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Cited by 226Fungal and yeast genetics researchAntifungal resistance and susceptibilityFungal Infections and Studies

Stage‐specific gene expression of Candida albicans in human blood

Open access
Fradin, Chantal, Kretschmar, Marianne, Nichterlein, Thomas, Gaillardin, Claude, D’Enfert, Christophe, Hube, Bernhard·2003·Molecular Microbiology
DOI 10.1046/j.1365-2958.2003.03396.x
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Abstract

Summary: The pathogenic fungus Candida albicans commonly causes mucosal surface infections. In immunocompromised patients, C. albicans may penetrate into deeper tissue, enter the bloodstream and disseminate within the host causing life‐threatening systemic infections. In order to elucidate how C. albicans responds to the challenge of a blood environment, we analysed the transcription profile of C. albicans cells exposed to human blood using genomic arrays and a cDNA subtraction protocol. By combining data obtained with these two methods, we were able to identify unique sets of different fungal genes specifically expressed at different stages of this model that mimics bloodstream infections. By removing host cells and incubation in plasma, we were also able to identify several genes in which the expression level was significantly influenced by the presence of these cells. Differentially expressed genes included those that are involved in the general stress response, antioxidative response, glyoxylate cycle as well as putative virulence attributes. These data point to possible mechanisms by which C. albicans ensures survival in the hostile environment of the blood and how the fungus may escape the bloodstream as an essential step in its systemic dissemination.

AI snapshot

Written from the paper’s full text.

TL;DR

Candida albicans rapidly reprograms transcription after exposure to human blood, with stage-specific expression of protein synthesis, stress/antioxidant, glycolytic/glyoxylate cycle, fermentation and hyphal-associated genes. Combining microarrays and cDNA subtraction, and validating selected genes in i.v. infected mice, the study identifies candidate mechanisms for survival in blood and escape into tissue.

Key findings

  • Within 60 min in blood, 32% of genes on the arrays were up- or downregulated; 1754 of 2002 ORFs (87.5%) were expressed in at least one of nine conditions, with 12% highly expressed and 20% moderately expressed; about 35% of differentially expressed genes encoded proteins of unknown function.
  • Early (10 min) blood exposure strongly induced protein synthesis genes (e.g., EF3 13.2-fold, EFB1 6.3-fold, RPL32 6.9-fold, RPS10 3.1-fold, THS1 44.1-fold) while glycolytic and glyoxylate cycle genes were downregulated (PGI1 47.8-fold, ENO1 4.5-fold, MLS1 162.5-fold, ICL1 12-fold); later stages showed increased glycolytic and glyoxylate transcripts (PFK2 16.4-fold and PGK1 41.7-fold at 20 vs 10 min; MLS1 and ICL1 >20-fold upregulated after 60 min).
  • Antioxidant genes (TRR1, CAT1, IPF2431, SOD1) increased in blood, with up to 10-fold lower transcript levels in plasma; hyphal-associated genes (HWP1, ECE1, HYR1, SAP4–6, PLB5) increased over time, with >55% germ tubes at 60 min and >90% hyphae in plasma versus >50% in blood.
  • In i.v. infected mice, selected genes (MLS1, ICL1, CAT1, TRR1, PHR2, PRA1, ECE1, HWP1, ACT1, EFB1, SSB1) were confirmed by RT-PCR; in human blood, 92% of C. albicans cells were bound or phagocytosed by leucocytes at 10 min, and 46% were ingested by 60 min.

Methods

  • C. albicans SC5314 was precultured in Lee’s medium (25°C, pH 4.5) or YPD, then incubated in whole heparinized human blood or plasma at 37°C under semi-aerobic conditions for 10, 20, 30 and 60 min, with YPD and calf serum controls.
  • Transcript profiling used arrays of duplicate PCR products representing 2002 C. albicans genes, DIG-labelled cDNA, triplicate hybridizations and a twofold differential-expression threshold; suppressive subtractive hybridization compared 10-min samples with 20-, 30- and 60-min samples, with Northern blot and RT-PCR validation.
  • In vivo, six mice were injected i.v. with 2 × 10⁷ or 2 × 10⁸ cells, blood was collected at 20 or 35 min (2000–60 000 cfu per sample), cDNA was PCR-amplified with SMART technology and hybridized to arrays; leucocyte binding/phagocytosis was scored microscopically.

Limitations

  • The paper states that preculture conditions influenced gene expression, especially early in blood; SMART PCR may not amplify all cDNAs equally and some genes may have been missed; not all mouse expression patterns matched the human blood model, and endothelial or other in vivo factors were not captured.
  • The paper notes heparin had only minor overall effects but could process Int1 into a superantigen; the array covered only 2002 genes rather than the whole genome.
  • Evident from the text: the human blood experiments used blood from one donor, and the model relies on semi-aerobic incubation and a short time course.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1046/j.1365-2958.2003.03396.x

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 39 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    When cells were transferred to blood, a high level of transcripts involved in protein synthesis was detected as early as 10 min after inoculation.

    “In contrast, when cells were transferred to the blood environment, a high level of different transcripts involved in protein synthesis was detected as early as 10 min after inoculation (Table 2).”
    Quote in the paperSubstantial claim
  • Findingown data

    Expression in at least one of nine conditions tested was observed for 1754 ORFs (87.5%) of the 2002 C. albicans genes analysed.

    “Expression in at least one out of the nine different conditions tested was observed for 1754 ORFs (87.5%) of the 2002 C. albicans genes analysed.”
    Quote in the paperSubstantial claim
  • Findingown data

    Among differentially expressed genes identified on the membrane, approximately 35% encoded proteins of unknown function.

    “Among the differentially expressed genes identified on the membrane, ª 35% encoded proteins of unknown function.”
    Quote in the paperNot a substantial claim
  • Findingown data

    RPL32 and RPS10 were 6.9- and 3.1-fold upregulated compared with preculture cells.

    “ribosomal proteins such as RPL32 and RPS10 (6.9-and 3.1-fold upregulation)”
    Quote in the paperNot a substantial claim
  • Findingown data

    PFK2 and PGK1 were 16.4 and 41.7 times enhanced after 20 min of incubation compared with 10 min.

    “This was particularly clear for PFK2 and PGK1 encoding phosphofructokinase and phosphoglycerate kinase, the expression of which was 16.4 and 41.7 times enhanced after 20 min of incubation compared with 10 min.”
    Quote in the paperSubstantial claim
  • May combine two claims. 58
  • Classified as probably not a substantial claim. 30

  • May combine two claims.

    Findingown data

    Genes involved in energy production accounted for 8% of all downregulated but only 1% of all upregulated genes after inoculation into blood.

    “This would be supported by the fact that, overall, genes involved in energy production accounted for 8% of all downregulated but only 1% of all upregulated genes after inoculation of the cells into blood.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Twelve per cent of all genes were highly expressed and 20% were moderately expressed.

    “Twelve per cent of all genes were highly expressed ( M x ≥ 2Av; where M x = mean signal for gene x and Av = average signal intensity) (Murad et al ., 2001a), and 20% were moderately expressed (0.5Av ≥ M x ≥ 2Av).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Genes encoding protein synthesis products represented 12% of upregulated and 1% of downregulated genes.

    “Genes encoding for protein synthesis products represented 12% of the upregulated and only 1% of the downregulated genes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Preculture conditions influenced the general expression pattern at 10 min in blood (correlation coefficient 0.75), and this effect decreased at 30 min (correlation coefficient 0.83).

    “Although preculture conditions did influence the general expression pattern at 10 min in blood (correlation coefficient 0.75; Fig. 2D), this effect decreased at later stages of the incubation (correlation coefficient 0.83 at 30 min; Fig. 2E).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    EF3 and EFB1 were 13.2- and 6.3-fold upregulated compared with preculture cells.

    “This set of genes included transcripts for elongation factors such as EF3 and EFB1 (Colthurst et al., 1991;Maneu et al., 1996;13.2-and 6.3-fold upregulated compared with the preculture cells)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The general expression profile in YPD was clearly different from cells exposed to blood, with correlation coefficients of 0.72 at 10 min and 0.71 at 30 min.

    “The general expression profile in YPD was clearly different from cells exposed to blood, resulting in correlation coefficients of 0.72 and 0.71 at 10 and 30 min respectively (Fig. 2F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At 10 min in blood, 46% of differentially expressed genes were downregulated and 54% were upregulated compared with preculture.

    “When array data obtained from preculture samples (incubated in PBS, pH 7.0, at 37∞C for 30 min) and the samples from the earliest time of incubation of C. albicans in blood (10 min) were compared, 46% of all differentially expressed genes were found to be downregulated, whereas 54% were upregulated (Fig. 2C).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    SOD2 was not expressed in cells exposed to blood, but only in YPD cultures.

    “As SOD2 was not expressed in cells exposed to blood, but only in YPD cultures”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Transcripts of stress-related genes were still detected at different time points, and HSP6, DDR48 and SSC1 were again strongly upregulated in later stages.

    “However, transcripts of these genes were still detected at the different time points of incubation and, in some cases, as for HSP6, DDR48 and SSC1, were again strongly upregulated in the later stages.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    PDC11 and ADH5 were identified by SSH and found to be expressed more at 60 min compared with 10 min.

    “In addition, a pyruvate decarboxylase gene, PDC11, responsible for the decarboxylation from pyruvate to acetaldehyde and CO 2 , and a third putative alcohol dehydrogenase gene, ADH5, were identified by SSH (Table 1) and found to be expressed more at 60 min compared with 10 min.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    SOD1 was highly expressed in YPD cultures and blood, but not in plasma.

    “Because SOD1 was highly expressed in YPD cultures and blood, but not in plasma”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    PHR1 was detected but not induced when cells were transferred into blood.

    “Consequently, genes that are usually expressed at alkaline pH, such as the pH-responsive glycosyl transferase gene PHR1 (Saporito-Irwin et al., 1995), were detected, but not induced when cells were transferred into blood.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    PHR2 was 20-fold upregulated when cells were incubated in blood and was consistently expressed at high levels at all time points compared with preculture.

    “Interestingly, PHR2, a gene specifically expressed at acidic pH values (Mühlschlegel and Fonzi, 1997), was 20-fold upregulated when cells were incubated in blood and was consistently expressed at high levels at all time points compared with the preculture.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    ADH1 and ADH2 were expressed more in cells incubated in YPD compared with blood, and their expression in blood was influenced by preculture conditions.

    “In addition, we found that ADH1 and ADH2 were expressed more in cells incubated in YPD medium compared with cells exposed to blood and that their expression in blood was influenced by the preculture conditions”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    SAP4, SAP5 and SAP6 were increasingly expressed in blood with the highest expression level at 60 min.

    “In addition, three genes of the secretory aspartic proteinases (SAP) gene family, SAP4, SAP5 and SAP6, which are also known to be hyphalassociated genes (Hube et al., 1994), were increasingly expressed in blood with the highest expression level at 60 min.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    SSB1 was upregulated in early phases but downregulated during later stages of infection.

    “In contrast, the heat shock protein gene SSB1 (Maneu et al., 1997) was upregulated in the early phases, but downregulated during the later stages of infection (Fig. 5).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Genes encoding enzymes involved in the glyoxylate cycle were highly downregulated after inoculation into blood, and their expression increased during infection.

    “In a similar fashion to those genes encoding glycolytic enzymes, genes encoding enzymes involved in the glyoxylate cycle, which allows microorganisms to use two-carbon compounds as carbon sources to produce glucose, were highly downregulated after inoculation of the blood, and their expression increased during the infection (Fig. 4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    PLB5 was upregulated after 20 min of incubation in blood and clustered with the hyphal-specific genes.

    “Furthermore, the expression of a gene of the phospholipase B family, the phospholipase 5 gene PLB5, was upregulated after 20 min of incubation in blood and clustered with the hyphal-specific genes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the early stages of the artificial bloodstream infection, there was a high level of expression of genes involved in protein synthesis and low levels of transcription of genes encoding glycolytic enzymes.

    “In the early stages of the artificial bloodstream infection, we observed a high level of expression of genes involved in protein synthesis and low levels of transcription of genes encoding glycolytic enzymes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The genes encoding glycolytic enzymes were upregulated in the late stages of blood infection, and the glucose concentration decreased during the time course.

    “Nevertheless, the fact that the genes encoding glycolytic enzymes were upregulated in the late stages of blood infection cannot be explained by high glucose concentrations, as the glucose concentration decreased during the time course (not shown).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Expression of the heat shock protein increased during the time course, and transcripts were detectable at all time points, showing a response to some blood components.

    “However, expression of the heat shock protein increased during the time course, and transcripts were detectable at all time points, showing a response to some blood components.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The SSH technology confirmed the existence of gene transcription for a large number of genes with putative or unknown functions, identified transcripts of genes not present on the array and identified unknown ORFs that had not been annotated in the Candida genome project.

    “In addition, the SSH technology confirmed the existence of gene transcription for a large number of genes with putative or unknown functions, identified transcripts of genes not present on the array and identified unknown ORFs that had not been annotated in the Candida genome project.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    PHR2 was upregulated after 10 min in blood and was found to be constantly expressed at all time points.

    “Even though the expression of PHR1 may have indicated the adaptation to an alkaline environment, PHR2 was upregulated after 10 min in blood and was found to be constantly expressed at all time points.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Except for IPF2431, which was expressed at all time points to similarly high levels, the expression of detoxification genes increased with the time of exposure to blood.

    “Except for IPF2431, which was expressed at all time points to similarly high levels, the expression of these genes increased with the time of exposure to blood.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Around 280 genes were more than twofold upregulated, and more than 240 genes were at least twofold downregulated within the first 10 min of exposure to blood.

    “Around 280 genes were found to be more than twofold upregulated, and more than 240 genes were at least twofold downregulated within the first 10 min of exposure to blood.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Genes coding for proteins involved in protein synthesis are upregulated in the early stages of experimental bloodstream infection, but downregulated in the later stages.

    “Genes coding for proteins involved in protein synthesis are upregulated in the early stages, but downregulated in the later stages.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Findingown data

    The expression level of genes involved in glycolysis, fermentation and the glyoxylate cycle in a nutrient-rich medium was compared with their expression in blood, and the influence of preculture condition on the expression of these genes in blood was assessed.

    “Comparison of the expression level of genes involved in glycolysis, fermentation and the glyoxylate cycle in a nutrient-rich medium compared with their expression in blood and the influence of preculture condition on the expression of these genes in blood.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    A number of genes known to be hyphal specific, such as SAP4-6, HWP1 and HYR1, were increasingly expressed during the time course, and higher expression levels were observed in plasma compared with blood.

    “Consequently, a number of genes known to be hyphal specific, such as SAP4-6, HWP1 and HYR1, were increasingly expressed during the time course, and higher expression levels were observed in the plasma compared with blood.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The known heat shock protein SSB1 is clearly upregulated at the early stages, but downregulated during the later stages of infection.

    “whereas the known heat shock protein SSB1 is clearly upregulated at the early stages, but downregulated during the later stages of infection”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The influence of preculture conditions on stress-related gene expression decreases noticeably after 30 min in blood, with upregulation of these genes during the time course in blood.

    “This influence decreases noticeably after 30 min in blood, showing an upregulation of these genes during the time course in blood.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Genes involved in protein synthesis (elongation factors, tRNA synthetases and ribosomal proteins) are expressed during incubation in blood at 10, 20, 30 and 60 min and in YPD at 10 and 30 min.

    “List of genes involved in protein synthesis (elongation factors, tRNA synthetases and ribosomal proteins) expressed during incubation in blood at 10, 20, 30 and 60 min and in YPD at 10 and 30 min.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    The alkaline-regulated gene PHR1 and the acidic-regulated gene PHR2 are constitutively expressed at all time points.

    “The alkaline-regulated gene PHR1 and the acidic-regulated gene PHR2 are constitutively expressed at all time points.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    During the time course experiment, oxygen concentrations decreased.

    “During the time course experiment, oxygen concentrations decreased”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    It is likely that C. albicans has to express a distinct set of genes to adapt to the bloodstream and to attach to and penetrate through the endothelial layer in order to invade new tissue.

    “It is likely that the fungus has to express a distinct set of genes, which will enable the cells to adapt to the bloodstream and allow them to attach to and penetrate through the endothelial layer in order to invade new tissue.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Host cells influenced the gene expression of C. albicans most at 20 and 30 min, but had less influence at 60 min.

    “indicating that the host cells influenced the gene expression of C. albicans most at the 20 and 30 min time points, but had less influence on gene expression at 60 min.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    RT-PCR and Northern blot analysis confirmed the array data.

    “Reverse transcriptase (RT)-PCR (not shown) and Northern blot analysis (Fig. 1) confirmed the array data.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In immunocompromised patients, C. albicans may penetrate into deeper tissue, enter the bloodstream and disseminate within the host, causing life-threatening systemic infections.

    “In immunocompromised patients, C. albicans may penetrate into deeper tissue, enter the bloodstream and disseminate within the host causing life-threatening systemic infections.”
    • Also stated in: § Introduction · plain
      “Once invaded into deeper tissue, C. albicans can then enter the bloodstream and disseminate within the host (Odds, 1988;Mellado et al ., 2000).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Calderone and Fonzi, 2001

      Not checked in the free run.

    • cites Odds, 1988

      Not checked in the free run.

    • cites Mellado et al., 2000

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    A highly reproducible expression pattern was observed for all duplicates, indicating homogeneous spotting of the DNA samples.

    “A highly reproducible expression pattern was observed for all duplicates, indicating a homogeneous spotting of the DNA samples.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Different attributes, including adhesion factors, the yeast-to-hyphal transition and hydrolytic enzyme secretion, are necessary for penetration of C. albicans through epithelial and endothelial layers.

    “Different attributes, among which are adhesion factors, the yeast-to-hyphal transition and hydrolytic enzyme secretion, are necessary for penetration of C. albicans through the epithelial and endothelial layers (Hube et al ., 1997;Sanglard et al ., 1997;Ibrahim et al ., 1998;Brown and Gow, 1999;Sundstrom, 1999;Ernst, 2000;Phan et al ., 2000;Felk et al ., 2002).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Hube et al., 1997

      Not checked in the free run.

    • cites Sanglard et al., 1997

      Not checked in the free run.

    • cites Ibrahim et al., 1998 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Each hybridization experiment was performed in triplicate, and a gene was defined as differentially expressed when at least twofold changes were detected between time points or experiments.

    “Each hybridization experiment was performed in triplicate, and a gene was defined as differentially expressed when at least twofold changes in expression were detected between two different time points of the same experiment or between the same time point of two different experiments.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The data point to possible mechanisms by which C. albicans ensures survival in the hostile blood environment and escapes the bloodstream as an essential step in systemic dissemination.

    “These data point to possible mechanisms by which C. albicans ensures survival in the hostile environment of the blood and how the fungus may escape the bloodstream as an essential step in its systemic dissemination.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The experimental model of incubating C. albicans in human blood or plasma mimics bloodstream infections.
    • Rests on an assumption: The blood environment is hostile to C. albicans.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    C. albicans remains the primary pathogenic fungus in most types of systemic fungal infections.

    “Bloodstream infections caused by fungi have increased dramatically in the last 10 years, and C. albicans remains the primary pathogenic fungus in most types of systemic fungal infections (Edmond et al., 1999;Harbarth et al., 1999;Pfaller et al., 2000).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Edmond et al., 1999

      Not checked in the free run.

    • cites Harbarth et al., 1999

      Not checked in the free run.

    • cites Pfaller et al., 2000

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Previous transcriptional analysis studies of S. cerevisiae under anaerobic conditions showed that genes involved in respiratory sugar metabolism had little or no repression under anaerobic conditions and that ADH2 was even more highly expressed under aerobic conditions compared with anaerobic conditions.

    “However, previous transcriptional analysis studies of S. cerevisiae under anaerobic conditions have shown that genes involved in respiratory sugar metabolism showed little or no repression under anaerobic conditions and that ADH2 was even more highly expressed under aerobic conditions compared with anaerobic conditions (ter Linde et al., 1999)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites ter Linde et al., 1999

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The increased expression of ADH1 and ADH2 may indicate an increasing lack of oxygen in the cells.

    “which may indicate an increasing lack of oxygen in the cells.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Bloodstream infections caused by fungi have increased dramatically in the last 10 years.

    “Bloodstream infections caused by fungi have increased dramatically in the last 10 years, and C. albicans remains the primary pathogenic fungus in most types of systemic fungal infections (Edmond et al., 1999;Harbarth et al., 1999;Pfaller et al., 2000).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Edmond et al., 1999

      Not checked in the free run.

    • cites Harbarth et al., 1999

      Not checked in the free run.

    • cites Pfaller et al., 2000

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    The later upregulation of glycolytic genes could possibly be explained by low intracellular energy levels at that time.

    “and could possibly be explained by the presence of low intracellular energy levels at this time.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    These data very likely reflect the response of C. albicans to oxidative stress in order to survive phagocytosis or to act against oxidative components secreted by leucocytes.

    “These data very likely reflect the response of C. albicans to oxidative stress in order to survive phagocytosis or to act against oxidative components secreted by leucocytes, which can kill microorganisms without phagocytosing them.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Macrophages predominantly kill C. albicans through non-oxidative mechanisms, whereas neutrophils, the main class of leucocytes in the blood, eliminate this fungus via the production of toxic oxygen metabolites.

    “Although macrophages predominantly kill C. albicans through non-oxidative mechanisms (Lehrer, 1975;Diamond and Haudenschild, 1981), neutrophils, the main class of leucocytes in the blood, eliminate this fungus via the production of toxic oxygen metabolites (Diamond et al., 1980;Thompson and Wilton, 1992).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Lehrer, 1975

      Not checked in the free run.

    • cites Diamond and Haudenschild, 1981

      Not checked in the free run.

    • cites Diamond et al., 1980

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    These data could indicate that cells possess high levels of cellular energy at this early stage of infection, which may result from the relatively high level of glucose in blood and/or internal stocks of carbohydrates accumulated during preculture growth.

    “These data could indicate that cells possess high levels of cellular energy at this early stage of infection, which may result from the relatively high level of glucose in blood (ª 0.6-1.0g l -1 ) and/or internal stocks of carbohydrates that may have been accumulated during the preculture growth.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    SOD1 probably has a function in the antioxidative response to both leucocytes and intracellular oxygen components, as it was highly expressed in YPD cultures and blood, but not in plasma.

    “However, as SOD1 was highly expressed in YPD cultures and blood, but not in plasma, this gene probably has a function in the antioxidative response to both leucocytes and intracellular oxygen components.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    C. albicans catalase has been described as an important fungal defence factor, which prevents killing by neutrophils.

    “C. albicans catalase has been described as an important fungal defence factor, which prevents killing by neutrophils (Diamond et al., 1980).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Diamond et al., 1980

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    MDH1 may not be the homologous counterpart of ScMDH2, as MDH1 was more expressed in YPD compared with blood.

    “However, as MDH1 was more expressed in YPD compared with blood, this gene may not be the homologous counterpart of ScMDH2.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The glyoxylate cycle enables microorganisms to grow on acetate or fatty acids as sole carbon sources and may be an important adaptation of pathogenic microorganisms such as Mycobacterium tuberculosis or C. albicans.

    “The glyoxylate cycle enables microorganism to grow on acetate or fatty acids as sole carbon sources and may be an important adaptation of pathogenic microorganisms such as Mycobacterium tuberculosis or C. albicans (McKinney et al., 2000;Lorenz and Fink, 2001).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites McKinney et al., 2000

      Not checked in the free run.

    • cites Lorenz and Fink, 2001

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The Ssa4 protein is expressed during stressful conditions, is highly immunogenic and can enhance host susceptibility to C. albicans and may thus modulate pathogenicity.

    “It has been shown that the Ssa4 protein is expressed during stressful conditions, is highly immunogenic and can enhance host susceptibility to C. albicans and may thus modulate pathogenicity (Bromuro et al., 1998).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bromuro et al., 1998 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    As the expression of SSA4 was dependent on the presence of blood cells, this modulation may occur via leucocytes and may indicate a possible specific virulence mechanism of C. albicans based on a distinct host response.

    “As the expression of SSA4 was dependent on the presence of blood cells, this modulation may occur via leucocytes and may indicate a possible specific virulence mechanism of C. albicans based on a distinct host response.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Glycolytic enzymes can function in either the degradation of glucose or glyconeogenesis, which may explain the simultaneous expression of both pathways.

    “Furthermore, the fact that glycolytic enzymes can function in either the degradation of glucose or glyconeogenesis may also explain the apparently conflicting data of a simultaneous expression of both pathways.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    In S. cerevisiae, ScMdh2 is the isozyme that preferentially functions in the glyoxylate cycle, whereas ScMdh1 is probably restricted to activity in mitochondria.

    “In S. cerevisiae, ScMdh2 is the isozyme that preferentially functions in this cycle, whereas ScMdh1 is probably restricted to activity in mitochondria (Minard and McAlister-Henn, 1991).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Minard and McAlister-Henn, 1991

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The expression of glyoxylate cycle genes is likely to reflect a direct or indirect response to host cells, as all these genes were significantly upregulated in blood compared with plasma.

    “As all these genes were significantly upregulated in blood compared with plasma, their expression is likely to reflect a direct or indirect response to host cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    An additional independent regulation of PRA1 may occur under certain circumstances, and PRA1 does not play a dominant role during growth in blood.

    “Although it has been shown that both genes are regulated by the zinc finger transcriptional factor RIM101 (Porta et al., 1999;Davis et al., 2000;El Barkani et al., 2000), our data suggest that an additional independent regulation may occur under certain circumstances and that PRA1 does not play a dominant role during growth in blood.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Porta et al., 1999

      Not checked in the free run.

    • cites Davis et al., 2000

      Not checked in the free run.

    • cites El Barkani et al., 2000

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The artificial incubation in PBS before inoculation in the blood caused stress to the fungal cells, most likely influenced by the temperature shift from Lee's medium (25°C) to the PBS buffer (37°C), and C. albicans seems to have the ability to adapt well to the blood environment.

    “This suggests not only that the artificial incubation in PBS before inoculation in the blood caused stress to the fungal cells, most likely influenced by the temperature shift from the Lee's medium (25∞C) to the PBS buffer (37∞C), but also that C. albicans seems to have the ability to adapt well to the blood environment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Survival of C. albicans in the bloodstream appears to be possible under certain circumstances and seems to depend on the expression of a distinct set of genes that triggers adaptation to this environment.

    “Although C. albicans is rapidly eliminated from the blood in the normal host, survival of this fungus in the bloodstream appears to be possible under certain circumstances and seems to depend on the expression of a distinct set of genes, which triggers the adaptation to this environment.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: C. albicans is rapidly eliminated from the blood in the normal host.

  • May combine two claims.

    Interpretationown data

    C. albicans seemed to be physiologically active in blood, as the expression of various genes encoding components of the protein synthesis machinery was highly upregulated in the early stages, enabling the fungus to respond quickly to the specific demands of the blood conditions.

    “Despite being exposed to a hostile environment, C. albicans seemed to be physiologically active, as the expression of various genes encoding components of the protein synthesis machinery was highly upregulated in the early stages, thus enabling the fungus to respond quickly to the specific demands of the blood conditions.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    C. albicans may be able to use both glycolytic and glyoxylate pathways at the same time, in contrast to S. cerevisiae, as an opportunistic microorganism living in host microniches with limited and/or changing nutrient sources.

    “C. albicans, as a opportunistic microorganism living in host microniches with rather limited and/or changing nutrient sources, may be able to use both pathways at the same time, in contrast to S. cerevisiae.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: In S. cerevisiae, cells use either the glycolytic pathway when carbohydrates are available or the glyoxylate cycle in the absence of glucose, but do not upregulate both sets of genes at the same time.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    mRNA levels in Northern blots were measured relative to ribosomal RNAs by loading approximately equal amounts of total RNA in each lane.

    “mRNA levels were measured relative to the ribosomal RNAs by loading approximately equal amounts of total RNA in each lane of the Northern blots.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Membranes were successfully reprobed for up to six times without significant loss of signal intensities.

    “Membranes were successfully reprobed for up to six times without significant loss of signal intensities.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    C. albicans is able to use haem and haemoglobin as an alternative source of iron.

    “However, it is known that C. albicans is able to use haem and haemoglobin as an alternative source of iron (Moors et al., 1992), and extra-cellular hydrolytic enzymes such as phospholipases (encoded by PLB genes) and proteinases (encoded by SAP genes) may be involved in these activities.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Moors et al., 1992

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Eighteen cycles of amplification was found to be the optimal number of PCR cycles for cDNA amplification.

    “Amplified cDNAs were obtained after 18 cycles of amplification, which was found to be the optimal number of PCR cycles.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The concentration of C. albicans cDNAs was estimated and adjusted after an additional series of RT-PCRs with different numbers of PCR cycles using the ACT1 primers because the number of Candida cells varied in the different blood samples.

    “As the number of Candida cells varied in the different blood samples, the concentration of C. albicans cDNAs was estimated and adjusted after an additional series of RT-PCRs with different numbers of PCR cycles using the ACT1 primers.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Serum components are well known to induce dimorphism of C. albicans efficiently.

    “Serum components are well known to induce dimorphism of C. albicans efficiently (Brown and Gow, 1999;Feng et al., 1999;Ernst, 2000).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Brown and Gow, 1999

      Not checked in the free run.

    • cites Feng et al., 1999

      Not checked in the free run.

    • cites Ernst, 2000

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The mean of signal intensities of triplicate experiments are shown.

    “The mean of signal intensities of triplicate experiments are shown.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    To ensure examination of products from the exponential phase of PCR, three different cycles (25, 30 and 35) were performed for each primer pair.

    “To ensure that we examined products from the exponential phase of PCR, three different cycles (25, 30 and 35) were performed for each primer pair, and the products were analysed on agarose gels.”
    • Also stated in: § Mouse infection and in vivo transcript profiling · plain
      “To ensure that we examined products from the exponential phase of PCR, three different cycles (25, 30 and 35; for details, see Experimental procedures) were performed for each primer pair, and the products were analysed on agarose gels.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Signal intensities in the cluster analysis were normalized to the mean of all expressed genes.

    “Signal intensities were normalized to the mean of all expressed genes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Correlation coefficients for duplicate experiments were >0.94 in all cases.

    “Correlation coefficients for duplicate experiments were >0.94 in all cases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The observed expression pattern closely resembles the expression pattern during bloodstream infections, as the vast majority of highly expressed genes investigated had a similar expression pattern in the artificial model and in cells isolated from infected animals.

    “However, as the vast majority of highly expressed genes investigated had a similar expression pattern in our artificial model mimicking bloodstream infections and in cells isolated from infected animals, we concluded that the observed expression pattern closely resembles the expression pattern during bloodstream infections.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Standard controls included reactions with genomic DNA templates to prove the efficiency of the PCR.

    “Further standard controls included reactions with genomic DNA templates to prove the efficiency of the PCR.”
    • Also stated in: § Mouse infection and in vivo transcript profiling · plain
      “A control PCR with genomic DNA template was performed to confirm the efficiency of each primer pair.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The same amounts of cDNAs were used for all further PCRs to detect the transcripts of different genes.

    “The same amounts of cDNAs were then used for all further PCRs to detect the transcripts of different genes (Fig. 7).”
    • Also stated in: § Mouse infection and in vivo transcript profiling · plain
      “The same amount of cDNA was used for all PCRs.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    At least 200 C. albicans cells were scored per slide in the phagocytosis assay.

    “At least 200 C. albicans cells were scored per slide, and data were expressed as the percentage of cells unbound, bound or phagocytosed by leucocytes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All experiments were done in triplicate.

    “All experiments were done in triplicate.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Hyphal-associated hydrolases such as phospholipases and proteinases may help the fungus to survive phagocytosis by granulocytes and support penetration through endothelial layers.

    “Hyphal-associated hydrolases linked to the cellular surface or secreted into the extracellular space, such as phospholipases and proteinases, may not only help the fungus to survive phagocytosis by granulocytes, but also support penetration through endothelial layers.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The yeast-to-hyphal transition, hyphal-associated factors and hydrolytic enzymes have been described as factors involved in invasion processes.

    “The yeast-to-hyphal transition, hyphal-associated factors and hydrolytic enzymes have been described as factors involved in these processes (Odds, 1994;Hube et al., 1997;Sanglard et al., 1997;Ibrahim et al., 1998;Clemons et al., 2000;Phan et al., 2000;Felk et al., 2002).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Odds, 1994

      Not checked in the free run.

    • cites Hube et al., 1997

      Not checked in the free run.

    • cites Sanglard et al., 1997

      Not checked in the free run.

80 of 80

  • The paper relies on this without support.

    The dissemination of C. albicans in the bloodstream is an essential step in systemic candidosis.

    “As the dissemination of C. albicans in the bloodstream is an essential step in systemic candidosis”

  • The paper relies on this without support.

    No infection model has so far been used with this new technology to investigate the transcript profile of a pathogenic microorganism.

    “No infection model has so far been used with this new technology to investigate the transcript profile of a pathogenic microorganism.”

  • The paper relies on this without support.

    The experimental model of incubating C. albicans in human blood or plasma mimics bloodstream infections.

    “this model that mimics bloodstream infections”

  • The paper relies on this without support.

    The blood environment is hostile to C. albicans.

    “the hostile environment of the blood”

  • The paper relies on this without support.

    Oxidative agents are one of the components of human blood that may cause stress in Candida cells.

    “Oxidative agents are one of the components of human blood that may cause stress in Candida cells.”

  • The paper relies on this without support.

    Stimulated leucocytes are a possible source of oxygen radicals that may cause oxidative stress.

    “A possible source of oxygen radicals, which may cause oxidative stress, are stimulated leucocytes.”

  • The paper relies on this without support.

    Very little is known about how C. albicans can survive in the bloodstream and escape to invade new organs.

    “However, very little is known about how the fungus can survive in this new and hostile environment and how it can escape to invade new organs.”

  • The paper relies on this without support.

    Pathogenic fungi adapt to changing environmental conditions by expressing genes necessary for optimal growth or viability.

    “Like other microorganisms, pathogenic fungi have to adapt to changing environmental conditions by expressing genes necessary for optimal growth or viability.”

  • The authors state this as an assumption.

    The higher expression of SSB1 was correlated with the necessity of folding newly produced proteins.

    “we assumed that the higher expression of SSB1 was correlated with the necessity of folding newly produced proteins.”

  • The paper relies on this without support.

    The blood is a rather microaerobic or semi-aerobic environment.

    “Although the blood is a rather microaerobic or semi-aerobic environment, the gene expression pattern of C. albicans cells exposed to blood (under experimental semiaerobic conditions) reflected oxidative stress.”

  • The paper relies on this without support.

    The concentration of iron is very low in blood.

    “Although the concentration of iron is known to be very low in blood, the expression pattern of two key genes of the iron metabolism of C. albicans, FTR1 and FTR2 (Ramanan and Wang, 2000), reflected no iron-limited conditions for the fungus.”

  • The paper relies on this without support.

    C. albicans is rapidly eliminated from the blood in the normal host.

    “Although C. albicans is rapidly eliminated from the blood in the normal host, survival of this fungus in the bloodstream appears to be possible under certain circumstances and seems to depend on the expression of a distinct set of genes, which triggers the adaptation to this environment.”

  • The paper relies on this without support.

    In S. cerevisiae, cells use either the glycolytic pathway when carbohydrates are available or the glyoxylate cycle in the absence of glucose, but do not upregulate both sets of genes at the same time.

    “In S. cerevisiae, cells use either the glycolytic pathway when carbohydrates are available or the glyoxylate cycle in the absence of glucose, but do not upregulate both sets of genes at the same time.”

  • The paper relies on this without support.

    Microorganisms that are able to achieve the glyoxylate cycle can produce energy and grow in lipid-rich environments such as host cells.

    “Microorganisms that are able to achieve this cycle can produce energy and grow in lipidrich environments such as host cells.”

  • The paper relies on this without support.

    During systemic infections, C. albicans is able to escape from the bloodstream and can penetrate into deeper tissue.

    “During systemic infections, however, C. albi-cans is able to escape from the bloodstream and can penetrate into deeper tissue.”

  • The paper relies on this without support.

    C. albicans expresses different molecules on its surface, which facilitate binding of the fungus to different host cells, such as endothelial cells.

    “C. albicans expresses different molecules on its surface, which facilitate binding of the fungus to different host cells, such as endothelial cells.”
16 of 16

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Moderate-expression range cannot contain any genes

    Minor

    The stated moderate-expression criterion requires the mean signal to be at most 0.5 times the average and at least 2 times the average. For positive signal intensities, no gene can meet that criterion, despite the reported 20%.

  • IPF1222 probe has a different identifier in the primer table

    Minor

    The Northern blot caption identifies its probe as IPF1222, but the table of primers used for these experiments lists IPF2222 instead.

  • Antioxidant gene label differs between results and discussion

    Minor

    The results identify CAT1 as highly expressed in preculture cells, whereas the discussion gives the corresponding gene as CTA1.

  • PRA1 is claimed among RT-PCR confirmations but absent from the cited figure's results

    Minor

    The text says RT-PCR confirmed PRA1 and cites Fig. 7, but the figure caption's exhaustive list of displayed PCR results names ten genes and omits PRA1.

  • Highly expressed genes have conflicting thresholds

    Minor

    The paper first defines highly expressed genes as having a signal at least twice the average, but later calls genes highly expressed when their signal exceeds half the average.

5 of 5

The citation lists haven’t been fetched yet

References 65 · Cited by 226

Authors
Fradin, C., Kretschmar, M., Nichterlein, T., Gaillardin, C., D’Enfert, C., & Hube, B.
Affiliations
  • Robert Koch Institute (DE)
  • Heidelberg University (DE)
  • Centre National de la Recherche Scientifique (FR)
Corresponding author
Hube, Bernhard
ORCID
Venue
Molecular Microbiology
Publisher
Wiley
Published
2003-03
Volume
47
Issue
6
Pages
1523-1543
ISSN
  • 0950-382X (ISSN-L)
  • 1365-2958
DOI
10.1046/j.1365-2958.2003.03396.x
OpenAlex
W2117464846
Semantic Scholar
0f1f953f9244ebf22d363633ee773da36dd45a2a
Cited by
226
References
65
Citations by year
2026: 1 · 2025: 4 · 2024: 3 · 2023: 3 · 2022: 6 · 2021: 6 · 2020: 8 · 2019: 6 · 2017: 6 · 2016: 9 · 2015: 15 · 2014: 20 · 2013: 8 · 2012: 11
FWCI
5.99
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 4 d)
Locations
  • Molecular Microbiology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Burroughs Wellcome Fund
  • European Commission
  • University of Aberdeen
  • Trinity College Dublin
  • Robert Koch Institut
  • Stanford Bio-X
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
Keywords
Candida albicans, bloodstream infection, systemic candidiasis, gene expression, human blood, plasma, host-pathogen interaction, stress response, antioxidant response, glyoxylate cycle, virulence factors
MeSH terms
Adaptation, Physiological, Animals, Antioxidants, Blood, Candida albicans, Candidiasis, Enzymes, Fermentation, Fungal Proteins, Glycolysis, Glyoxylates, Heparin, Humans, Leukocytes, Gene Expression Regulation, Fungal, Cluster Analysis, DNA, Complementary, Oxidative Stress, Oligonucleotide Array Sequence Analysis, Molecular Diagnostic Techniques, Hyphae, Mice

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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