737 Matching Annotations
  1. Feb 2026
    1. Our next goal was to define the molecular signatures of each TSC hamartomatous lesion type using genome-wide DNA methylation and transcript profiling. Unsupervised clustering of DNA methylation array data revealed lesion

      [Paragraph-level] PMCID: PMC5481739 Section: RESULTS PassageIndex: 12

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses the somatic DNMT3A-V716F mutation and its predicted effect on methyltransferase activity, indicating that the variant alters molecular function. Oncogenic: The mention of the somatic DNMT3A-V716F mutation in the context of a tumor suggests that it contributes to tumor development or progression.

      Gene→Variant (gene-first): 1788:V716F

      Genes: 1788

      Variants: V716F

    1. To analyze the response of KB1(L1363P)P mammary tumors to HRR deficiency-targeted therapy, we performed orthotopic transplantations with spontaneous donor tumors as previously described. To capture the heterogeneity of K

      [Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 15

      Evidence Type(s): Predictive, Oncogenic, Functional

      Justification: Predictive: The passage discusses the response of KB1(L1363P)P mammary tumors to targeted therapies, indicating that these tumors responded significantly better to cisplatin and the PARP inhibitor AZD2461, which correlates the variant with treatment response. Oncogenic: The variant is associated with tumor development and progression, as it is discussed in the context of mammary tumors and their response to therapies, suggesting a role in cancer biology. Functional: The passage describes how the variant affects the ability of tumor cells to induce RAD51 foci in response to gamma-radiation, indicating an alteration in molecular function related to DNA repair mechanisms.

      Gene→Variant (gene-first): 7158:L1363P 7158:p.L1363P

      Genes: 7158

      Variants: L1363P p.L1363P

    2. The embryonic lethality of Brca1LP/LP mice indicates that an intact BRCA1 coiled-coil domain is functionally important in vivo, in line with its requirement for BRCA1-mediated HRR. To analyze whether the functional defec

      [Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 11

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage discusses how the Brca1 p.L1363P variant contributes to tumor formation and accelerates tumor development in a mouse model, indicating its role in tumor progression. Functional: The passage indicates that the Brca1 p.L1363P variant has a functional defect that compromises BRCA1-mediated homologous recombination repair (HRR), suggesting an alteration in molecular function.

      Gene→Variant (gene-first): 7158:L1363P 7158:p.L1363P

      Genes: 7158

      Variants: L1363P p.L1363P

    3. To verify whether mouse Brca1 p.L1363P phenocopies human BRCA1 p.L1407P, we analyzed Brca1LP/LP;Trp53Delta/Delta (LP/LP) mutant and Brca1LP/+;Trp53Delta/Delta (LP/+) control MEFs for BRCA1-PALB2 interaction and HRR defec

      [Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 9

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The passage discusses increased sensitivity to cisplatin and PARP1 inhibition in the context of the Brca1 p.L1363P variant, indicating a correlation with treatment response. Functional: The variant p.L1363P is shown to severely attenuate BRCA1-PALB2 binding, which alters the molecular function related to homologous recombination repair (HRR).

      Gene→Variant (gene-first): 672:leucine to proline 7158:p.L1363P 672:p.L1407P

      Genes: 672 7158

      Variants: leucine to proline p.L1363P p.L1407P

    4. BRCA1 p.L1363P is unable to bind PALB2 and shows hypomorphic activity in HRR

      [Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 8

      Evidence Type(s): Functional

      Justification: Functional: The passage indicates that the variant p.L1363P alters the binding ability of BRCA1 to PALB2 and affects its activity in homologous recombination repair (HRR), demonstrating a change in molecular function.

      Gene→Variant (gene-first): 7158:p.L1363P

      Genes: 7158

      Variants: p.L1363P

    5. In the complete absence of TP53, Brca1LP/LP mice developed apparently normal until at least E13.5, although no postnatal survival was observed upon compound heterozygous intercrosses (Table 3). This allowed us to isolate

      [Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 7

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses the evaluation of the functional consequences of the Brca1 p.L1363P variant, indicating that it alters molecular or biochemical function.

      Gene→Variant (gene-first): 7158:p.L1363P

      Genes: 7158

      Variants: p.L1363P

    6. For a first functional analysis of Brca1 p.L1363P in vivo, heterozygous Brca1LP mice were intercrossed and their offspring was genotyped. No Brca1LP/LP mice were born; therefore, embryos were analyzed at different stages

      [Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 5

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses a functional analysis of the Brca1 p.L1363P variant, indicating that it alters embryonic development and leads to growth defects in mice, which demonstrates its impact on molecular or biochemical function. Oncogenic: The analysis of the Brca1 p.L1363P variant in the context of embryonic development and its comparison to Brca1-null mice suggests that it may contribute to tumor development or progression, as it is associated with severe phenotypes similar to pathogenic mutations in Brca1.

      Gene→Variant (gene-first): 7158:p.L1363P

      Genes: 7158

      Variants: p.L1363P

    7. We used CRISPR/Cas9-mediated genome editing in FVB mouse zygotes to model the BRCA1 coiled-coil domain VUS c.4220T>C p.L1407P, which disrupts the interaction of BRCA1 with PALB2. The BRCA1 coiled-coil domain is well cons

      [Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 3

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the variant p.L1407P disrupts the interaction of BRCA1 with PALB2 and predicts that it disables the alpha-helical structure of the coiled-coil domain, indicating an alteration in molecular function. Oncogenic: The use of CRISPR/Cas9 to model the BRCA1 variant in mice suggests that the variant contributes to tumor development or progression, as it is being studied in the context of a gene essential for embryonic development and cancer biology.

      Gene→Variant (gene-first): 672:4220T>C 7158:p.L1363P 672:p.L1407P

      Genes: 672 7158

      Variants: 4220T>C p.L1363P p.L1407P

    1. Although activating mutations of FGFR3 are frequent in bladder tumors, little information is available on their specific effects in urothelial cells or the basis for the observed mutation spectrum. We investigated the ph

      [Paragraph-level] PMCID: PMC2789045 Section: ABSTRACT PassageIndex: 1

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the FGFR3 mutations (S249C, Y375C, and K652E) alter molecular signaling pathways, specifically the phosphorylation of various proteins, indicating a change in biochemical function. Oncogenic: The passage describes how the mutant FGFR3 variants induce morphological transformation, cell proliferation, and anchorage-independent growth, which are indicative of their role in tumor development and progression.

      Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C

      Genes: 2261

      Variants: K652E S249C Y375C

    1. Results: After combining the result of the two stages, 4 SNPs were significantly associated with HNSCC survival (rs16879870 at 6q14.3: adjusted HR = 2.02, 95%CI = 1.50-2.73, P = 3.88 x 10-6; rs2641256 at 17p13.2: adjuste

      [Paragraph-level] PMCID: PMC7099049 Section: ABSTRACT PassageIndex: 3

      Evidence Type(s): Prognostic, Functional

      Justification: Prognostic: The passage discusses the association of SNPs with HNSCC survival, indicating that these variants correlate with disease outcome, specifically overall survival, independent of therapy. Functional: The passage mentions that the genotype of rs16879870 and rs854936 is significantly associated with the expression of specific genes in cancer tissues, suggesting that these variants alter molecular function.

      Gene→Variant (gene-first): NA:rs16879870 388325:rs2641256 341019:rs2761591 NA:rs854936

      Genes: NA 388325 341019

      Variants: rs16879870 rs2641256 rs2761591 rs854936

    1. Mutations in SF3B1 have been identified across several cancer types. This key spliceosome component promotes the efficient mRNA splicing of thousands of genes including those with crucial roles in the cellular response t

      [Paragraph-level] PMCID: PMC7612475 Section: ABSTRACT PassageIndex: 1

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The K700E mutation in SF3B1 increases cellular sensitivity to ionising radiation and various chemotherapeutic agents, including PARP inhibitors, indicating a correlation with treatment response. Functional: The K700E mutation alters HR efficiency and induces unscheduled R-loop formation, replication fork stalling, and defective replication fork restart, demonstrating an impact on molecular function.

      Gene→Variant (gene-first): 23451:K700E

      Genes: 23451

      Variants: K700E

    1. Macrodactyly is a discrete congenital anomaly consisting of enlargement of all tissues localized to the terminal portions of a limb, typically within a 'nerve territory'. The classic terminology for this condition is 'li

      [Paragraph-level] PMCID: PMC3542862 Section: ABSTRACT PassageIndex: 1

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage discusses somatic mutations in PIK3CA (including R115P, E542K, H1047L, and H1047R) that contribute to the pathophysiology of macrodactyly, indicating their role in tumor development or progression through activation of the PI3K/AKT signaling pathway. Functional: The passage mentions that the identified mutations lead to AKT activation, which indicates that these variants alter molecular or biochemical function related to cell signaling pathways.

      Gene→Variant (gene-first): 5290:E542K 5290:H1047L 5290:H1047R 5163:R115P

      Genes: 5290 5163

      Variants: E542K H1047L H1047R R115P

    1. PIK3CA encoding the phosphoinositide 3-kinase (PI3K) p110alpha catalytic subunit is frequently mutated in cancer, with mutations occurring widely throughout the primary sequence. The full set of mechanisms underlying how

      [Paragraph-level] PMCID: PMC9837058 Section: ABSTRACT PassageIndex: 1

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage discusses how mutations in PIK3CA, including G1049R, H1047R, and M1043I/L, contribute to the activation of the PI3K pathway, indicating their role in tumor development or progression. Functional: The passage describes how specific mutations alter the conformation and binding properties of the p110alpha subunit, indicating that these variants affect molecular function related to PI3K activation.

      Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043I/L

      Genes: 5290

      Variants: G1049R H1047R M1043I/L

    2. We also compared HDX-MS differences in full-length p110alpha-p85alpha between WT, H1047R and DeltaC in the presence and absence of pY (Supplementary Fig. 6). The binding of pY led to significant increases for all three c

      [Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 19

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the H1047R variant alters the binding interactions and structural dynamics of the protein in response to pY binding, indicating a change in molecular function.

      Gene→Variant (gene-first): 5290:H1047R

      Genes: 5290

      Variants: H1047R

    3. The H1047R, G1049R, and the DeltaCter constructs showed similar significant increases compared to the WT in the kinase domain (Fig. 5A-C). These included regions covering 850-858 (hinge between the N and C lobes), the ac

      [Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 18

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the H1047R and G1049R variants alter the molecular interactions and conformations within the kinase domain, indicating a change in biochemical function related to the protein's activity. Oncogenic: The evidence suggests that the H1047R and G1049R variants contribute to activation through disruption of the inhibitory conformation, which is indicative of their role in tumor development or progression.

      Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043L 5290:N1068fs

      Genes: 5290

      Variants: G1049R H1047R M1043L N1068fs

    4. HDX-MS experiments were carried out for 4-5 timepoints of exchange (3 s at 1 C, 3, 30, 300, and 3000 s at 20 C) for each complex. The full set of all peptides analysed for both p110alpha and p85alpha are shown in the Sou

      [Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 17

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses changes observed for the H1047R variant in the context of HDX-MS experiments, indicating that it alters molecular or biochemical function, specifically in terms of perturbations in conformation.

      Gene→Variant (gene-first): 5290:H1047R

      Genes: 5290

      Variants: H1047R

    5. To test if C-terminal mutations worked by disrupting the inhibitory interaction with the C-terminus, we carried out HDX-MS studies on six constructs of full-length p110alpha (WT, M1043L, H1047R, G1049R, N1068fs, and a co

      [Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 16

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how C-terminal mutations, including M1043L, H1047R, G1049R, and N1068fs, affect the inhibitory interaction with the C-terminus, indicating an alteration in molecular function. Oncogenic: The mention of "oncogenic mutation" in relation to M1043L, H1047R, and G1049R suggests that these somatic variants contribute to tumor development or progression.

      Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043L 5290:N1068fs

      Genes: 5290

      Variants: G1049R H1047R M1043L N1068fs

    6. For these mutants, we had difficulty in obtaining sufficient yield of the proteins for extensive biophysical analysis. To circumvent this, we used the kinase dead variants to characterise their membrane binding using pro

      [Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 14

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the variants H1047R, G1049R, M1043L, and N1068fs alter membrane binding and ATPase activity, indicating changes in molecular function. Oncogenic: The variants are described in the context of their effects on membrane binding and ATPase activity, which suggests a role in tumor development or progression.

      Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043L 5290:N1068fs

      Genes: 5290

      Variants: G1049R H1047R M1043L N1068fs

    7. We characterised the intrinsic ATPase activity of each p110alpha mutant (Fig. 4A + B), and while this assay does not measure biologically relevant PIP3 activity, it can measure intrinsic differences in PI3K activity inde

      [Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 13

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses the intrinsic ATPase activity of the p110alpha mutants, indicating that the variants G1049R, H1047R, and M1043L alter molecular function by exhibiting significantly increased ATPase activity compared to wild type. Oncogenic: The context of the passage implies that the variants are somatic mutations in a cancer-related gene, contributing to tumor development or progression through their altered biochemical activity.

      Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043L 5290:N1068fs

      Genes: 5290

      Variants: G1049R H1047R M1043L N1068fs

    8. To understand the regulatory mechanisms underlying the inhibitory interface with the C-terminus we analysed the most frequent oncogenic mutants that occur at or near this interface. While H1047R/L is the most frequent mu

      [Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 12

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage discusses frequent oncogenic mutants and their role in tumor samples, indicating that these variants contribute to tumor development or progression. Functional: The analysis of the mutants and their binding to full-length p85alpha suggests that these variants alter molecular or biochemical function, specifically in the context of their interaction with regulatory complexes.

      Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:H1047R/L 5290:M1043L 5290:M1043L/I 5290:N1044K 5290:N1068fs

      Genes: 5290

      Variants: G1049R H1047R H1047R/L M1043L M1043L/I N1044K N1068fs

    9. While the disengagement of the ABD and p85 being involved in membrane binding provides a molecular rationale for activation by oncogenic mutations in the ABD, C2, and helical domains, it does not fully explain the molecu

      [Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 11

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage discusses the H1047R mutation in the context of its role in activating the kinase domain and increasing membrane binding, indicating its contribution to tumor development or progression. Functional: The passage describes how the H1047R mutation alters the molecular interactions and structural organization of the kinase domain, affecting its binding properties and functionality.

      Gene→Variant (gene-first): 5290:H1047R 5290:His1047 5290:Met1043

      Genes: 5290

      Variants: H1047R His1047 Met1043

    10. When comparing our data to the full set of missense oncogenic mutations in the ABD, ABD-RBD linker, C2, helical and the N-lobe of the kinase domain we find that all mutations found in >30 tumours except one (E726K) are l

      [Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 9

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage discusses the E726K variant in the context of oncogenic mutations and its association with conformational changes that contribute to tumor development, indicating its role in cancer progression. Functional: The passage describes how the E726K variant leads to conformational changes affecting the interaction between the ABD and p85 with the catalytic core, suggesting an alteration in molecular function.

      Gene→Variant (gene-first): 5290:E726K

      Genes: 5290

      Variants: E726K

    11. We have extensively characterised the membrane binding of the p110alpha/p85alpha complex using HDX-MS, however, the disengagement of the ABD and p85 from the catalytic core has likely complicated the analysis of membrane

      [Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 8

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the N345K variant affects the molecular interactions and binding of the p110alpha/p85alpha complex to membranes, indicating an alteration in biochemical function.

      Gene→Variant (gene-first): 5290:N345K

      Genes: 5290

      Variants: N345K

    12. This data comparing the full-length heterodimer vs p110alpha core allowed us to define the effect of ABD removal on the contact site at the ABD-RBD linker. This region still is protected from exchange at early time point

      [Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 4

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage discusses oncogenic mutants (N345K, G106V, and G118D) and their expected role in promoting ABD/iSH2 disengagement, indicating their contribution to tumor development or progression. Functional: The data suggests that the variants alter the dynamics of the ABD-p85 complex and its interaction with the p110alpha catalytic core, indicating a change in molecular function related to binding and mobility.

      Gene→Variant (gene-first): 5290:G106V 5290:G118D 5290:N345K

      Genes: 5290

      Variants: G106V G118D N345K

    13. To investigate the role of the ABD domain/p85 regulatory subunit in controlling PI3K enzyme activity, we needed a construct that allowed us to interrogate the dynamic effects of full ABD disengagement. We engineered and

      [Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 2

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses the D915N mutation in the context of its effect on protein conformation and membrane binding, indicating that it alters molecular function as assessed by HDX-MS experiments.

      Gene→Variant (gene-first): 5290:D915N

      Genes: 5290

      Variants: D915N

    1. To examine the biologic effects of ERBB2 E401G in cancer cells, we evaluated the proliferative and invasive capacities of H460 cells. We found that cells expressing ERBB2 S310F exhibited a significantly higher proliferat

      [Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 16

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses the effects of the ERBB2 E401G and S310F variants on the proliferative and invasive capacities of cancer cells, indicating that these variants alter molecular or biochemical functions related to cell behavior. Oncogenic: The evaluation of the proliferative and invasive capacities of cells expressing the ERBB2 variants suggests that these somatic variants contribute to tumor development or progression.

      Gene→Variant (gene-first): 2176:E401G 2064:S310F

      Genes: 2176 2064

      Variants: E401G S310F

    2. Our simulation data showed that the activating mechanisms of ERBB2 E401G and S310F were related to the EGFR-HER2 heterodimer. The dimerization partner appears to be an important determinant of signaling activity. The two

      [Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 14

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the variants E401G and S310F alter the phosphorylation of downstream signaling pathway proteins, indicating a change in molecular function related to the MAPK pathway. Oncogenic: The evidence suggests that the variants contribute to tumor development or progression by activating signaling pathways associated with cancer, specifically through the ERBB2 dimerization and its effects on downstream signaling.

      Gene→Variant (gene-first): 2176:E401G 2064:S310F

      Genes: 2176 2064

      Variants: E401G S310F

    3. In a previous simulation study, the dimer interfaces of both the EGFR homodimer and the EGFR-HER2 heterodimer were destabilized when the EGFR lost EGF (a specific ligand of EGFR). We therefore conducted MD simulations of

      [Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 12

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the E401G and S310F mutations affect the dimer interface stability of the EGFR-HER2 complex, indicating that these variants alter molecular interactions and stability.

      Gene→Variant (gene-first): 2176:E401G 2064:S310F

      Genes: 2176 2064

      Variants: E401G S310F

    4. HER2 p.(E401G) stabilizes ligand-free EGFR HER2 heterodimer

      [Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 10

      Evidence Type(s): Functional

      Justification: Functional: The passage indicates that the variant p.(E401G) alters the stability of the ligand-free EGFR HER2 heterodimer, which suggests a change in molecular function.

      Gene→Variant (gene-first): 2176:p.(E401G)

      Genes: 2176

      Variants: p.(E401G)

    5. C-terminal phosphorylation of HER family proteins is caused by dimerization followed by trans-autophosphorylation, in which one receptor subunit of the dimer phosphorylates the other. Among the HER family proteins, EGFR,

      [Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 9

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the variants E401G and S310F lead to increased phosphorylation levels of HER2 and EGFR, indicating that these variants alter molecular function related to protein activity. Oncogenic: The context of the passage suggests that the variants E401G and S310F contribute to tumor development or progression by enhancing the phosphorylation of key HER family proteins involved in oncogenesis.

      Gene→Variant (gene-first): 2176:E401G 2064:S310F

      Genes: 2176 2064

      Variants: E401G S310F

    6. Identification of potential dimerization partners of HER2 E401G protein

      [Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 8

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses the identification of potential dimerization partners of the HER2 E401G protein, indicating that the variant alters molecular interactions.

      Gene→Variant (gene-first): 2176:E401G

      Genes: 2176

      Variants: E401G

    7. Next, we analyzed C-terminal phosphorylation of HER2 using conventional SDS/PAGE and Western blotting. Compared with cells expressing ERBB2 WT, cells expressing ERBB2 S310F (a positive control variant elevating C-termina

      [Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 7

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the variants S310F and E401G alter the C-terminal phosphorylation of HER2, indicating a change in molecular function.

      Gene→Variant (gene-first): 2176:E401G 2064:S310F

      Genes: 2176 2064

      Variants: E401G S310F

    8. First, we examined whether E401G can form disulfide-linked dimers using SDS/PAGE under non-reducing conditions (for preserving disulfide bonds) and Western blotting. Compared with cells expressing ERBB2 WT, H460 cells ex

      [Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 6

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses the ability of the variants E321G, E401G, and S310F to form disulfide-linked dimers, indicating that these variants alter molecular function related to protein interactions.

      Gene→Variant (gene-first): 7157:E321G 2176:E401G 2064:S310F

      Genes: 7157 2176 2064

      Variants: E321G E401G S310F

    9. To examine the functional properties of ERBB2 E401G, an ECD III variant, we evaluated two types of mechanisms of activation of ECD variants previously reported: formation of disulfide-linked dimers and elevation of C-ter

      [Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 5

      Evidence Type(s): Functional

      Justification: Functional: The passage mentions the evaluation of mechanisms for multiple ERBB2 variants, including E321G, E401G, S310F, and D845A, which suggests that these variants are being assessed for their biochemical functions.

      Gene→Variant (gene-first): 2064:D845A 7157:E321G 2176:E401G 2064:S310F

      Genes: 2064 7157 2176

      Variants: D845A E321G E401G S310F

    10. ERBB2 E401G has functional properties similar to those of S310F

      [Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 4

      Evidence Type(s): Functional

      Justification: Functional: The passage indicates that ERBB2 E401G has functional properties similar to S310F, suggesting that these variants alter molecular or biochemical function.

      Gene→Variant (gene-first): 2176:E401G 2064:S310F

      Genes: 2176 2064

      Variants: E401G S310F

    11. A 67-year-old Japanese woman, previous healthy, presented with right inguinal pain with no family history of cancer. Fluorodeoxyglucose (FDG)-positron emission tomography with CT showed increased FDG accumulation in the

      [Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 3

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage describes the ERBB2 E401G variant as a somatic mutation that is associated with ERBB2 gene amplification, indicating its contribution to tumor development or progression. Functional: The passage mentions that multiple computational tools supported a deleterious effect of the ERBB2 E401G variant on the encoded gene product, suggesting that it alters molecular or biochemical function.

      Gene→Variant (gene-first): 2176:E401G

      Genes: 2176

      Variants: E401G

  2. Oct 2025
  3. Aug 2025
    1. Disease: Von-willebrand Disease (Vicenza)

      Model organism: Mice

      Variant: VWF NM_000552.5 c:3614G>A p.(R1205H), E3 module of D3 domain

      Patient Phenotypes: enhanced VWF clearance, reduced plasma VWF:Ag ratio (Reduced half-life).

      Other substitutions at the R1205 position results in similar enhanced VWF clearance. (Cysteine and Serine) Ref DOIs: (10.1111/jth.12875) (10.1160/TH07-09-0565)

      Suggests VWF-R1205 plays a specific roles in regulating VWF clearance in vivo. They authors finding demonstrage significant conformational changes to WVF-D'D3 region. Conformational changes trigger an enhanced macrophage-mediated clearance which is most likely modulated through SR-AI and LRP1 VWF clearance receptors.

    1. why was I able to do that okay because I You can hear the melody was going 355 1 7 55 5 6 54 right. It's harder to say it than it is to play it. Um that goes 3 55 51 7 uh 5 32. Right? So I'm able to hear the scale degrees. I'm able to hear the chords 6 1 54.

      As soon as I heard him sing in movable do or in scale degrees instead of fixed do or absolute note names (A-G), I subscribed. It's a rare kind of teacher who does that, unfortunately.

      一聽到這位老師用1-7數字(或相對的「可移動Do」唱名系統)來表達旋律: 3551 755654 3551 7532 而不是絕對音名(A-G),例如(假設是G調): B D D G 升F D D E D C ... 我就追蹤他頻道了,因為懂得會用 scale degree 音階級數來表達的老師,十個大概不到一個,大多西方(英美)的音樂老師好像從小都是學了絕對音名A-G那一套,對學習功能和聲和和弦與主音之間關係,一點幫助都沒有!

  4. Apr 2025
  5. Mar 2025

    Tags

    Annotators

  6. Jan 2025
  7. Sep 2023
  8. Aug 2023
  9. Jul 2023
    1. The notion of functional integration as a basis for biological identity was fully developed only in the 19th century, where it was transformed by the rise of both cell and evolutionary theory. Herbert Spencer
      • Herbert Spencer fully developed Digby's concept into the modern concept of functional integration
        • Spencer introduced the term "survival of the fittest"
        • ‘He tried to unite complex new findings about metabolism and organismic development with evolution and the seeming correspondence of organisms to their environments.
          • In The Principles of Biology (1864), Spencer wrote
            • a biological individual is one in which
            • the interdependence of the parts allows it to function and
            • respond to environmental change as a whole.
          • That is: ‘any concrete whole having a structure which enables it,
            • when placed in appropriate conditions,
        • to continuously adjust its internal relations to external relations, - so as to maintain the equilibrium of its functions.’
    2. Digby’s answer was to say that the wholeness comes from the system being functionally interdependent and integrated.
      • Digby’s answer to the fundamental question:
        • What is it that unites the parts of a system into a living individual? was the precursor to the biological concept of functional integration:
        • wholeness comes from the system being functionally interdependent and integrated.
          • the activities in one part of the system are brought about
          • by a cause external to the part where it occurs (interdependence);
          • and the mutual workings of the parts account for the behaviour of the system as a whole,
          • making this activity internal to the entire system (integration).
          • Here is an example using an Elephant
            • An elephant’s heart pumps blood only because it’s supplied with
              • energy from the digestive system,
              • oxygen from the respiratory system, and
              • support from the skeletal system.
            • All those bits working in tandem is what makes it possible for an elephant to walk around doing elephant things.
  10. Jun 2023
  11. Nov 2022
    1. Automated personalization, localization, recommendation, f iltering, classif ication, evaluation, aggregation, synthetization, or ad hoc generation of information are similarly pervasive practices that do not require explicit user input to select, sequence, arrange, or modulate some set of digital items
  12. Sep 2022
  13. Jul 2022
  14. Jun 2022
  15. Apr 2022
    1. Wine experts, meanwhile, know about surface-level characteristics like grapesand regions—but they think about wine in terms of function: wines that areluscious and fruity, good for pairing with spicy food; wines that are big and boldand can stand up to a hearty meal; wines that are fizzy and festive, fit for acelebration. “Luscious,” “Big,” and “Fizzy” are, in fact, three of the eightcategories Wesson devised for his stores (the others are “Soft,” “Fresh,” “Juicy,”“Smooth,” and “Sweet”).

      As an example of deep functional classification by experts, sommelier Joshua Wesson uses the functional categories luscious, big, fizzy, soft, fresh, juicy, smooth, and sweet to describe wines for customers rather than using the more straightforward and surface level grape varietal descriptors that are otherwise used to categorize wines in stores. These higher level functional classifications also assist in choosing a wine for pairing far more subtly than the extraneous grape types and regions which may carry little informational value to wine novices.

      Link to https://hypothes.is/a/uw_vPsHyEey1vX9dfqaNvA

  16. Jan 2022
    1. Douaud, G., Lee, S., Alfaro-Almagro, F., Arthofer, C., Wang, C., McCarthy, P., Lange, F., Andersson, J. L. R., Griffanti, L., Duff, E., Jbabdi, S., Taschler, B., Winkler, A. M., Nichols, T. E., Collins, R., Matthews, P. M., Allen, N., Miller, K. L., & Smith, S. M. (2021). Brain imaging before and after COVID-19 in UK Biobank (p. 2021.06.11.21258690). https://doi.org/10.1101/2021.06.11.21258690

    1. What does a Functional Design have to offer? https://en.itpedia.nl/2019/01/16/wat-heeft-een-functioneel-ontwerp-te-bieden/ A functional design is a specification of the functions of the software that the end_users have agreed to. Many companies have a software_developer handbook that describes what topics a functional design should cover. This article looks at the steps of functional design in the context of software development.

  17. Nov 2021
    1. (the VTA is also part ofthis system, but is too small to image with standard fMRImethods, but see [35] for successful imaging methods).

      All imaging studies face questions of validity and should (and many do) link to comprehensive details on instrumentation, methodology, and interpretation. Apparently, the professional consensus remains that, properly executed and interpreted, fMRI and other functional imaging techniques based on detection of oxygenation can lead to highly valid conclusions. (See Nautil.us article.)

  18. Oct 2021
  19. Aug 2021
    1. ZIO ecosystem libraries generally do not directly expose any functional abstractions but still expose a highly compositional interface because their design is based on algebraic properties like this. Users don't have to learn about these abstractions unless they want to, they just get to benefit from better library design.
  20. Jul 2021
    1. Using multiple copies of a neuron in different places is the neural network equivalent of using functions. Because there is less to learn, the model learns more quickly and learns a better model. This technique – the technical name for it is ‘weight tying’ – is essential to the phenomenal results we’ve recently seen from deep learning.

  21. Jun 2021
  22. May 2021
  23. Mar 2021
    1. Put another way, it’s become clear to me over time that the problems with data races and memory safety arise when you have both aliasing and mutability. The functional approach to solving this problem is to remove mutability. Rust’s approach would be to remove aliasing. This gives us a story to tell and helps to set us apart. A note on terminology: I think we should refer to aliasing as sharing. In the past, we’ve avoided this because of its multithreaded connotations. However, if/when we implement the data parallelism plans I have proposed, then this connotation is not at all inappropriate. In fact, given the close relationship between memory safety and data races, I actually want to promote this connotation.
  24. Feb 2021
    1. “Functional programming language” is not a clearly defined term. From the various properties that are typically associated with functional programming I only want to focus on one: “Immutability” and referential transparency.

      I mean not clearly defined seems wrong, there are common accepted characteristics that make a language functional.

  25. Jan 2021
    1. The changes we needed to make to main to reassign post mean that this implementation doesn’t quite follow the object-oriented state pattern anymore: the transformations between the states are no longer encapsulated entirely within the Post implementation. However, our gain is that invalid states are now impossible because of the type system and the type checking that happens at compile time! This ensures that certain bugs, such as display of the content of an unpublished post, will be discovered before they make it to production.

      This is really an amazing chapter for comparing (some aspects) of object oriented and functional programming, and I have to admit I still prefer the functional approach as a default.

  26. Dec 2020
    1. Note: The examples in Listings 10-17, 10-18, and 10-24 declare variables without giving them an initial value, so the variable name exists in the outer scope. At first glance, this might appear to be in conflict with Rust’s having no null values. However, if we try to use a variable before giving it a value, we’ll get a compile-time error, which shows that Rust indeed does not allow null values.
  27. Nov 2020
    1. As it becomes more clear what are specific functional jobs to be done, we see more specialized apps closely aligned with solving for that specific loop. And increasingly collaboration is built in natively to them. In fact, for many reasons collaboration being natively built into them may be one of the main driving forces behind the venture interest and success in these spaces.

      As it becomes more clear what the functional job to be done is, we see more specialized apps aligned with solving that specific loop. Collaboration is increasingly built natively into them.

  28. Oct 2020
    1. All validators can be used independently. Inspried by functional programming paradigm, all built in validators are just functions.

      I'm glad you can use it independently like:

      FormValidation.validators.creditCard().validate({
      

      because sometimes you don't have a formElement available like in their "main" (?) API examples:

      FormValidation.formValidation(formElement
      
  29. Sep 2020
    1. It turns out that even the length of time an element has been mounted is an important piece of state that determines what pixels the user sees. And some of this state can’t simply be lifted into our application state.

      What this means is that our desire to express UI using pure functions is in direct conflict with the very nature of the DOM. It’s a great way to describe a state => pixels transformation — perfect for game rendering or generative art — but when we’re building apps on the web, the idea chafes against the reality of a stateful medium.

    2. Functions have lots of interesting and useful properties. You can isolate them. You can compose them. You can memoize them. In other words, functional UI feels correct, and powerful, in a way that wasn’t true of whatever came before it. I think this is why people get quasi-religious about React. It’s not that it’s Just JavaScript. It’s that it’s Just Functions. It’s profound.

    1. A paradigm is a model or pattern. In JavaScript, there are a number of popular paradigms including object-oriented programming (OOP) and functional programming (FP). Paradigms are more important than is sometimes recognized. They help form mental models for solving problems. Becoming well-versed in the principles of a given paradigm can help accelerate development by providing mental shortcuts for solving the challenges that arise while building applications. They can also help produce higher quality software.
  30. Jun 2020
    1. In systems engineering and requirements engineering, a non-functional requirement (NFR) is a requirement that specifies criteria that can be used to judge the operation of a system, rather than specific behaviors. They are contrasted with functional requirements that define specific behavior or functions

      This is a strange term because one might read "non-functional" and interpret in the sense of the word that means "does not function", when instead the intended sense is "not related to function". Seems like a somewhat unfortunate name for this concept. A less ambiguous term could have been picked instead, but I don't know what that would be.

  31. Apr 2020
  32. Feb 2020
  33. Jan 2020
  34. Nov 2019
  35. May 2019
    1. However, it is still often stated that the other orbital energies have no physical meaning, and that it is a pity that nothing like Koopmans' theorem to give meaning to the other occupied orbital energies exists. The truth could not be more different: it has been established22–25 that the KS orbital energies of the valence levels in molecules approximate the experimental ionization energies much more closely (typically at 0.1 eV level) than the Hartree–Fock orbital energies do (difference with IPs typically ∼1 eV).

      This is really one of the more spicy takes here. KS orbitals having no physical interpretation is often heard in the community, and here is a list of references and evidence that they do have physical significance.

  36. Jan 2019
  37. Nov 2018
    1. That is using a specific tool for a specific use case. You don’t actually have a table view of your data. Once it’s in a table, man, you’re good. That is the modeling. A sequel database table, you have this amazing high-level language for doing all sorts of cool operations with it.To turn this into some class hierarchy, it’s almost criminal. There, I said it. It’s like you’re throwing away the power that you have.

      about a situation when you sometime want an is-a relationship but in most cases just have it as loosely structured (table-like) data format

  38. Sep 2018
  39. Aug 2018
  40. Apr 2018
  41. Aug 2017
    1. Since Clojure uses the Java calling conventions, it cannot, and does not, make the same tail call optimization guarantees. Instead, it provides the recur special operator, which does constant-space recursive looping by rebinding and jumping to the nearest enclosing loop or function frame. While not as general as tail-call-optimization, it allows most of the same elegant constructs, and offers the advantage of checking that calls to recur can only happen in a tail position.

      Clojure's answer to the JVM's lack to tail call optimization

  42. Apr 2016
    1. In Switzerland, one of my recent ancestors was functionally illiterate. Because of this, she “signed away” most of her wealth. Down the line, I’m one of her very few heirs. So, in a way, I lost part of my inheritance due to illiteracy.

      Explained further in the screencast. My paternal grandfather’s mother came from a well-to-do Schneider family and was a devout Christian, but she “read” the Bible upside-down, according to my paternal grandmother.

  43. Mar 2016
  44. Jul 2015