Unexplored therapeutic opportunities in the human genome

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

IMPC analysis of 1,751 unique gene knockouts found human disease genes enriched for essential genes.

“Their recent analysis of 1,751 unique gene knockouts found that human disease genes are enriched for essential genes38”

• cites [38] Dickinson, M. E. et al. High-throughput discovery of novel developmental phenotypes. Nature 537, 508–514 (2016). sourceSupported

May combine two claims.

52 non-olfactory GPCRs are categorized as Tdark, and new screening platforms have begun the process of illuminating them.

“Although 52 non-olfactory GPCRs are categorized as Tdark, the availability of new screening platforms to discover chemical matter for these GPCRs has begun the process of illumination64,67,68.”

• cites [64] Huang, X.-P. et al. Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65. Nature 527, 477–483 (2015). sourceSupported
  Experimental — accuracy not yet measured
• cites [67] Kroeze, W. K. et al. PRESTO-Tango as an open-source resource for interrogation of the druggable human GPCRome. Nat. Struct. Mol. Biol. 22, 362–369 (2015). sourcePartly supported

  The Results and Discussion describe PRESTO-TANGO screening of poorly annotated and orphan GPCRs and the discovery of new ligand–receptor interactions, supporting the claim that a screening platform has begun to illuminate understudied receptors. The paper does not give a count of 52 non-olfactory GPCRs or classify them as Tdark; its Abstract instead discusses more than 100 orphan GPCRs. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [68] Lansu, K. et al. In silico design of novel probes for the atypical opioid receptor MRGPRX2. Nat. Chem. Biol. 13, 529–536 (2017). sourcePartly supported

  The Abstract describes new physical and computational screening approaches for finding ligands for understudied GPCRs, and the Results report their use to identify compounds active at MRGPRX receptors. That supports the claim that screening platforms have begun to illuminate these receptors. The paper does not give the figure of 52 non-olfactory GPCRs or categorize that group as Tdark; its Abstract instead discusses approximately 120 orphan or understudied non-olfactory GPCRs. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

Nearly 59% of these GPCR disease associations stem from text mining, and 48 GPCRs have confirmed associations from at least two information channels.

“Whereas the majority of these associations (nearly 59%) stem from text mining69, 48 GPCRs have confirmed associations from at least two information channels.”

• cites [69] Pafilis, E. et al. The SPECIES and ORGANISMS Resources for Fast and Accurate Identification of Taxonomic Names in Text. PLoS ONE 8, e65390 (2013). sourceCould not verify

  The Introduction and the ORGANISMS web resource section describe text mining for organism names, not GPCR–disease associations. Searches for GPCRs, disease associations, 59%, and information channels found no passage supporting the cited percentage. The citation is attached to the 59% text-mining statement, not the separate count of 48 GPCRs. (LLM, conf=0.77)

  Experimental — accuracy not yet measured

• AssumptionRests on an assumption: Text-mined disease associations are valid enough to count as confirmed human disease associations.

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

Alterations in GPCR signalling are implicated in the pathogenesis and treatment of many disorders, including neuropsychiatric, immunological, gastrointestinal, cardiac, renal, hormonal and infectious disorders.

“Alterations in GPCR signalling are implicated in the pathogenesis and treatment of neuropsychiatric55, immunological56, gastrointestinal57,58, cardiac59, renal, hormonal, infectious60 and many other disorders53,54.”

• cites [53] Wacker, D., Stevens, R. C. & Roth, B. L. How ligands illuminate GPCR molecular pharmacology. Cell 170, 414–427 (2017). sourceSupported
• cites [54] Roth, B. L., Irwin, J. J. & Shoichet, B. K. Discovery of new GPCR ligands to illuminate new biology. Nat. Chem. Biol. 13, 1143–1151 (2017). sourcePartly supported

  The Abstract (page unavailable) describes GPCRs as frequent therapeutic targets, and the sections on maraviroc/CCR5 and biased agonists discuss HIV, psychiatric disorders and heart failure. The passages do not establish the full list of disorder categories—particularly gastrointestinal, renal and hormonal disorders—or the broad claim about their pathogenesis. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [55] Roth, B. L., Sheffler, D. J. & Kroeze, W. K. Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat. Rev. Drug Discov. 3, 353–359 (2004). sourceNot checked — no full text of the source
• cites [56] Hernandez, P. A. et al. Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Nat. Genet. 34, 70–74 (2003). sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

Tclin assignment relied on exhaustive manual searches of primary literature and drug labels to identify mechanism-of-action links.

“Classification into this TDL category was achieved through exhaustive manual querying of primary literature and drug labels for MoA assignments with respect to molecular (protein) targets9”

• cites [9] Santos, R. et al. A comprehensive map of molecular drug targets. Nat. Rev. Drug Discov. 16, 19–34 (2017). sourceSupported

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

GPCRs are membrane-bound cell-surface receptors that transduce signals via heterotrimeric G proteins, arrestins and other cellular transducers.

“GPCRs are membrane-bound, cell-surface receptors that transduce signals via interactions with heterotrimeric G proteins, arrestins and other cellular transducers53,54.”

• cites [53] Wacker, D., Stevens, R. C. & Roth, B. L. How ligands illuminate GPCR molecular pharmacology. Cell 170, 414–427 (2017). sourceSupported
• cites [54] Roth, B. L., Irwin, J. J. & Shoichet, B. K. Discovery of new GPCR ligands to illuminate new biology. Nat. Chem. Biol. 13, 1143–1151 (2017). sourceSupported

May combine two claims.

GPCRs are the largest family of druggable targets in the human genome, with 20-30% of approved drugs acting on them.

“GPCRs represent the largest family of druggable targets in the human genome9, with between 20% and 30% of approved drugs acting on them53,54.”

• cites [9] Santos, R. et al. A comprehensive map of molecular drug targets. Nat. Rev. Drug Discov. 16, 19–34 (2017). sourcePartly supported

  In the citing sentence, this source is cited for the drug-percentage claim, not the preceding ‘largest family’ claim. The Drugs, targets and therapeutic areas section reports that rhodopsin-like GPCRs account for the therapeutic effect of 33% of approved small-molecule drugs, rather than 20–30% of approved drugs generally. Our copy provides no page number for the passage. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [53] Wacker, D., Stevens, R. C. & Roth, B. L. How ligands illuminate GPCR molecular pharmacology. Cell 170, 414–427 (2017). sourceSupported
• cites [54] Roth, B. L., Irwin, J. J. & Shoichet, B. K. Discovery of new GPCR ligands to illuminate new biology. Nat. Chem. Biol. 13, 1143–1151 (2017). sourceSupported

May combine two claims.

In-depth analysis found that ketamine's active metabolite HNK does not block the NMDA receptor, instead displays sustained AMPA receptor activation and lacks ketamine-related side effects.

“However, in-depth analysis of the antidepressant effects of ketamine found that its active metabolite (2R,6R)-hydroxynorketamine (HNK) does not block the NMDA receptor. Instead, HNK displays sustained activation of α-amino-3hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors and lacks ketamine-related side effects81.”

• cites [81] Zanos, P. et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533, 481–486 (2016). sourceSupported
  Experimental — accuracy not yet measured

May combine two claims.

Pretreatment biopsies matched to post-treatment surgical specimens showed overall concordance of transcriptional kinase response to trametinib, with FRK highest mean increase and cytoplasmic BMX highest mean decrease.

“Pretreatment biopsies matched to post-treatment surgical specimens showed overall concordance of the transcriptional kinase response to trametinib, with FRK (Tchem) exhibiting the highest mean increase and cytoplasmic BMX (also Tchem) exhibiting the highest mean decrease among patients in response to a 7-day drug treatment.”

• cites [75] Zawistowski, J. S. et al. Enhancer remodeling during adaptive bypass to MEK inhibition is attenuated by pharmacologic targeting of the P-TEFb complex. Cancer Discov. 7, 302–321 (2017). sourcePartly supported

  The Results section, “MEK inhibition induces a transcriptomic/kinome response in patient TNBC tumors” (page unavailable), reports concordant transcriptional responses in four matched basal-like tumors, with FRK showing the highest mean increase and BMX the highest mean decrease after seven days of trametinib. It does not describe BMX as cytoplasmic or label FRK and BMX “Tchem”; it also limits the concordance finding to patients 1, 2, 3, and 5, rather than all patients. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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

Ketamine has been postulated to act as a noncompetitive NMDA antagonist and has been used off-label as an antidepressant.

“For example, the anaesthetic ketamine, which has been postulated to act as a noncompetitive N-methyl-d-aspartate (NMDA) antagonist79, has been used off-label as an antidepressant80.”

• cites [79] Berman, R. M. et al. Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry 47, 351–354 (2000). sourceNot checked — no full text of the source
• cites [80] Kirby, T. Ketamine for depression: the highs and lows. Lancet Psychiatry 2, 783–784 (2015). sourceSupported

Classified as probably not a substantial claim.

The paper suspects that artificial divisions are another reason funding to study Tdark proteins is scarce.

“We suspect this to be another reason why funding to study Tdark proteins is scarce: for functionally enigmatic proteins, or the ‘ignorome’ (REF. 85), anticipating which organ, disease or phenotype is relevant may be far from trivial.”

• cites [85] Pandey, A. K., Lu, L., Wang, X., Homayouni, R. & Williams, R. W. Functionally enigmatic genes: a case study of the brain ignorome. PLoS ONE 9, e88889 (2014). sourceSupported

Classified as probably not a substantial claim.

Despite attempts to overcome this problem, the paper is not aware of an unbiased, easy mechanism to capture negative results.

“Although there are attempts to overcome this problem86, we are not aware of the existence of an unbiased, easy mechanism to capture negative results.”

• cites [86] Pfeffer, C. & Olsen, B. R. Editorial: Journal of negative results in biomedicine. J. Negat. Results Biomed. 1, 2 (2002). sourceSupported

May combine two claims.

Tdark proteins tend not to be studied by many funded NIH R01 grants and are significantly less discussed in patents than proteins in other TDLs.

“Tdark proteins tend not to be the object of study for many funded NIH R01 grants and are significantly less discussed in patents compared with proteins in other TDLs.”

May combine two claims.

Most kinase-targeting clinical candidates are aimed at oncology, whereas GPCR- and ion channel-targeting clinical candidates are aimed at central nervous system disorders.

“most of the kinase-targeting clinical candidates are aimed at oncology applications, whereas GPCRs and ion channel-targeting clinical candidates are aimed at central nervous system disorders”

The quote only partly states this claim.

Many proteins that bind approved drugs with high affinity remain in Tchem because Tclin requires MoA evidence.

“many proteins known to interact with approved drugs, even with high affinity, remain in the Tchem category”

May combine two claims.

Among Tclin targets, 259 (79.7%) are single proteins, 39 (12%) are complex multiprotein targets, and 25 (8.3%) are multiple proteins for non-selective drugs.

“The majority (259 or 79.7%) of these targets are single proteins, whereas 39 (12%) are complex multiprotein targets. Only 25 targets (8.3%) are comprised of multiple proteins for non-selective drugs”

May combine two claims.

Most targeted Tchem proteins are kinases (93 unique enzymes), followed by GPCRs (31 unique receptors) and ion channels (13), with seven targets from other families.

“Most targeted proteins are kinases (93 unique enzymes), followed by GPCRs (31 unique receptors) and ion channels (13), with seven targets from other families”

May combine two claims.

827 GPCRs, including 421 olfactory GPCRs, are tracked by IDG KMC; 96 are Tclin and 113 are Tchem, none olfactory.

“Currently 827 GPCRs — including 421 olfactory GPCRs — are tracked by IDG KMC; of these, 96 are Tclin and 113 are Tchem (none of which are olfactory).”

May combine two claims.

Tbio-disease associations are rare for druggable families such as nuclear receptors, ion channels and GPCRs, which are more likely to be Tclin or Tchem.

“It appears that Tbio-disease associations are quite rare for druggable families such as nuclear receptors, ion channels and GPCRs, as these families are more likely to be in the Tclin or Tchem category.”

May combine two claims.

Based on DrugCentral, the paper found 50 approved kinase inhibitors, including 40 small-molecule protein kinase inhibitors, of which 32 are FDA-approved, one FDA-approved protein kinase activator ingenol mebutate, and FDA-approved PIK3CD inhibitor idelalisib.

“Based on DrugCentral, we found 50 approved kinase inhibitors, including 40 small-molecule protein kinase inhibitors, of which 32 are FDA-approved, one FDA-approved protein kinase activator (ingenol mebutate) and the phosphoinositide 3-kinase subunit-δ (PIK3CD) small-molecule inhibitor idelalisib, which is also FDA-approved.”

• AssumptionRests on an assumption: DrugCentral annotations accurately reflect drug-target interactions.

May combine two claims.

Of 62 GPCRs with significant IMPC phenotype calls, 24 are Tbio and 7 Tdark; 15 are associated with neurological and behavioural phenotypes.

“Of 62 GPCRs for which significant phenotype calls have been reported by IMPC (Supplementary Table S8), 24 are Tbio and 7 are Tdark; of these, 15 are associated with neurological and behavioural phenotypes.”

May combine two claims.

Of 447 genes with significant fold changes in GSE26835, only 26 are Tclin and 61 Tchem, while the majority (268 Tbio, 92 Tdark) are understudied.

“Of the 447 genes with significant fold changes in the GSE26835 set, only 26 are Tclin and 61 are Tchem, whereas the majority (268 Tbio, 92 Tdark) are understudied (see also Supplementary Box S5).”

May combine two claims.

Alpk3, a Tdark kinase, when knocked out, raises embryonic and perinatal death rates; adults that survive show serious heart abnormalities.

“knockouts of the Tdark kinase gene Alpk3 have increased embryonic and perinatal lethality, with the surviving adults displaying severe heart defects”

May combine two claims.

Five of the six highlighted targets are modulated by at least one approved drug, placing them in Tclin.

“Five of these six targets are modulated by at least one approved drug, which places them in the Tclin category.”

May combine two claims.

The same distribution patterns across TDL categories appear in every data type and show statistically significant differences.

“Distribution trends within TDL categories are consistently reproduced across all data types in FIG. 2a and have statistically significant differences (Supplementary Table S4).”

May combine two claims.

As of November 2017, IDG-coordinated IMPC production produced 568 new knockout strains: 166 GPCRs, 141 ion channels, 238 kinases, and 23 nuclear receptors.

“As of November 2017, 568 new knockout strains had been produced: 166 GPCRs, 141 ion channels, 238 kinases and 23 nuclear receptors”

May combine two claims.

IDG submitted 482 Tbio genes; 184 mouse lines were generated, and 145 had observed phenotypes.

“Of 482 Tbio genes submitted by IDG (135 GPCRs, 133 ion channels, 200 kinases and 14 nuclear receptors), 184 mouse lines were produced, with 145 phenotypes observed.”

May combine two claims.

Adgrd1, a Tbio GPCR, when knocked out, causes reproductive problems including female infertility and skeletal abnormalities including lower bone mineral density.

“knockouts of the Tbio GPCR gene Adgrd1 display reproductive defects, such as female infertility, and skeleton phenotype defects, such as decreased bone mineral density”

May combine two claims.

Including olfactory GPCRs, 618 proteins are Tdark or Tbio; 126 non-olfactory and 51 olfactory GPCRs have significant human disease associations via OMIM, GWAS and text mining.

“Including olfactory GPCRs, 618 proteins are classified as Tdark or Tbio; of these, 126 non-olfactory GPCRs and 51 olfactory GPCRs have significant associations with human diseases via OMIM, GWAS and text mining.”

• AssumptionRests on an assumption: Text-mined disease associations are valid enough to count as confirmed human disease associations.

May combine two claims.

IDG submitted 119 Tdark genes to IMPC; 45 mouse lines resulted, and 41 had observed phenotypes.

“Of the 119 Tdark genes (51 GPCRs, 36 ion channels and 32 kinases) submitted by IDG to IMPC, 45 mouse lines were produced, with 41 phenotypes observed.”

May combine two claims.

For 80% of the strains, phenotype information exists, and abnormalities appear across many biological systems.

“Phenotype data are available for 80% of these strains, with abnormalities detected in numerous biological systems, including those related to development, immune function, metabolism and behaviour.”

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

355 ion channel pore-forming and auxiliary subunits are tracked by IDG KMC.

“Currently, 355 ion channel pore-forming and auxiliary subunits are tracked by IDG KMC (TABLE 1; Supplementary Table S3).”

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

Unlike GPCRs or kinases, neither ion channel pore-forming subunits nor auxiliary subunits share characteristic motifs.

“Unlike GPCRs or kinases, neither pore-forming subunits nor auxiliary subunits share characteristic motifs.”

Classified as probably not a substantial claim.

TABLE 5 shows ten Tbio or Tdark kinases amplified in TCGA and their RNA expression in TNBC cells.

“TABLE 5 shows ten Tbio or Tdark kinases whose amplification is observed in the TCGA database, together with their RNA expression in triple-negative breast cancer (TNBC) cells.”

May combine two claims.

About 100 ion channel modulators including auxiliary subunits are reported, but no systematic list of cell type-specific auxiliary subunits for all ion channels is available.

“About 100 ion channel modulators, including auxiliary subunits, are reported, but to our knowledge, a systematic list of cell type-specific auxiliary subunits for all ion channels is not available.”

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

LRRC8B, LRRC8C and LRRC8D are Tdark, LRRC8A is Tbio; ORAI1 is Tchem, ORAI2 and ORAI3 are Tbio; except anoctamin 1 (Tclin), all other anoctamins are Tbio.

“Currently, LRRC8B, LRRC8C and LRRC8D subunits are classified as Tdark, with the exception being the subunit LRRC8A (Tbio); ORAI1 is annotated as Tchem, wheras the ORAI2 and ORAI3 proteins are annotated as Tbio. With the exception of anoctamin 1 (Tclin), all other anoctamins are labelled Tbio.”

Probably not a substantial claim: may not pass S4 (based).

No scalable systems are currently available to study localization of functional ion channel complexes.

“Currently, there are no scalable systems available to study the localization of functional complexes.”

May combine two claims.

Understudied Tbio and Tdark kinases share characteristics including poorly defined integration in signalling networks, poorly defined function and regulation, lack of antibodies, and lack of selective chemical tools.

“Some of the characteristics shared by understudied Tbio and Tdark kinases include poorly defined integration of the kinase in signalling networks, poorly defined function and regulation, lack of activation-loop phospho-antibodies or immunohistochemistry-grade antibodies, and lack of selective chemical tools for functional characterization.”

May combine two claims.

Seven additional FDA-approved antibodies target HER2, EGFR, VEGFR2 and PDGFRα, and an FDA-approved HER2-targeting antibody-drug conjugate trastuzumab emtansine exists.

“An additional seven FDA-approved antibodies target the receptor tyrosine kinases human epidermal growth factor receptor 2 (HER2; also known as ERBB2), epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor 2 (VEGFR2) and platelet-derived growth factor receptor-α (PDGFRα), and there is also an FDA-approved HER2-targeting antibody-drug conjugate, trastuzumab emtansine (”

May combine two claims.

As of March 2017, mouse lines for 4,165 human genes have been produced with phenotypes available, and 2,788 have statistically significant phenotype calls.

“As of March 2017, mouse lines corresponding to 4,165 human genes have been produced, with phenotypes available, 2,788 of which have resulted in statistically significant phenotype calls.”

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

IMPC has targeted 238 kinases with 114 knockouts having significant phenotype; 22 are of current interest for phase 2 IDG.

“Currently, the IMPC has targeted 238 kinases with 114 knockouts having a significant phenotype; of the latter, 22 are of current interest for phase 2 of the IDG programme.”

Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

These questions have yet to find a computer-driven, reliable answer.

“These, and other similar questions, have yet to find a computer-driven, reliable answer.”

May combine two claims.

According to DrugCentral, sorafenib inhibits 114 kinases with only 9 MoA-related targets, while sunitinib inhibits 263 kinases with 9 MoA-related targets.

“According to data in DrugCentral, sorafenib inhibits 114 kinases, of which only 9 are associated MoArelated targets, whereas sunitinib inhibits 263 kinases, of which 9 are MoA-related targets.”

• AssumptionRests on an assumption: DrugCentral annotations accurately reflect drug-target interactions.

May combine two claims.

The NIH launched the IDG initiative in 2014 to map knowledge gaps around proteins and promote understudied druggable proteins.

“the US National Institutes of Health launched the Illuminating the Druggable Genome (IDG) initiative in 2014”

• Also stated in: § Illuminating the Druggable Genome. · plain

  “the US National Institutes of Health (NIH) launched the Illuminating the Druggable Genome (IDG) initiative in 2014”

Classified as probably not a substantial claim.

The Tchem cut-offs were set so that roughly 90% of activity values for drugs with a confirmed mechanism against a target in that family would be included.

“we required the bio-activity of at least one small molecule to be above a specific cut-off chosen to include about 90% of the bioactivity values of drugs with a confirmed MoA for a target from that protein family”

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

TDL assignments except Tclin were performed without human curation.

“Except for Tclin, TDL assignments were performed without human curation.”

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

The first three data types were used to assign TDL for Tbio and Tdark, while the other four provide independent validation of the criteria.

“Whereas the first three data types were used to assign the TDL category for proteins in the Tbio and Tdark categories, the other four data types — derived from separate text corpora and repositories — provide independent validation of our criteria for categorization overall.”

May combine two claims.

Lack of tools leads to lack of interest, and lack of interest reduces the probability that such tools will be developed.

“Lack of tools leads to lack of interest, and lack of interest diminishes the probability of such tools being developed.”

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

For every Tchem target, selectivity was not incorporated into the assignment.

“Selectivity, though important both in vivo and in vitro, could not be factored in for all Tchem targets”

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

Valvular heart disease is associated with anorectic agents such as fenfluramine and antimigraine medications such as ergotamine via serotonin 5-HT2B receptor agonism.

“For example, valvular heart disease is associated with anorectic agents, such as fenfluramine, and antimigraine medications, such as ergot-amine, via serotonin 5-HT2B receptor agonism66.”

• cites [66] Roth, B. L. Drugs and valvular heart disease. N. Engl. J. Med. 356, 6–9 (2007). sourceNot checked — no full text of the source

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

Wu and colleagues found 38 small-molecule protein kinase inhibitors.

“Wu and colleagues74 found 38 small-molecule protein kinase inhibitors.”

• cites [74] Wu, P., Nielsen, T. E. & Clausen, M. H. Small-molecule kinase inhibitors: an analysis of FDA-approved drugs. Drug Discov. Today 21, 5–10 (2016). sourceNot checked — no full text of the source

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

Off-target actions within the GPCR class can be associated with severe and life-threatening side effects.

“As with other druggable target classes, off-target actions within the GPCR class can be associated with severe and lifethreatening side effects.”

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

The association between schizophrenia and Fzd3 mutants remains controversial.

“For example, Adgrb2-mutant mice (Tbio) showed significant antidepressant-like behaviour compared with wild-type mice70, whereas the association71 between schizophrenia and Fzd3 mutants (T) remains controversial72,73.”

• cites [71] Katsu, T. et al. The human frizzled-3 (FZD3) gene on chromosome 8p21, a receptor gene for Wnt ligands, is associated with the susceptibility to schizophrenia. Neurosci. Lett. 353, 53–56 (2003). sourceNot checked — no full text of the source
• cites [72] Wei, J. & Hemmings, G. P. Lack of a genetic association between the frizzled-3 gene and schizophrenia in a British population. Neurosci. Lett. 366, 336–338 (2004). sourceNot checked — no full text of the source
• cites [73] Jeong, S. H., Joo, E. J., Ahn, Y. M., Lee, K. Y. & Kim, Y. S. Investigation of genetic association between human Frizzled homolog 3 gene (FZD3) and schizophrenia: results in a Korean population and evidence from meta-analysis. Psychiatry Res. 143, 1–11 (2006). sourceNot checked — no full text of the source

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

Several FXR agonists are currently in clinical development.

“Currently, several FXR agonists are in clinical development52.”

• cites [52] Hambruch, E., Kinzel, O. & Kremoser, C. On the pharmacology of farnesoid X receptor agonists: give me an 'A', like in 'acid'. Nucl. Recep. Res. 3, 101207 (2016). sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S4 (based).

The ~600-member human kinome is highly druggable using competitive and allosteric small-molecule inhibitors.

“The ~600-member human kinome (Supplementary Table S3) is made up of protein kinases, in addition to metabolic and lipid kinases, and is highly druggable using both competitive and allosteric small-molecule inhibitors.”

Classified as probably not a substantial claim.

The paucity of antibodies and small molecules diminishes the ability to subject Tdark proteins to scientific inquiry.

“Indeed, the paucity of antibodies and small molecules (criteria that help define Tbio and proteins diminishes our ability to subject Tdark proteins to scientific inquiry.”

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

The TDL classification scheme provides a convenient way to partition human targets and highlights focus or lack of science and drug discovery efforts.

“The TDL classification scheme provides a convenient way to partition human targets that highlights the focus (or lack thereof) of science and drug discovery efforts on different targets.”

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

The only other deliberate targeted effort to study Tdark proteins besides IDG is IMPC.

“As mentioned above, the only other deliberate targeted effort to study Tdark proteins in addition to IDG is the IMPC.”

May combine two claims.

Through TDL groupings, knowledge accumulation and deficits can be highlighted for target families, with the common theme that much is known but a large fraction of the proteome remains understudied.

“Through the use of the TDL groupings, we can highlight knowledge accumulation, as well as deficits, for a variety of target families, with a common theme being that while much is known, there remains a large fraction of the proteome that is understudied.”

Probably not a substantial claim: may not pass S4 (based).

Ion channels mediate signalling within cells, between cells, and between cells and their environment.

“Ion channels mediate signalling within cells, between cells, and between cells and their environment.”

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

These artificial divisions can prevent scientists from achieving a translational, integrative view of gene and protein function.

“These artificial divisions can prevent scientists from achieving a translational, integrative view of gene and protein function.”

May combine two claims.

IDG KMC enables quantitative demonstration of a knowledge deficit for dark and understudied proteins, underscoring the need for basic science.

“The IDG KMC enables us to quantitatively demonstrate the existence of a knowledge deficit with respect to dark and understudied proteins, which underscores the need for basic science and its major role in illuminating gene functions and roles in human disease.”

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

Non-positive facts fit poorly to current publishing and citation paradigms.

“However, such non-positive facts fit poorly to current publishing and citation paradigms.”

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

LRRC8 heteromers form volume-regulated anion channels, ORAI proteins assemble to form CRACs, and anoctamins are olfactory calcium-activated chloride channels.

“For example, leucine-rich repeat-containing protein 8 (LRRC8) heteromers form82 volume-regulated anion channels (VRACs), and ORAI proteins assemble to form83 calcium-releaseactivated calcium channels (CRACs), whereas anoctamins are olfactory calcium-activated chloride channels (CACCs)84.”

• cites [82] Pedersen, S. F., Klausen, T. K. & Nilius, B. The identification of a volume-regulated anion channel: an amazing Odyssey. Acta Physiol. 213, 868–881 (2015). sourceNot checked — no full text of the source
• cites [83] Niemeyer, B. A. Changing calcium: CRAC channel (STIM and Orai) expression, splicing, and posttranslational modifiers. Am. J. Physiol. Cell Physiol. 310, C701–709 (2016). sourceNot checked — no full text of the source
• cites [84] Dauner, K., Lissmann, J., Jeridi, S., Frings, S. & Möhrlen, F. Expression patterns of anoctamin 1 and anoctamin 2 chloride channels in the mammalian nose. Cell Tissue Res. 347, 327–341 (2012). sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

Confirmed disease associations or receptor deorphanization remain major incentives to allocate resources and further study Tdark proteins.

“Confirmed associations with a specific disease, or receptor deorphanization (TABLE 4), remain major incentives to allocate resources and further study of Tdark proteins.”

Probably not a substantial claim: may not pass S4 (based).

Most ion channels have paralogues that function redundantly.

“Moreover, most ion channels have paralogues that function redundantly.”

Probably not a substantial claim: may not pass S4 (based).

A key challenge for IDG KMC and other drug discovery data analysts is reliable predictions about next experiments, phenotypes and pathways.

“Finally, a key challenge faced by IDG KMC, and perhaps by other data analysts working in drug discovery, is that of reliable predictions: when examining Tdark proteins in particular, experimentalists would like to know what experiment to do next, what phenotypic changes should be examined first and which pathway is relevant in a specific disease.”

Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

This distinction breaks down in nature, as the same genes and pathways likely interact regardless of organ, albeit context-specifically.

“This distinction breaks down in nature, as we are likely to observe the interplay between the same genes and pathways regardless of organ, albeit in a contextspecific manner.”

Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

Modern medicine often employs artificial distinctions by organ or disease, and these separations carry into research.

“Modern medicine often employs artificial distinctions in terms of what and how biological systems are studied: segregated by organ (for example, ophthalmology and cardiology) or by disease (for example, oncology and infectious diseases), medical specialty separations carry over into the research arena, both in academia and industry.”