1. Last 7 days
  2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
    Exploring Disulfide Bridge as a Tool to Improve Pioglitazone’s Neuroprotective Potential: Toward the Development of Prolonged‐Acting MAO‐B/PPARγ Modulators
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  3. chemistry-europe.onlinelibrary.wiley.com chemistry-europe.onlinelibrary.wiley.com
    Light-Activated Communication Between Synthetic and Living Cells via Photoresponsive Membranes
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    N‐Doped Carbon Quantum Dots From Bauhinia purpurea With Anti‐Inflammatory and Wound‐Healing Properties
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  5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
    Triterpenoids and Lignans From Schisandra henryi subsp. yunnanensis A. C. Smith
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    Synthesis and Biological Evaluation of Aryl(Benzofuran‐5‐yl)‐[1,2,4]Triazolo[4,3‐a]Pyridine Derivatives as Anticancer Agents
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    Chiral Coumarin Enantiomers From Prangos pabularia Roots: Absolute Configuration, Tyrosinase Activation, and Anti‐Vitiligo Potential in B16F10 Cells
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    Novel Triazole‐Linked Xanthine‐Steroid Hybrids: Molecular Docking and In Vitro Evaluation Against α‐Glucosidase and MCF‐7 Cells
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    Repurposing Camellia sinensis Roots and Ginkgo biloba Leaves for Multiple Myeloma via Wnt/β‐Catenin–Dependent Cell Cycle Arrest and Apoptosis
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    Antioxidant and Cytotoxic Potential of an Undescribed Lignan Isolated From the Pooled Stem and Leaf Extract of Conocarpus lancifolius
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    Design, Synthesis, In Vitro Evaluation, and Molecular Docking of 4‐Substituted Anilides as Histone Deacetylase Inhibitors and Potential Anticancer Agents
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    Nudiloid Z, a New Labdane‐Type Diterpenoid From Callicarpa nudiflora With Anti‐Inflammatory Activity
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    Ellagitannins From the Seed Coat of Euryale ferox and Their Inhibitory Effects on LPS‐Induced Inflammation in RAW264.7 Cells
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    A Novel Series of Flavone‐Cinnamic Acid Hybrid Derivatives as Hypoglycemic Agents: Design, Synthesis, and Activity Studies
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    Anatomical Characteristics of Tongue‐Innervating Mechanoreceptors
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    Insights Into Phenolic Components of Gentianae Radix Et Rhizoma: Chemotaxonomic Markers Exploring Based on UPLC–Q‐TOF–MS Profiling and HPLC Quantification Coupled With Chemometric Analysis, and Anti‐Inflammatory Mechanism Digesting Using Network Pharmacology Analysis Approach
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    1,2,4‐Triazole‐Acetamide Conjugates as hEGFR Inhibitors: Synthesis, Anticancer Evaluation, and In Silico Studies
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    Synthesis of New Pyrazolo[1,5‐a]Pyrazin‐4(5H)‐One Derivatives and Effects on PI3K Protein Levels in A549 Lung Adenocarcinoma Cell Line
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    Chemical Profiles and Bioactivities of Brazilian Amazonian Solanum Species: Antioxidant, Cytotoxic, and Anti‐Metastatic Properties
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    Chinese Yam Polysaccharide Ameliorates Obesity by Promoting Lipolysis Via the cAMP/PKA Signaling Pathway
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    IL‐6 Upregulates CD73 in Human Placental Mesenchymal Stem Cells to Promote ATRA‐Induced NB4 Cell Differentiation in Acute Promyelocytic Leukemia
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    Preoperative Avapritinib for Localized PDGFRA‐Mutant GIST: Marked Pathologic Response, but Limited Feasibility at Standard Dosing
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    Glycopolymeric nanoparticles transported by activated platelets protect ischemic myocardium by alleviating PANoptosis through targeting macrophage Dectin-1
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    Data Analysis Planning and Reporting for Confirmatory Multi‐Lab Preclinical Trials: A Tutorial
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    Biophysical Characterization and Proteomic Analysis of Small Extracellular Vesicles Derived From Different Neural Cell Lines
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    Intratumoral Hypoxia Triggers Mitochondrial BHLHE40 ROS Sensing Pathway to Promote Radioresistance in Triple‐Negative Breast Cancer
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    Immediate Growth Control in Response to Boiling Histotripsy is Prognostic for Intratumoral Immune Activation
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    Introducing Borsantrazole: A Trifunctional Boron‐Based Pyrazole That Extends the Lifespan of Amyotrophic Lateral Sclerosis Mice
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    Astrocytic LMP2 Coordinates NF‐κB and TGF‐β1/Smad3 Signaling to Drive Neuroinflammation after Cerebral Ischemia/Reperfusion
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    Polychip‐A High‐Throughput Droplet Microfluidics Platform for Interrogating Microbial Interactions
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    Photoresponsive Granular Hydrogels Enable Spatiotemporal Control of Matrix Mechanics and MSC Behavior
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    Identification of (20R)‐protopanaxadiol from Panax ginseng as a novel anti‐SARS‐CoV‐2 compound
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    Light-driven thermotropic hydrogel with nanomodulator enables lipid intervention and cavity delivery for postsurgical tumor therapy
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    Focal hippocampal subfield atrophy in cognitively impaired relative to cognitively unimpaired older adults is associated with memory ability
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  36. agentfactory.panaversity.org agentfactory.panaversity.org
    The AI Agent Factory — A Definitive Book and Ecosystem for the Agent Era | The AI Agent Factory
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    1. junaidca 01 Aug 2026
      the current state, and the trend line only points one way. So the honest question is no longer "how do I stay smarter than AI?" — that race is over before it starts. The question is: what do you still need, when intelligence itself is cheap?

      Is this coorect

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  39. doc.rust-lang.org doc.rust-lang.org
    What is Ownership? - The Rust Programming Language
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  40. www.um.es www.um.es
    Lenguaje-de-programacion-JavaScript-1.pdf
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    1. Ginosaurus99 01 Aug 2026
      Esta documentación discutirá principalmente el uso de JavaScript en un entorno de navegadorWeb, por lo que es esencial que sepas codificación HTML y CSS. Conocer PHP puede ser unaventaja.

      XD

    3. Ginosaurus99 01 Aug 2026
      Ahora te encuentras en el inicio de la documentación que trata sobre el lenguaje WebJavascript. Durante la lectura aprenderás a hacer dinámicas tus páginas web y hacerlas muchomás atractivas para los visitantes.

      Texto chistoso jajaj

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  41. sharktastica.co.uk sharktastica.co.uk
    The 70-year anniversary of two important IBM Selectric patents
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  42. www.reddit.com www.reddit.com
    Happy 65th birthday to the IBM Selectric!
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  43. sharktastica.co.uk sharktastica.co.uk
    patents | Admiral Shark's Keyboards FTP
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  44. 019f8ff9-72cd-78ff-b5bc-dca023e02b01-8080.eur-1.aiven.app 019f8ff9-72cd-78ff-b5bc-dca023e02b01-8080.eur-1.aiven.app
    Deploy on Amazon EKS
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    Why Kubernetes?
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  46. typewriterdatabase.com typewriterdatabase.com
    1938 Royal KHM on the Typewriter Database
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  47. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
    ABCA4-associated retinopathy complicated by didanosine-associated retinal toxicity
    1
    1. Vibhor 01 Aug 2026
      ABCA4-associated retinopathy complicated by didanosine-associated retinal toxicity

      PMID: 41561667

      Gene: ABCA4

      HGNC ID: 34

      Case#: patient 66, male, Italy

      DiseaseAssertion: STGD

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0000505, HP:0000551, HP:0000546

      CaseHPOFreeText: best-corrected visual acuity (BCVA) was 20/400 in both eyes, mild myopia, both eyes were pseudophakic, extensive bilateral chorioretinal atrophy involving both the posterior pole and the peripheral retina, widespread mottled hypoautofluorescence in the mid-periphery, along with pronounced macular hypoautofluorescence, significant central retinal thinning, an enlarged foveal depression, outer retinal hyper-reflectivity associated with extensive atrophy of both the RPE and the underlying choroid, dense epiretinal membrane (ERM) was also identified in the right eye, large central hypofluorescent zone involving the macular region and extending beyond the vascular arcades

      CasePreviousTesting: n/a

      GenotypingMethod: Next-Generation Sequencing

      PreviouslyPublished: n/a

      Variant: c.1714C > T p. (Arg572∗)

      ClinVar: 620085 https://www.ncbi.nlm.nih.gov/clinvar/variation/620085/?term=620085%5BVariation+ID%5D

      gnomAD: 0.000001859 https://gnomad.broadinstitute.org/variant/1-94063158-G-A?dataset=gnomad_r4

      Variant: c.2461T > A p. (Trp821Arg)

      ClinVar: 99136 https://www.ncbi.nlm.nih.gov/clinvar/variation/99136/?term=99136%5BVariation+ID%5D

      gnomAD: 0.000008054 https://gnomad.broadinstitute.org/variant/1-94055237-A-T?dataset=gnomad_r4

      Variant: c.4417C>А p. (Leu1473Met)

      ClinVar: 546600 https://www.ncbi.nlm.nih.gov/clinvar/variation/546600/?term=546600%5BVariation+ID%5D

      gnomAD: 0.00005762 https://gnomad.broadinstitute.org/variant/1-94029567-G-T?dataset=gnomad_r4

      General Gene:ABCA4 HGNC:34 PMID:41561667 automated_hgnc:34 automated_hgnc_source:hgnc_tag ClinGen ABCA4 Annotations
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    pmc.ncbi.nlm.nih.gov/articles/PMC12813201/
  48. www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
    Antioxidant Saffron and Central Retinal Function in ABCA4-Related Stargardt Macular Dystrophy
    1
    1. Vibhor 01 Aug 2026
      Antioxidant Saffron and Central Retinal Function in ABCA4-Related Stargardt Macular Dystrophy

      PMID: 31618812

      Gene: ABCA4

      HGNCID: HGNC:34

      Patients: a group of 31 Stargardt disease/fundus flavimaculatus patients (14 males, 17 females) with an established ABCA4 genotype, accumulated prospectively over an interval of 12 months at the outpatient service of the Institution, were included in this study.

      MonDO: MONDO:0019353

      CaseInfo: Case 11, Male, 12yo. Compound het c.5882G > A; p.Gly1961glu (Pathogenic in ClinVar); c.6764G > T,p.Ser2255Ile

      DiseaseAssertion: Stargardt disease/fundus flavimaculatus

      FamilyInfo: Not provided

      CasePresentingHPOs: HP:0007769, HP:0000608, HP:0012045 (Peripheral retinal degeneration, Macular degeneration, Retinal flecks)

      CaseHPOFreeText: cone-rod pattern of retinal dysfunction

      GenotypingMethod: Mutation screening was performed by single-strand conformation polymorphism (SSCP) strategy of the whole coding region of ABCA4. Direct sequencing was also performed on siblings of probands and parents, when available, to confirm segregation of alleles.

      MultipleGeneVariants: (1) GeneName: ABCA4

      (1)Variant: c.5882G > A; p.Gly1961glu

      (1) CAID: CA119132

      (1) gnomAD: 0.01250 (gnomadv4.0.0, Grpmax Filtering AF, South Asian) https://gnomad.broadinstitute.org/variant/1-94008251-C-T?dataset=gnomad_r4

      (2) GeneName: ABCA4

      (2) Variant: c.6764G>T (p.Ser2255Ile)

      (2) CAID: CA202970

      (2) gnomAD: 0.4845 (gnomadv4.0.0, Grpmax Filtering AF, African/African-American) https://gnomad.broadinstitute.org/variant/1-93996161-C-A?dataset=gnomad_r4

      PMID:31618812 Gene:ABCA4 HGNC:34 General CAID:CA202970 Individual CAID:CA119132 MONDO:0019353 automated_hgnc:34 automated_hgnc_source:hgnc_tag ClinGen ABCA4 Annotations
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    ncbi.nlm.nih.gov/pmc/articles/PMC6835540/
  49. www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
    Psychophysical Measurement of Rod and Cone Thresholds in Stargardt Disease with Full-Field Stimuli
    1
    1. Vibhor 01 Aug 2026
      13. 34/F31.021.06OD−68.3−23.32p.Gly818Glu; p.Cys1488Arg

      Case#: Pt 13, 34yo, female

      DiseaseAssertion: Stargardt

      FamilyInfo: n/a

      CasePresentingHPOs:

      CaseHPOFreeText: stage 3 (resorbed flecks), logMAR acuity: OD=1.02 OS 1.06, FST Rod Blue Stimulus (dB) OD= −68.3, FST Cone Red stimulus (dB) OD=−23.3, FST Group 2 (elevated cone and normal rod FST thresholds)

      CaseNotHPOs:

      CaseNotHPOFreeText:

      GenotypingMethod:

      PreviouslyPublished:

      Variant: p.Gly818Glu; p.Cys1488Arg

      ClinVar: 99135

      CAID: CA227000

      SupplementalData: n/a

      ClinVarID: 99135 CA227000 CaseInfo Individual automated_hgnc:34 automated_hgnc_source:CAID ClinGen ABCA4 Annotations
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    ncbi.nlm.nih.gov/pmc/articles/PMC4145077/
  50. www.nature.com www.nature.com
    Biochemical defects in ABCR protein variants associated with human retinopathies
    2
    1. Vibhor 01 Aug 2026
      Over 200 ABCA4 sequence variants have been reported so far in patients with STGD and other retinopathies1,5,6,7,8,9,10,11,12,13,14,15,16,17. We have examined 33 missense mutations, 3 small in-frame deletions and 1 frameshift near the carboxy terminus (Table 1 and Fig. 2), including those mutations most commonly encountered in STGD patients1,5,6,7,8,9,10,11 and several that were reported in AMD patients15. As an initial step in assessing protein folding and stability, we analysed each ABCR variant by immunoblotting and azido-ATP labelling (Fig. 3). Mutations that cause small deletions (delVVAIC1681 and delPAL1761) or introduce charged amino acids into predicted transmembrane domains (G851D and G1886E) produce greatly reduced amounts of protein. Among the ABCR variants that are expressed with normal or nearly normal yield, azido-ATP labelling revealed a subset that is defective in ATP binding. A variety of mutations that lie outside of the nucleotide-binding domains (NBDs) can impair azido-ATP labelling, including L541P, predicted to reside adjacent to a transmembrane domain, and W1408R, which resides between the homologous halves of ABCR (Fig. 2). These data suggest that ATP binding to the NBDs is allosterically coupled to conformational changes in or near the transmembrane regions. Moreover, some mutations within either of the two NBDs abolish or nearly abolish all azido-ATP labelling, as seen, for example, with variants T971N, L1971R, G1977S and E2096K, implying allosteric coupling between the two NBDs, as described for P-glycoprotein22,23.Table 1 Naturally occurring ABCR variants produced in transfected 293 cellsFull size tableFigure 2: Locations of 37 naturally occurring ABCR sequence variants and 4 synthetic mutations.The predicted transmembrane topography and domain structure of ABCR is based on the hydropathy profile and sequence alignment with other ABC transporters. The cytosolic face of the membrane is downward. NBD, nucleotide binding domain; HH, highly hydrophobic domain shared with other members of the ABC1/ABCR subfamily of ABC transporters. A, B and C indicate the sequence motifs characteristic of nucleotide binding folds. Asterisks denote the four synthetic mutations.Full size imageFigure 3: Protein yield and ATP-binding capacity of 37 naturally occurring ABCR variants produced in transiently transfected 293 cells.Membranes were analysed by immunoblotting with affinity-purified anti-ABCR antibodies (top) and photoaffinity labelling with α-32P azido-ATP (bottom). We loaded 1 μg (immunoblotting) or 2.5 μg (azido-ATP labelling) of total membrane protein, as determined by Bradford assay, per track. The mutations that reside in NBD-1 and NBD-2 are indicated above the corresponding lanes. The relative levels of the different variant proteins and the extent of azido-ATP labelling were observed to be highly reproducible in multiple independent experiments. ABCR (large arrowhead); an endogenous 55-kD protein (small arrowhead) serves as an internal control for azido-ATP labelling. Molecular mass standards are shown on the left in kD.Full size imageThe combination of immunoblotting and azido-ATP labelling revealed defects in more than 75% of the variants tested. Among the variants with reduced yield and/or ATP binding are G863A and delG863, the two protein products of a guanosine2588→cytosine mutation that both generates a glycine-to-alanine substitution at codon 863 and activates a cryptic splice acceptor site in exon 17 that results in the removal of codon 863 from approximately 50% of the transcripts10. This is the most common allele among STGD patients in Northern Europe, representing roughly 20% of disease-associated alleles. It is also present at a frequency of approximately 3% in the general population in Northern Europe and approximately 1% in the United States population7,9,10. Genotype-phenotype correlations suggest that it is a mild allele and that it leads to STGD only when paired with a more severe allele10. Relative to wild type, the G863A variant is subtantially impaired and the delG863 variant is mildly impaired (Fig. 3).

      This variant was transfected into HEK 293 cells and appears to show reduced expression and ATP-binding capacity, but no quantities were provided

      ExperimentalAssay ExperimentalAssay:ABCA4Expression ClinVarID:7879 CAID:CA119128 automated_hgnc:34 automated_hgnc_source:CAID ClinGen ABCA4 Annotations
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    nature.com/articles/ng1000_242
  51. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
    Towards Uncovering the Role of Incomplete Penetrance in Maculopathies through Sequencing of 105 Disease-Associated Genes
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    pubmed.ncbi.nlm.nih.gov/38540785/
  52. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
    Whole exome sequencing detects homozygosity for ABCA4 p.Arg602Trp missense mutation in a pediatric patient with rapidly progressive retinal dystrophy
    1
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    pubmed.ncbi.nlm.nih.gov/24444108/
  53. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
    Phenotypes of 16 Stargardt macular dystrophy/fundus flavimaculatus patients with known ABCA4 mutations and evaluation of genotype-phenotype correlation
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    pubmed.ncbi.nlm.nih.gov/12192456/
  54. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
    Correlating the Expression and Functional Activity of ABCA4 Disease Variants With the Phenotype of Patients With Stargardt Disease
    1
    1. Vibhor 01 Aug 2026
      Patient 4, a 30-year-old individual with the deleterious c.213dupG/p.Ile73Asnfs*26 frameshift mutation and the c.1654G>A/p.Val552Ile missense mutation, displayed mild STGD1 with stage 2 FC and 20/30 VA. The p.Ile73Asnfs*26 mutation is classified as a pathogenic mutation, whereas the p.Val552Ile mutation is classified as likely neutral. Biochemical analysis of the p.Val552Val, however, suggests that this is a mild mutation at a functional level consistent with the clinical assessment of patient 4 (see Discussion section for additional information).

      Case#: Garces Patient 4, Canada

      DiseaseAssertion: mild STGD1

      FamilyInfo:

      CasePresentingHPOs:

      CaseHPOFreeText: 30yo, VA=20/30, FC=Stage 2 (flecks throughout the posterior pole, anterior to the vascular arcades and nasal to the optic disc and relatively normal ERGs but with prolonged dark adaptation)

      CaseNotHPOs:

      CaseNotHPOFreeText:

      GenotypingMethod: screened for mutations in the ABCA4, CNGB3, and ELOVL4 genes

      PreviouslyPublished: n/a

      Variant: c.213dupG/p.Ile73Asnfs*26; c.1654G>A/p.Val552Ile

      CAID: CA239745

      SupplementalData:

      CaseInfo Individual CAID:CA239745 automated_hgnc:34 automated_hgnc_source:CAID ClinGen ABCA4 Annotations
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    pmc.ncbi.nlm.nih.gov/articles/PMC5937799/
  55. journals.healio.com journals.healio.com
    Novel Heterozygous Variant in RP1L1 Gene With Retinitis Pigmentosa Phenotype: A Case Report | Ophthalmic Surgery, Lasers and Imaging Retina
    1
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    journals.healio.com/doi/10.3928/23258160-20251020-01
  56. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
    Antisense oligonucleotide therapy corrects splicing in the common Stargardt disease type 1-causing variant ABCA4 c.5461-10T>C
    1
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    pmc.ncbi.nlm.nih.gov/articles/PMC9999166/
  57. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
    Non-exomic and synonymous variants in ABCA4 are an important cause of Stargardt disease
    1
    1. Vibhor 01 Aug 2026
      V1 H1 Exon 36.1–3 G>A chr1:94,484,001 c.5196+1137G>A 4 4 0 0

      Case#: Braun Family 3 Proband (from left to right, top to bottom of available pedigrees), female

      DiseaseAssertion: Stargardt

      FamilyInfo: Both parents are unaffected, but only mother has genotype information available since father is deceased. c.1622T>C (p.L541P) and c.3113C>T (p.A1038V) complex variants were maternally inherited.

      CasePresentingHPOs:

      CaseHPOFreeText: "five or more of the following features of ABCA4-associated retinal disease: decreased visual acuity before age 20, decreased visual acuity as the first visual symptom, symmetrical fundus findings, pisciform flecks, beaten metal macular atrophy, bulls-eye maculopathy, peripapillary sparing, vermillion fundus, masked choroid on fluorescein angiography, nummular pigment overlying extensive macular atrophy, central outer retinal atrophy on optical coherence tomography and central scotomas on Goldmann perimetry."

      CaseNotHPOs:

      CaseNotHPOFreeText:

      GenotypingMethod: one plausible disease-causing mutation detected in ABCA4 after assessing the entire coding sequence and canonical retinal splice junctions with automated bidirectional Sanger sequencing using an ABI 3730 sequencer

      PreviouslyPublished: n/a

      Variant: c.5196+1137G>A; c.1622T>C (p.L541P) and c.3113C>T (p.A1038V) complex variant

      ClinVar: 438100

      CAID: CA26843511

      SupplementalData: pedigree in fig s2

      ClinVarID:438100 CAID:CA26843511 CaseInfo Individual FamilyInfo automated_hgnc:34 automated_hgnc_source:CAID ClinGen ABCA4 Annotations
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    pmc.ncbi.nlm.nih.gov/articles/PMC3842174/
  58. www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
    Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy
    1
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    ncbi.nlm.nih.gov/pmc/articles/PMC5859282/
  59. www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
    Combined Genetic and High-Throughput Strategies for Molecular Diagnosis of Inherited Retinal Dystrophies
    1
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    ncbi.nlm.nih.gov/pmc/articles/PMC3917917/
  60. www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
    ABCA4-related retinopathies in Lebanon
    1
    1. Vibhor 01 Aug 2026
      The proband of family 31, F31:II.1, carries a homozygous missense variant within exon 42 of the ABCA4 gene.

      This variant is well-known in exon 42, [M2]: c.5882G > A; p.(Gly1961Glu), rs1800553. The father of the affected patient was deceased; however, the mother was found to be homozygous for the wild type (WT) allele. According to the ACMG standards, M2 is likely pathogenic.

      CaseInfo automated_hgnc:34 automated_hgnc_source:rsID ClinGen ABCA4 Annotations
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    ncbi.nlm.nih.gov/pmc/articles/PMC11061736/
  61. www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
    Cis-acting modifiers in the ABCA4 locus contribute to the penetrance of the major disease-causing variant in Stargardt disease
    1
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    ncbi.nlm.nih.gov/pmc/articles/PMC8255130/
  62. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
    Retinoid Binding Properties of Nucleotide Binding Domain 1 of the Stargardt Disease-associated ATP Binding Cassette (ABC) Transporter, ABCA4
    1
    1. Vibhor 01 Aug 2026
      The plots of fluorescence anisotropy changes of 11-cis-retinal with wild type and mutant NBD1 protein titrations are shown in Fig. 6, A–C. The binding of mutant G863A was significantly attenuated as indicated by the drastic right shift of the binding isotherm as well as its inability to achieve saturation in the presence of a high concentration of protein (Fig. 6A). Nonlinear regression analysis gave Kd of 8.0 ± 1.3 × 10−8 m, 8.0 ± 2.0 × 10−6 m, and 4.0 ± 1.4 × 10−6 m for the wild type and R943Q and P940R mutations, respectively (Fig. 6 and Table 1). As a consequence of Stargardt disease mutations, 100-fold (R943Q) to 50-fold (P940R) decreases in the binding affinity of the NBD1 domain for 11-cis-retinal were observed. The retinal binding of the G863A mutant was severely attenuated, and the Kd was ≥1.0 × 10−5 m.

      The effects of this variant on 11-cis-retinal interaction with the NBD1 was evaluated via fluorescence anisotropy. The binding of mutant G863A was significantly attenuated (Kd was ≥1.0 × 10−5 m) as indicated by the drastic right shift of the binding isotherm as well as its inability to achieve saturation in the presence of a high concentration of protein (Fig. 6A).

      ExperimentalAssay ClinVarID:7879 CAID:CA119128 automated_hgnc:34 automated_hgnc_source:CAID ClinGen ABCA4 Annotations
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    pmc.ncbi.nlm.nih.gov/articles/PMC3531725/
  63. iovs.arvojournals.org iovs.arvojournals.org
    Asymmetric Inter-Eye Progression in Stargardt Disease
    1
    1. Vibhor 01 Aug 2026
      All reported ABCA4 variants (Supplementary Table S1) were classified as follows:

      Patient 38 has this variant and also c.5882G>A p.(Gly1961Glu) (Supplement 4-supplementary table 1). Phase is unknown and more specific phenotype information is not provided.

      clinical diagnosis of STGD1 was supported by the presence of ≥1 (likely) pathogenic ABCA4 variants with a follow-up data of ≥6 months on FAF imaging.

      CaseInfo Individual CA285825 SupplementalTable automated_hgnc:34 automated_hgnc_source:CAID ClinGen ABCA4 Annotations
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    iovs.arvojournals.org/article.aspx
  64. academic-oup-com.libproxy.lib.unc.edu academic-oup-com.libproxy.lib.unc.edu
    ABCA4 mutations causing mislocalization are found frequently in patients with severe retinal dystrophies
    1
    1. Vibhor 01 Aug 2026
      The measurement of ATPase activity has been the only assay available to study the effects of mutations on ABCA4 function. We employed this assay to examine the effects of [L541P; A1038V], R602W and C1490Y mutations on in vitro ATP hydrolysis. Constructs containing wild-type and mutated ABCA4 cDNAs, tagged with the eight amino acid bovine opsin C-terminal epitope (1D4), were expressed in COS7 cells and proteins were purified on a 1D4 affinity column. CHAPS-solubilized ABCA4 was incubated subsequently with ATP, and the hydrolysis rate was estimated with the charcoal method (31).The rate of ATP hydrolysis of the complex allele [L541P; A1038V] was decreased to 68.1% of wild-type ABCA4 (Fig. 3).

      ATPase activity in COS7 cells showed decreased activity (68.1% of wild-type), indicating that this variant impacts protein function (PS3_Supporting; PMIDs). However, this is not a cell type that is counted for PS3 evidence by the ABCA4 VCEP.

      ExperimentalAssay ExperimentalAssay:ATPaseActivity CA226911 automated_hgnc:34 automated_hgnc_source:CAID ClinGen ABCA4 Annotations
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    academic-oup-com.libproxy.lib.unc.edu/hmg/article-abstract/14/19/2769/617455
  65. onlinelibrary.wiley.com onlinelibrary.wiley.com
    Stargardt Disease with Preserved Central Vision: identification of a putative novel mutation in ATP-binding cassette transporter gene
    1
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    onlinelibrary.wiley.com/doi/10.1111/j.1755-3768.2009.01848.x
  66. people.eecs.berkeley.edu people.eecs.berkeley.edu
    russell-bbvabook17-pbai.pdf
    2
    1. 1aviel 01 Aug 2026
      The right time to worry about a potentially serious problemfor humanity depends not on when the problem will occur, but on how much time isneeded to devise and implement a solution that avoids the risk.

      This is very interesting to me and was worth highlighting.

    2. 1aviel 01 Aug 2026
      On September 11, 1933, renowned physicist Ernest Rutherford stated, with utterconfidence: “Anyone who expects a source of power in the transformation of these atomsis talking moonshine.” On September 12, 1933, physicist Leo Szilard invented the neutron-induced nuclear chain reaction.

      Save this. Good thing to bring up.

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    people.eecs.berkeley.edu/~russell/papers/russell-bbvabook17-pbai.pdf
  67. academic-oup-com.ezproxy.library.wwu.edu academic-oup-com.ezproxy.library.wwu.edu
    The Fruit of that Forbidden Tree
    10
    1. gabbere 01 Aug 2026
      That is, whenever one has a moral reason in favor of performing an action

      is there a meaningful difference in having a moral reason in favor of performing an action and having a moral reason in favor of not performing an action?

    2. gabbere 01 Aug 2026
      the sad story of the nearly five-thousand-year-old bristlecone pine (nicknamed, of all things, Prometheus) which was cut down in 1964 in the attempt to discover its age

      rage!

    3. gabbere 01 Aug 2026
      Unbridled, it can quickly run from drinking in the splendor of the finest poetry, prose, paintings, and perfumes to delving into the allurements of idle seduction and sadism to exploring the aesthetics of maiming and murder, with an openness to anything in between.

      Though this sentence has a warning tone, this seems to be the center aim of Tantra.

    4. gabbere 01 Aug 2026
      the forbidding of anything, even knowledge, makes available a great good—the good of obedience.

      Is forbidding the only way to make available the good of obedience? For example, aligning ones actions and being with the Dao, or 'way' is the aim of many Daoists. This appears a form of obedience-- a self- alignment with a higher order. But the Dao does not forbid alternative alignments of ones actions and being. However, the good of harmonization, similar enough to suggest synonymy with obedience, is available if one does.

    5. gabbere 01 Aug 2026
      , it can open gulfs between oneself and those one does (and should) care for most,

      the other points did not land on me, but this one painfully does

    6. gabbere 01 Aug 2026
      sful inquiry can produce effects other than adding to one’s store of knowledge. Instead of being improving or edifying or uplifting, some kinds of knowledge can be psychologically damaging, horrifying even, and thereby interfere with the acquisition or retention of w

      If the ultimate goal of life is to best love the world (or God, if thats your framework), and something can only be loved to the extent that it is known, then the pursuit of life should be any and all encounters with truth (even the horrifying, damaging, and painful). also, if everything in the world is a word of god, should we not read as much of Gods word as we can?

    7. gabbere 01 Aug 2026
      appreciation, respect, friendship, caretaking, and love freely given and received. It takes no great imagination to see how achieving a balance between such welfare goods

      one could "have" welfare goods, as in having respect or friendship, but one could also interpret human encounters with such goods in terms of 'knowing respect" and "knowing friendship". With this broad concept of knowledge, encounters with these welfare goods is viewed as, rather than a possession of welfare goods or a positive psycholgical effect caused by welfare goods, an acquisition of knowledge by acquaintance of welfare goods. 'knoweldge of knoweldge' is then only one form of knowledge

    8. gabbere 01 Aug 2026
      Knowledge is not just one desirable outcome among several; it should be the pre-eminent goal of our exploration of the world.5

      are there different kinds of knowledge, only some of which are a threat? say, is experiential, non-conceptual knowledge different and somehow less or more threatening than propositional knowledge?

    9. gabbere 01 Aug 2026
      garding the reply are made clear as Eve is beguiled by the serpent to her fall. Still, it is now commonplace to view opportunities to acquire knowledge as invitations to an uncontested good rather than as temptations to be weighed or examined, and the suggestion that knowledge is to be censored or its acquisition impeded often sparks outrage.

      is it knowledge that threatens or the pairing of knowledge with adam and eves nature? ex a spark only threatens fire if it meets dry wood.

    10. gabbere 01 Aug 2026
      contemporary students is why we should privilege knowledge over right action or virtue or individual flourishing.

      or is the kind of knowledge we should seek in inquiry the type which neccessarly changes us, makes us virtuous, a kind of knowledge identical with being and action

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    academic-oup-com.ezproxy.library.wwu.edu/book/62479/chapter/557311685
  68. 019f8ff9-72cd-78ff-b5bc-dca023e02b01-8080.eur-1.aiven.app 019f8ff9-72cd-78ff-b5bc-dca023e02b01-8080.eur-1.aiven.app
    Is Migration Assistant right for you?
    2
    1. padmashreemp 01 Aug 2026
      Use a managed-cloud path (Amazon EKS on AWS or GKE on GCP) if you also want the deployment tooling to prepare the cloud environment around the migration.

      This statement can come after the "If you answered “yes” to most". It kind of breaks the checklist flow

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    019f8ff9-72cd-78ff-b5bc-dca023e02b01-8080.eur-1.aiven.app/latest/migration-assistant/is-migration-assistant-right-for-you/
  69. bio.libretexts.org bio.libretexts.org
    2.6.2.1: Cycads and Ginkos
    1
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    bio.libretexts.org/Bookshelves/Botany/Botany_(Ha_Morrow_and_Algiers)/02:_Biodiversity_(Organismal_Groups)/2.06:_Seed_Plants/2.6.02:_Gymnosperms/2.6.2.01:_Cycads_and_Ginkos
  70. 019f8ff9-72cd-78ff-b5bc-dca023e02b01-8080.eur-1.aiven.app 019f8ff9-72cd-78ff-b5bc-dca023e02b01-8080.eur-1.aiven.app
    Migration Assistant for OpenSearch
    3
    1. padmashreemp 01 Aug 2026
      1 Is Migration Assistant right for you?

      "Assess your migration" link is missed. If I follow these steps instead of "Getting Started", I might miss "Assess your migration"

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    019f8ff9-72cd-78ff-b5bc-dca023e02b01-8080.eur-1.aiven.app/latest/migration-assistant/
  71. www.scifuture.org www.scifuture.org
    Objective Moral Ontology Should Inform AI Alignment – Science, Technology & the Future
    3
    1. 1aviel 01 Aug 2026
      A being’s suffering gives any sufficiently capable agent a pro tanto reason to reduce it, because suffering is a real negative condition for the subject undergoing it. That reason can be outweighed by other reasons, but it is not created by anyone’s approval.

      Double

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    scifuture.org/objective-moral-ontology-should-inform-ai-alignment/
  72. 127.0.0.1:5500 127.0.0.1:5500
    workspace-extractor 現行仕様マップ（入力・出力・処理順）
    8
    2. pool.kou 01 Aug 2026
      会議全体を見る必要があるため大きめ
      1. Map → Reduce 正規化（推奨の主軸）

      Map: 各チャンクから候補テーマを独立に抽出。この段では重複を気にしない（＝プロンプトが軽くなり、チャンクを並列処理できる） Reduce: 全チャンクの候補テーマ名＋カテゴリ＋（可能なら1行の根拠）と、DBの既存nearby-topicsを1プロンプトに入れ、「同一テーマの統合・既存テーマへの名寄せ・正規名の決定」だけをやらせる dialogue-digest が既に map/reduce ＋チェックポイント再開の基盤を持っているので（仕様マップ§9でも「共通基盤化すべき」と指摘済み）、構造の流用先があります。副産物として、現行から存在する表記ゆれ問題そのものの修正にもなります。

      1. チャンクのオーバーラップ（補助策）

      境界をまたぐ議論が文脈ごと切れて「テーマとして認識されない」ことへの対策として、10〜15%程度の重複を持たせる。ただしこれは取りこぼしへの対策であって、名前の割れは防げません（むしろ重複候補は増える）。Reduce があって初めて成立する補助策です。現行の splitMdBySpeakers が発言境界で切るのは維持すべき良い性質です。

    5. pool.kou 01 Aug 2026
      この差が設計を歪めている箇所が2つある。 既定の CLI モードでは systemPrompt も JSON Schema も効かないため、全ステージが 「system 文字列 + 空行 + 本文」を1本の user プロンプトに連結する方式になっている。 dialogue-digest が NDJSON + {"record_type":"end"} サーティネルという独自の壊れにくい形式を採ったのも、 Structured Outputs が使えないことへの対処である。 Gemini 経路では prompts.json の *_model が完全に無視される。 モデルは GEMINI_{STAGE}_MODEL → GEMINI_MODEL → gemini-2.5-flash の順で解決される。 しかも topic-aggregation は env 名が GEMINI_TOPIC-AGGREGATION_MODEL（ハイフン入り）になり、実質設定できない。

      一本設計にしてきれいにする

    6. pool.kou 01 Aug 2026
      "counters": [ { "name": "short", "max_tokens": 6000000, "window_hours": 5 }, { "name": "weekly", "max_tokens": 90000000, "window_hours": 168 } ]

      リミットは不要

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    127.0.0.1:5500/apps/local-extractor/docs/current-pipeline.html
  73. viva.pressbooks.pub viva.pressbooks.pub
    Critical Reading
    1
    1. Kmbrlysan 01 Aug 2026
      Example Questions to Ask a Text

      THINK topic, main argument, examples to support the argument, way they organized it, how does the word choice support the argument.

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    viva.pressbooks.pub/compreader/chapter/critical-reading/
  74. tesda-course.pages.dev tesda-course.pages.dev
    Lesson 4 · Interpret a simple chart or table — TESDA Foundational Skills
    1
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    tesda-course.pages.dev/build/lit-2a-l4
  75. tesis.pucp.edu.pe tesis.pucp.edu.pe
    SORIA_PALACIOS_ANDRES_ELIAS_INTERVENCION_ARTICULADA.pdf
    1
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    tesis.pucp.edu.pe/server/api/core/bitstreams/a9e68522-f1fa-404e-851f-a586a9184cfa/content
  76. www.americanyawp.com www.americanyawp.com
    A case of sexual violence during Reconstruction, 1866 | The American Yawp Reader
    1
    1. gcozzo 31 Jul 2026
      One of them then laid hold of me and hit me in the side of my face, and holding my throat, choked me. Lucy tried to get out of the window when one of them knocked her down and choked her. They drew their pistols and said they would shoot us and fire the house if we did not let them have their way with us. All seven of the men violated us two. Four of them had to do with me, the rest with Lucy.

      Reconstruction visibly failed to protect vulnerable people. Even with proof in court of horrific violence against black women authorities failed to deliver justice. Reconstruction did good politically but it failed its main goal of having long term equality and safety. 

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    americanyawp.com/reader/reconstruction/a-case-of-sexual-violence-during-reconstruction-1866/
  77. stylo.ecrituresnumeriques.ca stylo.ecrituresnumeriques.ca
    Les inquiétudes de l’amour dans Mathilde (1667) de Madeleine de Scudéry
    4
    1. senspublic 31 Jul 2026
      les fonctions ne faisaient alors pas l’unanimité,

      L'attitude plus précise de l'époque est détaillée plus bas, mais on pourrait croire que le « alors » dans cette phrase sous-entend que l'astrologie fait désormais l'unanimité, ou que cela a été le cas à un moment dans l'histoire, alors qu'il ne semble pas que cela fut jamais le cas. Peut-être serait-il préférable de seulement inscrire « [...] les fonctions ne faisaient pas l'unanimité ».

      révision linguistique
    2. senspublic 31 Jul 2026
      (sous le masque transparent du Moyen Âge tardif mis en scène dans la nouvelle). En Avignon, Mathilde se voit inculquer un fort attachement

      Il semble que l'ajout d'un marqueur de relation ne ferait pas de mal entre ces deux phrases, puisque l'on passe à un plan de l'article de plus haut niveau à un retour au plus près de la diégèse : on lirait peut-être plus naturellement « [...] du Moyen Âge tardif mis en scène dans la nouvelle). En effet, en Avignon [...] ». Un saut de paragraphe pourrait également faire l'affaire.

      suite des idées structure
    4. senspublic 31 Jul 2026
      tout ce qui – tyrannie, mariage et passions – risque d’entraver cette liberté ou d’en montrer l’illusion.

      La logique nous indique qu'il faut comprendre ici que l'inquiétude est générée par tout ce qui « montr[e] l'illusion » « d'entraver cette liberté », mais la formulation actuelle pourrait aussi laisser entendre que l'inquiétude est générée par ce qui pourrait montrer l'illusion de cette liberté. Il serait préférable de reformuler la phrase afin de clarifier.

      révision linguistique
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    stylo.ecrituresnumeriques.ca/api/v1/htmlArticle/6441626e819f650013b6ba32
  78. www.odmp.org www.odmp.org
    Keeper Andrew Van Kuren
    1
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    odmp.org/officer/23405-keeper-andrew-van-kuren
  79. blackpast.org blackpast.org
    Home
    1
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    blackpast.org/
  80. news.google.com news.google.com
    L'abeille de la Nouvelle-Orleans - Google News Archive Search
    1
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    news.google.com/newspapers
  81. en.wikipedia.org en.wikipedia.org
    Robert Charles riots - Wikipedia
    1
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    en.wikipedia.org/wiki/Robert_Charles_riots
  82. www.crafins.com www.crafins.com
    Beste Beauty-Shops Österreich 2026: Kosmetik und Parfum online kaufen
    23
    1. Nadine1307 31 Jul 2026
      Wer regelmäßig bestellt, kann außerdem von Treueprogrammen oder Kundenkonten profitieren.

      Better: Wenn Sie regelmäßig bestellen, können Sie außerdem von Treueprogrammen oder einem Kundenkonto profitieren.

    3. Nadine1307 31 Jul 2026
      Für speziellere Anforderungen gibt es jedoch bessere Alternativen: Niche Beauty für exklusive Marken, parfumdreams für Aktionen, Notino für besonders große Auswahl, Flaconi für einen unkomplizierten Bestellprozess, Marionnaud für persönliche Beratung und BIPA für den täglichen Beauty-Einkauf.

      Sounds very unnatural and like AI. Better:

      Je nach Ihren Bedürfnissen kann jedoch auch ein anderer Shop besser passen. Niche Beauty eignet sich für exklusive Marken, parfumdreams für attraktive Angebote und Notino für eine besonders große Auswahl. Flaconi überzeugt mit einem unkomplizierten Bestellprozess, Marionnaud mit persönlicher Beratung und BIPA für den täglichen Beauty-Einkauf.

    4. Nadine1307 31 Jul 2026
      Punkte und Gutscheine laufen über das in Österreich weit verbreitete Bonusprogramm, das viele ohnehin nutzen.

      Sounds more natural:

      Punkte und Gutscheine erhalten Sie über ein Bonusprogramm, das viele Menschen in Österreich bereits nutzen.

    5. Nadine1307 31 Jul 2026
      Über 10.000 Produkte aus Parfum, Pflege und Make-up, dazu Marken, die im österreichischen Handel exklusiv geführt werden, sowie eigene Marken.

      Sounds too much like AI. Better:

      Das Sortiment umfasst mehr als 10.000 Produkte aus den Bereichen Parfum, Pflege und Make-up. Dazu kommen exklusive Marken, die in Österreich nur dort erhältlich sind, sowie Eigenmarken.

    6. Nadine1307 31 Jul 2026
      Eines der attraktivsten Verhältnisse im Feld, vor allem wenn ohnehin mehrere Produkte gleichzeitig im Warenkorb liegen.

      Das Preis-Leistungs-Verhältnis fällt besonders attraktiv aus. Vor allem dann, wenn Sie mehrere Produkte gleichzeitig bestellen.

    7. Nadine1307 31 Jul 2026
      Nach eigenen Angaben wurden seit der Gründung über eine Million Kundinnen und Kunden in mehr als 100 Ländern beliefert.

      Das Unternehmen hat nach eigenen Angaben seit der Gründung mehr als eine Million Kundinnen und Kunden beliefert. Die Bestellungen gingen in über 100 Länder.

    8. Nadine1307 31 Jul 2026
      Sorgfältige Verpackung und zwei frei wählbare Gratisproben pro Bestellung, dazu Punkte und Vorteile über das Programm THE CLUB.

      Here too. Better:

      Jede Bestellung wird sorgfältig verpackt. Außerdem erhalten Sie zwei frei wählbare Gratisproben und profitieren mit THE CLUB von Punkten und weiteren Vorteilen.

    9. Nadine1307 31 Jul 2026
      Weil das Sortiment bewusst klein gehalten ist, stolpert man über Marken, die in einem Katalog mit Zehntausenden Artikeln untergehen würden.

      Same here. Better:

      Das Sortiment ist bewusst überschaubar. Dadurch entdecken Sie leichter Marken, die in sehr grossen Shops oft untergehen.

    10. Nadine1307 31 Jul 2026
      2011 in Hamburg gegründet und von Anfang an auf internationale Nischen- und Luxusmarken konzentriert, viele davon in Österreich sonst schwer zu bekommen.

      Too long sentence. Better:

      Das Unternehmen wurde 2011 in Hamburg gegründet. Von Anfang an lag der Fokus auf internationalen Nischen- und Luxusmarken, die in Österreich oft nur schwer erhältlich sind.

    12. Nadine1307 31 Jul 2026
      Dazu die Beauty Card mit Punkten und Direktrabatten sowie zwei Gratisproben ab zehn Euro Bestellwert.

      Does not sounds like a real sentence. Better:

      Zusätzlich bietet die Beauty Card Punkte, Direktrabatte und ab einem Bestellwert von zehn Euro zwei Gratisproben.

    13. Nadine1307 31 Jul 2026
      Der Parfumfinder hilft online bei der Duftauswahl, in ausgewählten Filialen gibt es eine Hautanalyse mit Messgerät sowie kostenlose Make-up- und Pflegeberatung.

      Sounds very unnatural. Better:

      Der Parfumfinder unterstützt Sie online bei der Wahl des passenden Dufts. In ausgewählten Filialen können Sie zudem eine Hautanalyse mit Messgerät sowie eine kostenlose Make-up- und Pflegeberatung in Anspruch nehmen.

    14. Nadine1307 31 Jul 2026
      Koreanische Hautpflege mit Marken wie COSRX, Beauty of Joseon, Anua oder Missha, dazu vegane Kosmetik und zertifizierte Naturkosmetik.

      Sounds more like human: Das Sortiment umfasst koreanische Hautpflege von Marken wie COSRX, Beauty of Joseon, Anua oder Missha. Ergänzt wird das Angebot durch vegane Kosmetik und zertifizierte Naturkosmetik.

    15. Nadine1307 31 Jul 2026
      Bis zu 1.500 Marken, von Prestige-Labels wie Yves Saint Laurent, Chanel oder Charlotte Tilbury über Rituals bis zu Marken, die man aus der Drogerie kennt.

      Sounds more like human:

      Das Sortiment umfasst bis zu 1.500 Marken. Dazu gehören Luxusmarken wie Yves Saint Laurent, Chanel oder Charlotte Tilbury ebenso wie Rituals und viele bekannte Drogeriemarken.

    20. Nadine1307 31 Jul 2026
      Ein Beauty-Shop ist mehr als eine Preisliste. Ob eine Bestellung am Ende zufriedenstellt, hängt davon ab, ob die gewünschte Marke überhaupt geführt wird, ob man sich im Shop zurechtfindet, was die Lieferung nach Österreich kostet und was passiert, wenn etwas zurückgehen soll. Wir haben deshalb sieben Kriterien angelegt:

      Sounds a lot like AI and the sentece is really long. Better:

      Ein Beauty-Shop ist weit mehr als eine einfache Preisliste. Entscheidend ist, ob du deine Wunschmarken findest und dich im Shop gut zurechtfindest. Auch die Versandkosten nach Österreich und die Rückgabemöglichkeiten spielen eine wichtige Rolle. Erst das Zusammenspiel dieser Punkte entscheidet darüber, ob eine Bestellung wirklich überzeugt. Deshalb haben wir sieben Kriterien für unseren Vergleich festgelegt.

    23. Nadine1307 31 Jul 2026
      Der Beauty-Handel im Netz ist in Österreich unübersichtlich geworden. Es gibt die klassischen Parfümerien mit Filialen in der Innenstadt, die reinen Online-Händler mit Sortimenten, die in kein Regal der Welt passen würden, die Spezialisten für Marken, die man sonst nur auf Reisen entdeckt, und die Drogerien, aus denen die halbe Pflegeroutine ohnehin schon kommt. Alle liefern nach Österreich. Miteinander vergleichbar sind sie kaum.

      This part sounds a lot like AI and does not make really sense. Better:

      Der Beauty-Handel im Internet ist in Österreich inzwischen kaum noch überschaubar. Neben klassischen Parfümerien mit Filialen in den Innenstädten gibt es reine Online-Shops mit einem riesigen Sortiment. Hinzu kommen spezialisierte Anbieter, die Marken führen, die viele nur aus dem Urlaub kennen, sowie Drogerien, bei denen ohnehin ein grosser Teil der täglichen Pflege gekauft wird. Nach Österreich liefern sie heute fast alle. Trotzdem lassen sich die Angebote nur schwer miteinander vergleichen.

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    crafins.com/p/DG-V01-kurier/
  83. www.biorxiv.org www.biorxiv.org
    Fatty Acid Synthase associates with nuclear-derived cytoplasmic dsRNA molecules and influences antiviral innate immune response
    4
    1. EMBOpress 31 Jul 2026

      Note: This response was posted by the corresponding author to Review Commons. The content has not been altered except for formatting.

      Learn more at Review Commons

      Reply to the reviewers

      Reviewers’ comments:

      Reviewer #1 (Evidence, reproducibility and clarity (Required)):

      This manuscript identifies a potential connection between FASN, endogenous dsRNAs, and innate immune signaling. The authors show that FASN depletion increases cytoplasmic dsRNA staining, enhances IFN transcription and restricts Sindbis virus replication. Overall, the basic observation seems to be solid and well-controlled. Depending on which journal this is being considered for, the central mechanism could be better developed and elucidated to entail more molecular details. As it currently stands, several important questions, especially ones regarding the FASN-RNA interactions remain unresolved.

      Major comments

      The conclusion that FASN regulates dsRNA accessibility rather than dsRNA abundance requires further support. The authors show increased J2 staining without major changes in the global dsRNA landscape by J2-RIP-seq. However, alternative explanations could be: (1) changes in dsRNA structure or length distribution could affect J2 recognition, i.e. epitope masked by FASN binding; (2) differences in RNA-protein complex assembly could influence J2 accessibility; (3) Altered subcellular localization of dsRNAs could increase immunofluorescence signals without substantially affecting RIP-seq recovery. 2. The nature of the FASN-RNA interaction remains unclear. The authors demonstrate that FASN associates with a subset of endogenous RNAs, but it is not clear whether this interaction is sequence-specific, structure-specific, or largely nonspecific. Are there common sequence motifs, secondary structures, repetitive elements, or specific transcript classes enriched among FASN-associated RNAs? Without a clearer understanding of RNA selectivity, it remains difficult to evaluate the biological significance of the observed interactions. 3. The study would be significantly strengthened by complementation experiments. Although the FASN knockout phenotype is convincing, add-back experiments are needed to demonstrate specificity and probe potential mechanisms. Reconstitution with wild-type FASN should rescue the dsRNA and immune phenotypes. Furthermore, domain-specific mutants or catalytic mutants (e.g., palmitoylation) could help distinguish whether the observed effects depend on FASN enzymatic activity, a specific protein domain, or a non-canonical RNA-binding function. Such experiments would greatly improve the mechanistic depth of the study. It will also address whether the observed dsRNA increase phenotype is irreversible.

      The manuscript proposes that increased endogenous dsRNA sensing drives the inflammatory phenotype in FASN-deficient cells. However, direct evidence for enhanced PRR engagement is currently lacking. Although MDA5 and MAVS knockdown experiments suggest a possible contribution of this pathway, the observed knockdown effects are relatively modest and needs to be repeated by CRISPR knockout. Does FASN, MAVS double knockout cells rescue the slow growth phenotype? In addition, direct measurements of PRR activation, such as MDA5-RNA association, MAVS activation, IRF3 phosphorylation, or related downstream signaling events, were not examined. 5. The antiviral phenotype observed during Sindbis virus infection is interesting, but the underlying mechanism remains uncertain. The authors propose that enhanced endogenous dsRNA sensing contributes to viral restriction, yet alternative explanations related to altered lipid metabolism, impaired membrane remodeling, or other consequences of FASN deficiency cannot be excluded. Especially when MDA5 and MAVS knockdown effect appears modest. Additional experiments disrupting interferon signaling or innate immune sensing pathways using the FASN, MAVS double knockout cells would help determine whether the antiviral phenotype is directly linked to the proposed dsRNA sensing mechanism.

      Reviewer #1 (Significance (Required)):

      This manuscript identifies a potential connection between FASN, endogenous dsRNAs, and innate immune signaling. The authors show that FASN depletion increases cytoplasmic dsRNA staining, enhances IFN transcription and restricts Sindbis virus replication. Overall, the basic observation seems to be solid and well-controlled. Depending on which journal this is being considered for, the central mechanism could be better developed and elucidated to entail more molecular details. As it currently stands, several important questions, especially ones regarding the FASN-RNA interactions remain unresolved.

      Reviewer #2 (Evidence, reproducibility and clarity (Required)):

      The manuscript by Pasquier and colleagues investigates the role of fatty acid synthase (FASN) in the regulation of innate immune signaling through its interaction with endogenous dsRNAs. The authors build upon their previous study, in which they identified FASN as a potential dsRNA-binding protein. They show that FASN knockout results in increased cytoplasmic dsRNA detection accompanied by the induction of inflammation-related genes. Subsequent multi-omics analyses reveal that FASN associates with dsRNAs derived from nuclear genome-encoded transcripts in multiple contexts. Interestingly, FASN depletion does not alter the overall expression of these dsRNAs but increases their detection by the J2 antibody. Functionally, FASN depletion enhances innate immune responses to dsRNA stimulation and Sindbis virus infection.

      While the study provides evidence supporting an proviral role for FASN, the manuscript lacks mechanistic insight into this phenomenon. In particular, it remains unclear how FASN depletion enhances dsRNA detection without altering endogenous dsRNA abundance. The following points should be addressed:

      1) The main limitation of the manuscript is the absence of a mechanistic explanation for how FASN depletion leads to increased dsRNA detection without affecting expression. Does the increased dsRNA detection require a direct interaction between FASN and dsRNAs? The authors should provide additional evidence to clarify whether FASN binding masks dsRNA epitopes or regulates dsRNA accessibility to recognition by J2 and innate immune sensors.

      2) The authors show that FASN directly binds nuclear genome-encoded transcripts. It would be important to perform RNA-FISH for selected FASN-interacting RNAs to determine whether their cellular localization or J2-detectable signal is altered in FASN-depleted cells.

      3) In Figure 2B, the authors demonstrate enrichment of inflammation-related gene signatures in FASN knockout cells. However, the magnitude of induction is not clear. How does the inflammatory response compare with canonical innate immune activation, such as viral infection or poly(I:C) stimulation? Although Figure 2A partially addresses this point, many of the highlighted genes are not directly associated with inflammatory responses.

      4) For the transcripts directly associated with FASN, do they contain predicted dsRNA-forming regions or known structured RNA elements? The current data do not sufficiently demonstrate whether these transcripts indeed form dsRNA structures. Although some are enriched in J2 immunoprecipitation, additional structural analyses, including computational prediction of dsRNA regions, would strengthen the conclusion.

      5) The authors should further investigate whether the enhanced antiviral activity observed upon FASN depletion is mediated by elevated endogenous dsRNA sensing. Are dsRNA sensors such as PKR, MDA5, or RIG-I more strongly activated in FASN knockout cells? Do these sensors exhibit increased binding to endogenous dsRNAs following FASN depletion?

      Reviewer #2 (Significance (Required)):

      Main strength: Uncover the proviral role of FASN via regulation of endogenous dsRNAs

      Limitations: Molecular mechanism on how FASN depletion increases the accessibility of dsRNAs without affecting their expression. Also, need better characterization of FASN-binding RNAs, especially their secondary structure.

      Reviewer #3 (Evidence, reproducibility and clarity (Required)):

      Summary The manuscript entitled, "Fatty Acid Synthase associates with nuclear-derived cytoplasmic dsRNA molecules and influences antiviral innate immune response," by Pasquier et al. identifies an unexpected function for FASN as an endogenous dsRNA-associated protein and explores the relationship between FASN, cellular dsRNA homeostasis, and antiviral innate immunity. Using FASN knockout cells, the authors demonstrate that depletion of FASN results in accumulation of cellular dsRNA, characterize the endogenous dsRNA species associated with FASN, and show that loss of FASN is accompanied by increased expression of interferon-stimulated genes and restriction of SINV replication. The biochemical characterization of FASN-associated dsRNAs together with the accompanying transcriptomic analyses provide compelling evidence that FASN interacts with a distinct subset of endogenous dsRNAs, representing a novel function for this metabolic enzyme.

      While evidence is presented that FASN can associate with endogenous dsRNA, several aspects of the proposed functional model extend beyond what is directly demonstrated by the data. In particular, the manuscript presents dsRNA accumulation, innate immune activation, and viral restriction as a consequence of FASN-mediated dsRNA regulation. However, it remains unclear whether these downstream phenotypes arise specifically from the newly described RNA-binding activity of FASN or instead reflect broader cellular consequences of FASN deficiency, including alterations in lipid metabolism and protein palmitoylation. Likewise, although the authors identify a population of FASN-associated dsRNAs, the relationship between these transcripts and the dsRNAs that accumulate following FASN depletion remains insufficiently resolved, making it difficult to mechanistically understand how FASN regulates dsRNA homeostasis. Overall, the manuscript provides a number of intriguing observations regarding FASN association with endogenous dsRNA. However, the functional relationship between these findings and the proposed effects on dsRNA homeostasis and innate immunity would benefit from additional clarification before the mechanistic model can be fully supported.

      Major Concerns

      It remains unclear whether the inflammatory and antiviral phenotypes observed following FASN depletion are attributable to FASN's newly described dsRNA-binding activity or to the broader metabolic consequences of losing FASN. The manuscript presents dsRNA accumulation, induction of ISGs, and restriction of SINV as downstream consequences of FASN-mediated dsRNA regulation. While these observations are compelling, they remain correlative and do not distinguish between effects arising from dsRNA regulation versus the numerous metabolic changes expected following loss of FASN. In particular, reduced palmitate production and altered protein palmitoylation are well-established consequences of FASN depletion and have documented roles in MAVS signaling and antiviral immunity. This distinction is important because the principal claim of the manuscript is not simply that FASN depletion alters innate immunity, but that its RNA-binding activity is proposed to underlie these effects. At present, the data support an association between these phenotypes but fall somewhat short of demonstrating that the observed immune response is specifically driven by FASN-mediated regulation of endogenous dsRNA.

      1. While the manuscript does provide evidence that FASN associates with a subset of endogenous dsRNAs, the relationship between these RNAs and those that accumulate following FASN depletion remains unclear. The authors conclude that FASN regulates dsRNA homeostasis, yet also show that transcripts associated with FASN do not measurably accumulate in knockout cells. This creates a disconnect between RNA association and functional regulation that is not adequately resolved.

      An overlap analysis comparing the dsRNA populations identified in wt and KO cells would help clarify whether FASN regulates a stable population of transcripts or whether broader remodeling of the dsRNA landscape occurs following FASN loss. More generally, the manuscript would be stronger if it helps clarify or distinguish the observation that FASN binds endogenous dsrna from the conclusion that it regulates cellular dsRNA homeostasis; the latter is not fully supported with the presented data.

      Minor concerns

      The mitochondrial localization of dsRNA needs additional validation. Specifically, Fig 3A requires quantitative analysis of mitochondrial abundance, while Fig 3C could be strengthened through orthogonal validation of mitochondrial localization (e.g., microscopy-based co-localization or further purification of the mitochondrial fraction). Inclusion of an RNase control would also help demonstrate that the enrichment is specific to dsRNA.

      The role of the ADAR depletion experiments within the overall narrative is somewhat unclear. Consider either integrating these data more directly into the proposed model or reducing their emphasis. Along similar lines, Fig 4B should clarify whether the increased FASN-dsRNA association reflects greater binding or simply increased abundance of both FASN and dsRNA following 5-Aza treatment. • Several aspects of the data presentation needs clarification. These include the rationale for selecting IFIT1 for validation (Fig 2A), the relationship between proteins highlighted in the Fig 4 volcano plot and those selected for immunoblot validation, the apparent reduction in tubulin complicating interpretation of the SINV capsid blot (Fig 5B), and the conclusion that J2-positive puncta are distinct from SINV RNA without co-localization analysis. • Several figures could be improved for presentation. Quantification of the J2 signal in Fig S1C (analogous to Fig 1D) and improved labeling of the volcano plots would improve readability. • Several minor editorial revisions are recommended. These include describing ACP as a carrier/tethering rather than catalytic domain, citing Fig S2 in the Results, defining the long form of NES in the Fig 2 legend, removing redundant panel descriptions in the Fig 3G legend, correcting the missing text on page 14, and resolving the duplicated figures and formatting issues present throughout the manuscript.

      Reviewer #3 (Significance (Required)):

      Strengths Nice extension of FASN biology beyond its canonical metabolic role Introduces FASN as a potential endogenous dsRNA-binding protein Broad interest for the RNA biology and innate immunity communities

      Limitations RNA binding not fully demonstrated with higher-resolution approaches such as more precise CLIP approaches

      Mechanistic link between FASN dsRNA homeostasis and innate immune activation remains incomplete

      Advance Good conceptual advance but is more descritive than mechanistic

      Audience: RNA biology RNA-binding proteins Innate immunity Host-virus interactions Moonlighting metabolic enzymes

      Revision plan:

      1. General Statements:

      We thank the three reviewers for their careful evaluation of our manuscript and for their constructive comments. We are encouraged that all reviewers considered the central observations of the study to be robust and appreciated the conceptual advance provided by the identification of a previously unrecognized association between FASN and endogenous dsRNAs, together with its impact on antiviral innate immunity.

      We also acknowledge the fact that the main limitation of the current manuscript is the mechanistic understanding of how FASN regulates endogenous dsRNA accessibility and how this relates to innate immune activation. We agree that strengthening the mechanistic aspects of the study will substantially improve the manuscript. Nonetheless, dissecting the full mechanism may require more time which goes beyond the scope of this paper.

      Based on the comments of the three reviewers, our revision plan will therefore focus on three major objectives:

      • further characterizing the endogenous RNAs associated with FASN,
      • strengthening the mechanistic aspects linking increased accessibility of endogenous dsRNAs to FASN depletion,
      • providing additional evidence linking endogenous dsRNA accessibility to innate immune priming and antiviral activity. Importantly, we also intend to clarify our proposed model. Our data do not suggest that loss of FASN induces a strong spontaneous interferon response comparable to that triggered by viral infection or poly(I:C) stimulation. We rather propose that FASN depletion establishes a primed state by increasing the accessibility of a subset of endogenous dsRNAs to innate immune sensors, thereby lowering the threshold for antiviral activation upon subsequent challenge. We will revise the manuscript to better communicate this model, improving data presentation throughout the manuscript and discussion to clearly distinguish experimentally supported conclusions from mechanistic interpretations.

      __2. __Description of the planned revisions:

      Further characterization of FASN-associated endogenous RNAs

      To better define the RNA population associated with FASN, we will perform additional bioinformatic analyses using our existing RIP-seq datasets. These analyses will include:

      • characterization of transcript classes (coding and non-coding RNAs);
      • analysis of sequence composition and motif enrichment;
      • prediction of RNA structural features (including GC content, normalized minimum free energy, paired nucleotide fraction and predicted stem length);
      • analysis of overlap with repetitive elements (including Alu, LINE and LTR elements);
      • comparison of predicted structural and sequence features of FASN-associated RNAs and J2-enriched RNAs;

      • additional comparisons between dsRNA populations identified in wild-type and FASN knockout cells. These analyses will help determine whether FASN preferentially associates with specific classes of endogenous RNAs. Based on the shortlisted RNAs, we will also test selected FASN-associated transcripts by RT-qPCR following RNase III treatment, to determine whether they are forming dsRNA with or without FASN depletion.

      • Strengthening the link between endogenous dsRNA accessibility and innate immune activation To provide more evidence that increased accessibility of endogenous dsRNAs results in enhanced innate immune sensing, we plan to further examine activation of dsRNA sensing pathways.

      Specifically, we will assess activation of downstream signaling components (including IRF3 activation) and further investigate the association of endogenous dsRNAs with innate immune sensors by examining MDA5 recruitment to J2-positive dsRNA complexes. Where technically feasible, we will also evaluate the spatial proximity between endogenous dsRNAs and MDA5 by microscopy-based approaches.

      To strengthen the link between endogenous dsRNA sensing and the primed inflammatory phenotype, we also plan to generate polyclonal CRISPR/Cas9 MDA5 or MAVS knockout cell populations in combination with FASN depletion by siRNA treatment, and evaluate the effects on interferon-responsive gene expression such as IFIT1.

      • Relationship between RNA binding and the metabolic functions of FASN Several reviewers raised the important question of whether the observed immune phenotypes arise from FASN-mediated regulation of endogenous dsRNAs or from broader metabolic consequences of FASN deficiency.

      To address this point, we plan to complement our genetic analyses with pharmacological inhibition of FASN catalytic activity using independent inhibitors and assess their effects on endo-dsRNA accumulation and Sindbis virus replication. We also plan to evaluate whether supplementation with exogenous palmitate rescues the observed phenotypes. These experiments will help distinguish catalytic from non-canonical functions of FASN in regulating endo-dsRNA accessibility and antiviral responses.

      Where feasible, we will also attempt complementation experiments using ectopic expression of wild-type FASN in FASN knockout cells.

      Additional manuscript improvements

      We will incorporate the requested additional quantifications, improve figure presentation and labeling, clarify the rationale for selected validation experiments, expand the discussion of alternative mechanistic models, and address the editorial and presentation issues identified by the reviewers.

      __3. __Description of analyses that authors prefer not to carry out:

      Although we agree that additional mechanistic studies would further strengthen the manuscript, we believe that several of the experiments suggested by the reviewers extend beyond the scope of this work.

      In particular, generation and characterization of multiple FASN domain-specific or RNA-binding mutants is currently not feasible. FASN is a large multifunctional enzyme containing several catalytic domains and no canonical RNA-binding domain has yet been defined. Consequently, designing mutants that specifically disrupt RNA binding while preserving enzymatic activities would be possible but difficult to deliver within the timeframe of this revision. Instead, we propose to address the reviewers' concerns through complementary pharmacological approaches (using FASN inhibitors), palmitate supplementation experiments and wild-type FASN complementation where feasible.

      Similarly, while high-resolution CLIP approaches would provide valuable information regarding FASN binding sites on the RNA, these technically demanding experiments fall beyond the scope of the current revision. We believe that the additional computational analyses, biochemical validation and functional experiments described above will substantially strengthen the conclusions regarding the interaction between FASN and endogenous structured RNAs.

      Finally, although generation of stable double knockout cell lines (e.g. FASN/MAVS or FASN/MDA5) could provide additional mechanistic insight, we consider that this could take too much time. Instead, we plan to generate polyclonal CRISPR/Cas9 knockout populations of MAVS or MDA5 in combination with siFASN to strengthen the causal relationship between endogenous dsRNA sensing and the observed primed immune phenotype.

      PeerReviewed
    2. EMBOpress 31 Jul 2026

      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 #3

      Evidence, reproducibility and clarity

      Summary

      The manuscript entitled, "Fatty Acid Synthase associates with nuclear-derived cytoplasmic dsRNA molecules and influences antiviral innate immune response," by Pasquier et al. identifies an unexpected function for FASN as an endogenous dsRNA-associated protein and explores the relationship between FASN, cellular dsRNA homeostasis, and antiviral innate immunity. Using FASN knockout cells, the authors demonstrate that depletion of FASN results in accumulation of cellular dsRNA, characterize the endogenous dsRNA species associated with FASN, and show that loss of FASN is accompanied by increased expression of interferon-stimulated genes and restriction of SINV replication. The biochemical characterization of FASN-associated dsRNAs together with the accompanying transcriptomic analyses provide compelling evidence that FASN interacts with a distinct subset of endogenous dsRNAs, representing a novel function for this metabolic enzyme. While evidence is presented that FASN can associate with endogenous dsRNA, several aspects of the proposed functional model extend beyond what is directly demonstrated by the data. In particular, the manuscript presents dsRNA accumulation, innate immune activation, and viral restriction as a consequence of FASN-mediated dsRNA regulation. However, it remains unclear whether these downstream phenotypes arise specifically from the newly described RNA-binding activity of FASN or instead reflect broader cellular consequences of FASN deficiency, including alterations in lipid metabolism and protein palmitoylation. Likewise, although the authors identify a population of FASN-associated dsRNAs, the relationship between these transcripts and the dsRNAs that accumulate following FASN depletion remains insufficiently resolved, making it difficult to mechanistically understand how FASN regulates dsRNA homeostasis. Overall, the manuscript provides a number of intriguing observations regarding FASN association with endogenous dsRNA. However, the functional relationship between these findings and the proposed effects on dsRNA homeostasis and innate immunity would benefit from additional clarification before the mechanistic model can be fully supported.

      Major Concerns

      1. It remains unclear whether the inflammatory and antiviral phenotypes observed following FASN depletion are attributable to FASN's newly described dsRNA-binding activity or to the broader metabolic consequences of losing FASN. The manuscript presents dsRNA accumulation, induction of ISGs, and restriction of SINV as downstream consequences of FASN-mediated dsRNA regulation. While these observations are compelling, they remain correlative and do not distinguish between effects arising from dsRNA regulation versus the numerous metabolic changes expected following loss of FASN. In particular, reduced palmitate production and altered protein palmitoylation are well-established consequences of FASN depletion and have documented roles in MAVS signaling and antiviral immunity.

      This distinction is important because the principal claim of the manuscript is not simply that FASN depletion alters innate immunity, but that its RNA-binding activity is proposed to underlie these effects. At present, the data support an association between these phenotypes but fall somewhat short of demonstrating that the observed immune response is specifically driven by FASN-mediated regulation of endogenous dsRNA. 2. While the manuscript does provide evidence that FASN associates with a subset of endogenous dsRNAs, the relationship between these RNAs and those that accumulate following FASN depletion remains unclear. The authors conclude that FASN regulates dsRNA homeostasis, yet also show that transcripts associated with FASN do not measurably accumulate in knockout cells. This creates a disconnect between RNA association and functional regulation that is not adequately resolved.

      An overlap analysis comparing the dsRNA populations identified in wt and KO cells would help clarify whether FASN regulates a stable population of transcripts or whether broader remodeling of the dsRNA landscape occurs following FASN loss. More generally, the manuscript would be stronger if it helps clarify or distinguish the observation that FASN binds endogenous dsrna from the conclusion that it regulates cellular dsRNA homeostasis; the latter is not fully supported with the presented data.

      Minor concerns

      • The mitochondrial localization of dsRNA needs additional validation. Specifically, Fig 3A requires quantitative analysis of mitochondrial abundance, while Fig 3C could be strengthened through orthogonal validation of mitochondrial localization (e.g., microscopy-based co-localization or further purification of the mitochondrial fraction). Inclusion of an RNase control would also help demonstrate that the enrichment is specific to dsRNA.
      • The role of the ADAR depletion experiments within the overall narrative is somewhat unclear. Consider either integrating these data more directly into the proposed model or reducing their emphasis. Along similar lines, Fig 4B should clarify whether the increased FASN-dsRNA association reflects greater binding or simply increased abundance of both FASN and dsRNA following 5-Aza treatment.
      • Several aspects of the data presentation needs clarification. These include the rationale for selecting IFIT1 for validation (Fig 2A), the relationship between proteins highlighted in the Fig 4 volcano plot and those selected for immunoblot validation, the apparent reduction in tubulin complicating interpretation of the SINV capsid blot (Fig 5B), and the conclusion that J2-positive puncta are distinct from SINV RNA without co-localization analysis.
      • Several figures could be improved for presentation. Quantification of the J2 signal in Fig S1C (analogous to Fig 1D) and improved labeling of the volcano plots would improve readability.
      • Several minor editorial revisions are recommended. These include describing ACP as a carrier/tethering rather than catalytic domain, citing Fig S2 in the Results, defining the long form of NES in the Fig 2 legend, removing redundant panel descriptions in the Fig 3G legend, correcting the missing text on page 14, and resolving the duplicated figures and formatting issues present throughout the manuscript.

      Significance

      Strengths

      Nice extension of FASN biology beyond its canonical metabolic role Introduces FASN as a potential endogenous dsRNA-binding protein Broad interest for the RNA biology and innate immunity communities

      Limitations

      RNA binding not fully demonstrated with higher-resolution approaches such as more precise CLIP approaches Mechanistic link between FASN dsRNA homeostasis and innate immune activation remains incomplete

      Advance

      Good conceptual advance but is more descritive than mechanistic

      Audience

      RNA biology RNA-binding proteins Innate immunity Host-virus interactions Moonlighting metabolic enzymes

      PeerReviewed
    3. EMBOpress 31 Jul 2026

      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 #2

      Evidence, reproducibility and clarity

      The manuscript by Pasquier and colleagues investigates the role of fatty acid synthase (FASN) in the regulation of innate immune signaling through its interaction with endogenous dsRNAs. The authors build upon their previous study, in which they identified FASN as a potential dsRNA-binding protein. They show that FASN knockout results in increased cytoplasmic dsRNA detection accompanied by the induction of inflammation-related genes. Subsequent multi-omics analyses reveal that FASN associates with dsRNAs derived from nuclear genome-encoded transcripts in multiple contexts. Interestingly, FASN depletion does not alter the overall expression of these dsRNAs but increases their detection by the J2 antibody. Functionally, FASN depletion enhances innate immune responses to dsRNA stimulation and Sindbis virus infection.

      While the study provides evidence supporting an proviral role for FASN, the manuscript lacks mechanistic insight into this phenomenon. In particular, it remains unclear how FASN depletion enhances dsRNA detection without altering endogenous dsRNA abundance. The following points should be addressed:

      1) The main limitation of the manuscript is the absence of a mechanistic explanation for how FASN depletion leads to increased dsRNA detection without affecting expression. Does the increased dsRNA detection require a direct interaction between FASN and dsRNAs? The authors should provide additional evidence to clarify whether FASN binding masks dsRNA epitopes or regulates dsRNA accessibility to recognition by J2 and innate immune sensors.

      2) The authors show that FASN directly binds nuclear genome-encoded transcripts. It would be important to perform RNA-FISH for selected FASN-interacting RNAs to determine whether their cellular localization or J2-detectable signal is altered in FASN-depleted cells.

      3) In Figure 2B, the authors demonstrate enrichment of inflammation-related gene signatures in FASN knockout cells. However, the magnitude of induction is not clear. How does the inflammatory response compare with canonical innate immune activation, such as viral infection or poly(I:C) stimulation? Although Figure 2A partially addresses this point, many of the highlighted genes are not directly associated with inflammatory responses.

      4) For the transcripts directly associated with FASN, do they contain predicted dsRNA-forming regions or known structured RNA elements? The current data do not sufficiently demonstrate whether these transcripts indeed form dsRNA structures. Although some are enriched in J2 immunoprecipitation, additional structural analyses, including computational prediction of dsRNA regions, would strengthen the conclusion.

      5) The authors should further investigate whether the enhanced antiviral activity observed upon FASN depletion is mediated by elevated endogenous dsRNA sensing. Are dsRNA sensors such as PKR, MDA5, or RIG-I more strongly activated in FASN knockout cells? Do these sensors exhibit increased binding to endogenous dsRNAs following FASN depletion?

      Significance

      Main strength: Uncover the proviral role of FASN via regulation of endogenous dsRNAs

      Limitations: Molecular mechanism on how FASN depletion increases the accessibility of dsRNAs without affecting their expression. Also, need better characterization of FASN-binding RNAs, especially their secondary structure.

      PeerReviewed
    4. EMBOpress 31 Jul 2026

      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

      This manuscript identifies a potential connection between FASN, endogenous dsRNAs, and innate immune signaling. The authors show that FASN depletion increases cytoplasmic dsRNA staining, enhances IFN transcription and restricts Sindbis virus replication. Overall, the basic observation seems to be solid and well-controlled. Depending on which journal this is being considered for, the central mechanism could be better developed and elucidated to entail more molecular details. As it currently stands, several important questions, especially ones regarding the FASN-RNA interactions remain unresolved.

      Major comments

      1. The conclusion that FASN regulates dsRNA accessibility rather than dsRNA abundance requires further support. The authors show increased J2 staining without major changes in the global dsRNA landscape by J2-RIP-seq. However, alternative explanations could be: (1) changes in dsRNA structure or length distribution could affect J2 recognition, i.e. epitope masked by FASN binding; (2) differences in RNA-protein complex assembly could influence J2 accessibility; (3) Altered subcellular localization of dsRNAs could increase immunofluorescence signals without substantially affecting RIP-seq recovery.
      2. The nature of the FASN-RNA interaction remains unclear. The authors demonstrate that FASN associates with a subset of endogenous RNAs, but it is not clear whether this interaction is sequence-specific, structure-specific, or largely nonspecific. Are there common sequence motifs, secondary structures, repetitive elements, or specific transcript classes enriched among FASN-associated RNAs? Without a clearer understanding of RNA selectivity, it remains difficult to evaluate the biological significance of the observed interactions.
      3. The study would be significantly strengthened by complementation experiments. Although the FASN knockout phenotype is convincing, add-back experiments are needed to demonstrate specificity and probe potential mechanisms. Reconstitution with wild-type FASN should rescue the dsRNA and immune phenotypes. Furthermore, domain-specific mutants or catalytic mutants (e.g., palmitoylation) could help distinguish whether the observed effects depend on FASN enzymatic activity, a specific protein domain, or a non-canonical RNA-binding function. Such experiments would greatly improve the mechanistic depth of the study. It will also address whether the observed dsRNA increase phenotype is irreversible.
      4. The manuscript proposes that increased endogenous dsRNA sensing drives the inflammatory phenotype in FASN-deficient cells. However, direct evidence for enhanced PRR engagement is currently lacking. Although MDA5 and MAVS knockdown experiments suggest a possible contribution of this pathway, the observed knockdown effects are relatively modest and needs to be repeated by CRISPR knockout. Does FASN, MAVS double knockout cells rescue the slow growth phenotype? In addition, direct measurements of PRR activation, such as MDA5-RNA association, MAVS activation, IRF3 phosphorylation, or related downstream signaling events, were not examined.
      5. The antiviral phenotype observed during Sindbis virus infection is interesting, but the underlying mechanism remains uncertain. The authors propose that enhanced endogenous dsRNA sensing contributes to viral restriction, yet alternative explanations related to altered lipid metabolism, impaired membrane remodeling, or other consequences of FASN deficiency cannot be excluded. Especially when MDA5 and MAVS knockdown effect appears modest. Additional experiments disrupting interferon signaling or innate immune sensing pathways using the FASN, MAVS double knockout cells would help determine whether the antiviral phenotype is directly linked to the proposed dsRNA sensing mechanism.

      Significance

      This manuscript identifies a potential connection between FASN, endogenous dsRNAs, and innate immune signaling. The authors show that FASN depletion increases cytoplasmic dsRNA staining, enhances IFN transcription and restricts Sindbis virus replication. Overall, the basic observation seems to be solid and well-controlled. Depending on which journal this is being considered for, the central mechanism could be better developed and elucidated to entail more molecular details. As it currently stands, several important questions, especially ones regarding the FASN-RNA interactions remain unresolved.

      PeerReviewed
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  84. docs.python.org docs.python.org
    1. Whetting Your Appetite — Python 3.6.0 documentation
    1
    1. PedroSLeite 31 Jul 2026
      It is also a handy desk calculator.

      Devido ao facto de ser uma linguagem intepretada, é rápido realizar a sua execução, sendo uma boa calculadora por exemplo

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  85. www.biorxiv.org www.biorxiv.org
    Integrated genomics and transcriptomics reveal mechanisms of extreme dietary adaptation in vampire bats
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    1. rrlemur 31 Jul 2026

      Hi Mariella! I tried writing you directly on ResearchGate but it wouldn't let me.<br /> Anyway, very interesting study. Congratulations. I had a few questions. First, when were samples taken for pH and tissue transcriptomics with respect to feeding? I might expect we could see not just differences across species but over time with respect to a feeding event within an individual.

      Second, you seem to be characterizing the vampire stomach as an absorptive organ. But then I have to wonder, why does it exist? Why not simply reduce the stomach and let the blood meal go straight to the intestine? I mean, at least for water absoprtion, we showed that it was higher in the vampire intestine than the stomach. We suggested that the stomach served as a storage chamber for social food sharing (and gastric processing), but that while the bloodmeal was in this storage chamber, they might as well start doing some water absorption.

      I would think along similar lines for what you are showing here. There's reduced or no acidity, reduced pepsin (so, reduced to no traditional gastric processing), and improved absorption of some nutrients. But then couldn't the bloodmeal just go straight to the intestine for all that absorption? It seems to me that the increased absorption is more incidental than the primary function of the vampire stomach. Or is there perhaps some feature of the vampire stomach absorption that trades off with absorption in the intestine?

      Third: Any evidence of upregulated aquaporins in the intestine? You only noted upregulation in the stomach. I have been curious about this as a mechanism for intestinal water absorption across species with different dietary water loads.

      Again, great study, Cheers- Eddy Price

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  86. www.stemcell.com www.stemcell.com
    ICC Staining Epithelial Organoids
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  87. www.planalto.gov.br www.planalto.gov.br
    Del3689Compilado
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    1. Natashams 31 Jul 2026
      competência do juiz das garantias

      O STF decidiu, por unanimidade, atribuir interpretação conforme à primeira parte do caput do art. 3º-C do CPP, incluído pela Lei nº 13.964/2019, para esclarecer que as normas relativas ao juiz das garantias não se aplicam às seguintes situações: a) processos de competência originária dos tribunais, os quais são regidos pela Lei nº 8.038/1990; b) processos de competência do tribunal do júri; c) casos de violência doméstica e familiar; e d) infrações penais de menor potencial ofensivo;

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  88. www.goodreads.com www.goodreads.com
    A quote by Frank Lloyd Wright
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