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www.youtube.com www.youtube.com
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34:00 ... 34:40 "why is it that we dont make vitamin C, but guinea pigs do?"<br /> some people say this is an acquired nutrient deficiency, curable by eating olive leafs.<br /> The Restoration of Vitamin C Synthesis in Humans<br /> by Thomas E. Levy, MD, JD and Ron Hunninghake, MD<br /> https://orthomolecular.org/resources/omns/v18n14.shtml
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- Aug 2024
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drive.google.com drive.google.com
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Case: Patient Proband SS, Female, Caucasian
DiseaseAssertion: UCD/OTCD
FamilyInfo: De novo inheritance, no family history of disease
CasePresentingHPOs: Hyperammonemia (HP:0001987), oroticaciduria (HP:0003218), Childhood onset (HP:0011463)
CaseHPOFreeText:
CaseNOTHPOs: Positive allopurinol test
CaseNOTHPOFreeText:
CasePreviousTesting: Genomic DNA isolated from peripheral blood leukocytes or cultured skin fibroblasts. Amplification by PCR used. SSCP analysis performed. Sequencing of both free and immobilized single strands carried out by dideoxy chain termination method.
SupplementalData: Table 1: Mutations in the Ornithine Transcarbamylase Gene of 17 Females
Variant: NM_000531.6:c.77+1G>A
ClinVarID: 97313
CAID: CA224773
gnomAD:
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drive.google.com drive.google.com
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Case: Female Patient #1, Female, Japanese
DiseaseAssertion: UCD/OTCD
FamilyInfo: N/A
CasePresentingHPOs: Childhood onset (HP:0011463)
CaseHPOFreeText: Onset at 2 years
CaseNOTHPOs:
CaseNOTHPOFreeText: 16% OTC activity
CasePreviousTesting:
Variant: NM_000531.5:c.67C>T (p.Arg23*)
ClinVarID: 97292
CAID: CA224742
gnomAD:
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drive.google.com drive.google.com
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Case: Patient #38, Female, Chinese
DiseaseAssertion: UCD/OTCD
FamilyInfo: No family history of disease, mutation is inherited
CasePresentingHPOs: Hyperammonemia (HP:0001987), oroticaciduria (HP:0003218), vomiting (HP:0002013), coma (HP:0001259), lethargy (HP:0001254), seizures (HP:0001250), childhood onset (HP:0011463)
CaseHPOFreeText: Elevated plasma ammonia at 190 umol/L (Normal: 9-30 umol/L), Elevated urinary orotate at 202 mmol/mmol creatinine (Normal: 0-1.5 mmol/mmol creatinine)
CaseNOTHPOs:
CaseNOTHPOFreeText: Normal plasma glutamine at 13.5 umol/L (Normal: 6-30 umol/L), Normal plasma citrulline at 15.75 umol/L (Normal: 7-35 umol/L)
CasePreviousTesting: gDNA extracted from peripheral blood leukocytes. PCR all coding exons and exon–intron boundaries of the OTC gene using 9 pairs of synthetic oligonucleotide primers, and the primer sequences and annealing temperature. PCR products were then purified and bidirectionally sequenced. The library was sequenced using Illumina HiSeq4000 and generated 150 bp paired-end reads. Data analysis was performed as previously described [Sun Y, Hu G, Liu H, Zhang X, Huang Z, Yan H, et al. Further delineation of the phenotype of truncating KMT2A mutations: the extended Wiedemann–Steiner syndrome. Am J Med Genet A. 2017;173:510–4.]. Multiplex ligation-dependent probe amplification analysis was performed for samples in which Sanger sequencing or WES failed to detect any disease-causing mutation.
Variant: NM_000531.6:c.67C>T (p.Arg23*)
ClinVarID: 97292
CAID: CA224742
gnomAD:
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drive.google.com drive.google.com
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Case: Patient #4, Female, Caucasian
DiseaseAssertion: UCD/OTCD
FamilyInfo: N/A
CasePresentingHPOs: Hyperammonemia (HP:0001987),
CaseHPOFreeText: Elevated plasma ammonia concentration at 123 uM/L
CaseNOTHPOs:
CaseNOTHPOFreeText: Anxiety, plasma citrulline at 2 uM/L
CasePreviousTesting: N/A
Variant: NM_000531.5:c.67C>T (p.Arg23*)
ClinVarID: 97292
CAID: CA224742
gnomAD:
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drive.google.com drive.google.com
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Case: Patient #16, Male
DiseaseAssertion: UCD/OTCD
FamilyInfo: N/A
CasePresentingHPOs: Neonatal onset (HP:0003623), Hyperammonemia (HP:0001987)
CaseHPOFreeText:
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: N/A
Variant: NM_000531.6: c.77+2dupT
ClinVarID: 567293
CAID: CA891844248
gnomAD:
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Case: Patient #50, Male
DiseaseAssertion: UCD/OTCD
FamilyInfo: N/A
CasePresentingHPOs: Neonatal onset (HP:0003623), Hyperammonemia (HP:0001987)
CaseHPOFreeText:
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: N/A
Variant: NM_000531.6: c.174G>A (p.Trp58*)
ClinVarID: 97127
CAID: CA224490
gnomAD:
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Case: Patient #85, Male
DiseaseAssertion: UCD/OTCD
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText:
CaseNOTHPOs: Late Onset
CaseNOTHPOFreeText: Milder phenotype
CasePreviousTesting: N/A
Variant: NM_000531.6: c.298+1G>T
ClinVarID: 97160
CAID: CA224544
gnomAD:
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Case: Patient #32, Female
DiseaseAssertion: UCD/OTCD
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText:
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: N/A
Variant: NM_000531.6: c.140dup (p.(Asn47LysfsTer8))
ClinVarID:
CAID:
gnomAD:
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Case: Patient #7, Female
DiseaseAssertion: UCD/OTCD
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText:
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: N/A
Variant: NM_000531.6: c.29_32del (p.Asn10fs)
ClinVarID: 97157
CAID: CA224540
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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Case: Patient #15, Female
DiseaseAssertion: UCD/OTCD
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText:
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
Variant: NM_000531.6: c.77+1G>A
ClinVarID: 97313
CAID: CA224773
gnomAD:
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- Jul 2024
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drive.google.com drive.google.com
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Case: patient #10, Male, Argentine
Disease Assertion: UCD/OTCD
Family Info: family history of the disease,
Case Presenting HPOs: Neonatal onset(HP:0003623), Hyperammonemia HP:0001987
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: The OTC gene mutations were identified using PCR amplification, classical sequencing (Sanger), and multiplex ligation-dependent probe amplification.10,11 Mutations were identified by comparison with the GenBank reference sequence for human OTC (GenBank entries: NG_008471.1, NP 000522.3, NM 000531.5, NC 000023.11) Missense mutations were analyzed using different computational algorithms: CLUSTALW2 (http://www.clustal.org/clustal2/), SIFT (http://blocks.fhcrc.org/sift/SIFT.html),Polyphen2(http://genetics.bwh.harvard.edu/pph/),PoPMuSiC(http://babylone.ulb.ac.be/popmusic/), and SIFT Indel(http://siftdna.org/www/SIFT_indels2.html).
Supplemental Data: Table 1 Notes: died at 6 months and had 2 brothers that died a neonatal stage
Variant: NM_000531.6: c.540+1G>A
ClinVarID: 1458773
CAID: CA412724226
gnomAD: X-38381340-A-T
Gene Name: OTC (ornithine transcarbamylase)
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drive.google.com drive.google.com
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Case: Korean, Male
DiseaseAssertion: OTCD
FamilyInfo: n/a
CasePresentingHPOs: HP:0003623, HP:0001987, HP:0003218 (Neonatal onset, Hyperammonemia, Oroticaciduria)
CaseHPOFreeText: Elevated plasma ammonia concentration of 856 umol/L (Normal range 10-35 umol/L), Normal plasma citrulline concentration of 18.9 umol/L (Normal range 10-45 umol/L), Elevated urinary orotate of 3677.4 mmol/mmol creatinine (Normal range 0.3-6 mmol/mmol creatinine)
CasePreviousTesting: OTC Mutation Analysis, In Vitro Expression Study
Variant: c.853del (p.(Gln285ArgfsTer4))
ClinVarID: n/a
CAID: n/a
gnomAD: n/a
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drive.google.com drive.google.com
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Case: patient#5 , female, Italian
Disease Assertion: UCD/OTCD
Family Info:
Case Presenting HPOs: irritability(HP:0000737), lethargy(HP:0001254), vomiting(HP:0002013), Oriticaciduria (HP:0003218), low plasma citrulline (HP:0003572), Elevated circulating alanine aminotransferase concentration(HP:0031964), Elevated circulating aspartate aminotransferase concentration (HP:0031956), childhood onset (HP:0011463)
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: Total RNA was isolated from peripheral blood lymphocytes or lymphoblastoid cell lines and from frozen liver biopsy as described in Chomczynski and Sacchi (1987). For each patient two cDNA syntheses were performed: 10mg of total RNA with 800-1000 ng of oligo dT or 500ng of specific primer NR, mapping in the 3’UTR of OTC cDNA Identification of genetic lesions by amplification of the OTC mRNA, expressed in the liver tissue and intestine, from a non-specific tissue like PBL or lymphoblastoid cell lines. Some mutations, particularly those affecting splicing sites, may have a different expression in liver and PBL . In females, including manifesting carriers, this method allows the identification of deletions and gene rearrangements with certainty, but mutations, decreasing mRNA stability, are unlikely to be detected because the normal allele will constitute the majority of the RNA available for RT-PCR and will be preferentially amplified.
Supplemental Data: Case report section Notes: Hepatomegaly. This mutation, previously reported (Reish et al., 1993), has been correlated with a lethal disease form in a male patient, therefore the mild phenotype in our patient could be explained by a not completely unfavorable X-lyonization
Variant: NM_000531.6: c.928G>T(p.Glu310*)
ClinVarID: 97361
CAID: CA224838
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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drive.google.com drive.google.com
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Case: 24 yo Laotse patient , female
Disease Assertion: UCD/OTCD
Family Info:
Case Presenting HPOs:Hyperammonemia(HP:0001987), Adult onset (HP:0003581), Elevated circulating alanine aminotransferase concentration(HP:0031964), Elevated circulating aspartate aminotransferase concentration(HP:0031956), oriticaciduria(HP:0003218), Aminoaciduria(HP:0003355, Prolonged prothrombin time(HP:0008151), Cerebral edema(HP:0002181),
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: " Genomic DNA from the patient was isolated from cultivated fibroblasts. Nine pairs of primers were designed from the published sequence of the OTC gene6,7 to allow amplification of all 10 exons including adjacent intron sequences. Single-strand conformational polymorphism analysis of the polymerase chain reaction–amplified individual exon 8 yielded an unusual migration pattern of exon 9
Supplemental Data: Case report section Notes: Patient had a pregnancy 2 years prior and lost the baby. In this case report, She was a 14weeks pregnant(2nd pregnancy) 24yo . She died during this of severe hyperammonemia 5 days after being administered amino acids through parenteral nutrition. She developed signs of encephalopathy stage 4 with maximal dilated unresponsive pupils, brisk oculocephalic reflex, and severe hyperventilation, requiring mechanical ventilation. MRI revealed revealed diffuse cortical edema with loss of white to gray matter distinction. Increased excretion of Gly, Gln, Ser, Thr, and Lys was found in her urine. Treatment with benzoate was started but didn't save the patient.
Variant: NM_000531.6: c.892_893del(p.Trp298Aspfs*15)
ClinVarID: 97348
CAID: CA224820
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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drive.google.com drive.google.com
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Case: patient #11, female, 35yo, slovenian
Disease Assertion: UCD/OTCD
Family Info: family history of the disease,
Case Presenting HPOs: Adult onset(HP:0003581), hyperammonemia(HP:0001987), protein avoidance (HP:0002038)
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: Sequencing was performed at a 3rd-party sequencing center using a standardized seq of procedures following PCR-free WGS library preparation protocol Illumina TrueSeq DNA Nano and sequenced on Illumina NovaSeq 6000 platform with a mean autosomal depth greater than 30×. Variants were interpreted by a medical doctor specialized in the NGS sequencing data analysis and those classified as likely pathogenic or pathogenic according to the ACMG/AMP standards and guidelines were considered for reporting, while variants of uncertain clinical significance, were not considered. Likely pathogenic and pathogenic variants were further evaluated by the referring clinical geneticist and were considered and reported if they were classified as both a likely diagnostic finding and if they were compatible with the clinical presentation of referral.
Supplemental Data: Table 4 and section 3.1(Case description) Notes:
Variant: NM_000531.6: c.540+265G>A
ClinVarID: 449382
CAID: CA658658977
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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drive.google.com drive.google.com
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Case: patient #113, Male
Disease Assertion: UCD/OTCD
Family Info:
Case Presenting HPOs: Neonatal onset(HP:0003623), Hyperammonemia HP:0001987
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: GDNA from blood, cultured skin fibroblasts, liver from patients suspected for otc deficiency was used to amplify all 10 exons and exon/intron boundaries using primers listed in Table 1. The amplified DNA fragments were then screened by single-strand conformational polymorphism (SSCP) and the abnormally migrating DNA fragments were sequenced directly from PCR products (w/o subcloning) to identify the mutation. The amino acid residue substitution created by the mutation is examined using an alignment of 26 OTCase sequences from 23 species.
Supplemental Data: Table 4 Notes:
Variant: NM_000531.6: c.867+1G>A
ClinVarID: 97342
CAID: CA224813
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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pages.cs.wisc.edu pages.cs.wisc.edu
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volatile int counter = 0;
作用:确保了对变量的直接内存访问 在C语言中,
volatile
关键字的主要作用是: 1. 防止编译器对变量进行优化 编译器通常会对程序进行优化,以提高运行效率。但是对于一些与硬件密切相关的变量,编译器优化可能会导致一些意料之外的结果。volatile
关键字可以告诉编译器,该变量可能会被意外因素影响,因此每次使用该变量时都要重新从内存中读取。这就防止了编译器对该变量进行优化和缓存。 2. 用于多线程编程 在多线程编程中,如果多个线程访问同一个变量,而该变量没有被适当地保护,就可能导致竞态条件。将变量声明为volatile
可以确保每个线程都直接从内存中读取变量的值,而不是使用寄存器中的值。这样可以避免一些并发访问的问题。 3. 访问硬件寄存器volatile
关键字常用于访问内存映射的硬件寄存器,如设备的控制寄存器。这些寄存器的值可能会被硬件异步修改,所以编译器不应该对访问这些寄存器的代码进行优化。 需要注意的是,volatile
关键字本身并不能解决所有的并发问题,它只是确保了对变量的直接内存访问。在多线程编程中,仍然需要采用适当的同步机制,如互斥锁、信号量等,来保护共享数据。 总之,volatile
关键字的作用是防止编译器对变量进行优化,确保直接从内存中读取变量的值,这在硬件编程和多线程编程中非常有用。
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www.liberation.fr www.liberation.fr
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Eine extreme hitzewelle in marokko hat in einer stadt im landesinneren an einemTag meh als 20 Todesopfer gefordert. Vorausgegangen. waren mehrere andere Hitzewellen. Sie sind laut einer Studie mit höchster Wahrscheinlichkeit der Erderhitzung durch Treibhausgase zuzuschreiben. https://www.liberation.fr/environnement/climat/maroc-une-vague-de-chaleur-sans-precedent-entraine-la-mort-de-plus-de-20-personnes-en-24-heures-20240725_YHPM3UEXSFDYLB7PYXNA5LO5F4/
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drive.google.com drive.google.com
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Case: patient is named case #2, male
Disease Assertion: UCD/OTCD
Family Info:
Case Presenting HPOs: Hyperammonemia (HP:0001987), oriticaciduria (HP:0003218), low plasma citrulline (HP:0003572), neonatal onset(HP:0003623), Hyperglutaminemia (HP:0003217)
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: GDNA was isolated from lymphocytes. To examine the small mutations in the coding region of the OTC gene, all 10 exons and their flanking intron regions were amplified using PCR, and the nucleotide sequences of the amplified products were determined. To determine the intron 5 sequence of case 2, PCR was performed using primers OTCex5F and OTCint5R, and primers OTCint5F and OTCex6R (Table 1, Fig. 3). The amplified products were subcloned into the pT7 vector and the inserted DNA was sequenced using an automated DNA sequencer. Allopurinol test
Supplemental Data: TABLE 1, Notes:
Variant: NM_000531.6: c.540+265G>A
ClinVarID: NA
CAID: CA658658977
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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drive.google.com drive.google.com
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Case: patient #20, Male
Disease Assertion: UCD/OTCD
Family Info: NA
Case Presenting HPOs: Hyperammonemia (HP:0001987), oriticaciduria (HP:0003218), low plasma citrulline (HP:0003572), neonatal onset (HP:0003623)
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: Genomic DNA was isolated using PUREGENE blood kit from peripheral leukocytes of patients and related family members with informed consents. Amplification by PCR of all 10 exons of the OTC gene was performed using nine pairs of primers designed to span all exons and their adjacent intronic regions. PCR products were subsequently sequenced using ABI3100 Genetic analyzer with BigDye termination ver.3.0.To analyze the activity of OTC protein expressed in the COS-7, high-pressure liquid chromatographic (HPLC) analysis was performed with a Water system, consisting of a model 510 pump and a UV-visible 420 detector.
Supplemental Data: Table 1 Notes:
Variant: NM_000531.6: c.796_805del(p.Ile265AspfsX20)
ClinVarID: NA
CAID: CA2695233326
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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drive.google.com drive.google.com
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Case: patient #1, female Disease Assertion: UCD/OTCD
Family Info:
Case Presenting HPOs: Hyperammonemia (HP:0001987), Juvenile onset (HP:0003621)
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: "DNA samples were obtained from either peripheral white blood cells or liver biopsies of probands. Patient 1 total liver RNAs were extracted by the acid-phenol-guanidium method and reverse-transcribed in cDNA by hexanucleotide priming using Superscript 11' (Life Technologies, Cergy-Pantoia, France). First strand cDNA was further PCR-amplified using forward and reverse primers specificons 7 and 9 of the OTC gene, respectively. Sequence comparisons were conducted using the FASTA option of the BISANCE package. Secondary protein conformational changes induced by sequence mutations were predicted using the algorithms of the BISANCE package. Nucleotidic changes potentially altering splice sites were studied using the Senapathy's algorithm from the BISANCE package."
Supplemental Data: TABLE 1, Notes:
Variant: NM_000531.6: c.731_739del(p.Leu244Profs)
ClinVarID: 97307
CAID: CA224765
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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drive.google.com drive.google.com
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Case: patient #273, Male
Disease Assertion: UCD/OTCD
Family Info: NA
Case Presenting HPOs: Neonatal onset (HP:0003623)
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: NA
Supplemental Data: Supplemental table file Notes:
Variant: NM_000531.6: c.818del (p.Glu273Glyfs*16)
ClinVarID: 97338
CAID: CA224807
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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drive.google.com drive.google.com
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Case: patient MW
Disease Assertion: UCD/OTCD
Family Info: NA
Case Presenting HPOs: NA
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: NA
Supplemental Data: NA Notes: mutation might cause exon 8 kipping durring splicing.
Variant: NM_000531.6: c.718-2A>G
ClinVarID: 97303
CAID: CA224761
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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drive.google.com drive.google.com
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Case: patient #5, male, German Disease Assertion: UCD/OTCD
Family Info: Family history of the disease, Variant found in mother of the patient
Case Presenting HPOs: infantile onset (HP:0003593), oritic aciduria(HP:0003218), hyperammonemia(HP:0001987), hyperglutaminemia(HP:0003217), low plasma citrulline (HP:0003572)
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: Liver tissues were used to extract RNA that was later used to synthesize cDNA. The products were compared to healthy controls in order to detect variants. gDNA, in order to determine the size of deletions in patient 3 and 4 , a set of intronic primers presumably flanking the deletions was used and specific primers allowed sequencing of exactly those critical regions(sequencing on paper). To estimate the relevance of the identified intronic variants in terms of their capability to induce splicing, we used a score developed by Shapiro and Senapathy. This splice score offers information about the usage of a certain splice site
Supplemental Data: TABLE 1, Notes: died at 11 months, was given medication and low protein diet and was asymptomatic during that time. Died from sever cerebral edema.
Variant: NM_000531.6: c.1005+1091C>G
ClinVarID: N/A
CAID: CA2695233334
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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Case: patient #1, male, turkish
Disease Assertion: UCD/OTCD
Family Info: Family history of the disease, Variant found in mother of the patient
Case Presenting HPOs: infantile onset (HP:0003593), coma(HP:0001259), episodic hyperammonemia(HP:0001951), oriticaciduria(HP:0003218)
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: Liver tissues were used to extract RNA that was later used to synthesize cDNA. The products were compared to healthy controls in order to detect variants. gDNA, in order to determine the size of deletions in patient 3 and 4 , a set of intronic primers presumably flanking the deletions was used and specific primers allowed sequencing of exactly those critical regions(sequencing on paper). To estimate the relevance of the identified intronic variants in terms of their capability to induce splicing, we used a score developed by Shapiro and Senapathy. This splice score offers information about the usage of a certain splice site
Supplemental Data: TABLE 1, Notes: very mild movement disorder, the diagnosis was prenatal so measures were taken from birth,. 2 biopsies were performed and the revealed respectively a 30% and 50 % decrease on OTC activity.
Variant: NM_000531.6: c.867+1126A>G
ClinVarID: 571311
CAID: CA891843643
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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Case: patient #2, male, Saudi Arabian
Disease Assertion: UCD/OTCD
Family Info: Family history of the disease, Variant found in mother of the patient, Brother died of hyperammonemic crisis
Case Presenting HPOs: intellectual disability (HP:0001249), Neonatal onset (HP:0003623), seizure(HP:0001250), episodic hyperammonemia(HP:0001951), intellectual disability (HP:0001249)
Case HPO FreeText: hyperammonemic encephalopathy
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: Liver tissues were used to extract RNA that was later used to synthesize cDNA. The products were compared to healthy controls in order to detect variants. gDNA, in order to determine the size of deletions in patient 3 and 4 , a set of intronic primers presumably flanking the deletions was used and specific primers allowed sequencing of exactly those critical regions(sequencing on paper). To estimate the relevance of the identified intronic variants in terms of their capability to induce splicing, we used a score developed by Shapiro and Senapathy. This splice score offers information about the usage of a certain splice site
Supplemental Data: TABLE 1, Patient was severely mentally retarded after the age of 2. Low OTC activity
Variant: NM_000531.6: c.540+265G>A(p.Gln180_Glu181insX4)
ClinVarID: 449382
CAID: CA658658977
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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drive.google.com drive.google.com
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Case: no patient #ID, female Disease Assertion: UCD/OTCD
Family Info: NA
Case Presenting HPOs: NA
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: NA
Supplemental Data: TABLE 1, Notes: NA
Variant: NM_000531.6: c.665del(p.(Gly222ValfsTer8)
ClinVarID: 97289
CAID: CA224738
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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Not done!!!
Case: no patient #ID, female Disease Assertion: UCD/OTCD
Family Info: NA
Case Presenting HPOs: NA
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: NA
Supplemental Data: TABLE 1, Notes: NA
Variant: NM_000531.6: c.664-1delG
ClinVarID: 97289
CAID: CA224738
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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Case: no patient #ID, female Disease Assertion: UCD/OTCD
Family Info: NA
Case Presenting HPOs: NA
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: NA
Supplemental Data: TABLE 1, Notes: NA
Variant: NM_000531.6: c.663+2T>C
ClinVarID: 97285
CAID: CA224732
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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Case: no patient #ID, male Disease Assertion: UCD/OTCD
Family Info: NA
Case Presenting HPOs: NA
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: NA
Supplemental Data: TABLE 1, Notes: NA
Variant: NM_000531.6: c.663+1G>A
ClinVarID: 97283
CAID: CA224730
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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Case: no patient #ID, female Disease Assertion: UCD/OTCD
Family Info: NA
Case Presenting HPOs: NA
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: NA
Supplemental Data: TABLE 1, Notes: NA
Variant: NM_000531.6: c.77+1G>T
ClinVarID: 97314
CAID: CA224774
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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-
drive.google.com drive.google.com
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Case: no patient ID#, 36yo donor , female
Disease Assertion: UCD/OTCD
Family Info:
Case Presenting HPOs: adult onset (HP:0003581), oriticaciduria (HP:0003218), irritability (HP:0000737), protein avoidance
Case HPO FreeText: hyperammonemic encephalopathy
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: N/A
Supplemental Data: TABLE 1, She is vegeterian. The symptoms of OTCD started showing after the patient donated 60% of liver to her sibling. the information reported in this is the biochemical results during hyperammonemic episode following the transplantation. the patient became irritable and confused, and her level of consciousness deteriorated markedly. After hemodialysis the patient recovered.
Variant: NM_000531.6: c.429T>A(p.Tyr143*)
ClinVarID: 1072591
CAID: CA412723166
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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-
there was a paper that came out a few years ago showing that five degrees at the pace we're doing would be 00:40:13 is like easily sufficient to reproduce some of these catastrophes in Earth history
for - climate crisis - 5 deg C could reproduce similar levels of catastrophes as those in early earth history
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www.mdpi.com www.mdpi.com
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If warming reaches or exceeds 2 °C this century, mainly richer humans will be responsible for killing roughly 1 billion mainly poorer humans through anthropogenic global warming, which is comparable with involuntary or negligent manslaughter.
for - quote - exceeding 2 Deg C may result in a billion deaths - Joshua Pearce
quote - exceeding 2 Deg C may result in a billion deaths - Joshua Pearce - (see below) - If warming reaches or exceeds 2 °C this century, - mainly richer humans will be responsible for killing roughly 1 billion mainly poorer humans - through anthropogenic global warming, - which is comparable with involuntary or negligent manslaughter.
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drive.google.com drive.google.com
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Case: no patient ID#, male
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs: Neonatal onset (HP:0003623)
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: GDNA was extracted from blood or liver tissues using salt and ethanol precipitation. multiplex amplification for exons 1, 5 and 9 to screen male patients with large deletions. Band intensities were measured using a molecular dynamics phosphoimager.
Supplemental Data: TABLE 2
Variant: NM_000531.6: c.541-2A>G
ClinVarID: 97243
CAID: CA224675
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
-
Case: no patient ID#, male
Disease Assertion: UCD/OTCD
Family Info:
Case Presenting HPOs: Neonatal onset (HP:0003623)
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: GDNA was extracted from blood or liver tissues using salt and ethanol precipitation. multiplex amplification for exons 1, 5 and 9 to screen male patients with large deletions. Band intensities were measured using a molecular dynamics phosphoimager.
Supplemental Data: TABLE 2,
Variant: NM_000531.6: c.437C>G(p.Ser146*)
ClinVarID: 97201
CAID: CA224606
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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-
drive.google.com drive.google.com
-
Case: patient #573, male
Disease Assertion: UCD/OTCD
Family Info:
Case Presenting HPOs:hyperammonemia (HP:0001987), Neonatal onset (HP:0003623)
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: GDNA extracted from blood leukocytes using the proteinase K/phenol extraction procedure on a model 340 A nucleic acid extractor (Applied Biosystems). 5mg samples of DNA were digested with BamHI, MspI, or TaqI restriction endonuclease, electrophoresed through 1 % agarose gels, and transferred to a nylon membrane by standard procedures. The blots were then hybridized with a radiolabeled full-length cDNA probe for human OTC.
Supplemental Data: TABLE 3,
Variant: NM_000531.6: c.67C>T(p.Arg23*)
ClinVarID:97292
CAID: CA224742
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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Case: patient SM, male
Disease Assertion: UCD/OTCD
Family Info:
Case Presenting HPOs: Hyperammonemia (HP:0001987), Neonatal onset (HP:0003623)
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: GDNA extracted from blood leukocytes using the proteinase K/phenol extraction procedure on a model 340 A nucleic acid extractor (Applied Biosystems). 5mg samples of DNA were digested with BamHI, MspI, or TaqI restriction endonuclease, electrophoresed through 1 % agarose gels, and transferred to a nylon membrane by standard procedures. The blots were then hybridized with a radiolabeled full-length cDNA probe for human OTC.
Supplemental Data: TABLE 3,
Variant: NM_000531.6: c.274C>T(p.Arg92*)
ClinVarID:97151
CAID: CA224530
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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drive.google.com drive.google.com
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Case: patient from family 1, male
Disease Assertion: UCD/OTCD
Family Info: Family history of the disease
Case Presenting HPOs: coma(HP:0001259), lethargy(HP:0001254), hyperammonemia (HP:0001987), Neonatal Onset HP:0003623
Case HPO FreeText: Poor feeding, poor spirit
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: Genomic DNA was extracted using the QIAamp DNA Blood Midi Kit (Qiagen, Duesseldorf, Germany). Quality control assessment of DNA samples was performed using the NanoDrop 2000 ultra-microvolume nucleic acid and protein spectrophotometer (Thermo, Waltham, MA, USA). The purity of DNA was required to be between 1.8 and 2.0.
Supplemental Data: TABLE 1, admitted to neonatal department because of poor feeding, poor spirit, coma, and lethargy. The maternal grandmother of the proband in this family had given birth to 3 boys and 2 girls. Two boys died within 1 month after birth
Variant: NM_000531.6: c.867+1G>C
ClinVarID:N/A
CAID: CA412723994
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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drive.google.com drive.google.com
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Case: patient #5, female
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs: Neonatal onset (HP:0003623)
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: gDNA testing involves PCR amplification of all 10 exons and exon/intron boundaries followed by screening for mutations or sequencing of all fragments, For these patients, confirmation of the diagnosis requires enzymatic assays. No specifications about the test
Supplemental Data: TABLE 1
Variant: NM_000531.6: c.53del (p.His18Profs*20)
ClinVarID: 97239
CAID: CA224671
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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Case: patient #85, female
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs:
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: gDNA testing involves PCR amplification of all 10 exons and exon/intron boundaries followed by screening for mutations or sequencing of all fragments, For these patients, confirmation of the diagnosis requires enzymatic assays. No specifications about the test
Supplemental Data: TABLE 1
Variant: NM_000531.6: c.449_451del(p.Leu151Trpfs*36)
ClinVarID: N/A
CAID: CA2759533410
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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Case: patient #154, male
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs: Neonatal onset (HP:0003623)
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: gDNA testing involves PCR amplification of all 10 exons and exon/intron boundaries followed by screening for mutations or sequencing of all fragments, For these patients, confirmation of the diagnosis requires enzymatic assays. No specifications about the test
Supplemental Data: TABLE 1
Variant: NM_000531.6: c.664-1G>A
ClinVarID: 97288
CAID: CA224811
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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Case: patient #188, male
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs: Neonatal onset (HP:0003623)
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: gDNA testing involves PCR amplification of all 10 exons and exon/intron boundaries followed by screening for mutations or sequencing of all fragments, For these patients, confirmation of the diagnosis requires enzymatic assays. No specifications about the test
Supplemental Data: TABLE 1
Variant: NM_000531.6: c.835C>T(p.Gln279*)
ClinVarID: 97341
CAID: CA224811
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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Case: patient #213, male
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs: Neonatal onset (HP:0003623)
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: gDNA testing involves PCR amplification of all 10 exons and exon/intron boundaries followed by screening for mutations or sequencing of all fragments, For these patients, confirmation of the diagnosis requires enzymatic assays. No specifications about the test
Supplemental Data: TABLE 1
Variant: NM_000531.6: c.962C>A(p.Ser321*)
ClinVarID: 97373
CAID: CA224859
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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Case: patient #220, male
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs: Neonatal onset (HP:0003623)
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: gDNA testing involves PCR amplification of all 10 exons and exon/intron boundaries followed by screening for mutations or sequencing of all fragments, For these patients, confirmation of the diagnosis requires enzymatic assays. No specifications about the test
Supplemental Data: Table 1
Variant: NM_000531.6: c.1005+2T>C
ClinVarID: 97090
CAID: CA224431
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
Tags
- ClinVar: 97341
- c.53delA
- PMID:11793468
- c.1005+2T>C
- Gene: OTC
- Mutation: Frameshift
- CAID: CA224811
- c.664-1G>A
- ClinVar: 97239
- ClinVar: 97090
- ClinVar: 97373
- CAID: CA224671
- CAID: CA224737
- CAID: CA224859
- c.449_451delC
- Mutation: Nonsense
- ClinVar: 97288
- c.962C>A
- CAID: CA224431
- Mutation: Splicing LOF
- CAID: CA2759533410
- c.835C>T
Annotators
URL
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drive.google.com drive.google.com
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Case: patient #335, female
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs:
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: No specific functional tests indicated
Supplemental Data: In supplemental data files
Variant: NM_000531.6: c.861_862insAC (p.Met288Thrfs*2)
ClinVarID: N/A
CAID: CA2759522140
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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Case: patient #303, female
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs:
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: No specific functional tests indicated
Supplemental Data: In supplemental data files
Variant: NM_000531.6: c.766G>T(p.256Gly*)
ClinVarID: 870326
CAID: CA412722685
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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Case: patient #212, female
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs:
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: No specific functional tests indicated
Supplemental Data: In supplemental data files
Variant: NM_000531.6:c.561delA(p.Gly188Valfs*18)
ClinVarID: N/A
CAID: CA2499307429
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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Case: patient #198, male
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs: Neonatal onset (HP:0003623)
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: No specific functional tests indicated
Supplemental Data: In supplemental data files
Variant: NM_000531.6:c.538C>T(p.Gln180*)
ClinVarID: N/A
CAID: CA412724187
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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-
drive.google.com drive.google.com
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Case: patient #16, female, Japanese
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs:
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: The severity of missense mutations was assessed using conservation and solvent accessible area of the replaced amino acid, calculated destabilization of mutant proteins and their SIFT and PolyPhen2 scores
Supplemental Data: Kido_et_al_2022_fgene_Data Sheet 2
Variant: NM_000531.6:c.77+1G>T
ClinVarID: 97314
CAID: CA224774
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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drive.google.com drive.google.com
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Case: patient #55, male, Japanese
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs: Seizure (HP:0001250), Hyperammonemia (HP:0001987), Intellectual disability (HP:0001249)
Case HPO FreeText: abnormal brain MRI and brain waves, acute liver failure, corneal opacity
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: The mRNA ref seq were, wherein the “A” nucleotide of the start codon ATG constituted as +1 numbering of the cDNA sequence. Met encoded by the start codon ATG also represented +1 for the amino acid numbering as set forth by the preprotein seq. PolyPhen-2, SIFT, and I-Mutant 3 tools were used for predicting the potential impact of an amino acid alteration in missense mutations on the function of each enzyme.
Supplemental Data: Table 1
Variant: NM_000531.6:c.c.929_931del(p.Glu310Valfs*45)
ClinVarID: 858012
CAID: CA916083888
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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Case: patient #56, female, Japanese
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs: ,Hyperammonemia (HP:0001987)
Case HPO FreeText: N/A
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: The mRNA ref seq were, wherein the “A” nucleotide of the start codon ATG constituted as +1 numbering of the cDNA sequence. Met encoded by the start codon ATG also represented +1 for the amino acid numbering as set forth by the preprotein seq. PolyPhen-2, SIFT, and I-Mutant 3 tools were used for predicting the potential impact of an amino acid alteration in missense mutations on the function of each enzyme.
Supplemental Data: Table 1, patient had a liver transplant at 12yo.
Variant: NM_000531.6:c.940G>T(p.Glu314*)
ClinVarID: N/A
CAID: CA412726302
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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Case: patient #52, female, Japanese
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs: ,Hyperammonemia (HP:0001987)
Case HPO FreeText: N/A
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: The mRNA ref seq were, wherein the “A” nucleotide of the start codon ATG constituted as +1 numbering of the cDNA sequence. Met encoded by the start codon ATG also represented +1 for the amino acid numbering as set forth by the preprotein seq. PolyPhen-2, SIFT, and I-Mutant 3 tools were used for predicting the potential impact of an amino acid alteration in missense mutations on the function of each enzyme.
Supplemental Data: Table 1
Variant: NM_000531.6:c.894G>A(p.Trp298*)
ClinVarID: N/A
CAID: CA412725724
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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Case: patient #51, male, Japanese
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs: neonatal(HP:0003623), intellectual disability (HP:0001249), seizure (HP:0001250),Hyperammonemia (HP:0001987)
Case HPO FreeText: Hypertonus, Autism, Acute liver failure. very high blood ammonia
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: The mRNA ref seq were, wherein the “A” nucleotide of the start codon ATG constituted as +1 numbering of the cDNA sequence. Met encoded by the start codon ATG also represented +1 for the amino acid numbering as set forth by the preprotein seq. PolyPhen-2, SIFT, and I-Mutant 3 tools were used for predicting the potential impact of an amino acid alteration in missense mutations on the function of each enzyme.
Supplemental Data: Table 1
Variant: NM_000531.6:c.867+1G>C
ClinVarID: N/A
CAID: CA412723994
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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Case: patient #50, male, Japanese
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs: Seizure HP:0001250, hyperammonemia HP: 0001987
Case HPO FreeText: Hepatomegaly, Abnormal brain MRI and brain waves, Acute liver failure, Corneal opacity
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: The mRNA ref seq were, wherein the “A” nucleotide of the start codon ATG constituted as +1 numbering of the cDNA sequence. Met encoded by the start codon ATG also represented +1 for the amino acid numbering as set forth by the preprotein seq. PolyPhen-2, SIFT, and I-Mutant 3 tools were used for predicting the potential impact of an amino acid alteration in missense mutations on the function of each enzyme.
Supplemental Data: Table 1
Variant: NM_000531.6:c.834_840del(p.Gln279Serfs*8)
ClinVarID: N/A
CAID: CA2695233329
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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-
drive.google.com drive.google.com
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Case: no patient ID, Female
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs: HP:0001951, HP: 0001987
Case HPO FreeText: episodic hyperammonemia, hyperammonemia
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: "Genomic DNAs were extracted from leukocytes, The ten exons and intron-exon boundaries of the OTC gene were PCR amplified and analyzed by Sanger sequencing on an ABI3100 sequencer. Intragenic deletions/duplications were searched for by Multiple Ligation Probe Dependent Amplification assay. Potential impact of non truncating variants on mRNA and protein was predicted using Splice Site Prediction. OTC variants were split into two groups, “severe” and “mild,” based on their impact on the clinical phenotype and on the OTC protein.
Supplemental Data: Table 3, All nuclear family members were tested but no information about their genotype. the condition to be part of this study was the presence of at least one heterozygous female in the pedigree of the patient.
Variant: NM_000531.6:c.1052delA(p.Lys351Serfs*44)
ClinVarID: 915468
CAID: CA1139667400
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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Case: no patient ID, Female
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs: HP:0003623, HP: 0001987
Case HPO FreeText: Neonatal onset, hyperammonemia
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: "Genomic DNAs were extracted from leukocytes, The ten exons and intron-exon boundaries of the OTC gene were PCR amplified and analyzed by Sanger sequencing on an ABI3100 sequencer. Intragenic deletions/duplications were searched for by Multiple Ligation Probe Dependent Amplification assay. Potential impact of non truncating variants on mRNA and protein was predicted using Splice Site Prediction. OTC variants were split into two groups, “severe” and “mild,” based on their impact on the clinical phenotype and on the OTC protein.
Supplemental Data: Table 3, All nuclear family members were tested but no information about their genotype. the condition to be part of this study was the presence of at least one heterozygous female in the pedigree of the patient.
Variant: NM_000531.6:c.766G>T(p.Gly256*)
ClinVarID: 870326
CAID: CA412722685
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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Case: no patient ID, Female
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs: HP:0001951, HP: 0001987
Case HPO FreeText: episodic hyperammonemia, hyperammonemia
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: "Genomic DNAs were extracted from leukocytes, The ten exons and intron-exon boundaries of the OTC gene were PCR amplified and analyzed by Sanger sequencing on an ABI3100 sequencer. Intragenic deletions/duplications were searched for by Multiple Ligation Probe Dependent Amplification assay. Potential impact of non truncating variants on mRNA and protein was predicted using Splice Site Prediction. OTC variants were split into two groups, “severe” and “mild,” based on their impact on the clinical phenotype and on the OTC protein.
Supplemental Data: Table 3, All nuclear family members were tested but no information about their genotype. the condition to be part of this study was the presence of at least one heterozygous female in the pedigree of the patient.
Variant: NM_000531.6:c.568dupA(p.Thr190Asnfs*35)
ClinVarID: 870328
CAID: CA916083887
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
-
Case: no patient ID, male
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs: HP:0003623, HP: 0001987
Case HPO FreeText: Neonatal onset, hyperammonemia
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: "Genomic DNAs were extracted from leukocytes, The ten exons and intron-exon boundaries of the OTC gene were PCR amplified and analyzed by Sanger sequencing on an ABI3100 sequencer. Intragenic deletions/duplications were searched for by Multiple Ligation Probe Dependent Amplification assay. Potential impact of non truncating variants on mRNA and protein was predicted using Splice Site Prediction. OTC variants were split into two groups, “severe” and “mild,” based on their impact on the clinical phenotype and on the OTC protein.
Supplemental Data: Table 3, All nuclear family members were tested but no information about their genotype. the condition to be part of this study was the presence of at least one heterozygous female in the pedigree of the patient.
Variant: NM_000531.6:c.217-2A>G(IVS2)
ClinVarID: 915470
CAID: CA412716751
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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-
drive.google.com drive.google.com
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Case: Patient #27, male, Korean
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs: HP:0003593, HP:0003218, HP: 0001987
Case HPO FreeText: Infantile onset, oroticaciduria, hyperammonemia
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: "Potential impact of mutations on OTC function and/or folding assessed by multiple alignments of orthologous protein sequences and human OTC and structural data from Protein Data Bank (1C9Y and available orthologs). In M patients, the approximate extent of the deletions assessed by inspection of presence/absence of PCR products. In F patients, the deletions determined by the SALSA multiplex ligation probe amplification (MLPA) KIT P079 OTC (MRC-Holland, Amsterdam, the Netherlands) and the Affymetrix Human SNP 6.0 array (Santa Clara, CA). Sequence spanning 38,211,736 – 38,300,703 bp region on chromosome X (GRCh37) and including OTC was scanned for motifs CCTCCCT, CCTCCTT, CCTCCCTT, CCCCACCCC, CCNCCNTNNCCNC, GGNGGNAGGG and their complements known as being associated with recombination hotspots. Repeats capable of non-B DNA structure formation implicated in double strand breaks (DSBs) were sought by complexity analysis . X-inactivation ratio determined by analysis of methylation status of the human androgen-receptor locus (HUMARA)
Supplemental Data: Table 1&2, The minimum plasma ammonia, orotic acid and Gln+Glu concentrations depends on certain age range: Plasma ammonia: neonates <90μmol/l, other <60μmol/l. Urinary orotic acid: 0–1year <6.6mmol/mol creatinine, 1 – 10 years <3.5 mmol/mol creatinine, over 10 years <2.4 mmol/mol creatinine. Serum glutamate + glutamine: 0 – 1 month 200–1200μmol/l, 1 month–1year 200–1100μmol/l, 1year–18years 200–900μmol/l, over 18years 200–800μmol/l.
Variant: NM_000531.6:c.929_931del(p.Glu310Valfs*45)
ClinVarID: N/A
CAID: CA916083888
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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Case: Patient #37, female, Korean
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs: HP:0011463, HP:0003218, HP: 0001987
Case HPO FreeText: Childhood onset, oroticaciduria, hyperammonemia
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: "Potential impact of mutations on OTC function and/or folding assessed by multiple alignments of orthologous protein sequences and human OTC and structural data from Protein Data Bank (1C9Y and available orthologs). In M patients, the approximate extent of the deletions assessed by inspection of presence/absence of PCR products. In F patients, the deletions determined by the SALSA multiplex ligation probe amplification (MLPA) KIT P079 OTC (MRC-Holland, Amsterdam, the Netherlands) and the Affymetrix Human SNP 6.0 array (Santa Clara, CA). Sequence spanning 38,211,736 – 38,300,703 bp region on chromosome X (GRCh37) and including OTC was scanned for motifs CCTCCCT, CCTCCTT, CCTCCCTT, CCCCACCCC, CCNCCNTNNCCNC, GGNGGNAGGG and their complements known as being associated with recombination hotspots. Repeats capable of non-B DNA structure formation implicated in double strand breaks (DSBs) were sought by complexity analysis . X-inactivation ratio determined by analysis of methylation status of the human androgen-receptor locus (HUMARA)
Supplemental Data: Table 1&2, The minimum plasma ammonia, orotic acid and Gln+Glu concentrations depends on certain age range: Plasma ammonia: neonates <90μmol/l, other <60μmol/l. Urinary orotic acid: 0–1year <6.6mmol/mol creatinine, 1 – 10 years <3.5 mmol/mol creatinine, over 10 years <2.4 mmol/mol creatinine. Serum glutamate + glutamine: 0 – 1 month 200–1200μmol/l, 1 month–1year 200–1100μmol/l, 1year–18years 200–900μmol/l, over 18years 200–800μmol/l.
Variant: NM_000531.6:c.1043delA(p.Gln348Argfs*47)
ClinVarID: N/A
CAID: CA2695233335
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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Case: Patient #35, female, Korean
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs: HP:0011463, HP:0003218, HP: 0001987
Case HPO FreeText: childhood onset, oroticaciduria, hyperammonemia
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: "Potential impact of mutations on OTC function and/or folding assessed by multiple alignments of orthologous protein sequences and human OTC and structural data from Protein Data Bank (1C9Y and available orthologs). In M patients, the approximate extent of the deletions assessed by inspection of presence/absence of PCR products. In F patients, the deletions determined by the SALSA multiplex ligation probe amplification (MLPA) KIT P079 OTC (MRC-Holland, Amsterdam, the Netherlands) and the Affymetrix Human SNP 6.0 array (Santa Clara, CA). Sequence spanning 38,211,736 – 38,300,703 bp region on chromosome X (GRCh37) and including OTC was scanned for motifs CCTCCCT, CCTCCTT, CCTCCCTT, CCCCACCCC, CCNCCNTNNCCNC, GGNGGNAGGG and their complements known as being associated with recombination hotspots. Repeats capable of non-B DNA structure formation implicated in double strand breaks (DSBs) were sought by complexity analysis . X-inactivation ratio determined by analysis of methylation status of the human androgen-receptor locus (HUMARA)
Supplemental Data: Table 1&2, This is a large deletion. The minimum plasma ammonia, orotic acid and Gln+Glu concentrations depends on certain age range: Plasma ammonia: neonates <90μmol/l, other <60μmol/l. Urinary orotic acid: 0–1year <6.6mmol/mol creatinine, 1 – 10 years <3.5 mmol/mol creatinine, over 10 years <2.4 mmol/mol creatinine. Serum glutamate + glutamine: 0 – 1 month 200–1200μmol/l, 1 month–1year 200–1100μmol/l, 1year–18years 200–900μmol/l, over 18years 200–800μmol/l.
Variant: NM_000531.6:c.853C>T(p.Gln285*)
ClinVarID: N/A
CAID: CA412723777
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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Case: Patient #34, female, Korean
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs: HP:0011463, HP:0003218, HP: 0001987
Case HPO FreeText: childhood onset, oroticaciduria, hyperammonemia
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: "Potential impact of mutations on OTC function and/or folding assessed by multiple alignments of orthologous protein sequences and human OTC and structural data from Protein Data Bank (1C9Y and available orthologs). In M patients, the approximate extent of the deletions assessed by inspection of presence/absence of PCR products. In F patients, the deletions determined by the SALSA multiplex ligation probe amplification (MLPA) KIT P079 OTC (MRC-Holland, Amsterdam, the Netherlands) and the Affymetrix Human SNP 6.0 array (Santa Clara, CA). Sequence spanning 38,211,736 – 38,300,703 bp region on chromosome X (GRCh37) and including OTC was scanned for motifs CCTCCCT, CCTCCTT, CCTCCCTT, CCCCACCCC, CCNCCNTNNCCNC, GGNGGNAGGG and their complements known as being associated with recombination hotspots. Repeats capable of non-B DNA structure formation implicated in double strand breaks (DSBs) were sought by complexity analysis . X-inactivation ratio determined by analysis of methylation status of the human androgen-receptor locus (HUMARA)
Supplemental Data: Table 1&2, This is a manifesting heterozygote. Serum Gln+Glu was considered elevated. The minimum plasma ammonia, orotic acid and Gln+Glu concentrations depends on certain age range: Plasma ammonia: neonates <90μmol/l, other <60μmol/l. Urinary orotic acid: 0–1year <6.6mmol/mol creatinine, 1 – 10 years <3.5 mmol/mol creatinine, over 10 years <2.4 mmol/mol creatinine. Serum glutamate + glutamine: 0 – 1 month 200–1200μmol/l, 1 month–1year 200–1100μmol/l, 1year–18years 200–900μmol/l, over 18years 200–800μmol/l.
Variant: NM_000531.6:c.717+1G>T(IVS7+1G>T)
ClinVarID: 97298
CAID: CA224753
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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Case: Patient #30, female, Korean
DiseaseAssertion: UCD/OTCD
FamilyInfo: N/A
CasePresentingHPOs: HP:0011463, HP:0003218
CaseHPOFreeText: childhood onset, oroticaciduria,
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: "Potential impact of mutations on OTC function and/or folding assessed by multiple alignments of orthologous protein sequences and human OTC and structural data from Protein Data Bank (1C9Y and available orthologs). In M patients, the approximate extent of the deletions assessed by inspection of presence/absence of PCR products. In F patients, the deletions determined by the SALSA multiplex ligation probe amplification (MLPA) KIT P079 OTC (MRC-Holland, Amsterdam, the Netherlands) and the Affymetrix Human SNP 6.0 array (Santa Clara, CA). Sequence spanning 38,211,736 – 38,300,703 bp region on chromosome X (GRCh37) and including OTC was scanned for motifs CCTCCCT, CCTCCTT, CCTCCCTT, CCCCACCCC, CCNCCNTNNCCNC, GGNGGNAGGG and their complements known as being associated with recombination hotspots. Repeats capable of non-B DNA structure formation implicated in double strand breaks (DSBs) were sought by complexity analysis . X-inactivation ratio determined by analysis of methylation status of the human androgen-receptor locus (HUMARA)
Supplemental Data: Table 1&2, Serum Gln+Glu was considered elevated, the minimum plasma ammonia, orotic acid and Gln+Glu concentrations depends on certain age range: Plasma ammonia: neonates <90μmol/l, other <60μmol/l. Urinary orotic acid: 0–1year <6.6mmol/mol creatinine, 1 – 10 years <3.5 mmol/mol creatinine, over 10 years <2.4 mmol/mol creatinine. Serum glutamate + glutamine: 0 – 1 month 200–1200μmol/l, 1 month–1year 200–1100μmol/l, 1year–18years 200–900μmol/l, over 18years 200–800μmol/l.
Variant: NM_000531.6:c.491C>G(p.Ser164*)
ClinVarID: 97220
CAID: CA224642
gnomAD:
GeneName: OTC (ornithine transcarbamylase)
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Case: Patient #6, male, Korean
DiseaseAssertion: UCD/OTCD
FamilyInfo: N/A
CasePresentingHPOs: HP:0011463, HP:0001987, HP:0003218
CaseHPOFreeText: Neonatal onset, hyperammonemia, oroticaciduria,
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: "Potential impact of mutations on OTC function and/or folding assessed by multiple alignments of orthologous protein sequences and human OTC and structural data from Protein Data Bank (1C9Y and available orthologs). In M patients, the approximate extent of the deletions assessed by inspection of presence/absence of PCR products. In F patients, the deletions determined by the SALSA multiplex ligation probe amplification (MLPA) KIT P079 OTC (MRC-Holland, Amsterdam, the Netherlands) and the Affymetrix Human SNP 6.0 array (Santa Clara, CA). Sequence spanning 38,211,736 – 38,300,703 bp region on chromosome X (GRCh37) and including OTC was scanned for motifs CCTCCCT, CCTCCTT, CCTCCCTT, CCCCACCCC, CCNCCNTNNCCNC, GGNGGNAGGG and their complements known as being associated with recombination hotspots. Repeats capable of non-B DNA structure formation implicated in double strand breaks (DSBs) were sought by complexity analysis . X-inactivation ratio determined by analysis of methylation status of the human androgen-receptor locus (HUMARA)
Supplemental Data: Table 1&2, the minimum plasma ammonia, orotic acid and Gln+Glu concentrations depends on certain age range: Plasma ammonia: neonates <90μmol/l, other <60μmol/l. Urinary orotic acid: 0–1year <6.6mmol/mol creatinine, 1 – 10 years <3.5 mmol/mol creatinine, over 10 years <2.4 mmol/mol creatinine. Serum glutamate + glutamine: 0 – 1 month 200–1200μmol/l, 1 month–1year 200–1100μmol/l, 1year–18years 200–900μmol/l, over 18years 200–800μmol/l.
Variant: NM_000531.6:c.461_471del(p.Glu154Alafs*18)
ClinVarID: N/A
CAID:CA2695233305
gnomAD:
GeneName: OTC (ornithine transcarbamylase)
Tags
- ClinVar: 97220
- c.461_471del
- Gene: OTC
- CAID: CA412723777
- c.853C>T
- CAID: CA2695233305
- Mutation: Frameshift
- CAID:CA2695233335
- c.1043delA
- PMID: 23278509
- CAID: CA916083888
- CAID: CA224642
- Mutation: Nonsense
- c.491C>G
- CAID: CA224753
- ClinVar: 97298
- c.929_931del
- c.717+1G>T
- Mutation: Splicing LOF
Annotators
URL
-
-
drive.google.com drive.google.com
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Case: Patient #15, male, Korean
DiseaseAssertion: UCD/OTCD
FamilyInfo: N/A
CasePresentingHPOs: HP:0011463, HP:0001987, HP:0003218, HP:0003572
CaseHPOFreeText: Neonatal onset, hyperammonemia, oroticaciduria, low plasma citrulline
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: Genomic DNA was extracted from peripheral blood leukocytes. A total of 10 coding exons and exon–intron boundaries of the OTC gene were amplified by PCR with customized primers. PCR products were directly sequenced with the same primers . Sequencing results were compared with the established human OTC sequences(NM_000531.5). Multiplex ligation-dependent probe amplification analysis was performed for patients in whom no OTC mutations were identified by direct sequencing using the OTC MLPA kit.
Supplemental Data: Table 1, mother is a carrier, no range was given for blood ammonia concentration, range given in the tables for glutamine and urine orotate is slightly different than the one in the results paragraphs.
Variant: NM_000531.6:c.796_805del(p.Ile265_Gly268delinsAspfs*19)
ClinVarID: N/A
CAID:CA2695233326
gnomAD:
GeneName: OTC (ornithine transcarbamylase)
-
Case: Patient #45, female, Korean
DiseaseAssertion: UCD/OTCD
FamilyInfo: variant in mother (father not tested) and brother
CasePresentingHPOs: HP:0003593, HP:0001987, HP:0003218
CaseHPOFreeText: infantile onset, hyperammonemia, oroticaciduria
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: Genomic DNA was extracted from peripheral blood leukocytes. A total of 10 coding exons and exon–intron boundaries of the OTC gene were amplified by PCR with customized primers. PCR products were directly sequenced with the same primers . Sequencing results were compared with the established human OTC sequences(NM_000531.5). Multiplex ligation-dependent probe amplification analysis was performed for patients in whom no OTC mutations were identified by direct sequencing using the OTC MLPA kit.
Supplemental Data: Table 1, mother is a carrier, the mutation was also found in patient 13(her brother), no range was given for blood ammonia concentration, range given in the tables for glutamine and urine orotate is slightly different than the one in the results paragraphs.
Variant: NM_000531.6c.664_667delinsAC(p.Gly222Thrfs*2)
ClinVarID: N/A
CAID:CA2695233319
gnomAD:
GeneName: OTC (ornithine transcarbamylase)
-
Case: Patient #42, female, Korean
DiseaseAssertion: UCD/OTCD
FamilyInfo: N/A
CasePresentingHPOs: HP:0011463, HP:0001987, HP:0003218
CaseHPOFreeText: Childhood onset, hyperammonemia, oroticaciduria
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: Genomic DNA was extracted from peripheral blood leukocytes. A total of 10 coding exons and exon–intron boundaries of the OTC gene were amplified by PCR with customized primers. PCR products were directly sequenced with the same primers . Sequencing results were compared with the established human OTC sequences(NM_000531.5). Multiplex ligation-dependent probe amplification analysis was performed for patients in whom no OTC mutations were identified by direct sequencing using the OTC MLPA kit.
Supplemental Data: Table 1, no range was given for blood ammonia concentration, range given in the tables for glutamine and urine orotate is slightly different than the one in the results paragraphs.
Variant: NM_000531.6:c.958C>T(p.Arg320*)
ClinVarID: 97371
CAID:CA285809
gnomAD:
GeneName: OTC (ornithine transcarbamylase)
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Case: Patient #44, female, Korean
DiseaseAssertion: UCD/OTCD
FamilyInfo: variant in mother (father not tested)
CasePresentingHPOs: HP:0011463, HP:0001987, HP:0003218, HP:0003217
CaseHPOFreeText: Childhood onset, hyperammonemia, oroticaciduria, hyperglutaminemia
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: Genomic DNA was extracted from peripheral blood leukocytes. A total of 10 coding exons and exon–intron boundaries of the OTC gene were amplified by PCR with customized primers. PCR products were directly sequenced with the same primers . Sequencing results were compared with the established human OTC sequences(NM_000531.5). Multiplex ligation-dependent probe amplification analysis was performed for patients in whom no OTC mutations were identified by direct sequencing using the OTC MLPA kit.
Supplemental Data: Table 1, mother is a carrier, no range was given for blood ammonia concentration, range given in the tables for glutamine and urine orotate is slightly different than the one in the results paragraphs.
Variant: NM_000531.6:c.799_800insA (p.Ser267Lysfs*26)
ClinVarID: N/A
CAID:CA2695233327
gnomAD:
GeneName: OTC (ornithine transcarbamylase)
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-
drive.google.com drive.google.com
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Case: Patient #30, male, Chinese
DiseaseAssertion: UCD/OTCD
FamilyInfo: no family history of the disease
CasePresentingHPOs: HP:0003593, HP:0001987, HP:0003218
CaseHPOFreeText: infantile onset, hyperammonemia, oroticaciduria
CaseNOTHPOs:
CaseNOTHPOFreeText: No neurological damage
CasePreviousTesting: gDNA extracted from peripheral blood leukocytes. PCR all coding exons and exon–intron boundaries of the OTC gene using 9 pairs of synthetic oligonucleotide primers, and the primer sequences and annealing temperature. PCR products were then purified and bidirectionally sequenced. The library was sequenced using Illumina HiSeq4000 and generated 150 bp paired-end reads. Data analysis was performed as previously described [Sun Y, Hu G, Liu H, Zhang X, Huang Z, Yan H, et al. Further delineation of the phenotype of truncating KMT2A mutations: the extended Wiedemann–Steiner syndrome. Am J Med Genet A. 2017;173:510–4.]. Multiplex ligation-dependent probe amplification analysis was performed for samples in which Sanger sequencing or WES failed to detect any disease-causing mutation.
SupplementalData: Table 3, drug treatment(L-arginine, L-Citrulline, sodium benzoate, and sodium phenylbutyrate)
Variant: NM_000531.6:c.929_931del(p.Glu310Valfs*45)
ClinVarID: 858012
CAID:CA916083888
gnomAD:
GeneName: OTC (ornithine transcarbamylase)
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Case: Patient #61, female, Chinese
DiseaseAssertion: UCD/OTCD
FamilyInfo:
CasePresentingHPOs: HP:0011463, HP:0001987, HP:0003218, HP:0003572
CaseHPOFreeText: childhood onset, hyperammonemia, oroticaciduria, low plasma citrulline
CaseNOTHPOs:
CaseNOTHPOFreeText: neurological damage
CasePreviousTesting: gDNA extracted from peripheral blood leukocytes. PCR all coding exons and exon–intron boundaries of the OTC gene using 9 pairs of synthetic oligonucleotide primers, and the primer sequences and annealing temperature. PCR products were then purified and bidirectionally sequenced. The library was sequenced using Illumina HiSeq4000 and generated 150 bp paired-end reads. Data analysis was performed as previously described [Sun Y, Hu G, Liu H, Zhang X, Huang Z, Yan H, et al. Further delineation of the phenotype of truncating KMT2A mutations: the extended Wiedemann–Steiner syndrome. Am J Med Genet A. 2017;173:510–4.]. Multiplex ligation-dependent probe amplification analysis was performed for samples in which Sanger sequencing or WES failed to detect any disease-causing mutation.
SupplementalData: Table 3, drug treatment(L-arginine, L-Citrulline, sodium benzoate, and sodium phenylbutyrate)
Variant: NM_000531.6:c.868-1G>C
ClinVarID: N/A
CAID:CA412725475
gnomAD:
GeneName: OTC (ornithine transcarbamylase)
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Case: Patient #52, female, Chinese
DiseaseAssertion: UCD/OTCD
FamilyInfo: family history of the disease, variant in probands mother and father
CasePresentingHPOs: HP:0011463, HP:0001987, HP:0003218, HP:0003572
CaseHPOFreeText: childhood onset,, hyperammonemia, oroticaciduria, low plasma citrulline
CaseNOTHPOs:
CaseNOTHPOFreeText: neurological damage
CasePreviousTesting: gDNA extracted from peripheral blood leukocytes. PCR all coding exons and exon–intron boundaries of the OTC gene using 9 pairs of synthetic oligonucleotide primers, and the primer sequences and annealing temperature. PCR products were then purified and bidirectionally sequenced. The library was sequenced using Illumina HiSeq4000 and generated 150 bp paired-end reads. Data analysis was performed as previously described [Sun Y, Hu G, Liu H, Zhang X, Huang Z, Yan H, et al. Further delineation of the phenotype of truncating KMT2A mutations: the extended Wiedemann–Steiner syndrome. Am J Med Genet A. 2017;173:510–4.]. Multiplex ligation-dependent probe amplification analysis was performed for samples in which Sanger sequencing or WES failed to detect any disease-causing mutation.
SupplementalData: Table 3, inherited mutation, drug treatment(L-arginine, L-Citrulline, sodium benzoate, and sodium phenylbutyrate), low protein diet treatment, and continuous veno venous hemodialfiltration
Variant: NM_000531.6:c.703C>T
ClinVarID: N/A
CAID: CA412721652
gnomAD:
GeneName: OTC (ornithine transcarbamylase)
-
Case: Patient #20, male, Chinese
DiseaseAssertion: UCD/OTCD
FamilyInfo:
CasePresentingHPOs: HP:0011463, HP:0001987, HP:0003218
CaseHPOFreeText: childhood onset, hyperammonemia, oroticaciduria
CaseNOTHPOs:
CaseNOTHPOFreeText: No neurological damage
CasePreviousTesting: gDNA extracted from peripheral blood leukocytes. PCR all coding exons and exon–intron boundaries of the OTC gene using 9 pairs of synthetic oligonucleotide primers, and the primer sequences and annealing temperature. PCR products were then purified and bidirectionally sequenced. The library was sequenced using Illumina HiSeq4000 and generated 150 bp paired-end reads. Data analysis was performed as previously described [Sun Y, Hu G, Liu H, Zhang X, Huang Z, Yan H, et al. Further delineation of the phenotype of truncating KMT2A mutations: the extended Wiedemann–Steiner syndrome. Am J Med Genet A. 2017;173:510–4.]. Multiplex ligation-dependent probe amplification analysis was performed for samples in which Sanger sequencing or WES failed to detect any disease-causing mutation.
SupplementalData: Table 3, drug treatment (L-arginine, L-Citrulline, sodium benzoate, and sodium phenylbutyrate), deceased
Variant: NM_000531.6:c.794G>A(p.Trp265*)
ClinVarID: N/A
CAID:CA412722994
gnomAD:
GeneName: OTC (ornithine transcarbamylase)
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Case: Patient #60, female, Chinese
DiseaseAssertion: UCD/OTCD
FamilyInfo: family history of the disease
CasePresentingHPOs: HP:0011463, HP:0001987, HP:0003218, HP:0003572
CaseHPOFreeText: childhood onset,, hyperammonemia, oroticaciduria, low plasma citrulline
CaseNOTHPOs:
CaseNOTHPOFreeText: neurological damage
CasePreviousTesting: gDNA extracted from peripheral blood leukocytes. PCR all coding exons and exon–intron boundaries of the OTC gene using 9 pairs of synthetic oligonucleotide primers, and the primer sequences and annealing temperature. PCR products were then purified and bidirectionally sequenced. The library was sequenced using Illumina HiSeq4000 and generated 150 bp paired-end reads. Data analysis was performed as previously described [Sun Y, Hu G, Liu H, Zhang X, Huang Z, Yan H, et al. Further delineation of the phenotype of truncating KMT2A mutations: the extended Wiedemann–Steiner syndrome. Am J Med Genet A. 2017;173:510–4.]. Multiplex ligation-dependent probe amplification analysis was performed for samples in which Sanger sequencing or WES failed to detect any disease-causing mutation.
SupplementalData: Table 3, inherited mutation, drug treatment(L-arginine, L-Citrulline, sodium benzoate, and sodium phenylbutyrate), low protein diet treatment, and continuous veno venous hemodialfiltration
Variant: NM_000531.6:c.718-1G>A
ClinVarID: N/A
CAID: CA412722112
gnomAD:
GeneName: OTC (ornithine transcarbamylase)
-
Case: Patient #58, female, Chinese
DiseaseAssertion: UCD/OTCD
FamilyInfo: variant pin proband's mother and father CasePresentingHPOs: HP:0003593, HP:0002038, HP:0001987, HP:0003218, HP:0003572
CaseHPOFreeText: infantile onset , protein avoidance, hyperammonemia, oroticaciduria, low plasma citrulline
CaseNOTHPOs: N/A
CaseNOTHPOFreeText: neurological damage
CasePreviousTesting: gDNA extracted from peripheral blood leukocytes. PCR all coding exons and exon–intron boundaries of the OTC gene using 9 pairs of synthetic oligonucleotide primers, and the primer sequences and annealing temperature. PCR products were then purifed and bidirectionally sequenced. The library was sequenced using Illumina HiSeq4000 and generated 150 bp paired-end reads. Data analysis was performed as previously described [Sun Y, Hu G, Liu H, Zhang X, Huang Z, Yan H, et al. Further delineation of the phenotype of truncating KMT2A mutations: the extended Wiedemann–Steiner syndrome. Am J Med Genet A. 2017;173:510–4.]. Multiplex ligation-dependent probe amplifcation analysis was performed for samples in which Sanger sequencing or WES failed to detect any disease-causing mutation.
SupplementalData: Table 3, low protein diet treatment and drug treatment(L-arginine, L-Citrulline, sodium benzoate, and sodium phenylbutyrate), neurological damage
Variant: NM_000531.6:c.540+265G>A
ClinVarID: 449382
CAID: CA658658977
gnomAD:
GeneName: OTC (ornithine transcarbamylase)
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Case: Patient #3, male, Chinese
DiseaseAssertion: UCD/OTCD
FamilyInfo: Family history of the disease, variant in probands mother and father
CasePresentingHPOs: HP:0003623, HP:0001987, HP:0003218
CaseHPOFreeText: neonatal, hyperammonemia , oroticaciduria
CaseNOTHPOs: N/A
CaseNOTHPOFreeText: No neurological damage
CasePreviousTesting: gDNA extracted from peripheral blood leukocytes. PCR all coding exons and exon–intron boundaries of the OTC gene using 9 pairs of synthetic oligonucleotide primers, and the primer sequences and annealing temperature. PCR products were then purified and bidirectionally sequenced. The library was sequenced using Illumina HiSeq4000 and generated 150 bp paired-end reads. Data analysis was performed as previously described [Sun Y, Hu G, Liu H, Zhang X, Huang Z, Yan H, et al. Further delineation of the phenotype of truncating KMT2A mutations: the extended Wiedemann–Steiner syndrome. Am J Med Genet A. 2017;173:510–4.]. Multiplex ligation-dependent probe amplification analysis was performed for samples in which Sanger sequencing or WES failed to detect any disease-causing mutation.
SupplementalData: Table 3, no therapy received, mutation inherited, family history, deceased
Variant: NM_000531.6:c.579G>A
ClinVarID: N/A
CAID: CA412725369
gnomAD:
GeneName: OTC (ornithine transcarbamylase)
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Case: Patient #59, female, Chinese
DiseaseAssertion: UCD/OTCD
FamilyInfo: variant in proband's mother and father
CasePresentingHPOs: HP:0003621, HP:0001987, HP:0003218, HP:0003217
CaseHPOFreeText:juvenile onset, hyperammonemia , oroticaciduria, hyperglutaminemia
CaseNOTHPOs: N/A
CaseNOTHPOFreeText: No neurological damage
CasePreviousTesting: gDNA extracted from peripheral blood leukocytes. PCR all coding exons and exon–intron boundaries of the OTC gene using 9 pairs of synthetic oligonucleotide primers, and the primer sequences and annealing temperature. PCR products were then purified and bidirectionally sequenced. The library was sequenced using Illumina HiSeq4000 and generated 150 bp paired-end reads. Data analysis was performed as previously described [Sun Y, Hu G, Liu H, Zhang X, Huang Z, Yan H, et al. Further delineation of the phenotype of truncating KMT2A mutations: the extended Wiedemann–Steiner syndrome. Am J Med Genet A. 2017;173:510–4.]. Multiplex ligation-dependent probe amplification analysis was performed for samples in which Sanger sequencing or WES failed to detect any disease-causing mutation.
SupplementalData: Table 3, drug treatment(L-arginine, L-Citrulline, sodium benzoate, and sodium phenylbutyrate)
Variant: NM_000531.6:c.664-1G>A
ClinVarID: 97288
CAID: CA224737
gnomAD:
GeneName: OTC (ornithine transcarbamylase)
Tags
- PMID: 33272297
- c.718-1G>A
- CAID:CA412722112
- CAID: CA412725369
- CAID:CA412721652
- Gene: OTC
- CAID: CA412722994
- Mutation: Frameshift
- cDNA: c.540+265G>A
- c.664-1G>A
- c.579G>A
- c.703C>T
- CAID: CA412725475
- CAID: CA224737
- ClinVar: 858012
- CAID: CA916083888
- c.794G>A
- Mutation: Nonsense
- ClinVar:97288
- c.929_931del
- Mutation: Splicing LOF
- c.868-1G>C
- CAID: CA658658977
Annotators
URL
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- May 2024
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www.theguardian.com www.theguardian.com
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Im südlichen Teil Brasiliens fvel in diesem Frühjahr in 10 Tagen so viel Regen wie sonst in einem ganzen Jahr. Es handelt sich um die größte klimabedingte Katastrophe im Bundesstaat Rio Grande del Sol der bereits im vergangenen Jahr von zwei großen Überschwemmungen betroffen war. Die extremen Regenfälle, die es so früher in dieser Region nicht gab, werden von Forschenden auf die globale Erhitzung und mit ihr verbundene Klimaphänomene zurückgeführt. Ausführlicher hintergrundartikel im Guardian der sich auf eine Reihe von Studien und Interviews mit Forschenden bezieht. https://www.theguardian.com/global-development/article/2024/may/10/brazil-is-reeling-from-catastrophic-floods-what-went-wrong-and-what-does-the-future-hold
Tags
- Überschwemmungen in Brasilien Oktober 2023
- the National Institute of Meteorology (Inmet) ind
- Rio Grande do Sul
- Joel Goldenfum
- by: Jorge C Carrasco
- Science Panel for the Amazon
- José Antonio Marengo
- expert: Carlos Nobre
- Überschwemmungen in Brasilien April und Mai 2024
- Wagner Rodrigues Soares
- Porto Alegre
- Metsul Meteorologia
- Civil Defense
- Brazil
- Natalie Unterstell
- Marcelo Dutra da Silva
- Institute of Advanced Studies (IAE)
- Überschwemmungen in Brasilien September 2023
- increasing risk of floodings
Annotators
URL
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aacrjournals.org aacrjournals.org
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RRID:IMSR_RJ:BALB-C-NUDE
DOI: 10.1158/1078-0432.CCR-23-2951
Resource: RRID:IMSR_RJ:BALB-C-NUDE
Curator: @scibot
SciCrunch record: RRID:IMSR_RJ:BALB-C-NUDE
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RRID:IMSR_RJ:BALB-C-NUDE
DOI: 10.1158/1078-0432.CCR-23-2951
Resource: RRID:IMSR_RJ:BALB-C-NUDE
Curator: @scibot
SciCrunch record: RRID:IMSR_RJ:BALB-C-NUDE
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there is a neuron in a seans that responds to temperature and if you take a normal temperature worm 00:36:26 and you put it in high temperature
for - paradigm shift - evolutionary biology - epigenetic's critical role in inheritance - experimental proof - C. Elegan - Oded Rechavi
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english.tau.ac.il english.tau.ac.il
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for - Oded Rechavi - neurobiology - gene centrism - critique - from - youtube podcast interview - book - Understanding Living Systems - Ray Noble - Denis Noble
summary - Rechavi performed experiments with C Elegan and demonstrated that it possesses a type of neuron that - produces RNA that in response to elevated temperature change is transmitted to reproductive cells so that the offsprings encode it in the genome, and it is better adapted to deal with elevated temperatures
question - How many species do this? Is it generally found throughout nature?
from - outube podcast interview - book - Understanding Living Systems - Ray Noble - Denis Noble - https://hyp.is/OUlGVBXrEe-iaBeZhH_4DQ/docdrop.org/video/oHZI1zZ_BhY/
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- Apr 2024
- Mar 2024
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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RRID:IMSR_RJ:BALB-C-NUDE
DOI: 10.1158/2159-8290.CD-23-0954
Resource: IMSR_RJ:BALB-C-NUDE
Curator: @scibot
SciCrunch record: RRID:IMSR_RJ:BALB-C-NUDE
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aacrjournals.org aacrjournals.org
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RRID:IMSR_ORNL:IE-BALB
DOI: 10.1158/1535-7163.MCT-22-0681
Resource: RRID:IMSR_ORNL:IE-BALB-C
Curator: @abever99
SciCrunch record: RRID:IMSR_ORNL:IE-BALB-C
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- Feb 2024
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52.53.155.43 52.53.155.43
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RRID:IMSR_RJ:BALB-C-
DOI: 10.1158/2159-8290.cd-23-0954
Resource: IMSR_RJ:BALB-C-NUDE
Curator: @abever99
SciCrunch record: RRID:IMSR_RJ:BALB-C-NUDE
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www.figma.com www.figma.comFigma1
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testing the account
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universities and public libraries have completed the“retrospective conversions” of their catalogs to computer databases(frequently with the help of federal Title II-C money, as part of the“Strengthening Research Library Resources” program),
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www.brighteon.com www.brighteon.com
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0:03 vitamin C: see also http://orthomolecular.org/resources/omns/v18n14.shtml -- The Restoration of Vitamin C Synthesis in Humans. by Thomas E. Levy and Ron Hunninghake. contrary to popular belief, we humans can produce vitamin C in our body. our vitamin C deficiency is not a genetic defect, but an aquired weakness, because of false nutrition. adding olive oil and olive leaf to the nutrition increases the vitamin C levels in the body. vitamin C is also relevant in fighting cancer (natural cancer cures, Frederick Klenner, Linus Pauling)
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pressbooks.online.ucf.edu pressbooks.online.ucf.edu
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Shall find it–being grown perfect–in himself. Believing, he receives it when the soul Masters itself, and cleaves to Truth, and comes– Possessing knowledge–to the higher peace,
Arjuna struggles with moral decisions while serving his country. Jnana Yoga, often known as the "Yoga of Knowledge," is a highly profound kind of yoga that emphasizes realizing one's own transience and pursuing self-realization. Arjuna's journey through this Yoga illustrates the transformational potential of knowledge by serving as a metaphor for the seeker's journey towards enlightenment. In the face of adversity facing the challenges of line ones Dharma must still be fulfilled. This understanding reveals the moral and ethical beliefs Hindu philosophies operated by. Nonetheless philosophy like this can be applied to our own lives. Regardless of the mountain present in front of us, it is important that we seek and fulfill our life's purpose. .
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Monday had been a walk around the deer park within the walls ofMagdalen College. C. S. Lewis had said that the circular path was the perfectlength for any problem. It was true.
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- Jan 2024
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www.msnbc.com www.msnbc.com
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“A second Trump term is game over for the climate — really!”
for - quote - Michael Mann - quote - a Second Trump presidency - polycrisis - politics and climate crisis - climate mitigation strategy - voting in 2024 U.S. election - adjacency - Michael Mann - 2nd Trump presidency - exceeding planetary boundaries - exceeding 1.5 Deg C - Gen Z voting
adjacency - between - Michael Mann - 2nd Trump presidency - exceeding planetary boundaries - exceeding 1.5 Deg C - Trump's presidency is existential threat to humanity - Gen Z voting - 2024 election - adjacency statement - Michael Mann's quote " A second Trump term is game over for the climate - really" applies to the 2024 election if Trump becomes the Republican nominee. - Trumps dismal environmental record in his 2016 to 2020 term speaks for itself. He would do something similiar in 2025 if he were the president. G - Given there are only 5 years and 172 days before we hit the dangerous threshold of burning through all the carbon budget for humanity, - https://climateclock.world/ - It is questionable whether Biden's government alone can do enough, but certainly if Trump won the 2024 election, his term in office would create a regression severe enough to put the Paris Climate goal of staying within 1.5 Deg C out of reach, and risk triggering major planetary tipping points - A Biden government is evidence-based and believes in anthropogenic climate change and is already taking measures to mitigate it. A Trump government is not evidence-based and is supported by incumbent fossil fuel industry so does not have the interest of the U.S. population nor all of humanity at heart. - Hence, the 2024 U.S. election can really determine the fate of humanity. - Gen Z can play a critical role for humanity by voting against a government that would, in leading climate scientists Michael Mann's words, be game over for a stable climate, and therefore put humanity and unimaginable risk. - Gen Z can swing the vote to a government willing to deal with the climate crisis over one in climate denial so voting activists need to be alerted to this and create the right messaging to reach Gen Z - https://hyp.is/LOud7sBBEe6S0D8itLHw1A/circle.tufts.edu/latest-research/41-million-members-gen-z-will-be-eligible-vote-2024
Tags
- polycrisis - politics - climate crisis
- quote - Michael Mann
- climate mitigation strategy - voting in the 2024 U.S. election
- polycrisis - political crisis - climate crisis
- quote - A second Trump presidency - climate disaster
- adjacency - Michael Mann - 2nd Trump presidency - exceeding planetary boundaries - exceeding 1.5 Deg C - Gen Z voting
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( 1) The rearranging of the file, as I have already said, isone way. One simply dumps out heretofore disconnectedfolders, mixing up their contents, and then re-sorts themmany times. How often and how extensively one does thiswill of course vary with different problems and the devel-opment of their solutions. But in general the mechanics ofit are as simple as that.
The first part of "sociological imagination" for Mills is what I term combinatorial creativity. In his instance, at varying intervals he dumps out disconnected ideas, files and resorts them to find interesting potential solutions.
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www.repubblica.it www.repubblica.it
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now we are facing a high risk of overshooting 1.5°C - at best - for several decades. Currently, we must admit that we do not know what the consequences are of such an overshoot, i.e., we do not know how long time the big tipping point systems - like the Gulf Stream or the Coral Reef systems, can cope with high risk temperatures above 1.5°C.
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for: quote - Johan Rockstrom, quote - uncertainty at 1.5 Deg C for years
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quote: Johan Rockstrom
- now we are facing a high risk of overshooting 1.5°C - at best - for several decades. Currently, we must admit that we do not know what the consequences are of such an overshoot, i.e., we do not know how long time the big tipping point systems - like the Gulf Stream or the Coral Reef systems, can cope with high risk temperatures above 1.5°C.
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- Dec 2023
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www.heilpflanzen-welt.de www.heilpflanzen-welt.de
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Polyphenole sind ein Grundstoff für die körpereigene Vitamin C Synthese.
Die "offizielle Geschichte" behauptet, Menschen haben einen Gendefekt, der die Vitamin C Synthese verhindert... aber das ist eine Lüge, wie so viele andere "offizielle Geschichten" auch. Siehe auch: Official Stories. by Liam Scheff. Official stories exist to protect officials.
http://orthomolecular.org/resources/omns/v18n14.shtml
The Restoration of Vitamin C Synthesis in Humans
The full importance of vitamin C remains unappreciated by most health care practitioners today, as it is the most important nutrient in the body, and daily intake must be multigram in amount to even approach the benefits that vitamin C affords the body when optimally present. It has been well-established that the higher the blood levels of vitamin C, the longer and healthier the life.
The inability of most human livers to make vitamin C from glucose appears to be a combination of genetic and epigenetic defects. However, it has been discovered that the intake of hydroxytyrosol (HT) in the form of a quality olive leaf extract allows most of the consumers to substantially increase their blood levels of vitamin C. It would appear that HT effectively overcomes an epigenetic translation defect allowing the formation of GULO which can then complete the synthesis of vitamin C in the liver. And while the underlying genetic details remain to be clarified and completely understood, multiple studies have indicated that many humans do make vitamin C in utero and after birth, clearly indicating that the ability to synthesize vitamin C is a lost ability, rather than one that was never present. This also indicates that epigenetic (acquired) defects likely play the major role in adults not having the ability to make vitamin C.
Limited and small experiments have also indicated that humans supplementing HT not only have the return of the ability to make vitamin C, but also the ability to make much larger amounts of vitamin C when faced with acute toxic and/or infectious oxidative stress in the blood. This ability would be profoundly synergistic with all other beneficial treatments for different medical conditions.
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twitter.com twitter.com
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Brian Stephenson@bstephen2·Aug 5, 2020As for the Pirnie collection, not counted it, but I am slowly going through it for my online #ChessProblem database: http://bstephen.me.uk/meson/meson.pl?opt=top… . Also going through several boxes of the White-Hume Collection which I have.
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www.resilience.org www.resilience.org
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for: climate solutions - low economic growth, Jason Hickel,
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climateuncensored.com climateuncensored.com
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For a flip-of-a-coin chance of staying at or below 1.5°C we have, globally, just five to eight years of current emissions before we blow our carbon budget
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for: 1.5 Deg C target - 50/50 chance
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comment
- What most people don't recognize and pay attention to is 50/50 chance that is part of the 1.5 Deg C target.
- The world is up in arms about the 1.5 Deg C target when it ONLY GIVES US A 50/50 CHANCE!
- These are not great odds! In fact, THESE ODDS ARE TERRIBLE! What if you were given those chances in your cancer treatment? You would be concerned, wouldn't you?
- So what would an intervention closer to 90% chance of staying under 1.5 Deg C look like? If people consider today's intervention impossible, then a 90% chance would be beyond impossible. This is the nature of the challenge we face!
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i have absolutely no doubt about that if we go even to three degrees warming and we're about 1.2 right at the moment above pre-industrial temperatures but if we go to even three degrees warming there isn't an ecosystem on the planet 00:35:24 that will not be shredded by that and there's no prospect for anything resembling liberal democracy to serve to survive in a world that's three degrees warmer than it was pre-industrial times
- for: 3 Deg C world - catastrophic
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sonec.org sonec.org
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Common objective on a local level, like a specific problemNeighbourhood cooperation to build better relationships, without a specific objectiveAn individual takes the initiative to build a neighbourhood community, driven by a visionof a better world.
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for: question - SONEC alignment to earth system boundaries
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question
- Stop Reset Go's objective is to find global community partners who can help motivate a local community strategy aligned with the tight timeframe to stay under 1.5 Deg C.
- Is SONEC open to working on a strategic to empower communities in this way?
- We can offer it as an optional framework that the community can integrate into their final framework
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It may be that the climate denialists, even in the 1980s, knew this very well. They denied global heating because they saw it meant social and political change on a scale never seen before. An economic system that had made millions rich and billions at least comfortable would collapse. For those who’ve benefited from the system, death is less frightening than poverty.
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for: quote - staying under 1.5 Deg C
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quote: staying under 1.5 Deg C
- It may be that the climate denialists, even in the 1980s, knew this very well.
- They denied global heating because they saw it meant social and political change on a scale never seen before.
- An economic system that had made millions rich and billions at least comfortable would collapse.
- For those who’ve benefited from the system, death is less frightening than poverty.
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Cutting emissions back to bring global temperatures down to 1.5 C or 2 C would be the equivalent of shutting down China, the United States, India, Japan and Russia.
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for: stats - staying under 1.5 Deg C
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stats: staying under 1.5 Deg C
- is equivalent to shutting down the economies of China, the US, India, Japan and Russia
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Not large enough for most index card collections, but you have to love this listing for this photo of a man snuggling up to his card index:
Original photo from their website:
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picturing.climatecentral.org picturing.climatecentral.org
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for: visualizations - sea level rise at 3 Deg C
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comment
- Look to canal cities like Venice or Amsterdam for inspiration because if it cities are salvagable, parts of them will become canal cities.
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- Nov 2023
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In a scenario that hits global net zero emissions by 2050, declines in demand are sufficiently steep that no new long lead-time conventional oil and gas projects are required. Some existing production would even need to be shut in. In 2040, more than 7 million barrels per day of oil production is pushed out of operation before the end of its technical lifetime in a 1.5 °C scenario.
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for: stats - oil and gas industry - steep drop in production
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stats - oil and gas industry - steep drop in production
- no new fields can be developed to meet a 1.5 Deg C scenario
- any new developments face the certain risk of being a stranded asset
- by 2040, 7 million less barrels of oil are produced each day to meet a 1.5 Deg C scenario
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If all national energy and climate goals are reached, this value is lower by 25%, and by 60% if the world gets on track to limit global warming to 1.5 °C.
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for: stats - fossil fuel industry - valuation in a 1.5 Deg C world
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stats: fossil fuel industry - valuation in a 1.5 Deg C world
- current 2023 valuation: 6 trillion USD
- current NDCs met (short of a 1.5 Deg C world): 4.5 trillion USD
- 1.5 Deg C world: 2.4 trillion USD
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if governments deliver in full on their national energy and climate pledges, then oil and gas demand would be 45% below today's level by 2050 and the temperature rise could be limited to 1.7 °C. If governments successfully pursue a 1.5 °C trajectory, and emissions from the global energy sector reach net zero by mid-century, oil and gas use would fall by 75% to 2050.
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for: Nationally Determined Contributions insufficient to meet 1.5 Deg C, NDC insufficient to meet 1.5 Deg C
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stats: climate change - NDC
- current NDCs
- 45% reduction in fossil fuel usage by 2050
- NDCs to meet 1.5 Deg C
- 75% reduction in fossil fuel usage by 2050
- current NDCs
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Tags
- NDCs insufficient to meet 1.5 Deg C
- stats - oil and gas industry - no new fields to meet 1.5 Deg C
- stats - climate change - NDC
- stats - fossil fuel industry - valuation in a 1.5 Deg C world
- stats - oil and gas industry - steep drop in production to meet 1.5 Deg C
- Nationally Determined Contributions insufficient to meet 1.5 Deg C.
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And so, in colonialcircumstances, the bard could become symptomatic and symbolic of theeducation of Africans and Caribbeans into a passive, subservient rela-tionship to dominant colonial culture
Point C
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When the man-monster, brutalised by long continued torture, be-gins, 'This island's mine, by Sycorax my mother, which thou takestfrom me', we have the whole case of the aboriginal against aggressivecivilisation dramatised before us. I confess I felt a sting of con-science-vicariously suffered for my Rhodesian friends, notablyDr. Jameson-when Caliban proceeded to unfold a similar caseto that of the Matebele
"it services decolonialism by possibly enganging within the reader a sense of empathy for caliban"
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hat that's going to mean is that a lot of the things um that again that this wealthy say onethird of our society has normalized will have to change the size of our houses 00:12:01 we shouldn't be building really huge houses anymore I would also go further and say if we are really serious about climate change we need to think about the very large properties that we have which there are many of in our society 00:12:12 that need to be divided to make good quality and reasonable sized houses for say three or four families rather than just one family no more second homes and where second homes are in areas where other 00:12:25 people need to live they are no longer allowed to exist so no more second homes
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for: staying within 1.5 Deg C - elites - lifestyle changes - property and building
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example:
- Vancouver, B.C. has artificially inflated property market
- Local Vancouver city government does not want to change bylaws that advantage elites
- Climate change equity issues need to become part of the argument
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reference
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github.com github.com
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I guess we should look at what CRuby does here but the autoload logic in CRuby seems particularly unreadable.
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Local file Local file
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craftsmanship
this single word for some humanists is likely to call forward the idea of
Mills, C. Wright. “On Intellectual Craftsmanship (1952).” Society 17, no. 2 (January 1, 1980): 63–70. https://doi.org/10.1007/BF02700062.
I know it did for me...
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www.youtube.com www.youtube.com
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I think you should all know that I did not come here tonight to make fun of Don Rickles. Neither did I come here to trade barbs, because it would take a comedian to do the first and a true wit to do the second.
Instead, I've come here tonight to say something nice about Don Rickles. And for that, you have to have an actor. —George C. Scott, at a roast of Don Rickles
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paultough.com paultough.com
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assume
Why it's important to check our assumptions.
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- Oct 2023
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52.53.155.43 52.53.155.43
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RRID:IMSR_ORNL:IE-BALB
DOI: 10.1158/1535-7163.mct-22-0681
Resource: IMSR_ORNL:IE-BALB-C
Curator: @jmitrevska
SciCrunch record: RRID:IMSR_ORNL:IE-BALB-C
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- Sep 2023
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The remaining global carbon budget for a 50% chance of holding the 1.5°C line is down to crumbs, adding up to a meagre 250 billion tons of carbon dioxide, equivalent to 6-7 years of global emissions at the current pace. This gives us no choice, but to have all countries, businesses, citizens across the entire world working collectively and unified to solve the planetary crisis.
- for: .5 deg c - chances
- comment
- In Johan’s interview with Kevin Anderson, he articulates that when we account for:
- the conservative nature of IPCC, which means it doesn’t account for much outlier, cutting edges research and is already outdated ( ie doesn’t contain tipping point elements, latest research in Antarctica and Greenland (Jason Box)
- only a 50% chance
- low likelihood of scaling NET in a meaningful way
- when just is added to safe boundaries, 1 deg C is the real threshold
- it already implies that we have at small chance of staying under 1.5 deg C
- In Johan’s interview with Kevin Anderson, he articulates that when we account for:
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docdrop.org docdrop.org
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these are not represented in the models, they're not in the global carbon budget estimates, they're not in the IPCC.
- for: carbon budget - underestimate, IPCC - underestimate, 1.5Deg C - underestimate, question, question - revise 1.5 Deg C target downwards?
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highlight
- the 1.5 Deg C target does not account for cascading tipping points. In fact the cascading tipping point research is not accounted for in any of:
- current climate models
- global carbon estimates
- IPCC
- the implications are that the carbon budget is even smaller than the current number.
- the implications are that 1.5 Deg C is not the threshold we should be aiming for, but even less. We are now at 1.2 so it has to be 1.3 or 1.4.
- the 1.5 Deg C target does not account for cascading tipping points. In fact the cascading tipping point research is not accounted for in any of:
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question
- Given the underestimates, should the target actually be revised downwards to 1.3 or 1.4 deg C?
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- Aug 2023
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www.lesswrong.com www.lesswrong.com
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hi-tec-c coleto especially recommended
nice recommendation here :)
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kilcullenbridge.blogspot.com kilcullenbridge.blogspot.com
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- Jul 2023
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docdrop.org docdrop.org
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the graph you see here shows the two Alternatives we have 00:12:22 either we really radically reduce emissions and come to Net Zero by 2040 with limited overshoot
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for: bend the curve, planetary boundaries, planetary tipping points, 1.5 Degree, overshoot 1.5 Degree C
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two alternatives
- come to net zero by 2040 with limited overshoot
- come to net zero by 2060 with 3 decades of overshoot to 1.6, 1.7 Deg C
- first alternative is no longer viable
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learn.microsoft.com learn.microsoft.com
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Q: What is global namespace? The global namespace is the namespace that contains namespaces and types that aren't declared inside a named namespace
Q: How to use? ::global
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In C# 9.0 and later versions, when you use top-level statements in a Program.cs file, there is no default namespace defined.
IF "there is no default namespace defined" = "without any namespace declaration" -> the code in Program.cs belongs to the global namespace since there is no default or explicit namespace specified in the file
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We lament the man who, properly desiring to wrestle atfirst hand with the problems that the great poets and philos-ophers have raised, yet contents himself with the "results"and "findings" of modern science.
1952 variation of C. P. Snow's Two Cultures thesis (1959).
See also earlier comment on p xxi: https://hypothes.is/a/2BGWXiIAEe6WZyd5bbGl3g
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Six serologically negative sows were infected by intranasal instillation of porcinecytomegalovirus (PCMV) between 31 and 85 days of pregnancy. Four sows showedan afebrile anorexia and lethargy 14-25 days after infection and all 6 developedsignificant increases in indirect immunofluorescent (IIF) antibody titres within35 days. Virus was recovered from nasal and/or cervical swabs from 2 sowsduring life and from lung macrophage cultures after death.At term the sows were killed and their fetuses harvested by caesarean section.The number of mummified and stillborn fetuses increased from 4/63 in 6 previouslitters to 18/60 in the 6 present litters. Nine of 43 fetuses born alive were rearedin isolators for up to 6 weeks but the majority were killed for examination on theday of birth. Virus was isolated from 16 piglets from 4 of the 6 litters examined;it was isolated most frequently from lungs and liver but also from spleen, kidney,brain and nasal mucosa. Unsuckled day-old pigs had insignificant IIF titres,irrespective of whether they were excreting virus or not. The 5 congenital excretorswhich were reared all died within 7 days but no deaths occurred among their 4litter-mates. Post-natal infection of 2 of these piglets reared in contact withcongenitally infected pigs was suggested by the recovery of virus from nasal swabs17 and 27 days after birth and the subsequent rise in IIF titre to 1/256 by day 42.
在妊娠31 ~ 85天期间,通过鼻内注射猪巨细胞病毒(PCMV)感染了6头血清学阴性的母猪。4只小鼠感染后14 ~ 25 d出现发热性厌食和嗜睡,35 d内间接免疫荧光(IIF)抗体滴度均显著升高。从2头母猪生前的鼻腔和/或宫颈拭子和死后的肺巨噬细胞培养中检出病毒
在足月时,母猪被杀死,它们的胎儿被剖腹产。
木乃伊和死产胎儿的数量从之前6胎的4/63增加到现在6胎的18/60。43例活产胎儿中有9例在隔离器中饲养长达6周,但大多数在出生当天被杀死以进行检查。从6窝4窝的16头仔猪中分离出病毒;
肺、肝多发,脾、肾、脑、鼻黏膜多发。 未哺乳日龄猪的IIF滴度不显著,与是否排出病毒无关。饲养的5只先天性排泄体均在7 d内死亡,4只滴母均无死亡。其中2头仔猪与先天性感染猪有过接触,经17日和27日鼻拭子检出病毒,提示其产后感染。到第42天,IIF滴度上升到1/256。
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github.com github.com
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github.com github.com
- Jun 2023
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www.freecodecamp.org www.freecodecamp.org
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www.nytimes.com www.nytimes.com
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Die Rauchwolken der riesigen Waldbrände in Kanada bedrohen zum zweiten Mal die Gesundheit der Einwohnerinnen und Einwohner großer Teil der USA. In vielen Städten erreicht der Air Quality Index Werte von über 200. Ab 100 sind Menschen mit Atmwegsbeschwerden akut gefährdet.
https://www.nytimes.com/2023/06/28/us/canada-wildfire-smoke-air-quality-midwest.html
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www.wellappointeddesk.com www.wellappointeddesk.com
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https://www.wellappointeddesk.com/2014/06/epic-refill-guide-rollerball-gel-and-ballpoints/
A solid list of pen refills and compatible options.
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- Apr 2023
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良い3Dコンフォメーションを得るには、ほとんどの場合、まず初めに水素原子を分子に付加すること上手くいきます。
considering hydrogen is must?
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github.com github.com
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Local file Local file
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Mills, C. Wright. “On Intellectual Craftsmanship (1952).” Society 17, no. 2 (January 1, 1980): 63–70. https://doi.org/10.1007/BF02700062.
Cross reference published version from 1959, 1980: https://hypothes.is/a/7NmPckD4Ee2-r1NbihZN2A
Read on 2022-10-01 14:10
annotation target: urn:x-pdf:0138200b4bfcde2757a137d61cd65cb8
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ohlone.instructure.com ohlone.instructure.com
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and he thought we ought to take advantage of it. Then he walked behind the podium and started the day’s lecture.
This is a very interesting sentence! It's just the end of the paragraph. But it sums up the point: all the actions up to this point were because of this statement. This is something that has to be faced, no matter how bloody, no matter what camp, no matter what opinion, this is what medical students should do.
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The amphitheater buzzed.
"The amphitheater buzzed." The first paragraph has already mentioned quietness, but the word 'buzzed' is used here. It highlights the sharp contrast and expresses the students' fear of cutting a dog's chest.
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wshuyi.medium.com wshuyi.medium.com
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CTS通用类型系统 CLR公共语言运行库,负责管理.net库开发的程序的执行
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- Mar 2023
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mode80.github.io mode80.github.io
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So why aren't more people using Nim? I don't know! It's the closest thing to a perfect language that I've used by far.
Nim sounds as the most ideal language when comparing to Python, Rust, Julia, C#, Swift, C
Tags
Annotators
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developer.apple.com developer.apple.com
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https://www.ebay.com/itm/364064561931 Vintage The CE Ward Co. Wood Index Card File Box HTF
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- Feb 2023
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medium.com medium.com
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- Title: Faster than expected
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subtitle: why most climate scientists can’t tell the truth (in public) Author: Jackson Damien
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This is a good article written from a psychotherapist's perspective,
- examining the psychology behind why published, mainstream, peer reviewed climate change research is always dangerously lagging behind current research,
- and recommending what interventions could be be taken to remedy this
- This your of scientific misinformation coming from scientists themselves
- gives minimizers and denialists the very ammunition they need to legitimise delay of the urgently needed system change.
- What climate scientists say In public is far from what they believe in private.
- For instance, many climate scientists don't believe 1.5 Deg. C target is plausible anymore, but don't say so in public.
- That reticence is due to fear of violating accepted scientific social norms,
- being labeled alarmist and risk losing their job.
- That creates a collective cognitive dissonance that acts as a feedback signal
- for society to implement change at a dangerously slow pace
- and to not spend the necessary resources to prepare for the harm already baked in.
- The result of this choice dissonance is that
- there is no collective sense of an emergency or a global wartime mobilisation scale of collective behaviour.
- Our actions are not commensurate to the permanent emergency state we are now in.
- The appropriate response that is suggested is for the entire climate science community to form a coalition that creates a new kind of peer reviewed publishing and reporting
- that publicly responds to the current and live knowledge that is being discovered every day.
- This is done from a planetary and permanent emergency perspective in order to eliminate the dangerous delays that create the wrong human collective behavioural responses.
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HOW CAN CLIMATE SCIENTISTS ALLOW THEMSELVES TO TELL THE TRUTH?
- The author suggests 5 different steps that will enable and empower scientists to tell the truth at scale:
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- Admit that rigid adherence to their academic methods, in this astonishingly rapid context, leads directly to their failure to communicate the truth. For one thing, it is widely held on the scientific community that staying under 1.5 Deg. C is no longer plausible.
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- Form a unified global coalition. Work with communications and psychology experts to present as accurate and as current information as possible
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- Coalition takes actions to announce a permcrisis requiring responding to new live information in real time, bot wait every 7 years for the next IPCC report
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- The author suggests 5 different steps that will enable and empower scientists to tell the truth at scale:
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- climate change psychology
- Current climate research outdated
- Climate change is worse than reported
- eco anxiety
- climate psychology
- permanent emergency
- climate alarmist
- climate change misinformation
- Climate change underestimated
- climate change alarmist
- Climate permacrisis
- permacrisis.
- 1.5 Deg C o longer plausible
- eco-anxiety
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one finds in Deutsch’s catalogue one implementation of what LorraineDaston would later term ‘mechanical objectivity’, an ideal of removing the scholar’s selffrom the process of research and especially historical and scientific representation (Das-ton and Galison, 2007: 115-90).
In contrast to the sort of mixing of personal life and professional life suggested by C. Wright Mills' On Intellectual Craftsmanship (1952), a half century earlier Gotthard Deutsch's zettelkasten method showed what Lorraine Datson would term 'mechanical objectivity'. This is an interesting shift in philosophical perspective of note taking practice. It can also be compared and contrasted with a 21st century perspective of "personal" knowledge management.
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subscriber.politicopro.com subscriber.politicopro.com
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The long-term consequences of Russia’s war are less clear. But experts are concerned it may also lock in more future fossil fuel dependence as places like Europe search for replacements for Russian fuel.
- Russian war may increase usage of fuels
- this could make reaching the 1.5 Deg C target more difficult
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Most of them are, in general, moving in the right direction. They just aren’t aggressive enough yet to be consistent with the kind of transformative social change required to achieve the 1.5 C target.
- climate change actions
- Most of the climate actions are moving in the right direction.
- but they just aren’t aggressive enough yet to achieve the 1.5 C target.
- right direction, wrong speed
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- Jan 2023
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cubox.pro cubox.pro
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备受瞩目的C罗则不在其中,因为依照此前披露的秘密协议原件显示,上面只有帕拉蒂奇的签名,C罗并未签字。齐利亚尼辣评:“为数不多的几位没有签署2019-20和2020-21赛季虚假减薪协议的人之一。他不会有被禁赛的风险。简而言之,他有最聪明的、或者说是最不蠢的经纪人。(回看当初)他们把他带到了尤文,他则将她拖进了谷底。”虽然已经与门德斯关系破裂,但葡萄牙经纪大鳄的谨慎,则帮助C罗躲过一劫。
门德斯的专业性。
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docdrop.org docdrop.org
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1.5 degrees Celsius is the safe boundary this aligns with the intergovernmental panel on climate change with one difference we emphasize that this is a physical limit push it beyond that point 00:05:23 and we risk permanent damage on societies and the world economy
!- first boundary : 1.5 deg C is a physical boundary - we cannot it it we want to retain a planet safe for human civilization - “ If the world breaches 1.5C, we are likely to trigger at least five tipping points, including the irreversible melting of the Greenland ice sheet and loss of the world’s tropical coral reef systems. This will be devastating for future generations. It will literally change the world, and yet every month we use 1% of the remaining carbon budget for 1.5ºC.” From earth commission website: https://earthcommission.org/news/earth-commission-news/pioneering-science-reveals-set-of-earth-system-boundaries-that-can-secure-a-safe-and-just-planet-for-all/
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within the next decade we are at risk of pushing ourselves outside of the safe 00:10:15 boundary of 1.5 degrees Celsius
!- 1.5 deg C boundary : at risk of exceeding in the next decade
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matt.might.net matt.might.net
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I used vim and make for my universal IDE.
vim and make serve well as universal IDE for most programming languages (maybe apart from C#?)
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- Dec 2022
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When writing history, there are rules to be followed and evidence to be respected. But no two histories will be the same, whereas the essence of scientific experiments is that they can be endlessly replicated.
A subtle difference here between the (hard) sciences and the humanities. Every human will bring to bear a differently nuanced perspective.
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docdrop.org docdrop.org
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so let's take the headline budgets and let's adjust them to today November 00:13:16 2022. so these are the the two probabilities that we're using um that's the budget that we have left for two degrees Centigrade that's the budget we've got for 1.5 and these are the years you have 00:13:29 so you know 1.5 nine and a half years of current emissions if the current emissions stayed static we'd have nine and a half years oh a bit worrying um that's about half a percent a bit 00:13:43 under half a percent every month for two degrees centigrade and one percent so every month we're using one percent of the 50 50 chance of 1.5 degrees Centigrade which is not anyway a safe 00:13:54 threshold every month one percent of the budget
!- key takeaway : time remaining to decarbonize to 1.5 Deg C limit - 9.5 years remaining referenced to Nov 2022 - consuming roughly 1% of remaining 380 Gigaton budget every month, or about 11 % every year.
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www.zhihu.com www.zhihu.com
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java nio使用的是水平触发还是边缘触发?
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为什么bs虚函数表的地址(int*)(&bs)与虚函数地址(int*)*(int*)(&bs) 不是同一个?
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www.zhihu.com www.zhihu.com
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现代C/C++编译器有多智能?能做出什么厉害的优化?
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www.zhihu.com www.zhihu.com
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如何理解编程语言中「操作符」(operator)的概念?
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www.zhihu.com www.zhihu.com
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应该怎么理解编程语言中的协变逆变?
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www.zhihu.com www.zhihu.com
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async/await异步模型是否优于stackful coroutine模型?
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www.zhihu.com www.zhihu.com
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为什么C/C++等少数编程语言要区分左右值?
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www.zhihu.com www.zhihu.com
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c++中,引用和指针的区别是什么?
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C++ 中,如果指针换了被指向的东西,那被指向的原来的东西(是被 new 出来的)所占的内存会立刻被释放吗?
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www.zhihu.com www.zhihu.com
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是否有可能发现一段内存被野指针修改了?
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www.zhihu.com www.zhihu.com
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全局指针变量指向栈上的对象的问题?
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www.zhihu.com www.zhihu.com
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c++是否应避免使用普通指针,而使用智能指针(包括shared,unique,weak)?
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www.zhihu.com www.zhihu.com
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什么情况下 C++ 需要垃圾处理机制?
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www.zhihu.com www.zhihu.com
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free一块修改过的malloc指针会发生什么?
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在c或者c++中为什么free() 和delete释放内存,不直接在函数内部实现指针等于NULL,而是将其设置为野指针呢?
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www.zhihu.com www.zhihu.com
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为什么滑铁卢大学让大一学生从不实用的racket语言学起而不是直接上手C语言?
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www.zhihu.com www.zhihu.com
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如何评价王垠的 《讨厌的 C# IDisposable 接口》?
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www.zhihu.com www.zhihu.com
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如何评价《王垠:C 编译器优化过程中的 Bug》?
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www.zhihu.com www.zhihu.com
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Objective-C是动态语言吗?为什么?
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www.zhihu.com www.zhihu.com
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高级语言为什么要添加数据类型?
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www.zhihu.com www.zhihu.com
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能否从编译原理的角度详细的描述一下模板编译的过程?
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www.zhihu.com www.zhihu.com
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玩模板元编程走火入魔是一种怎样的体验?
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www.zhihu.com www.zhihu.com
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C++ 模板元编程的应用有哪些,意义是什么?
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www.zhihu.com www.zhihu.com
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如何正确地学习 C++ 的模板和模板元编程?
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www.zhihu.com www.zhihu.com
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stdin、stdout、stderr 标准流本质上到底是什么?
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www.zhihu.com www.zhihu.com
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Scheme语言的优势?
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www.zhihu.com www.zhihu.com
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在C语言中,可不可以实现使用一个字符串变量的内容为函数名,调用一个函数?
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www.zhihu.com www.zhihu.com
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如何理解 C++ 中的深拷贝和浅拷贝?
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www.zhihu.com www.zhihu.com
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怎么样才算是精通 C++?
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www.zhihu.com www.zhihu.com
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新手应该如何读Google V8引擎源代码?
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www.zhihu.com www.zhihu.com
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编译器生成的汇编语句执行顺序为什么与C代码顺序不同?
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www.zhihu.com www.zhihu.com
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你读过的最好的 C++ 开源代码是什么?
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www.zhihu.com www.zhihu.com
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多线程编程的时候,使用无锁结构会不会比有锁结构更加快?
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www.zhihu.com www.zhihu.com
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以C++为核心语言的高频交易系统是如何做到低延迟的?
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www.allocine.fr www.allocine.fr
- Nov 2022
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www.youtube.com www.youtube.com
- Oct 2022
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In his essay ‘On Intellectual Craftsmanship’, appended to his The Sociological Imagination (1959), C. Wright Mills reassuringly remarks that ‘the way in which these categories change, some being dropped and others being added, is an index of your intellectual progress ... As you rearrange a filing system, you often find that you are, as it were, loosening your imagination.’
One's notes are an index of their intellectual progress. In sorting through and re-arranging them one "loosens their imagination".
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another long forgotten manual for students, History and Historical Research (1928) by C.G. Crump of the Public Record Office: ‘Never make a note for future use in such a form ... that even you yourself will not know what it means, when you come across it some months later.’
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archive.org archive.org
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There is a difference between various modes of note taking and their ultimate outcomes. Some is done for learning about an area and absorbing it into one's own source of general knowledge. Others are done to collect and generate new sorts of knowledge. But some may be done for raw data collection and analysis. Beatrice Webb called this "scientific note taking".
Historian Jacques Goutor talks about research preparation for this sort of data collecting and analysis though he doesn't give it a particular name. He recommends reading papers in related areas to prepare for the sort of data acquisition one may likely require so that one can plan out some of one's needs in advance. This will allow the researcher, especially in areas like history or sociology, the ability to preplan some of the sorts of data and notes they'll need to take from their historical sources or subjects in order to carry out their planned goals. (p8)
C. Wright Mills mentions (On Intellectual Craftsmanship, 1952) similar research planning whereby he writes out potential longer research methods even when he is not able to spend the time, effort, energy, or other (financial) resources to carry out such plans. He felt that just the thought experiments and exercise of doing such unfulfilled research often bore fruit in his other sociological endeavors.
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In "On Intellectual Craftsmanship" (1952), C. Wright Mills talks about his methods for note taking, thinking, and analysis in what he calls "sociological imagination". This is a sociologists' framing of their own research and analysis practice and thus bears a sociological related name. While he talks more about the thinking, outlining, and writing process rather than the mechanical portion of how he takes notes or what he uses, he's extending significantly on the ideas and methods that Sönke Ahrens describes in How to Take Smart Notes (2017), though obviously he's doing it 65 years earlier. It would seem obvious that the specific methods (using either files, note cards, notebooks, etc.) were a bit more commonplace for his time and context, so he spent more of his time on the finer and tougher portions of the note making and thinking processes which are often the more difficult parts once one is past the "easy" mechanics.
While Mills doesn't delineate the steps or materials of his method of note taking the way Beatrice Webb, Langlois & Seignobos, Johannes Erich Heyde, Antonin Sertillanges, or many others have done before or Umberto Eco, Robert Greene/Ryan Holiday, Sönke Ahrens, or Dan Allosso since, he does focus more on the softer portions of his thinking methods and their desired outcomes and provides personal examples of how it works and what his expected outcomes are. Much like Niklas Luhmann describes in Kommunikation mit Zettelkästen (VS Verlag für Sozialwissenschaften, 1981), Mills is focusing on the thinking processes and outcomes, but in a more accessible way and with some additional depth.
Because the paper is rather short, but specific in its ideas and methods, those who finish the broad strokes of Ahrens' book and methods and find themselves somewhat confused will more than profit from the discussion here in Mills. Those looking for a stronger "crash course" might find that the first seven chapters of Allosso along with this discussion in Mills is a straighter and shorter path.
While Mills doesn't delineate his specific method in terms of physical tools, he does broadly refer to "files" which can be thought of as a zettelkasten (slip box) or card index traditions. Scant evidence in the piece indicates that he's talking about physical file folders and sheets of paper rather than slips or index cards, but this is generally irrelevant to the broader process of thinking or writing. Once can easily replace the instances of the English word "file" with the German concept of zettelkasten and not be confused.
One will note that this paper was written as a manuscript in April 1952 and was later distributed for classroom use in 1955, meaning that some of these methods were being distributed from professor to students. The piece was later revised and included as an appendix to Mill's text The Sociological Imagination which was first published in 1959.
Because there aren't specifics about Mills' note structure indicated here, we can't determine if his system was like that of Niklas Luhmann, but given the historical record one could suppose that it was closer to the commonplace tradition using slips or sheets. One thing becomes more clear however that between the popularity of Webb's work and this (which was reprinted in 2000 with a 40th anniversary edition), these methods were widespread in the mid-twentieth century and specifically in the field of sociology.
Above and beyond most of these sorts of treatises on note taking method, Mills does spend more time on the thinking portions of the practice and delineates eleven different practices that one can focus on as they actively read/think and take notes as well as afterwards for creating content or writing.
My full notes on the article can be found at https://jonudell.info/h/facet/?user=chrisaldrich&max=100&exactTagSearch=true&expanded=true&addQuoteContext=true&url=urn%3Ax-pdf%3A0138200b4bfcde2757a137d61cd65cb8
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Thinking is a simultaneous struggle for conceptualorder and empirical comprehensiveness. You must notclose it up too soon---or you will fail to see all that youshould; you cannot leave it open forever----or you yourselfwill burst. It is this dilemma that makes reflection, onthose rare occasions when it is more or less successful, themost passionate endeavor of which a man is capable
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Thinking is a simultaneous struggle for conceptualorder and empirical comprehensiveness.
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I do not like to do empirical work if I can possibly avoidit. It m e a n s a great deal of trouble if one has no staff; if onedoes e m p l o y a staff, then the staff is often more troublethan the work itself. Moreover, they leave as soon as theyhave b e e n trained and made useful.
Ha!
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