EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery

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

Patients harboring EXOSC3 p.G31A present with absent tendon reflexes, significant neurogenic muscle atrophy, and survival typically limited to the first six months of life.

“patients harboring the EXOSC3 p.Gly31Ala (p.G31A) variant present with absent tendon reflexes, significant neurogenic muscle atrophy, and survival typically limited to the first six months of life25,36.”

• cites [25] sourcePartly supported

  The mutation-description passage (section labeled Abstract; page unavailable) identifies Gly31Ala in affected Families 4 and 9, and Methods > Clinical characterization reports neurogenic muscle atrophy in the PCH1 cohort. Our copy does not establish absent tendon reflexes or survival typically limited to six months for Gly31Ala carriers; the atrophy finding is not stated specifically for those carriers. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [36] sourceNot checked — no full text of the source

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

Catalytic activities of the RNA exosome are mediated by associated 3'−5' exonucleases EXOSC10 and DIS3 or accessory factors such as MTR4, while core components including EXOSC3 provide structural stability and facilitate substrate recognition and/or RNA threading.

“The catalytic activities of the RNA exosome are mediated by associated 3’−5’ exonucleases EXOSC10 and DIS3 or accessory factors such as the RNA helicase MTR4, while core components including EXOSC3 provide structural stability and facilitate substrate recognition and/or RNA threading through the protein complex core39–43.”

• cites [39] 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
• cites [40] sourcePartly supported

  Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites [41] 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
• cites [42] 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
• cites [43] 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

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

EXOSC3 encodes a core structural component of the RNA exosome complex and contains an RNA binding S1 domain, although weak RNA binding is displayed in vitro outside of the context of the full complex.

“EXOSC3 encodes a core structural component of the RNA exosome complex and contains an RNA binding S1 domain, although weak RNA binding is displayed in vitro outside of the context of the full complex38.”

• cites [38] sourcePartly supported

  The Structural overview section identifies yeast Rrp40 as an exosome subunit with an S1 domain, and the RNA-binding properties section reports little or no detectable RNA binding by isolated Rrp40 in vitro. The paper does not identify EXOSC3 or test its protein product directly; its full-complex binding experiment uses archaeal Rrp4 rather than Rrp40. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

The RNA exosome plays central roles in ribosomal RNA processing (rRNA) and defects in rRNA processing have been identified in yeast and fly models expressing EXOSC3 variants.

“The RNA exosome also plays central roles in ribosomal RNA processing (rRNA) and defects in rRNA processing have been identified in yeast and fly models expressing EXOSC3 variants15,48.”

• cites [15] sourceSupported
• cites [48] sourcePartly supported

  The Introduction identifies pre-rRNA processing as a major exosome function, and the Abstract reports defective pre-rRNA processing in yeast expressing EXOSC3/Rrp40p variants. This paper does not report an EXOSC3-variant fly model, so it supports the yeast portion but not the fly portion of the cited sentence. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

Variants in genes encoding several subunits of the RNA exosome complex have been linked to PCH, including EXOSC3 (PCH1B), EXOSC8 (PCH1C), EXOSC9 (PCH1D), and provisionally EXOSC1 (PCH1F).

“variants in genes encoding several subunits of the RNA exosome complex have been linked to PCH, including EXOSC3 (PCH1B), EXOSC8 (PCH1C), EXOSC9 (PCH1D), and provisionally EXOSC1 (PCH1F)15–25.”

• cites [15] sourcePartly supported

  The Introduction states that mutations in RNA exosome structural-subunit genes cause distinct PCH subtypes, and the Results explicitly link EXOSC3 to PCH1b. The References list disease-associated EXOSC8 and EXOSC9 variants, but our copy does not specify their PCH1C or PCH1D labels, or mention the proposed EXOSC1–PCH1F link (pages unavailable). (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [16] sourcePartly supported

  The Introduction links EXOSC3, EXOSC8 and EXOSC9 to subtypes of PCH type 1, and the Discussion proposes EXOSC1 as a candidate gene, supporting the provisional wording. Our copy does not specify the subtype labels PCH1B, PCH1C, PCH1D or PCH1F, so it does not verify those assignments. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [17] sourceNot checked — no full text of the source
• cites [18] sourcePartly supported

  The Introduction links EXOSC3 mutations to PCH1b. The References list studies concerning EXOSC8-associated cerebellar hypoplasia and EXOSC9-associated PCH1D, but the passages do not identify EXOSC8 as PCH1C or mention a provisional EXOSC1–PCH1F link. Those specific parts of the attributed list are not supported by our copy. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [19] sourceNot checked — no full text of the source
• cites [20] sourcePartly supported

  The Discussion identifies EXOSC3 variants as PCH1B and EXOSC8 variants as PCH1C, and proposes EXOSC9-associated disease as PCH1D (page unavailable). Our copy does not link EXOSC1 to PCH1F, even provisionally; the Introduction describes EXOSC1 only as a subunit of the exosome. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [21] sourceNot checked — no full text of the source
• cites [22] sourceCould not verify

  The Abstract identifies Exosc3 as an RNA exosome subunit, but discusses its role in mouse B cells, not pontocerebellar hypoplasia. Searches for PCH, pontocerebellar hypoplasia, and the specified gene–subtype links found no passage in our copy addressing the claimed disease associations. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [23] sourceNot checked — no full text of the source
• cites [24] sourcePartly supported

  The Discussion links EXOSC3 mutations to PCH1 and reports pathogenic EXOSC8 mutations in patients with cerebellar hypoplasia and spinal muscular atrophy. Our copy identifies EXOSC9 as an exosome subunit, but does not link EXOSC9 or EXOSC1 variants to PCH; it also does not give the listed PCH subtype labels. No page numbers are available in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

PCH1B patients who are carriers of compound heterozygous EXOSC3 D132A/G191D variants present with milder disease, without involving the pons, and show intrafamilial variability.

“PCH1B patients who are carriers of compound heterozygous EXOSC3 D132A/G191D variants present with milder disease, without involving the pons, and show intrafamilial variability23,53,54.”

• cites [23] sourceNot checked — no full text of the source
• cites [53] sourcePartly supported

  The Discussion (page unavailable) identifies D132A and G191D in patients with PCH1B and describes phenotypes associated with both variants as moderate. It reports those variants as homozygous in its patients, not as a D132A/G191D compound-heterozygous pair. The cited passages do not establish absence of pontine involvement or intrafamilial variability. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [54] sourceNot checked — no full text of the source

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

PCH1B is characterized by marked hypotonia, progressive cerebellar atrophy, and motor neuron dysfunction.

“PCH1B is a subtype characterized by marked hypotonia, progressive cerebellar atrophy, and motor neuron dysfunction and caused by variants in the EXOSC3 gene15,18,21–23,25.”

• cites [15] sourcePartly supported

  The Introduction identifies PCH1b as a pontocerebellar hypoplasia subtype linked to EXOSC3/Rrp40 variants, and the References list an EXOSC3 study whose title mentions spinal motor neuron degeneration. Our copy does not characterize PCH1b by marked hypotonia or progressive cerebellar atrophy; the Discussion’s progressive defects concern mushroom bodies in flies, not the human cerebellum. No page numbers were provided for these passages. (LLM, conf=0.81)

  Experimental — accuracy not yet measured
• cites [18] sourcePartly supported

  The Introduction (page not provided) describes PCH1b as caused by EXOSC3 mutations and characterized by cerebellar atrophy and spinal motor neuron degeneration. It does not specify marked hypotonia or say that the cerebellar atrophy is progressive. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [21] sourceNot checked — no full text of the source
• cites [22] sourceCould not verify

  The Methods (SHM) and Extended Data passages concern Exosc3 function in B cells, not PCH1B. Searches for PCH1B symptoms and EXOSC3-associated pontocerebellar hypoplasia found no passage in our copy addressing hypotonia, cerebellar atrophy, or motor neuron dysfunction. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [23] sourceNot checked — no full text of the source
• cites [25] sourcePartly supported

  The Methods’ Clinical characterization section (page unavailable) reports hypotonia from birth, prominent cerebellar atrophy, and confirmed spinal motor neuron disease; the Abstract links EXOSC3 mutations to PCH1. The paper describes progressive microcephaly and suggests a cerebellar degenerative process, but these passages do not establish that the cerebellar atrophy itself was progressive. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

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

The RNA exosome has specialized functions in RNA splicing and regulation of AU-rich element (ARE)-containing transcripts.

“In addition to RNA turnover, the RNA exosome has specialized functions in RNA splicing and the regulation of AU-rich element (ARE)-containing transcripts44–47.”

• cites [44] sourcePartly supported

  The Discussion (page not available in our copy) reports a connection between splicing factors and recruitment of the nuclear RNA exosome for mRNA degradation. It does not establish that the exosome regulates splicing itself, and no passage found in searches for “AU-rich” or “ARE-containing transcripts” addresses regulation of those transcripts. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [45] sourcePartly supported

  The Abstract and Discussion report that the exosome regulates splicing, including through effects on spliceosome components. The passages from our copy do not address regulation of AU-rich element (ARE)-containing transcripts; searches for that term and AU-rich mRNA regulation found no supporting passage. Page numbers were not provided. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [46] sourceCould not verify

  No passage from our copy was returned for searches about ARE-containing mRNA degradation or RNA splicing. Without a matching passage, the copy does not establish which parts of the citing sentence this source supports. (LLM, conf=0.65)

  Experimental — accuracy not yet measured
• cites [47] sourcePartly supported

  The Introduction (page unavailable) describes AU-rich binding proteins targeting RNAs to the exosome, and the Results section on AU-rich mRNA targeting reports altered targeting of ARE-containing transcripts in EXOSC3 variant cells. The copy describes snRNA processing but does not establish a specialized function for the exosome in RNA splicing; a search for splicing found no supporting passage. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

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

Correlation between the mRNAs for the paired RNA-Seq relative to the global proteomics datasets showed lower positive Pearson correlation values ranging from 0.333 - 0.378 for all genotypes tested.

“Correlation between the mRNAs for the paired RNA-Seq relative to the global proteomics datasets showed lower positive Pearson correlation values ranging from 0.333 – 0.378 for all genotypes tested which is consistent with prior studies on transcriptome / proteome correlation82–84.”

• cites [82] sourceSupported
• cites [83] sourceSupported
• cites [84] sourceSupported

May combine two claims.

A total of 455 transcripts were shared between the two datasets and pathway analysis revealed significant enrichment in transcripts of proteins of medium expression levels associated with the cerebellum and its white matter processes (HPA:0091042) (p-value = 0.004).

“A total of 455 transcripts were shared between the two datasets and pathway analysis revealed significant enrichment in transcripts of proteins of medium expression levels associated with the cerebellum and its white matter processes (HPA:0091042) using the Human Protein Atlas via the gost function of the gprofiler2 R package (p-value = 0.004, 58).”

• cites [58] sourceSupported

May combine two claims.

Many transcripts differentially expressed in all five datasets were noncoding RNAs, which are well established targets for the RNA exosome and can include PROMPTs, antisense transcripts, and long noncoding RNAs.

“Many of the transcripts that were differentially expressed in all five datasets were noncoding RNAs, which are well established to be targets for the RNA exosome and can include PROMPTs, antisense (AS) transcripts, and long noncoding RNAs (lncRNAs) as shown in Fig. 2B61–67.”

• cites [61] sourcePartly supported

  The Introduction (page unavailable) says the RNA exosome processes small noncoding RNAs and targets transcripts from pervasive transcription for degradation, explicitly including human PROMPTs. It does not identify antisense transcripts or lncRNAs as examples, and it does not report the citing authors’ five-dataset comparison. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [62] sourcePartly supported

  The Introduction (p. 1) identifies noncoding RNAs, including cryptic unstable transcripts, as targets of exosome-mediated degradation and describes antisense noncoding transcription. It does not establish PROMPTs or long noncoding RNAs as examples of those targets. The five-dataset observation is the citing paper’s own result, not a finding attributed to this source. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [63] sourceSupported
• cites [64] sourceSupported
• cites [65] sourcePartly supported

  The Introduction (page unavailable) says the nuclear exosome degrades CUTs, and the Results (page unavailable) report an antisense noncoding transcript upregulated after RRP6 deletion. The Introduction also identifies CUT281 as an antisense long noncoding RNA. Our copy does not identify PROMPTs as exosome targets; the statement about transcripts shared across five datasets belongs to the citing paper's own analysis. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [66] sourcePartly supported

  The Introduction identifies yeast cryptic unstable transcripts, stable unannotated transcripts, and short promoter-associated RNAs as exosome substrates; the Discussion also describes degradation of the first two classes. This supports the general point that noncoding RNAs are exosome targets, but our copy does not specifically identify PROMPTs, antisense transcripts, or lncRNAs as those targets. The observation about differential expression across five datasets appears to be the citing authors’ own finding, not a finding attributed to this source. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [67] sourcePartly supported

  The Introduction and Results section on CUTs and SUTs identify noncoding RNAs as exosome targets, supporting the general point. Our copy does not establish the listed examples—PROMPTs, antisense transcripts, and lncRNAs—as exosome targets. The statement about differential expression across five datasets is the citing authors’ own result, not a finding attributed to this source. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

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

Association of DIS3 and EXOSC10 with the RNA exosome decreases catalytic efficiency through allosteric effects.

“It has also been suggested that association of DIS3 and EXOSC10 with the RNA exosome decreases catalytic efficiency through allosteric effects42,69.”

• cites [42] sourcePartly supported

  The Discussion section, “The role of the exosome channel in substrate recruitment” (page unavailable), reports some inhibition of Dis3 activity by the exosome ring. But it also says the channel may increase PIN-domain endonuclease activity through better RNA binding. The paper does not establish that association of both DIS3 and EXOSC10 decreases catalytic efficiency through allosteric effects; it says the authors did not study the Rrp6-containing exosome in vitro. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [69] sourceSupported

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

The SKI complex works with the RNA exosome in the cytoplasm to carry out mRNA decay and mRNA quality-control regulation.

“subunits of the SKI complex that works with the RNA exosome in the cytoplasm to carry out mRNA decay and mRNA quality-control regulation91,92.”

• cites [91] sourceSupported
• cites [92] sourceNot checked — no full text of the source

May combine two claims.

Other RNA exosome subunits with reduced abundance by global proteomics had thermal stability largely unaffected, indicating their depletion may occur through mechanisms independent of protein destabilization, such as altered synthesis or degradation pathways including orphan protein decay.

“In contrast, while other subunits of the RNA exosome exhibited reduced abundance by global proteomics, their thermal stability remained largely unaffected, indicating that their depletion may occur through mechanisms independent of protein destabilization, such as altered synthesis or degradation pathways that could include orphan protein decay89.”

• cites [89] sourcePartly supported

  Split into 2 atoms — 1 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

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

DDX59 has recently been implicated in the degradation of the nuclear noncoding RNA MALAT1, whose levels are also regulated by the RNA exosome.

“DDX59 has recently been implicated in the degradation of the nuclear noncoding RNA MALAT1 whose levels are also regulated by the RNA exosome88.”

• cites [88] sourcePartly supported

  The Results section (page not provided) shows that DDX59 knockout stabilizes MALAT1(C8351G), a form with a stability-compromised 3′ end; it also reports that RNA Exosome components are required for degradation of that form. The claim omits this qualification: the same section reports no major effect of DDX59 knockout on endogenous wild-type MALAT1 during the measured time course or on its steady-state levels. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

The Integrator complex plays a role in premature RNA Polymerase II transcription termination of mRNAs and in processing of other small RNAs through mechanisms that require the RNA exosome.

“The Integrator complex is known to play a role in premature RNA Polymerase II transcription termination of mRNAs in addition to processing of other small RNAs through mechanisms that require the RNA exosome85–87.”

• cites [85] sourceSupported
• cites [86] sourceNot checked — no full text of the source
• cites [87] sourcePartly supported

  The Results and Discussion report that Integrator cleaves nascent mRNAs to promote premature transcription termination and also processes other RNA classes, including snRNAs. The Discussion says the RNA exosome degrades the short products of mRNA cleavage, but does not establish that processing those other small RNAs requires the exosome. The supplied passages have section labels but no page numbers. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

Prior work has shown that MPP6 associates with C1D and MTR4 in protein-protein interaction studies.

“Prior work has shown that MPP6 associates with the nucleic acid-binding protein C1D and MTR4 in protein-protein interaction studies90.”

• cites [90] sourceSupported

Classified as probably not a substantial claim.

ZMYM3 interacts with the RNA endonuclease RNAse H2, which resolves DNA-RNA hybrids.

“ZMYM3 has been shown to interact with the RNA endonuclease RNAse H2, which resolves DNA-RNA hybrids104.”

• cites [104] sourceSupported

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

DDX59 has recently been implicated in noncoding RNA degradation along with multiple subunits of the RNA exosome.

“The DEAD-box helicase DDX59, which has recently been implicated in noncoding RNA degradation along with multiple subunits of the RNA exosome, was also significantly upregulated at both transcript and protein levels88.”

• cites [88] sourceSupported

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

The Integrator complex copurified with the RNA exosome in prior work showing the role of both Integrator and the RNA exosome in premature RNAPII transcription termination.

“The Integrator complex copurified with the RNA exosome in prior work showing the role of both Integrator and the RNA exosome in premature RNAPII transcription termination87.”

• cites [87] sourcePartly supported

  The Results (Figure 3C–D; page not available) show RNA exosome components enriched in Integrator subunit purifications, supporting copurification. The Results (Figure 7) and Discussion attribute premature transcription termination to Integrator, but describe the RNA exosome as degrading the short RNAs after cleavage, not as itself causing termination. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

Shared DATs included several RNAs with known enrichment in the cerebellum and transcripts with AU-rich elements, which could contribute to reduced neuronal health/survival in individuals with PCH1B.

“However, shared DATs included several RNAs that have known enrichment in the cerebellum as well as enrichment in transcripts with AU-rich elements, that could contribute to reduced neuronal health/survival in individuals with PCH1B in agreement with prior work93,94.”

• cites [93] sourcePartly supported

  The Discussion (page unavailable in our copy) reports that an AU-rich element-binding protein destabilizes an mRNA involved in synaptic plasticity in Aplysia. It does not establish that the shared transcripts are cerebellum-enriched or that they contribute to reduced neuronal health or survival in people with PCH1B. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [94] sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

The change in charge accompanying the EXOSC3 G19D perturbation was accounted for using a post-simulation analytic correction (AC).

“The change in charge accompanying the EXOSC3 G19D perturbation was accounted for using a post-simulation analytic correction (AC)75.”

• cites [75] sourcePartly supported

  The Methods section (“Analytic correction,” page unavailable) says a post-simulation AC was applied to account for charge-changing EXOSC3 perturbations. The paper identifies the relevant aspartate variant as G191D in the Discussion, not G19D; the cited passages do not support the residue number in the claim. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

Prior work has suggested that the cerebellum may have a high requirement for RNA exosome function such that loss of RNA exosome expression, function, and/or insufficient protein complex formation in patients with EXOSC3 pathogenic variants lead to pathology.

“Prior work has suggested that the cerebellum may have a high requirement for RNA exosome function such that loss of RNA exosome expression, function, and/or insufficient protein complex formation in patients with EXOSC3 pathogenic variants lead to pathology110.”

• cites [110] sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

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

A post-alchemical correction was applied to the ΔΔG results.

“A routine λD simulation was performed and then a post-alchemical correction141 was applied to the ΔΔG results (Eq. 1).”

• cites [141] sourceSupported

Classified as probably not a substantial claim.

Literature broadly has reported common co-regulation of genes in protein complexes at both transcription and translational levels.

“This is a unique finding since literature broadly has reported common co-regulation of genes in protein complexes at both transcription and translational levels96–102.”

• cites [96] sourcePartly supported

  The Results section (‘Characterizing the unknown’; page unavailable) says functionally related genes in microbial genomes can have co-regulatory relationships, and the paper discusses operonic relationships. It does not establish that genes encoding protein complexes are commonly co-regulated at both transcriptional and translational levels. (LLM, conf=0.78)

  Experimental — accuracy not yet measured
• cites [97] sourcePartly supported

  The Background says transcriptional co-regulation of protein-complex genes was well studied, and the Conclusions report translational co-regulation among interacting proteins. But the Abstract Background calls this the first quantitative global-scale evidence for translational co-regulation among associated proteins, so the claim overstates how broadly earlier literature had reported it at both levels. Our copy provides no page numbers for these sections. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [98] sourceNot checked — no full text of the source
• cites [99] sourceNot checked — no full text of the source
• cites [100] sourcePartly supported

  The Introduction (page not supplied) describes co-expression of genes encoding interacting proteins and discusses protein complexes, supporting the transcription-level portion of the claim. The paper does not establish co-regulation at the translational level; its Across species/Single species section cautions that gene expression does not always reflect protein abundance. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [101] sourcePartly supported

  The Conclusions and Discussion report strong gene-expression correlations for protein pairs in permanent complexes and note that a few large complexes appear in both protein-interaction and co-expression networks. The paper does not report co-regulation at the translational level, and it describes the overall relationship between expression and protein interactions as weak. Page numbers are unavailable in our copy. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [102] sourceNot checked — no full text of the source

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

ZMYM3 is a transcriptional regulator whose mutation is associated with neurodevelopmental delay.

“ZMYM3 is a transcriptional regulator whose mutation is associated with neurodevelopmental delay103.”

• cites [103] sourceSupported

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

RNAse H2 acts redundantly with the RNA-DNA helicase Senataxin, which recruits the RNA exosome to the genome through a direct interaction with EXOSC9.

“Interestingly, RNAse H2 has been shown to act redundantly with the RNA-DNA helicase Senataxin, which recruits the RNA exosome to the genome through a direct interaction with EXOSC9105,106.”

• cites [105] sourcePartly supported

  The Introduction and Discussion report that SETX and RNase H2 cooperate to remove switch-region R loops in B cells, supporting the redundancy claim in that setting. The Discussion mentions the RNA exosome as another factor that can remove these structures, but our copy does not say that senataxin recruits it to the genome or interacts directly with EXOSC9 (no page numbers are provided). (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [106] sourcePartly supported

  The Results and Discussion report a SUMO-dependent association between Senataxin (SETX) and the exosome subunit Rrp45, with colocalization in stress-induced nuclear foci. They do not show that RNase H2 acts redundantly with SETX; their RNase H experiment used RNase H1. The authors also say that attempts to demonstrate a direct interaction using purified proteins were unsuccessful, so the claim of direct binding is stronger than their evidence. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

EXOSC3 G191 variant proteoforms show reduced protein abundance and thermal stability measured by global proteomics and PISA.

“consistent with reduced protein abundance and thermal stability measured by global proteomics and PISA”

May combine two claims.

The catalytic exonuclease DIS3 and multiple independent RNA processing pathways are upregulated in EXOSC3 p.G191 variants.

“In contrast, the catalytic exonuclease DIS3 and multiple independent RNA processing pathways were upregulated, indicating compensatory recalibration of RNA metabolism.”

May combine two claims.

The transcriptome of EXOSC3 p.G191 cell lines shows extensive changes in transcript levels along with potentially compensatory increases in RNA processing related factors including DIS3.

“We show that the transcriptome of EXOSC3 p.G191 cell lines shows extensive changes in transcript levels along with potentially compensatory increases in RNA processing related factors including DIS3.”

May combine two claims.

We successfully generated heterozygous G191C/+, heterozygous G191D/+, and homozygous G191D/G191D clonal cell lines, alongside single-cell isolated parental controls.

“We successfully generated heterozygous G191C/+, heterozygous G191D/+, and homozygous G191D/G191D clonal cell lines, alongside single-cell isolated parental controls.”

May combine two claims.

G191 homozygous and heterozygous variants lead to altered EXOSC3 transcript isoform expression including a short form that is fully destabilized through molecular dynamics simulations.

“As a consequence, G191 homozygous and heterozygous variants lead to altered EXOSC3 transcript isoform expression including a short form that we show is fully destabilized through molecular dynamics simulations.”

May combine two claims.

In the RNA exosome complex, d1, d2, and d3 interactions persist due to structural constraints of the assembled complex, but are weaker with elongated distances (~3-4 Å).

“In the RNA exosome complex, d1, d2, and d3 interactions persist due to structural constraints of the assembled complex, but are weaker with elongated distances (~3–4 Å).”

May combine two claims.

In the absence of these structural elements, the S1 domain loses its integrity and, in our model, undergoes complete unfolding/destabilization.

“In the absence of these structural elements, the S1 domain loses its integrity and, in our model, undergoes complete unfolding / destabilization, as observed in representative MD simulations (compare Figs. 3D & E & S5 A & B).”

May combine two claims.

Heterozygous EXOSC3 G191D/+ samples were close but distinctly separated from G191D/G191D samples, suggesting many genotype-based transcript alterations were observed in both homozygous and heterozygous clonal cell lines.

“Heterozygous EXOSC3 G191D/+ samples were close but distinctly separated from G191D/G191D samples, suggesting that many of the genotype-based transcript alterations were observed in both the homozygous and heterozygous clonal cell lines.”

May combine two claims.

The EXOSC3 G191 dataset displayed lower total numbers of DATs when compared to the siRNA datasets with a high degree of DAT overlap identified between all three EXOSC3 G191 cell lines.

“The EXOSC3 G191 dataset displayed lower total numbers of DATs when compared to the siRNA datasets with a high degree of DAT overlap identified between all three EXOSC3 G191 cell lines (Fig. S2C).”

May combine two claims.

G191D and G191C variants disrupt these three hydrogen bonds to varying degrees, with G191D disrupting them to a greater extent than G191C.

“However, G191D and G191C variants disrupt these three hydrogen bonds to varying degrees, with G191D disrupting them to a greater extent than G191C (compare Fig. 4B to 4C).”

Classified as probably not a substantial claim.

Of the 7,784 proteins detected, we quantified 6,856 including all RNA exosome subunits and a number of relevant cofactors.

“Of the 7,784 proteins detected, we quantified 6,856 including all RNA exosome subunits and a number of relevant cofactors.”

May combine two claims.

In G191D, the hydrophobic contacts by V192 and G191D break while in G191C, the G191C/β4 association is partially disrupted and M190 hydrophobic packing is sometimes lost.

“In G191D, the hydrophobic contacts by V192 and G191D break (Fig. 4E) while in G191C, the G191C/β4 association is partially disrupted and M190 hydrophobic packing is sometimes lost (Fig. 4E).”

May combine two claims.

Both G191D and G191C exhibited increased ΔRMSD ̄backbone in βL5 and the L5 C-terminal region (residues 187-190), with more pronounced effects in unbound EXOSC3.

“Both G191D and G191C exhibited increased ΔRMSD¯backbone in βL5 and the L5 C-terminal region (residues 187–190), with more pronounced effects in unbound EXOSC3.”

May combine two claims.

G191D displayed higher ΔRMSD ̄backbone than G191C, reinforcing the stronger impact of its structural destabilization.

“Due to its greater frequency of detachment, G191D displayed higher ΔRMSD¯backbone than G191C, reinforcing the stronger impact of its structural destabilization.”

May combine two claims.

Sashimi plots show decreases in exon 3-related junction usage and a corresponding increase in exon 2 to exon 4 junction usage.

“These data show decreases in exon 3-related junction usage and a corresponding increase in exon 2 to exon 4 junction usage (Fig. 3C).”

May combine two claims.

PROMPTs are not significantly increased in EXOSC3 G191 cell lines and may in fact decrease on average relative to control cell levels.

“This analysis revealed that PROMPTs are also not significantly increased in EXOSC3 G191 cell lines and may in fact decrease on average relative to control cell levels.”

May combine two claims.

The shorter isoform of EXOSC3 was not detected in quantitative proteomics studies and could not be detected by western blotting using an N-terminal specific EXOSC3 antibody.

“These findings were supported by a lack of detection of the shorter isoform of EXOSC3 in any of our quantitative proteomics studies (discussed below) and an inability to detect the shorter isoform of EXOSC3 by western blotting using an N-terminal specific EXOSC3 antibody with beta-actin as a loading control (Fig. S5C).”

May combine two claims.

EXOSC3 G191C/+ cell lines exhibited increased abundance of 3,229 transcripts and decreased abundance of 3,602 transcripts.

“EXOSC3 G191C/+ cell lines exhibited increased abundance of 3,229 transcripts and decreased abundance of 3,602 transcripts (Figure S1C).”

May combine two claims.

In native G191 EXOSC3, V192 packs against hydrophobic residues within the interior of the S1 β-barrel, M190 packs into the hydrophobic surface between the S1 β-barrel and the Kh domain, and G191 associates tightly with β4.

“In native G191 EXOSC3, V192 packs against hydrophobic residues within the interior of the S1 β-barrel (orange surface), M190 packs into the hydrophobic surface between the S1 β-barrel and the Kh domain (blue surface), and G191 associates tightly with β4 (Fig. 4D).”

May combine two claims.

Cerebellum enriched transcripts showed allele-specific changes amongst EXOSC3 p.G191 variants with SYT11 and UNC80 also showing gene dosage related changes.

“Interestingly, the cerebellum enriched transcripts showed allele specific changes amongst the EXOSC3 p.G191 variants with Synaptotagmin-11 (SYT11) and UNC80 also showing gene dosage related changes (Fig. 1C and Fig. S1E).”

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

After filtering lowly expressed transcripts, we quantified 45,109 transcripts, including 18,915 protein-coding genes, 14,772 long non-coding RNAs, 6,414 pseudogenes, 831 microRNAs, 744 small nuclear RNAs, and 317 small nucleolar RNAs.

“After filtering out lowly expressed transcripts across all samples, we quantified 45,109 transcripts, including 18,915 protein-coding genes, 14,772 long non-coding RNAs, 6,414 pseudogenes (processed and unprocessed), 831 microRNAs (miRNAs), 744 small nuclear RNAs (snRNAs), and 317 small nucleolar RNAs (snoRNAs).”

May combine two claims.

G191C alternates between states where only d1 or all three hydrogen bonds are broken, while G191D exhibits more frequent and pronounced destabilization of all three βL5-β4 interactions.

“Instead, G191C alternates between states where only d1 or all three hydrogen bonds are broken, while G191D exhibits more frequent and pronounced destabilization of all three βL5-β4 interactions.”

May combine two claims.

G191D alone altered EXOSC3's ΔΔGbind by slightly less than 1 kcal/mol, while G191C displayed minimal impact on binding.

“This investigation revealed that while G191D alone altered EXOSC3’s ΔΔGbind by slightly less than 1 kcal/mol, G191C displayed minimal impact on binding.”

May combine two claims.

Principal component analysis revealed strong genotype-specific effects with control vs. variant separating in PC1 (46% variance) and G191D vs. G191C genotypes separating in PC2 (24% variance).

“Principal component analysis of the average transcript abundance for each genotype revealed strong genotype specific effects with control vs. variant separating in PC1 (46% variance) and G191D vs. G191C genotypes separating in PC2 (24% variance, Fig. S1D).”

May combine two claims.

The alternative splicing event replaces the last 117 residues of EXOSC3 with six different residues, leading to the loss of the entire C-terminal KH domain as well as the β4 and β5 strands of the S1 β-barrel.

“We first explored the alternative splicing event that replaces the last 117 residues of EXOSC3 with six different residues, leading to the loss of the entire C-terminal KH domain as well as the β4 and β5 strands of the S1 β-barrel.”

May combine two claims.

For EXOSC3, thermal stability was significantly reduced in G191D/G191D homozygous cells, whereas G191C/+ and G191D/+ heterozygous variants exhibited more subtle changes.

“For EXOSC3, thermal stability was significantly reduced in G191D/G191D homozygous cells, whereas G191C/+ and G191D/+ heterozygous variants exhibited more subtle changes”

May combine two claims.

No changes in either MTR4 protein abundance or MTR4 protein stability were observed.

“We did not observe changes in either MTR4 protein abundance or MTR4 protein stability”

May combine two claims.

MPP6 significantly decreased in both global abundance and PISA-measured thermal stability in all EXOSC3 G191 datasets.

“MPP6 significantly decreased in both global abundance and PISA-measured thermal stability in all EXOSC3 G191 datasets (Fig. 6A, E & F).”

May combine two claims.

As a consequence, total EXOSC3 protein abundance is significantly decreased, as is the abundance of eight of the nine core subunits of the RNA exosome.

“As a consequence, total EXOSC3 protein abundance is significantly decreased as is the abundance of eight of the nine core subunits of the RNA exosome (Fig. 5).”

May combine two claims.

Neither EXOSC1 nor MPP6 levels were significantly altered with EXOSC3 overexpression in the control cell line.

“Although neither EXOSC1 or MPP6 levels were significantly altered with EXOSC3 overexpression in the control cell line”

May combine two claims.

EXOSC3 showed a 50% reduction in protein abundance across all three EXOSC3 G191 genotypes, with statistically significant fold changes of 0.475 (G191C/+), 0.45 (G191D/+), and 0.504 (G191D/G191D) relative to control.

“Across the four biological replicates, EXOSC3 showed a 50% reduction in protein abundance across all three genotypes, with statistically significant fold changes of 0.475 (G191C/+), 0.45 (G191D/+), and 0.504 (G191D/G191D) relative to control (Fig. 5B).”

May combine two claims.

Heterozygous EXOSC3 G191 variants appear to cause system disruption that is less severe than the homozygous EXOSC3 G191D/G191D cells but still extensive.

“Our findings identified several striking results, including that heterozygous EXOSC3 G191 variants appear to cause system disruption that is less severe than the homozygous EXOSC3 G191D/G191D cells but still extensive.”

May combine two claims.

Our analyses revealed significant and widespread changes in gene expression (DATs) and splicing profiles in EXOSC3 G191 variant cells.

“Our analyses revealed significant and widespread changes in gene expression (DATs) and splicing profiles in EXOSC3 G191 variant cells.”

May combine two claims.

The G191C-bound MPP6 α2 displayed a per-residue RMSD backbone of 1-2 Å, and G191D produced a much larger effect of 2-6 Å.

“the G191C-bound MPP6 α2 displayed a per-residue RMSD¯backbone of 1–2 Å, and the G191D produced a much larger effect of 2–6 Å (Fig. 6D).”

May combine two claims.

MD analysis suggested that, as a result of EXOSC3 G191 missense variants, the L5, βL5, and S1/KH linker structures could form into a single unstructured loop, disrupting normal interactions with MPP6 in the RNA exosome complex and the KH domain in EXOSC3.

“MD analysis suggested that, as a result of EXOSC3 G191 missense variants, the L5, βL5, and the S1/KH linker structures could form into a single unstructured loop (Fig. 4D-F), disrupting normal interactions with MPP6 in the RNA exosome complex and the KH domain in EXOSC3.”

May combine two claims.

Comprehensive analysis revealed that EXOSC3 has large predicted changes in protein folding ranging from ΔΔGfold of 4.37-6.12 kcal/mol, with the largest changes occurring due to the G191D sequence variant.

“This comprehensive analysis revealed that EXOSC3 has large predicted changes in protein folding ranging from ΔΔGfold of 4.37–6.12 kcal/mol, with the largest changes occurring due to the G191D sequence variant.”

May combine two claims.

DIS3 levels increase significantly in all EXOSC3 G191 variants with no concurrent change in DIS3 thermal stability.

“Since DIS3 levels increase significantly in all EXOSC3 G191 variants with no concurrent change in DIS3 thermal stability”

May combine two claims.

All nine of the RNA exosome core components (Exo9) were significantly decreased in global abundance, as was the 3'−5' exonuclease EXOSC10 that associates with the cap subunits including EXOSC3.

“Interestingly, all nine of the RNA exosome core components (collectively also known as Exo9) were significantly decreased in global abundance as was the 3’−5’ exonuclease EXOSC10 that associates with the cap subunits including EXOSC3.”

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

RNA exosome activity is essential in all eukaryotes that have been assessed, including humans.

“RNA exosome activity is essential in all eukaryotes that have been assessed, including humans, where the core RNA exosome subunits EXOSC1–10, the DIS3 exonuclease, and the MTR4 RNA exosome RNA helicase have all been identified as common essential in the Dependency Map (DepMap) project 31,32.”

• cites [31] sourceNot checked — no full text of the source
• cites [32] NA. (2025). Broad DepMap.Not 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.

We analyzed n = 4 biological replicates per genotype and sequenced at an average depth of 259.82 ± 38.1 million reads per sample.

“We analyzed n = 4 biological replicates per genotype and sequenced at an average depth of 259.82 ± 38.1 million (mean ± SD) reads per sample.”

May combine two claims.

Variant-induced alternative splicing, RNA exosome complex destabilization, and adaptive network responses link to phenotypic variability in EXOSC3 p.G191-associated disease.

“Together, these findings link variant-induced alternative splicing, RNA exosome complex destabilization, and adaptive network responses to phenotypic variability in EXOSC3 p.G191-associated disease.”

Classified as probably not a substantial claim.

The involvement of an alternative splicing event associated with G191 variants could explain the higher degree of disease heterogeneity observed in EXOSC3 p.G191 carriers.

“The involvement of an alternative splicing event associated with G191 variants could explain the higher degree of disease heterogeneity observed in EXOSC3 p.G191 carriers.”

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

Patients with homozygous EXOSC3 p.D132A can live up to the second decade of life.

“patients with homozygous EXOSC3 p.Asp132Ala (p.D132A) variant can live up to the second decade of life37.”

• cites [37] sourceNot checked — no full text of the source

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

Four paired cell growths were used for multi-omics experiments to minimize batch effects between omics experiments.

“For subsequent analyses, four paired cell growths were used for multi-omics experiments to minimize batch effects between omics experiments.”

May combine two claims.

Upregulation of DIS3 and multiple independent RNA processing pathways indicates compensatory recalibration of RNA metabolism.

“indicating compensatory recalibration of RNA metabolism”

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

Pearson correlation coefficients between the biological replicate measurements for the proteomics datasets ranged from 0.980 - 0.991 for EXOSC3 G191D/G191D homozygous cell lines and from 0.965 - 0.993 for the isogenic controls.

“Pearson correlation coefficients between the biological replicate measurements for the proteomics datasets ranged from 0.980 – 0.991 for EXOSC3 G191D/G191D homozygous cell lines and from 0.965 – 0.993 for the isogenic controls (Fig. S6).”

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

This analysis excludes possible reorganizational free energy penalties that may be needed to fold variant EXOSC3s into a suitable binding conformation, which would likely impact the true ΔΔGbind.

“This analysis excludes possible reorganizational free energy penalties that may be needed to fold variant EXOSC3s into a suitable binding conformation, which would likely impact the true ΔΔGbind.”

May combine two claims.

Increased expression of the exonuclease subunits could compensate for reduced overall RNA exosome complex activity, especially in the case of DIS3 which has been shown to be functional independent of the fully assembled RNA exosome complex in vitro and recently in cells.

“Increased expression of the exonuclease subunits could compensate for reduced overall RNA exosome complex activity, especially in the case of DIS3 which has been shown to be functional independent of the fully assembled RNA exosome complex in vitro and recently in cells68.”

• cites [68] sourceNot checked — no full text of the source

May combine two claims.

Disruptions result from steric and electrostatic clashes introduced by the variant sidechains, as well as unfavorable dihedral angles sampled by non-Gly residues.

“Disruptions result from steric and electrostatic clashes introduced by the variant sidechains, as well as unfavorable dihedral angles sampled by non-Gly residues.”

May combine two claims.

The isoform switch likely represents a critical alteration in the regulation of EXOSC3 transcripts in G191 variants, further implicating the variant in disrupting normal RNA homeostasis.

“This isoform switch likely represents a critical alteration in the regulation of EXOSC3 transcripts in G191 variants, further implicating the variant in disrupting normal RNA homeostasis.”

Classified as probably not a substantial claim.

Three biological replicates per condition were used for global proteomics analysis to assess system-wide changes that are EXOSC3 dependent.

“Three biological replicates per condition were used for global proteomics analysis to assess the system-wide changes that are EXOSC3 dependent.”

May combine two claims.

Cellular compensation occurs at both the transcript and protein levels and involves adjustments within the RNA exosome complex itself and throughout a variety of other RNA processing and decay pathways.

“Our multiomics studies show that cellular compensation occurs at both the transcript and protein levels and involves adjustments within the RNA exosome complex itself and throughout a variety of other RNA processing and decay pathways.”

May combine two claims.

Comparison to deep RNA sequencing studies in EXOSC3 D132A/D132A cells suggested that many of the changes are allele-specific, with EXOSC3 G191D/G191D causing more extensive DATs.

“Interestingly, comparison to deep RNA sequencing studies performed in EXOSC3 D132A/D132A cells suggested that many of the changes are allele-specific with EXOSC3 G191D/G191D causing more extensive DATs.”

May combine two claims.

G191 variants primarily impact the thermal stability of EXOSC3 and its direct binding partners, potentially disrupting interactions within the RNA exosome complex.

“These findings suggest that G191 variants primarily impact the thermal stability of EXOSC3 and its direct binding partners, potentially disrupting interactions within the RNA exosome complex (Fig. 6A).”

May combine two claims.

EXOSC3 protein levels are relatively lower than its decrease in transcript levels, possibly as a consequence of protein destabilization and related turnover.

“suggesting that the EXOSC3 protein levels are relatively lower than its decrease in transcript levels, possibly as a consequence of protein destabilization and related turnover (described in Fig. 4).”

May combine two claims.

Tissue specific diseases such as PCH1B are associated with cell or tissue-specific pathway disruption, suggesting that other human cells may be able to recalibrate or adjust to disease-associated variants.

“Tissue specific diseases such as PCH1B are associated with cell or tissue-specific pathway disruption, suggesting that other human cells may be able to recalibrate or adjust to disease-associated variants.”

• AssumptionRests on an assumption: Tissue specific diseases such as PCH1B are associated with cell or tissue-specific pathway disruption.

May combine two claims.

Considering that carriers of single copy EXOSC3 variants do not present with PCH1B, the findings suggest that either the overall abundance of EXOSC3 and/or the protein instability are the likely cause of human neurodegenerative disease.

“Considering that carriers of single copy EXOSC3 variants do not present with PCH1B, these findings suggest that either the overall abundance of EXOSC3 and/or the protein instability are the likely cause of human neurodegenerative disease.”

• AssumptionRests on an assumption: Carriers of single copy EXOSC3 variants do not present with PCH1B.

May combine two claims.

The G191C variant may cause allele-specific changes in C1D association and/or recruitment to the RNA exosome.

“suggesting that the G191C variant may cause allele-specific changes in C1D association and/or recruitment to the RNA exosome (Fig. 6E&F, Figs. S7A & S8A).”

May combine two claims.

Since heterozygous carriers of EXOSC3 G191 variants do not show symptoms of disease, cells are able to compensate for EXOSC3 functional disruption as observed.

“Since heterozygous carriers of EXOSC3 G191 variants do not show symptoms of disease, this clearly suggests that cells are able to compensate for EXOSC3 functional disruption as we have observed in these studies.”

• AssumptionRests on an assumption: Heterozygous carriers of EXOSC3 G191 variants do not show symptoms of disease.

Classified as probably not a substantial claim.

Alternative splicing events with an FDR < 0.05 in the change of inclusion level were regarded as differentially observed.

“Alternative splicing events with an FDR < 0.05 in the change of inclusion level were regarded as differentially observed”

Classified as probably not a substantial claim.

Twelve 300 ns MD simulations were performed of the RNA exosome-bound and unbound native EXOSC3.

“Twelve 300 ns MD simulations were performed of the RNA exosome-bound and unbound native EXOSC3.”

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

Upregulation of subunits of the Integrator complex could potentially increase the efficiency of RNA exosome recruitment when the complex is in limited abundance or possibly compensate for its decrease through Integrator endonuclease activity.

“Upregulation of subunits of the Integrator complex could potentially increase the efficiency of RNA exosome recruitment when the complex is in limited abundance or possibly compensate for its decrease through Integrators endonuclease activity.”

Classified as probably not a substantial claim.

Differentially expressed genes were considered to be genes with an FDR-adjusted (Benjamini-Hochberg) p-value less than or equal to 0.05.

“Differential expressed genes were considered to be genes with an FDR-adjusted (Benjamini-Hochberg) p-value less than or equal to 0.05.”

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

Final relative free energy differences were calculated with WHAM, and statistical errors were estimated using bootstrapping.

“Final relative free energy differences were calculated with WHAM144, and statistical errors were estimated using bootstrapping.”

• cites [144] sourceNot checked — no full text of the source

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

DIS3 is one of the catalytic subunits of the RNA exosome, although it has also recently been shown to function independently of the RNA exosome complex in the cytoplasm.

“DIS3 is one of the catalytic subunits of the RNA exosome although it has also recently been shown to function independently of the RNA exosome complex in the cytoplasm68.”

• cites [68] sourceNot checked — no full text of the source

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

The HEK293T cell line was screened for template-based repair using AscI digestion, and clones positive for the repair were Sanger sequenced for the G191 variant.

“The HEK293T cell line were screened for template-based repair using AscI digestion and those clones that are positive for the repair were Sanger sequenced for the G191 variant.”

Classified as probably not a substantial claim.

Prior RNA-seq studies using transient siRNA-based knockdown of EXOSC3 found that noncoding RNAs increase.

“in contrast to prior RNA-seq studies using transient siRNA-based knockdown of EXOSC3 where noncoding RNAs increase59,60.”

• cites [59] sourceNot checked — no full text of the source
• cites [60] sourceNot checked — no full text of the source

May combine two claims.

Thermal stability changes did not reach significance in the heterozygous cell lines, likely due to the presence of the reference EXOSC3 allele.

“thermal stability changes did not reach significance in the heterozygous cell lines, likely due to the presence of the reference EXOSC3 allele.”

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

The first fifth of each production simulation was excluded as equilibration prior to determination of the free energy changes.

“The first fifth of each production simulation was excluded as equilibration prior to determination of the free energy changes.”

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

Percolator False Discovery Rate (FDR) was set to a strict setting of 0.01 and a relaxed setting of 0.05.

“Percolator False Discovery Rate (FDR) was set to a strict setting of 0.01 and a relaxed setting of 0.05.”

May combine two claims.

Other RNA processing factors are upregulated because of decreased RNA exosome function, and those system-wide changes can be reversed with RNA exosome rescue.

“These findings suggest that not only are other RNA processing factors being upregulated because of decreased RNA exosome function, but that those system wide changes can be reversed with RNA exosome rescue.”

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

Optimal biases were obtained after a cumulative of 200-500 ns of sampling.

“Optimal biases were obtained after a cumulative of 200–500 ns of sampling.”

Classified as probably not a substantial claim.

Differential splicing events were required to have an absolute fold-change of inclusion level > 10% between control and variant.

“absolute fold-change of inclusion level > 10% between control and variant”

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

All other EXOSC3 variants (bound and unbound EXOSC3 G191C, bound and unbound EXOSC3 G191D, and unbound EXOSC3alt) were performed for 300 ns in triplicate.

“All other EXOSC3 variants (bound and unbound EXOSC3 G191C, bound and unbound EXOSC3 G191D, and unbound EXOSC3alt) were performed for 300 ns in triplicate.”

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

Mutations were confirmed by Sanger sequencing.

“Mutations were confirmed by Sanger sequencing (Genewiz) using appropriate sequencing primers.”

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

In the estimation of size factors, the vector of counts aligned to the ERCC Spike-In was used as the controlGenes argument in the function estimateSizeFactors.

“In the estimation of size factors, the vector of counts aligned to the ERCC Spike-In was used as the controlGenes argument in the function estimateSizeFactors.”

Classified as probably not a substantial claim.

Differential splicing events were required to have ≥10 support junction reads in all samples of control and mutant.

“having ≥10 support junction reads in all samples of control and mutant”

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

These atoms were restrained to preserve the structure of the RNA exosome complex around EXOSC3 in the truncated model.

“These atoms were restrained to preserve the structure of the RNA exosome complex around EXOSC3 in the truncated model.”

Classified as probably not a substantial claim.

Five replicate λD production simulations were run for the RNA exosome-bound, unbound, and unfolded EXOSC3 systems.

“Finally, five replicate λD production simulations were run for the RNA exosome-bound, unbound, and unfolded EXOSC3 systems.”

Classified as probably not a substantial claim.

RNA was isolated from four replicate growths of each genotype.

“RNA was isolated from four replicate growths of each genotype using the TRIzol reagent-based extraction Zymo Direct-zol RNA prep kit.”

May combine two claims.

DIS3 does not require Exo9 to escape orphan protein decay, making it unique among all RNA exosome subunits.

“our findings also suggest that DIS3 does not require Exo9 to escape orphan protein decay, making it unique among all RNA exosome subunits.”

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

The first fifth of each simulation was discarded as equilibration prior to trajectory analysis.

“The first fifth of each simulation was discarded as equilibration prior to trajectory analysis.”

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

Reporter ion quantification was allowed with S/N threshold of 10 and co-isolation threshold of 30%.

“Reporter ion quantification was allowed with S/N threshold of 10 and co-isolation threshold of 30%.”

Classified as probably not a substantial claim.

Only proteins quantified in all samples with a protein-level FDR ≤ 0.05 were retained for analysis.

“Only proteins quantified in all samples with a protein-level FDR ≤ 0.05 were retained for analysis.”