ライフサイエンスコーパス: de novo

1 /or by rare but severe coding variants, many de novo.

2 ng to predictively design this functionality de novo.

3 ozygous GBF1 variants, two of which occurred de novo.

4 een spin labels fast enough to fold proteins de novo.

5 ecture of the 19-subunit regulatory particle de novo.

6 to annotate transcriptional units identified de novo.

7 nzyme that can efficiently add methyl groups de novo.

8 ive (of which 95% were inherited and 5% were de novo), 1 was inherited X-linked recessive, and 1 was

9 nt (of which 12% were inherited and 88% were de novo), 27% (10 of 37) were autosomal recessive (of wh

10 status up to 10 years in 1,800 patients with de novo 3-vessel and/or left main coronary artery diseas

11 patients (55%) overall and in 23/38 (61%) of de novo ablation patients.

12 fully compensate for each other in removing de novo acetyls on H4 in vivo Proteomics of nascent chro

13 athematical modeling indicate a high rate of de novo acquired resistance to these drugs relative to p

14 tenance activity and possibly possesses weak de novo activity, leading to spontaneous 'epimutations'.

15 ortium identified patients who had undergone de novo AF ablation.

16 presenting cells and by actively suppressing de novo alloreactive B cell responses.

17 genetic and molecular features distinct from de novo AML.

18 ine was able to detect 18 unique variants (8 de novo and 10 x-linked, all validated), including 12 ne

19 iology and rhythm phenotypes of fetuses with de novo and inherited LQTS variants and identify risk fa

20 duals with high or low IQ and after removing de novo and known recurrent neuropsychiatric CNVs.

21 Unexpectedly, de novo and maintenance methylation activity is reduced

22 ges and metabolic stress occurs through both de novo and pre-existing chromatin interactions which re

23 a limited capacity to synthesize amino acids de novo and therefore must obtain oligopeptides from its

24 bility to distinguish germline (inherited or de novo) and somatic mutations is often limited by the l

25 S REARRANGED METHYLTRANSFERASE 2 (DRM2), the de novo Arabidopsis DNA methyltransferase, is crucial to

26 ing on context, bis-ANS can both induce LLPS de novo as well as prevent formation of homotypic liquid

27 ffecting these same motif classes track with de novo ASM.

28 ation using a modified reference genome or a de novo assembled genome can alter histone H3K4me1 and H

29 eages paired with fully-annotated, finished, de novo assembled genomes.

30 omise between modified reference genomes and de novo assembled genomes.

31 Compared to the reference genome, our de novo assembled O. nubilalis mitochondrial genomes con

32 De novo-assembled genomes were used to understand genomi

33 Incorporating seven linked-read de novo assemblies and three existing assemblies, the Vi

34 of white lupin (2n = 50, 451 Mb), as well as de novo assemblies of a landrace and a wild relative.

35 De novo assembly of a human genome using nanopore long-r

36 monstrate that our pipeline, which relies on de novo assembly, can also be used to detect contaminati

37 ng and iterative mapping" approach, conducts de novo assembly, filters and disentangles the assembly

38 iplatelet therapy driven largely by reducing de novo atherothrombotic ischemic events.

39 previously postulated as we uncovered active de novo biosynthesis and substantial levels of accumulat

40 Stressed cells increase de novo biosynthesis of ceramides, which return to sub-t

41 izes cellular acetate and contributes to the de novo biosynthesis of fatty acids and Leu; peroxisome-

42 e to form quinolinic acid, the precursor for de novo biosynthesis of nicotinamide adenine dinucleotid

43 ine palmitoyltransferase (SPT) catalyses the de novo biosynthesis of sphingolipids but also produces

44 cts were present in the dry grain, but their de novo biosynthesis started immediately after water upt

45 ncover differences in nucleotide salvage and de novo biosynthesis using a histologically heterogeneou

46 We present recent examples of de novo biosynthetic pathway discovery that employ vario

47 ring this process, autophagosomes are formed de novo by membrane fusion events leading to phagophore

48 osa, and postaxial polydactyly; he harbors a de novo c.748G>C (p.Glu250Gln) variant affecting the kin

49 is method in mouse fetal liver, and identify de novo cell-type-specific chromatin architectures assoc

50 aintenance on human centromeres by promoting de novo CENP-A deposition.

51 During tethering, de novo centromeres sometimes prevail, causing the loss

52 This method forms a key step of de novo characterization of nucleotide modifications, sh

53 ol throughout the various cell compartments, de novo cholesterol synthesis enriched this lipid in the

54 rted to the ER resulting in normalization of de novo cholesterol synthesis.

55 Analyses of wild-type (WT) chromosomes and de novo circular minichromosomes revealed that meiosis-s

56 iated mRNA decay components, suggesting that de novo CNOT1 variants are likely haploinsufficient hypo

57 In summary, we provide strong evidence that de novo CNOT1 variants cause neurodevelopmental delay wi

58 e report on 39 individuals with heterozygous de novo CNOT1 variants, including missense, splice site,

59 cleotide variants/indels (dnSNVs/indels) and de novo copy number variants (dnCNVs).

60 c machine-learning algorithms, we identified de novo copy number variants at 15q25.2 and 15q11.2 as b

61 g characteristic (ROC) curve was 0.97 in the de novo cross-validation when evaluated using 910 drugs.

62 Patients with de novo damaging variants were 2.4 times more likely to

63 tute promising pharmacological tools for the de novo design and identification of LDH tetramerization

64 ss the implications of these results for the de novo design of SBP-surface binding systems.

65 Using de novo designed three-stranded coiled coils (TRI and Gr

66 onstrated the catalytic potential of simple, de novo-designed heme proteins.

67 ce and nonhuman primates, cocktails of three de novo-designed immunogens induced robust neutralizing

68 own-conversion properties, are attached to a de novo-designed protein, conferring entirely novel func

69 R, NAND, NOR, XNOR, and NOT gates built from de novo-designed proteins.

70 De novo determination of regulatory interactions require

71 MS remained stable, but increase in size and de novo development of PHOMS were also observed.

72 d TE loci such as BANCR may represent potent de novo developmental regulatory elements that can be in

73 Herein, a minimalistic, de novo dipeptide, Fmoc-Lys(Fmoc)-Asp, as an hydrogelato

74 e potential to be approved more quickly than de novo discovered medicines on new targets.

75 Furthermore, paclitaxel treatment induced de novo diurnal DEGs, suggesting reciprocal interaction

76 disorders has been achieved by studying rare de novo (DN) coding variants.

77 d perhaps similar Dnmt3b isoforms facilitate de novo DNA methylation during embryonic development and

78 Here, we analyze de novo DNA methylation in mouse embryonic fibroblasts (

79 with Dnmt3a and Dnmt3b to contribute to the de novo DNA methylation that governs early steps of ESC

80 The de novo DNA methyltransferases Dnmt3a and Dnmt3b play cr

81 atients who carry a previously unidentified, de novo, dominant variant in ACOX1 (p.N237S) also exhibi

82 , first acute rejection episode, malignancy, de novo donor specific antibody, posttransplant diabetes

83 ange (TTR) have been associated with risk of de novo donor-specific antibodies (dnDSA).

84 h the same phenotype with the development of de novo donor-specific antibody (DSA) after kidney trans

85 3 < 30 mL/min/1.73 m (HR, 2.61; P = 0.011), de novo donor-specific antibody development (HR, 4.09; P

86 as linear, without a safe threshold at which de novo DSA did not occur.

87 d DQB(1) alleles could also help to minimize de novo DSA formation and potentially improve transplant

88 Twenty-three recipients (24.2%) developed de novo DSA within 1-year posttransplant.

89 is coincided with the presence and number of de novo DSA.

90 esis by exploiting our ability to live image de novo ECM development in Drosophila to quantify produc

91 esistant TB are urgently needed to avert the de novo emergence of MDR-TB during treatment.

92 De novo emergence of MDR-TB was assumed where the genomi

93 resistant strains, may effectively restrict de novo emergence of resistance even though they cannot

94 re, we systematically characterize how these de novo emerging coding sequences impact fitness in budd

95 during lineage acquisition, and formation of de novo enhancers characterizes the acquisition of innat

96 l trials testing rational agents to overcome de novo enzalutamide resistance.

97 e, deletion of just the B boxes impaired the de novo establishment of the heterochromatic domain.

98 roductive frameshifting could rapidly evolve de novo, even in essential genes.

99 on of new gene-regulatory networks(1,2), the de novo evolution of genes(3) and the proliferation of p

100 accumulated in the inflamed brain, providing de novo expression of proteins encoded by cargo messenge

101 Similarly, on nonmacrocycles, de novo fitting produced occupancy-weighted ensembles of

102 the mouse submandibular gland, we show that de novo formation of acini involves induction of cellula

103 formation of root hairs and pollen tubes or de novo formation of cell plates during plant cytokinesi

104 sium of hindlimb muscle in mice leads to the de novo formation of myofibres in the mice.

105 led to activation of preformed loops and to de novo formation of new promoter/enhancer interactions.

106 De novo formation of the double-membrane compartment aut

107 We report here six individuals with de novo frameshift variants in NOVA2 affected with a sev

108 , by duplication of large genomic regions or de novo, from previously non-coding DNA.

109 abo (M2M) a resource that meets the need for de novo functional screening of genome-scale metabolic n

110 and epileptic encephalopathy (DEE) caused by de novo gain-of-function mutations of sodium channel Na(

111 y coordinated and can occur independently of de novo gene expression during starvation.

112 chromatography-tandem mass spectrometry with de novo-generated standards and an isotopic dilution str

113 hes to genetically engineer high HbF include de novo generation of naturally occurring hereditary per

114 De novo genic and copy number variants are enriched in p

115 Based on de novo genome assemblies and additional whole-genome re

116 Genomics approaches, including de novo genome assemblies and gene annotations for the p

117 Short-read metagenomic sequencing and de novo genome assembly of the human gut microbiome can

118 scribe a reference-free workflow for diploid de novo genome assembly that combines the chromosome-wid

119 of MIWI2 in mouse fetal gonocytes undergoing de novo genome methylation and identify a previously unk

120 se expression is restricted to the period of de novo genome methylation.

121 gh expression of the rate-limiting enzyme of de novo GTP synthesis is associated with shorter surviva

122 Classifier-positive DLBCL patients (de novo) had an ORR of 44%, median progression-free surv

123 DAA start, 36 of 452 (8%) patients developed de novo HCC, 4-year cumulative probability being 9% (95%

124 30, P = 0.04) were independent predictors of de novo HCC.

125 he host as Leishmania lacks the capacity for de novo heme synthesis and does not contain cytosolic ir

126 se during which Xist RNA spreads and induces de novo heterochromatinization across a female X chromos

127 capes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating muta

128 Recently, two de novo heterozygous mutations in the gene encoding TRPM

129 De novo heterozygous pathogenic variants in STXBP1 are a

130 e performed based on prior HF history (i.e., de novo HF vs. worsening chronic HF) and treatment with

131 Formation of de novo HFs recapitulated embryonic HF development, and

132 ignaling, consistent with recently described de novo HLHS mutations associated with abnormal endocard

133 Distinguishing preexisting and de novo immunity will be critical for our understanding

134 uctive structures evolved, which genes occur de novo in male gametophytes of angiosperms, and to whic

135 ous c.388G>A, p.Gly130Arg variant, occurring de novo in one case, another patient carrying a differen

136 POLG, herein referred to as ORF-Y that arose de novo in placental mammals.

137 The duplication arose de novo in three mothers where grandparental testing was

138 Most mutations occurred de novo, indicating possible interference with reproduct

139 Continuous lytic cell lysis and de novo infection allowed LEC culture to remain infected

140 De novo infection can counter this washout.

141 results therefore imply that suppression of de novo infection may reduce the risk of malignant trans

142 r that provides viral progeny for continuous de novo infection of tumor origin cells, and potentially

143 o evidence of hypoxia gene expression in HBV de novo infection, HBV infected human liver chimeric mic

144 Both sites are important for polymerase de novo initiation and elongation activities and essenti

145 ating that repressor alleles are produced by de novo insertion at an exceptional rate.

146 aman scattering microscopy was used to probe de novo intracellular lipid content.

147 lect data from nine additional patients with de novo KCNN2 variants (one nonsense, one splice site, s

148 ive fibrotic nodules, identical to end-stage de novo lesions, were found and were presumed to represe

149 is the first step in mapping host-influenced de novo lipid A modifications, such as those associated

150 studies demonstrated that the inhibition of de novo lipid biosynthesis by interfering with nematode

151 type characterized by dysregulated epidermal de novo lipid synthesis, altered lipid lamellae structur

152 that closure of NE holes relies on regulated de novo lipid synthesis, providing a link between lipid

153 Hepatic de novo lipogenesis (DNL) contributes to steatosis in in

154 Metabolic labeling of de novo lipogenesis (DNL) using (2)H(2)O revealed that 5

155 ession of the critical fatty acid uptake and de novo lipogenesis genes Pparg, Mogat1, Cd36, Acaab1, F

156 c KRAS promotes a gene expression program of de novo lipogenesis in non-small cell lung cancer (NSCLC

157 Fructose intake triggers de novo lipogenesis in the liver(4-6), in which carbon p

158 itochondrial citrate synthesis to facilitate de novo lipogenesis, and genetic ablation of ACO2 reduce

159 (ChREBP), a key regulator of glycolysis and de novo lipogenesis, is increased in GSD 1a.

160 ot Scc2 while that created by Scc2-dependent de novo loading at replication forks requires the Ctf18-

161 reactivation, engram neurons use a subset of de novo long-range interactions, where primed enhancers

162 ation, we identified twelve individuals with de novo loss-of-function (LoF) variants in protein phosp

163 Rice domestication tended to select de novo, loss-of-function, coding variation, while maize

164 trans-acting factors that determine general de novo m(6)A deposition and modulate cell type-specific

165 De novo macrolide resistance was detected in 4.6% of cas

166 At least one de novo MDRO was detected in 27 patients (35.1%) during

167 te gene-edited dicotyledonous plants through de novo meristem induction.

168 De Novo metalloprotein design assesses the relationship

169 sease but worse compared with those who have de-novo metastatic disease.

170 nesis but is essential for piRNA-directed TE de novo methylation and silencing.

171 ive chromatin remodelling activities and the de novo methylation apparatus through SPOCD1.

172 find that Dnmt3a is exclusively required for de novo methylation at both TSS regions and gene bodies

173 vo with DNMT3L and DNMT3A, components of the de novo methylation machinery, as well as with constitue

174 th epilepsy revealed a previously unreported de novo missense variant in KCNA2, which encodes voltage

175 A de novo missense variant, p.Ser644Gly, was identified in

176 identified three unrelated individuals with de novo missense variants in CDK19, encoding a cyclin-de

177 Here, we report that de novo missense variants in MAPK1, encoding the mitogen

178 protein-derived l-[1-13C]-phenylalanine into de novo mitochondrial protein increased dose-dependently

179 not available for the vast majority of these de novo monogenic neurodevelopmental disorders because o

180 ers (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-co

181 De novo mutations arising on the paternal chromosome mak

182 endelian disorders and the prioritization of de novo mutations associated with complex neurodevelopme

183 Moreover, previous analyses of germline de novo mutations examined pedigrees (and not germ cells

184 we provide strong evidence that prioritized de novo mutations in autism probands point to a small se

185 g trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases.

186 m this hypothesis with the identification of de novo mutations in LMNB1 in seven individuals with pro

187 Our findings collectively indicate that de novo mutations in LMNB1 result in a dominant and dama

188 e has historically arisen through convergent de novo mutations in Plasmodium falciparum parasite popu

189 The characterization of de novo mutations in regions of high sequence and struct

190 Through trio exome sequencing we identified de novo mutations in SLC12A2 in six children with neurod

191 crimination/associative learning, unlike the de novo mutations in unaffected siblings.

192 The EIF2B1 de novo mutations were found to map to the same protein

193 sweeps within the last few thousand years on de novo mutations, mainly in noncoding regions.

194 test to identify gene-specific enrichment of de novo mutations.

195 ticity proceeded from standing variation and de novo mutations; shown how antagonistic pleiotropy and

196 aze learning promotes oligodendrogenesis and de novo myelination in the cortex and associated white m

197 ate mutation of additional genes involved in de novo NAD synthesis as potential causes of complex bir

198 De novo neoantigen-specific CD4(+) and CD8(+) T cell res

199 This study demonstrates de novo neuroendocrine differentiation of the human pros

200 vertheless, many advanced tumors demonstrate de novo or acquired treatment resistance, and ongoing re

201 cohort of nine individuals with mono-allelic de novo or inherited variants in KDM4B.

202 new enzyme paradigms and metabolic networks de novo, organisms have evolved strategies to neutralize

203 Our results contribute to understanding a de novo origin of bioluminescence and the corresponding

204 n cancers, in which all primary tumors arise de novo, ovarian epithelial cancers are primarily import

205 ears +/- 11; 11 women), 29 participants with de novo Parkinson disease (64 years +/- 10; 19 men), and

206 2014 and October 2015 for participants with de novo Parkinson disease, advanced Parkinson disease, a

207 y oriented filopodial protrusion, building a de novo path along which their nuclei can return to the

208 ase study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB.

209 ical superior colliculus visual responses in de novo PD patients are present early in the course of t

210 When applied to de novo prediction of CDR H3 loop structures, DeepH3 ach

211 This enabled de novo prediction of ECF sigma specificity, which we co

212 H-RAS(V12) breast cancer cells by inhibiting de novo proline biosynthesis and impairing spheroidal gr

213 De novo protein design has succeeded in generating a lar

214 When applied to de novo protein design, this approach designs sequences

215 ontrols the training-induced upregulation of de novo protein synthesis, including increase of Arc, Eg

216 carbene transferase activity in a completely de novo protein, but also of enzyme-catalyzed ring expan

217 nveils a previously undescribed mechanism of de novo protein-coding gene evolution.

218 for creating a virtually unlimited number of de novo proteins supporting diverse pocket structures.

219 Using vdMs, we designed six de novo proteins to bind the drug apixaban; two bound wi

220 ns; however, a non-biased examination of the de novo proteome in this process is lacking.

221 ectrometry (GCIB-SIMS) to directly visualize de novo purine biosynthesis by a multienzyme complex, th

222 hondrion-derived one-carbon units needed for de novo purine biosynthesis.

223 e 5'-monophosphate (ZMP), an intermediary of de novo purine biosynthetic pathway, and depletion of AT

224 ucleotide synthesis, and cisplatin inhibited de novo purine synthesis and DNA synthesis, with amino a

225 ression was mediated primarily via enhancing de novo purine synthesis because inhibiting purine synth

226 ms are the inhibition of a key enzyme of the de novo pyrimidine synthesis pathway, dihydroorotate deh

227 which may serve as a good example for future de novo qAOP development for chemical and nonchemical st

228 hypertrophic growth via regulation of pol II de novo recruitment and pause-release; the latter repres

229 fections with MDROs, and 13 cases (16.9%) of de novo/recurrent SBP.

230 n (n = 35), persistent infection (n = 14) or de novo rejection (n = 11) 6 months following a standard

231 cell-ECM adhesions and sarcomeres assembling de novo remains untested.

232 nestic responses in sensitized recipients or de novo responses in nonsensitized patients who are nona

233 evidence bearing on the question of whether de novo ribozymes would be quantitatively more promiscuo

234 imal length of the RNA template for in vitro de novo RNA synthesis using the purified RSV polymerase

235 ctivation complex (CAP-TAC) with and without de novo RNA transcript.

236 De novo variants, especially de novo SCN5A variants, were strongly associated with a

237 AOGP utilized de novo sequencing for O-glycans and a database search s

238 orrect peptide annotation or can be used for de novo sequencing.

239 able peaks lists that can be used to support de novo sequencing.

240 acellular serine is limited, EpdSCs activate de novo serine synthesis, which in turn stimulates alpha

241 replication and without the need for further de novo sfRNA synthesis could form a "preemptive strike"

242 rom child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels

243 ce, but not an SPT-deficient strain, reduces de novo SL production and increases liver ceramides.

244 Of thousands of de novo SNPs identified, 2677 were informative in M. fus

245 Source has opened the possibility to native de novo structure determinations by the use of intrinsic

246 ata indicating that the intermediates of the de novo syntheses of purines and histidine, 5-aminoimida

247 This de novo synthesis creates opportunities for the preparat

248 ene invalidations in single hepatocytes, Epo de novo synthesis led to its secretion, to splenic eryth

249 d has been dissected into three major steps: de novo synthesis of a [2Fe-2S] cluster on a scaffold pr

250 Challenges to the de novo synthesis of bacteriochlorophyll a (BChl a), the

251 ns of multiple phagosomal TLRs, resulting in de novo synthesis of Cxcl2, amplification of neutrophil

252 spatial long-term memory (LTM) requires the de novo synthesis of distinct sets of proteins; however,

253 of human prostate cancer exhibits increased de novo synthesis of fatty acids, but the molecular driv

254 PDH1 catalyzes the rate-limiting step in the de novo synthesis of guanine nucleotides, impacting the

255 o generate TAG, as well as being involved in de novo synthesis of TAG.

256 hosphate synthetase (UMPS) in the pyrimidine de novo synthesis pathway in cell lines, pluripotent cel

257 rious sources, both exogenously supplied FA, de novo synthesised FA, or FA derived from lipolysis, to

258 it many important biological activities, but de novo synthetic access to these molecules is highly ch

259 derivatives and are a preferred choice over de novo synthetic routes.

260 preferentially experience these heat-induced de novo Tc1 insertions.

261 However, it is unclear how de novo telomere addition (dnTA) is regulated at DNA dou

262 The healing of broken chromosomes by de novo telomere addition, while a normal developmental

263 aris somatic chromosome ends are recapped by de novo telomere healing.

264 rounds of synthesis generate microhomologies de novo that are sufficiently long that synthesis is mor

265 re we describe an enzyme designed completely de novo that hydrolyzes ATP.

266 methods still struggle to accurately predict de novo the structures of large proteins, membrane prote

267 n aerobic organisms, which can synthesize it de novo through a conserved pathway.

268 rolonged gene expression is not dependent on de novo transcription, but that apc/ebp mRNA synthesized

269 rmed the L. camara leaf (LCL) and root (LCR) de novo transcriptome analyses.

270 age of conditioned-threat responses, whereas de novo translation in protein kinase Cdelta-expressing

271 We show that de novo translation in somatostatin-expressing inhibitor

272 distribution in host genomes using multiple de novo transposon insertion datasets in both plants and

273 es prior to treatment would be predictive of de novo treatment resistance.

274 De novo treatment with RAASi in patients hospitalized wi

275 We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 in

276 The de novo Ugandan model contained similar characteristics

277 Mtb can synthesize vitamin B(12) (cobalamin) de novo, uptake of cobalamin has been linked to pathogen

278 s-Beuren syndrome identified a frameshifting de novo variant in a major GABA(A)R gene, GABRA1 This tr

279 tified three patients with heterozygous MPP5 de novo variants (DNV) and global developmental delay (G

280 We analyzed exome sequencing data for de novo variants (DNVs) in a new sample of 613 schizophr

281 The de novo variants c.362G>A (p.Arg121Gln) and c.430G>A (p.

282 incidence estimates for disorders caused by de novo variants can guide patient advocacy groups, clin

283 (patient and parent trios), we identified 66 de novo variants in 66 genes including potentially delet

284 We identified two functional de novo variants in a pRE for autism risk gene SLC6A1, a

285 By contrast, de novo variants in patients without extra-cardiac anoma

286 Here, we report two individuals with de novo variants in the C-terminal region of TOMM70.

287 tic similarity analysis for individuals with de novo variants in the same gene.

288 YO7A and CHD7, respectively, consistent with de novo variants or dominant inheritance with incomplete

289 heart disease undergoing open-heart surgery, de novo variants were associated with worse transplant-f

290 genes: 27 carried the family variant, 11 had de novo variants, and 1 was indeterminate.

291 AED exposure does not increase the burden of de novo variants, and that this mechanism is not a major

292 De novo variants, especially de novo SCN5A variants, wer

293 =1.61x10(-05)) than that of patients with no de novo variants.

294 patients (11.7%) had clinically significant de novo variants.

295 in-hospital mortality and the occurrence of de-novo ventricular arrhythmias (non-sustained or sustai

296 humans, C. elegans is able to synthesize LA de novo via a lipoyl-relay pathway, and suggest that thi

297 found a reduction in all-cause mortality in de novo vitamin D users compared with nonusers (hazard r

298 of the majority of prion variants that arise de novo While these systems are well described, how they

299 e vast majority of enhancers are established de novo without prior priming in earlier stages.

300 les fast, selective, and gated flow of water de novo would remain challenging, suggesting a need for