phenotype, including

62 ypes in patients and rodent models of GALNT2-CDG suggest that there are multiple non-redundant protei

63 In behavioural studies, GALNT2-CDG mice demonstrated cerebellar motor deficits, decreas

64 Patients with GALNT2-CDG generally exhibit a syndrome characterized by global

65 he underlying causes of complex human GALNT3-CDG phenotypes.

66 se model, which partially phenocopies GALNT3-CDG, with WT mice and used a multicomponent approach usi

67 d that the candidate cancer druggable genes (CDG) are clinically meaningful and divided the CDG into

68 nonical than canonical cancer-driving genes (CDGs).

69 st cases of chronic desquamative gingivitis (CDG) are shown by direct immunofluorescence (DIF) to be

70 cause congenital disorders of glycosylation CDG-type Ia and type Ib, respectively.

71 in congenital disorders of O-glycosylation (CDG) and influence a broad array of biological functions

72 ype II congenital disorder of glycosylation (CDG) and the blood manganese levels were below the detec

73 Congenital disorders of glycosylation (CDG) are a group of metabolic diseases due to defects in

74 Congenital disorders of glycosylation (CDG) are a group of more than 160 inborn errors of metab

75 Congenital disorders of glycosylation (CDG) are a group of multisystemic disorders resulting fr

76 Congenital disorders of glycosylation (CDG) are a group of rare metabolic diseases, due to impa

77 The congenital disorders of glycosylation (CDG) are characterized by defects in N-linked glycan bio

78 Congenital disorders of glycosylation (CDG) are inherited autosomal-recessive diseases that imp

79 ly 50 congenital disorders of glycosylation (CDG) are known, but many patients biochemically diagnose

80 human congenital disorders of glycosylation (CDG) are mutations in the phosphomannomutase gene PMM2,

81 Congenital disorders of glycosylation (CDG) are rare genetic disorders due to impaired glycosyl

82 Congenital disorders of glycosylation (CDG) are rare genetic disorders with a spectrum of clini

83 a rare congenital disorder of glycosylation (CDG) caused by mutations in GNE that limit the productio

84 erited congenital disorder of glycosylation (CDG) consisting of neurodevelopmental delay and variable

85 and a Congenital Disorder of Glycosylation (CDG) due to the exquisite sensitivity of glycosyltransfe

86 f the congenital disorders of glycosylation (CDG) has a mutation (911T-->C ) that changes a phenylala

87 es of congenital disorders of glycosylation (CDG) have been associated with specific mutations within

88 drome congenital disorders of glycosylation (CDG) have mutations in the gene encoding Cog7p, a member

89 linked congenital disorder of glycosylation (CDG) in three unrelated families.

90 rom 31 congenital disorder of glycosylation (CDG) patients compared with normal controls.

91 es of congenital disorders of glycosylation (CDG) which are caused by mutations in different isoforms

92 common congenital disorder of glycosylation (CDG), phosphomannomutase 2 (PMM2)-CDG, is caused by muta

93 s with congenital disorder of glycosylation (CDG), type Ib (MPI-CDG or CDG-Ib) have mutations in phos

94 causes congenital disorder of glycosylation (CDG)-Ia, a broad spectrum disorder with developmental an

95 uses a congenital disorder of glycosylation (CDG)-Ib (MPI-CDG).

96 own as congenital disorder of glycosylation (CDG)-IIc, a rare human disorder characterized by psychom

97 ly of congenital disorders of glycosylation (CDG).

98 wn as congenital disorders of glycosylation (CDG).

99 g as a congenital disorder of glycosylation (CDG).

100 rtain congenital disorders of glycosylation (CDG).

101 ype of congenital disorder of glycosylation (CDG).

102 common congenital disorder of glycosylation (CDG).

103 human congenital disorders of glycosylation (CDG).

104 pected congenital disorder of glycosylation (CDG).

105 ype II congenital disorder of glycosylation (CDG-II) caused by mutations in the conserved oligomeric

106 an 30 congenital disorders of glycosylation (CDGs) are associated with this pathway, including RFT1-C

107 Congenital disorders of glycosylation (CDGs) are caused by defects in genes that participate in

108 Congenital disorders of glycosylation (CDGs) are disorders of abnormal protein glycosylation th

109 Congenital disorders of glycosylation (CDGs) are metabolic deficiencies in glycoprotein biosynt

110 Congenital disorders of glycosylation (CDGs) comprise a large heterogeneous group of metabolic

111 Congenital disorders of glycosylation (CDGs) form a genetically and clinically heterogeneous gr

112 Congenital disorders of glycosylation (CDGs) form a group of rare diseases characterized by hyp

113 fatal congenital disorders of glycosylation (CDGs) in humans.

114 ype I congenital disorders of glycosylation (CDGs) with defective N-glycosylation.

115 alled congenital disorders of glycosylation (CDGs).

116 f the congenital disorders of glycosylation (CDGs).

117 human congenital disorder of glycosylation, CDG-IIc (also known as LAD-II), which is also the result

118 Cyclic di-GMP (CDG) is a promising mucosal vaccine adjuvant.

119 The efficiency of custom density gradients (CDGs) to recover high islet yield was compared with pred

120 n of islets were recovered using ATGS-guided CDGs (85.9%+/-18.0%) compared with the SDG method (69.2%

121 Using ATGS-guided CDGs maximizes the islet recovery for successful transpl

122 ht to develop a clinical decision guideline (CDG) to inform influenza testing decisions for those adu

123 ty of individuals with compound heterozygous CDGs.

124 However, CDG-Ia patients do not benefit from mannose supplementat

125 (2)-P-P-dolichol, without hypoglycosylation, CDG-Ia fibroblasts grown with physiological glucose.

126 e) in a large cohort of patients with type I CDG (mean age, 9 years), together with reduced LDL-C and

127 ts with the 2 most prevalent types of type I CDG, ALG6 (asparagine-linked glycosylation protein 6)-de

128 glycoforms, is unusual among dominant type I CDGs.

129 The most common form, CDG type Ia (CDG-Ia), results from a deficiency of the enzyme phospho

130 ing congenital disorder of glycosylation Ib (CDG-Ib), but oral mannose supplements normalize glycosyl

131 e of estrogen in the treatment of idiopathic CDG.

132 ctin ligand expression reminiscent of LAD-II/CDG-IIc.

133 ngenital disorder of glycosylation type IIb (CDG-IIb), also known as MOGS-CDG.

134 In CDG cells carrying the GFP construct, a 25% decrease of

135 to analyze steady-state LLO compositions in CDG-Ia fibroblasts.

136 T, and 43 variants of DDOST are described in CDG patients, of which 34 are classified as variants of

137 l versus idiopathic) and expression of ER in CDG gingiva.

138 patically produced N-linked glycoproteins in CDG-Ia blood are hypoglycosylated.

139 issing link" to explain hypoglycosylation in CDG-Ia patients.

140 y known mutations in other genes involved in CDG, i.e. PMM2 (CDG-Ia; 91 patients) and MPI (CDG-Ib; 10

141 We review the dietary management in CDG with a focus on two subgroups: N-linked glycosylatio

142 Here, we report somatic mosaicism in CDG, and our work stresses the importance of combining b

143 cytokine and Ab responses were unaltered in CDG/Ag-immunized IFNAR(-/-) mice.

144 ansferrin do not have mutations in any known CDG genes.

145 Hence, we delineate MAGT1-CDG as a disorder associated with two different clinical

146 Upon labeling with [(3)H]mannose, CDG-Ia fibroblasts have been widely reported to accumula

147 ation type IIb (CDG-IIb), also known as MOGS-CDG.

148 much longer than the previous report of MOGS-CDG, in a child who died at 74 days of age.

149 two siblings, aged 6 and 11 years, with MOGS-CDG and biallelic MOGS (mannosyl-oligosaccharide glucosi

150 r (3'-5')-cyclic-di-guanosine-monophosphate (CDG) is a promising mucosal adjuvant candidate that acti

151 Because most CDGs have been described in only a few individuals, our

152 DG, i.e. PMM2 (CDG-Ia; 91 patients) and MPI (CDG-Ib; 10 patients).

153 ever, mothers who are at risk for having MPI-CDG children and who consume mannose during pregnancy ho

154 isorder of glycosylation (CDG), type Ib (MPI-CDG or CDG-Ib) have mutations in phosphomannose isomeras

155 osphomannose isomerase-deficient CDG-Ib (MPI-CDG) cells and complementation with PMM2 in PMM2-deficie

156 ital disorder of glycosylation (CDG)-Ib (MPI-CDG).

157 ygous mutations of PMM2 (PMM2-CDG), MPI (MPI-CDG), ALG3 (ALG3-CDG), ALG12 (ALG12-CDG), DPAGT1 (DPAGT1

158 e Mpi ablation is embryonic lethal, a murine CDG-Ib model will require hypomorphic Mpi alleles.

159 We describe a new CDG, due to a deficiency of DPM2.

160 Notably, CDG induces IFNlambda, but not IFNbeta, in vivo.

161 oduction in the mucosal adjuvant activity of CDG in vivo and revealed a novel IFN-I stimulation-indep

162 was shown to proceed via the adenylation of CDG, which activates it to form the newly discovered ami

163 Intranasal administration of CDG did not induce TNF-alpha, IL-1beta, IL-6, IL-12, or

164 Gingival tissue from 24 cases of CDG and one case of ordinary gingivitis were studied for

165 It has been suggested that those cases of CDG may be hormone (estrogen) mediated and may be treate

166 biomarker to assess gene complementation of CDG-I patient cells and to monitor improved glycosylatio

167 e describe two siblings with a fatal form of CDG caused by a mutation in the gene encoding COG-7, a s

168 The recent discovery of a form of CDG, caused in part by a COG4 missense mutation changing

169 agnostic framework for the identification of CDG defects involving trafficking proteins.

170 We identified two in vivo mechanisms of CDG.

171 ls to better understand the pathogenicity of CDG-associated TMEM165 mutations.

172 We describe a new type of CDG caused by mutations in the steroid 5alpha-reductase

173 These cases represent a new type of CDG in which the molecular defect lies in a protein that

174 be very useful for uncovering other types of CDG as well.

175 ns of MPYS and advanced our understanding of CDG as a mucosal vaccine adjuvant.

176 Different forms of CDGs can be recognized by altered isoelectric focusing (

177 To improve the diagnosis of these groups of CDGs, we have developed serum or plasma N- and O-glycan

178 A subgroup of CDGs can be attributed to disturbed Golgi homeostasis.

179 Current diagnostic testing of CDGs largely relies on indirect analysis of glycosylatio

180 entify 22 candidate proteins that convey OGT-CDG.

181 GT Congenital Disorder of Glycosylation (OGT-CDG) have been reported and characterized.

182 GT congenital disorder of glycosylation (OGT-CDG).

183 the dysregulated gene expression seen in OGT-CDG models.

184 d or unique altered pathways impacted in OGT-CDG patients will provide a better understanding of the

185 O-GlcNAcylation and neurodevelopment in OGT-CDG.

186 One hypothesis for the etiology of OGT-CDG is that loss of OGT activity leads to hypo-O-GlcNAcy

187 the heterogenous phenotypic features of OGT-CDG seen clinically, the variable biochemical effects of

188 hesis attributing the pathophysiology of OGT-CDG to mutations segregating with this disorder disrupti

189 ypotheses aim to explain the etiology of OGT-CDG, with a prominent hypothesis attributing the pathoph

190 e primarily neural-specific phenotype of OGT-CDG.

191 cal effects of mutations associated with OGT-CDG, and the use of animal models to understand this dis

192 ional variants have been associated with OGT-CDG, some of which are currently undergoing investigatio

193 The carboxylate moiety on CDG is converted subsequently to a nitrile to yield preQ

194 of glycosylation (CDG), type Ib (MPI-CDG or CDG-Ib) have mutations in phosphomannose isomerase (MPI)

195 propose to call this new disorder CDG-IIh or CDG-II/COG8.

196 of monosaccharide therapy for several other CDG.

197 trate deficiencies in GNE myopathy and other CDGs.

198 Other measures were the Nijmegen Pediatric CDG Rating Scale (NPCRS), a syllable repetition test (PA

199 benefit of galactose supplementation in PGM1-CDG-affected individuals and obtain significant insights

200 s, we found that galactose treatment of PGM1-CDG fibroblasts metabolically re-wires their sugar metab

201 se was administered to individuals with PGM1-CDG and was shown to markedly reverse most disease-relat

202 iencies, one with TMEM165-CDG, two with PGM1-CDG, and three with SLC35A2-CDG, and one patient with co

203 We define PGM3-CDG as a treatable immunodeficiency, document the power

204 A congenital disorder of glycosylation (PIGA-CDG), an ultra-rare CDG typically presenting with seizur

205 ts in Drosophila neurological models of PIGA-CDG.

206 und that the loss of CNTN2 also rescues PIGA-CDG-specific phenotypes, including seizures and climbing

207 identified two brothers (probands) with PIGA-CDG, presenting with epilepsy and mild developmental del

208 presents with symptoms associated with PIGA-CDG.

209 s in other genes involved in CDG, i.e. PMM2 (CDG-Ia; 91 patients) and MPI (CDG-Ib; 10 patients).

210 osylation (CDG), phosphomannomutase 2 (PMM2)-CDG, is caused by mutations in PMM2 that limit availabil

211 Both Pmm2(R137H/F115L) mouse and PMM2-CDG patient-derived fibroblasts displayed reductions in

212 Here we report a morpholino-based PMM2-CDG model in zebrafish.

213 Congenital disorder of glycosylation (PMM2-CDG) results from mutations in pmm2, which encodes the p

214 2 congenital disorder of glycosylation [PMM2-CDG]) causes cerebellar syndrome and strokelike episodes

215 ion with PMM2 in PMM2-deficient CDG-Ia (PMM2-CDG) cells partially corrected hypoglycosylation based o

216 lycogen abnormalities recently found in PMM2-CDG patients.

217 ed growth seen both in our model and in PMM2-CDG patients.

218 y participate in cerebellar syndrome in PMM2-CDG.

219 afe and improves cerebellar syndrome in PMM2-CDG.

220 A clinical trial included PMM2-CDG patients, with a 6-month first-phase single acetazol

221 we report the first zebrafish model of PMM2-CDG and uncover novel cellular insights not possible wit

222 s marked GDP-mannose decrease, PBMCs of PMM2-CDG patients had higher UDP-glucose (UDP-Glc), UDP-galac

223 This functional mouse model of PMM2-CDG, in vitro assays and identification of the novel gp1

224 AZATAX is the first clinical trial of PMM2-CDG.

225 ompound heterozygous mutations of PMM2 (PMM2-CDG), MPI (MPI-CDG), ALG3 (ALG3-CDG), ALG12 (ALG12-CDG),

226 d mononucleated cells (PBMCs), of seven PMM2-CDG patients and ten control healthy donors.

227 lopmental abnormalities consistent with PMM2-CDG patients, including craniofacial defects and impaire

228 similar to those found in patients with PMM2-CDG.

229 revalent alleles found in patients with PMM2-CDG.

230 ibroblasts of individuals with MPI- and PMM2-CDGs.

231 The fluorogenic probe CDG-3 is based on cephalosporin with substitutions at th

232 A refined green fluorescent probe (CDG-OMe) enabled the successful detection of live pathog

233 r of glycosylation (PIGA-CDG), an ultra-rare CDG typically presenting with seizures, hypotonia, and n

234 or functional testing of clinically relevant CDG variants to complement genome sequencing and support

235 Metabolic investigations revealed CDG-I, pointing to a defect in protein N-glycosylation i

236 associated with this pathway, including RFT1-CDG which results from defects in the membrane protein R

237 The majority of RFT1-CDG mutations map to highly conserved regions of the pro

238 In a trial with 50 clinical samples, CDG-3 detected tuberculosis with 90% sensitivity and 73%

239 G, two with PGM1-CDG, and three with SLC35A2-CDG, and one patient with combined type I and type II of

240 profiling from two individuals with SLC39A8-CDG showed similar but more severe alterations in branch

241 congenital disorder of glycosylation (SRD5A3-CDG) is a rare disorder of N-linked glycosylation.

242 ongenital disorders of glycosylation (SRD5A3-CDG) patients and healthy controls.

243 viously underdescribed feature of the SRD5A3-CDG disorder that is progressive and may lead to serious

244 We present here a dominant form of STT3A-CDG that, because of the presence of abnormal transferri

245 Additional cases of STT3B-CDG may be missed by transferrin analysis and will requi

246 with a more specific fluorogenic substrate, CDG-3.

247 The patients with subtypes CDG-Ia and CDG-Ib have mutations in the genes encoding p

248 congenital disorder of glycosylation termed CDG IIb.

249 Finally, we found that CDG activates STING-dependent, but IRF3 stimulation-inde

250 Instead, we found that CDG activates STING-dependent, IFN-I-independent TNF-alp

251 Second, we found that CDG selectively activated pinocytosis-efficient-DCs, lea

252 Here, we showed, in mice, that CDG elicits stronger Ab and TH responses than the mammal

253 We showed previously that CDG activates stimulator of IFN genes (STING)-dependent

254 The CDG had a sensitivity and specificity of 94.1% and 36.6%

255 G) are clinically meaningful and divided the CDG into known, reliable and potential gene sets.

256 n whether STING or IFN-I is required for the CDG adjuvant activity in vivo.

257 or allografts was significantly lower in the CDG group.

258 Using standard DIF analysis, 11 of the CDG cases were diagnosed as benign mucous membrane pemph

259 Impaired glycosylation of TMEM165-CDG arises from a lack of Mn(2+) within the Golgi.

260 hree with COG deficiencies, one with TMEM165-CDG, two with PGM1-CDG, and three with SLC35A2-CDG, and

261 ate the mechanism of conversion of CPH(4) to CDG.

262 carboxy-5,6,7,8-tetrahydropterin (CPH(4)) to CDG in the third step of the biosynthetic pathway to all

263 of mutations in human GCS1 that give rise to CDG IIb.

264 The cardinal clinical features of UGGT1-CDG involve developmental delay, intellectual disability

265 cal, and molecular characterization of UGGT1-CDG, broadening the spectrum of N-linked glycosylation d

266 e genotype-phenotype relationship underlying CDG-1a.

267 iscovered CDNs are expected to be on unknown CDGs.

268 om families affected by genetically unsolved CDGs and identified four individuals with different muta

269 to identify the genetic defect in an untyped CDG patient, and we found a 22 bp deletion and a missens

270 confirming the defective gene in an untyped CDG patient.

271 t many patients biochemically diagnosed with CDG do not have mutations in known genes.

272 lasts and lymphoblasts from 23 patients with CDG-Ia (range 0-15.3% of control, average 4.9+/-4.7%) an

273 electric focusing, to diagnose patients with CDG-Ia and to identify heterozygotes when clinically ind

274 We evaluated two siblings with CDG-IIb who presented with multiple neurologic complicat

275 ong a group of unresolved case subjects with CDG.

276 ical failure of dietary mannose therapy with CDG-Ia patients are discussed.

277 stream of HMG-CoA reductase, associated with CDGs, hypercholesterolemia, neurodegeneration, and cance

278 rifications, more islets were recovered with CDGs (81.9%+/-28.0%) than SDGs (55.8%+/-22.8%; P=0.03).