Brca1 p.L1363P shows a defect in mammary tumor suppression
[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 10
Evidence Type(s): Oncogenic
Justification: Oncogenic: The variant p.L1363P is associated with a defect in mammary tumor suppression, indicating its contribution to tumor development or progression.
Gene→Variant (gene-first): 7158:p.L1363P
Genes: 7158
Variants: p.L1363P
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
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
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
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
Homozygous Brca1 p.L1363P (FVB) mice die during embryonic development
[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 4
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage indicates that the homozygous variant p.L1363P in Brca1 leads to embryonic lethality in mice, suggesting that it contributes to tumor development or progression.
Gene→Variant (gene-first): 7158:p.L1363P
Genes: 7158
Variants: p.L1363P
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
Generation of Brca1 p.L1363P (FVB) mice
[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 2
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 7158:p.L1363P
Genes: 7158
Variants: p.L1363P
MIB-1 labeling indices correlated with the diagnosis and grade assigned prior to H3 K27M IHC testing (Table 1). For the adult cohort, 1 case met WHO criteria for diffuse astrocytoma, WHO grade II (MIB-1 < 1%), 7 cases me
[Paragraph-level] PMCID: PMC5822176 Section: RESULTS PassageIndex: 6
Evidence Type(s): Diagnostic
Justification: Diagnostic: The passage discusses the correlation of MIB-1 labeling indices with the diagnosis and grade of tumors, indicating that the K27M variant is associated with specific tumor classifications.
Gene→Variant (gene-first): 3417:K27M
Genes: 3417
Variants: K27M
The known lower frequency of ATRX mutation/loss of ATRX nuclear immunostaining in only 10 - 15% of H3 K27M-mutant tumors makes this feature less amenable to comparisons between the 2 cohorts. However, of the 7 adult case
[Paragraph-level] PMCID: PMC5822176 Section: RESULTS PassageIndex: 5
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 3417:K27M
Genes: 3417
Variants: K27M
Four cases had other morphologies at initial biopsy, including pure GG (n = 3, pediatric) and PA (n = 1, adult) histologies. One of the GGs was a 16-year-old girl with an original biopsy demonstrating a pure thalamic GG
[Paragraph-level] PMCID: PMC5822176 Section: RESULTS PassageIndex: 4
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage discusses the transformation of tumors associated with the K27M variant, indicating its role in tumor development and progression, particularly in the context of glioblastoma transformation.
Gene→Variant (gene-first): 3417:K27M
Genes: 3417
Variants: K27M
Table 1 summarizes the ages, gender, anatomical location, initial histological diagnoses, and p53 IHC labeling indices discerned prior to H3 K27M IHC in the 28 H3 K27M-mutant tumors identified in our databases. There wer
[Paragraph-level] PMCID: PMC5822176 Section: RESULTS PassageIndex: 2
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the identification of H3 K27M-mutant tumors and provides demographic information, indicating that the variant is associated with specific histological diagnoses and patient characteristics. Oncogenic: The mention of H3 K27M in the context of tumors suggests that this somatic variant contributes to tumor development or progression, as it is identified in mutant tumors.
Gene→Variant (gene-first): 3417:K27M
Genes: 3417
Variants: K27M
Background: H3 K27M mutation was originally described in pediatric diffuse intrinsic pontine gliomas (DIPGs), but has been recently recognized to occur also in adult midline diffuse gliomas, as well as midline tumors wit
[Paragraph-level] PMCID: PMC5822176 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Diagnostic, Prognostic, Oncogenic
Justification: Diagnostic: The passage discusses the H3 K27M mutation's association with various tumor types, indicating its role in defining and classifying these tumors, particularly in pediatric and adult cohorts. Prognostic: The passage mentions survival outcomes for patients with H3 K27M-mutant tumors, comparing mean survival times between adults and pediatric patients, which indicates a correlation with disease outcome. Oncogenic: The H3 K27M mutation is described as contributing to tumor development in various glioma types, indicating its role as a somatic variant involved in tumor progression.
Gene→Variant (gene-first): 3417:K27M
Genes: 3417
Variants: K27M
To identify somatic mutations in paediatric diffuse intrinsic pontine gliomas (DIPGs), we performed whole genome sequencing of 7 DIPGs and matched germline DNA, and targeted sequencing of an additional 43 DIPGs and 36 no
[Paragraph-level] PMCID: PMC3288377 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the frequency of the p.K27M mutation in DIPGs and its association with this specific subtype of brain tumors, indicating its role in defining or classifying the disease. Oncogenic: The p.K27M and p.G34R mutations are described as somatic mutations found in pediatric gliomas, suggesting their contribution to tumor development or progression.
Gene→Variant (gene-first): 3021:p.G34R 3021:p.K27M
Genes: 3021
Variants: p.G34R p.K27M
CDK4/6 inhibition with endocrine therapy is now a standard of care for advanced estrogen receptor positive breast cancer. Mechanisms of CDK4/6 inhibitor resistance have been described pre-clinically, with limited evidenc
[Paragraph-level] PMCID: PMC6368247 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the emergence of the ESR1 Y537S mutation in the context of resistance to CDK4/6 inhibitors, indicating a correlation with treatment response and resistance. Oncogenic: The mention of the ESR1 Y537S mutation as a new driver mutation suggests that it contributes to tumor development or progression, particularly in the context of breast cancer.
Gene→Variant (gene-first): 5728:Y537S
Genes: 5728
Variants: Y537S
Twenty-seven patients with a median age of 49 years (range 23-82) were treated with BRAF inhibitors. Eleven patients received dabrafenib with trametinib, and 16 were treated with vemurafenib. Patients received 150 mg of
[Paragraph-level] PMCID: PMC5122709 Section: RESULTS PassageIndex: 3
Evidence Type(s): Predictive, Diagnostic, Oncogenic
Justification: Predictive: The passage discusses patients treated with BRAF inhibitors, specifically mentioning the BRAF V600E mutation, which correlates with response to these therapies. Diagnostic: The passage states that all patients tested positive for the BRAF V600E mutation, indicating its use in defining or confirming the presence of a specific subtype of melanoma. Oncogenic: The BRAF V600E mutation is implicated in the development of melanoma, suggesting its role as a somatic variant contributing to tumor progression.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
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
Conclusion: Our findings suggested that the SNPs (rs16879870, rs2641256, rs2761591, rs854936) might play a crucial role in prognosis of HNSCC.
[Paragraph-level] PMCID: PMC7099049 Section: ABSTRACT PassageIndex: 4
Evidence Type(s): Prognostic
Justification: Prognostic: The passage indicates that the SNPs are suggested to play a crucial role in the prognosis of HNSCC, which correlates with disease outcome.
Gene→Variant (gene-first): NA:rs16879870 388325:rs2641256 341019:rs2761591 NA:rs854936
Genes: NA 388325 341019
Variants: rs16879870 rs2641256 rs2761591 rs854936
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
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
Mutations in the KRAS oncogene are found in more than 90% of patients with pancreatic ductal adenocarcinoma (PDAC), with Gly-to-Asp mutations (KRASG12D) being the most common. Here, we tested the efficacy of a small-mole
[Paragraph-level] PMCID: PMC9900321 Section: ABSTRACT PassageIndex: 3
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the efficacy of a small-molecule KRASG12D inhibitor, MRTX1133, in treating pancreatic ductal adenocarcinoma, indicating a correlation between the Gly-to-Asp mutation and response to therapy. Oncogenic: The Gly-to-Asp mutation in the KRAS oncogene is described as contributing to tumor development in pancreatic ductal adenocarcinoma, as it is found in more than 90% of patients with this cancer type.
Gene→Variant (gene-first): 3845:Gly-to-Asp
Genes: 3845
Variants: Gly-to-Asp
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
Mutations in KRAS and BRAF were associated with inferior PFS and OS of mCRC patients compared with patients with non-mutated tumors. KRAS exon 2 mutation variants were associated with heterogeneous outcome compared with
[Paragraph-level] PMCID: PMC4999563 Section: ABSTRACT PassageIndex: 9
Evidence Type(s): Prognostic, Diagnostic
Justification: Prognostic: The passage indicates that KRAS G12C and G13D mutations are associated with inferior progression-free survival (PFS) and overall survival (OS) in mCRC patients, suggesting a correlation with disease outcome independent of therapy. Diagnostic: The mention of KRAS mutations being associated with heterogeneous outcomes compared to unmutated tumors implies that these variants can be used to classify or define a disease subtype in mCRC.
Gene→Variant (gene-first): 3845:G12C 3845:G13D
Genes: 3845
Variants: G12C G13D
In 664 tumors, no mutation was detected, 462 tumors were diagnosed with KRAS-, 39 patients with NRAS- and 74 patients with BRAF-mutation. Mutations in KRAS were associated with inferior progression-free survival (PFS) an
[Paragraph-level] PMCID: PMC4999563 Section: ABSTRACT PassageIndex: 7
Evidence Type(s): Prognostic, Diagnostic
Justification: Prognostic: The passage discusses the correlation of KRAS mutations, including specific variants like G12C and G13D, with inferior overall survival (OS) and progression-free survival (PFS), indicating their impact on disease outcome independent of therapy. Diagnostic: The passage mentions that mutations in KRAS were diagnosed in tumors, indicating that these mutations are used to classify or define the disease.
Gene→Variant (gene-first): 3845:G12C 3845:G12D 3845:G12V 3845:G13D
Genes: 3845
Variants: G12C G12D G12V G13D
In this pooled analysis of metastatic colorectal cancer patients, mutations in KRAS, and BRAF were associated with inferior progression-free and overall survival compared with patients with non-mutated tumors. KRAS exon
[Paragraph-level] PMCID: PMC4999563 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Prognostic, Diagnostic
Justification: Prognostic: The passage discusses how KRAS G12C and G13D mutations correlate with inferior progression-free and overall survival in metastatic colorectal cancer patients, indicating their prognostic significance. Diagnostic: The mention of KRAS mutations being associated with tumor characteristics suggests their role in classifying or defining the disease subtype in colorectal cancer.
Gene→Variant (gene-first): 3845:G12C 3845:G13D
Genes: 3845
Variants: G12C G13D
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
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
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
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
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
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
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
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
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
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
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
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
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
Mutation of several genes, most notably TP53 or ASXL1 transcriptional regulator 1 (ASXL1), were shown to cause a broad pattern of drug resistance. Interestingly, a few drugs trended more sensitive to TP53 mutant cases, s
[Paragraph-level] PMCID: PMC6280667 Section: RESULTS PassageIndex: 9
Evidence Type(s): Predictive
Justification: Predictive: The passage discusses the correlation of mutations, including those in splicing components like ZRSR2, with sensitivity to various drugs, indicating a relationship between the variant and treatment response.
Gene→Variant (gene-first): 8233:serine/arginine
Genes: 8233
Variants: serine/arginine
To examine tumor forming capacity in vivo, we constructed H460 cells that stably express ERBB2 (Fig. 8a) and assessed tumor growth after subcutaneous inoculation of these cells into mice. On the 21st day after transplant
[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 17
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage discusses the tumor forming capacity of cells expressing the ERBB2 E401G variant, indicating that this somatic variant contributes to tumor development as evidenced by increased tumor growth in vivo.
Gene→Variant (gene-first): 2176:E401G
Genes: 2176
Variants: E401G
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
Biological effects of ERBB2 E401G
[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 15
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 2176:E401G
Genes: 2176
Variants: E401G
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
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
To confirm whether HER2 homodimers or EGFR-HER2 heterodimers are more relevant to the mechanisms of ERBB2 E401G and S310F activation, we analyzed HER-family dimers using microsecond-timescale MD simulations. With regard
[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 11
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 2176:E401G 2064:S310F
Genes: 2176 2064
Variants: E401G S310F
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)
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
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
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
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
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
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
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
Detection of ERBB2 E401G VUS in a patient with CUP
[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 2
Evidence Type(s): Diagnostic
Justification: Diagnostic: The passage mentions the detection of the ERBB2 E401G variant of uncertain significance (VUS) in a patient, indicating its use in defining or classifying a disease context, specifically in a patient with cancer of unknown primary (CUP).
Gene→Variant (gene-first): 2176:E401G
Genes: 2176
Variants: E401G
After collapsing smMIPs with the same barcode, we achieved > 150-fold coverage for 85% of the protein coding sequences for KRAS, BRAF, HRAS, NRAS, and MAP2K1. Because KRAS codon p.12G and BRAF codon p.600V somatic mutati
[Paragraph-level] PMCID: PMC6938308 Section: RESULTS PassageIndex: 2
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage indicates that KRAS codon p.12G and BRAF codon p.600V somatic mutations have been linked to brain AVMs, suggesting their role in defining or classifying the disease. Oncogenic: The mention of likely somatic disease-causing mutations, including KRAS mutations (p.G12D and p.G12V) and BRAF mutations (p.V600E and p.Q636X), indicates that these variants contribute to tumor development or progression.
Gene→Variant (gene-first): 3845:p.12G 673:p.600V 3845:p.G12D 3845:p.G12V 673:p.Q636X 673:p.V600E
Genes: 3845 673
Variants: p.12G p.600V p.G12D p.G12V p.Q636X p.V600E
EGFR mutation analysis in non-small-cell lung cancer (NSCLC) patients is currently standard-of-care. We determined the uptake of EGFR testing, test results and survival of EGFR-mutant NSCLC patients in the Netherlands, w
[Paragraph-level] PMCID: PMC8307492 Section: ABSTRACT PassageIndex: 4
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the association of the L858R variant with overall survival (OS) in patients treated with first-line EGFR inhibitors, indicating its relevance to treatment response. Oncogenic: The L858R variant is mentioned in the context of EGFR mutations in non-small-cell lung cancer (NSCLC), suggesting its role in tumor development or progression as part of the broader analysis of clinically actionable EGFR mutations.
Gene→Variant (gene-first): 1956:L858R
Genes: 1956
Variants: L858R
HOXC10 is overexpressed in 51% of primary KRAS-mutant tumors (Figure 3A; TCGA, >= 2SD over expression in normal lung), consistent with observations in cell lines (Figure 2B). By analyzing KRAS-mutant tumor/normal matched
[Paragraph-level] PMCID: PMC10805385 Section: RESULTS PassageIndex: 17
Evidence Type(s): Oncogenic, Predictive
Justification: Oncogenic: The passage discusses the overexpression of HOXC10 in KRAS-mutant tumors, specifically mentioning the genotype KRAS G12C/TP53 G245V, indicating that these somatic variants contribute to tumor development or progression. Predictive: The passage mentions the efficacy of combined MEK/BET inhibitors causing tumor regression in KRAS-mutant patient-derived xenograft models, suggesting a correlation between the variants and response to therapy.
Gene→Variant (gene-first): 3845:G12C 7157:G245V
Genes: 3845 7157
Variants: G12C G245V
This drug combination was also tested on NCI "Rasless" MEFs carrying KRASG12C or KRASG12D mutations. KPT9274 synergized with MRTX849 at all dose combinations yielding suppressed growth of KRASG12C-mutant MEFs (Supplement
[Paragraph-level] PMCID: PMC10690049 Section: RESULTS PassageIndex: 7
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the response of KRASG12D mutant MEFs to a drug combination, indicating that the variant is associated with resistance to growth inhibition by the therapies tested. Oncogenic: The KRASG12D variant is implicated in tumor behavior, as it is described in the context of MEFs (mouse embryonic fibroblasts) and their growth characteristics, suggesting a role in tumor development or progression.
Gene→Variant (gene-first): 3845:G12D
Genes: 3845
Variants: G12D
KRAS G12C-mutant MIA PaCa-2 (PDAC) and NCI-H358 (NSCLC) cells were exposed to MRTX849/AMG510 and KPT9274 at different dose combinations. As shown in Fig. 2A and B, all three dose combinations tested demonstrated synergis
[Paragraph-level] PMCID: PMC10690049 Section: RESULTS PassageIndex: 6
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the response of KRAS G12C-mutant cells to specific therapies, indicating a correlation between the variant and sensitivity to the drugs MRTX849/AMG510 and KPT9274. Oncogenic: The variant KRAS G12C is implicated in tumor development, as the passage describes its presence in cancer cell lines and their proliferation in response to treatment, suggesting a role in cancer progression.
Gene→Variant (gene-first): 3845:G12C
Genes: 3845
Variants: G12C
especially democratic at all levels.
for - post-growth economy - democratic at every level
you should be way more worried about AI because it's like a flood of millions of new digital immigrants that are Nobel Prize level
for - quote - millions of Nobel Prize level digital immigrants
We don't micromanage the cells. We figured out a a message that says, "Build an eye here." And the reason that works is because we're dealing with an aential material.
for - adjacency - not micromanaging the cell - high level instruction - Michael Levin
this level the level L acts as an environment returning an observation
for - comparison - multi-level agents - scaffolding
level environment.
for - definition - level environment - the level environment for each agent at that respective local level of a multi-level, hierarchical intelligent system
we don't tell the cells explicitly to uh contract or relax
for - adjacency - inter level communication - environmental steering - this is very interesting (and obvious) but far from trivial. - adjacency - meditation - interlevel communication - enlightenment? - could we naturalistically frame meditation that leads to non dual awareness, or enlightenment - as being a way for higher level agents - to get in touch with / communicate with - lower level agents - in a multi-agent environment?
question - could we interpret enlightenment as an ecosystem goal of intentional whole system environmental steering? This suggests a new term: - new definition - intentional whole system environmental steering - when environmental steering is intentional done at the highest level for the wellbeing of every level - The author uses the example of hunger as being a high level experience driven by lower level needs - This could qualify as an intentional whole system environmental steering so the term doesn't distinguishing enlightenment drive as anything special. We need some other distinguishing quality
multi-level cognition
for - definition - multi-level cognition
So here I'm going to show you here. Look, it's it's it's blue here. It's crawling along mining its business. Then eventually the satches bang, it turns green. Okay, the voltage changes immediately and then it joins it joins a collective.
for - adjacency - group think - cellular level - cultural level - Michael Levin
example of communication looks like
for - example - cellular level communication - Michael Levin
it has the ability to correct towards a large scale outcome.
for - example - higher level collective intelligence overriding lower level intelligence - axelottle
all intelligence is collective intelligence in the sense that every agent is made of parts, all of us. And what you want is for the agent to have a causal power uh that is not the same as uh simply tracking the microates, the particles
for - quote - consciousness vs cellular level intelligence - Michael Levin - key insight - high level governance (consciousness) vs low level intelligence adjacency hierarchical control - high level consciousness - low level micro intelligence quote - consciousness vs cellular level intelligence - Michael Levin - all intelligence is collective intelligence in the sense that - every agent is made of parts, all of us. - And what you want is for the (high level) agent to have a causal power that is not the same as simply tracking the microstates, the particles.
key insight - high level governance (consciousness) vs low level intelligence - This is a very important observation - It says that a multi-cellular being such as a human being can have consciousness that has agency for the entire organism and governs at that high level, and it must have this beyond just the cognition and intelligence at the lower cellular and subcellular level
Upgrading tools would frequently break compatibility with existing data. And it was difficult to make different tools interoperate if they couldn’t agree exactly on the format of their underlying JSON data.
Why should the app even know let alone care about which version of the serialization format is in play?
Washington Post-Artikel (mit Links zur Quelle) zu den Forschungen von Ki-Wen Seo und anderen zu den Veränderungen im globalen Wasserkreislauf durch die Erderhitzung. Für den Anstieg des Meeresspiegels war die Austrocknung großer Gebiete auf dem Festland wenigstens in einigen Jahren wichtiger als das Schmelzen des grönländischen Eisschilds. Mit hoher Wahrscheinlichkeit handelt es sich bei dem Wasserverlust um ein irreversibles Phänomen. Es zwingt zu dauerhaften Veränderungen in der Landwirtschaft https://www.washingtonpost.com/climate-environment/2025/03/27/earth-soil-moisture-drying-sea-level-study/
equivalent level ofeducation.
I believe that the more realistic choice of words is equivalent level of educational opportunity. With a classroom as varied as Mrs. Johnson’s, as are most classrooms, how can you really measure the level of education? You can measure what you have exposed to and what they have been successful at regurgitating.
for - Christine Wamsler - Lund University - homepage - from - youtube - Mindfulness World Community - Awareness, Care and Sustainability for Our Earth - https://hyp.is/GCUJ1APHEfCcr_vvv3lAFw/www.youtube.com/watch?v=CTUc_0GroGM
to - paper - An Interdisciplinary Model to Foster Existential Resilience and Transformation
to - paper - Engaging high-income earners in climate action : Policy insights from survey experiments
to - paper - Revolutionising sustainability leadership and education : addressing the human dimension to support flourishing, culture and system transformation
to - The System Within : Addressing the inner dimensions of sustainability and systems change
research areas - sustainable cities - collaborative governance - city-citizen collaboration - citizen participation - sustainability and wellbeing - sustainability transformation - inner development goals - inner transformation - inner transition - existential sustainability
for - futures study - multi-level perspective - MLP
what we want in our bodies is a mind melt of cells that cells forget about their own little ego and start identifying with a larger Collective of the organ and the way cells do that is through bioelectricity it is what Michael Levan calls a cognitive glue
for - multi-scale competency architecture - groups of individuals coalesce into an individual at a higher level - SOURCE - Youtube - Bioelectric fields: A Paradigm Shift in Biology - Michael Levin - 2025, Jan
Relevance Realization is taking place at a level fundamentally deeper than the level of belief.
for - Relevance realization is pre-conceptual - it takes place at a level deeper than the level of beliefs - source - Meaning crisis - episode 33 - The Spirituality of Relevance Realization - Wonder/Awe/Mystery/Sacredness - John Vervaeke - to - YouTube conversation - Micheal Levin, John Vervaeke, Gregg Henrique - 2024 // ,- comment - In light of studying a John's concept of relevance realisation now, - after partially annotating the - Micheal Levin, - John Vervaeke, - Gregg Henrique - YouTube conversation, I should return to that annotation to - finish it and - take a more critical look for comparison between - Micheal Levin's goal oriented behaviour definition of life that drives and expanding cognitive light cone and - John Vervaeke's relevance realisation
to - YouTube conversation - Micheal Levin, John Vervaeke, Gregg Henrique - 2024 - https://hyp.is/go?url=https%3A%2F%2Fwww.youtube.com%2Fwatch%3Fv%3DrAlmzRTbGDE&group=world
Communicate the base intent of our design in simple, deep story. Evaluate choices by how they elaborate and strengthen the story.
for - A Transcender Manifesto - addendum - it is critical to move beneath the story level - Deep Humanity
you have to have the power of stewardship first of all you have to have stewards representing the voice of nature
for - adjacency - regenerative company - need to have voices that represent nature - cross scale translation of earth system boundaries to company level
Adjacency - between - regenerative company - need to have voices that represent nature - cross scale translation of earth system boundaries - adjacency relationship - Regenerative companies need to have voices that represent nature - This means we need to be aware of how the activities of our company is impacting nature - This means we need to have cross scale translation of earth system boundaries to the local community, and finally to our company levels
we now realize the base pairs come to join each other up together as the system unravels and forms a new pair of DNA molecules well up to a point it does and that point is known to be accurate to about one in 10,000 base pairs now if you and I wrote an article and there was only one typo in a 10,000w article we'd be very pleased but this is nowhere near enough for a DNA sequence of three billion base pairs there would be half a million at least of Errors
for - DNA replication accuracy - 1 in 10,000 - too high for successful replication - another higher level mechanism to correct for these errors - need a whole body for that - Denis Noble
TRSP Desirable Characteristics It is recognised that a repository may offer different levels of curation to different digital objects.
TRSP Desirable Characteristics
The life cycle status of the repository: is it still being developed or in production and accepting data submissions? The latter does not exclude that some (re)development, enhancement or maintenance may be ongoing, as happens in any mature system.
TRSP Desirable Characteristics Review and annotation of the data performed by the repository (e.g. via a data submission tool that enforces some curation, or by its curation team): are there a set of minimum curation steps that repository performs on the submitted data? Is there a webpage or document that describes the type of curation done? This criteria is also related to the Data and Metadata Standards criteria.
the Mythic religions of like I'm going to kill you because my Mythic God has a different name from yours and that's that's the level of 2.0 like concrete operational like literally if the word is different I'll kill you that that is the level of the Sacred right
for - the word "sacred" - sacred 2.0 - low level of the sacred
if you built buildings you'll know that what's worse a dysfunctional seven stage or dysfunctional first stage it's all the footings it's all the foundations
for - developmental journey - building metaphor - most important problem to fix is foundational - first level problems - John Churchill
around the AI is um the problem right now as I understand it
for - progress traps - AI - created by mind level that created all our existing problems - AI is not AI but MI - Mineral Intelligence
we form naturally Collective intelligences as just human groups and we can see this show up in for example the way that a group of of of sports like a team of sports people will come together and they will produce something which clearly has a quality of intelligence that is different than um just you five or 12 people showing up randomly
for - collective intelligence - properties of the higher level whole - that are missing in the lower level individuals that constitute it - example sports team - Jordan Hall
I don't think you can prove it but I wonder if what what it would feel like I think is is um synchronicity
for - topic for further research - higher level of living system - indicator of - Micheal Levin - synchronicity
Adjacency - between - Jordan Hall / Michael Levin conversation - hyperobject - cognitive light cone - lower level indicator of higher level - enlightenment / awakening Frederico Faggin experience - meditation - adjacency statement - Federico Faggin's experience of inter level awareness was - his profound awakening experience transcending even oneness - That was an indicator event that shattered his belief that he was alone, shuttered in existential isolation - and showed him that he was a part of a much larger system - In general, at the level of humans and human consciousness, - awakening and enlightenment experiences described throughout human history in many different - times and - places - could be interpreted as reaching upwards to a higher level in our lower level cognitive light cone
I was visualizing um you know kind of two two two neurons in the brain talking to each other
for - inter-level awareness - Micheal Levin - metaphor - 2 neurons conversing with each other
Your application code should not be dealing with PID files, log redirection or other low-level concerns.
Eine aufwändige Expedition erforscht, ob die Sedimente in den unteren Zonen eines großen grönländischen Gletschers Barrieren gegen warmes Meerwasser bilden, die den Prozess des Abschmelzens verlangsamen und sich vielleicht sogar verstärken lassen. Hauptziel ist, den unaufhaltsamen Anstieg des Meeresspiegels besser modellieren zu können. Ausführliche Reportage im Guardian
how do you know if, if, and when you are part of a larger cognitive system, right?
for - question - how do you know when you are part of a larger cognitive system? - answer - adjacency - synchronicity - lower level example - two neurons talking to each other - Michael Levin - Mark Solms foundation theory of affect
question - how do you know when you are part of a larger cognitive system? - answer - adjacency - synchronicity - lower level example - two neurons talking to each other - Michael Levin - Mark Solms foundation theory of affect
adjacency - between - answer - synchronicity - lower level example - two neurons talking to each other - Michael Levin - Mark Solms foundational theory of affect - adjacency relationship - This is a very interesting question and Michael Levin provides a very interesting answer - First, it is very interesting that Mark Solms points out that affect is foundational to cognition - This is evident once we begin to think of the fundamental goals of any individual of any species is to optimize survival - The positive or negative affects that we feel are a feedback signal that measures how successful we are in our efforts to survive - Hence, it is more accurate to ask: - How do you know if and when you are part of a larger affective-cognitive system? - Levin illustrates the multi-level nature of simultaneous consciousness by looking at two neurons "in dialogue" with each other, and potentially speculating about a "higher level of consciousness", which is in fact, the level you and I operate at and take for granted - This speculative question is very important for it also can be generalized to the next layer up, - Do collectives of humans, each one experiencing itself a unified, cohesive inner perspective, constitute a higher level "collective consciousness"? - If we humans experience feelings and thinking whilst we have a well defined physical body, then - what does a society feel and think whilst not having such a well defined physical body?
I would really argue there hasn't been a better time to make music and there hasn't been a better time to consume and listen to music
for - question - Is music worse because entry level is lower? - Musicians response - Bernth's response
With Sysbox, containers can run system-level software such as systemd, Docker, Kubernetes, K3s, buildx, legacy apps, and more seamlessly & securely.
Erschienen: 2024-05-17 Genre:: Studienbericht Selbst in einem optimistischen Szenario (44 cm Meeresspiegel-Anstieg) werden bis 2100 mehr als ein Drittel der Feuchtgebiete in der Nähe der Mittelmeerküsten überschwemmt sein. In der Camargue ist das Wasser bereits um 15 cm gestiegen. Möglich sind in diesem Jahrhundert bis zu 1,61 Meter Anstieg. Eine neue Studie erfasst systematisch die Folgen der globalen Erhitzung für diese besonders bedrohten und besonders schwer zu schützenden Lebensräume. https://www.liberation.fr/environnement/biodiversite/en-camargue-la-montee-des-eaux-menace-le-paradis-des-flamants-roses-20240517_L6LRO3TY2ZD4FESAHWAWGA32YY/
Die französische Regierung plant die Anpassung an eine Temperatursteigerung um 4° bis zum Ende des Jahrhunderts. Die Libération gibt einen Überblick darüber, wie Frankreich dann aussehen wird.
elative to the period 1995–2014, global mean sea level is conservatively projected to rise 0.15–0.29 m by 2050, and 0.28–1.01 m by 2100 (109).
Die weltwetterorganisation WMO fast in ihrem Bericht über 2023 die Daten verschiedener Services zusammen und kommt zu dramatischen Aussagen über die Entwicklung der Temperatur auf der Erdoberfläche insbesondere insgesamt und besonders an der Oberfläche der Meere. Gleichzeitig ergibt eine Studie der BU Wien dass die Prognosen vieler, darunter großer starken über die Entwicklung der Emissionen deutlich zu optimistisch sind. https://www.derstandard.de/story/3000000212370/weltwetterorganisation-zeichnet-duesteres-bild-vom-klima-des-letzten-jahres
Der Standard informiert über zwei Studien, die unter anderem den Zusammenhang von Stadtentwicklung und globaler Erhitzung betreffen. Vor allem in den USA wird für die Mehrzahl der großen Städte eine Schrumpfung vorausgesagt, verstärkt durch die Folgen der Erhitzung. Die Studie verwendet ist Szenarien des IPCC. Unter anderem ergibt sich daraus die Forderung, die Stadtplanung nicht mehr vor allem an der Vorstellung von wachsenden Städten auszurichten. https://www.derstandard.de/story/3000000203501/tausende-us-staedte-koennten-bis-2100-zu-geisterorten-werden
In einigen Zonen des Mittelmeers steigt der Meeresspiegel dreimal so schnell wie bisher angenommen. Italien, vor allem das Veneto und die Emilia Romagna. ist davon besonders betroffen. Einer neuen Studie zufolge könnten die Schäden durch Bedrohung von Küstengebieten in Europa bis 2100 827 Milliarden Euro kosten, wenn die globale Temperatur um 4° bzw. der Meeresspiegel um 75 cm steigt. https://www.repubblica.it/green-and-blue/2024/01/19/news/crisi_clima_innalzamento_mari_effetti_pil_costi_regioni-421918563/
Studie: https://iopscience.iop.org/article/10.1088/1748-9326/ad127e
Web assimilation is the extent of organizational use of web technologies in facilitating e-commerce strategies and activities. Our definition focuses on the relative success of firms (as compared to other firms in the industry) in incorporating the Web technology into its e-commerce strategies and activities. This definition is consistent with perspectives on Type III IS innovations, with earlier treatments of IT assimilation at the organizational level (Armstrong and Sambamurthy 1999), and reflects our interest in understanding firms as innovation systems for attaining differential levels of technology assimilation success (Fichman 2001). We regard the level of assimilation to be one of the visible outcomes of the stream of structuring actions across the firm. Further, we anticipate the differential level of assimilation success across firms to be linked to the nature of the institutional enablers or the metastructuring actions within those firms.
Definition and further explanation of the mean of Web Asssimilation.
for - Rainbow body - Deep Humanity - superorganism - multi-level communication - adjacency between - contemplative practice - direct experience of body's cellular activity
summary - Father Tiso and his catholic lineage combined with scholarship in Tibetan studies places him in a unique position for interfaith dialogue - His research interest in investigating the extraordinary and unexplained Tibetan meditation phenomena of Rainbow Body manifested by the greatest practitioners at the time of death (including contemporary ones) sheds light on the Rainbow Body phenomena in many spiritual traditions and challenges the scientific community to come up with an explanation for it. - If scientifically proven true, it offers an extraordinary possibility of human potential - Contemplation could be the practice technique that could directly bridge normal human consciousness with the microscopic world around us, which to date, is only accessible through scientific instrumentation.
question - Does deep contemplative practice offers a direct access to the microscopic reality? - If so, how does it accomplish this direct communication with human cells, and indeed, even the universe itself? - Father Tiso shares centuries old recorded visual drawings of experiences reported by Rainbow Body practitioners and speculates whether these drawings represent direct experience of the cellular scale of our human form - Indeed, could it even be at the quantum level of experience, since rainbows are an optical phenomenal?
It prevents duplicate work as the DRI has a complete picture of the entire project.
Bangladesch ist dem Climate Risk Index zufolge das am siebtstärksten von den Folgen der globalen Erhitzung betroffene Land. Bis zur Mitte des Jahrhunderts wird dort mit 20 Millionen Binnenflüchtlingen aufgrund der Erhöhung des Meeresspiegels gerechnet. Die Regierung vertritt die Interessen der wirtschaftlichen Elite und reagiert zunehmend mit harter Repression auf Opposition. Reportage über junge AktivistInnen in Bangladesch anlässlich der Wahlen, an denen die wichtigsten Oppositionsparteien nicht teilnehmen. https://www.repubblica.it/green-and-blue/2024/01/05/news/bangladesh_elezioni_cambiamento_climatico-421819356/
Einer neuen Studie zufolge wird der Anstieg des Meeresspiegels bis 2150 in einigen Regionen des Mittelmeer, unter anderem durch geologische Prozesse, dreimal so hoch sein wie bisher angenommen. Damit sind 38.500 Quadratkilometer, davon 10.000 in Italien, von Überschwemmungen bedroht. https://www.greenandblue.it/2023/12/29/news/mediterraneo_coste_rischio_inondazione-421776898/
Studie: https://iopscience.iop.org/article/10.1088/1748-9326/ad127e
SoNeC is a framework for citizen participation.
for: transition - at local level, community owned production cooperatives
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for: visualizations - sea level rise at 3 Deg C
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Zwei neue Studien zeigen, dass in Grönland sowohl kleinere Gletscher außerhalb des großen Eisschilds als auch das Schelfeis viel schneller abschmelzen als im vergangenen Jahrhundert. Das Schelfeis s im Norden Grönland hat seit 1978/35% seines Volumens verloren. Wenn Abschnitte des shelf Eis kollabieren, was in diesem Jahrhundert bereits dreimal der Fall war, verdoppelt sich die Abschmelzgeschwindigkeit der Gletscher dahinter.
https://www.nytimes.com/2023/11/09/climate/greenland-glaciers-ice-melt.html
ou certainly have a light cone that does not belong to any of your pieces
for: individual / collective gestalt, Deep Humanity, superorganism, multi-level superorganism, major evolutionary transition, MET, cognitive light cone, umwelt
paraphrase
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for: superorganism, multi-level superorganism, collective intelligence, individual-collective gestalt, Michael Levin,
title: Cell Intelligence in Physiological and Morphological Spaces
From inert matter to the global society life as multi-level networks of processes
Küsten-Ökosysteme können sich nur eingeschränkt an eine schnelle Erhöhung des Meeresspiegels anpassen. Über 90% der Mangrovenwälder, Korallenriffe und Gezeitensümpfe würden bei einen Temperaturanstieg um 3° nicht mit dem schnellen Anstieg des Meeresspiegels Schritt halten und damit die Fähigkeit verlieren, CO2 zu binden, wie eine neue Studie prognostiziert. https://www.liberation.fr/environnement/biodiversite/rechauffement-climatique-les-ecosystemes-cotiers-risquent-detre-noyes-par-la-montee-des-eaux-20230830_OHOQ4F5XRRA4RCJLRZEWHTJYRE/
Julian Huxley
ot very many happy thingshappened in the lives of the three Baudelaire youngsters.
Not strictly true. Plenty of happy things happen throughout the lives of the Baudelaire orphans. This series shows us that it's the little things that count. the grim nature of the series is part of the charm of it.
Eine neue Modellierung der Witterung der globalen Erhitzung auf die Gletscher der Arktis i und Antarktis und auf ihreWechselwirkungen mit den Ozeanen ergibt, dass der Meeresspiegel bis Mitte der kommenden Jahrhunderts um anderthalb Meter steigen wird, wenn die Temperatur derbAtmosphäre um mehr als 1,8 Gerade steigt.
As a result, the tax creditfor 2022 will be based on the 2021 federal poverty lines.2021 Poverty Lines for the 48 Contiguous States and the District of ColumbiaFor families/households with more than 8 persons, add $4,540 for each additional person (100% Poverty Line)Persons in family/household 100% Poverty Line 138% Poverty Line 400% Poverty Line1 $12,880 $17,774 $51,5202 $17,420 $24,040 $69,6803 $21,960 $30,305 $87,8404 $26,500 $36,570 $106,0005 $31,040 $42,835 $124,1606 $35,580 $49,100 $142,3207 $40,120 $55,366 $160,4808 $44,660 $61,631 $178,6402021 Poverty Lines for AlaskaFor families/households with more than 8 persons, add $5,680 for each additional person (100% Poverty Line)Persons in family/household 100% Poverty Line 138% Poverty Line 400% Poverty Line1 $16,090 $22,204 $64,3602 $21,770 $30,043 $87,0803 $27,450 $37,881 $109,8004 $33,130 $45,719 $132,5205 $38,810 $53,558 $155,2406 $44,490 $61,396 $177,9607 $50,170 $69,235 $200,6808 $55,850 $77,073 $223,4002021 Poverty Lines for HawaiiFor families/households with more than 8 persons, add $5,220 for each additional person (100% Poverty Line)Persons in family/household 100% Poverty Line 138% Poverty Line 400% Poverty Line1 $14,820 $20,452 $59,2802 $20,040 $27,655 $80,1603 $25,260 $34,859 $101,0404 $30,480 $42,062 $121,9205 $35,700 $49,266 $142,8006 $40,920 $56,470 $163,6807 $46,140 $63,673 $184,5608 $51,360 $70,877 $205,440
FPL is based on year prior to tax year. Ex:- for 2022 tax year FPL table is 2021
2023 Poverty Guidelines for the 48 Contiguous States and the District of ColumbiaPersons in family/householdPoverty guideline1$14,580219,720324,860430,000535,140640,280745,420850,560 For families/households with more than 8 persons, add $5,140 for each additional person.
federal poverty level (FPL)
HHS Poverty Guidelines for 2023 The 2023 poverty guidelines are in effect as of January 19, 2023. Federal Register Notice, January 19, 2023 - Full text. The Poverty Guidelines API is now available with the 2023 data. Join our listserv to stay up-to-date on the latest news regarding the poverty guidelines. 2023 POVERTY GUIDELINES FOR THE 48 CONTIGUOUS STATES AND THE DISTRICT OF COLUMBIA Persons in family/household Poverty guideline 1 $14,580 2 $19,720 3 $24,860 4 $30,000 5 $35,140 6 $40,280 7 $45,420 8 $50,560 For families/households with more than 8 persons, add $5,140 for each additional person. 2023 POVERTY GUIDELINES FOR ALASKA Persons in family/household Poverty guideline 1 $18,210 2 $24,640 3 $31,070 4 $37,500 5 $43,930 6 $50,360 7 $56,790 8 $63,220 For families/households with more than 8 persons, add $6,430 for each additional person. 2023 POVERTY GUIDELINES FOR HAWAII Persons in family/household Poverty guideline 1 $16,770 2 $22,680 3 $28,590 4 $34,500 5 $40,410 6 $46,320 7 $52,230 8 $58,140 For families/households with more than 8 persons, add $5,910 for each additional person. Resources Prior Poverty Guidelines and Federal Register References A chart with percentages (e.g., 125 percent) of the guidelines (PDF) Frequently Asked Questions (FAQs) on the Poverty Guidelines and Poverty Poverty guidelines — gross or net income The poverty line for a state or city The number of poor people in a state or city How the poverty line was developed Further Resources on Poverty Measurement, Poverty Lines, and Their History ASPE research on poverty The Census Bureau's Poverty Home Page
Federal Poverty Level (FPL) 2023
there's a landlord tax the the one percent in their day were the landlords you have to tax away the land rent and make that the public uh tax base not income not taxes on consumer goods not taxes on capital because you want good capital investment you want fortunes to 00:45:07 be made in a good way that add to the economy's productivity you don't want them to be made in a predatory bad way uh the whole fight to tax economic rent and to even recognize that most income is unearned when you talk about the uh income disparity almost all this disparity is unearned income it's economic rent it's not income that's made by increasing uh production 00:45:33 it's not income that's made by increasing living standards it's just predatory rent seeking from special privileges that the wealthy have gained from government and today it's not the landlord class anymore as it was in the 19th century it's the financial class and the raw materials class uh and uh without dealing uh with this uh cl structure i don't uh the system is going 00:45:57 to shrink and shrink and we've seen this before we saw it in rome the same kind of polarization and concentration of wealth in the roman empire well the last stage of that is feudalism so we're back to what rosa luxemburg said the choice is between socialism and barbarism basically and uh there's no other way to do it you can't solve the problems within the existing system 00:46:23 because it's controlled already by the one percent
Micheal Hudson : tax the rent seeking class or face barbarism like in Rome - The situation today is degrading in the same way Rome degraded into feudalism - rent seeking class today is not the landlord class, but the financial and raw materials class that are making large fortunes from rent seeking - that is the system level reform necessary today
This is different than row-level security because row-level security is going to allow you to restrict the actual data that’s shown to them not the actual report that’s shown
Teachers’ Use of Technology in Elementary Reading Lessons
-I will download this full article through EBSCO
-This article will provide me with teaching strategies that use technology in elementary reading lessons.
-rating 8/10
McDermott, P., & Gormley, K. A. (2016). Teachers’ use of technology in elementary reading lessons. Reading Psychology, 37(1), 121-146.
Elementary Teachers’ Views about Teaching Design, Engineering, and Technology
This article will provide me with insight on the views elementary teachers have on design, engineering and technology.
rating 8/10
Hsu, M. C., Purzer, S., & Cardella, M. E. (2011). Elementary teachers’ views about teaching design, engineering, and technology. Journal of Pre-College Engineering Education Research (J-PEER), 1(2), 5.
Elementary School Teachers and Teaching with Technology
This article will provide me insight into teaching with technology at the elementary school level.
rating 6/10
Varol, F. (2013). Elementary School Teachers and Teaching with Technology. Turkish Online Journal of Educational Technology-TOJET, 12(3), 85-90.
Perhaps in addition to reparations, we should be taking a closer look at poverty in general. We need to raise up the poorest among us. This will ease the political issue of whites who feel like they're being (unfairly) left behind. It should be a multi-racial effort.
We need to have a second Resonstruction.
In a recent paper published in Nature Climate Change, scientists found that major sea-level rise from the melting of the Greenland ice cap is now ‘inevitable’ even if the burning of fossil fuels were to halt overnight. Using satellite observations of Greenland ice loss and ice cap from 2000 to 2019, the team found the losses will lead to a minimum rise of 27 cm regardless of climate change.
A great example of the lag that large, complex systems exhibit when responding to significant input changes.
Lag is something that humans are woefully weak at recognizing and understanding. This, and other systems concepts are what we need to add to the curriculum at all levels of education, to change this very significant shortcoming of "common knowledge".
London, U. C. (2021, December 13). Unwillingness to have booster vaccine most common in groups with highest infection rates. https://medicalxpress.com/news/2021-12-unwillingness-booster-vaccine-common-groups.html
Zimmer, C. (2021, September 21). An extra J. & J. shot substantially boosts protection against Covid, the company reports. The New York Times. https://www.nytimes.com/2021/09/21/health/johnson-and-johnson-shot.html
Hamblin, J. (2021, December 9). Perspective | Omicron won’t keep us from ending the pandemic. We’re doing that ourselves. Washington Post. https://www.washingtonpost.com/outlook/2021/12/09/omicron-coronavirus-individual-threat/
(((Howard Forman))). (2022, January 30). New York City Update Cases down 67%. Positive rate down to 3.8%, lowest since 12/12. Hospital census down 33%, lowest since 12/28. New admits lowest since 12/21. Getting closer and closer to pre-Omicron levels. Https://t.co/c6H98PUA0E [Tweet]. @thehowie. https://twitter.com/thehowie/status/1487582265551077387
Dean, N. E. (2021, September 21). Hmm okay. J&J two dose results are a bit more complicated, with different results globally versus within the US. https://t.co/prFUorU8LE [Tweet]. @nataliexdean. https://twitter.com/nataliexdean/status/1440318770665324560
Sample, I. (2022, January 25). Long Covid: Doctors find ‘antibody signature’ for patients most at risk. The Guardian. https://www.theguardian.com/society/2022/jan/25/doctors-find-antibody-signature-long-covid
1.10 Look at the machine from the higher level.
1.10 Look at the machine from the higher level.
Interestingly, Rails doesn't see this in their test suite because they set this value during setup:
boredom, as it does not fully engage the attention, while a too difficult one produces anxiety, as theperson becomes afraid to fail. Only a task that is challenging enough will engender the level ofintense, but tranquil, concentration that characterizes flow. There are two ways to control thebalance between challenges and skills: changing the intrinsic difficulty of the task, and changing theperson’s ability to cope with the task. At first sight, balance could be achieved by proposing arelatively easy task at which the person is not particularly skilled. But a more advanced model seesflow as emerging from high skills applied to difficult challenges (Fig. 1). In this more complexmodel (Nakamura & Csikszentmihalyi, 2002), limited skills applied to limited challenges merelyproduce apathy, as there is not much to create interest.This means that a good mobilization system not only should present goals that are difficultto reach, but provide the additional abilities necessary to handle that difficulty. This is the “newskills” feature that characterizes a truly compelling technology: you will feel most stimulated to usea tool if it allows you to tackle challenges that you could not tackle without it—albeit in such a waythat its use is fully intuitive and transparent. Eventually, a good tool should start to feel like anaugmentation or extension of yourself—the way a stick extends the reach of your arm, a telescopeextends your vision, and a notebook extends your memory.
Balance between difficulty of task and level of skills Task that is too easy produces boredom, too difficult produces anxiety. Flow state exists when the difficulty is balanced with the skill level.
New technologies and processes are new tools that are exciting to learn because they allow us to engage old problems in novel new ways. When we innovate and solve problems using novel techniques, it increases our level of engagement and satisfaction.
Realisable service level efficiency improvements could38reduce upstream energy demand by 45% in 2050.
increasing service level efficiency can play a major role in reducing upstream energy demands.
Operational Level Agreement – The OLA
The purpose of an Operational Level Agreement (OLA) is to ensure that the SLA is met within the supplier's organization. This article contains a checklist to check whether an OLA is complete.
Principles of Shaping
When we shape the work, we need to do it at the right level of abstraction: not too vague and not too concrete. Product managers often err on one of these two extremes.
are evaluated simultaneously, a phenomenon referred to as instruction-level paral-lelism.
什么是指令并行?
Study finds brain changes similarly to Alzheimer’s after COVID-19. (n.d.). The Jerusalem Post | JPost.Com. Retrieved March 31, 2022, from https://www.jpost.com/health-and-wellness/coronavirus/article-696565
Capybara can get us part of the way there. It allows us to work with an API rather than manipulating the HTML directly, but what it provides isn't an application specific API. It gives us low-level API methods like find, fill_in, and click_button, but it doesn't provide us with high-level methods to do things like "sign in to the app" or "click the Dashboard item in the navigation bar".
Each highlighted statement expresses political talking points aligned to induce trump-like support.
Trump introduced new marketing and strategy, formulated using concepts and metrics mastered by Reality TV and Hollywood and then paired with advertising propaganda and "selling" techniques to create a "Brand". This is after-all Donald Trump, this is what he does, has done and is the only way he has found to make money. Trump built the "brand" (just barely) while teetering on self destruction.
His charismatic persona became "the glue" that allowed creative narratives to stick to certain types of people in-spite of risk. Trump learned OTJ how to capture a specific type of audience.
The mistake people make about Trump is assuming his audience to be "Joe Six-Pack", redneck's with limited education! This assumption does not have merit on its own.<br /> * There is a common "follower" theme among his audience that is exploited by those who: * Bought the "licensing rights" to the master-class Trump "how-to" course.
ReconfigBehSci on Twitter: ‘RT @bhrenton: Preliminary look into the visitor locations to https://t.co/j5ei0O4u1e mapped with new COVID-19 cases shows some overlaps, bu…’ / Twitter. (n.d.). Retrieved 13 February 2022, from https://twitter.com/SciBeh/status/1483697294373531652
Another company, Pietra, connects influencers with manufacturers in order to help them launch their own product lines.
When manufacturers, like Pietra, help influencers manufacture their own product lines, we've taken another step from big celebrities having their own product lines (think Martha Stewart cookware and other lifestyle plays her company has made).
This is splitting the difference between the Tupperware parties of old where you're empowering your users to sell your product and having celebrities sell your product.
What is the next step along this evolutionary path of breaking down the sales funnel? Can it be disintermediated further?
Another example of this are the thousands of small Etsy shops that are churning out products as intermediaries. An example of this is the proliferation of sticker companies that are selling somewhat custom designs for 2-3x the going rate and adding a rather large mark up for themselves. In this case there are at least some modest creative pieces being added in the value chain, but at what overall cost?
Will everyone be a manufacturer? When does it all become Amway?
Halliday, J., & correspondent, J. H. N. of E. (2022, January 17). ‘Christmas was awful’: On the Omicron frontline at the Royal Preston hospital. The Guardian. https://www.theguardian.com/world/2022/jan/17/christmas-was-awful-on-the-omicron-frontline-at-the-royal-preston-hospital
Drury, P. J. (2021, December 31). the crowd: Three forms of Covid leadership. The Crowd. https://drury-sussex-the-crowd.blogspot.com/2021/12/three-forms-of-covid-leadership.html
Yong, E. (2021, December 16). America Is Not Ready for Omicron. The Atlantic. https://www.theatlantic.com/health/archive/2021/12/america-omicron-variant-surge-booster/621027/
ReconfigBehSci on Twitter: ‘T cell immunologist getting very upset at people arguing that high levels of transmission are a good thing’ / Twitter. (n.d.). Retrieved 12 January 2022, from https://twitter.com/SciBeh/status/1481178244678402048
bless her pero tangina
felt
Mills, M. C., & Rüttenauer, T. (2021). The effect of mandatory COVID-19 certificates on vaccine uptake: Synthetic-control modelling of six countries. The Lancet Public Health, 0(0). https://doi.org/10.1016/S2468-2667(21)00273-5
After all, imagine we framed the problem differently, the way itmight have been fifty or 100 years ago: as the concentration ofcapital, or oligopoly, or class power. Compared to any of these, aword like ‘inequality’ sounds like it’s practically designed toencourage half-measures and compromise. It’s possible to imagineoverthrowing capitalism or breaking the power of the state, but it’snot clear what eliminating inequality would even mean. (Which kindof inequality? Wealth? Opportunity? Exactly how equal would peoplehave to be in order for us to be able to say we’ve ‘eliminatedinequality’?) The term ‘inequality’ is a way of framing social problemsappropriate to an age of technocratic reformers, who assume fromthe outset that no real vision of social transformation is even on thetable.
A major problem with fighting to "level the playing field" and removing "inequality" is that it doesn't have a concrete feel. What exactly would it mean to eliminate inequality? What measures would one implement? To fix such a problem the issue needs to be better defined. How can the issue be better framed so that it could be fought for or against?
Holder, Josh. ‘Tracking Coronavirus Vaccinations Around the World’. The New York Times, 29 January 2021, sec. World. https://www.nytimes.com/interactive/2021/world/covid-vaccinations-tracker.html.
Kojima, N., & Klausner, J. D. (2021). Protective immunity after recovery from SARS-CoV-2 infection. The Lancet Infectious Diseases, 0(0). https://doi.org/10.1016/S1473-3099(21)00676-9
BK Titanji #ILookLikeAScientist. (2021, November 2). I simply can’t get over this graph @FT https://t.co/Uozp7yBs9n [Tweet]. @Boghuma. https://twitter.com/Boghuma/status/1455493059534376963
Skimmed opening paragraphs in physical newspaper. Want to revisit. This sounds like the sort of "pulling oneself up by one's bootstraps" that actually works.
Nuance and ambiguity are essential to good fiction. They are also essential to the rule of law: We have courts, juries, judges, and witnesses precisely so that the state can learn whether a crime has been committed before it administers punishment. We have a presumption of innocence for the accused. We have a right to self-defense. We have a statute of limitations.
Great quote by itself.
How useful is the statute of limitations in cases like slavery in America? It goes against a broader law of humanity, but by pretending there was a statue of limitations for going against it, we have only helped to institutionalize racism in American society. The massive lack of a level playing field makes it all the harder for the marginalized to have the same freedoms as everyone else.
Perhaps this is why the idea of reparations is so powerful for so many. It removes the statue of limitations and may make it possible to allow us to actually level the playing field.
Related:
Luke 12:48 states, "From everyone who has been given much, much will be demanded; and from the one who has been entrusted with much, much more will be asked." Is this simply a statement for justifying greater taxes for the massively wealth?
I created a social justice metaphor library to help explain concepts like why you can't just create a "level playing field" without acknowledging the economic impacts of history (see, even saying it like that is complicated).
I love that Dave has started a list of these useful social justice metaphors.
I got side tracked by the idea this morning and submitted a handful I could think of off the top of my head.
I'm curious if there are any useful ones in the neurodiversity space? I feel like I need more of these myself.
If you're looking for a slightly higher level API built on the same technology, you may want to check out watir or capybara.
Mahase, E. (2021). Covid-19: Just a third of blood cancer patients had antibodies against delta variant after two vaccine doses, study finds. BMJ, 375, n2623. https://doi.org/10.1136/bmj.n2623
Wilson, C. (2021, September 9). Blood test could reveal who is most likely to get severe covid-19. New Scientist. https://www.newscientist.com/article/2289718-blood-test-could-reveal-who-is-most-likely-to-get-severe-covid-19/
Blais, J., Babchishin, K. M., & Hanson, R. K. (2021). Improving our Risk Communication: Standardized Risk Levels for BARR-2002R. PsyArXiv. https://doi.org/10.31234/osf.io/2xr3m
The rate of GMSL rise for 2006–2015 of 3.6 mm yr–1 (3.1–4.1 mm yr–1, very likely range), is unprecedented over the last century
That's only for 2006-2015 period. So 许艺炜 & 胡修棉 is bullshiting when they write "自工业革命以来，全球海平面以3.6mm/yr速度上升（IPCC, 2019）"
We shouldn’t be giving Covid boosters while millions wait for a first dose | Andrew Pollard and Seth Berkley | The Guardian. (n.d.). Retrieved August 17, 2021, from https://www.theguardian.com/commentisfree/2021/aug/13/covid-boosters-dose-vaccine
Seth Trueger. (2021, August 3). Time lapse of community prevelence from 7/1 to 8/1 https://t.co/mPomRzshLG [Tweet]. @MDaware. https://twitter.com/MDaware/status/1422649454293835778
Shrotri, M., Navaratnam, A. M. D., Nguyen, V., Byrne, T., Geismar, C., Fragaszy, E., Beale, S., Fong, W. L. E., Patel, P., Kovar, J., Hayward, A. C., & Aldridge, R. W. (2021). Spike-antibody waning after second dose of BNT162b2 or ChAdOx1. The Lancet, 398(10298), 385–387. https://doi.org/10.1016/S0140-6736(21)01642-1
The Culture of Resentment Revisited. (2021, March 11). EU vs DISINFORMATION. https://euvsdisinfo.eu/the-culture-of-resentment-revisited/
"Many North American music education programs exclude in vast numbers students who do not embody Euroamerican ideals. One way to begin making music education programs more socially just is to make them more inclusive. For that to happen, we need to develop programs that actively take the standpoint of the least advantaged, and work toward a common good that seeks to undermine hierarchies of advantage and disadvantage. And that, inturn, requires the ability to discuss race directly and meaningfully. Such discussions afford valuable opportunities to confront and evaluate the practical consequences of our actions as music educators. It is only through such conversations, Connell argues, that we come to understand “the real relationships and processes that generate advantage and disadvantage”(p. 125). Unfortunately, these are also conversations many white educators find uncomfortable and prefer to avoid."
When we use a GraphQL API there are two kinds of errors we may encounter: Network Errors and GraphQL Errors from the API. Since it's common to encounter either of them, there's a CombinedError class that can hold and abstract either.
This kind of error handling does express error state (either via HTTP 500 or by the top-level "errors" key), but it doesn’t take advantage of GraphQL’s type system and can only express one error at a time.
In general, top-level errors should only be used for exceptional circumstances when a developer should be made aware that the system had some kind of problem. For example, the GraphQL specification says that when a non-null field returns nil, an error should be added to the "errors" key. This kind of error is not recoverable by the client. Instead, something on the server should be fixed to handle this case. When you want to notify a client some kind of recoverable issue, consider making error messages part of the schema, for example, as in mutation errors.
“System tests” is a common naming for automated end-to-end tests in the Rails world. Before Rails adopted this name, we used such variations as feature tests, browser tests
Milman, O., Yelin, I., Aharony, N., Katz, R., Herzel, E., Ben-Tov, A., Kuint, J., Gazit, S., Chodick, G., Patalon, T., & Kishony, R. (2021). Community-level evidence for SARS-CoV-2 vaccine protection of unvaccinated individuals. Nature Medicine, 1–3. https://doi.org/10.1038/s41591-021-01407-5
For me the diagrams make it easier to talk about what the tests do without getting bogged down by how they do it.
I’m going to add the API Server as an actor to my first test sequence to give some granularity as to what I’m actually testing.
For features like websocket interactions, a single full-stack smoke test is almost essential to confirm that things are going as planned, even if the individual parts of the interaction are also covered by unit tests.
How to test at the correct level?
As many things in life, deciding what to test at each level of testing is a trade-off:
Unit tests are usually cheap, and you should consider them like the basement of your house
A system test is often better than an integration test that is stubbing a lot of internals.
Only test the happy path, but make sure to add a test case for any regression that couldn’t have been caught at lower levels with better tests (for example, if a regression is found, regression tests should be added at the lowest level possible).
White-box tests at the system level (formerly known as System / Feature tests)
Black-box tests at the system level (aka end-to-end or QA tests)
White-box tests at the system level (aka system or feature tests)
For a «zoom out» view of my current data, here is a table-free working test :
SQL: experimenting with table-free data
First of all, I would start off presenting yourself: Dear XYZ support team I am the web developer in charge of example.com website. By presenting you this way, you are establishing the frame to treat you, hinting that you should be presupposed to be somewhat proficient, so they could choose to answer in a more technical detail.
Feel free to hint, brag, or both! The best CS reps should easily take a hint from clear language and a signature like John Appleseed, JavaScript/Ruby Developer, but any will catch on with a simple line like "I know what I'm doing, so I'd appreciate an extra-technical explanation!"
One solution that fixed this issue with my ISP was that when I went through the first and second line and got in touch with the people that fixed my problem, I asked them if they could give me one of their personal numbers in case the same problem happened again. The problem did occur a couple more times, and I just directly called the same guy.