DOI: 10.1016/j.celrep.2026.117621

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What is this?

面白いw

今時っぽーーーい

他に合わせて ... とかにしてもいいかも?

このオプションはなくてもよさそう https://prek.j178.dev/reference/cli/#prek-sample-config

ドキュメントがZensicalだ!!

されています

の方が素直かなぁ

so this is Ted's Zig Zag Data Structure

which is a 3x3 grid arrangement, or card as in Playn

I notice now that gender expression is becoming much more varied between just strictly masculine presenting or feminine presenting. Now it is also becoming more acceptable to do so. It is prevalent especially online and in T.V. media, where you can see someone who identifies as male put on feminine presenting makeup while also keeping their beard.

Social identities are important as they tie us to our peer groups and help people identify things we like and groups we associate with. I found another example of social identities and as a plus it is pink (my favorite color).

This was really enlightening to hear. I had known that everybody thought about who they were and what they were doing with their life or what they wanted to do (duh, everyone thinks), but it never really sunk in for me. Especially when I would get into that cycle of "you're not doing enough, you need to be trying harder," and I never truly though about how everyone struggles with this journey. So I really appreciate this addition as I struggle with this specific structure a lot in my personal life.

Person Name

PMID: 32562209

Gene: CTLA4

HGNC: 2505

Disease: autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

MONDO: 0014493

InheritancePattern: autosomal dominant

Prevalence: <1 in 1,000,000

Penetrance: The penetrance of the phenotype among carriers of pathogenic variants is incomplete.

PMID: 33956248

Gene: CTLA4, LRBA

HGNC: 2505, 1742

Disease: CTLA4 haploinsufficiency

MONDO: MONDO:0014493

InheritancePattern: AD (haploinsufficiency)

Prevalence: <1 in 1,000,000

Penetrance: incomplete

Case#: Grammatikos_2021_Case2, female, 10 months (onset) 25 y.o. (report), origin not reported

DiseaseAssertion: CTLA4 haploinsufficiency

FamilyInfo: Mother and brother are also affected. Extensive family history of autoimmune phenotypes in Figure S1.

CasePresentingHPOs: HP:0002315, HP:000340, HP:0003394, HP:0004313, HP:0012115, HP:0001878, HP:0007565, HP:0001744, HP:0004315, HP:0006577, HP:0002090, HP:0002829, HP:0005263, HP:0006532, HP:0033542, HP:0032174, HP:0002110, HP:0011473 (headache, peripheral paresthesia, muscle cramps, hypogammaglobulinemia, autoimmune hepatitis, hemolytic anaemia, cafe au lait spots, splenomegaly, low IgG, macronodular cirrhosis, fungal pneumonia, arthralgia, antral gastritis, recurrent bacterial pneumonias, bronchial wall thickening, diffuse tree-in-bud infiltrates, bronchiectasis, focal total villous atrophy)

CaseHPOFreeText: Severe lesion in right cerebellar hemisphere and left superior frontal gyrus. Evan's syndrome, bronchial associated lymphoid hyperplasia, intestinal metaplasia, intraepithelial lymphocytes

CaseNotHPOs: HP:0001369, HP:0012538 (artritis, response to gluten)

CaseNotHPOFreeText: n/a

CasePreviousTesting: 2 benign polymorphisms found in perforin gene. Other genes tested: Fas, Fas ligand, Caspase 10, Caspase 8, NRAS. Heterozygous VUS found in LRBA gene.

GenotypingMethod: not specified. It says, "Following her mother’s diagnosis of CTLA4 haploinsufficiency, she was confirmed to have the same genetic mutation." Mother was tested using NGS + Sanger

PreviouslyPublished: not reported

Variant: NM_005214.4(CTLA4):c.81_82insT (p.Leu28fs) heterozygous

ClinVarID: 644629

CAID: CA645516071

gnomAD: not found

SupplementalData: Figure S1 shows extensive family history

Case#: P12, sex: n/a, age: n/a, ethnicity: n/a

DiseaseAssertion: n/a

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.326G>A (p.Gly109Glu)

ClinVar ID: 542071

gnomAD: 0.0002354 https://gnomad.broadinstitute.org/variant/2-203870802-G-A?dataset=gnomad_r4

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P11, Female, German, age: n/a, alive at the time of publication

DiseaseAssertion: Severely affected based on a CHAI score of 18.75%

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.326G>A (p.Gly109Glu)

ClinVar ID: 542071

gnomAD: 0.0002354 https://gnomad.broadinstitute.org/variant/2-203870802-G-A?dataset=gnomad_r4

SupplementalData: Yes, all data regarding the patient was found in Table1.

PMID: 24610295

Gene: PIK3CD

HGNC: 8977

Disease: Activated PI3K delta syndrome

Case#: Patient 6 (P6) is an 18-year-old Chinese male.

DiseaseAssertion: Patients are asserted to have "CTLA4 haploinsufficiency (CTLA-4 h).

FamilyInfo: Patient denied family history of inborn error of immunodeficiency. The patient's father harbors the same CTLA4 variant as the patient. No symptoms are reported in the patient's father.

CasePresentingHPOs: HP:0001954 (Recurrent fever), HP:0012735 (Cough), HP:0002829 (Arthralgia), HP:0002113 (Pulmonary infiltrates), HP:0002716 (Lymphadenopathy), HP:0006532 (Recurrent pneumonia), HP:0004313 (Decreased circulating immunoglobulin concentration

CaseHPOFreeText: MRI of knees showed patchy abnormal signals in the right femoral and lateral condylar regions suggestive of bone marrow edema, with surrounding soft tissue edema. Mild joint effusion and suprapatellar bursa fluid were also noted. Treatment with avatacept was started and at the six-month follow-up the patient reported clinical improvement. He had no fever or sputum production and symptoms of lymphadenopathy and joint pain had improved.

CaseNotHPOs: HP:0001386 (Joint swelling), HP:0000988 (Skin rash), HP:0002014 (Diarrhea), HP:0003493 (Antinuclear antibody positivity), HP:0034092 (Anti-cyclic citrullinated peptide antibody positivity), HP:0002923 (Rheumatoid factor positive), HP:0032230 (Cytoplasmic antineutrophil antibody positivity)

CaseNotHPOFreeText:

CasePreviousTesting: None noted.

GenotypingMethod: Genotyping was performed via whole exome sequencing.

PreviouslyPublished No prior article is known to contain information on the same proband.

Variant: The patient is heterozygous for the NM_005214.4 CTLA4):c.436G>A(p.Gly146Arg) variant.

ClinVar: 849622

gnomAD: This variant has an allele frequency of 0.000001696 in gnomAD v4.1.1. (https://gnomad.broadinstitute.org/variant/chr2-203870912-G-A?dataset=gnomad_r4)

SupplementalData: There is no supplemental data.

Case#: Patient 1 (P1) is a 24-year-old Chinese female.

DiseaseAssertion: Patients are asserted to have "CTLA4 haploinsufficiency (CTLA-4 h).

FamilyInfo: The patient's father carries the same CTLA4 variant as the patient but has been asymptomatic. No other family history reported.

CasePresentingHPOs: HP:0031245 (Productive cough), HP:0002105 (Hemoptysis), HP:0001878 (Hemolytic anemia), HP:0006532 (Recurrent pneumonia), HP:0004313 (Decreased circulating immunoglobulin concentration, HP:0033608 (Pulmonary nodule), HP:0002716 (Lymphadenopathy), HP:0001596 (Alpecia),

CaseHPOFreeText: Patient first presented at age 14 with respiratory symptoms. She was hospitalized at age 16 with hemolytic anemia and recurrent pulmonary infections. Lab work showed hypogammaglobinemia. Chest CT showed scattered solid and ground-glass density nodules bilaterally in the lungs, Lung biopsy demonstrated lymphocytic infiltration and siderophages. Treatment with corticosteroids achieved temporary remission, but the patient relapsed with dose tapering. She developed Evans syndrome, alopecia, and skin lesions. Disease stabilized with weekly subcutaneous abatacept (125mg) and the interval was subsequently extended to once every 4 weeks.

CaseNotHPOs: HP:0003493 (Antinuclear antibody positivity), HP:0032230 (Cytoplasmic antineutrophil antibody positivity).

GenotypingMethod: Genotyping was performed by whole exome sequencing.

PreviouslyPublished: No prior article is known to contain information on the same proband.

Variant: The patient is heterozygous for the NM_005214.4(CTLA4):c.155G>T(p.Gly52Val) variant.

ClinVar: 1420586

gnomAD: The variant was not found in gnomAD v4.1.1.

SupplementalData: No supplemental data provided.

Case#: Ayrignac_2020_Patient_3, female, 42 y.o. (onset), origin unknown

DiseaseAssertion: CTLA4-related haploinsufficiency

FamilyInfo: unremarkable family history

CasePresentingHPOs: HP:0001138, HP:0000009, HP:0000572, HP:0020036, HP:0002015, HP:0002167, HP:0001285, HP:0002346, HP:0001272, HP:0002719, HP:0002720, HP:0004315, HP:0002923, HP:0002110 (bilateral axonal optic neuropathy, bladder urgency, vision loss, upper limb dysmetria, speech/swallowing disorder, spastic tetra paresis, head tremor, cerebellar atrophy, recurrent infections, IgA and IgG deficiency, autoantibodies [rheumatoid factor], bronchiectasis)

CaseHPOFreeText: white matter and deep basal ganglia FLAIR hyperintensities

CaseNotHPOs: lymphoproliferation

CaseNotHPOFreeText: abnormal CSF analysis

CasePreviousTesting: CSF analysis, "multiple panel gene excluded the main known causes of inherited leukoencephalopathy, cerebellar ataxia, and mitochondrial diseases."

GenotypingMethod: mini-exome analysis

PreviouslyPublished: n/a

Variant: NM_005214.5(CTLA4):c.151C>T (p.Arg51Ter)

ClinVarID: 161109

CAID: CA173992

gnomAD: not reported

SupplementalData: n/a

Case#: P23, Male, diagnosed at age 7

DiseaseAssertion: APDS

FamilyInfo:

CaseHPOFreeText: cytomegalovirus, lymphadenopathy, EBV lymphadenitis, B cell lymphoma, IgA vasculitis

GenotypingMethod: Unclear, possibly WES ("In a previous study (15), we reviewed clinical and routine immunological features of 15 APDS patients diagnosed in our center by next-generation sequencing (NGS). In the present study, we extended our previous study...")

Variant: E81K

CAID: CA338300169

gnomAD: absent from gnomAD v2.1.1

SupplementalData: Table S1

PMID: 29375547

Gene: CTLA4

HGNC: 2505

Disease: autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

MONDO: 0014493

InheritancePattern: autosomal dominant

Prevalence: <1 in 1,000,000

Penetrance: The penetrance of the phenotype among carriers of pathogenic variants is incomplete.

Case#: IV.2, a 15 year old male realtive, unknown age of onset

CaseHPOFreeText: Ear, nose and throat infections; Dermatitis

Variant: c.379T >G variant in CTLA4

GenotypingMethod: high-throughput sequencing

CAID: CA350138665

Case#: 20-year-old Spanish man

DiseaseAssertion: Immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferation

FamilyInfo: Maternally inherited CTLA4 variant and paternally inherited CLEC7A variant. Patient's mother had been diagnosed with mild sarcoidosis, dysphagia with eosinophilic infiltrates of esophagus, low IgM, and decreased percentages of memory B cells.

CasePresentingHPOs: HP:0100651 (Type I diabetes mellitus) HP:0001045 (Vitiligo) HP:0001047 (Atopic dermatitis) HP:0002205 (Recurrent respiratory infections) HP:0001541 (Ascites) HP:0002014 (Diarrhea) HP:0410151 (Eosinophilic infiltration of the esophagus) HP:0410147 (Eosinophilic infiltration in the stomach mucosa) HP:0033351 (Candida esophagitis) HP:0100806 (Sepsis) HP:0032061 (Hypereosinophilia) HP:0032064 (Gastrointestinal eosinophilia)

CaseHPOFreeText: Type 1 diabetes was diagnosed at 15 months old. Patient has a history of severe enteritis. Investigations, which were undertaken due to hypereosinophilia and eosinophilic infiltration, revealed a clonal γδ T cell band, characterized as reactive, with subsequent exclusion of FIP1L1-FDGFRA and PDGFRB rearrangements, as well as any abnormal karyotype. Sepsis was due to Salmonella typhi and Clostridium difficile infection.

Article provides functional evidence of CLEC7A variant affecting phenotype of this patient. Their data suggest that partial loss of DECTIN-1 in a patient with CTLA-4h may enhance IDAIL penetrance and confer additional unique phenotypes, with persistent marked hypereosinophilia as the most remarkable uncommon clinical manifestation.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Whole-genome sequencing was performed on the patient's whole blood sample. The variants were confirmed with Sanger sequencing. Presence of a somatic CTLA4 variant was ruled out with high-coverage WGS of sorted peripheral T cells.

GenotypingMethod: Whole-genome sequencing was performed on the patient's whole blood sample. The variants were confirmed with Sanger sequencing. Presence of a somatic CTLA4 variant was ruled out with high-coverage WGS of sorted peripheral T cells.

PreviouslyPublished: No

Variant: NM_005214.5:c.208C>T p.Arg70Trp

ClinVar: 161114

CAID: CA173999

gnomAD: 0.000001313 https://gnomad.broadinstitute.org/variant/2-203870684-C-T?dataset=gnomad_r4

Variant: NM_197947.3:c.547C>T p.Leu183Phe

ClinVar: 717363

CAID: CA6443934

gnomAD: 0.01719 https://gnomad.broadinstitute.org/variant/12-10123309-G-A?dataset=gnomad_r4

SupplementalData: Detailed clinical info and and immunological test results can be found in Supplementary Materials.f

Case#: Schwab_2018_CaseVV.II.1, male, 7 .o. (onset) 13 y.o. (report), origin in Saudi Arabia, reported Caucasian ethnicity

DiseaseAssertion: CTLA4 haploinsufficiency

FamilyInfo: Same variant observed in the father. Consanguinity reported

CasePresentingHPOs: HP:0002086, HP:0005523, HP:0011024, HP:0004313, HP:0002720, HP:0001744, HP:0002240, HP:0011947, HP:0002090, HP:0002110, HP:0031035, HP:0002242 (respiratory involvement, lymphoproliferation, gastrointestinal involvement, hypogammaglobulinemia, low IgA, splenomegaly, hepatomegaly, upper and lower RTIs, pneumonia, bronchiectasis, chronic infection, enteropathy, cytopenia (ITP))

CaseHPOFreeText: low IgM, Lymphocytic or granulomatous organ infiltration (lung, liver, gut), GLILD

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

GenotypingMethod: unknown

PreviouslyPublished: no

Variant: c.359_359delG; p.A121fs*23

ClinVarID: not found

CAID: CA2573320362

gnomAD: not found

SupplementalData: extensive phenotype data in figure S1

Case#: Angulo_2014_P8, M, 6 months (onset), origin in Slovenia

DiseaseAssertion: APDS

FamilyInfo: de novo confirmed

CasePresentingHPOs: HP:0002783, HP:0410018, HP:0002716, HP:0002014, HP:0032247, HP:0031693, HP:0001433, HP:0000620, HP:0030877, HP:0002720, HP:0003496, HP:0410303, HP:0032218, HP:0010976, HP:0030374, HP:0030388, HP:0030381 (recurrent LRTI, recurrent ear infections, massive generalized lymphadenopathy, cryptosporidium parvum diarrhoea, CMV and EBV infections, hepatosplenomegaly, chronic dacriocystitis requiring surgical intervention, mixed obstructive/restrictive FEV1/FVC, decreased IgA, increased IgM, decreased haemophilus B antibodies, decreased CD4+ T cells, decreased B cells, decreased IgM memory B cells; CD19+ CD27+ IgD+, decreased Class-switched memory B cells; CD19+ CD27+ IgD–, as % of CD19+, increased transitional B cells; CD19+ CD38+ IgM+, as % of CD19+

CaseHPOFreeText: decreased CD25+ as % CD3+, mastocytoma, increased CD8+ T cells, CD4+ CD25– CD127– as % of CD4+ T cells, increased CD8+ CD25– CD127– as % of CD8 T cells, as % of CD19+)

CaseNotHPOs:

CaseNotHPOFreeText: malignancy, abnormal CD4+ CD25+ CD127- as % of CD4+ regulatory T cells

CasePreviousTesting: fibroblast and blood samples taken to evaluate somaticism. Findings indicate the mutation was germline.

GenotypingMethod: WES and Sanger, followed by genome for parental confirmation.

PreviouslyPublished: not reported

Variant: heterozygous NM_005026.5:c.3061G>A (p.E1021K)

ClinVarID: 88675

CAID: CA145460

gnomAD: Not present in gnomAD

SupplementalData: Phenotypic info in table S2

Note: could lacrimal gland obstruction be considered atopy for phenotype scoring?

Case#: 19 year old, Indian, male

DiseaseAssertion: APDS

FamilyInfo: Neither parent carried this mutation, suggesting a de novo origin.

CaseHPOFreeText: referred for the evaluation of chronic active EBV disease. The patient’s medical history revealed congenital stenosis of the left bronchus, recurrent sinopulmonary infections, and autism spectrum disorder with an IQ of 80–86. EBV seroconversion was identified at 7 years of age when the patient presented idiopathic abdominal lymphadenopathy. Furthermore, a previous laboratory examination revealed IgA deficiency and low IgG2 and IgG4 levels without an overarching diagnosis. Four months before presentation, the patient developed fatigue, fever, night sweats, hepatosplenomegaly, anemia, hepatitis, weight loss of 10 kg, and lymphadenopathy (Fig. 1). Serum EBV copy numbers were repeatedly > 1500/mL. Histology of the three lymph nodes did not reveal any evidence of malignant lymphoma, but rather a markedly positive EBV-encoded RNA (EBER). Chronically active EBV was diagnosed, and rituximab therapy of 500 mg weekly during 4 weeks was initiated. A stable condition without any additional immunosuppressive drugs was achieved for 3 months after which he developed high spiking fever, pneumonia, progressive lymphadenopathy, severe unexplained cardiomyopathy with progressive anemia, thrombocytopenia, and hyperferritinemia (Table ​(Table1).1). Malignant lymphoma was excluded and hemophagocytosis was detected in the bone marrow (Fig. 3A, B). The patient therefore fulfilled six out of eight diagnostic HLH-04 criteria (Table ​(Table2)2) [7]. His clinical status quickly deteriorated, and he developed acute respiratory distress syndrome and multiple organ failure. Salvage therapy was initiated with high-dose steroids, sirolimus, and intravenous immunoglobulin. PI3K delta inhibitors were withheld due to heart and respiratory failure. Etoposide was withheld due to leucopenia and severe sepsis with systemic infection (hospital acquired pneumonia with H. influenza, not responding to treatment). Within 1 month, the patient died from cardiac failure with refractory pulmonary edema.

CasePreviousTesting: whole exome sequencing (confirmed by Sanger sequencing)

GenotypingMethod: whole exome sequencing (confirmed by Sanger sequencing)

Variant: heterozygous c.3074A > C, p.Glu1025Gly mutation in the PIK3CD gene (NM_005026.3)

CAID: CA16617216

gnomAD: absent from gnomAD v2.1.1

Case#: P2, 10 year old boy

DiseaseAssertion: APDS

CaseHPOFreeText: presented with recurrent otitis media and sinusitis since his first year of life. He had an adenoidectomy at 3 years of age. He presented with high IgM but normal IgG and IgA serum levels (Table 1). The serum levels of IgG2 (0.23; N: 0.56) and IgG4 (<0.002; N: 0.018) subclasses were low.

CasePreviousTesting: Thus, mutations known to cause APDS1 or APDS2 were searched and excluded by Sanger sequencing

GenotypingMethod: For P2 and P3, a targeted Next-Generation sequencing of a primary immunodeficiencies gene panel including PIK3CD and PIK3R1 was performed

Variant: A heterozygous G to A mutation at position 9775907 (GRCh37; NM_005026.3) in the PIK3CD gene was detected. The mutation leads to an amino acid substitution from glycine to aspartic acid at position 124 (G124D) located in the linker region between the ABD and the RBD at the N-terminal part of p110δ (Figure 1A).

CAID: CA338300460

gnomAD: absent from gnomAD v2.1.1

Case#: proband, M, Age of Report: 8 y.o., Ethnicity: British.

CasePresentingHPOs: HP:0008846 (Severe intrauterine growth retardation), HP:0004322 (Short stature), HP:0004325 (Decreased body weight), HP:0040195 (Decreased head circumference), HP:0001510 (Growth delay), HP:0011968 (Feeding difficulties/behavioral feeding difficulties), HP:0001263 (Global developmental delay/psychomotor development delay), HP:0000252 (Microcephaly), HP:0000684 (Delayed eruption of teeth/Dentition), HP:0100543 (Cognitive impairment/delayed intellectual development), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0011220 (Prominent forehead), HP:0000582 (Upslanted palpebral fissure/upward-slanting palpebral fissures), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0100678 (Premature skin wrinkling/Thin, wrinkled skin), HP:0001187 (Hyperextensibility of the finger joints), HP:0010485 (Hyperextensibility at elbow), HP:0009125 (Lipodystrophy)

CaseHPOFreeText:The proband, 8 years of age, is the first child of non-consanguineous Caucasian parents. There are no manifestations of SHORT syndrome in the family. There is no family history of microcephaly or intellectual disability. Following an otherwise uneventful pregnancy, delivery was induced at 38 weeks of gestation on discovery of severe intrauterine growth restriction. His birth weight was 1.97 kg (<0.4th centile, −3.7 SD).

Despite adequate nutritional intake, the patient's growth was significantly delayed. At 12 months of age, his weight was 6.88 kg (<0.4th centile, −3.2 SD), length was 69.5 cm (1st centile, −2.98 SD) and head circumference was 39.5 cm (<0.4th centile, −5.26 SD). Enteral tube feeding was initiated at 9 months of age, which the patient continues to remain dependent on today. Despite extensive investigation of the proband's feeding disorder, no organic cause was identified, and he was diagnosed with behavioral feeding difficulties. Follow-up consultations revealed a persistent development delay and sustained striking microcephaly. Dentition did not start until the age of 2.5 years. At 6 years of age, his weight was 16.2 kg (1st centile, −2.39SD), length was 105.4 cm (1st centile, −2.47 SD) and head circumference was 43.8 cm (<0.4th centile, −6.16 SD). Skeletal survey and extensive endocrine investigation did not find any abnormalities. The patient has not been formally diagnosed with diabetes and is awaiting an oral glucose tolerance test.

Intellectual and psychomotor development is moderate to severely delayed. The patient first walked at 20 months, first smiled at 3 months and spoke his first words aged 3 years. At his current age of 8 years, he attends a special needs school and requires substantial multidisciplinary support. Magnetic resonance imaging of the brain and electroencephalogram performed at 12 months of age was normal. Neurometabolic investigation was also normal. Recurrent ophthalmology investigations revealed a myopic left eye and hypermetropic right eye at 4 years of age. No anterior chamber defects were noted and his ocular pressure was reported as normal. His hearing was formally assessed and reported as normal.

Facial dysmorphic features are subtle but present (see Figure 2): triangular face, prominent forehead, broad eyebrows, slight upward-slanting palpebral fissures, and hypoplastic alae nasi leading to an impression of low columnella nasi. The patient has thin, wrinkled skin with visible veins, most prominently seen on his chest wall. He has hyperextensibility in his finger and elbow joints. Of note, local lipodystrophy of his proximal finger phalanges is also observed.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Skeletal survey and extensive endocrine investigation did not find any abnormalities. The patient has not been formally diagnosed with diabetes and is awaiting an oral glucose tolerance test.

No anterior chamber defects were noted and his ocular pressure was reported as normal.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Chromosome breakage studies, Angelman methylation studies and a 60 gene developmental delay and epilepsy panel were normal. Comparative genomic hybridization microarray identified a likely benign maternally inherited Xp11.4 duplication (GRch X:38646145-38687854). Trio-exome sequencing revealed a de novo heterozygous missense variant, c.1456G>A (p.Ala486Thr) in PIK3R1 (NM_181523.3).

Variant: NM_181523.3:c.1456G>A (p.Ala486Thr).

ClinVar: N/A.

CAID: CA359881414.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo:N/A.

CasePMIDs: N/A.

PMID 23861857

Heterozygous patient - Is a second variant unidentified? Or is this a dominant negative variant? Or misdiagnosed due to limited genotyping method in 2013?

PMID: 19679072

Gene: PIK3CD

HGNC: 8977

I find it interesting that men have higher perceptions of self-efficacy than women. Is it because boys are raised to be more confident and outgoing, while girls are taught to be more demure and soft spoken? Is this because masculine traits are seen as more positive? An example of this is that I am a very loud and outgoing person, but some people find it harsh or annoying. This seems like it could be because of our 'standards' for women versus men. This picture helped me understand self perception theory and goes along with the higher self efficacy.

This is something I find really important. There have been many times where I'm trying to explain to someone that you cannot just change or start out perceiving yourself in a positive way. Our experiences and cultures will always effect how we see ourselves. For example; if your family is always telling you "you are dumb and worthless," you will believe it and it will effect how you see yourself. It takes a lot of work to change how we perceive ourselves, especially since these factors are ingrained into us from birth.

Honestly this one just made me sad. As someone who has lived in a bigger body for most of their life, it always hurt to be the butt end of the joke. Media portrayals of fat people made boys in all the classes think it was okay to do some not very nice things, however, I do think we are starting to move in a more positive direction with how we show people in bigger bodies because of advocates.

where left off

They may have had more luck in findings pieces that suited their criteria if they allowed non-academic works. The 90s have been referred to as the "Gold Age" of print (e.g., news papers, magazines, etc.) as a cultural influence. They were daily staples in peoples lives and could have included incredible potential for this review.

I wonder if this remains an issue of performativity on behalf of the university (similar to what was described during Thursdays readings), or if the policies in place are uninformed/ ineffective. I have seen people describe Universities as "all lip service" when they assume that hanging pride flags during June makes them "inclusive". It's incredibly disingenuous on the part of the school.

wasd

これもちゃんと噛み合ってる

Because Google gets most of the searches, it collects more data, which helps it improve its search quality. This creates a cycle that keeps Google ahead.

割と綺麗に対応しててよい記事

人生も自分の力量にあった自由を設計しないといけないね。とまとめられそう

I think you are missing a word at the beginning of this sentence.

"Between"

Or equal access to law enforcement. This could be a great opportunity to discuss the "code of the street" literature and how unreliable law enforcement potentially contributes to a heavy reliance on guns.

Insightful! I appreciate the inclusion of this information, as it will certainly resonate with students. I can see several discussion questions stemming from this data.

Spacing issue

I appreciate the inclusion of each scholar's bio. Very insightful information.

To improve clarity, I recommend reiterating the contemporary time period by adding a transition like "typically"

"Typically, when we apply this word to a person, we suggest that they are an extremist."

Great example!

I noticed an extra space here.

I think the inclusion of a chart based on the most recent FBI data would strengthen this point.

un

https://www.reddit.com/r/typewriters/comments/1uttoqn/what_do_you_use_your_typewriter_for_read_body/

Total expenditure

Very useful

importance housing

You could mention Gresham Sykes work on the "Pains of Imprisonment." You could also mention Megan Comfort's work on how the "pains of imprisonment" extend to family and significant others.

I agree. People tend to gather with their own "group" because it makes them feel safe. As a result, many are unwilling to spend the time and energy engaging with people from different cultural backgrounds, even though such interactions can broaden their perspectives and be highly beneficial.

Importance of Villa Constitución

https://ri.conicet.gov.ar/handle/11336/127971

Useful re right-wing terrorist ideology

Key point

Point

important on camaron

stolen photos

this section is so informative which includes the factors that affect FI. Barriers, experiences, and potential solutions may look different across campuses.

This issue is so common within this population that it has become normalized which can lead to the disparity becoming desensitized

I wonder if scholarships were taken into account and meal plans seem common on campus but they typically involve additional costs which may be a financial barrier for some students

this is interesting. it highlights an underserved and often overlooked population affected by this disparity.

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Reply to the reviewers

The authors do not wish to provide a response at this time.

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Referee #3

Evidence, reproducibility and clarity

Summary

The authors observe that proteasomal protein and activity is increased in skeletal muscle of mice fed a high fat diet. Concordant with this, they find increased expression of Nfe2l1 (NRF1), an ER localized protein that can be cleaved to produce a transcription factor that activates a set of genes that includes most proteasome subunits. To test the role of Nfe2l1 in the response to high fat feeding, the authors generated muscle specific KO of Nfe2l1 and characterized the muscles using fiber typing, proteomic, ubiquitinomic, RNAseq and metabolomic analysis on the muscle of these mice. Gastrocnemius muscle fast twitch fibers appeared most affected and modulated towards slow twitch phenotype, whilst soleus muscle appeared unaffected. Mitochondrial function was decreased as were levels of complex III. Ubiquitinome analysis showed differential ubiquitination of proteins involved in muscle structure and function and increased K48 ubiquitin chain linkages. Metabolomic studies showed altered amino acid metabolism, glucose metabolism and induction of a Warburg effect. Finally, upon high fat feeding, the Nfe2l1 mKO mice gained less weight, had higher energy expenditure, and were more insulin sensitive.

Major comments

1. The authors have conducted a multi-omics analysis of the skeletal muscle of mice bearing a muscle specific KO of Nfe2l1 and have attempted to integrate the findings. However, despite reading the manuscript several times, I have trouble trying to identify the key message of the paper and so feel that a lot of data was presented, but without a clear sense of how all the data (or some of it) really ties together. I suggest that the authors identify the main message, select the relevant data for the main body of the text and assign the remaining data to supplementary figures. The discussion should emphasize the main message.
2. Metabolically, the most impressive result was the minimal weight gain on high fat feeding. The authors vaguely suggest that Nfe2l1 might be a therapeutic target 'to preserve muscle mass and healthy metabolism in obesity and beyond'. Since the main effect of Nfe2l1 seemed to be downregulation of the proteasome, should the authors have tested the effects of low dose proteasome inhibitors in WT mice to mimic the partial loss of proteasome activity seen in the Nfe2l1 mKO on the response to high fat feeding? This could confirm or support the idea that the main effect is due to Nfe2l1 modulation of the proteasome.
3. The authors claim that there is rewiring of the UPS in obesity through the induction of Nfe2l1. What do the authors mean by rewiring? If the main effect of Nfe2l1 is to modulate proteasome activity, presumably all upstream processes (ubiquitination by various E3s) are affected. Indeed, in the ubiquitinomic analysis in figure 4F, there do not appear any pathways that are downregulated. Regardless, there is no data presented to show that specific pathways of ubiquitination are altered and therefore 'rewired'. The 'rewiring' strikes me as a fancy term used inappropriately here.
4. I was surprised that the authors did not use the tamoxifen inducible Cre to inactivate Nfe2l1 in adult muscle. As such, the interpretation of the results of their study is limited by the effects of loss of Nfe2l1 during development and so inhibit to some degree potential links to translation. The authors should note this limitation in their discussion.
5. Relevant to the above point about KO from development, in the first characterization of the mKO of Nfe2l1, (Figures 2G, 2I) the muscles actually look dystrophic. There appear to be central nuclei in the muscle of the mKO in Fig 2G and sarcomeric dysorganization in Fig 2I and the authors mention the presence of inflammatory cytokines and regenerative isoforms (Fig 2H) in the muscle. Are the mKO dystrophic, undergoing damage and regeneration? This is an important point to address with quantification of central nuclei, inflammatory cytokine expression, infiltration by mononuclear cells, fibrosis, blood levels of creatine kinase.

Minor comments

1. Abstract - the authors used the fancy term 'hormetic'. My understanding is that this refers to a phenomenon where effects at low dose (usually positive) are different or opposite from effects at high dose (usually negative). I didn't see such a biphasic phenomenon in the Nfe2li mKO mice. Also the authors should specify that it is a muscle specific KO.
2. Text on page 3 'In human muscle, we noted that NFE2L1 is highly expressed, at much higher levels compared to other established muscle regulators, such as NFE2L2 or PPARGC1A (Fig. 1K)'. Discerning the importance of a transcription factor by comparing its expression at the mRNA level is dubious. It is the protein that acts and the extent of gene transcriptional activity that is important.
3. Figure 2A-C - The mKO mice are smaller and have less lean mass and fat mass. Were the mKO mice born with smaller muscles and therefore had trouble feeding or competing for breast milk prior to weaning? This again relates to the issue of not having used a tamoxifen inducible KO. Are the muscle sizes proportionate to body weight or more importantly body length or tibial length?
4. Figure 2G - As mentioned in general comment 5, the mKO muscle looks dystrophic. Also the % fibers of each type should be quantified to demonstrate the fiber type shifting. This should ideally be done in the complex zone of the gastrocnemius where all the fiber types are present. Also, the fibers look bigger in the mKO. It is standard to do an analysis of the distribution of cross-sectional areas of the muscle fibers and this can be done in a fiber specific manner from the stained images in the middle panels (with laminin staining added to delineate the fibers).
5. Figure 2J - remarkably complex III (cytochrome C reductase) levels are significantly decreased. Any explanation for this? Does Nf2el1 bind to the promoter or regulate its transcription?
6. Figure 2H - state in legend whether the 'relative expression levels' are for protein or for mRNA.
7. Figure 3C, 3G - why does the trypsin-like activity of the proteasome go up when the other 2 activities of the proteasome go down?
8. Figure 4E - Why is there a set of proteasome genes that are upregulated in the mKO? Most of these (except Psmd9/Rnp4) encode subunits of the PA28 activator. Is this a compensatory response or a response to inflammation in the dystrophic muscle? This needs some comment in the paper.
9. Figure 5D, text page 8 - 'we found several genes to be oppositely regulated between soleus and GC'. What genes were these and are they enriched in a particular pathway e.g. one that modulates fiber type phenotype?
10. Figure 6D, 6E - The increased energy expenditure and increased food intake may simply be due to increased heat loss from the smaller mKO mice (they have a relatively larger body surface area).
11. Figures 7A, 7B - Was the body composition different in the mKO mice fed a high fat diet vis WT HFD mice?
12. Figure 7E - What is the insulin tolerance like when normalized to starting glucose?
13. Discussion - Please insert figure numbers in the discussion so reader can refer back to the data on which the conclusions in the discussion are being made.
14. Figure 1G and Discussion first paragraph - It would be more quantitatively precise to measure the ubiquitinated proteins by western blot (as done in Fig 3I) than to sum up the ubiquitin linkages.
15. Discussion para 2, ref 26. This reference is to a paper on effects of lipid peroxidation on muscle atrophy in aging or disuse and not to obesity. Revise to be more precise.
16. Discussion page 12 last para - 'some components of the proteasome'. As mentioned earlier, these appear to be mostly subunits of the PA28 proteasome activator. Should state this and discuss.
17. Discussion page 13, para 3 and extended data Fig 2A-2D. What is the significance of the higher FGF21 and GDF15 expression in mKO muscle? Could they be involved in the improved glucose tolerance or the decreased fat mass respectively?
18. Methods section 2.8 - many abbreviations for reagents that are not defined e.g. SDC, CAA, TCEP, etc
19. Methods 2.11 - the authors did whole muscle proteomics and ubiquitinomics which they recognized would be limited by the overwhelming representation by myofibrillar proteins. Did they try any manoeuvres to enhance detection of non-myofibrillar proteins?
20. Methods, section 2.13 - the mitochondria were quantified by protein assay. Since the 8000g pellet used to isolate the mitochondria may contain other proteins, should the mitochondria be quantified in a more specific way e.g. assaying several mitochondrial proteins or measuring mitochondria DNA content? This is important vis a vis figure 2L which showed decreased mitochondrial respiration in the mKO.
21. Extended data Fig 1D. Were these measures of markers of atrophy done at the protein level or mRNA level? They should be done at the mRNA level as this is a more sensitive and precise marker of atrophy than the protein levels (which don't change as much and for which many antibodies are not specific).
22. There is a lot of useful omics data here. Where will they be shared for use by the research community?

Referees cross-commenting

The overall tenor of the three reviews is similar. Comments are both overlapping and complementary. I realize that I forgot two other specific comments:

• (a) In extended fig 1C, the authors quantify the slower migrating LC3B-I band, but it is the faster migrating lipidated LC3B-II band that is a marker of autophagasomes that should have been quantified.
• (b) Some references e.g. 37, 40 are missing information.

Significance

The authors have carried out what appears to be a thorough multi-level omics study of a muscle specific KO of Nfe2l1. It appears to have been technically well done, but I do not have expertise in such analyses and so cannot be rigorously critical in this aspect. (My expertise is in UPS function in skeletal muscle.) The major limitations of the present manuscript are highlighted in my major comments.

In view of the important role of Nfe2l1 in regulation of expression of the proteasome, the muscle specific KO provided a partial inhibition of proteasome activity and therefore a unique view into the role of the proteasome in muscle particularly under the condition of high fat feeding. Therefore, the potential audience could be quite broad including researchers in muscle biology, UPS and obesity. However, Nfe2l1 has other effects besides induction of expression of proteasome genes, thereby limiting the confidence that all effects observed are related to the modulation of the proteasome and the consequences of such modulation on levels of UPS substrates

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Referee #2

Evidence, reproducibility and clarity

In this paper, Lemmer and colleagues explore the role of the endoplasmic reticulum (ER)-resident transcription factor Nfe2l1 in muscle metabolism in mice following high-fat diet (HFD). Here, the authors made the interesting observation that HFD is associated with increased proteasome activity in skeletal muscles (Fig.1), a process known to rely on Nfe2l1 and confirmed by Figs. 2 and 3. By using a tissue-specific Nfe2l1 knockout (KO) mouse model, the authors show that Nfe2l1 is also critical in preserving mitochondria and oxidative phosphorylation in muscles during HFD (Figs. 4, 5 and 6). Finally, the authors show that fast/glycolytic muscle fiber growth in Nfe2l1 KO mice is accompanied by reduced body weight and improved glucose tolerance (Fig. 7).

This paper is potentially interesting and addresses the important issue of energy metabolism regulation in diet-induced obesity (DIO) using an original mouse model. However, the argument presented in this paper has sometimes logical gaps, making it difficult for the reader to connect all the dots. For instance, what is the relationship between proteasome function and energy metabolism in DIO? Is there any relationship at all? Ultimately, Nfe2l1 has other target genes than the proteasome ones, particularly those related to mitophagy process (PMID: 30135079, this paper should be cited and discussed) which could easily explain the observations made by the authors regarding respiration and metabolism...

1. The authors failed to explain why muscle cells upregulate their proteasomes during HFD. My prediction is that this happening because of increased protein synthesis which itself occurs as a consequence of sustained mTOR signaling. Increased translation would then result in increased supply of defective ribosomal products (DRiPs) which need to be timely cleared by the ubiquitin-proteasome system (UPS). I leave to the authors the possibility to address this hypothesis experimentally.
2. The authors consistently show a correlation between HFD and increased Nfe2l1 expression. These observations, however, do not imply that Nfe2l1 is activated in DIO. The authors should assess Nfe2l1 processing - or at least nuclear translocation - in muscles over time
3. If Nfe2l1 is indeed activated by HFD, what would be the stimulus? Compromised proteasome function? Oxidative stress? Cholesterol changes? This point needs to be clarified.
4. Fig. 1C: the increased proteasome subunit expression in DIO seems minuscule... How about Western-blotting the native gel for proteasome subunits to check whether the observed proteasome activity matches the proteasomes amounts under these conditions?
5. Fig. 2J: a densitometry quantification of the WB would be welcome.
6. Fig. 2K. captions are incomplete. What is PMG, SUC or FCCP?
7. Discussion:" Furthermore, we found that some components of proteasome activity are higher in cells or tissues lacking Nfe2l1, indicating a potential compensatory posttranslational modification of proteasome function." What components?? Is it shown in the manuscript? Unclear.
8. Discussion: Next to changes in total amount and activity, we also found that proteasome subunits accumulated in a hyperubiquitylated state (Extended Data Fig. 1A), but the relevance of this observation will need further investigation. These proteasome subunits are not assembled ones, but likely derive from DRiPs, as a consequence of increased translation (see point 1).
9. Discussion: "Clearly, disturbances in UPS and ERAD cause ER stress and inflammation (10), which we also observe in our model." Where are the data in this regard? Do the authors mean Fig. 5B? I do not see any convincing data on inflammation here (BTW, what is Gm11517?).

Significance

General assessment:

As previously discussed, this work from Bartel's lab is interesting but not suitable for publication in its present form. It should be revised to clarify the role of Nfe2l1-induced proteasomes in DIO.

Advance

Although the role of Nfe2l in mitochondrial function is known (PMID: 30135079, this paper should be cited and discussed), the consequences on energy metabolism in skeletal muscles described in this paper are novel.

Audience

If appropriately revised, this manuscript should be of interest to a wide readership.

Note: This preprint has been reviewed by subject experts for Review Commons. Content has not been altered except for formatting.

Learn more at Review Commons

Referee #1

Evidence, reproducibility and clarity

Summary:

In the manuscript entitled "Nfe2l1-mediated proteasome function controls muscle energy metabolism in obesity", Lemmer and colleagues observe elevated 20S proteasome activity along with increased expression of the transcription factor Nfe2l1, a known stimulator of proteasome subunit biogenesis, in muscle tissue of diet-induced obese mice. To understand the role of Nfe2l1 in regulating skeletal muscle proteostasis, they use siRNA to knockdown Nfe2l1 in cultured C2C12 muscle cells and cross Nfe2l1 floxed mice with and Acta1-Cre line to KO Nfe2l1 specifically in muscle fibers. Nfe2l1mKO mice show reduced body and muscle size, impaired enzymatic activity of some proteasome subunits, an accumulation of ubiquitylated proteins, a fast-to-slow shift in muscle fiber phenotype and metabolic abnormalities, including impaired mitochondrial function and mild increases in relative energy expenditure. Multi-omics analysis at transcript, protein, ubiquitinated protein and metabolite levels indicate a strong influence of Nfe2l1 loss on muscle homeostasis. These affects appear to predominately affect fast-type (i.e. Gastrocnemius) rather than slow-type (i.e. soleus) muscles. Finally, Nfe2l1mKO mice fail to gain weight on a high fat diet and are therefore spared the typical metabolic alterations associated with obesity.

Major comments:

1. The authors push the idea that the UPS, via Nfe2l1, plays an 'adaptive' role in regulating muscle proteostasis, however, all signaling experiments investigating the effect of muscle fiber Nfe2l1 KO are performed under basal conditions.
2. Due to the use of ACTA1-Cre to conditionally KO Nfe2l1 in muscle fibers, Nfe2l1 is also absent during development. It is therefore difficult to distinguish the acute effects of Nfe2l1 on muscle proteostasis from those that may result from developmental impairment. It is conceivable that remodeling of muscle architecture would be more active during development than in mature muscle and therefore perhaps more sensitive to impairments in proteasome biogenesis. Use of an inducible Cre system (e.g. the tamoxifen inducible HSA-MerCreMer model) and/or the addition of acute Nfe2l1 overexpression experiments would be needed to dissociate acute, primary effects of Nfe2l1 from the secondary features of long term Nfe2l1 KO and disruption of proteostasis.
3. It is unclear what the HFD experiments reported in Figure 7 add to our understanding of the role of Nfe2l1 in skeletal muscle. I could understand if an inducible Nfe2l1mKO system was used to test the role of Nfe2l1 in already obese mice... but a failure of a mouse displaying myopathic features to put on weight is not the same as an alteration that improves metabolic health. As Nfe2l1mKO mice do not become obese, the authors are unable to directly test what role the upregulation of muscle Nfe2l1 plays in maintaining proteostasis in obesity. On the other hand, I find it hard to conclude that the absence of muscle Nfe2l1 is beneficial for metabolic health if fed a HFD, especially given the reported increase in p62 and LC3B (indicative of autophagy impairment) and the impaired muscle mitochondrial function. Further investigations in older mice would be required to determine the long-term impact of muscle Nfe2l1 KO on whole-body health under both normal and high-fat diet feeding conditions.
4. The authors note several interesting muscle phenotypes, including a fast-to-slow fiber type transition and an increased expression of neonatal myosin heavy chain isoforms (Myh3 & 8). The representative images seem to indicate that IIA (green) fibers are larger in Nfe2l1mKO mice. I would recommend quantifying fiber type-specific cross sectional area in Gastrocnemius muscle sections from these mice, as well as confirming the increased 'regeneration' phenotype by quantifying the prevalence of centralized nuclei.
5. Figure 3D: Why would Nfe2l1 KD lead to a larger increase in ubiquitylated proteins after proteasome inhibition? If Nfe2l1 KD reduces proteasome subunit gene expression (presumably also protein content) and proteasome activity (although this effect is rather mild), then blocking a proteasome with lower activity should lead to a lower accumulation of ubiquitylated proteins, despite an accumulation of ubiquitylated proteins under basal conditions.
6. Fig3C&G: The finding that Nfe2l1 KD/KO mildly reduces chymotrypsin-like and caspase-like (in mice) activity, but strongly increases trypsin-like activity is surprising. As these activities are mediated by different Beta subunits within the 20S core particle, it would be important to also test whether protein levels of PSMB5 (Chymotrypsin), PSMB6 (Caspase) and PSMB7 (trypsin) are altered by Nfe2l1 in accordance with differences in their measured activity.
7. The authors have a tendency to use vague terms to describe changes in proteostasis resulting from Nfe2l1 KO, for example: 'recalibration', 'adaptive', 'fine-tuning', 'remolding', 'remodeling', 'rewiring'. While it is understandable that Nfe2l1 and the UPS will have different roles under different conditions, the use of vague language makes it difficult to understand whether they are referring to reduced or increased proteasome activity. Please be clear and precise as the direction of the changes observed. The same goes for the extension of conclusions made on measures of proteasome activity to mean activity of the UPS / protein breakdown. Specific examples are described within the minor comments section.

Minor comments:

Introduction: Nfe2l1 does not restore proteasome activity per se, but stimulates proteasome subunit biogenesis and thereby increases proteasome content. This would not necessarily influence activity, which also relies on the presence of substrate/ubiquitination.

Introduction: 'we investigate remodeling of the muscle UPS in obesity and define the role of Nfe2l1 as a new regulator of muscle biology'. This statement is an overreach, particularly seeing as a role for Nfe2l1 has already been described in skeletal muscle, albeit under a different context (ref. 29).

Results: "Of note, leptin levels in chow-fed animals were indifferent". I guess this is a typo? Should be 'different' not 'indifferent'.

Results: "These global changes are in line with the notion that UPS is activity is rewired and metabolism impacted by HFD feeding." Please use specific language to describe the changes you see.

Results: "The data supported the hypothesis that Nfe2l1 stimulates protein degradation via the proteasome, as the dominant lysine-linkage was the proteasome-targeting linkage K48, accounting for more than 86 % and being significantly higher in muscle of mKO mice compared to tissue of WT controls (Fig. 4G)." While it is clear that depleting a protein contributing to proteasome biogenesis would impair proteasome function, this would not be sufficient to say that Nfe2l1 promotes protein degradation via the proteasome. So far, there is no evidence that increasing Nfe2l1 increases protein degradation.

Figure 1L: What is the unit of measurement for gene expression?

Figure 2G: There appears to be significant freeze damage in H&E and SDH sections from Nfe2l1mKO mice. Perhaps you can find better representative images.

Results: "In summary, these results establish Nfe2l1 as an adaptive regulator of proteasomal activity and ubiquitylation in cultured myocytes". Why do these results establish Nfe2l1 as an 'adaptive' regulator? These are steady state conditions. Results so far would only indicate that Nfe2l1 controls proteasome subunit biogenesis in myocytes, which is well known in other cell types and has also been shown in skeletal muscle tissue.

Results: "The proteome showed many significantly regulated proteins and in general a higher protein load in the mKO condition (Fig. 4A), potentially caused by impaired proteasomal protein degradation." What is meant by a 'higher protein load'

Discussion: "Here, we show that proteasomal activity and management of ubiquitin levels in muscle is a regulated and critical process in obesity, as proteasome levels and function are increased in obesity." This is actually not shown. As Nfe2l1 KO mice do not become obese, it is unclear what role this increase plays under the conditions of obesity.

Discussion: "Interestingly, at the same time, total ubiquitin levels are largely unchanged, which suggests a dynamic recalibration of the rates of protein synthesis and degradation, including the processes necessary for ubiquitylation and its targets". The authors seem to be interpreting ex vivo proteasome activity assays as a readout of protein breakdown rates in vivo. These Proteasome activity assays are only a readout of proteasome content, not activity, since substrate entry into the 26S proteasome is tightly controlled by its cap structure. Ex vivo, substrates able to independently access the inside of the 20S proteasome (and hence the active protease sites) are provided in abundance.

Discussion: "However, overall proteasomal activity was lower and ubiquitin levels higher, indicating the predominant role of Nfe2l1 determining rates of UPS in myocytes." The reduction in activity was not so strong that it could be considered predominant. Furthermore, proof is only provided for Nfe2l1 regulating proteasome content... not rates of UPS breakdown, which also relies on the ubiquitination part of the system.

Discussion: "There seems to be profound crosstalk between proteostatic mechanisms in muscle, as we found in the proteome of Nfe2l1 mKO muscle that autophagy pathways are markedly upregulated, including p62 and LC3B levels (Extended Data Fig. 1B-C)". This should be first introduced into the results section.

Discussion: "Uncoupling of mitochondria and loss of mitochondrial membrane potential in myocytes are associated with the induction of FGF21 (33), a myokine that is implicated in regulating energy metabolism. We find that FGF21 and GDF15 expression were higher in muscle of mKO mice compared to WT controls, and for GDF15 also plasma levels were elevated (Extended Data Fig. 2A-D)." This should be included in results section.

Significance

General assessment: after identifying increased proteasome activity and an associated increase in Nfe2l1 expression in the muscle of obese mice, this work provides strong evidence that muscle fiber Nfe2l1 expression is necessary for muscle fiber development / homeostasis, with wide ranging effects of muscle fiber Nfe2l1 KO, including on body and muscle size, fiber type composition and mitochondrial content and function. On the other hand, muscle fiber Nfe2l1 KO mice fail to become obese, making it hard to draw conclusions on the role of increased Nfe2l1 in the muscle of obese mice.

Advance: This study complements recent work showing a role for increased Nfe2l1 expression in maintaining proteostasis under a different proteostatic challenge, and suggests a role for muscle Nfe2l1 in response to obesity.

Audience: This study is likely to be of interest to readers interested in proteostasis, the UPS and muscle biology.

Expertise: Muscle proteostasis and aging.

john killed Mrs. Wright after they got married, just like he killed the bird. so Mrs. Wright killed him the same why he killed her happiness.

this is when they discover that she did it

the bird was killed the same why Mr. Wright was killed

insight into Mr. and Mrs. Wrights life together

metaphor for John wright

the bird is a metaphor for Mrs. Wright before her marriage

the sewing reflects Mrs. Wrights mental state leading up to the murder.

ironic because later they are the ones to find the motive

important allusion to how Mrs. wright killed her husband

the men are focused on the physical evidence wile the women see the emotional causes.

Mrs hale obviously has more information yet the attorney is not interested in hearing about it.

Mrs hale knows more about how Mrs wright and John than it seems

shows the men's attitudes towards women

expands on the sheriffs incompetence, didn't bother to look in the kitchen for clues.

yet again, not concerned for her well being

guilt or fear of being caught

obvious lie and attempt to deceive

more concerned with seeing john than asking if everything is alright

strange or suspicious behavior

seems like an excuse

example of incompetence of the police.

something of little importance or value.

Briefing : Faciliter l'Accès et le Maintien au Logement des Personnes Sans Domicile en Occitanie

Ce document de synthèse analyse les enjeux, les données de cadrage et les solutions innovantes présentés lors du webinaire organisé par la plateforme d'observation sociale (POS) Occitanie concernant l'accès au logement des personnes sans domicile.

Résumé Exécutif

La situation du logement des personnes sans domicile en France et en Occitanie est marquée par une tension extrême entre une demande croissante et une offre de logements sociaux insuffisante.

En 2025, la France compte 350 000 personnes sans domicile, tandis qu'en Occitanie, plus de 155 000 ménages attendent un logement social.

La politique publique actuelle, portée par le plan « Logement d'abord 2023-2027 », vise à rompre avec le parcours classique « en escalier » (passage par plusieurs étapes d'hébergement) pour privilégier un accès direct et rapide au logement autonome.

L'analyse souligne que l'accès au logement seul ne suffit pas : l'accompagnement social global, le maintien d'une veille post-accès et la prise en charge de la santé mentale sont les piliers indispensables pour garantir la stabilité des parcours et prévenir les ruptures de bail.

I. Cadrage et Réalités du Sans-Abritisme en 2025-2026

1. Définitions et Diversité des Profils

Le terme « sans domicile » recouvre plusieurs réalités précaires :

• Personnes à la rue : Sans aucune solution d'abri.

• Lieux non prévus pour l'habitation : Voitures, parkings, bidonvilles, campements et squats.

• Structures d'hébergement : Centres d'hébergement et de réinsertion sociale (CHRS), centres d'urgence, hôtels sociaux, lits d'accueil médicalisés (LAM) ou appartements de coordination thérapeutique (ACT).

2. Données Statistiques Clés

| Indicateur | Échelle Nationale (2025) | Région Occitanie (2025/2026) | | --- | --- | --- | | Nombre de personnes sans domicile | 350 000 | 33 000 (demandeurs au 115) | | Places d'hébergement disponibles | 203 000 | 11 682 | | Demande de logements sociaux | \- | 155 000 ménages (+5% en un an) | | Part du logement social dans le parc | \- | 11,7 % (inférieur à la moyenne nationale) | | Logements sociaux produits par an | \- | ~10 000 (dont 3 200 PLAI) |

L'Occitanie se place au 7ème rang national avec 1,8 place d'hébergement pour 1000 habitants, mais fait face à une saturation majeure, particulièrement dans les métropoles de Toulouse et Montpellier.

II. La Stratégie « Logement d'Abord » et ses Objectifs

Le plan national 2023-2027 repose sur le principe que l'accès au logement doit être le plus rapide possible, sans préjuger de la capacité des personnes à « savoir habiter ».

Les quatre objectifs majeurs :

• Casser le parcours en escalier : Accès direct au logement social sans étapes intermédiaires obligatoires.

• Accompagnement individualisé : Un suivi sur mesure basé sur la confiance réciproque.

• Respect du choix : Intégrer le consentement et les souhaits de la personne.

• Objectifs de production : Attribution de 145 000 logements sociaux au niveau national et création de 30 000 places en intermédiation locative (IML).

III. Obstacles et Freins à l'Insertion par le Logement

Les acteurs de terrain identifient plusieurs barrières critiques :

• Pénurie structurelle : Un manque de petits logements (T1/T2) pour les personnes isolées et de grands logements pour les familles nombreuses.

La rotation dans le parc social est en baisse, limitant les nouvelles entrées.

• Complexité administrative : Des délais de traitement longs et des procédures d'attribution rigides, particulièrement pour les publics sans papiers ou les femmes victimes de violences conjugales fuyant sans documents.

• Inadaptation géographique : Des logements situés dans des zones rurales sans accès aux pôles de santé, à l'emploi ou à la mobilité, ce qui engendre un risque d'isolement majeur.

• Santé mentale et précarité : L'absence de prise en charge des troubles psychiques et des addictions fragilise le maintien dans les lieux.

« Le logement, c'est tout un ensemble.

Si vous l'envoyez dans un endroit où il n'y a pas de mobilité, pas de pôle de santé, la personne va être complètement perdue. » — Jean-François Bouilleri, CRPA Occitanie.

IV. Innovations et Dispositifs d'Accompagnement

Face à ces défis, des expérimentations locales montrent des résultats probants :

1. La Veille Sociale Post-Logement (SAO de l'Aude)

Mise en place en septembre 2025, cette mission de « aller vers » assure un suivi téléphonique régulier (à 1, 3, 6, 9, 12 et 18 mois) des ménages accédant au logement autonome sans accompagnement social préalable.

• Résultats : Sur 64 ménages suivis, aucun n'a fait l'objet d'une procédure d'expulsion.

• Rôle : Médiation entre le bailleur et le locataire, dédramatisation des difficultés financières et réorientation vers le droit commun.

2. Équipe Mobile en Santé Mentale (Altemed, Montpellier)

Ce dispositif pluridisciplinaire (travailleur social, infirmier, pair-aidant) intervient directement dans le parc social pour accompagner les locataires présentant des troubles psychiatriques.

• Approche : Fondée sur le rétablissement (considérer la personne avant la maladie).

• Efficacité : 76 % des personnes sollicitées acceptent l'accompagnement, bien qu'elles soient initialement très éloignées des systèmes de soins classiques.

3. Engagements des Bailleurs Sociaux

Les bailleurs développent des outils spécifiques pour sécuriser les parcours :

• Bail de sauvegarde : Un bail glissant spécifique pour les ménages menacés d'expulsion (dernier recours).

• Gestion sociale interne : Recrutement de travailleurs sociaux par les bailleurs pour détecter précocement les impayés.

• Protocoles spécifiques : Accords locaux pour faciliter l'accès au logement des femmes victimes de violences (ex: individualisation des ressources sans avis d'imposition commun).

V. Perspectives et Recommandations Régionales

La feuille de route régionale de l'Occitanie (issue de la circulaire du 24 juillet 2025) définit six axes majeurs pour améliorer la fluidité de l'hébergement vers le logement :

• Identification des ménages en long séjour : Mise à jour systématique des évaluations sociales.

• Amplification de l'accès au logement social : Uniformisation des pratiques de cotation et de gestion en flux.

• Mobilisation du contingent préfectoral : Utilisation de 100 % de la part de l'État pour les publics prioritaires.

• Renforcement de l'accompagnement santé/emploi : Approche multidimensionnelle de l'insertion.

• Réforme des SIAO : Faire de l'accès au logement un objectif obligatoire et impondérable.

• Pérennisation des budgets : Garantir la continuité des financements (FNAVDL, équipes mobiles) pour stabiliser les structures d'accompagnement.

Conclusion : Le succès du passage de la rue au logement repose sur la capacité des acteurs (État, bailleurs, associations, collectivités) à coordonner leurs interventions et à maintenir un soutien humain bien au-delà de la simple remise des clés.

“Đâu” is used as a question word referring to places.

In other words, “Đâu” = “Where”.

Vietnamese English – Trong ảnh này, đâu là bạn? In this picture, where are you? – Bạn sinh ra ở đâu? Where were you born? Literally: You were born where? – Bạn đến từ đâu? Where are you from? Literally: You are from where? – Anh muốn đi đâu? Where do you want to go? Literally: You want to go where? As you can see, “Ở đâu” and “Từ đâu” are two variations of “Đâu“.

They are formed by adding prepositions before “đâu“:

“Ở“ means “in/at“. “Từ” means “From“.

1. Asking About Numbers with “MẤY” "Mấy" in Vietnamese

"Mấy" means "how many" and is used to ask about a small quantity or number.

Structure:

Mấy + Noun = How many + Noun

Examples Con mấy tuổi? — How old are you, kid? (Literally: Kid, how many years old are you?) Bạn biết mấy thứ tiếng? — How many languages do you know? Lớp học có mấy sinh viên? — How many students are in the class? Mấy người sẽ tới đây? — How many people will come here? Basic Numbers Vietnamese English Không 0 Một 1 Hai 2 Ba 3 Bốn 4 Năm 5 Sáu 6 Bảy (also spelled Bẩy) 7 Tám 8 Chín 9 Mười 10

BÀI TẬP 3 Điền từ đúng

1/ A: Anh đang sống ? B: Tôi đang sống ở thành phố New York.

2/ A: Bạn tuổi? B: Mình năm nay 21 tuổi.

3/ A: Em học ? B: Em đang học ngành Tiếng Hàn Quốc.

4/ A: Bạn thích những ? B: Mình thích tiếng Anh, tiếng Hàn và tiếng Trung.

5/ A: Bạn nói được ? B: Tôi chỉ nói được hai ngôn ngữ: Tiếng Anh và Tiếng Việt. You got 5 out of 5 points 5/5

Sửa từ để tạo câu hỏi đúng.

(Correct the question words)

1/

• Bạn đến từ nước đâu?

• Tôi đến từ Việt Nam.

"Đâu" => nào

2/

• Bạn đang sống ở gì?

• Tôi đang ở thành phố New York.

"Gì" => đâu

3/

• Nhà bạn có nào người?

• Gia đình tôi có 5 thành viên.

"Nào" => mấy

4/

• Bạn học ngành bao nhiêu?

• Tôi học ngành Tiếng Việt.

"Bao nhiêu" => gì

5/

• Em là sinh viên năm bao nhiêu?

• Em đang học năm 4.

"Bao nhiêu" => mấy

6/

• Anh làm công việc đâu?

• Tôi là giáo viên.

"Đâu" => gì

This unfortunately accounts for a lot of the projects that even the author here has probably given his endorsement.

The build process for most programs is basically unjustifiable if you rule out "this is just how building software works, and it's what you should expect to have to deal with" as a valid defense.

Rob Pike makes the argument that mouse use isn't actually all that inefficient.

There's a category error here. Many TUIs are actually GUIs that are limited to a brutalist set of drawing primitives—the ones compatible with terminal emulators. That's generally how the term is used, even if the expansion is literally "Text User Interface".

There's also the mistake here of conflating GUIs with the absence of keyboard accessibility. That need not be the case. There are plenty of GUI apps that are fully functional using just the keyboard...

I am aware that I'm "on the wrong side" of this in the way that Kesteloot describes—and I have been, even before I read his piece—but I'm totally divorced from the kind of customization fetishes that you see from the Vimmaxxing crowd, and I've become aware in the last year or so that there's a way that too narrow a focus can lead to misleading results in the same way that microbenchmarks can be (often are) not indicative of broader, macro-scale performance of real world applications.

Things that feel efficient can have measurable productivity gains elsewhere, even if they aren't actually all that efficient (or are objectively slower). Things that feel inefficient, even if they aren't, can be maddening and demoralizing, totally deflating one's will in the long run (over the course of an hour or a whole day), leading to faster exhaustion and a malaise that would have otherwise not been encountered.

Lawrence Kesteloot makes this point in his piece "Java for Everything".

(Aside: I’m on the wrong side of a different decision, the one to use vim for code editing. I feel very efficient when using vim, as code flies around the terminal, and I feel sluggish using Eclipse, and justify my choice with this efficiency argument. But surely all my gains are lost the first time I have to look up who calls a particular function, or when I have to look up the methods of an object manually. I recognize that I’m wrong on this one in the same way that dynamic language apologists are about their choice.)

(Side note: I suspect the author of this piece would disagree with Kesteloot's titular conclusion.)

The last word is important. This is a personality thing.

I remember being weirded out early on when crossing different online cultural contexts every time I strayed into an open source project where the folks on the bugtracker there couldn't handle the first part of the most common pattern for improving things: describing how a piece software currently does something that sucks, acknowledging that it could and should handle things differently, and then either writing the patch or indicating a willingness to accept one.

An uncanny number of personalities would get hung up on the "this sucks" part. I've even had people who consider themselves to be well-meaning but are otherwise uninvolved with the project and don't know that I'm the current maintainer appear in the comments and quarrel with me in response to a description I posted about some defect and/or a prescription—whether it's some UI interaction that I knowingly overlooked and failed to properly address in some earlier changeset and am documenting the this-sucksness of the current state of affairs or whether it's a bonafide regression I unknowingly introduced with some earlier fix.

TEST.... The Dr said, "Blah blah blah... blah blah!!...".

cf Sarmiento on gauchos

experimenting with this archived search page

https://indy.peergos.me/web/local.gateway/ipfs/?t=search-is.vernunft.propositional@google&cid=bafybeif5chwlvuao7bqmqga7rcy5bvo3vqbasinwvoihz7bvlqdobcdmqe

why 'evaluation lens'?

But isn't this mostly relevant to rich country job markets? Is it reflective of an AI-impacted job market? Are recommended systems responsible for a large share of the job-match and productivity value?

there should be a link amnd/or tooltip to the full description of each of these

is this auto/updated?

why not recover the API cost here as well as implied processing cost from headless runs

should we/can we reeasonably incoprporate Unjournal prioritization ratings for this haere? Need to check with the team to understand the terms under which those were given/shared. NB David Reinstein gives full permission to share/report any of his prioritization ratings, but would want to consider before releasing his discussion content in Coda.

to isolate, seclude, or set apart

Lesli give various examples covering the WIDA and goes in depth covering what it does to the readers. She covers the oppositions side before explaining why her side is correct making her writing even stronger

dictates alot of things language education based k-12 in 29 states in america

My personal experiences make me side with this argument. Growing up as a non-English speaking family I've always felt like writing with harsh grammer and vocabulary expectations made writing feel boring and made me steer from it.

Author uses a question to make the reader think to themselves.

Author introduces the evidence by showing the quality of the source she used. I will aim to use this method in my writing.

Lesli make a very strong argument here that I might save for future writing. It never occurred to me that native speakers also struggle with "academic language". This shows that academic language is difficult to everyone and schools pushing one correct language could be a mistake

The premise of "acquiring academic language" confuses me. Society pushes a standard of using complex english in high level academic texts. However, in this article Lesli is using relatively simple grammer and it makes her point stronger to her audience.

Useful quote I can use in my paper and one of Lesli key points in her essay.