Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model

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

Expression of MNB/DYRK1A or Dyrk1a induces neuronal differentiation in neural cell lines.

“Expression of MNB/DYRK1A or Dyrk1a induces neuronal differentiation in neural cell lines (Kelly and Rahmani, 2005; Yang et al., 2001)”

• cites Kelly and Rahmani, 2005 sourcePartly supported

  The Results and Discussion report that DYRK1A expression enhances neuronal differentiation in PC12 cells, including neurite outgrowth and neuronal marker expression. The experiments involved NGF treatment, however, so this paper supports potentiation of NGF-mediated differentiation, not that DYRK1A expression alone induces it. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Yang et al., 2001 sourceDisputed

  The Results (page not supplied) explicitly report that transient expression of wild-type Dyrk1 had no apparent effect on neuronal differentiation in H19-7 cells. The paper instead finds that kinase-deficient Dyrk1 reduces differentiation induced by bFGF, supporting a role for Dyrk1 activity but not the claim that its expression induces differentiation. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

Subtracting one copy of Dyrk1a at conception from otherwise trisomic mice improved cognitive, neurological and Alzheimer disease-like phenotypes.

“Subtracting one copy of Dyrk1a at conception from otherwise trisomic mice improved cognitive, neurological and Alzheimer disease-like phenotypes (Garcia-Cerro et al., 2014; Garcia-Cerro et al., 2017) and improved T-maze and contextual fear conditioning tests (Jiang et al., 2015).”

• cites Garcia-Cerro et al., 2014 sourcePartly supported

  The Experimental Animals section describes trisomic offspring with one fewer Dyrk1A copy, and Results I reports improved working and reference memory; the Discussion also reports rescued hippocampal LTP and improved neuromorphological measures. The paper does not report improvement in Alzheimer disease-like phenotypes. Results II says motor coordination and other tested motor functions were unaffected, so the broad claim of neurological improvement needs qualification. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Garcia-Cerro et al., 2017 sourceNot checked — no full text of the source

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

Quantification of both mRNA and protein levels in brains of individuals with DS from fetal to adult stages have shown that not all trisomic genes are dysregulated or expressed at 1.5-fold.

“Quantification of both mRNA and protein levels in brains of individuals with DS from fetal to adult stages have shown that not all trisomic genes are dysregulated or expressed at 1.5-fold (Lockstone et al., 2007; Mao et al., 2005; Mao et al., 2003).”

• cites Lockstone et al., 2007 sourcePartly supported

  The Discussion (page unavailable) reports that only a subset of chromosome 21 genes was up-regulated in adult Down syndrome brain and that adult mRNA increases sometimes exceeded 1.5-fold. It also says fetal-brain mRNA up-regulation fit the 1.5-fold model. The paper discusses protein findings from a parallel study, but does not establish the claim about protein levels across fetal-to-adult stages. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Mao et al., 2005 sourcePartly supported

  The Discussion (page unavailable) says that only a subset of expressed chromosome 21 transcripts was elevated in the tissues studied, supporting the claim that not all trisomic genes are dysregulated. But this study measured RNA in fetal tissues, not protein levels or brains across fetal-to-adult stages; its Conclusion says the relationship between RNA and protein levels was unknown. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites Mao et al., 2003 sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

A frequent assumption regarding gene dosage effects in trisomy is that expression of all trisomic genes is upregulated according to the gene copy number (1.5-fold) in every cell in the body throughout the lifespan.

“A frequent assumption regarding gene dosage effects in trisomy is that expression of all trisomic genes is upregulated according to the gene copy number (1.5-fold) in every cell in the body throughout the lifespan of the individual, though some have reported dosage compensation for some genes (Ait Yahya-Graison et al., 2007; Hwang et al., 2021; Kahlem et al., 2004; Lyle et al., 2004).”

• cites Ait Yahya-Graison et al., 2007 sourceSupported
• cites Hwang et al., 2021 sourcePartly supported

  The Results (Transcriptome Analyses; page not provided) report an average 1.5-fold increase in expression for most genes on trisomic chromosomes in the fibroblast cell lines studied. They also report outliers, and the Discussion limits its conclusion to average mRNA levels. The paper does not establish that all trisomic genes are upregulated 1.5-fold in every cell throughout an individual's lifespan. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites Kahlem et al., 2004 sourcePartly supported

  The Abstract (page unavailable) says it is widely assumed that trisomic Chr21 genes have transcript levels about 50% above normal. But the Gene Dosage Effects section reports that several genes escape the 1.5-fold pattern, and the Discussion says whole-tissue measurements cannot establish expression in every cell or at every developmental stage. The source therefore supports the description of a frequent assumption, but not its extension to all genes in every cell throughout life. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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

DYRK1A is a serine-threonine kinase that utilizes autophosphorylation to enhance activity and stabilize itself, regulates many downstream proteins and transcription factors, and has a crucial role during brain development.

“DYRK1A is a serine-threonine kinase that utilizes autophosphorylation to enhance activity and stabilize itself, regulates many downstream proteins and transcription factors, and has a crucial role during brain development (Ahn et al., 2006; Arron et al., 2006; Atas-Ozcan et al., 2021; Branchi et al., 2004; Canzonetta et al., 2008; Hammerle et al., 2011; Martinez de Lagran et al., 2004; Park and Ch”

• cites Ahn et al., 2006 sourceNot checked — no full text of the source
• cites Arron et al., 2006 sourceNot checked — no full text of the source
• cites Atas-Ozcan et al., 2021 sourceSupported

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

Some have reported dosage compensation for some genes.

“A frequent assumption regarding gene dosage effects in trisomy is that expression of all trisomic genes is upregulated according to the gene copy number (1.5-fold) in every cell in the body throughout the lifespan of the individual, though some have reported dosage compensation for some genes (Ait Yahya-Graison et al., 2007; Hwang et al., 2021; Kahlem et al., 2004; Lyle et al., 2004).”

• cites Ait Yahya-Graison et al., 2007 sourceSupported
• cites Hwang et al., 2021 sourcePartly supported

  The Results section on posttranscriptional regulation reports that proteins encoded by 97 of 281 triplicated genes were attenuated, supporting compensation at the protein level. But their mRNA levels rose about 1.5-fold, and the Discussion says the findings support a lack of dosage compensation of human autosomes at the RNA level. The citation therefore supports the claim only if dosage compensation includes protein-level attenuation, not compensation of gene expression. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Kahlem et al., 2004 sourceSupported

May combine two claims.

Trisomic DYRK1A has been linked to aberrant brain development, brain pathology, and impaired cognitive phenotypes in individuals with DS and DS mouse models.

“Trisomic DYRK1A has been linked to aberrant brain development, brain pathology, and impaired cognitive phenotypes in individuals with DS and DS mouse models (Arron et al., 2006; Becker et al., 2014; Dowjat et al., 2007; Duchon and Herault, 2016; Liu et al., 2008).”

• cites Arron et al., 2006 sourceNot checked — no full text of the source
• cites Becker et al., 2014 sourceNot checked — no full text of the source
• cites Dowjat et al., 2007 sourcePartly supported

  The Abstract (page unavailable) reports increased brain DYRK1A in DS subjects and Ts65Dn mice, discusses a possible role in brain development, and links altered DYRK1A expression to cognitive deficits. It does not link DYRK1A overexpression to brain pathology; its discussion of AD-like pathology instead says that pathology appears to have limited influence on DYRK1A levels. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

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

No differences in DYRK1A expression were found in the cerebral cortex of 1 to 3-year-old individuals with DS, but significantly increased expression of DYRK1A in 10 to 30 and ≥ 40-year-old individuals with DS was observed.

“No differences in DYRK1A expression were found in the cerebral cortex of 1 to 3-year-old individuals with DS, but significantly increased expression of DYRK1A in 10 to 30 and ≥ 40-year-old individuals with DS was observed.”

• cites Dowjat et al., 2007 sourceSupported

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

An approximate 1.5-fold increase in DYRK1A from brain homogenates from 15-month-old Ts65Dn mice was observed.

“An approximate 1.5-fold increase in DYRK1A was found in homogenates from brains from human adults with DS and ~ 1.5-fold increase in DYRK1A from brain homogenates from 15-month-old Ts65Dn mice was observed (Liu et al., 2008).”

• cites Liu et al., 2008 sourcePartly supported

  The Results report approximately 1.5-fold greater Dyrk1A expression in Ts65Dn mouse brains than in littermate controls. The passages in our copy do not specify that the mice were 15 months old, so that age qualifier is not supported. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

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

Trisomy of genes on human chromosome 21 leads to the ~80 clinical phenotypes associated with DS.

“Trisomy of genes on human chromosome 21 (Hsa21)—the smallest human chromosome with 46.7 Mbp of DNA that contains 233 protein coding, 423 noncoding, and 188 pseudogenes (ensembl.org)—leads to the ~80 clinical phenotypes associated with DS (Antonarakis et al., 2020).”

• cites Antonarakis et al., 2020 sourcePartly supported

  The Abstract states that trisomy 21 causes Down syndrome and its many clinical manifestations. The Genetics of DS section discusses how triplicated genes may contribute to those manifestations, but our copy does not give a count of approximately 80 clinical phenotypes. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

DYRK1A has been identified as a target for therapeutic drug development in DS.

“DYRK1A has been identified as a target for therapeutic drug development in DS (Becker et al., 2014; De la Torre and Dierssen, 2012; Duchon and Herault, 2016).”

• cites Becker et al., 2014 sourceNot checked — no full text of the source
• cites De la Torre and Dierssen, 2012 sourceNot checked — no full text of the source
• cites Duchon and Herault, 2016 sourceSupported

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

Cognitive impairment is a hallmark DS phenotype affecting all individuals with Ts21.

“Cognitive impairment is a hallmark DS phenotype affecting all individuals with Ts21 (Antonarakis et al., 2020) with regions of disproportionately small brain volume including the cerebrum, cerebellum, and hippocampus (Aylward et al., 1999; Kesslak et al., 1994; Pinter et al., 2001; Raz et al., 1995; Weis et al., 1991).”

• cites Antonarakis et al., 2020 sourcePartly supported

  The Abstract describes intellectual disability as a common feature of Down syndrome, and the Management > Neurodevelopment section describes a cognitive profile with a wide range of functioning (page numbers unavailable). Neither passage establishes that cognitive impairment affects every individual with trisomy 21; the claim’s universal qualifier is unsupported. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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

Recent evidence suggests that sex chromosome complement may play an important role in sex differences in brain (beyond the classic organizational model), including large adult sex differences in brain regional transcriptome expression profiles and in expression of neuroinflammatory mediators of immune signaling.

“Recent evidence suggests that sex chromosome complement may play an important role in sex differences in brain (beyond the classic organizational model), including large adult sex differences in brain regional transcriptome expression profiles and in expression of neuroinflammatory mediators of immune signaling (McCarthy, 2020).”

• cites McCarthy, 2020 sourcePartly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

May combine two claims.

Total protein provides a stable reference measure that accounts for variation in protein loading and in the amount of protein transferred to the membrane, and can have superior linearity over a range of concentrations when compared to using a single reference protein.

“Total protein provides a stable reference measure that accounts for variation in protein loading and in the amount of protein transferred to the membrane (Welinder and Ekblad, 2011), and can have superior linearity over a range of concentrations when compared to using a single reference protein (Aldridge et al., 2008; Eaton et al., 2013).”

• cites Welinder and Ekblad, 2011 sourceNot checked — no full text of the source
• cites Aldridge et al., 2008 sourceNot checked — no full text of the source
• cites Eaton et al., 2013 sourceSupported

May combine two claims.

At P15, DYRK1A was significantly overexpressed in the hippocampus, cerebral cortex, and cerebellum of male Ts65Dn mice compared to euploid littermate controls; expression in P15 females was not significantly higher in any brain region tested.

“At P15, DYRK1A was significantly overexpressed in the hippocampus, cerebral cortex, and cerebellum of male Ts65Dn mice compared to euploid littermate controls; expression in P15 females was not significantly higher in any brain region tested (Hawley et al., 2022).”

• cites Hawley et al., 2022 sourceSupported

May combine two claims.

Total protein as a loading control can provide a more consistent measure for sample normalization than use of a single housekeeping protein, as it may show better linearity with variation in protein loading and controls for differences in protein transfer to the membrane during Western blot.

“The choice to use total protein as a loading control was informed by demonstrations that it can provide a more consistent measure for sample normalization than use of a single housekeeping protein, as it may show better linearity with variation in protein loading (Eaton et al., 2013) and it controls for differences in protein transfer to the membrane during the Western blot procedure (Welinder and”

• cites Eaton et al., 2013 sourceSupported
• cites Welinder and Ekblad, 2011 sourceNot checked — no full text of the source

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

Ts65Dn mouse brain/tissue at 5 months of age yielded no difference in Dyrk1a mRNA expression, but at 12 months Dyrk1a expression was elevated in Ts65Dn mice compared to controls.

“Ts65Dn mouse brain/tissue at 5 months of age yielded no difference in Dyrk1a mRNA expression, but at 12 months Dyrk1a expression was elevated in Ts65Dn mice compared to controls (Choi et al., 2009).”

• cites Choi et al., 2009 sourceSupported

May combine two claims.

The new data show that similar sex differences extended to P18 (except for cerebral cortex), P21, and P24, implicating important sex differences in DYRK1A levels in Ts65Dn mice that emerge during the third postnatal week.

“The P15 data were included in our previous report (Hawley et al., 2022), and the new data show that similar sex differences extended to P18 (except for cerebral cortex), P21, and P24, implicating important sex differences in DYRK1A levels in Ts65Dn mice that emerge during the third postnatal week.”

• cites Hawley et al., 2022 sourceSupported

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

A study of the circulating proteome did not test for differences in DYRK1A protein expression specifically but did find differences in protein expression in general between males and females.

“A study of the circulating proteome did not test for differences in DYRK1A protein expression specifically but did find differences in protein expression in general between males and females (Sullivan et al., 2017).”

• cites Sullivan et al., 2017 sourceSupported

May combine two claims.

Ts65Dn male mice group housed and given chronic daily gavage of EGCG or vehicle for three weeks starting on P42 showed increased DYRK1A expression at P68 only in the cerebral cortex and not in the cerebellum or hippocampus.

“In contrast, Ts65Dn male mice group housed and given chronic daily gavage of EGCG or vehicle for three weeks starting on P42 showed increased DYRK1A expression at P68 only in the cerebral cortex and not in the cerebellum or hippocampus (Goodlett et al., 2020).”

• cites Goodlett et al., 2020 sourcePartly supported

  The Results (DYRK1A protein levels; page unavailable) report higher DYRK1A protein levels in 68-day-old trisomic males only in the cerebral cortex, compared with euploid mice; EGCG had no significant effect. The Methods (Animals and EGCG treatment; pages unavailable) confirm group housing and daily EGCG or vehicle gavage from P42, but treatment continued through P68—about 26 days, not three weeks. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

DYRK1A protein levels were significantly increased 1.3 to 1.8-fold in homogenized brains of 7 to 8-month-old Ts65Dn as compared to control mice.

“DYRK1A protein levels were also significantly increased 1.3 to 1.8-fold in homogenized brains of 7 to 8-month-old Ts65Dn as compared to control mice (Dowjat et al., 2007).”

• cites Dowjat et al., 2007 sourceSupported

May combine two claims.

DYRK1A was elevated in P15 Ts65Dn male but not female mice.

“Furthermore, we recently showed that DYRK1A was elevated in P15 Ts65Dn male but not female mice (Hawley et al., 2022).”

• cites Hawley et al., 2022 sourceSupported

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

DYRK1A expression in the cerebellum, hippocampus, and cerebral cortex of 2 to 3-month Ts65Dn and control mice showed that DYRK1A was not overexpressed in the cerebellum or hippocampus but was overexpressed in the cerebral cortex of Ts65Dn mice.

“DYRK1A expression in the cerebellum, hippocampus, and cerebral cortex of 2 to 3-month Ts65Dn and control mice showed that DYRK1A was not overexpressed in the cerebellum or hippocampus but was overexpressed in the cerebral cortex of Ts65Dn mice (Goodlett et al., 2020; Stringer et al., 2017a).”

• cites Goodlett et al., 2020 sourceSupported
• cites Stringer et al., 2017aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

DYRK1A may self-regulate by autophosphorylation, which may enhance its own kinase activity while reducing its degradation.

“DYRK1A may also self-regulate by autophosphorylation which may enhance its own kinase activity while reducing its degradation (Atas-Ozcan et al., 2021).”

• cites Atas-Ozcan et al., 2021 sourceSupported

Probably not a substantial claim: may not pass S2 (checkable).

A targeted gene or set of genes hypothesized to have a major influence on a phenotype due to overexpression in DS may be a therapeutic focus.

“Alternatively, a targeted gene or set of genes hypothesized to have a major influence on a phenotype due to overexpression in DS may be a therapeutic focus (Korbel et al., 2009; Lyle et al., 2009).”

• cites Korbel et al., 2009 sourcePartly supported

  The Results and Discussion link increased chromosome 21 gene dosage to Down syndrome phenotypes and describe using the map to refine candidate genes. They do not propose targeting those genes as a therapeutic approach; the therapeutic-focus portion of the claim is not supported by our copy. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites Lyle et al., 2009 sourcePartly supported

  The Introduction and Genotype–phenotype correlations section say that identifying chromosome 21 genes or small regions contributing to specific Down syndrome phenotypes is a goal of the research. They do not propose targeting those genes as a therapeutic approach or establish that overexpression of a particular gene or set of genes has a major influence on a phenotype. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

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

The substrates regulated by DYRK1A phosphorylation are located in both the nucleus and cytosol, and this regulation is likely to be tissue- and time-specific.

“The substrates regulated by DYRK1A phosphorylation are located in both the nucleus and cytosol, and this regulation is likely to be tissue and time-specific (Arron et al., 2006; Chen-Hwang et al., 2002; de Graaf et al., 2004; Kaczmarski et al., 2014; Marti et al., 2003; Woods et al., 2001).”

• cites Arron et al., 2006 sourceNot checked — no full text of the source
• cites Chen-Hwang et al., 2002 sourcePartly supported

  The Results and Discussion (pages unavailable) identify DYRK1A-phosphorylated substrates in rat-brain cytosol, including dynamin 1. The paper also lists potential substrates such as transcription factors, but does not establish that the substrates it studies are located in both the nucleus and cytosol or that DYRK1A phosphorylation regulates them in a tissue- and time-specific manner. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites de Graaf et al., 2004 sourcePartly supported

  The introductory passage (labeled Abstract in our copy; page unavailable) identifies nuclear transcription factors as DYRK1A substrates and says cytoplasmic proteins have been reported to be phosphorylated by DYRK1A, while cautioning that those proteins might instead be targets of DYRK2 or DYRK3. The Discussion identifies additional nuclear substrates. Neither passage supports the claim that DYRK1A phosphorylation is likely to be tissue- and time-specific. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

DYRK1A/Dyrk1a overexpression results in more cells in the G1/0 phase versus S or G2/M phase, leading to cell proliferation deficits, premature cell exit and differentiation, and the nuclear export of Cyclin D1.

“In addition, DYRK1A/Dyrk1a overexpression results in more cells in the G1/0 phase versus S or G2/M phase, leading to cell proliferation deficits, premature cell exit and differentiation, and the nuclear export of Cyclin D1 (Najas et al., 2015; Soppa et al., 2014).”

• cites Najas et al., 2015 sourcePartly supported

  The Results (page unavailable) show that DYRK1A-overexpressing mouse radial-glial progenitors have longer G1 and S phases and reduced nuclear Cyclin D1. They do not show that a larger fraction of cells is in G1/G0 rather than S or G2/M, or directly demonstrate Cyclin D1 export in these embryos. The reported premature cell exit and differentiation are not supported: the Results report similar cell-cycle exit rates at E14.5 and fewer differentiating neurons early in neurogenesis. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Soppa et al., 2014 sourceSupported

May combine two claims.

Transient expression of Dyrk1a could promote cell cycle exit, and its subsequent downregulation allows cells to undergo neuronal differentiation.

“Thus, the transient expression of Dyrk1a could promote cell cycle exit, and its subsequent down regulation allows cells to undergo neuronal differentiation (Hammerle et al., 2008; Hammerle et al., 2011).”

• cites Hammerle et al., 2008 sourceNot checked — no full text of the source
• cites Hammerle et al., 2011 sourceSupported

May combine two claims.

Normalization of Dyrk1a copy number restored levels of Cyclin D1, the number of intermediate progenitors, and the production of neurons at multiple developmental time points.

“Normalization of Dyrk1a copy number restored levels of Cyclin D1, the number of intermediate progenitors, as well as the production of neurons at multiple developmental time points (Najas et al., 2015).”

• cites Najas et al., 2015 sourceSupported

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

Post transcriptional regulation and turnover, especially of trisomic proteins, was shown to account for differences between transcriptome and proteome products.

“Post transcriptional regulation and turnover, especially of trisomic proteins, was shown to account for differences between transcriptome and proteome products.”

• cites Liu et al., 2017 sourceSupported

Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

Overexpression of DYRK1A is hypothesized to cause cell cycle dysregulation in mouse models of DS, including at the G1/S phase.

“an overexpression of DYRK1A (observed in the current study) is hypothesized to cause cell cycle dysregulation in mouse models of DS (Haydar and Reeves, 2012) including the G1/S phase”

• cites Haydar and Reeves, 2012 sourcePartly supported

  In “The dorsal forebrain phenotype: under-production of excitatory neurons” (page not provided), the paper says DYRK1A is triplicated in DS and several mouse models, and reports that Dyrk1a overexpression inhibits neural-precursor proliferation and promotes premature differentiation. It links this effect partly to Cyclin D1 degradation, but does not specifically identify dysregulation at the G1/S phase. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

Changes in mRNA and protein levels correlated only weakly both when assessing individuals with DS as compared to those without DS and when comparing a discordant trisomic twin pair.

“changes only correlated weakly both when assessing individuals with DS as compared to those without DS and when comparing a discordant trisomic twin pair”

• cites Liu et al., 2017 sourceSupported

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

DYRK1A can phosphorylate and possibly regulate Cyclin D1 (G1-to-S phase transition and cell proliferation) and p27 (neuronal differentiation and cell cycle exit).

“This mechanism of action could be attributed to the ability of DYRK1A to phosphorylate and possibly regulate Cyclin D1 (G1-to-S phase transition and cell proliferation) and p27 (neuronal differentiation and cell cycle exit) (Frank and Tsai, 2009; Hindley and Philpott, 2012; Najas et al., 2015; Tejedor and Hammerle, 2011).”

• cites Frank and Tsai, 2009 sourcePartly supported

  The Cell cycle section describes cyclin D complexes promoting G1 progression, and the Neuronal differentiation and migration section links p27Kip1 to neuronal differentiation and inhibition of G1 CDKs (page numbers unavailable). But no passage found for DYRK1A phosphorylating or regulating either protein; the paper instead describes CDK5 phosphorylating p27Kip1. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites Hindley and Philpott, 2012 sourcePartly supported

  The Cyclins and CDKis sections (page numbers unavailable) link cyclin D1 to proliferation and p27kip1 to neuronal differentiation and cell-cycle exit. They do not say that DYRK1A phosphorylates or regulates either protein, so the proposed mechanism is not supported by this source. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites Najas et al., 2015 sourcePartly supported

  The Results show that DYRK1A phosphorylates Cyclin D1 at T286 and links reduced Cyclin D1 to altered cell-cycle progression in neural progenitors (page unavailable). The Discussion mentions reports of increased p27 levels in cell culture, but does not show DYRK1A phosphorylating p27; it found no p27 change in the embryos studied and identifies Cyclin D1, not p27, as the likely mediator. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S1 (asserted). May combine two claims.

Overexpression of DYRK1A is hypothesized to alter developmental trajectories and cause cognitive, skeletal, and other DS-related phenotypes.

“the overexpression of DYRK1A is hypothesized to alter developmental trajectories and cause cognitive, skeletal, and other DS-related phenotypes (Duchon and Herault, 2016)”

• cites Duchon and Herault, 2016 sourcePartly supported

  The “Dyrk1A Dosage and Neurodevelopmental Diseases” section says DYRK1A overexpression contributes to DS cognitive dysfunction, while the “DYRK1A Dosage Variation and Impact on Cellular and Molecular Mechanisms” section describes altered neuronal differentiation and other developmental effects. Neither section links overexpression to skeletal phenotypes, so that part of the attributed claim is unsupported by our copy (no page numbers are available). (LLM, conf=0.85)

  Experimental — accuracy not yet measured

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

With the development of the Ts66Yah and other DS mouse models, the contributions of these non-Hsa21 genes are becoming understood.

“With the development of the Ts66Yah and other DS mouse models, the contributions of these non-Hsa21 genes are becoming understood (Duchon et al., 2022; Xing et al., 2023).”

• cites Duchon et al., 2022 sourceSupported
• cites Xing et al., 2023 sourceSupported

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

The majority of therapeutics to date administered to Ts65Dn mice across ages have targeted specific neurotransmitter systems or aberrant neural pathways, based on their contribution to cognitive and behavioral phenotypes.

“The majority of therapeutics to date administered to Ts65Dn mice across ages have targeted specific neurotransmitter systems or aberrant neural pathways, based on their contribution to cognitive and behavioral phenotypes (Lorenzon et al., 2023).”

• cites Lorenzon et al., 2023 sourcePartly supported

  In “What this paper adds” (page unavailable), the review says neurotransmitter-based therapies were long the most popular symptomatic treatments and links neurotransmitter dysfunction to cognitive impairment in Down syndrome. Its account of preclinical research concerns Down syndrome mouse models generally; it does not establish that a majority of treatments administered to Ts65Dn mice across ages targeted neurotransmitter systems or aberrant neural pathways. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

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

In trisomic fibroblasts, some trisomic transcripts were upregulated but the corresponding proteins were not (or vice versa), and those differences are hypothesized to reflect post transcriptional regulation, maintenance of stoichiometry of protein complexes, or buffering.

“Others have shown in trisomic fibroblasts that some trisomic transcripts were upregulated but the corresponding proteins were not (or vice versa), and hypothesize those differences reflect post transcriptional regulation, maintenance of stoichiometry of protein complexes, or buffering (Liu et al., 2017).”

• cites Liu et al., 2017 sourceSupported

May combine two claims.

Ts65Dn E11.5 embryos contain 1.5-fold more DYRK1A protein and display significant decreases in Cyclin D1 levels.

“Ts65Dn E11.5 embryos contain 1.5-fold more DYRK1A protein and display significant decreases in Cyclin D1 levels.”

• cites Najas et al., 2015 sourceSupported

May combine two claims.

An unexpected significant sex difference was seen on P6 in the effects of functional reduction of Dyrk1a in euploid mice (from two to one copy), in which females showed significant reductions in DYRK1A expression in all three brain regions whereas males showed no significant changes in any region.

“Fourth, an unexpected significant sex difference was seen on P6 in the effects of functional reduction of Dyrk1a in euploid mice (from two to one copy), in which females showed significant reductions in DYRK1A expression in all three brain regions whereas males showed no significant changes in any region.”

May combine two claims.

On P15, Ts65Dn males showed significant overexpression compared to euploid littermates in all three brain regions, with increases in the hippocampus (1.4-fold, p = 0.009), cerebral cortex (1.9-fold, p < 0.001), and cerebellum (2.1-fold, p = 0.007).

“In contrast, P15 Ts65Dn males showed significant overexpression as compared to euploid littermates in all three brain regions, with increases in the hippocampus (1.4-fold, p = 0.009), cerebral cortex (1.9-fold, p < 0.001), and cerebellum (2.1-fold, p = 0.007) (Fig. 1F).”

May combine two claims.

The large increase in mRNA expression in trisomic P0 males in both forebrain and cerebellum contrasts with the lack of significant protein overexpression in the same animals in either region, and this mismatch was confirmed by the lack of significant correlation between mRNA and protein in either brain region (r = +0.18 for forebrain; r = 0.0 for cerebellum) in trisomic P0 males.

“The large increase in mRNA expression in trisomic P0 males in both forebrain and cerebellum (Fig. 3D) contrasts with the lack of significant protein overexpression in the same animals in either region (Fig. 1B), and this mismatch was confirmed by the lack of significant correlation between mRNA and protein in either brain region (r = +0.18 for forebrain; r = 0.0 for cerebellum) in trisomic P0”

May combine two claims.

At P12, DYRK1A expression was significantly upregulated in male Ts65Dn in the hippocampus (1.2-fold, p = 0.010) and cerebellum (1.2-fold, p = 0.014), but did not reach significance in the cerebral cortex.

“In males, DYRK1A expression was significantly upregulated in the hippocampus (1.2-fold, p = 0.010) and in cerebellum (1.2-fold, p = 0.014), but did not reach significance in the cerebral cortex.”

May combine two claims.

For trisomic females, the largest mean increase in DYRK1A expression relative to euploid littermates was on P6 (mean fold increases of 2.49, 2.90, 2.79 for hippocampus, cortex, and cerebellum, respectively) and P6 also showed the most variable expression levels (CVs = 0.73, 0.28, 0.68, respectively).

“Notably, for trisomic females the largest mean increase in DYRK1A expression relative to euploid littermates was on P6 (mean fold increases of 2.49, 2.90, 2.79 for hippocampus, cortex, and cerebellum, respectively) and P6 also showed the most variable expression levels (CVs = 0.73, 0.28, 0.68, respectively).”

May combine two claims.

In the female Ts65Dn,Dyrk1a+/+/− offspring with two copies of Dyrk1a on an otherwise trisomic mouse, DYRK1A levels were significantly reduced relative to Ts,Dyrk1a+/+/+ mice in the cerebellum (p = 0.024; d = 1.21), and the Ts,Dyrk1a+/+/− levels were comparable to Eu,Dyrk1a+/+ littermates.

“In the female Ts65Dn,Dyrk1a+/+/− offspring with two copies of Dyrk1a on an otherwise trisomic mouse, DYRK1A levels were significantly reduced relative to Ts,Dyrk1a+/+/+ mice in the cerebellum (p = 0.024; d = 1.21), and the Ts,Dyrk1a+/+/− levels were comparable to Eu,Dyrk1a+/+ littermates.”

May combine two claims.

At P15, male offspring of (Ts65Dn × Dyrk1a+/−) matings showed DYRK1A expression that was significantly higher in male Ts,Dyrk1a+/+/+ compared to Eu, Dyrk1a+/+ littermates in the cerebral cortex (p = 0.037; d = 1.23) and non-significant increases in the cerebellum (p = 0.113; d = 1.06).

“At P15, an age when elevated DYRK1A levels were present in male but not female trisomic mice in the developmental study, male offspring of (Ts65Dn × Dyrk1a+/−) matings (Fig. 2D) showed DYRK1A expression that was significantly higher in male Ts,Dyrk1a+/+/+ compared to Eu, Dyrk1a+/+ littermates in the cerebral cortex (p = 0.037; d = 1.23) and non-significant increases in the cerebellum (p = 0.113; d”

May combine two claims.

Ts65Dn males at P0 showed significant elevations in Dyrk1a mRNA compared to euploid littermates in both the forebrain (3.3-fold; p = 0.004, d = 1.56) and the cerebellum (4.3-fold; p = 0.005, d = 1.48).

“Ts65Dn males at P0 (Fig. 3D) showed significant and large elevations as compared to euploid littermates in both the forebrain (3.3-fold; p = 0.004, d = 1.56) and the cerebellum (4.3-fold; p = 0.005,d = 1.48).”

May combine two claims.

For male Ts65Dn mice, the first day of significant DYRK1A overexpression was on P6 (mean fold increases of 3.28, 3.12, 2.25, and CVs of 0.49, 0.77, 0.54, respectively) and DYRK1A remained significantly elevated at all subsequent ages except for P12 cortex.

“For male Ts65Dn mice, the first day of significant DYRK1A overexpression was on P6 (Fig. 1D, mean fold increases of 3.28, 3.12, 2.25, and CVs of 0.49, 0.77, 0.54, respectively) and DYRK1A remained significantly elevated at all subsequent ages except for P12 cortex.”

May combine two claims.

There was a general concordance of overexpression of Dyrk1a mRNA and protein at P6, and the changes in magnitude were more similar in females than males.

“There was a general concordance of overexpression of Dyrk1a mRNA and protein at P6, and the changes in magnitude were more similar in females than males.”

May combine two claims.

Dyrk1a copy number reduction in the male euploid mice (Eu,Dyrk1a+/−) did not significantly affect DYRK1A expression in the cerebral cortex or cerebellum, but there was a trend toward significance in the hippocampus (p = 0.062; d = 0.97).

“Dyrk1a copy number reduction in the male euploid mice (Eu,Dyrk1a+/−) did not significantly affect DYRK1A expression in the cerebral cortex or cerebellum, but there was a trend toward significance in the hippocampus (p = 0.062; d = 0.97).”

May combine two claims.

For female mice on P6, there was significant overexpression of DYRK1A in the Ts65Dn (Ts,Dyrk1a+/+/+) as compared to euploid (Eu, Dyrk1a+/+) offspring in the cerebellum (p = 0.032; d = 0.85) and trends for overexpression in the hippocampus (p = 0.093; d = 0.59) and cerebral cortex (p = 0.076; d = 0.64).

“For female mice on P6 (Fig. 2A), there was significant overexpression of DYRK1A in the Ts65Dn (Ts,Dyrk1a+/+/+) as compared to euploid (Eu, Dyrk1a+/+) offspring in the cerebellum (p = 0.032; d = 0.85) and trends for overexpression in the hippocampus (p = 0.093; d = 0.59) and cerebral cortex (p = 0.076; d = 0.64).”

May combine two claims.

Notable exceptions of multi-region upregulation included the lack of overexpression in the P12 female cerebellum despite upregulation in hippocampus and cerebral cortex, and significant overexpression in female P18 cerebral cortex but not the other regions.

“Notable exceptions of multi-region upregulation included the lack of overexpression in the P12 female cerebellum despite upregulation in hippocampus and cerebral cortex, and significant overexpression in female P18 cerebral cortex but not the other regions.”

May combine two claims.

Functional reduction of one copy of Dyrk1a (Ts,Dyrk1a+/+/−) significantly reduced DYRK1A as compared to male Ts,Dyrk1a+/+/+ mice in the cerebral cortex (p = 0.005) and cerebellum (p = 0.002), yielding large effect sizes (d = 1.96 and 2.24, respectively) and trending in the hippocampus (0.082; d = 0.92), reaching levels approximating those of euploid males.

“Functional reduction of one copy of Dyrk1a (Ts,Dyrk1a+/+/−) significantly reduced DYRK1A as compared to male Ts,Dyrk1a+/+/+ mice in the cerebral cortex (p = 0.005) and cerebellum (p = 0.002), yielding large effect sizes (d = 1.96 and 2.24, respectively) and trending in the hippocampus (0.082; d = 0.92), reaching levels approximating those of euploid males.”

May combine two claims.

During the perinatal period, female trisomic mice showed significant increases in DYRK1A relative to euploid littermates (~1.5-fold) whereas males did not.

“During the perinatal period, female trisomic mice showed significant increases in DYRK1A relative to euploid littermates (~1.5-fold) whereas males did not.”

May combine two claims.

Reduction of Dyrk1a copy number in female euploid mice (Eu, Dyrk1a+/−) significantly reduced DYRK1A in all three regions as compared to Eu,Dyrk1a+/+ mice, down to 43% of control in hippocampus (p = 0.004, d = 1.59), 58% of control in cerebral cortex (p = 0.030, d = 0.78), and 58% of control in cerebellum (p = 0.047, d = 0.93).

“Reduction of Dyrk1a copy number in female euploid mice (Eu, Dyrk1a+/−) significantly reduced DYRK1A in all three regions as compared to Eu,Dyrk1a+/+ mice, down to 43% of control in hippocampus (p = 0.004, d = 1.59), 58% of control in cerebral cortex (p = 0.030, d = 0.78), and 58% of control in cerebellum (p = 0.047, d = 0.93).”

May combine two claims.

For the females at P15, there were no significant group differences in any brain region, though there were non-significant trends toward increased expression in the hippocampus in Ts, Dyrk1a+/+/+ as compared to Eu,Dyrk1a+/+ females (p = 0.073; d = 0.87) and for the euploid knockdown to reduce hippocampal DYRK1A relative to Eu,Dyrk1a+/+ (p = 0.054; d = 0.98).

“For the females at P15 (Fig. 2C), there were no significant group differences in any brain region, though there were non-significant trends toward increased expression in the hippocampus in Ts, Dyrk1a+/+/+ as compared to Eu,Dyrk1a+/+ females (p = 0.073; d = 0.87) and for the euploid knockdown to reduce hippocampal DYRK1A relative to Eu,Dyrk1a+/+ (p = 0.054; d = 0.98).”

May combine two claims.

The Ts,Dyrk1a+/+/+ male mice showed significant increases in Dyrk1a mRNA expression relative to the Eu,Dyrk1a+/+ mice in all three regions: hippocampus [2.6-fold; p ≤0.001, d = 2.6]; cerebral cortex [2.0-fold; p = 0.017, d = 1.4]; cerebellum [2.6-fold; p = 0.021, d = 1.5].

“As shown in Fig. 4, The Ts,Dyrk1a+/+/+ male mice showed significant increases in mRNA expression relative to the Eu,Dyrk1a+/+ mice in all three regions: hippocampus [2.6-fold; p ≤0.001, d = 2.6]; cerebral cortex [2.0-fold; p = 0.017, d = 1.4]; cerebellum [2.6-fold; p = 0.021, d = 1.5].”

May combine two claims.

Sex differences in the opposite direction were evident on and after P15, with only male trisomic mice showing significant DYRK1A overexpression.

“Sex differences in the opposite direction were evident on and after P15, with only male trisomic mice showing significant DYRK1A overexpression.”

May combine two claims.

For trisomic males, DYRK1A overexpression in both the cerebral cortex and the cerebellum were significantly greater than in the hippocampus (Bonferroni comparisons, p < 0.001 and p = 0.014, respectively).

“For trisomic males, DYRK1A overexpression in both the cerebral cortex and the cerebellum were significantly greater than in the hippocampus (Bonferroni comparisons, p < 0.001 and p = 0.014, respectively).”

May combine two claims.

At P12, DYRK1A was upregulated in female Ts65Dn compared to euploid littermates in the hippocampus (1.5-fold, p = 0.001) and cerebral cortex (1.3-fold, p = 0.026), with no significant differences in cerebellum.

“At P12 (Fig. 1E), DYRK1A was upregulated in female Ts65Dn as compared to euploid littermates in the hippocampus (1.5-fold, p = 0.001) and cerebral cortex (1.3-fold, p = 0.026), with no significant differences in cerebellum.”

May combine two claims.

Reduction of Dyrk1a copy number in the otherwise trisomic males (Ts, Dyrk1a+/+/−) significantly reduced DYRK1A levels relative to Ts, Dyrk1a+/+/+ males in all three regions (p = 0.035 for hippocampus; p = 0.002 for cerebral cortex; p = 0.006 for cerebellum), and the Ts, Dyrk1a+/+/− levels were comparable to levels found in Eu,Dyrk1a+/+ littermates.

“Reduction of Dyrk1a copy number in the otherwise trisomic males (Ts, Dyrk1a+/+/−) significantly reduced DYRK1A levels relative to Ts, Dyrk1a+/+/+ males in all three regions (p = 0.035 for hippocampus; p = 0.002 for cerebral cortex; p = 0.006 for cerebellum), and the Ts, Dyrk1a+/+/− levels were comparable to levels found in Eu,Dyrk1a+/+ littermates.”

May combine two claims.

On P3, trisomic females showed significant elevated DYRK1A in the forebrain (p = 0.028; d = 1.04) and approached significance in the cerebellum (p = 0.051; d = 0.88).

“On P3, trisomic females continued to show elevated DYRK1A that was significant in the forebrain (p = 0.028; d = 1.04) and approached significance in the cerebellum (p = 0.051; d = 0.88), whereas the males continued to show no significant differences in either region (Fig. 1C).”

May combine two claims.

In the comparisons of Ts,Dyrk1a+/+/+ and Ts,Dyrk1a+/+/− P6 males, no significant differences in mRNA expression were found between the two in any brain region, but levels of DYRK1A were significantly reduced (to near euploid levels) in all three regions in the Ts,Dyrk1a+/+/− mice.

“Also note the stark contrast in outcomes of mRNA and protein levels in the comparisons of Ts,Dyrk1a+/+/+ and Ts,Dyrk1a+/+/− P6 males: no significant differences in mRNA expression were found between the two in any brain region, but levels of DYRK1A were significantly reduced (to near euploid levels) in all three regions in the Ts,Dyrk1a+/+/− mice.”

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

Regions of disproportionately small brain volume in DS include the cerebrum, cerebellum, and hippocampus.

“Cognitive impairment is a hallmark DS phenotype affecting all individuals with Ts21 (Antonarakis et al., 2020) with regions of disproportionately small brain volume including the cerebrum, cerebellum, and hippocampus (Aylward et al., 1999; Kesslak et al., 1994; Pinter et al., 2001; Raz et al., 1995; Weis et al., 1991).”

• cites Aylward et al., 1999 sourceNot checked — no full text of the source
• cites Kesslak et al., 1994 sourceNot checked — no full text of the source
• cites Pinter et al., 2001 sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

DYRK1A is a leading candidate among Hsa21 genes identified as possible regulators of neurogenesis and long-term cognitive function.

“Among the genes on Hsa21 that have been identified as possible regulators of neurogenesis and long-term cognitive function, a leading candidate is Dual-specificity tyrosine-phosphorylated regulated kinase 1A (DYRK1A).”

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

Brains of 20-week-old fetuses with DS showed 1.5-fold upregulation of DYRK1A RNA.

“Brains of 20-week-old fetuses with DS showed 1.5-fold upregulation of DYRK1A RNA and brains of adult Ts65Dn mice showed a 2.1-fold increase of Dyrk1a RNA expression (Guimera et al., 1999).”

• cites Guimera et al., 1999 sourceNot checked — no full text of the source

May combine two claims.

Reducing DYRK1A protein levels in the hippocampus of 2-month-old Ts65Dn mice by stereotaxic injection of AAV-shDyrk1a improved synaptic plasticity but only corrected thigmotaxic abnormalities in the Morris water maze.

“Reducing DYRK1A protein levels in the hippocampus of 2-month-old Ts65Dn mice by stereotaxic injection of AAV-shDyrk1a improved synaptic plasticity but only corrected thigmotaxic abnormalities in the Morris water maze (Altafaj et al., 2013).”

• cites Altafaj et al., 2013 sourceNot checked — no full text of the source

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

Trisomic Dyrk1a has been implicated in the development of cerebellar granule and Purkinje cell neurons by its influence on the Sonic Hedgehog pathway.

“Trisomic Dyrk1a has been implicated in the development of cerebellar granule and Purkinje cell neurons by its influence on the Sonic Hedgehog pathway (Roper et al., 2006a) and in neuronal proliferation and cell cycle control in individuals with DS and DS mouse models (Stagni et al., 2018).”

• cites Roper et al., 2006aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

Sex is recognized as a contributing factor in brain development and differences between male and female gene expression are being reported more frequently in DS research.

“Sex is recognized as a contributing factor in brain development and differences between male and female gene expression are being reported more frequently in DS research.”

May combine two claims.

Results from this developmental study demonstrate spatial, temporal, and sex-specific expression of DYRK1A in a trisomic system.

“Results from this developmental study of trisomic Dyrk1a overexpression in the Ts65Dn DS mouse model demonstrate spatial, temporal, and sex-specific expression of DYRK1A in a trisomic system.”

May combine two claims.

During the perinatal period, DYRK1A is upregulated approximately 1.5-fold in female developing brain, but not male Ts65Dn as compared to control mice.

“Taken together, these data suggest that during the perinatal period DYRK1A is upregulated approximately 1.5-fold in female developing brain, but not male Ts65Dn as compared to control mice.”

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

Classically, the organizational effects of fetal sex steroids were produced during time-limited critical periods to shape enduring differences in male and female brain structure and function.

“Classically, the organizational effects of fetal sex steroids were produced during time-limited critical periods to shape enduring differences in male and female brain structure and function (Morris et al., 2004).”

• cites Morris et al., 2004 sourceNot checked — no full text of the source

May combine two claims.

To date, these data are the only reports of sex-specific DYRK1A expression in DS mouse models, emphasizing the limited analysis of effects sex has on protein or transcript quantities in trisomy and the importance of the demonstrated sex differences in DYRK1A expression in the developing brain in the current study.

“To date, these data are the only reports of sex-specific DYRK1A expression in DS mouse models, emphasizing the limited analysis of effects sex has on protein or transcript quantities in trisomy and the importance of the demonstrated sex differences in DYRK1A expression in the developing brain in the current study.”

May combine two claims.

The current study confirms that relative expression varies depending on the age of developing trisomic mice, suggesting that expression of triplicated Dyrk1a is controlled in a temporally specific manner-being overexpressed at some developmental ages and not at others.

“The current study confirms that relative expression varies depending on the age of developing trisomic mice, suggesting that expression of triplicated Dyrk1a is controlled in a temporally specific manner—being overexpressed at some developmental ages and not at others.”

May combine two claims.

Sex-dependent differences in DYRK1A expression that emerged by P15 in the developmental study were partially replicated at P15 in this constitutive knockdown study, such that trisomic males showed significant DYRK1A overexpression in the cerebral cortex in both studies whereas no significant differences in any brain region were evident in P15 females in either study.

“Second, sex-dependent differences in DYRK1A expression that emerged by P15 in the developmental study were partially replicated at P15 in this constitutive knockdown study, such that trisomic males showed significant DYRK1A overexpression in the cerebral cortex in both studies whereas no significant differences in any brain region were evident in P15 females in either study.”

The quote only partly states this claim.

Collectively, these contrasting outcomes both at P6 and at P15 all suggest the presence of emerging sex differences in developmental regulation of brain DYRK1A expression in a manner that depends on Dyrk1a gene copy number.

“Collectively, these contrasting outcomes both at P6 (trisomic overexpression in both sexes that requires three functional copies, but differences between sexes in euploid mice with one functional copy in which only females showed haploinsufficiency effects)”

May combine two claims.

Significant cerebellar deficits have been found in Ts65Dn mice at P6 and abnormal trisomic cerebellar development has been a therapeutic target at this stage; the hippocampus is also altered at P6 in Ts65Dn mice.

“Significant cerebellar deficits have been found in Ts65Dn mice at P6 and abnormal trisomic cerebellar development has been a therapeutic target at this stage (Das et al., 2013; Roper et al., 2006a); the hippocampus is also altered at P6 in Ts65Dn mice (Lorenzi and Reeves, 2006).”

• cites Das et al., 2013Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Roper et al., 2006aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Lorenzi and Reeves, 2006 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S2 (checkable).

These varied but limited results underscore the need for a systematic, longitudinal, tissue and sex-specific quantification of DYRK1A expression, especially at times when DYRK1A is thought to alter brain developmental processes.

“These varied but limited results underscore the need for a systematic, longitudinal, tissue and sex-specific quantification of DYRK1A expression, especially at times when DYRK1A is thought to alter brain developmental processes.”

• AssumptionRests on an assumption: Studies of a single trisomic gene, including DYRK1A, often lack systematic evaluation of multiple ages, both sexes, or multiple tissues.

May combine two claims.

The majority of previous studies of DYRK1A expression in DS mouse models have used adults and have reported significant elevations in DYRK1A protein levels, but many of these examined either whole brain homogenate or a single brain region.

“The majority of previous studies of DYRK1A expression in DS mouse models have used adults and have reported significant elevations in DYRK1A protein levels, but many of these examined either whole brain homogenate or a single brain region (reviewed in Stringer et al., 2017b).”

• cites Stringer et al., 2017bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

Brains of adult Ts65Dn mice showed a 2.1-fold increase of Dyrk1a RNA expression.

“Brains of 20-week-old fetuses with DS showed 1.5-fold upregulation of DYRK1A RNA and brains of adult Ts65Dn mice showed a 2.1-fold increase of Dyrk1a RNA expression (Guimera et al., 1999).”

• cites Guimera et al., 1999 sourceNot checked — no full text of the source

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

In 4 to 8-month-old Ts65Dn mice, DYRK1A was upregulated in the cortex, cerebellum, and hippocampus.

“In 4 to 8-month-old Ts65Dn mice, DYRK1A was upregulated in the cortex, cerebellum, and hippocampus (Ahmed et al., 2012).”

• cites Ahmed et al., 2012 sourceNot checked — no full text of the source

May combine two claims.

Sex-specific effects in trisomic DYRK1A overexpression were identified (in opposite directions) during two developmental periods, one in the perinatal period (E18.5-P3) and another in the third postnatal week (P15-P24).

“Sex-specific effects in trisomic DYRK1A overexpression were identified (in opposite directions) during two developmental periods, one in the perinatal period (E18.5-P3) and another in the third postnatal week (P15-P24).”

May combine two claims.

The lack of group differences in mRNA expression at P3 further highlights the developmental change in mRNA expression at P6, showing increases in trisomic mice of both sexes-generally consistent with the parallel emergence of the large increase in protein expression seen in trisomic mice at P6.

“The lack of group differences in mRNA expression at P3 further highlights the developmental change in mRNA expression at P6, showing increases in trisomic mice of both sexes—generally consistent with the parallel emergence of the large increase in protein expression seen in trisomic mice at P6.”

May combine two claims.

When treatment was given at birth to correct the cerebellar phenotype via a Sonic Hedgehog agonist, cerebellar structure was normalized and hippocampal-dependent learning, memory, and function were also improved.

“When treatment was given at birth to correct the cerebellar phenotype via a Sonic Hedgehog agonist, cerebellar structure was normalized and hippocampal-dependent learning, memory, and function were also improved (Das et al., 2013).”

• cites Das et al., 2013Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

At P68, Ts65Dn male mice maintained in individual cages after P25 showed no differences in DYRK1A in cerebral cortex and hippocampus but had significantly lower levels in the cerebellum as compared to euploid controls.

“At P68, Ts65Dn male mice maintained in individual cages after P25 showed no differences in DYRK1A in cerebral cortex and hippocampus but had significantly lower levels in the cerebellum as compared to euploid controls (Stringer et al., 2017a).”

• cites Stringer et al., 2017aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

The elevated DYRK1A protein at P6 could be directly affecting the observed hippocampal neurogenesis deficit via hyperphosphorylation of cell cycle proteins (i.e., Cyclin D1).

“which could be directly affecting the observed hippocampal neurogenesis deficit via hyperphosphorylation of cell cycle proteins (i.e., Cyclin D1)”

• AssumptionRests on an assumption: Connections between the well-established cortical, hippocampal, and cerebellar formation deficits in Ts65Dn mice and observable behavioral phenotypes at a specific age are not well understood.

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

At P5, DYRK1A is localized in the nucleus of cerebellar Purkinje cells in mice.

“At P5, DYRK1A was localized in the nucleus of cerebellar Purkinje cells (Hammerle et al., 2008)”

• cites Hammerle et al., 2008 sourceNot checked — no full text of the source

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

DYRK1A is expressed in non-trisomic ICR mice at several embryonic stages in cortical layers, forebrain neurons, and the nucleus of cells from the ventricular zone.

“DYRK1A is expressed in non-trisomic mice at several embryonic stages in cortical layers, forebrain neurons, and the nucleus of cells from the ventricular zone in ICR mice (Hammerle et al., 2008).”

• cites Hammerle et al., 2008 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Ts65Dn mice are the only DS mouse model currently characterized that exhibit early postnatal gene expression, neuroanatomical, and developmental behavioral deficits like those observed in DS.

“They are the only DS mouse model currently characterized that exhibit early postnatal gene expression, neuroanatomical, and developmental behavioral deficits like those observed in DS.”

• AssumptionRests on an assumption: Ts65Dn mice are the only DS mouse model currently characterized that exhibit early postnatal gene expression, neuroanatomical, and developmental behavioral deficits like those observed in DS.

May combine two claims.

The study is limited by its focus on tissue levels of DYRK1A; neither the cellular and sub-cellular localization of DYRK1A expression nor the kinase activity of DYRK1A was assessed.

“This study also is limited by its focus on tissue levels of DYRK1A; neither the cellular and sub-cellular localization of DYRK1A expression nor the kinase activity of DYRK1A was assessed”

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

Overexpression of DYRK1A protein may or may not follow overexpression of Dyrk1a mRNA due to posttranscriptional regulation including a lag in translation.

“Overexpression of DYRK1A protein may or may not follow overexpression of Dyrk1a mRNA due to posttranscriptional regulation including a lag in translation.”

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

Ts65Dn mice are one of many DS mouse models and have been the primary model used in DS preclinical neurobiological and neuro-behavioral research, including extensive use in testing therapies designed to normalize DS phenotypes.

“Ts65Dn mice are one of many DS mouse models and have been the primary model used in DS preclinical neurobiological and neuro-behavioral research, including extensive use in testing therapies designed to normalize DS phenotypes (Garcia-Cerro et al., 2017; Gardiner, 2015; Reeves et al., 1995).”

• cites Garcia-Cerro et al., 2017 sourceNot checked — no full text of the source
• cites Gardiner, 2015Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Reeves et al., 1995 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

As expression levels of trisomic genes are quantified, mRNA and protein levels could be different in any tissue at any developmental time.

“As expression levels of trisomic genes are quantified, mRNA and protein levels could be different in any tissue at any developmental time.”

May combine two claims.

The absence of a common protein homogenate standard limits the analyses to within-blot comparisons of trisomic samples relative to euploid samples (same sex, age, and brain region), precluding direct quantitative comparisons of changes in trisomic and euploid groups across age and sex.

“This limits our analyses to within-blot comparisons of trisomic samples relative to euploid samples (same sex, age, and brain region), precluding direct quantitative comparisons of changes in trisomic and euploid groups across age and sex.”

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

At P14, significant DYRK1A expression is detected in the external granular, molecular layer, and internal granule cell layer of the cerebral cortex.

“At P14, significant DYRK1A expression was detected in the external granular, molecular layer, and internal granule cell layer of the cerebral cortex (Marti et al., 2003).”

• cites Marti et al., 2003 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

Altered expression of DYRK1A at different points in development may lead to tissue- and sex-specific phenotypic alterations, necessitating differential gene-specific pharmacological treatments.

“Altered expression of DYRK1A at different points in development may lead to tissue- and sex-specific phenotypic alterations, necessitating differential gene specific pharmacological treatments.”

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

Newer DS mouse models may have more accurate face validity but may still lack many Hsa21 homologous genes.

“These newer models may have more accurate face validity but may still lack many Hsa21 homologous genes.”