DOI: 10.1007/s00429-026-03106-8

Resource: (Molecular Probes Cat# A-21202, RRID:AB_141607)

Curator: @scibot

SciCrunch record: RRID:AB_141607

What is this?

DOI: 10.1007/s00429-026-03106-8

Resource: (Thermo Fisher Scientific Cat# A10042, RRID:AB_2534017)

Curator: @scibot

SciCrunch record: RRID:AB_2534017

What is this?

DOI: 10.1007/s00429-026-03106-8

Resource: (Jackson ImmunoResearch Labs Cat# 705-546-147, RRID:AB_2340430)

Curator: @scibot

SciCrunch record: RRID:AB_2340430

What is this?

DOI: 10.1007/s00429-026-03106-8

Resource: (Thermo Fisher Scientific Cat# A-11057, RRID:AB_2534104)

Curator: @scibot

SciCrunch record: RRID:AB_2534104

What is this?

DOI: 10.1007/s00429-026-03106-8

Resource: (MP Bio Cat# 08780332, RRID:AB_2334928)

Curator: @scibot

SciCrunch record: RRID:AB_2334928

What is this?

DOI: 10.1007/s00429-026-03106-8

Resource: (Thermo Fisher Scientific Cat# A48255, RRID:AB_2890536)

Curator: @scibot

SciCrunch record: RRID:AB_2890536

What is this?

DOI: 10.1007/s00429-026-03106-8

Resource: (Cell Signaling Technology Cat# 7074, RRID:AB_2099233)

Curator: @scibot

SciCrunch record: RRID:AB_2099233

What is this?

DOI: 10.1007/s00429-026-03106-8

Resource: (Thermo Fisher Scientific Cat# ICN613561, RRID:AB_2334975)

Curator: @scibot

SciCrunch record: RRID:AB_2334975

What is this?

DOI: 10.1007/s00429-026-03106-8

Resource: (Thermo Fisher Scientific Cat# ICN634641, RRID:AB_2335006)

Curator: @scibot

SciCrunch record: RRID:AB_2335006

What is this?

DOI: 10.1007/s00429-026-03106-8

Resource: (Thermo Fisher Scientific Cat# NC0168237, RRID:AB_2334930)

Curator: @scibot

SciCrunch record: RRID:AB_2334930

What is this?

DOI: 10.1007/s00429-026-03106-8

Resource: (Vector Laboratories Cat# BA-1000, RRID:AB_2313606)

Curator: @scibot

SciCrunch record: RRID:AB_2313606

What is this?

DOI: 10.1007/s00429-026-03106-8

Resource: (Sigma-Aldrich Cat# A5441, RRID:AB_476744)

Curator: @scibot

SciCrunch record: RRID:AB_476744

What is this?

DOI: 10.1007/s00429-026-03106-8

Resource: (Cell Signaling Technology Cat# 7076, RRID:AB_330924)

Curator: @scibot

SciCrunch record: RRID:AB_330924

What is this?

DOI: 10.1007/s00429-026-03106-8

Resource: (Sigma-Aldrich Cat# A5060, RRID:AB_476738)

Curator: @scibot

SciCrunch record: RRID:AB_476738

What is this?

DOI: 10.1007/s00429-026-03106-8

Resource: (Actif SCETI Cat# PP-H7147-00, RRID:AB_1964214)

Curator: @scibot

SciCrunch record: RRID:AB_1964214

What is this?

DOI: 10.1007/s00429-026-03106-8

Resource: (Abcam Cat# ab16046, RRID:AB_2107107)

Curator: @scibot

SciCrunch record: RRID:AB_2107107

What is this?

DOI: 10.1007/s00429-026-03106-8

Resource: (Millipore Cat# MAB377, RRID:AB_2298772)

Curator: @scibot

SciCrunch record: RRID:AB_2298772

What is this?

DOI: 10.1007/s00429-026-03106-8

Resource: (Abcam Cat# ab18723, RRID:AB_732011)

Curator: @scibot

SciCrunch record: RRID:AB_732011

What is this?

DOI: 10.1007/s00429-026-03106-8

Resource: (Thermo Fisher Scientific Cat# 14-5698-82, RRID:AB_10854564)

Curator: @scibot

SciCrunch record: RRID:AB_10854564

What is this?

DOI: 10.1007/s00429-026-03106-8

Resource: (Santa Cruz Biotechnology Cat# sc-8066, RRID:AB_2088494)

Curator: @scibot

SciCrunch record: RRID:AB_2088494

What is this?

DOI: 10.1007/s00429-026-03106-8

Resource: (Santa Cruz Biotechnology Cat# sc-393324, RRID:AB_2737347)

Curator: @scibot

SciCrunch record: RRID:AB_2737347

What is this?

Traceback (most recent call last): File "/home/ubuntu/dashboard/py/create_release_tables.py", line 54, in format_anno_for_release parsedanno = HypothesisAnnotation(anno) File "/home/ubuntu/dashboard/py/hypothesis.py", line 192, in init t = row['document']['title'] TypeError: string indices must be integers

Traceback (most recent call last): File "/home/ubuntu/dashboard/py/create_release_tables.py", line 54, in format_anno_for_release parsedanno = HypothesisAnnotation(anno) File "/home/ubuntu/dashboard/py/hypothesis.py", line 192, in init t = row['document']['title'] TypeError: string indices must be integers

Traceback (most recent call last): File "/home/ubuntu/dashboard/py/create_release_tables.py", line 54, in format_anno_for_release parsedanno = HypothesisAnnotation(anno) File "/home/ubuntu/dashboard/py/hypothesis.py", line 192, in init t = row['document']['title'] TypeError: string indices must be integers

Traceback (most recent call last): File "/home/ubuntu/dashboard/py/create_release_tables.py", line 54, in format_anno_for_release parsedanno = HypothesisAnnotation(anno) File "/home/ubuntu/dashboard/py/hypothesis.py", line 192, in init t = row['document']['title'] TypeError: string indices must be integers

Traceback (most recent call last): File "/home/ubuntu/dashboard/py/create_release_tables.py", line 54, in format_anno_for_release parsedanno = HypothesisAnnotation(anno) File "/home/ubuntu/dashboard/py/hypothesis.py", line 192, in init t = row['document']['title'] TypeError: string indices must be integers

Traceback (most recent call last): File "/home/ubuntu/dashboard/py/create_release_tables.py", line 54, in format_anno_for_release parsedanno = HypothesisAnnotation(anno) File "/home/ubuntu/dashboard/py/hypothesis.py", line 192, in init t = row['document']['title'] TypeError: string indices must be integers

Traceback (most recent call last): File "/home/ubuntu/dashboard/py/create_release_tables.py", line 54, in format_anno_for_release parsedanno = HypothesisAnnotation(anno) File "/home/ubuntu/dashboard/py/hypothesis.py", line 192, in init t = row['document']['title'] TypeError: string indices must be integers

Traceback (most recent call last): File "/home/ubuntu/dashboard/py/create_release_tables.py", line 54, in format_anno_for_release parsedanno = HypothesisAnnotation(anno) File "/home/ubuntu/dashboard/py/hypothesis.py", line 192, in init t = row['document']['title'] TypeError: string indices must be integers

DOI: 10.1007/

Resource: (BioLegend Cat# 305118, RRID:AB_2566607)

Curator: @scibot

SciCrunch record: RRID:AB_2566607

What is this?

DOI: 10.1002/syn.70046

Resource: GraphPad Prism (RRID:SCR_002798)

Curator: @scibot

SciCrunch record: RRID:SCR_002798

What is this?

DOI: 10.1002/syn.70046

Resource: None

Curator: @scibot

SciCrunch record: RRID:AB_3097759

What is this?

DOI: 10.1002/syn.70046

Resource: (Millipore Cat# AB1506, RRID:AB_90710)

Curator: @scibot

SciCrunch record: RRID:AB_90710

What is this?

DOI: 10.1002/syn.70046

Resource: None

Curator: @areedewitt04

SciCrunch record: RRID:AB_90710

What is this?

DOI: 10.1002/syn.70046

Resource: None

Curator: @areedewitt04

SciCrunch record: RRID:AB_2113602

What is this?

DOI: 10.1002/syn.70046

Resource: None

Curator: @areedewitt04

SciCrunch record: RRID:AB_2113602

What is this?

DOI: 10.1002/jex2.70118

Resource: RRID:Addgene_41583

Curator: @scibot

SciCrunch record: RRID:Addgene_41583

What is this?

DOI: 10.1002/jex2.70118

Resource: (Bethyl Cat# A160-100P, RRID:AB_67107)

Curator: @scibot

SciCrunch record: RRID:AB_67107

What is this?

DOI: 10.1002/jex2.70118

Resource: None

Curator: @scibot

SciCrunch record: RRID:AB_3699318

What is this?

DOI: 10.1002/jex2.70118

Resource: (Roche Cat# 12013819001, RRID:AB_390917)

Curator: @scibot

SciCrunch record: RRID:AB_390917

What is this?

DOI: 10.1002/jex2.70118

Resource: (ATCC Cat# CRL-10852, RRID:CVCL_6974)

Curator: @scibot

SciCrunch record: RRID:CVCL_6974

What is this?

DOI: 10.1002/jcsm.70282

Resource: (RCB Cat# RCB0987, RRID:CVCL_0188)

Curator: @scibot

SciCrunch record: RRID:CVCL_0188

What is this?

DOI: 10.1002/cbic.202500972

Resource: (TKG Cat# TKG 0205, RRID:CVCL_0027)

Curator: @scibot

SciCrunch record: RRID:CVCL_0027

What is this?

DOI: 10.1002/alz.71334

Resource: None

Curator: @scibot

SciCrunch record: RRID:SCR_012499

What is this?

DOI: 10.1002/alz.71334

Resource: None

Curator: @scibot

SciCrunch record: RRID:SCR_023531

What is this?

DOI: 10.1002/aelm.202500689

Resource: Northwestern University Micro/Nano Fabrication Core Facility (RRID:SCR_017779)

Curator: @scibot

SciCrunch record: RRID:SCR_017779

What is this?

DOI: 10.1002/advs.202600010

Resource: (RRID:CVCL_0038)

Curator: @scibot

SciCrunch record: RRID:CVCL_0038

What is this?

DOI: 10.1002/advs.202600010

Resource: (ATCC Cat# CRL-3266, RRID:CVCL_6C21)

Curator: @scibot

SciCrunch record: RRID:CVCL_6C21

What is this?

DOI: 10.1002/advs.202524366

Resource: (RRID:CVCL_0006)

Curator: @scibot

SciCrunch record: RRID:CVCL_0006

What is this?

DOI: 10.1002/advs.202524337

Resource: Emory University Robert P. Apkarian Integrated Electron Microscopy Core Facility (RRID:SCR_023537)

Curator: @scibot

SciCrunch record: RRID:SCR_023537

What is this?

DOI: 10.1002/advs.202520109

Resource: (CLS Cat# 300168/p708_DU-145, RRID:CVCL_0105)

Curator: @scibot

SciCrunch record: RRID:CVCL_0105

What is this?

DOI: 10.1002/advs.202520109

Resource: (DSMZ Cat# ACC-256, RRID:CVCL_0395)

Curator: @scibot

SciCrunch record: RRID:CVCL_0395

What is this?

DOI: 10.1002/advs.202517369

Resource: (ATCC Cat# CL-173, RRID:CVCL_0123)

Curator: @scibot

SciCrunch record: RRID:CVCL_0123

What is this?

DOI: 10.1002/advs.202517369

Resource: (RRID:CVCL_GR23)

Curator: @scibot

SciCrunch record: RRID:CVCL_GR23

What is this?

DOI: 10.1002/advs.202517245

Resource: FastQC (RRID:SCR_014583)

Curator: @scibot

SciCrunch record: RRID:SCR_014583

What is this?

DOI: 10.1002/advs.202517245

Resource: (RRID:CVCL_B288)

Curator: @scibot

SciCrunch record: RRID:CVCL_B288

What is this?

DOI: 10.1002/advs.202517245

Resource: (RRID:CVCL_0063)

Curator: @scibot

SciCrunch record: RRID:CVCL_0063

What is this?

DOI: 10.1002/advs.202517245

Resource: RRID:Addgene_172284

Curator: @scibot

SciCrunch record: RRID:Addgene_172284

What is this?

DOI: 10.1002/advs.202517245

Resource: RRID:IMSR_JAX:000664

Curator: @scibot

SciCrunch record: RRID:IMSR_JAX:000664

What is this?

DOI: 10.1002/advs.202517245

Resource: Cytoscape (RRID:SCR_003032)

Curator: @scibot

SciCrunch record: RRID:SCR_003032

What is this?

DOI: 10.1002/advs.202517245

Resource: fastp (RRID:SCR_016962)

Curator: @scibot

SciCrunch record: RRID:SCR_016962

What is this?

DOI: 10.1002/advs.202517245

Resource: (RRID:CVCL_0291)

Curator: @scibot

SciCrunch record: RRID:CVCL_0291

What is this?

DOI: 10.1002/2211-5463.70245

Resource: (NCBI_Iran Cat# C621, RRID:CVCL_2106)

Curator: @scibot

SciCrunch record: RRID:CVCL_2106

What is this?

DOI: 10.1002/2211-5463.70245

Resource: (BCRC Cat# 60005, RRID:CVCL_0030)

Curator: @scibot

SciCrunch record: RRID:CVCL_0030

What is this?

DOI: 10.1002/2211-5463.70245

Resource: (DSMZ Cat# ACC-305, RRID:CVCL_0045)

Curator: @scibot

SciCrunch record: RRID:CVCL_0045

What is this?

DOI: 10.1002/2211-5463.70244

Resource: (DSMZ Cat# ACC-305, RRID:CVCL_0045)

Curator: @scibot

SciCrunch record: RRID:CVCL_0045

What is this?

DOI: 10.1136/jitc-2025-013507

Resource: None

Curator: @evieth

SciCrunch record: RRID:IMSR_JAX:004993

What is this?

DOI: 10.1136/jitc-2025-013507

Resource: None

Curator: @evieth

SciCrunch record: RRID:IMSR_CRL:027

What is this?

DOI: 10.1101/2025.07.16.663652

Resource: None

Curator: @dhovakimyan1

SciCrunch record: RRID:IMSR_JAX:000651

What is this?

DOI: 10.1101/2025.06.30.662293

Resource: None

Curator: @dhovakimyan1

SciCrunch record: RRID:Addgene_182307

What is this?

DOI: 10.1101/2025.06.30.662293

Resource: None

Curator: @dhovakimyan1

SciCrunch record: RRID:AB_571049

What is this?

DOI: 10.1101/2025.06.25.661480

Resource: None

Curator: @dhovakimyan1

SciCrunch record: RRID:IMSR_JAX:024714

What is this?

DOI: 10.1016/j.scr.2026.103984

Resource: None

Curator: @areedewitt04

SciCrunch record: RRID:AB_2645277

What is this?

DOI: 10.1016/j.molcel.2026.03.013

Resource: None

Curator: @areedewitt04

SciCrunch record: RRID:AB_1841064

What is this?

DOI: 10.1016/j.molcel.2026.03.013

Resource: None

Curator: @areedewitt04

SciCrunch record: RRID:AB_10545768

What is this?

DOI: 10.1016/j.jcmgh.2026.101782

Resource: None

Curator: @areedewitt04

SciCrunch record: RRID:AB_2943038

What is this?

DOI: 10.1016/j.isci.2026.115646

Resource: None

Curator: @areedewitt04

SciCrunch record: RRID:AB_2919886

What is this?

DOI: 10.1016/j.isci.2026.115627

Resource: None

Curator: @areedewitt04

SciCrunch record: RRID:AB_2112295

What is this?

DOI: 10.1016/j.isci.2026.115612

Resource: None

Curator: @areedewitt04

SciCrunch record: RRID:SCR_012763

What is this?

DOI: 10.1016/j.isci.2026.115612

Resource: None

Curator: @areedewitt04

SciCrunch record: RRID:SCR_001905

What is this?

DOI: 10.1016/j.isci.2026.115549

Resource: None

Curator: @areedewitt04

SciCrunch record: RRID:AB_778798

What is this?

DOI: 10.1016/j.isci.2026.115549

Resource: None

Curator: @areedewitt04

SciCrunch record: RRID:AB_2212642

What is this?

DOI: 10.1016/j.immuni.2026.03.011

Resource: None

Curator: @areedewitt04

SciCrunch record: RRID:IMSR_TAC:4234

What is this?

DOI: 10.1016/j.immuni.2026.03.011

Resource: None

Curator: @areedewitt04

SciCrunch record: RRID:AB_561284

What is this?

DOI: 10.1016/j.immuni.2026.02.005

Resource: None

Curator: @areedewitt04

SciCrunch record: RRID:AB_395938

What is this?

DOI: 10.1016/j.chembiol.2026.03.011

Resource: None

Curator: @areedewitt04

SciCrunch record: RRID:AB_2099233

What is this?

DOI: 10.1016/j.canlet.2026.218488

Resource: None

Curator: @areedewitt04

SciCrunch record: RRID:AB_2869082

What is this?

DOI: 10.1016/bs.mcb.2024.08.004

Resource: None

Curator: @evieth

SciCrunch record: RRID:AB_430834

What is this?

burn $5 for every $1

给你改一个更自然、学术一点的版本👇

⸻

Comment:

I find it interesting that platforms organized around minimal moderation can simultaneously foster creativity and amplify harmful behavior. This suggests that design choices around governance are not neutral, but actively shape the boundaries of acceptable discourse. It raises the question of whether “no rules” spaces inevitably reproduce certain forms of harm, rather than simply enabling free expression.

dweb.archive)

💻/asus/🧊/me/📓/2026/04/09/Premium：%20The%20Hater's%20Guide%20To%20The%20SaaSpocalypse%20(09_04_2026%2010：16：38).html

eLife Assessment

This valuable study aims to determine mechanisms underlying breast cancer initiation and tumour progression. The manuscript includes a solid set of transcriptomic and proteomic datasets from tumour samples and examines mitochondrial function within the tumours. While the underlying mechanisms linking expression changes to functional effects remain speculative. This paper provides a resource for researchers working on breast cancer and/or HER2-driven bioenergetics changes.

Reviewer #1 (Public review):

Summary:

In this manuscript, Frangos at al. used a transcriptomic and proteomic approach to characterise changes in HER2-driven mammary tumours compared to healthy mammary tissue in mice. They observed that mitochondrial genes, including OXPHOS regulators, were among the most down-regulated genes and proteins in their datasets. Surprisingly, these were associated with higher mitochondrial respiration, in response to a variety of carbon sources. In addition, there seems to be a reduction in mitochondrial fusion and an increase in fission in tumour tissues compared to healthy tissues.

Strengths:

The data are clearly presented and described.

The author reported very similar trends in proteomic and transcriptomic data. Such approaches are essential to have a better understanding of the changes in cancer cell metabolism associated with tumorigenesis.

The authors provided a direct link between HER2 inhibition and OXPHOS, strengthening the mechanistic aspect of the work.

Weaknesses:

The manuscript would have benefited from more ex-vivo approaches to further dissect mechanistic links and resolve the contradiction of elevated respiration with reduced expression of most associated proteins (but these points are clearly articulated in the discussion).

The results presented support the authors' conclusions, and limitations are addressed in the discussion. This work will likely impact the progression of the field, and the provided data will benefit the scientific community.

Comments on revisions:

The authors addressed all my concerns.

Reviewer #2 (Public review):

Frangos et al present a set of studies aiming to determine mechanisms underlying initiation and tumour progression. Overall, this work provides some useful datasets, further establishing mitochondrial dysfunction during the cellular transformation process.

A key strength is the coordinated analysis of transcriptomics and proteomics from tumour samples derived from a Neu-dependent mouse model for breast cancer. This analysis provides rigorous datasets that show robust patterns, including down-regulation across many components of mitochondrial OXPHOS that were generally consistent at both the mRNA and protein level. Parallel analysis of corresponding tumour samples thereby clearly shows the opposite trend of increased mitochondrial function, which is unexpected. As such, this work further establishes altered mitochondrial phenotypes in tumour contexts and further illustrates that mitochondrial function is not necessarily always tightly correlated with mitochondrial gene expression patterns.

Several key weaknesses remain. It remains unclear how increased mitochondrial function is being sustained despite wide decreases in mRNA and protein levels of OXPHOS components. In terms of mechanism, the study confirmed that pharmacologic EGFR inhibition decreases OXPHOS in a EGFR-dependent breast cancer line. However, it remains unclear if the cell culture system recapitulates other key observations of the tumour model (namely decreased expression with increased function).

Therefore, the mechanistic basis of increased mitochondrial function in light of decreased mitochondrial content remains speculative, as does the role of these changes for tumour initiation or progression.

Comments on revisions:

We agree with the overall findings of the study and appreciate that the claims in text and title have been appropriately toned down.

As additional suggestions eg for presentation, many of the graphics/labels are still too small to be useful. It would be interesting to see if this cell line is similar to the tumours in terms of all the phenotypes. The lapatinib experiment was good. I wonder how quick this drug affects the mitochondria. Also it would be interesting to see if these cells have higher OXPHOS than other non-transformed breast epithelial cells.

The WB on oxphos components is good with ab110413 but this looks like many subunits are detected so this should be made clear.

Author response:

The following is the authors’ response to the current reviews.

Reviewer #1 (Public review):

Comments on revisions: The authors addressed all my concerns.

We thank you for the positive review and feedback throughout the review process.

Reviewer #2 (Public review):

Comments on revisions: We agree with the overall findings of the study and appreciate that the claims in text and title have been appropriately toned down. As additional suggestions e.g. for presentation, many of the graphics/labels are still too small to be useful. It would be interesting to see if this cell line is similar to the tumours in terms of all the phenotypes. The lapatinib experiment was good. I wonder how quick this drug affects the mitochondria. Also it would be interesting to see if these cells have higher OXPHOS than other non-transformed breast epithelial cells. The WB on oxphos components is good with ab110413 but this looks like many subunits are detected so this should be made clear.

Thank you for these suggestions.

We have clarified in the Methods section (lines 475–476) the specific OXPHOS subunits detected using the Ab110413 antibody cocktail.

With respect to lapatinib, prior work has shown that lapatinib can alter the phosphoproteome within minutes to hours (PMID:22964224). In our experiments, however, NF639 cells were exposed to lapatinib for 24 hours - a timeframe in which transcriptional and translational remodeling are also expected to occur. Therefore, we cannot distinguish whether the observed suppression of OXPHOS reflects acute signaling effects or downstream changes in gene and protein abundance. Importantly, the purpose of this experiment was proof-of-principle: to determine whether HER2 signaling contributes to respiratory competency in a cell line derived from the same transgenic model as the intact tumor slices used in this study. Thus, while defining the precise kinetics of inhibition or comparing to benign/non-transformed cells would be interesting, these were not the primary objectives of the added experiments.

We have increased figure label sizes across all main figures.

The following is the authors’ response to the original reviews.

Public Reviews:

Reviewer #1 (Public review):

Summary:

In this manuscript, Frangos et al. used a transcriptomic and proteomic approach to characterise changes in HER2-driven mammary tumours compared to healthy mammary tissue in mice. They observed that mitochondrial genes, including OXPHOS regulators, were among the most down-regulated genes and proteins in their datasets. Surprisingly, these were associated with higher mitochondrial respiration, in response to a variety of carbon sources. In addition, there seems to be a reduction in mitochondrial fusion and an increase in fission in tumours compared to healthy tissues.

Strengths:

The data are clearly presented and described.

The author reported very similar trends in proteomic and transcriptomic data. Such approaches are essential to have a better understanding of the changes in cancer cell metabolism associated with tumourigenesis.

Weaknesses:

(1) This study, despite being a useful resource (assuming all the data will be publicly available and not only upon request) is mainly descriptive and correlative and lacks mechanistic links.

We appreciate this point. While the primary goal of our study was to assess mitochondrial adaptations with HER2-driven tumorigenesis, we agree strengthening the mechanistic interpretation would improve the impact of the data. To address this, we have provided experiments demonstrating HER2 inhibition in NF639 cells with lapatinib supresses respiratory capacity, directly supporting the interpretation that HER2 activity regulates respiratory function (Figure 10). We have expanded the discussion appropriately (lines 378-394). Both raw RNA-seq and proteomic data were deposited through GEO and the PRIDE repositories (accession numbers included in Data Availability Statement).

(2) It would be important to determine the cellular composition of the tumour and healthy tissue used. Do the changes described here apply to cancer cells only or do other cell types contribute to this?

We thank the reviewer for this suggestion; we have added experiments that have directly addressed this concern.

Cell type composition analysis by immunofluorescence was added (Figure 6) where we quantified epithelial, mesenchymal, endothelial, immune and stromal populations in our benign mammary tissue and tumor samples. We found no major shift in the dominant cell types that would confound transcriptomic data in whole tissues.

We integrated immunofluorescence data with a publicly available scRNA-seq dataset from human breast tumors which allowed us to estimate cell-type-specific expression of OXPHOS genes in our own samples. Despite the possibility of species differences, this is the only dataset of its kind, and we used this to generate an estimate of cell type weighted OXPHOS mRNA expression (Figure 6). This revealed that epithelial cells are likely the dominant contributors to OXPHOS gene expression for CIIV. All calculations are delineated in the Methods section.

(3) Are the changes in metabolic gene expression a consequence of HER2 signalling activation? Ex-vivo experiments could be performed to perturb this pathway and determine cause-effects.

Thank you for this suggestion – we have included an experiment directly testing this concept. We assessed mitochondrial respiration in NF639 HER2-driven mammary tumor epithelial cells in the presence or absence of the well-described dual tyrosine kinase inhibitor lapatinib. Lapatinib reduced basal, CI-linked and CI+II linked respiration without compromising mitochondrial integrity or coupling, demonstrating that HER2 activation regulates respiration in our model. This data is presented in Figure 10, and a new section has been added to the discussion describing the implications of this finding in the context of the current literature (lines 378-394).

(4) The data of fission/fusion seem quite preliminary and the gene/protein expression changes are not so clear cut to be a convincing explanation that this is the main reason for the increased mitochondria respiration in tumours.

We agree mitochondrial morphology and dynamics alone cannot fully account for the observed respiratory phenotype – this was emphasized in the discussion but has since been further clarified (lines 365-377). We retained the TEM and dynamics gene/protein data because they do support morphological differences consistent with enhanced fission. However, we have revised the tone of our interpretation to more explicitly acknowledge that these findings are correlative, and the updated discussion now emphasizes that the increased respiratory capacity in tumors is likely driven by multiple converging mechanisms.

Reviewer #2 (Public review):

Frangos et al present a set of studies aiming to determine mechanisms underlying initiation and tumour progression. Overall, this work provides some useful insights into the involvement of mitochondrial dysfunction during the cellular transformation process. This body of work could be improved in several possible directions to establish more mechanistic connections.

(5) The interesting point of the paper: the contrast between suppressed ETC components and activated OXPHOS function is perplexing and should be resolved. It is still unclear if activated mitochondrial function triggers gene down-regulation vs compensatory functional changes (as the title suggests). Have the authors considered reversing the HER2-derived signals e.g. with PI3K-AKT-MTOR or ERK inhibitors to potentially separate the expression vs. functional phenotypes? The root of the OXPHOS component down-regulation should also be traced further, e.g. by probing into levels of core mitochondrial biogenesis factors. Are transcript levels of factors encoded by mtDNA also decreased?

We appreciate this insight and agree that the discordance between mitochondrial content and function is fascinating and have addressed the concerns above in the following manner:

- We have altered the title – we agree we cannot definitively say that the enhanced respiratory capacity observed is compensatory.

- We have added experiments in NF639 cells in the presence of lapatinib, a tyrosine kinase inhibitor to interrogate whether HER2 is necessary for our functional outcome of interest – the enhanced respiratory capacity in the tumors. Lapatinib significantly suppressed respiration (Figure 10) demonstrating HER2 signaling directly regulates mitochondrial respiration.

- We have expanded the discussion to provide further comment on potential explanations for increased respiratory function and low mitochondrial content.

(6) The second interesting aspect of this study is the implication of mitochondrial activation in tumours, despite the downregulation of expression signatures, suggestive of a positive role for mitochondria in this tumour model. To address if this is correlative or causal, have the authors considered testing an OXPHOS inhibitor for suppression of tumorigenesis?

Previous studies have eloquently highlighted that directly or indirectly inhibiting mitochondria can supress growth in HER2-driven breast cancer (PMID:31690671) or alternatively, amplification of mt-HER2 enhances tumorigenesis (PMID: 38291340). In many solid tumors, this is the concept of preclinical and clinical studies using IACS-010759 or similar inhibitors of OXPHOS which do suppress growth but have significant off target effects in healthy tissues (PMID: 36658425, 3580228We have expanded the discussion to ensure the reader is aware of these previous contributions and highlighted the importance of future work delineating the role of enhanced respiratory function in HER2-driven mammary cancer (lines 378-394).

(7) A number of issues concerning animal/ tumour variability and further pathway dissection could be explored with in vitro approaches. Have the authors considered deriving tumourderived cell cultures, which could enable further confirmations, mechanistic drug studies and additional imaging approaches? Culture systems would allow alternative assessment of mitochondrial function such as Seahorse or flow cytometry (mitochondrial potential and ROS levels).

We thank the reviewer for this suggestion – we have addressed this in part by using the NF639 HER2driven tumor epithelial line which demonstrated that HER2 regulates our observed respiratory response. Unfortunately, the addition of tumor derived cell cultures was not feasible or within the scope of our study. Animal and tumor variability has been clarified in the Methods section (lines 424-429). Mitochondrial respiration experiments were performed in paired tissue (benign and tumor from same mouse). Transcriptomic, proteomic and histological analyses were performed on tumors and benign samples from different mice due to tissue limitations.

(8) The study could be greatly improved with further confirmatory studies, eg immunoblotting for mitochondrial components with parallel blots for phospho-signalling in the same samples. It would be interesting if trends could be maintained in tumour-derived cell cultures. It is notable that OXPHOS protein/transcript changes are more consistent (Figure 5, Supplementary Figure 4) than mitochondrial dynamics /mitophagy factors (Figure 8). Core regulatory factors in these pathways should be confirmed by conventional immunoblotting.

We thank the reviewer for this thoughtful comment. While we agree that additional confirmatory studies can be valuable, due to tissue quantity constraints and the number of assays required for our multi-omics analysis, extensive additional blots were not feasible. However, we had sufficient protein to provide select OXPHOS proteins to verify the proteomic data (now provided in S-Fig.4H). Furthermore, we have plotted the fold change of genes and proteins detected in both datasets and added this to Figure 4 (4A, B), further highlighting the consistency between our transcriptomic and proteomic findings. We believe that the highly consistent and concordant nature of our datasets collectively provides strong support for our central objective - determining whether mitochondrial content and respiratory function correlate in HER2-driven mammary tumors. The reproducibility of OXPHOS-related changes reinforces the robustness of our observations. We also appreciate the reviewer’s insight that OXPHOS alterations appear particularly consistent. In response, we have edited the discussion to further emphasize this point, especially in relation to the distinctive pattern observed for Complex V, which showed greater preservation relative to Complexes I–IV across several methods (lines 348-364). We comment on how this stoichiometric shift may contribute to intrinsic respiratory activation despite reduced mitochondrial content.

Recommendations for the authors:

Reviewer #2 (Recommendations for the authors):

Further Minor points.

(9) It would be helpful to know further details regarding the source of the tumour samples, particularly for the proteomics (N=5) and transcriptomics (N=6) datasets, since the exact timepoint of tissue harvest and number of tumours/mouse varied, according to the methods section. Were all samples from the omics studies from different mice (ie 11 mice)? B4 and B6 seem like outliers in mitochondrial transcriptomes. Are these directly paired eg with T4 and T6? Are the side-by-side pairs of Ben and Tum samples for blots in Figure 1 and Supplementary Figure 1 from the same mouse.

This has been clarified in the Methods section (lines 424-429). Mitochondrial respiration experiments were performed in paired tissue (benign and tumor from same mouse). Transcriptomic, proteomic and histological analyses were performed on tumors and benign samples from different mice due to tissue limitations.

(10) Further references and details are needed to support the methodology of the mitochondrial function tests (eg. nutrients vs pairing with complexes). What was the time point of nutrient supplementation? It would seem that the lipid substrates should take longer to activate OXPHOS than pyruvate/malate or succinate. Is this the case? Is there speculation as to why succinate supplementation is much more active than pyruvate+malate? What is +MD in Figure 6? The rationale for pooling data for Figure 7A is unclear since the categories appear to overlap: (pyruvate, malate, ADP) vs. (palmitoyl-carnitine, malate, ADP).

Thank you for this comment. We have expanded the methods (lines 515-531) to provide additional detail on the mitochondrial respiration protocol. Briefly, permeabilized tissues were exposed to substrates delivered at supraphysiological concentrations in a sequential protocol lasting ~30–60 minutes. Under these conditions, mitochondrial respiration reflects the maximal capacity to utilize each substrate rather than the physiological time course of substrate mobilization or uptake that would occur in vivo with the influence of blood flow and transport/substrate availability limitations.

(11) Many of the figures were blurry (Figure 1F, 2B) or had labels that were too small to be effective (Figures 1G, H, 2D-G, 3E-G, 5E-I, 7C, 8B).

The font size of figure labels has been increased where possible and all figures have been exported to maximize resolution.

I found it interesting how these design choices can shape not only how people use social media, but also how they behave on it. For example, whether messages are public or private can influence how honest or cautious people are when sharing their thoughts. Similarly, features like notifications that appear automatically might encourage people to check platforms more frequently, even when they did not originally intend to.

This makes me think that social media design is not neutral, but actively guides user behavior in subtle ways. Do you think platforms have a responsibility to consider the long-term effects of these design decisions on users’ habits and well-being?

This excerpt instantly brought to mind a behavior I recently noticed in the YouTube app. When I launch the app, YouTube Shorts immediately begin playing. I am not taken to see popular, recommended, or subscribed video feeds, a short plays instantly. I believe this feature is intended to lock users into infinite short form content scrolling upon opening the app. Personally, due to the addictiveness of short form content, I see this practice as unethical.

I didn't know that Amazon can also be considered social media:) It's actually interesting to know that a website/app only needs some features of a social platform to be categorized as social media. Given this, what are the preliminary factors that determine whether a web/app is social media or not since it's kind of vague when we decide which is and which is not?

From what I know about Virtue ethics, the values listed above are accurate but not sufficient since it hasn't touched on the aspect of community's flourishing. I believe that in order for a person to flourish, they have to also show their act of caring towards the others, in stead of only individual's flourishing.

这个是哪里的情况@Bold****

<< flip the web, document data container machine oriented approach

concept of data is machine oriented

separation content and presentation

is prioritizing the needs of the machine over human needs

Quite understandable in the olden days when machines were slow and small

flip - separation of content and presentation

Markdown allowed document creators to in ject formatting via keyboard

with its implicate structure needed for better faster comprehension

human's seek meaning and understanding

not data

document presentation is the master

presentation gives clues about significance, relevance interdependence of ideas

hypertext and links provides the means needed to follow interest and turn attentions

💻/asus/🧊/me/📓/2026/04/09

https://bafybeig4p2ux24is62s2qo4ocftrsw4plp22wfzlukntksp7nrkpfxfuwe.ipfs.dweb.link?filename=Hypothesis%20-%20DFOS%20(08_04_2026%2014%EF%BC%9A06%EF%BC%9A23).html

!4 - flip the Web

>> document as a data conatiner

dweb.archive

💻/asus/🧊/me/📓/2026/04/09/ separation%20of%20content%20and%20presentation%20-%20Brave%20Search%20(09_04_2026%2009：42：05).html

令人惊讶的是：我们常以为顶级安全公司依靠独家秘笈独步天下，但文章指出安全从来都是“团队运动”。几十年来，真正的防御者从不是在孤立中取得成功的，共享威胁情报才是生存法则。在AI时代，这种共享不仅没有减少，反而演变成了更深度的联盟行动。

令人惊讶的是：未来的网络安全防御者必须以“机器的速度”和“网络的规模”来运作。人类分析师的传统响应模式将彻底被淘汰，取而代之的是AI对抗AI的极速攻防战。安全防护的时间单位将从小时、分钟压缩到毫秒级别，这完全颠覆了传统的安全运营认知。

令人惊讶的是：Anthropic等公司的新型AI模型不仅仅是工具，它们直接触发了思科改变构建和保障产品的方式。这种由模型能力反向驱动工程流程重构的现象，说明AI已经不再是业务的附属品，而是正在成为定义行业基础设施形态的决定性力量。

令人惊讶的是：AI安全分析揭示的数据量之庞大、程度之深，已经彻底让传统的安全框架失效。过去几十年建立的安全防御体系，原本就不是为了处理这种维度的信息而设计的，这意味着整个网络安全行业可能需要被彻底重构，而不仅仅是简单的修补升级。

令人惊讶的是：文章披露了Anthropic尚未发布的全新AI模型“Claude Mythos Preview”的存在！思科已经在用这个未公开的模型对自己的产品进行压力测试，这不仅让我们首次窥见Anthropic下一代模型的命名，也说明顶级AI模型在发布前就已深度参与了全球网络防线的构建。

令人惊讶的是：思科在此低调地宣示了一个常被公众忽略的事实——他们实际上运营着支撑全球互联网运转的底层基础设施。这不仅是一家科技公司的商业版图，更意味着他们对全球数字世界的安全负有不可推卸的责任，这种基础设施级的垄断地位让人震撼。

令人惊讶的是：AI不仅是防御者的利器，更是黑客的“平民化”工具。它大幅降低了网络攻击的技术门槛，让原本不具备专业技能的人也能发动复杂且破坏力极强的攻击。这意味着未来的网络威胁不仅数量会激增，来源也将变得极其广泛且难以预测。

This reading helps me understand I am not the only one feeling this way. My college journey just stated and it of course will get easier. This tip is interesting to me because it's a nice reminder it'll all be OK. I learned to reference and come back to this resource when I have questions and may need to use some of the helpful links.

This sentence stands out to me a lot, I feel like it's directed towards me. This passage is saying it's going to get tough and you need to know where to go and who can assist you when you are struggling. I agree with this passage being a college student can get overwhelming. I am overwhelmed in my first week. Students need to be brave enough to say hey, I need help and it's important we need to know where to find it.

saco

大多数人认为强大的AI模型应该广泛普及以造福更多人。但作者明确表示不会公开发布这个最强大的模型，暗示了AI能力扩散可能带来的风险大于收益，这与技术民主化的主流观点相悖。

大多数人认为AI将增强防御能力，攻击与防御将同步提升。但作者预测未来将出现更多、更快、更复杂的攻击，这暗示了AI对攻击者的帮助可能大于对防御者的帮助，这是一个反直觉的观点。

大多数人认为开源社区有足够的安全能力和资源来维护关键基础设施。但作者明确指出开源维护者一直被单独应对安全问题，暗示了开源安全状况比普遍认为的要脆弱得多。

大多数人认为安全响应时间虽然缩短但仍有一定的缓冲期，让组织有时间应对新发现的漏洞。但作者认为AI已经将这个窗口从数月缩短到几分钟，这是一个根本性的转变，意味着传统的安全响应模式已经过时。

大多数人认为AI在安全领域仍处于辅助地位，需要人类专家的指导和监督。但作者认为AI已经超越几乎所有人类专家，能够自主发现和利用软件漏洞。这是一个颠覆性的观点，因为它挑战了人类在网络安全领域的传统主导地位。

This one feels more focused on a more traditional way of learning language. I can understand how that could help a little, but I think there is definitely a more efficient way to learn

This part made me think about how much the vibe of learning in more of a classroom setting is important. It’s not just about sitting there and taking in info on your own, because realistically not everyone is able to do that.

This feels like it’s setting up the main ways people understand learning. instead of there being just one “right” way to learn, there are different theories that explain it from different angles. It makes me think learning is more complex than it seems, and these are like the main perspectives to understand it.

Add the mandatory phone part here we discussed yeaterday

I like how this brings it back to real life. It kinda reminds me that we didnt learn language in a super formal way we just picked it up by being around it and using it. The example of Québec makes it feel relatable too like even just hearing a language in everyday situations can help you start learning without even trying that hard.

This made me snicker a little. In all reality it was completely unnecessary to say, but also so perfect!

the "American Dream" is a scam

more peopel need to be like this

People like this are few and far between but when you meet them it's healing

It's like a group mentality. When there's few in numbers, you can almost guarantee that there's less chance of things being wrong.

I disagree with this statement. You can be greatly disappointed in someone or something that you love deeply. Or at least I have been, but maybe that is just me

I have met so many people of many different faiths who believe this and it is not true. There needs to be a balance, just like with everything in life.

I like the way MLK said this. It is very true, too many people sit there in the comfort at safety of things staying just the way they are. Change is scary and so they do not accept it.

me too... me too

This is true wether you're truly oppressed or just think you are. Either way, if you crave freedom, it will manifest itself and there will be concequences (which can be good or bad)

Underwood is basically saying that just because topic modeling is useful doesn’t mean it should be the main way we analyze texts. I like how he points out that most research starts with a clear question, so we need tools that are more focused, like supervised models. It shows that digital tools aren’t one-size-fits-all.

This is significant because it shows that inequality is not always intentional but can still impact student success. It makes me think about how schools need to be proactive in evaluating their systems, especially for multilingual leaners who might otherwise be overlooked or placed at an advantage.

This is important because it shows how teachers can make their thinking visible, which helps students understand not just what to do but how to do it. I think this strategy is especially helpful for MLs because it supports both language and content learning a the same time.

These statements highlight how confidence and identity play a major role in learning, especially for multilingual learners. This reminds me of growth mindset because it focuses on effort rather than ability, and I think teachers can build this by creating inclusive environment where all students feel valued.

This idea is important because it shows that being a supportive teacher does not mean lowering expectations. I think this connects to real classrooms where students perform better when they feel both challenged and supported, but I wonder how teachers balance this with students who may need very different levels of support.

Based on the bulk rock composition, a certain mineral will crystallize before another based on the related binary phase diagram. If petrologists can see that one mineral crystallized before another, they can determine what side of the eutectic the bulk rock composition is on to cause the crystallization pattern observed.

As we learned in class, individual minerals have higher melting points than a combination of multiple minerals, which lowers the melting point of the system. The combination of Na2O+K2O, halogens, and Ca in the melt likely lowers the melting point to allow the temperature of the lava to be much lower than other lava compositions like basalts.

We learned in class that one way that the composition of magma can change during ascension is through assimilation of country rock, where the magma melts the surrounding rock and incorporates it into the melt. However, the expulsion of alkali-rich fluids blocks magma from entering fractures and incorporating the country rock.

Due to mantle under continents being fertile and enriched in incompatible elements. The lower percent of partial melting at the beginning of the formation of a parental melt will contain a higher concentration of incompatible elements that readily enter the melt, as they are incompatible with their source rock. As melting continues, compatible elements will dilute the concentration of incompatible elements.

Represented in binary phase diagrams by the solvus line, which the rock travels on after crystallization and minerals are altered because they can't continue to exist in the current configuration at certain temperatures and pressures.

This can be represented in P-T diagrams, where minerals can be stable only under certain pressure and temperature conditions, like olivine, but once they reach the surface and lower pressure, conditions are favored for transformations to other minerals or weathering occurs readily.

BĐS Tuấn 123 chuyên tư vấn đất đai

Possibly an example of replacement, especially in the case of Mg and Fe.

As melts crystallize in the crust, incompatible minerals like alkaline minerals will remain in the melt, which can move elsewhere, leaving a pluton to crystallize that is depleted in incompatible elements. Thus, plutonic carbonatites will be missing incompatible elements and fluid mobile elements that appear in the composition of erupted carbonatites.

Related to previous annotation, at continental rifts, mantle magma below is enriched in volatiles because it is fertile, so carbonatites can form in conjunction with alkaline magmas.

Dykes and veins are intrusions of magma that cross cut the layers that it goes through. Plugs are part of the volcanic plumbing system, where magma in the volcanic conduits solidifies before it can be erupted. Lavas are the result of magma being erupted from a volcano, usually in an effusive eruption from a shield or scoria cone. Pyroclastic falls occur as a result of explosive eruptions from a stratovolcano.

Igneous rocks are primarily classified on tertiary diagrams that record the percentage of the dominant minerals in the rock. Then the diagram is separated into rock classifications based on ranges of percentages of each mineral. In this case, such high percentages of carbonate minerals in an igneous rock classifies it as a carbonatite because this high percentage makes it distinct from other rocks with lower carbonate content.

Carbonatites can form as a result of nearby alkaline magmas because carbonatites and alkaline magmas are immiscible, that is they cannot mix like oil and water so carbonatite magma separates out. The formation of alkaline magmas is tied to mantle melt high in volatiles which make it evolve along a calc-alkaline trend, common in the fertile mantle under continental crust

This moment shows how Venus directly causes the whole story by making Cupid shoot Dis, proving how much the gods control human events.

This moment shows how powerful Perseus is because he proves the truth by turning Polydectes to stone instead of arguing.

This really got me wondering, why does eating the pomegranate force Persephone to stay in the underworld? I am wondering due to this what pomegranate symbolize and why does this have so much power?

This seemed significant to my eyes when I first read this because Persephone has been taken against her own will. This is now turning the whole meaning of the myth to something a lot darker and a very serious meaning behind it. This also got me thinking that myths cab feel things that real humans feel like not being able to be in control of certain situations or feeling separated from a loved one. These are feelings that us humans I feel like feel all the time so I thought it was interesting that these myths can connect to the same feelings. The other feeling that they can relate to is feeling sad since she "wept" as they went away, that is something real humans do very often.

I actually really liked what they were going for here how they were connecting myths to people today. I feel like even though the cultures are different, I feel like the ideas overall and the experiences are able to be related to one another.

I found this really interesting and unusual. It was strange that myths don't describe like real events, I guess is the best way to put it. Instead they represent more emotion and maybe beliefs. This got me thinking, if myths are not necessarily true, would this mean it could be true just in a much deeper meaning than the naked eye can see without thinking more into it?

The way I am interpreting this quote is that people are saying that they feel lost without myths. So I am thinking that we study other cultures to try and find meaning again. This got me thinking that myths are more important than just stories. I feel like they help people feel maybe more connected?

This is still the wrong way to do it. The right way to do it is to insulate your program from platform APIs entirely. It has the nice side benefit of making the code better, too.

stolen photos from Kleio Valentien (OF)

Probably scammer/fake account.

важность тарикатов

Similar to what the Palestinian social worker experience is.

Brabantio is saying, “Roderigo, I appreciate your effort, and I’ll repay you for the trouble you’ve taken.”

Roderigo is saying, “I’m coming to you honestly and with good intentions.”

Roderigo says Iago “hast had my purse as if the strings were thine,” which suggests Iago has been taking his money freely. What’s unclear to me is why Roderigo keeps trusting Iago financially even though he clearly feels used. Why doesn’t he break off the relationship if he already suspects Iago is exploiting him?

In short, the workbook given to students makes improper AI usage both "more difficult and less appealing". It allows for less stress via making procrastination less of a problem, and ensures the student using the workbook is invested in the content.

Good to know I did get the idea this journal is showing.

Once again, AI is best used as assistance when it is used, not as someone to do the work for you.

Required Annotation: In Cinthio’s tale, the Ensign’s wife is a quiet, almost background figure who spends her days with the Moor’s wife, but Shakespeare transforms her into Emilia, a character with moral force who ultimately exposes Iago’s plot. Shakespeare likely made this change to heighten the emotional and ethical stakes of the story, giving Desdemona an advocate who speaks truth when no one else will. By allowing Emilia to confront Iago and denounce his manipulation, Shakespeare shifts the meaning of the story toward silence showing how speaking out against wrongdoing becomes a form of resistance that Cinthio’s version never explores.

challenged me

personal connection

!!!!!!!!!!

Would hero still be looked up to and a powerful figure even if they had no imperfections? Ever human has imperfections, but if a hero had no imperfections would we still be able to relate?

I love when IRC gets brought up, because its an "old internet" system that I actually have experience using. I am 25 now, but around 2011-2013 I became interested in some online gaming communities that used IRC. In this context, it was used with a game mod or server plug-in that connected the game chat to an IRC server. Anyone on the IRC server could chat with in-game players, and in-game players could chat with the IRC users. I believe this was used so that community administrators would be able to monitor their server while on the go or working.

Doesnt seem author proposes this for humans.

Even if this vaccine was never replicated for humans, did they ever implement it at a wider level for swine populations to prevent spillover? seems relevant to what was discussed earlier.

This study was done primarily on pigs, and was the first report of its kind. Was it replicated for humans? If so what was the turnaround for Humans?

This is crazy fast to go from having a sequence to having hosts replicate a protein and prevent a virus from replicating. Definitely interesting to read about in comparison to the traditional egg methodology even if I didnt understand some of the jargon here. I would be curious to know in comparison the length of making the virus typically exactly.

Titers refer to virus concentration, so the virus was not detected essentially as time went on.