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    Importin α Characterizes a Micronuclear Environment Associated with Genomic Instability in Human Cancer Cells
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    1. EMBOpress 17 Oct 2025

      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

      Reviewer #1

      Summary:

      Miyamoto et al. report that importin α1 is highly enriched in a subfraction of micronuclei (about 40%), which exhibit defective nuclear envelopes and compromised accessibility of factors essential for the damage response associated with homologous recombination DNA repair. The authors suggest that the unequal localization and abnormal distribution of importin α1 within these micronuclei contribute to the genomic instability observed in cancer.

      Major comments:

      1.) It is crucial to quantitatively assess the localization of importin α1 in micronuclei (MN) across non-transformed MCM10A cells compared to transformed cell lines (MC7, HeLa, and MDA-MB-231). This analysis would help determine whether the localization of importin α1 in MN correlates with genomic stability in human cancer cells

      We appreciate the reviewer's thoughtful suggestion to compare non-transformed and transformed cell lines to evaluate importin α1 localization in MN. Given that HeLa cells are derived from cervical cancer rather than the mammary epithelium, we considered it inappropriate to directly compare them with non-transformed mammary epithelial MCF10A cells. Therefore, HeLa cells were analyzed separately to assess the effects of reversine treatment on importin α1 localization. The results indicated no significant difference between the treated and untreated HeLa cells. (Supplemental Fig. S2F in the revised manuscript). Regarding the comparison between MCF10A and the two cancer cell lines, MCF7 and MDA-MB-231, the proportion of importin α1-positive MN did not significantly differ across the cell lines, regardless of reversine treatment (Supplemental Fig. S3B, Untreated: p = 0.9850 and 0.5533; Reversine: p = 0.2218 and 0.9392). These results suggest that there is no clear difference in the localization of importin α1 in MN between the transformed and non-transformed cell lines tested. However, we acknowledge that this does not exclude the possibility that importin α1 localization to MN is linked to genomic instability under specific conditions.

      2.) While the authors provide some evidence indicating partial disruption of nuclear envelopes in MN (Figures 3 and S4), it is noteworthy that this phenomenon also occurs in importin α1-negative MN. Furthermore, according to the figure legends, the data presented in both figures stem from a single experiment. Current literature suggests that compromised nuclear envelope integrity is one of the major contributors to genomic instability, mediated through mechanisms such as chromothripsis and cGAS-STING-mediated inflammation arising from MN. Therefore, a more comprehensive quantification of nuclear envelope integrity-ideally comparing non-transformed MCM10A cells with transformed cell lines (MC7, HeLa, and MDA-MB-231)-is necessary to substantiate the connection between aberrant importin α1 behavior in MN and chromothripsis processes, as well as regulation of the cGAS-STING pathway linked to genomic instability in cancer cells.

      We thank the reviewer for the constructive suggestion to quantify nuclear envelope integrity more comprehensively. In response, we compared laminB1 localization at the MN membrane between importin α1-positive and -negative MN in MCF10A, MCF7, MDA-MB-231, and HeLa cells, and included these results in the revised manuscript (Fig. 4C). For each cell, the laminB1 intensity in the MN was normalized to that of the primary nucleus (PN). This analysis showed that laminB1 intensity was significantly lower in importin α1-positive MN across all cell lines, including non-transformed MCF10A cells. These findings support a close association between aberrant importin α1 accumulation and compromised nuclear envelope integrity, a key factor potentially linking MN to chromothripsis and cGAS-STING-mediated genomic instability.

      3.) The schematic illustration presented in Figure 8 does not adequately summarize all findings from this study nor does it clarify how the localization of importin α1 within MN might hypothetically influence genome stability. Although it is reasonable to propose that "importin α can serve as a molecular marker for characterizing the dynamics of MN" (Line 344), the authors assert (Line 325) that their findings, along with others, have "potential implications for the induction of chromothripsis processes and regulation of the cGAS-STING pathway in cancer cells." However, they fail to provide a clear or even hypothetical explanation regarding how their findings contribute to these molecular events. To address this gap, it would be essential for them to contextualize their results within existing literature that explores and links structural integrity deficits or aberrant DNA replication/damage responses in MN with chromothripsis and inflammation (e.g., PMID: 32601372; PMID: 32494070; PMID: 27918550; PMID: 28738408; PMID: 28759889).

      We agree that the previous schematic illustration (former Fig. 8) did not adequately summarize our findings and may have overstated our conclusions. Accordingly, we have removed this figure from the revised manuscript.

      To address the reviewer's concern, we performed additional analyses and included the results in the new Figure 8. These data show that, in addition to RAD51, both RPA2 and cGAS display mutually exclusive localization with importin α1 in MN. RPA2, a single-stranded DNA-binding protein, stabilizes damaged DNA and enables RAD51 filament assembly during homologous recombination repair. Previous studies have demonstrated that RPA2 accumulates in ruptured MN in a CHMP4B-dependent manner (PMID: 32601372). Likewise, cGAS is a cytosolic DNA sensor that localizes to ruptured MN and activates innate immune signaling through the cGAS-STING pathway, as widely reported (PMID: 28738408; 28759889; see also PMID: 32494070; 27918550).

      Our findings suggest an alternative scenario: even when nuclear envelope rupture occurs, importin α1-positive MN may remain inaccessible to DNA repair and sensing factors such as RPA2 and cGAS. This supports the view that importin α1 defines a distinct MN subset, separate from those characterized by the canonical DNA damage response or innate immune signaling factors. Furthermore, our overexpression experiments with EGFP-importin α1 (Fig. 7G, 7H) raises the possibility that importin α1 enrichment may impede the recruitment of DNA-binding proteins.

      Taken together, these results support the conclusion that importin α1 marks a unique MN state and provides a molecular framework for distinguishing between different MN environments. At the reviewer's suggestion, we have cited all the recommended references (PMID: 32601372, 32494070, 27918550, 28738408, and 28759889) in the revised manuscript to better contextualize our findings. We are grateful for the reviewer's thoughtful suggestions and literature recommendations, which helped us clarify the implications of our findings within the broader context of chromothripsis and cGAS-STING-mediated genomic instability.

      4.) Fig. 4D does not support the idea that importin α1 is euchromatin enriched: H3K9me3, H3K4me3 and H3K37me3 seem to be all deeply blue.

      We sincerely thank the reviewer for pointing out the important limitations of the original version of Fig. 4D, as also raised in minor comment #5. As the reviewer correctly noted, this figure was intended to demonstrate that importin-α1 preferentially localizes to euchromatin regions (H3K4me3 and H3K36me3) rather than heterochromatin (H3K9me3 and H3K27me3). However, we acknowledge that in the original figure, the predominantly blue tone of the heatmap made this interpretation unclear and that the Spearman's correlation coefficient for H3K36me3 was missing. In response, we have substantially revised the figure (now shown as Fig. 5E in the revised manuscript). Specifically, we improved the color scale for better visual distinction, added the missing Spearman's coefficients for H3K36me3, and strengthened the analysis by incorporating ChIP-seq data obtained with two independent antibodies against importin α1 (Ab1 and Ab2). We believe that these revisions provide a clear and more accurate representation of euchromatin enrichment of importin-α1, as originally intended.

      Indeed, the data presented by the authors do not adequately support a direct link between the presence of importin α1 in MN and genomic instability in human cancer cells. While the experimental correlations provided may not substantiate this connection definitively, they do lay a foundation for a grounded hypothesis and suggest the need for further research to explore this topic in greater depth. Additionally, it is worth noting that the evidence contributes to the growing list of nuclear proteins exhibiting abnormal behavior in micronuclei (MN). This highlights the significance of studying such proteins to understand their roles in genomic stability and cancer progression.

      Following the reviewer's suggestion, we carefully revised the manuscript to ensure that our statements are consistent with the scope of the data and do not overstate our conclusions. As part of this effort, we removed the schematic illustration (former Fig. 8), which might have overstated our findings, and refined the relevant text to prevent overinterpretation.

      To our knowledge, this study is the first to report the specific accumulation of importin α in MN. Our results suggest a previously unrecognized function of importin α beyond its canonical transport role and add to the growing list of nuclear proteins that exhibit abnormal behavior in MN. We hope that these findings will provide a conceptual and experimental basis for future studies aimed at clarifying the biological significance of MN heterogeneity and quality control in cancer biology.

      Additional experiments are necessary to quantitatively assess the localization of importin α1 in micronuclei (MN) across non-transformed MCM10A cells and transformed cell lines (MC7, HeLa, MDA-MB-231). This analysis would help determine whether the localization of importin α1 in MN correlates with genomic stability in human cancer cells.

      As part of our response to Major Comment 1, we conducted additional experiments to quantitatively compare importin α1 localization in MN between non-transformed MCF10A cells, breast cancer cell lines (MCF7 and MDA-MB-231), and HeLa cells. These results have been included in the revised manuscript (Supplemental Fig. S2F and Fig. S3B). The analyses showed no significant differences in the proportion of importin α1-positive MN among these cell lines, consistent with the reviewer's request for a more comprehensive evaluation.

      The authors claim that importin α1 preferentially localizes to euchromatic areas rather than heterochromatic regions within MN. While this assertion is supported by the immunofluorescence (IF) images presented in Figures 4A/B and S5A/B, it remains less clear for Figure S5C/B. To strengthen this claim, providing averages of IF distributions from multiple cells across independent experiments would be beneficial to draw more robust conclusions.

      We have quantified the co-localization of importin α1 with the euchromatin marker H3K4me3 and the heterochromatin marker H3K9me3 in micronuclei (MN) across four human cell lines (MCF10A, MCF7, MDA-MB-231, and HeLa). The results of this statistical analysis are included in the revised manuscript in Fig. 5C. These data provide quantitative evidence from independent experiments showing that importin α1 preferentially localizes to euchromatic regions within the MN, thereby supporting our initial observation.

      Furthermore, ChIP-seq data are presented to support the idea that importin α1 preferentially distributes over euchromatin areas in MN. However, as described, the epigenetic chromatin status indicated by these ChIP-seq experiments reflects that of the principal nucleus (PN), not specifically the status within MN in MCF7 cells. Given that MN represent only a small fraction of the cell population under normal culture conditions-likely less than 5% for HeLa cells as shown in Figure S2D-the relevance of this data is limited. Additionally, according to data presented in Figure 1B, importin α1 does not localize or distribute within the PN as it does in MN in MCF7 cells. Therefore, further experiments should be conducted to substantiate that importin α1 preferentially targets euchromatin areas within MN and to compare this distribution with that observed in the principal nucleus. Such studies could reveal potential abnormalities regarding the correlation between epigenetic chromatin status and importin α distribution in MN.

      As noted, these experiments were performed on whole-cell populations of MCF7 cells and therefore reflect the overall chromatin landscape, not specifically that of the MN. We fully acknowledge that MN constitute only a small fraction of the cell population under standard culture conditions (Supplemental Fig. S2D), and thus, the relevance of ChIP-seq data to MN must be interpreted with caution.

      Nevertheless, our intention in presenting these data was to illustrate that importin α1 preferentially associates with euchromatin regions marked by H3K4me3. To examine this more directly, we analyzed importin α1 localization in MN using immunofluorescence with histone modification markers across multiple cell lines. These analyses, together with the quantitative results now included in the revised manuscript (Fig. 5C), confirming that importin α1 preferentially localizes to euchromatic regions within MN.

      Taken together, although the ChIP-seq data were derived from whole-cell populations, the combined results from IF imaging and quantitative analysis support our interpretation that importin α1 retains its euchromatin-associating property within MN. We hope that these additional data will address the reviewer's concerns.

      To support the hypothesis that importin α1 inhibits RAD51 accessibility within MN, Figures 7D and E should be supplemented with thorough quantification and statistical analysis based on at least three independent experiments. This additional data would enhance confidence in their findings regarding RAD51 accessibility inhibition by importin α1.

      Following the reviewer's suggestion, we have added a new graph (Fig. 7F) in the revised manuscript. This figure presents the quantified frequency of RAD51-positive MN among importin α1-negative and importin α1-positive MN, analyzed across six microscopy fields (n = 6) from three independent experiments.

      To improve clarity and consistency, we reorganized the panels: representative RAD51 images are now shown in Fig. 7B, and the Cell #1 (low RAD51) vs. Cell #2 (high RAD51) classification with etoposide responsiveness is summarized in Fig. 7C. As illustrated in Figs. 7D and 7E, importin α1 and RAD51 exhibit mutually exclusive localization in MN. Fig. 7F provides a unified statistical summary at the population level.

      The results showed that the proportion of RAD51-positive MN was significantly lower among importin α1-positive MN than among importin α1-negative MN, providing robust quantitative support for the proposed mutual exclusivity between importin α1 localization and RAD51 accessibility in MN.

      We are grateful to the reviewer for this constructive suggestion, which helped us clarify and better support the central message of our study.

      The additional experiments proposed are controls and direct comparisons using the same techniques and experimental designs used by the authors, so it is reasonable that the authors can carry them out within a realistic timeframe.

      We appreciate the reviewer's thoughtful consideration of the feasibility of the additional experiments.

      Given the importance of reproducibility and the need to evaluate results based on imaging and quantitation, I strongly recommend that the authors include a detailed description of the optical microscopy procedures utilized in their study. This should encompass imaging conditions, acquisition settings, and the specific equipment used. Providing this information will enhance transparency and facilitate reproducibility. For reference, some valuable guidance on essential parameters for reproducibility can be found in Heddleston et al. (2021) (doi:10.1242/jcs.254144). Incorporating these details will not only strengthen the manuscript but also support other researchers in reproducing the findings accurately.

      Following the reviewer's suggestion, we have substantially revised the Materials and Methods sections in the main and supplemental manuscripts to provide detailed descriptions of the optical microscopy procedures, including the specifications of the imaging equipment, acquisition settings, and image processing parameters. These revisions follow the best practices recommended by Heddleston et al. (2021, J. Cell Sci., doi:10.1242/jcs.254144).

      We have also expanded the description of our quantitative image analysis using ImageJ, providing details on the parameters for MN identification and the measurement of colocalization rates between importin α and histone modifications. These additions ensured reproducibility and clarity.

      We believe that these modifications will enhance the reproducibility of our results and increase the value of our study for the research community. We sincerely appreciate the reviewer's helpful suggestions.

      Many of the plots and values in the manuscript lack appropriate statistical analysis, including p-values, which are not detailed in the figures or their legends. Furthermore, the Statistical Analysis section does not provide adequate information regarding the specific statistical tests employed or the criteria used to determine which analyses were applied in each case. To enhance the rigor and clarity of the study, it is essential that these issues be addressed prior to publication. A comprehensive presentation of statistical analysis will improve the reliability of the findings and allow readers to better understand the significance of the results. I recommend that the authors revise this section to include detailed explanations of all statistical methods used, along with corresponding p-values for all relevant comparisons.

      We sincerely appreciate the reviewer's constructive comments highlighting the importance of transparent and rigorous statistical analyses. In response, we have carefully revised all figure panels, figure legends, and the Materials and Methods (Statistical Analysis) section in both the main and the supplementary manuscripts.

      In the revised figure legends, we now provide the number of independent experiments and sample sizes (n), statistical tests applied (e.g., unpaired or paired two-tailed t-test, one-way ANOVA with Tukey's post-hoc test, two-way ANOVA with Sidak's multiple comparisons), data presentation format (mean {plus minus} SD), and corresponding p-values or significance indicators (*, **, ***). The Statistical Analysis section was also expanded to explain the rationale for selecting each statistical test, the criteria for significance, and the reporting of the replicates. These revisions ensure clarity, reproducibility, and transparency throughout the manuscript, directly addressing the reviewers' concerns. We are grateful for this valuable suggestion, which has significantly improved the rigor of our study.

      Minor comments:

      The authors claim that importin α1 exhibits remarkably low mobility in the micronuclei (MN) compared to its mobility in the principal nucleus (PN), as illustrated in Figure 1. However, based on the experimental design, this conclusion may not be appropriate. In the current setup, the FRAP experiment conducted in the PN measures the mobility of importin α1 molecules within the cell nucleus, where the influence of nuclear transport is likely negligible. Conversely, in the MN experiments shown, all molecules of importin α1 are bleached within a given MN. Consequently, what is being measured here primarily reflects the effects of nuclear transport rather than intrinsic molecular mobility. To accurately compare kinetics of nuclear transport, it would be essential to completely bleach the entire PN. If measuring molecular mobility between MN and PN is desired, only a small fraction of either MN or PN area/volume should be bleached during FRAP analysis. Additionally, it would be beneficial to include measurements of mobility for other canonical nuclear transport factors (e.g., RAN, CAS, RCC1) for comparative purposes. This broader context would allow for a more comprehensive understanding of importin α1 behavior relative to other factors involved in nuclear transport. Finally, utilizing cells that exhibit importin α1 signals in both PN and MN could further strengthen comparisons and provide more robust conclusions regarding its mobility dynamics.

      We thank the reviewer for their constructive suggestions regarding our FRAP analysis. To address the concern that the original comparison between PN and the micronuclei (MN) might have been biased by differences in bleaching areas, we performed new experiments in which both PN and MN were fully bleached within the same cells (Fig. 3A, and 3C). This approach allowed for a more direct comparison of importin α1 dynamics under equivalent conditions.

      These experiments revealed a markedly slower fluorescence recovery in MN than in PN, indicating reduced nuclear import and/or recycling efficiency of importin α1 in MN. In addition, we retained our original analysis to further characterize the heterogeneous mobility patterns of importin α1 in MN, identifying three distinct mobility classes: high, intermediate, and low (Fig. 3B, and 3D). Together, these results support our observation that importin α1 mobility is restricted in MN, likely due to altered nuclear transport dynamics.

      As suggested by the reviewer, we attempted partial bleaching of MN to assess intranuclear mobility. However, owing to the small size of MN, partial bleaching is technically challenging and inconsistent, with some MN recovering even during the bleaching process. Therefore, reliable quantification was not possible. For transparency, these data are provided as a Reviewer-only Figure but were not included in the revised manuscript.

      Finally, while we agree that examining other nuclear transport factors (e.g., RAN, CAS, RCC1) would be informative, our study focused on importin α1 dynamics. We consider these additional factors to be important directions for future investigations.

      Prior studies are referenced appropriately in general, but the authors missed some references (PMID: 32601372; PMID: 32494070; PMID: 27918550; PMID: 28738408; PMID: 28759889) that I consider key to put the present findings in frame with previous works which link the lack of structural integrity and/or aberrant DNA replication/damage responses in MN with Cchromothripsis and inflammation.

      We thank the reviewer for carefully pointing out the key references that are highly relevant to framing our findings in the context of previous studies on micronuclear instability, chromothripsis and inflammation. We fully agree with this suggestion.

      In the revised manuscript, we have cited these studies in both the Introduction and Discussion sections. Specifically, we incorporated these studies when discussing the structural fragility of MN, aberrant DNA replication, and the exposure of micronuclear DNA to cytoplasmic sensors, which mechanistically link MN rupture to chromothripsis and cGAS-STING-mediated immune activation. For example, we now refer to the study demonstrating RPA2 recruitment to ruptured MN in a CHMP4B-dependent manner (PMID: 32601372), reports showing defective replication and DNA damage responses in MN (PMID: 32494070; 27918550), and seminal studies establishing cGAS localization to ruptured MN and activation of innate immune signaling (PMID: 28738408; 28759889).

      By incorporating these references, we more clearly position our findings that importin α1 defines a distinct subset of MN lacking access to DNA repair and sensing factors such as RAD51, RPA2, and cGAS. This contextualization emphasizes that our data add to and extend the established view that compromised MN integrity underlies chromothripsis and inflammation by identifying importin α1 as a novel marker of an alternative MN microenvironment. We are grateful for this constructive recommendation, which has allowed us to strengthen the framing of our study in the existing literature.

      The figures presented in the manuscript are clear; however, where plots are included, they require appropriate statistical analysis. It is essential to display p-values on the plots or within their legends to provide readers with information regarding the significance of the results. Including this statistical information will enhance the interpretability of the data and strengthen the overall findings of the study. I recommend that the authors revise these sections accordingly before publication.

      In response, we have revised the relevant figure panels and their legends to clearly display the statistical significance, including p-values, where appropriate. Specifically, we added statistical annotations (p-values or significance markers such as asterisks) directly on the plots or in the corresponding legends, and clarified the number of replicates, statistical tests used, and definitions of error bars (mean {plus minus} SD). We believe that these revisions improve the interpretability and transparency of our results and strengthen the overall presentation of the data.

      __ 1.) In lines 134-135, it is stated that "up to 40% of the MN showed importin α1 accumulation under both standard culture conditions and the reversine treatment (Fig. S2F)." However, Figure S2F only displays percentages for reversine-treated cells, and there is no mention in the text or figures regarding the percentage of importin α1-positive MN determined by immunofluorescence (IF) under standard culture conditions. This discrepancy should be addressed.__

      Following the reviewer's comments, we revised Supplemental Fig. S2F shows a direct comparison of the proportion of importin α1-positive MN between untreated and reversine-treated HeLa cells based on indirect IF analysis. The Results section was updated accordingly (page 8, Lines 148-150): "We then examined whether reversine treatment affected the proportion of importin α1-positive MN. The results revealed that the MN formation rate for either untreated or treated cells was 36.2% {plus minus} 7.8 or 38.3% {plus minus} 8.8, respectively, with no significant difference (Fig. S2F). "

      We believe that this revision addresses the reviewer's concern by providing relevant quantitative data for the untreated condition.

      2.) In line 170, the authors state that "Cells in which overexpressed EGFP-importin α1 localized only in PN were excluded from the analysis (see Fig. 1E, top panels)." It is unclear why this exclusion was made. The authors should clarify whether they are referring to all constructs or only to the wild-type (WT) construct when mentioning EGFP-importin α1 localization solely in PN. This clarification is important as it may affect the results highlighted in line 173.

      In this section, we aimed to clarify that the quantitative analysis focused exclusively on cells harboring MN, as the purpose of the analysis was to compare the localization of EGFP-importin α1 between MN and PN. We excluded cells that contained no MN and showed EGFP-importin α1 localization only in the PN. This criterion was consistently applied to both wild-type and mutant constructs. To avoid confusion, we have removed the sentence "Cells in which overexpressed EGFP-importin α1 localized only in PN were excluded from the analysis (see Fig. 1E, top panels)." from the revised manuscript.

      3.) The statement in line 191 ("However, this antibody could not be further used in this context due to cross-reactivity with highly concentrated importin α1 in MN (Fig. S4)") is somewhat misleading. While it hints at a technical issue, it does not provide additional relevant information for understanding its implications for the rationale of the research. Moreover, Figure S4 is referenced but appears to refer specifically to panels S4D and E, which are not mentioned in the text. I recommend clarifying this point or removing it altogether.

      We agree with the reviewer that the statement "However, this antibody could not be further used in this context due to cross-reactivity with highly concentrated importin α1 in MN (Fig. S4)" was not essential for understanding the rationale of our study and could be misleading. In response, we have removed this sentence from the revised manuscript, along with the corresponding Supplementary Fig. S4.

      4.) Lines 197-199 contain a sentence that could be misleading and would benefit from clearer explanation. Although Figure 3D provides some clarity on this matter, no statistical analysis is included-only a bar plot is presented. A proper statistical analysis should be provided here to enhance understanding.

      In the revised manuscript, we performed one-way ANOVA followed by Holm-Sidak's multiple comparisons test to evaluate the MN localization ratio of EGFP-NES between Imp-α1-negative and Imp-α1-positive MN. This analysis revealed a statistically significant difference (**p

      5.) In lines 218-221, it states that importin α1 associates with euchromatin regions characterized by H3K4me3 and H3K36me3; however, Figure 4D lacks the Spearman's correlation coefficient value for H3K36me3 within the matrix. This omission needs correction.

      We thank the reviewer for this insightful comment. As addressed in response to Major comment #4, we have substantially revised Fig. 5 and added the missing Spearman's correlation coefficient value for H3K36me3 (now shown in Fig. 5E). These revisions, together with the overall improvements to the figure, more clearly illustrate the euchromatin enrichment of importin-α1.

      6.) For consistency in the experimental design aimed at identifying potential importin α1-interacting proteins, it would be more appropriate for Figures 5C/D to show IF data from MCF7 cells rather than HeLa cells.

      We sincerely apologize for the misstatements in the legends of the original Fig. 5C. The correct description is that this experiment was performed using MCF7 cells, and we have revised the legend accordingly in the revised manuscript (now Fig. 6C). In addition, because the original data in Fig. 5D were obtained from HeLa cells, we repeated this experiment using MCF7 cells and replaced the panel with new data (now Fig. 6D).

      7.) To substantiate claims that importin α1 inhibits RAD51 accessibility within MN, Figures 7D and E should include thorough quantitation and statistical analysis based on at least three independent experiments.

      As described above, we addressed this point by adding a new quantification and statistical analysis in Fig. 7F, based on six microscopy fields across three independent experiments. This analysis directly supports our claim that importin α1 inhibits RAD51 accessibility in the MN.

      We would also like to clarify that although the reviewer referred to Figs 7D and 7E, these two panels were designed to illustrate the same phenomenon-the mutually exclusive localization of importin α1 and RAD51 to distinct MN-shown in different contexts. Specifically, Fig. 7D presents examples from separate cells, each with MN containing either importin α1 or RAD51, while Fig. 7E shows a single cell containing two distinct MN, one enriched with importin α1 and the other with RAD51. Because both panels serve as illustrative examples of the same phenomenon, it would not be meaningful to quantify them independently as parallel datasets. Instead, we integrated the statistical analysis into a unified graph (Fig. 7F), which summarizes the frequency of RAD51-positive MN in relation to importin α1 status across the cell population, thereby supporting our interpretation that importin α1-positive MN represent a distinct subset that is less accessible to RAD51.

      8.) The meaning of lines 336-338-"Therefore, the enrichment of importin α1 in MN, along with its interaction with chromatin, may regulate the accessibility of RAD51 to DNA/chromatin fibers in MN and protect its activity"-is unclear. I suggest rephrasing this sentence for improved clarity and comprehension.

      We appreciate the reviewer's comment regarding the clarity of our statement in the Discussion (former lines 336-338). We agree that the original phrasing is ambiguous. To improve clarity and align with our results, we revised this section to emphasize that importin α1-positive MN represent a restricted environment from which DNA repair and sensing factors are excluded. Specifically, RAD51, RPA2, and cGAS showed mutually exclusive localization with importin α1, indicating that these MN are largely inaccessible to DNA-binding proteins (pages 20-21). This rephrasing removes the unclear phrase "protect its activity" and directly reflects our experimental findings, presenting a clearer interpretation that is consistent with the Results.

      9.) Fig. 1D: Numbers on the y-axis are missing, x-axis labeling is too small

      We appreciate the reviewer's careful examination of the figure. In the revised manuscript, we added numerical tick labels to both the x- and y-axes and increased the label font size to ensure clear readability, as shown in Fig. 1D. We also applied the same improvements to other fluorescence intensity plots, including Figs. 4A, 4B, 5A, 5B, 7H, and Supplemental Fig. S4C and S5A-S5F to ensure consistency in readability across the manuscript. We thank the reviewer for helping us improve the clarity and accuracy of our figure presentations.

      10.) Fig. 1F: As the PN/MN values of the three experiments are seemingly identical (third column) the distribution of the three individual data of the PN (first column) should mirror the distribution of the three individual data of the MN (second column). The authors might want to check why this is not the case.

      Upon re-examination of the source data, we identified and corrected a minor calculation error in one subset and regenerated the panel. After correction, the three independent PN/MN ratios were 3.1%, 2.9%, and 2.6%, rather than being identical. These corrected values were proportional to the corresponding PN and MN measurements and preserved the expected relationship between their distributions. Although the numerical differences were small, they demonstrated high reproducibility across independent experiments. These corrections do not alter the interpretation of Fig. 1F, and the distribution of PN/MN values is now consistent with the paired PN and MN data presented in the revised manuscript.

      Significance Micronuclei (MN) primarily arise from defects in mitotic progression and chromatin segregation, often associated with chromatin bridges and/or lagging chromosomes. MN frequently exhibit DNA replication defects and possess a rupture-prone nuclear envelope, which has been linked to genomic instability. The nuclear envelope of MN is notably deficient in crucial factors such as lamin B and nuclear pore complexes (NPCs). This deficiency may be attributed to the influence of microtubules and the gradient of Aurora B activity at the mitotic midzone, which inhibits the recruitment of proper nuclear envelope components. Additionally, several other factors may contribute to this process: for instance, PLK1 controls the assembly of NPC components onto lagging chromosomes; chromosome size and gene density positively correlate with the membrane stability of MN; and abnormal accumulation of the ESCRT complex on MN exacerbates DNA damage within these structures, triggering pro-inflammatory pathways.

      The work presented by Dr. Miyamoto and colleagues reveals the abnormal behavior of importin α1 in MN during interphase. According to their findings, it is reasonable to consider importin α1 as a molecular marker for characterizing MN dynamics. Furthermore, it could serve as a potential clinical marker if the authors provide additional experiments demonstrating significantly different localization patterns of importin α1 in transformed cells (e.g., MC7, HeLa, MDA-MB-231) compared to non-transformed cells (e.g., MCM10A).

      While the authors present some evidence indicating partial disruption of nuclear envelopes in MN (Figures 3 and S4), it is noteworthy that this phenomenon also occurs in importin α1-negative MN. Moreover, according to the figure legends, data for both figures originate from a single experiment. As such, convincing evidence linking the aberrant behavior of importin α1 in MN with chromothripsis processes or regulation of the cGAS-STING pathway-and its implications for genomic instability in cancer cells-remains lacking.

      Overall, it is not entirely clear what significance this advance holds for the field; while there are conceptual contributions made by this work, they do not appear sufficiently robust at this time. Further research is needed to clarify these connections and strengthen their conclusions regarding importin α1's role in MN dynamics and genomic instability.

      We sincerely appreciate the reviewer's thoughtful and constructive evaluation of the significance of our study. We agree that in the original submission, the conceptual contribution was not fully supported by sufficient evidence. In the revised manuscript, we have substantially strengthened our findings by incorporating new data on RPA2 and cGAS, in addition to RAD51. These results consistently show that importin α1-positive MN are largely inaccessible to multiple DNA-recognizing proteins-including DNA repair factors (RAD51 and RPA2) and the innate immune sensor cGAS-whereas importin α1-negative MN readily recruit these proteins. This broader dataset reinforces the concept that importin α defines a distinct and restricted MN subset, extending beyond our initial observation of RAD51 exclusion.

      By framing importin α as a molecular marker that discriminates between functionally distinct MN environments, our study conceptually advances the understanding of MN heterogeneity. This adds to the prior literature showing that defective nuclear envelope integrity underlies chromothripsis and cGAS-STING activation and positions importin α as a new marker for identifying MN that are refractory to these DNA repair and sensing pathways. While we agree that further work is necessary to directly link importin α enrichment to downstream genomic instability or inflammation in cancer, we believe that our revised data now provide a robust foundation for future investigations.

      Taken together, the revised manuscript presents a clearer and more comprehensive conceptual advance: importin α-positive MN represents a previously unrecognized molecular environment distinct from MN characterized by canonical DNA repair or sensing factors. We are grateful to the reviewer, whose constructive comments greatly improved the clarity, robustness, and overall impact of our study. We believe that these findings will be of particular interest to researchers studying the mechanisms of genomic instability, chromothripsis, and cancer biology.

      Reviewer #2

      Summary:

      The authors have shown that Importin α1, a nuclear transport factor, is enriched in subsets of micronuclei (MN) of cancer cells (MCF7 and HeLa) and, using FRAP, has an altered dynamics in MN. Moreover, the authors have shown that these levels of Importin α1 in the MN are likely not due to its traditional role for signal-dependent protein transport, as suggested by immunofluorescence of other factors important for this function. Additionally, cargo dynamics carrying NLS or NES signals were disrupted in Importin α1-positive micronuclei. Importin α1-positive micronuclei also appear to have a disrupted nuclear envelope, potentially explaining some of these cargo disruptions. The authors also demonstrated that Importin α colocalizes with proteins important for DNA replication, and p53 signaling using RIME, followed by immunofluorescence. Lastly, the authors show that Importin α and RAD51 have mutual exclusivity in the micronuclei.

      Major comments:

      1) A key issue is there are very few statistical tests used in this study. It is crucial to the interpretation of the data. We strongly urge the authors to re-analyze the data using appropriate statistical analyses. Along those lines, in many figures 1 or 2 images are shown without stating how many biological or technical replicates this is representative of or showing quantification of the anlyses. In general, the authors' statements would be strengthened by showing more examples and/or stating "N" in the figure legends or supplement.

      We sincerely thank the reviewer for emphasizing the importance of including sufficient statistical analyses and replication information. As noted in our response to Reviewer #1, we have carefully revised the manuscript to enhance statistical rigor and transparency throughout. Specifically, we expanded the Statistical Analysis section in the Materials and Methods section to provide a clear description of the statistical approaches used. In addition, all figure legends have been revised to explicitly state the number of biological replicates, sample sizes, statistical tests applied, and corresponding p-values or significance indicators. Representative images are consistently accompanied by quantitative analyses derived from multiple independent experiments.

      We believe that these comprehensive revisions directly address the reviewer's concerns and substantially improve the rigor, clarity, and interpretability of our manuscript.

      2) Using RIME and immunofluorescence, the authors identify factors that co-localize with Importin α1 in subsets of micronuclei (Figure 5), which is interesting, but there is no functional data associated with this result. Are the authors stating that these differences account for altered DNA damage or replication? It is unclear what the conclusion is beyond "some MN are different than others." Could the authors knockdown/knockout these factors to determine if they recruit Importin α1 into MN or the reciprocal? For many of these factors, they appear to be broadly present throughout the entire primary nucleus as well, indicating there is nothing unique about their MN localization.

      We agree that our original RIME and indirect IF analyses were primarily descriptive and lacked functional validation. To strengthen this aspect, we added new IF and quantification data (now presented in Fig. 8) showing that importin α1-positive MN are largely mutually exclusive with DNA repair and sensing factors such as RAD51, RPA2, and cGAS, whereas importin α1 frequently co-localizes with chromatin regulators identified by RIME, such as PARP1 and SUPT16H/FACT. These findings indicate that importin α1-positive MN define a distinct molecular environment enriched in replication- and chromatin-associated regulators but inaccessible to canonical DNA repair and sensing proteins.

      This combination of mutual exclusivity with DNA repair/sensing factors and frequent co-localization with chromatin regulators underscores the biological significance of importin α1 localization in MN, as it may contribute to localized chromatin stabilization through association with chromatin regulators while simultaneously restricting access to DNA repair and sensing factors. Thus, importin α1-positive MN represent a restricted subset with potential implications for genome stability and immune signaling, going beyond the descriptive notion that "some MN are different than others."

      Moreover, many chromatin regulators identified by RIME contain classical nuclear localization signals (NLSs), raising the possibility that importin α1 interacts with these proteins via their NLS sequences. We fully agree with the reviewer that knockdown or knockout experiments would be highly valuable to clarify whether such interactions actively recruit importin α1 into MN or occur reciprocally, and we regard this as an important direction for future investigations.

      3) In line 274, the authors state that MN highly enriched for Importin α1 inhibits RAD51 accessibility but this is an overstatement of the data. Instead, the authors show that RAD51 and importin α1 do not colocalize in micronuclei, albeit without quantification which weakens their argument. Also, the consequence of this "mutual exclusivity" is unclear. Can the authors inhibit or knockdown Importin α1 and show that RAD51 goes to all micronuclei? And how is this different than the data shown for factors in Figure 5? Some of those show colocalization with Importin α1-positive micronuclei and others do not. Could you perform live imaging of labeled Importin a1 and RAD51 and show that as Importin α1 accumulates in MN that RAD51 or other DNA repair factors are exported? An alternative experiment would be to show that the C-mutant, which is defective in nuclear export, now colocalizes with RAD51 in MN. Please reconcile this or show experiments to prove the statement above.

      We agree that our original wording "inhibits RAD51 accessibility" was not sufficiently supported by direct evidence, as it was based solely on the immunofluorescence data. Therefore, we have removed this statement from the Results section of the revised manuscript. To strengthen this point, we added a quantitative analysis (Fig. 7F) showing that RAD51 signals were significantly reduced in importin α1-enriched MN.

      Regarding the suggestion to perform knockdown experiments, we note that the depletion of KPNA2 (gene name of importin α1) has been reported to cause severe cell-cycle arrest (Martinez-Olivera et al, 2018; Wang et al, 2012). Consistent with these reports, we also found that siRNA-mediated knockdown of KPNA2 in our system strongly reduced MN induction upon reversine treatment, making it technically unfeasible to analyze RAD51 localization under these conditions. We also sincerely thank the reviewer for suggesting the live imaging experiments. We fully agree that such experiments would provide valuable mechanistic insights, and we regard this as an important direction for future research.

      In addition, to address the reviewer's concern about other DNA repair factors, we added new data (Fig. 8) showing that importin α1-positive MN are mutually exclusive with RPA2 and cGAS. RPA2 is a canonical single-strand DNA (ssDNA)-binding protein that stabilizes exposed ssDNA and facilitates RAD51 recruitment. It has been reported to accumulate in ruptured MN in a CHMP4B-dependent manner (Vietri et al, 2020). cGAS is a cytosolic DNA sensor that detects ruptured MN and activates innate immune signaling via the cGAS-STING pathway. Together with our RAD51 results, these data show that importin α1-positive MN are consistently segregated from multiple DNA-recognizing factors, including RAD51. Simultaneously, importin α1 co-localizes with chromatin regulators identified by RIME, such as PARP1 and SUPT16H/FACT. These findings support the view that importin α1-positive MN define a distinct molecular environment enriched in chromatin regulators but largely inaccessible to DNA repair and sensing factors. While the precise mechanism remains unclear, one possibility is that importin α1-associated chromatin interactions limit the access of DNA repair and sensing proteins. However, this interpretation is speculative and requires further investigation.

      4) In the Discussion, line 343-344 states that "importin α1 is uniquely distributed and alters the nuclear/chromatin status when enriched in MN," however this is not currently supported by the present data. The data presented shows correlation (albeit weak) between euchromatic modifications and Importin α1, and it does not definitively show that importin α1 is sufficient to alter the nuclear-chromatin status when enriched in the MN. More substantial experiments would be required to show whether Importin α1 plays an active role in these modifications.

      Following the reviewer's suggestion, in the revised manuscript, we removed this overstatement and rephrased the relevant sections of the Discussion. Rather than implying a causal role, we now describe the mutually exclusive localization of importin α1 with DNA repair and sensing factors (RAD51, RPA2, and cGAS), emphasize its preferential association with euchromatin regions marked by H3K4me3, and note its frequent co-localization with chromatin regulators identified by RIME, such as PARP1 and SUPT16H/FACT. These findings suggest that importin α1-positive MN define a distinct subset characterized by limited accessibility to DNA repair and sensing proteins, whereas cGAS-positive ruptured MN exemplify a state in which these proteins can accumulate.

      We also added a concluding statement that frames importin α1 as defining a previously unrecognized MN subset that is distinct from conventional ruptured MN. This revision provides a more accurate and appropriately cautious interpretation of our data while underscoring the conceptual advance of our study by clarifying how importin α1 localization reveals MN heterogeneity.

      Minor Comments

      1) Summary statement (page 3 Line 40): The use of "their" is confusing. Whose microenvironment are you referring to?

      We have rephrased the sentence as follows: The accumulation of importin α in micronuclei, followed by modulation of the microenvironment of the micronuclei, suggests the non-canonical function of importin α in genomic instability and cancer development. Thank you for this useful suggestion.

      2) In Abstract and introduction (page 4, Line 44 and page 5, line 59) it states that MN are membrane enclosed structures, but this is not always the case (see https://doi.org/10.1038/nature23449 as one example).

      While MN are typically surrounded by a nuclear envelope at the time of their formation during mitosis, we agree that this envelope can later rupture or fail to assemble completely, thereby exposing micronuclear DNA to the cytoplasm. To clarify this point, we revised the Introduction to explicitly acknowledge that MN may lose nuclear envelope integrity, which can have important consequences for genomic instability and immune activation inflammation. Specifically, we have added the following sentence to the Introduction (page 4, lines 77-80): "The nuclear envelope of MN can be partially or completely disrupted, allowing cytoplasmic DNA sensors, such as cyclic GMP-AMP synthase (cGAS), to access micronuclear DNA and trigger innate immune responses via the cGAS-STING pathway (Harding et al, 2017; Li & Chen, 2018; Mackenzie et al, 2017). "

      We hope this addition appropriately addresses the concerns raised by Reviewer #2 while incorporating the valuable suggestions from Reviewer #1 without altering the overall structure and flow of the manuscript.

      3) Given the fact that the RIME result identified proteins involved in DNA replication to be enriched with Importin α1, are these MN enriched in factors described in Fig. 5 simply localizing to MN that are in S phase, as described previously (doi: 10.1038/nature10802)?

      We sincerely thank the reviewer for raising this constructive perspective regarding the potential relationship between importin α1 enrichment in micronuclei (MN) and the S phase. Our RIME analysis identified chromatin-associated proteins, such as PARP1 and SUPT16H/FACT, which are often activated during replication stress and frequently function in the S phase. However, importin α1-positive MN were not exclusively associated with S-phase-specific molecules, and our data do not indicate that these MN are restricted to the S phase.

      Previous studies [e.g., (Crasta et al, 2012)] have established that MN are prone to replication defects and represent hotspots of genomic instability. The recovery of replication stress-responsive molecules, such as PARP1 and FACT, by RIME is therefore consistent with the biology of MN. Based on this valuable suggestion, we have revised the Discussion (page 19) to explicitly mention the potential involvement of replication-related proteins in importin α1-positive MN, as well as the possibility that importin α1 accumulation may contribute to replication defects in these structures. We are grateful to the reviewer for raising this important perspective, which has enabled us to place our findings in a broader mechanistic context.

      We are grateful to the reviewer for this important comment, which has allowed us to place our findings in a broader mechanistic context and outline directions for future research, including testing the relationship between importin α1-positive MN and established S-phase markers such as PCNA.

      4) The FRAP data is not very compelling. While it is clear there are differences between the PN and MN dynamics, what is driving these differences? Are these differences meaningful to the biology of the MN or PN? It is unclear what this data is contributing to the conclusions of the paper. Also, if the mobility of the MN is plotted on the same graph as the PN, the differences in MN mobility might not look as compelling.

      We respectfully emphasize that FRAP analysis is a key component of our study, as it provides important insights into the distinct dynamics of importin α1 in MN compared to PN.

      In the revised manuscript, we included new experiments (now shown in Fig. 3A and 3C) that directly compare the recovery kinetics of importin α1 in PN and MN in the same cells. By plotting the PN and MN recovery curves side by side, we aimed to improve clarity and provide a direct visualization of the pronounced differences in importin α1 dynamics between these compartments.

      Our FRAP results showed that importin α1 accumulated in both PN and MN but exhibited markedly reduced mobility in MN. These findings suggest that, unlike in the PN, canonical nucleocytoplasmic recycling of importin α1 is impaired in MN. Furthermore, the reduced mobility indicates that importin α1 is stably associated with chromatin or chromatin-associated factors in MN, consistent with our additional biochemical and imaging data showing preferential association with euchromatin (e.g., H3K4me3) and chromatin regulators.

      Taken together, the FRAP data provide functional evidence that complements our structural and molecular analyses, supporting our central conclusion that importin α1 accumulation in MN defines a restricted chromatin environment that influences the accessibility of DNA repair and sensing factors.

      5) In Results (line 117), you state that "the cytoplasm of those cell lines emitted quite strong signals" for Importin α1, but that phrasing is a little confusing. Yes, Importin α1 is in present the cytoplasm in most cells, but it appears you are referring to the enrichment in MN. I would recommend re-phrasing this statement to make your intent clearer.

      As the reviewer rightly noted, the original phrasing, "the cytoplasm of those cell lines emitted quite strong signals," was misleading, as it could suggest a broad cytoplasmic distribution of importin α1. Our observations showed that importin α1 accumulated specifically in MN located within the cytoplasm, but not in the cytoplasmic regions. To clarify this, we revised the Results section (page 7, lines 125-127) to read: " Next, we performed indirect immunofluorescence (IF) analysis on human cancer cell lines, including MCF7 and HeLa cells. Notably, we found that importin α1 accumulated prominently in MN located within the cytoplasm (MCF7 cells, Fig. 1B; HeLa cells, Fig. 1C; yellow arrowhead). " .

      We believe that this revised wording more accurately reflects our findings and addresses the reviewer's concerns.

      6) In Results (line 135, Figure S2E,F), the ratio of high, low or no Importin α1 intensity is confusing. Is this percentage relative to the total number of MN? It Is unclear what is meant by "whole number" of MN. Is Importin α1 intensity quantified or is it subjective?

      We apologize for the confusing terminology used in the original manuscript for Supplemental Fig. S2 and thank the reviewer for pointing it out. Although the reviewer did not specifically comment on the classification of importin α1 signal intensity as "high" or "low," we recognized that this approach relied on subjective visual assessment and lacked clearly defined thresholds. To improve clarity and objectivity, we have removed this classification and now analyze importin α1 localization in MN as simply positive or negative (revised Supplemental Fig. S2E). The previous graph (original Fig. S2F) was deleted. In addition, the frequency of Importin α1-positive MN has been reported in the Results section of the main text (page 8). We believe that these revisions have improved the clarity and reproducibility of our data presentation.

      7) Figure 2C is confusing. Are you counting MN with co-localization of Importin α1 and these factors? Please clarify.

      Figure 2C shows the percentage of importin α1-positive MN that displayed localization of importin β1, CAS, or Ran based on IF analysis. In other words, it represents the co-localization rates of these transport factors specifically within the subset of MN positive for importin α1. To improve clarity, we revised the y-axis label in Fig. 2C to "Localization in Impα1-positive MN (%)" and modified the figure legend accordingly. We have clarified this point in the Results section (page 9). We believe that these revisions resolve the confusion and clarify the scope of the analysis.

      8) Figure S3D quantification is very confusing and unclear. Also, how is this normalized? Are you controlling for total signal in each cell? And can the results of this experiment give you any mechanistic insight as to what is regulating MN localization beyond the interpretation of "MN localization is distinct from PN localization"? The "C-mutant" appears quite a bit different than the others. What might that indicate about the role of CAS/CSE1L in MN enrichment?

      We apologize for the confusion caused by the quantification in the Supplemental Fig. S3D (now revised as Fig. S4D). This figure shows the relative enrichment of EGFP-importin α1 in MN compared with that in PN for wild-type and mutant constructs. To control for nuclear size, fluorescence intensity was measured using a fixed circular ROI (1.5-2.0 µm in diameter) placed in both the MN and PN of the same cell, and MN/PN intensity ratios were directly plotted for individual cells (n = 8 per condition). This procedure is described in detail in the Results section (page 10).

      Regarding the C-mutant, the reduced MN/PN ratio primarily reflects increased importin α1 accumulation in the PN rather than a reduced retention in the MN. As discussed in the revised manuscript (page 18), this suggests that CAS/CSE1L-mediated nuclear export is active in the PN but may be impaired or uncoupled in the MN, possibly due to differences in nuclear envelope integrity or chromatin context. We believe that this clarification addresses the reviewer's concerns and highlights the mechanistic implications of the C-mutant phenotype.

      9) For Figures 3A,B and S4, are these images of single z-slices or projections? It would be helpful to clarify for your interpretations as to whether they are truly partial or diffuse or the membrane is in another z-plane. Also, how does the localization of Importin α1 different or similar to other factors that localize to MN with a compromised nuclear envelope, such as cGAS? If it is based on epigenetic marks, it should be different than cGAS, which primarily binds non-chromatinized DNA.

      We thank the reviewer for this valuable suggestion. All images shown in Figs 3A, 3B, and S4 in the original manuscript (now revised as Fig. 4A and 4B, with the original Fig. S4 omitted) were derived from single optical sections rather than projections. We would like to emphasize that similar discontinuities in signals for lamin proteins (including laminB1 and laminA/C) were consistently observed across multiple cells and independent experiments, indicating that these observations are not due to an artifact of image acquisition or a missing z-plane, but rather reflect a genuine partial loss of the MN membrane.

      In contrast to cGAS, which predominantly binds non-chromatinized DNA in ruptured MN, our data indicate that importin α1 preferentially localizes to MN regions enriched in euchromatin-associated histone modifications, such as H3K4me3. The new data presented in Fig. 8 further strengthen this point by directly comparing importin α1 with DNA-recognizing proteins such as cGAS and RPA2, which preferentially localize to MN lacking importin α1. Together, these results highlight that importin α1-positive MN constitute a distinct subset characterized by chromatin-associated localization and reduced accessibility to DNA repair and sensing proteins.

      10) In Results, it is unclear how Fig. 7B was calculated. Are the authors qualitatively assessing if RAD51 is there or looking for MN enrichment relative to PN? Additionally, in Fig. 7C, RAD51 localization is diffuse. It should be enriched in foci. I would recommend the authors repeat this experiment using pre-extraction then quantify RAD51 foci number and/or intensity.

      For the quantification shown in Fig. 7B of the original manuscript, we acquired images containing approximately 15-50 cells per condition and counted all the micronuclei (MN) in those fields. The percentage of RAD51-positive MN relative to the total MN was calculated. In the revised manuscript, we further refined this analysis by classifying RAD51-positive MN into two categories based on signal intensity: weak (Cell #1 type) and strong (Cell #2 type). For each condition, nine independent fields were analyzed (302 MN in untreated cells and 213 MN in etoposide-treated cells). This quantification revealed that etoposide treatment preferentially increased the proportion of MN with strong RAD51 accumulation (Fig. 7C, right panels), indicating enhanced DNA damage in MN. Thus, our analysis was quantitative rather than qualitative, based on systematic counting across multiple fields.

      Regarding the reviewer's suggestion of pre-extraction, we believe that this approach is technically difficult because MN are structurally fragile. Importantly, in the subset of MN with strong RAD51 accumulation, RAD51 was clearly present in foci rather than diffuse signals, as shown in the high-magnification images (Fig. 7E).

      Finally, in response to Reviewer #1, we performed a new quantitative analysis (Fig. 7F) focusing on the frequency of strongly RAD51-positive MN in relation to importin α1 status. This analysis confirmed the mutually exclusive relationship between RAD51 and importin α1 in MN and further strengthened our conclusions.

      11) In line 264, "notably" is misspelled.

      Thank you for pointing this out. We have corrected the spelling.

      12) In line 303, "scenarios" should be changed to the singular form.

      Thank you for this confirmation. We have corrected this to "scenario".

      13) In Figure legend, line 571-582, H3K27me3 is shown in Figure 4D, but the written legend does not mention this mark.

      We have added the marks in the legend for Fig. 5E.

      Significance: Overall, this paper shows compelling evidence for micronuclear localization of regulators of nuclear export, notably Importin α1. Of note, this occurs in subsets of MN that lack an intact nuclear envelope. And while it has been appreciated that compromised micronuclear envelopes lead to genomic instability, this is one of the first that demonstrate alteration in the nuclear envelope may disrupt import or export of nuclear proteins into micronuclei.

      A limitation of the study is that much of the work is based on immunofluorescence and lacks mechanism. While there is much correlative data showing that Importin α1 localizes to micronuclei with compromised envelopes, it is unclear whether Importin α1 drives micronuclear collapse or it is downstream of this process. Additionally, Importin α1 micronuclear localization anti-correlates with RAD51 but does colocalize with other DNA replication factors, yet it is unclear whether their localization is dependent on Importin α1 or its role in nuclear export. Currently, the audience for this manuscript would be focused to those interested in micronuclei. If these concerns about an active role for Importin α1 in micronuclear export are resolved, it would greatly increase the impact of this manuscript to those interested more broadly in genomic instability, DNA repair, and cancer.

      We thank the reviewer for positively evaluating our study and highlighting the importance of defining the biological significance of our findings. In the revised manuscript, we incorporated new data (Fig. 8) demonstrating that importin α1-positive MN are mutually exclusive not only with RAD51 but also with RPA2 and cGAS. These results clearly establish importin α1-positive MN as a distinct subset, defined by the enrichment of chromatin-associated proteins, while being largely inaccessible to canonical DNA repair and DNA-sensing factors.

      Consistent with this, our FRAP experiments and analysis of the CAS/CSE1L-binding mutant (C-mut) further indicated that the recycling dynamics of importin α1 were altered in MN compared to PN. In addition, importin α1 was enriched in lamin-deficient areas of MN, where electron microscopy revealed a fragile nuclear envelope morphology. Together with prior evidence, as discussed in the revised manuscript that recombinant importin α can inhibit nuclear envelope assembly in Xenopus egg extracts (Hachet et al, 2004), these findings raise the possibility that high local concentrations of importin α1 may actively contribute to impaired nuclear envelope formation or stability in MN.

      Such a distinct MN state may have important biological consequences. By limiting the access of DNA repair and DNA-sensing proteins, importin α1 accumulation may influence chromothripsis and immune activation, which, in turn, could play a role in tumor progression and genome instability. We believe that the identification of importin α1 as a marker defining such a restricted MN environment represents a conceptual advance that extends the relevance of our study beyond the MN field to the broader areas of genome instability, DNA repair, and cancer biology. We are grateful to the reviewer for encouraging us to strengthen the framing of our work, which has helped us clarify the novelty and impact of our findings.

      Reviewer #3

      Summary:

      This study reports that importin alpha isoforms enrich strongly in a subset of micronuclei in cancer cells and uses mutagenesis and immunostaining to define how this localization relates to importin alpha's nuclear transport function. This enrichment occurs even though importin-alpha-positive micronuclei also contain Ran and the importin alpha export factor CSE1L, indicating that importin a enrichment is not simply a consequence of the absence of components of the nuclear transport machinery that control its localization. Mutagenesis of importin a indicates that Mn enrichment persists even when the importin beta binding and NLS binding capacities of imp a are impaired. Potential importin alpha interacting proteins are identified by proteomics, although the relationship of these potential binding partners to micronucleus localization is unclear.

      1. In Figure S3, the authors show that mutagenesis of importin alpha's CSE1L binding domain decreases the ratiometric enrichment in Mn vs. Pn. However, is this effect occurring because th CSE1L binding mutant decreases Mn enrichment, or increases Pn enrichment? It seems that the latter is possible based on the images shown. If the Pn specifically becomes brighter on average in cells expressing the C-mut, while Mn remain similar in fluorescence intensity, that might suggest that CSE1L has less of an effect on importin alpha export in Mn compared to Pn.

      We appreciate the reviewer's insightful observations. In the revised analysis (now presented in Supplemental Fig. S4D), we quantified EGFP-importin α1 intensities in both PN and MN using fixed circular regions of interest. This revealed that the reduced MN/PN ratio observed in the CSE1L-binding mutant (C-mut) was mainly due to an increase in the PN signal rather than a decrease in the MN signal. These results are consistent with the reviewer's suggestion and indicate that CSE1L-mediated nuclear export is functional in PN but has a limited impact on MN.

      Importantly, this interpretation is supported by our FRAP experiments (Fig. 3), which show that importin α1 recycles normally in the PN but exhibits markedly reduced mobility in the MN. Together with our proteomic and colocalization analyses (Fig. 6), which identified importin α1 association with chromatin regulators such as PARP1 and SUPT16H/FACT, these findings suggest that importin α1 accumulates in MN not only because the recycling machinery is uncoupled but also because it forms stable interactions with chromatin-associated proteins. As discussed in the revised manuscript, this dual mechanism provides a plausible explanation for the persistent retention of importin α1 in MN and its role in defining a distinct MN environment.

      It is unclear from the text or the methods whether RIME identification of importin-alpha binding partners is performed in reversine-treated cells, which would increase the proportion of importin alpha in Mn, or in untreated cells. In either case, it seems likely that the majority of interactors identified would be cargoes that rely on importin alpha for import into the Pn. The rationale for linking these potential interactions to the Mn is unclear. While some of these factors are indeed shown enriched in Mn in Figure 5, the significance of this is also unclear. These points should be clarified.

      We thank the reviewer for raising this important point. The RIME assay was performed using whole-cell extracts from untreated wild-type MCF7 cells, which primarily identified importin α1-associated nuclear cargo proteins. To assess their potential relevance to MN, we screened the RIME candidates using immunofluorescence data provided by the Human Protein Atlas database and experimentally validated those showing clear MN localization by colocalization with importin α1. This two-step approach enabled us to highlight importin α1 interactors that are functionally relevant to MN biology rather than general nuclear cargoes.

      In response to the reviewer's concerns, we revised the Results section to clarify this rationale. Specifically, we added the explanation that "As importin α1 interactors are typically nuclear proteins, it is plausible that they reside not only in the primary nucleus but also in the MN. To test this possibility, we screened the identified candidates for MN localization using immunofluorescence images provided by the Human Protein Atlas (HPA) database (Pontén et al, 2008; Thul et al, 2017)." (page 14, lines 294-297).

      This is consistent with the idea that a wide range of nuclear proteins carrying NLS motifs can recruit importin α1 into the micronuclei, where they reside. This protein-driven enrichment of importin α1 may create a restricted microenvironment in which canonical DNA repair and sensing proteins, including RAD51, RPA2, and cGAS, are excluded, thereby defining a distinct subset of micronuclei with limited genome surveillance capacity.

      In Figure 6, the authors perform FRAP of importin alpha in Mn and show that it recovers much more slowly in Mn than in Pn. However, it appears from the images shown that the entire Mn was photobleached in each FRAP experiment. It thus is unclear whether the slow FRAP recovery is limited by slow diffusion of importin alpha within Mn/on Mn chromatin or impaired trafficking of importin alpha into and out of Mn. These distinct outcomes have distinct implications: either importin alpha is immobilized on Mn (eu)chromatin, or alternatively importin alpha is poorly transported into / out of Mn. This ambiguity could be resolved by bleaching a portion of a Mn and testing whether importin alpha diffuses within a single Mn.

      We thank the reviewer for this insightful comment regarding the interpretation of FRAP data. As the reviewer rightly pointed out, the original FRAP design-where the entire MN was photobleached-does not allow for a clear discrimination between the intranuclear immobilization of importin α1 and impaired trafficking into or out of the MN.

      In line with a similar suggestion from Reviewer #1, we attempted partial photobleaching of MN to evaluate whether importin α1 can diffuse within MN independently of nucleocytoplasmic transport. However, due to the small size of MN, precise targeting is technically challenging and recovery is often unreliable, with some MN even exhibiting partial recovery during the bleaching process itself. These data were not included in the revised figures; however, we provide representative examples as reviewer-only figures to illustrate these technical limitations.

      To further clarify the nuclear transport dynamics of importin α1, we redesigned our FRAP experiments to fully photobleach both the PN and MN within the same cells under identical conditions. These results, presented in revised Fig. 3A and 3C, demonstrate a markedly slower recovery of importin α1 in MN compared to PN, strongly suggesting that nucleocytoplasmic recycling of importin α1 is impaired in MN. Moreover, the reduced mobility of importin α1 in the MN is consistent with stable chromatin binding, limiting its ability to diffuse freely within the nuclear space.

      We believe that this additional analysis, prompted by the reviewer's comment, significantly strengthens the mechanistic interpretation of our FRAP data.

      References

      Crasta K, Ganem NJ, Dagher R, Lantermann AB, Ivanova EV, Pan Y, Nezi L, Protopopov A, Chowdhury D, Pellman D (2012) DNA breaks and chromosome pulverization from errors in mitosis. Nature 482: 53-58

      Hachet V, Kocher T, Wilm M, Mattaj IW (2004) Importin α associates with membranes and participates in nuclear envelope assembly in vitro. EMBO J 23: 1526-1535

      Martinez-Olivera R, Datsi A, Stallkamp M, Köller M, Kohtz I, Pintea B, Gousias K (2018) Silencing of the nucleocytoplasmic shuttling protein karyopherin a2 promotes cell-cycle arrest and apoptosis in glioblastoma multiforme. Oncotarget 9: 33471-33481

      Vietri M, Schultz SW, Bellanger A, Jones CM, Petersen LI, Raiborg C, Skarpen E, Pedurupillay CRJ, Kjos I, Kip E, Timmer R, Jain A, Collas P, Knorr RL, Grellscheid SN, Kusumaatmaja H, Brech A, Micci F, Stenmark H, Campsteijn C (2020) Unrestrained ESCRT-III drives micronuclear catastrophe and chromosome fragmentation. Nat Cell Biol 22: 856-867

      Wang CI, Chien KY, Wang CL, Liu HP, Cheng CC, Chang YS, Yu JS, Yu CJ (2012) Quantitative proteomics reveals regulation of karyopherin subunit alpha-2 (KPNA2) and its potential novel cargo proteins in nonsmall cell lung cancer. Mol Cell Proteomics 11: 1105-1122

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      Referee #3

      Evidence, reproducibility and clarity

      This study reports that importin alpha isoforms enrich strongly in a subset of micronuclei in cancer cells and uses mutagenesis and immunostaining to define how this localization relates to importin alpha's nuclear transport function. This enrichment occurs even though importin-alpha-positive micronuclei also contain Ran and the importin alpha export factor CSE1L, indicating that importin a enrichment is not simply a consequence of the absence of components of the nuclear transport machinery that control its localization. Mutagenesis of importin a indicates that Mn enrichment persists even when the importin beta binding and NLS binding capacities of imp a are impaired. Potential importin alpha interacting proteins are identified by proteomics, although the relationship of these potential binding partners to micronucleus localization is unclear.

      Significance

      1. In Figure S3, the authors show that mutagenesis of importin alpha's CSE1L binding domain decreases the ratiometric enrichment in Mn vs. Pn. However, is this effect occurring because th CSE1L binding mutant decreases Mn enrichment, or increases Pn enrichment? It seems that the latter is possible based on the images shown. If the Pn specifically becomes brighter on average in cells expressing the C-mut, while Mn remain similar in fluorescence intensity, that might suggest that CSE1L has less of an effect on importin alpha export in Mn compared to Pn.
      2. It is unclear from the text or the methods whether RIME identification of importin-alpha binding partners is performed in reversine-treated cells, which would increase the proportion of importin alpha in Mn, or in untreated cells. In either case, it seems likely that the majority of interactors identified would be cargoes that rely on importin alpha for import into the Pn. The rationale for linking these potential interactions to the Mn is unclear. While some of these factors are indeed shown enriched in Mn in Figure 5, the significance of this is also unclear. These points should be clarified.
      3. In Figure 6, the authors perform FRAP of importin alpha in Mn and show that it recovers much more slowly in Mn than in Pn. However, it appears from the images shown that the entire Mn was photobleached in each FRAP experiment. It thus is unclear whether the slow FRAP recovery is limited by slow diffusion of importin alpha within Mn/on Mn chromatin or impaired trafficking of importin alpha into and out of Mn. These distinct outcomes have distinct implications: either importin alpha is immobilized on Mn (eu)chromatin, or alternatively importin alpha is poorly transported into / out of Mn. This ambiguity could be resolved by bleaching a portion of a Mn and testing whether importin alpha diffuses within a single Mn.
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      Referee #2

      Evidence, reproducibility and clarity

      Summary:

      The authors have shown that Importin α1, a nuclear transport factor, is enriched in subsets of micronuclei (MN) of cancer cells (MCF7 and HeLa) and, using FRAP, has an altered dynamics in MN. Moreover, the authors have shown that these levels of Importin α1 in the MN are likely not due to its traditional role for signal-dependent protein transport, as suggested by immunofluorescence of other factors important for this function. Additionally, cargo dynamics carrying NLS or NES signals were disrupted in Importin α1-positive micronuclei. Importin α1-positive micronuclei also appear to have a disrupted nuclear envelope, potentially explaining some of these cargo disruptions. The authors also demonstrated that Importin α colocalizes with proteins important for DNA replication, and p53 signaling using RIME, followed by immunofluorescence. Lastly, the authors show that Importin α and RAD51 have mutual exclusivity in the micronuclei.

      Major comments:

      1. A key issue is there are very few statistical tests used in this study. It is crucial to the interpretation of the data. We strongly urge the authors to re-analyze the data using appropriate statistical analyses. Along those lines, in many figures 1 or 2 images are shown without stating how many biological or technical replicates this is representative of or showing quantification of the anlyses. In general, the authors' statements would be strengthened by showing more examples and/or stating "N" in the figure legends or supplement.
      2. Using RIME and immunofluorescence, the authors identify factors that co-localize with Importin α1 in subsets of micronuclei (Figure 5), which is interesting, but there is no functional data associated with this result. Are the authors stating that these differences account for altered DNA damage or replication? It is unclear what the conclusion is beyond "some MN are different than others." Could the authors knockdown/knockout these factors to determine if they recruit Importin α1 into MN or the reciprocal? For many of these factors, they appear to be broadly present throughout the entire primary nucleus as well, indicating there is nothing unique about their MN localization.
      3. In line 274, the authors state that MN highly enriched for Importin α1 inhibits RAD51 accessibility but this is an overstatement of the data. Instead, the authors show that RAD51 and importin α1 do not colocalize in micronuclei, albeit without quantification which weakens their argument. Also, the consequence of this "mutual exclusivity" is unclear. Can the authors inhibit or knockdown Importin α1 and show that RAD51 goes to all micronuclei? And how is this different than the data shown for factors in Figure 5? Some of those show colocalization with Importin α1-positive micronuclei and others do not. Could you perform live imaging of labeled Importin a1 and RAD51 and show that as Importin α1 accumulates in MN that RAD51 or other DNA repair factors are exported? An alternative experiment would be to show that the C-mutant, which is defective in nuclear export, now colocalizes with RAD51 in MN. Please reconcile this or show experiments to prove the statement above.
      4. In the Discussion, line 343-344 states that "importin α1 is uniquely distributed and alters the nuclear/chromatin status when enriched in MN," however this is not currently supported by the present data. The data presented shows correlation (albeit weak) between euchromatic modifications and Importin α1, and it does not definitively show that importin α1 is sufficient to alter the nuclear-chromatin status when enriched in the MN. More substantial experiments would be required to show whether Importin α1 plays an active role in these modifications.

      Minor Comments

      1. Summary statement (page 3 Line 40): The use of "their" is confusing. Whose microenvironment are you referring to?
      2. In Abstract and introduction (page 4, Line 44 and page 5, line 59) it states that MN are membrane enclosed structures, but this is not always the case (see https://doi.org/10.1038/nature23449 as one example).
      3. Given the fact that the RIME result identified proteins involved in DNA replication to be enriched with Importin α1, are these MN enriched in factors described in Fig. 5 simply localizing to MN that are in S phase, as described previously (doi: 10.1038/nature10802)?
      4. The FRAP data is not very compelling. While it is clear there are differences between the PN and MN dynamics, what is driving these differences? Are these differences meaningful to the biology of the MN or PN? It is unclear what this data is contributing to the conclusions of the paper. Also, if the mobility of the MN is plotted on the same graph as the PN, the differences in MN mobility might not look as compelling.
      5. In Results (line 117), you state that "the cytoplasm of those cell lines emitted quite strong signals" for Importin α1, but that phrasing is a little confusing. Yes, Importin α1 is in present the cytoplasm in most cells, but it appears you are referring to the enrichment in MN. I would recommend re-phrasing this statement to make your intent clearer.
      6. In Results (line 135, Figure S2E,F), the ratio of high, low or no Importin α1 intensity is confusing. Is this percentage relative to the total number of MN? It Is unclear what is meant by "whole number" of MN. Is Importin α1 intensity quantified or is it subjective?
      7. Figure 2C is confusing. Are you counting MN with co-localization of Importin α1 and these factors? Please clarify.
      8. Figure S3D quantification is very confusing and unclear. Also, how is this normalized? Are you controlling for total signal in each cell? And can the results of this experiment give you any mechanistic insight as to what is regulating MN localization beyond the interpretation of "MN localization is distinct from PN localization"? The "C-mutant" appears quite a bit different than the others. What might that indicate about the role of CAS/CSE1L in MN enrichment?
      9. For Figures 3A,B and S4, are these images of single z-slices or projections? It would be helpful to clarify for your interpretations as to whether they are truly partial or diffuse or the membrane is in another z-plane. Also, how does the localization of Importin α1 different or similar to other factors that localize to MN with a compromised nuclear envelope, such as cGAS? If it is based on epigenetic marks, it should be different than cGAS, which primarily binds non-chromatinized DNA.
      10. In Results, it is unclear how Fig. 7B was calculated. Are the authors qualitatively assessing if RAD51 is there or looking for MN enrichment relative to PN? Additionally, in Fig. 7C, RAD51 localization is diffuse. It should be enriched in foci. I would recommend the authors repeat this experiment using pre-extraction then quantify RAD51 foci number and/or intensity.
      11. In line 264, "notably" is misspelled.
      12. In line 303, "scenarios" should be changed to the singular form.
      13. In Figure legend, line 571-582, H3K27me3 is shown in Figure 4D, but the written legend does not mention this mark.

      Significance

      Overall, this paper shows compelling evidence for micronuclear localization of regulators of nuclear export, notably Importin α1. Of note, this occurs in subsets of MN that lack an intact nuclear envelope. And while it has been appreciated that compromised micronuclear envelopes lead to genomic instability, this is one of the first that demonstrate alteration in the nuclear envelope may disrupt import or export of nuclear proteins into micronuclei.

      A limitation of the study is that much of the work is based on immunofluorescence and lacks mechanism. While there is much correlative data showing that Importin α1 localizes to micronuclei with compromised envelopes, it is unclear whether Importin α1 drives micronuclear collapse or it is downstream of this process. Additionally, Importin α1 micronuclear localization anti-correlates with RAD51 but does colocalize with other DNA replication factors, yet it is unclear whether their localization is dependent on Importin α1 or its role in nuclear export. Currently, the audience for this manuscript would be focused to those interested in micronuclei. If these concerns about an active role for Importin α1 in micronuclear export are resolved, it would greatly increase the impact of this manuscript to those interested more broadly in genomic instability, DNA repair, and cancer.

      Reviewer's areas of expertise: Genomic instability, cancer epigenetics, and mitosis

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      Referee #1

      Evidence, reproducibility and clarity

      Summary:

      Provide a short summary of the findings and key conclusions (including methodology and model system(s) where appropriate). Miyamoto et al. report that importin α1 is highly enriched in a subfraction of micronuclei (about 40%), which exhibit defective nuclear envelopes and compromised accessibility of factors essential for the damage response associated with homologous recombination DNA repair. The authors suggest that the unequal localization and abnormal distribution of importin α1 within these micronuclei contribute to the genomic instability observed in cancer.

      Major comments:

      Are the key conclusions convincing?

      The conclusions drawn by the authors would benefit from additional supportive experiments and a more detailed explanation. 1. It is crucial to quantitatively assess the localization of importin α1 in micronuclei (MN) across non-transformed MCM10A cells compared to transformed cell lines (MC7, HeLa, and MDA-MB-231). This analysis would help determine whether the localization of importin α1 in MN correlates with genomic stability in human cancer cells 2. While the authors provide some evidence indicating partial disruption of nuclear envelopes in MN (Figures 3 and S4), it is noteworthy that this phenomenon also occurs in importin α1-negative MN. Furthermore, according to the figure legends, the data presented in both figures stem from a single experiment. Current literature suggests that compromised nuclear envelope integrity is one of the major contributors to genomic instability, mediated through mechanisms such as chromothripsis and cGAS-STING-mediated inflammation arising from MN. Therefore, a more comprehensive quantification of nuclear envelope integrity-ideally comparing non-transformed MCM10A cells with transformed cell lines (MC7, HeLa, and MDA-MB-231)-is necessary to substantiate the connection between aberrant importin α1 behavior in MN and chromothripsis processes, as well as regulation of the cGAS-STING pathway linked to genomic instability in cancer cells. 3. The schematic illustration presented in Figure 8 does not adequately summarize all findings from this study nor does it clarify how the localization of importin α1 within MN might hypothetically influence genome stability. Although it is reasonable to propose that "importin α can serve as a molecular marker for characterizing the dynamics of MN" (Line 344), the authors assert (Line 325) that their findings, along with others, have "potential implications for the induction of chromothripsis processes and regulation of the cGAS-STING pathway in cancer cells." However, they fail to provide a clear or even hypothetical explanation regarding how their findings contribute to these molecular events. To address this gap, it would be essential for them to contextualize their results within existing literature that explores and links structural integrity deficits or aberrant DNA replication/damage responses in MN with chromothripsis and inflammation (e.g., PMID: 32601372; PMID: 32494070; PMID: 27918550; PMID: 28738408; PMID: 28759889). 4. Fig. 4D does not support the idea that importin α1 is euchromatin enriched: H3K9me3, H3K4me3 and H3K37me3 seem to be all deeply blue.

      Should the authors qualify some of their claims as preliminary or speculative, or remove them altogether?

      Indeed, the data presented by the authors do not adequately support a direct link between the presence of importin α1 in MN and genomic instability in human cancer cells. While the experimental correlations provided may not substantiate this connection definitively, they do lay a foundation for a grounded hypothesis and suggest the need for further research to explore this topic in greater depth. Additionally, it is worth noting that the evidence contributes to the growing list of nuclear proteins exhibiting abnormal behavior in micronuclei (MN). This highlights the significance of studying such proteins to understand their roles in genomic stability and cancer progression.

      Would additional experiments be essential to support the claims of the paper? Request additional experiments only where necessary for the paper as it is, and do not ask authors to open new lines of experimentation.

      Additional experiments are necessary to quantitatively assess the localization of importin α1 in micronuclei (MN) across non-transformed MCM10A cells and transformed cell lines (MC7, HeLa, MDA-MB-231). This analysis would help determine whether the localization of importin α1 in MN correlates with genomic stability in human cancer cells. The authors claim that importin α1 preferentially localizes to euchromatic areas rather than heterochromatic regions within MN. While this assertion is supported by the immunofluorescence (IF) images presented in Figures 4A/B and S5A/B, it remains less clear for Figure S5C/B. To strengthen this claim, providing averages of IF distributions from multiple cells across independent experiments would be beneficial to draw more robust conclusions.

      Furthermore, ChIP-seq data are presented to support the idea that importin α1 preferentially distributes over euchromatin areas in MN. However, as described, the epigenetic chromatin status indicated by these ChIP-seq experiments reflects that of the principal nucleus (PN), not specifically the status within MN in MCF7 cells. Given that MN represent only a small fraction of the cell population under normal culture conditions-likely less than 5% for HeLa cells as shown in Figure S2D-the relevance of this data is limited. Additionally, according to data presented in Figure 1B, importin α1 does not localize or distribute within the PN as it does in MN in MCF7 cells. Therefore, further experiments should be conducted to substantiate that importin α1 preferentially targets euchromatin areas within MN and to compare this distribution with that observed in the principal nucleus. Such studies could reveal potential abnormalities regarding the correlation between epigenetic chromatin status and importin α distribution in MN. To support the hypothesis that importin α1 inhibits RAD51 accessibility within MN, Figures 7D and E should be supplemented with thorough quantification and statistical analysis based on at least three independent experiments. This additional data would enhance confidence in their findings regarding RAD51 accessibility inhibition by importin α1.

      Are the suggested experiments realistic in terms of time and resources? It would help if you could add an estimated cost and time investment for substantial experiments.

      The additional experiments proposed are controls and direct comparisons using the same techniques and experimental designs used by the authors, so it is reasonable that the authors can carry them out within a realistic timeframe.

      Are the data and the methods presented in such a way that they can be reproduced?

      Given the importance of reproducibility and the need to evaluate results based on imaging and quantitation, I strongly recommend that the authors include a detailed description of the optical microscopy procedures utilized in their study. This should encompass imaging conditions, acquisition settings, and the specific equipment used. Providing this information will enhance transparency and facilitate reproducibility. For reference, some valuable guidance on essential parameters for reproducibility can be found in Heddleston et al. (2021) (doi:10.1242/jcs.254144). Incorporating these details will not only strengthen the manuscript but also support other researchers in reproducing the findings accurately.

      Are the experiments adequately replicated and statistical analysis adequate?

      Many of the plots and values in the manuscript lack appropriate statistical analysis, including p-values, which are not detailed in the figures or their legends. Furthermore, the Statistical Analysis section does not provide adequate information regarding the specific statistical tests employed or the criteria used to determine which analyses were applied in each case. To enhance the rigor and clarity of the study, it is essential that these issues be addressed prior to publication. A comprehensive presentation of statistical analysis will improve the reliability of the findings and allow readers to better understand the significance of the results. I recommend that the authors revise this section to include detailed explanations of all statistical methods used, along with corresponding p-values for all relevant comparisons.

      Minor comments:

      Specific experimental issues that are easily addressable.

      The authors claim that importin α1 exhibits remarkably low mobility in the micronuclei (MN) compared to its mobility in the principal nucleus (PN), as illustrated in Figure 1. However, based on the experimental design, this conclusion may not be appropriate. In the current setup, the FRAP experiment conducted in the PN measures the mobility of importin α1 molecules within the cell nucleus, where the influence of nuclear transport is likely negligible. Conversely, in the MN experiments shown, all molecules of importin α1 are bleached within a given MN. Consequently, what is being measured here primarily reflects the effects of nuclear transport rather than intrinsic molecular mobility. To accurately compare kinetics of nuclear transport, it would be essential to completely bleach the entire PN. If measuring molecular mobility between MN and PN is desired, only a small fraction of either MN or PN area/volume should be bleached during FRAP analysis. Additionally, it would be beneficial to include measurements of mobility for other canonical nuclear transport factors (e.g., RAN, CAS, RCC1) for comparative purposes. This broader context would allow for a more comprehensive understanding of importin α1 behavior relative to other factors involved in nuclear transport. Finally, utilizing cells that exhibit importin α1 signals in both PN and MN could further strengthen comparisons and provide more robust conclusions regarding its mobility dynamics.

      Are prior studies referenced appropriately?

      Prior studies are referenced appropriately in general, but the authors missed some references (PMID: 32601372; PMID: 32494070; PMID: 27918550; PMID: 28738408; PMID: 28759889) that I consider key to put the present findings in frame with previous works which link the lack of structural integrity and/or aberrant DNA replication/damage responses in MN with Cchromothripsis and inflammation.

      Are the text and figures clear and accurate?

      The figures presented in the manuscript are clear; however, where plots are included, they require appropriate statistical analysis. It is essential to display p-values on the plots or within their legends to provide readers with information regarding the significance of the results. Including this statistical information will enhance the interpretability of the data and strengthen the overall findings of the study. I recommend that the authors revise these sections accordingly before publication.

      Do you have suggestions that would help the authors improve the presentation of their data and conclusions?

      1. In lines 134-135, it is stated that "up to 40% of the MN showed importin α1 accumulation under both standard culture conditions and the reversine treatment (Fig. S2F)." However, Figure S2F only displays percentages for reversine-treated cells, and there is no mention in the text or figures regarding the percentage of importin α1-positive MN determined by immunofluorescence (IF) under standard culture conditions. This discrepancy should be addressed.
      2. In line 170, the authors state that "Cells in which overexpressed EGFP-importin α1 localized only in PN were excluded from the analysis (see Fig. 1E, top panels)." It is unclear why this exclusion was made. The authors should clarify whether they are referring to all constructs or only to the wild-type (WT) construct when mentioning EGFP-importin α1 localization solely in PN. This clarification is important as it may affect the results highlighted in line 173.
      3. The statement in line 191 ("However, this antibody could not be further used in this context due to cross-reactivity with highly concentrated importin α1 in MN (Fig. S4)") is somewhat misleading. While it hints at a technical issue, it does not provide additional relevant information for understanding its implications for the rationale of the research. Moreover, Figure S4 is referenced but appears to refer specifically to panels S4D and E, which are not mentioned in the text. I recommend clarifying this point or removing it altogether.
      4. Lines 197-199 contain a sentence that could be misleading and would benefit from clearer explanation. Although Figure 3D provides some clarity on this matter, no statistical analysis is included-only a bar plot is presented. A proper statistical analysis should be provided here to enhance understanding.
      5. In lines 218-221, it states that importin α1 associates with euchromatin regions characterized by H3K4me3 and H3K36me3; however, Figure 4D lacks the Spearman's correlation coefficient value for H3K36me3 within the matrix. This omission needs correction.
      6. For consistency in the experimental design aimed at identifying potential importin α1-interacting proteins, it would be more appropriate for Figures 5C/D to show IF data from MCF7 cells rather than HeLa cells.
      7. To substantiate claims that importin α1 inhibits RAD51 accessibility within MN, Figures 7D and E should include thorough quantitation and statistical analysis based on at least three independent experiments.
      8. The meaning of lines 336-338-"Therefore, the enrichment of importin α1 in MN, along with its interaction with chromatin, may regulate the accessibility of RAD51 to DNA/chromatin fibers in MN and protect its activity"-is unclear. I suggest rephrasing this sentence for improved clarity and comprehension.
      9. Fig. 1D: Numbers on the y-axis are missing, x-axis labeling is too small
      10. Fig. 1F: As the PN/MN values of the three experiments are seemingly identical (third column) the distribution of the three individual data of the PN (first column) should mirror the distribution of the three individual data of the MN (second column). The authors might want to check why this is not the case.

      Significance

      • Describe the nature and significance of the advance (e.g. conceptual, technical, clinical) for the field.
      • Place the work in the context of the existing literature (provide references, where appropriate).

      Micronuclei (MN) primarily arise from defects in mitotic progression and chromatin segregation, often associated with chromatin bridges and/or lagging chromosomes. MN frequently exhibit DNA replication defects and possess a rupture-prone nuclear envelope, which has been linked to genomic instability. The nuclear envelope of MN is notably deficient in crucial factors such as lamin B and nuclear pore complexes (NPCs). This deficiency may be attributed to the influence of microtubules and the gradient of Aurora B activity at the mitotic midzone, which inhibits the recruitment of proper nuclear envelope components. Additionally, several other factors may contribute to this process: for instance, PLK1 controls the assembly of NPC components onto lagging chromosomes; chromosome size and gene density positively correlate with the membrane stability of MN; and abnormal accumulation of the ESCRT complex on MN exacerbates DNA damage within these structures, triggering pro-inflammatory pathways. The work presented by Dr. Miyamoto and colleagues reveals the abnormal behavior of importin α1 in MN during interphase. According to their findings, it is reasonable to consider importin α1 as a molecular marker for characterizing MN dynamics. Furthermore, it could serve as a potential clinical marker if the authors provide additional experiments demonstrating significantly different localization patterns of importin α1 in transformed cells (e.g., MC7, HeLa, MDA-MB-231) compared to non-transformed cells (e.g., MCM10A). While the authors present some evidence indicating partial disruption of nuclear envelopes in MN (Figures 3 and S4), it is noteworthy that this phenomenon also occurs in importin α1-negative MN. Moreover, according to the figure legends, data for both figures originate from a single experiment. As such, convincing evidence linking the aberrant behavior of importin α1 in MN with chromothripsis processes or regulation of the cGAS-STING pathway-and its implications for genomic instability in cancer cells-remains lacking. Overall, it is not entirely clear what significance this advance holds for the field; while there are conceptual contributions made by this work, they do not appear sufficiently robust at this time. Further research is needed to clarify these connections and strengthen their conclusions regarding importin α1's role in MN dynamics and genomic instability. - State what audience might be interested in and influenced by the reported findings.

      Scientist and health care professionals that research on mechanism of genomic instability and cancer - Define your field of expertise with a few keywords to help the authors contextualize your point of view. Indicate if there are any parts of the paper that you do not have sufficient expertise to evaluate.

      Mitosis, mitotic chromatin decondensation, nuclear reformation, hematopoietic cancers, light microscopy, image analysis.

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    1. senne 17 Oct 2025
      he Type I error rate

      want als er echt geen verschil is dus 0 heeft gelijk dan is f 1 dan weet je niet verwerpen dus dan maak je minder snel een false positive. het vergelijkt de verklaarde variatie en de onverklaarde variatie met elkaar

    2. senne 17 Oct 2025
      Both  and  are sums, so their size depends on the number of scores. To eliminate this inequality we calculate an average sum of squares, the so-called mean squares

      mean squeres vermindereen de afhankelijkheid van de grote van de aantal nummers op de totale optelsommen. Mean squares zijn een manier om de som van kwadraten te normaliseren door de vrijheidsgraden (degrees of freedom, df). Dit maakt het mogelijk om de variatie per eenheid te vergelijken, ongeacht de steekproefgrootte. dit zijn deze vormen mean square for the model, residuals en total. deze standaardiseren variatie zodat de variatie per eenheid kan worden vergeleden want de sommen zijn afhankelijk van n. mean of squares zijn dus onafhankelijk

    4. senne 17 Oct 2025
      between each observed data point and the grand mean.

      verschil elk geobserveerd punt zowel goed als error en de grand mean vervolgens kwadradeer je dit. je moet het zien als een waargenomen datapunt min de mean en dit in het kwadraad

    5. senne 17 Oct 2025
      efficients, the greater the deviation between the model and the null.

      parameters bepalen de vorm van het model hoe groter de coefficienten hoe groter de afwijking tussen het nulmodel en het model

    8. senne 17 Oct 2025
      p-value for significance, the mean difference for direction, the effect size for magnitude, and the confidence intervals for precision

      wat rapoteer je als het gaat om de repeated t/test. effectsize, mean differences, en de p waarde en confidence intervals

    10. senne 17 Oct 2025
      reduce error variance, thereby increasing statistical power and making it easier to detect true differences.

      echte verschillen zijn makkelijker te vinden in een repeated design omdat deze foutvariante verminder en zo de power toeneemt. de error verminderd omdat het corricceert voor individuele verschillen

    11. senne 17 Oct 2025
      the effect size in a repeated-measures design is large, and the confidence interval is narrower than in the inde

      als effect size groter is dan de confidence interval dan heeft er een nauwkirge schatting van het effect weergegeven

    12. senne 17 Oct 2025
      If the confidence interval around the mean difference excludes zero,

      als 0 niet in het confidence interval is benoemd versterkt dit de conclsuie dat er een effect is

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    viewer.athenadocs.nl/api/course/uva-psy-1007/UVA-PSY-1007-WEEK1-2526/
  21. arxiv.org arxiv.org
    Agentic Context Engineering: Evolving Contexts for Self-Improving Language Models
    1
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    arxiv.org/abs/2510.04618
  22. ecampus.paris-saclay.fr ecampus.paris-saclay.fr
    BE n°3 : Mise en place d’une boucle d’asservissement — M2 FESup - Automatique Continue
    1
    1. Denis_del_rey 17 Oct 2025
      Question n°12 : : Comment intègre-t-on une boucle d’asservissement en intensité. Et quel rôle a-t-elle

      Cette question est intéressante mais sans connaissance avant qu'il faut implémenter un capteur ça peut être rude à commencer

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    ecampus.paris-saclay.fr/pluginfile.php/4063593/mod_resource/content/14/html/ressources/3_BE_3.html
  23. ecampus.paris-saclay.fr ecampus.paris-saclay.fr
    Analyse harmonique des SLCI — M2 FESup - Automatique Continue
    1
    1. Denis_del_rey 17 Oct 2025
      C’est la représentation dans le plan complexe de H(jω) lorsque ω varie de 0 à l’infini. Image tikz Tracés dans le lieu de Nyquist \caption{Exemple de tracés dans le lieu de Nyquist} \label{exemple_nyquist}

      Il y a un problème d'affichage ici ainsi que dans la partie suivante

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    ecampus.paris-saclay.fr/pluginfile.php/4063593/mod_resource/content/14/html/ressources/1_Cours_Chapitre_3.html
  24. social-media-ethics-automation.github.io social-media-ethics-automation.github.io
    8.9. Bibliography
    2
    1. tyushossain 17 Oct 2025
      Why can't I use Artificial Intelligence tools to generate answers? - Help Center. 2023. URL: https://stackoverflow.com/help/ai-policy (visited on 2023-12-08).

      This link allows readers to understand certain policies about the general use of ai. It mentions how certain social media platforms or general apps (ex: stack overflow) are banning the overall use of ai because they believe one's original work is a reflection of themselves, and that you have to earn your freedom to have an opinion. It then begins to list certain types of ai tools that are seen as forbidden; it also mentions that ai has a limit, and there are ways for their programmers to know if what is shown is ai or not.

    2. gfong07 16 Oct 2025
      Christie Aschwanden. Science Isn’t Broken. FiveThirtyEight, August 2015. URL: https://fivethirtyeight.com/features/science-isnt-broken/ (visited on 2023-12-05).

      The article shows how it is much harder than it seems to correctly access data over a large scale. It is almost impossible to assume that two pieces of data correlate with each other. There have been examples that I was given when I was learning about this concept in Stats class where the consumption of margarine almost identically followed the rate of divorce in Maine. Clearly there is no true correlation between the two but it is a good reminder that it is really difficult to find true evidence of data correlation.

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    social-media-ethics-automation.github.io/book/bsky/ch08_data_mining/09_bibliography.html
  25. social-media-ethics-automation.github.io social-media-ethics-automation.github.io
    8.8. Reflections on Data Mining
    1
    1. tyushossain 17 Oct 2025
      Are you surprised by any of the things that can be done with data mining? Do you think there is information that could be discovered through data mining that social media companies shouldn’t seek out (e.g., social media companies could use it for bad purposes, or they might get hacked and others could find it)?

      I am not really surprised by most of the things that can be done with data mining because we live in an advanced society to a point where there's ai and programs that allow companies thrive. One thing I am surprised about data mining is how people can use it to track trends in terms of stocks or the general economy because at what point are they cheating the system? I think information that shouldn't be available for companies to seek in terms of social media are looking for popular individuals to use for campaigns or for leveraging marketing.

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    social-media-ethics-automation.github.io/book/bsky/ch08_data_mining/08_reflection_questions.html
  26. substack.com substack.com
    We Were Guaranteed a Haka
    1
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    substack.com/home/post/p-176207573
  27. www.npr.org www.npr.org
    NPR 'founding mother' Susan Stamberg has died
    1
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    npr.org/2025/10/16/1184880448/susan-stamberg-obituary
  28. drive.google.com drive.google.com
    218-133833_ch01_4P.indd
    1
    1. csimon808 17 Oct 2025
      Kinship requires both an understanding of the self-in-relation andthe ability to project, to position, oneself as part of an extended networkof relatives. We know our relations by virtue of our lived experiences, aswe understand those experiences in the context of cultural and historicalparadigms that give them substance. In this, relations expand beyond thematerial and toward the unknown—they are not just of this world, but ofthe beyond as well. They exist in the present, and toward iterative becom-ings that are neither past nor future, but both simul taneously. Relations area form of reckoning with time, space, and what vibrates between bodies—love, fear, joy, hope. Relations open pathways to thinking and being inreciprocity

      This is how I envision someone who uses the future imaginary as a theoretical framework to define a relationship from an indigenous perspective. Viewing relationships as a form of kinship with a reciprocal balance, where time is cyclical, is very "futuristic" in a sense. Yet, the grounding of indigenous culture and history anchors kinship to the here and now, making it relevant.

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    drive.google.com/file/d/1sWXGbNrpV7dRsPST3ad4ee-ayE4_F2gG/
  29. docdrop.org docdrop.org
    Myth of the Model Minority
    1
    1. elisesaucedo 17 Oct 2025
      In academia, we scholars are often taught to distance ourselves from our research

      I find it frustrating that academia teaches scholars to distance themselves from their research subject. Research becomes extractive and stagnant if a scholar is only looking to write a paper and talk about something, instead of really being immersed and have genuine care for what they are researching, or even having it be related to our own communtiities and lived experiences. When we separate our studies from the real world it becomes isolated and pointless.

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    docdrop.org/download_annotation_doc/Chou-and-Feagin-Myth-of-the-Model-Minority-Ch-1-Reality-of-A-n8pgt.pdf
  30. noblogo.org noblogo.org
    A Sócrates no le gustaba la escritura (este es un ensayo sobre la inteligencia artificial)
    2
    1. LeidyGomez 17 Oct 2025
      La inteligencia artificial es muy compleja y aún no nos ha demostrado que se justifique para ser inevitable y que sus críticos quedemos como Sócrates. *La industria de la inteligencia artificial argumenta que su producto mejorará tanto que los errores sí llegarán a ser evitables.

      Cierra el texto retomando el paralelo con Sócrates y deja una pregunta abierta sobre el futuro de la IA. Es un buen punto para un momento reflexivo, me gusta cómo el autor termina el texto dandonos como una cierta duda lo cual, nos invita a pensar si la IA realmente será tan necesaria como la escritura, sugiere que tal vez los críticos de la IA no están equivocados del todo, sino que están advirtiendo sobre un cambio que aún no comprendemos del todo. Esta reflexión nos hace pensar en la responsabilidad colectiva que tenemos frente al uso y los límites de la IA.

    2. GabrielaQB 17 Oct 2025
      A Sócrates no le convencía eso de escribir. Su argumento principal era que, al tener las ideas siempre a la mano en un dispositivo externo a la mente humana, esto atrofiaría nuestra memoria: ya no haríamos un esfuerzo por recordar largos poemas épicos, o largas listas de hechos científicos. Pero tampoco haríamos un esfuerzo por recordar nuestros propios argumentos sobre disquisiciones varias. Todo estaría por ahí, en papel o en piedra, listo para consultarse cuando se nos diera la gana.

      Fue interesantes porque Sócrates, el filósofo, no confiaba en la escritura porque pensaba que al externalizar el conocimiento en textos, nuestra memoria se volvería floja y solo tendríamos una simulación del saber, no el conocimiento de verdad. La ironía es que sabemos esto porque Platón, su estudiante, al final lo escribió el, la escritura se impuso a pesar de las críticas, igual que hoy pasa con la inteligencia artificial: hay un montón de gente que le tiene miedo o le hace críticas, pero el texto sugiere que, como con la escritura, la IA probablemente acabará triunfando y cambiándolo todo, aunque ahora nos cueste verlo.

      Maria Gabriela Quiroga B

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    noblogo.org/pablo/a-socrates-no-le-gustaba-la-escritura-este-es-un-ensayo-sobre-la-inteligencia
  31. docdrop.org docdrop.org
    Untitled
    1
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    docdrop.org/ocr/download/Gay_Alienable_Rights-1--1j1ni_ocr.pdf
  32. intarch.ac.uk intarch.ac.uk
    Contemplating Cognitive Things. Huggett. Internet Archaeol. 44.
    1
    1. gm007 17 Oct 2025
      when designers seek to make devices more 'user-friendly' and in the process disguise their mode of operation, it becomes all the more important to investigate the role of cognitive artefacts within archaeology and the relationships and dependencies that exist within the digital ecosystem we are creating.

      GIS interfaces are designed to simplify complex modeling decision behind neat buttons and sliders. My documentation resists that "user-friendly opacity" by explaining the slope factor, water barrier weight, and clusteering radius so that others could interpret or replicate the Silk Road model on their critical grounds.

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    intarch.ac.uk/journal/issue44/7/9.html
  33. intarch.ac.uk intarch.ac.uk
    Cognition and the Survey Instrument. Huggett. Internet Archaeol. 44.
    1
    1. gm007 17 Oct 2025
      As survey instrumentation becomes digital and increasingly automated, so the level of human engagement changes: the cognitive load is transferred to the digital device

      In my Silk Road project, this interpretive workload is divided between terrain-cost and clustering algorithms. The model “thinks” through slope resistance and caravanserai density, freeing me to consider problems of historical interpretation rather than raw computation. The shift represents another key aspect of Huggett’s cognition migrating into the tool.

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    intarch.ac.uk/journal/issue44/7/5.html
  34. medium.com medium.com
    A Guide to Competitive Analysis for UX Design
    1
    1. Kimberly_g 17 Oct 2025
      Understanding the landscape of competitors not only helps inform your design decisions but it also helps inform the overall product strategy. A UX competitive analysis uncovers valuable opportunities to create a superior product and stand out from the competition.

      I agree with this conclusion and find it highly practical, especially given how saturated the modern market is. In most industries today, there are already countless products and services competing for users’ attention, so understanding what others are doing is essential before proposing something new. Conducting a competitive analysis helps designers identify what works, what doesn’t, and where the gaps or pain points exist that could make users choose your design over existing ones. I also think this approach is efficient because learning from similar products is a low-stakes but high-value way to begin the design process. It allows you to avoid repeating mistakes that competitors have already made while also inspiring better, differentiated solutions.

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    medium.com/design-bootcamp/a-guide-to-competitive-analysis-for-ux-design-1ddafeb9a3e7
  35. intarch.ac.uk intarch.ac.uk
    Cognitive Coupling. Huggett. Internet Archaeol. 44.
    3
    1. gm007 17 Oct 2025
      Individualisation considers the level of adjustment or customisation available to the agent. At one extreme, this may tailor the device to the individual agent such that it becomes difficult for another to use it, or to adapt it for another task. On the other hand, a device may be easy to pick up, use and understand with little scope or need for improved efficiency or effectiveness, and hence it is not especially individualised. Furthermore, agent and artefact may both be adapted together in what Heersmink calls entrenchment, where the cognitive artefact is individualised according to the user's needs, and in turn the user's behaviour and cognition are adapted by the device in a manner reminiscent of the McLuhanite 'We shape our tools and thereafter our tools shape us' (Culkin 1968, 60). (Heersmink 2012, 52-3; 2015, 590-1).

      Cost-surface weights and clustering hyperparameters reflect my priors (slope, water gaps, caravanserai spacing). I’ll publish a config file and run ablations to avoid over-entrenching my personal settings.

    2. Meaghanrt16 16 Oct 2025
      Trust – we tend to trust the devices we employ (why would we use them otherwise?) but what is this trust based upon?

      I have heard stories of AI programs being incorrect about things and this definitely makes me more cautious when using applications - I try to use them as a secondary source, something to use after information has already been gathered.

      I'm curious to see if my trust in AI changes after being on the other side of things (not just a consumer), while trying to prove my hypothesis with a LLM trained by me.

    3. Meaghanrt16 16 Oct 2025
      Information flow between agent and artefact, including one-way flow (from artefact to agent, where we simply look at the artefact to extract the information we require), two-way flow (typically where we store information on the artefact and subsequently retrieve it); reciprocal flow (a two-way flow that is incremental, additive, and cyclical, so there is a continuous information exchange); and system flow (where there are multiple agents and multiple artefacts cooperating in the exchange) (Heersmink 2012, 49-50; 2015, 583-6).

      This specifically correlates to the hypothesis I will feed to the LLM relating to my topic - I want the LLM to analyze two historical artefacts and compare their relation to each other in order to figure out if one was influenced by the other. Information will be given to me from the LLM - if i train a program to search for this information, I will need to feed the program training/information to achieve an outcome.

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    intarch.ac.uk/journal/issue44/7/4.html
  36. academic.oup.com academic.oup.com
    3. How behaviour develops
    1
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    academic.oup.com/book/890/chapter/135480654
  37. onlinelibrary-wiley-com.brooklyn.ezproxy.cuny.edu onlinelibrary-wiley-com.brooklyn.ezproxy.cuny.edu
    Cognitive Behavior Therapies
    1
    1. Bmckinney12 17 Oct 2025
      Overview Andreas, age 22, was completing his final year in college and was majoring in computer science. He had worked hard in order to prepare himself for a career in information technology, getting good grades with the hope of landing a job in a top company after graduation. He was the only son of a wealthy family. His father was a well-known lawyer in their average-size hometown and his mother was a cardiologist. Andreas had always received lots of attention from his parents, and they ensured that he got a good education and had everything he wanted. Andreas described his parents as being very strict and critical, requiring that he work hard and receive good grades in order to increase his chances of doing something valuable with his life. What triggered Andreas' s depression was an event that took place at the beginning of the semester. At the end of summer holidays, a renowned multinational information technology company launched a contest inviting all students in their final year of computer science to submit a project on an emerging topic. The prize for this contest was a well-paid 6-month internship with the company, which for Andreas would have been the perfect start to a fabulous career. Twenty internships were awarded among more than 200 students who submitted projects, and Andreas was not among them. This made him feel terrible, especially because he had told his parents about this opportunity because he was confident he would be selected. When he received the news about not having been accepted, he initially did not tell his parents about it or about the fact that he was so depressed, lying to them about not receiving the results each time they asked about it. As a result of being rejected for the award and lying to his parents, Andreas developed strong feelings of shame, guilt, and hopelessness, thinking that he would never be as he had been before. He saw himself as a failure both to himself and to his parents. He had tried to prove his worth by winning the internship, and now that opportunity was gone. Andreas came to therapy after what he described as the worst period of his life in which he felt deeply depressed and experienced suicidal ideation. However, he did not intend to commit suicide and did not make any attempt, stating that he was very afraid of these thoughts. When he came to therapy he had not been to class for more than 3 weeks, and in the previous month he had only gone from time to time in his better moments. In the past 3 weeks, however, the depression had gotten so intense that he barely got out of house. He spent his time sleeping, playing video games, and thinking intensely about his situation and the fact that he would not be able to complete his graduation thesis. In the initial session Andreas was introduced to the CBT model and behavioral activation, and in subsequent sessions he learned how to identify and dispute dysfunctional negative automatic thoughts. After the third session, Andreas started attending classes again and was able to study for winter exams, although he was very stressed about them. He also got up the courage to tell his parents that he had not received the award. He said that they were critical but did not dwell on it. In this fourth session the focus was on his deeper cognitions—the intermediate and core beliefs. I used Andreas' s thought records from the previous week to initiate further exploration of his thoughts using the downward arrow technique to access deeper beliefs. At the end of the session we developed a behavioral experiment to test the functionality of these beliefs. What follows is the transcript of the fourth session.

      Both Andreas and Allison received CBT to challenge negative self beliefs, but Andreas’s therapy focused on perfectionism and conditional self-worth after losing an internship, while Allison’s addressed low self esteem and peer bullying. Andreas’s therapist targeted deep core beliefs, whereas Allison’s therapist used simpler thought challenging and behavior practice. Both learned to replace self criticism with healthier thinking and actions.

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    onlinelibrary-wiley-com.brooklyn.ezproxy.cuny.edu/reader/content/193ad139e85/10.1002/9781119375395/format/epub/OPS/c03.xhtml
  38. notebooklm.google.com notebooklm.google.com
    Google NotebookLM | Note Taking & Research Assistant Powered by AI
    3
    1. tiendat 17 Oct 2025
      A crucial operational maxim is to "be stubborn on the vision and flexible on the details," acknowledging that this flexibility is necessary because the world is changing [1].

      Important

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    notebooklm.google.com/notebook/1c3d7ed9-67f7-4306-a063-676868e32c44
  39. beautifulangle.com beautifulangle.com
    Tinsel - Beautiful Angle Letterpess Poster Tacoma WA
    1
    1. Nora_Gill 17 Oct 2025
      Tinsel$65.0024 in stockThe Tinsel letterpress poster was written, designed, carved and printed in November 2017, in Tacoma, Washington.24 in stock Tinsel quantity Add to cart Categories: 2017, November Tags: Christmas, Split Fountain Description DescriptionThe Tinsel letterpress poster is a three-color printer, using a splint fountain. The text was printed with vintage lead type. The image was created with a combination of a hand-carved linocut and an assortment of vintage lead borders. 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      TEXT- This poster encourages people to focus less on the material aspect like tinsel and lights and instead welcoming others and showing compassion. This poster through the use of "holy" and "prayers" shows Christian values, reminding others that the true spirit of Christmas is love, connection not materials. The font is bond and overall makes someone focus on the text.

      IMAGE- The background is diagonal gradient lines with yellow and sometimes orange, all coming together, symbolistic to people coming together. Lastly, there is a gradient of all the colors combined with the text "less tinsel more love" in cursive. This Overall the color usage gives off peace and more significance to the text.

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    URL

    beautifulangle.com/product/tinsel-is-a-beautiful-angle-poster-from-2017/
  40. www.nytimes.com www.nytimes.com
    Netflix Jumps Into Podcasts With Spotify Deal
    3
    1. lemonke 17 Oct 2025
      The appetite for video podcasts is enormous. According to a recent study by Cumulus Media, 72 percent of podcast listeners say they prefer shows with video.

      I think that this especially applies to my generation. It can be hard for us to just sit and listen to something without loosing focus. Our attention span is much greater when we can actually watch and see what's going on. That's what I think is so great about having this choice now to either just listen on Spotify or watch on Netflix.

    2. lemonke 17 Oct 2025
      “With video podcasts on the rise, our partnership with Spotify ensures we bring the full video versions of these top shows to Netflix and Spotify,” Lauren Smith, a vice president at Netflix, said in a statement. She added: “This offers more choice to creators and unlocks a completely new distribution opportunity.”

      I didn't think about this at first how big of an opportunity this is for the creators of the podcasts being able to have their videos on Netflix. It really opens up a whole new audience for them considering the millions of people subscribed to Netflix. I think it's really cool that this not only is a great opportunity for Netflix but also the podcast creators.

    3. lemonke 17 Oct 2025
      The streaming giant announced a partnership with the audio company Spotify on Tuesday that would bring numerous video podcasts on sports, culture, entertainment and true crime to Netflix early next year.

      As soon as I saw this article title I immediately was interested considering I use both Netflix and Spotify very often. I think this is actually super smart. Podcasts have increasingly became more and more popular, especially video versions where people can actually watch the podcast, so I imagine this will bring in a lot of money for the companies.

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    nytimes.com/2025/10/14/business/media/netflix-spotify-podcast-deal.html
  41. thewasteland.info thewasteland.info
    t. s. eliot – annotated
    5
    1. ellagoldsmith 17 Oct 2025
      DA

      In the final lines of the part (and the poem), we finally hear from the divine. I have established, throughout this part of the poem, an equality and symbiosis between the divine and the natural, whether that is the wind and the chapel or the thunder or the “third walking beside you.” With this in mind, the words from the Thunder, “DA,” stand out as a calling from the divine, perhaps a respite or a sign of holiness, in a waste land, where the lack or disappearance of a god has been repeatedly referenced. These words, from the Thunder to the readers and inhabitants of The Waste Land, perhaps signify an end to the perilous conditions that they have been living under, a savoir, at last, from the human-induced nightmare we have all been living in.

      Ira’s reading of the line “DA” stuck out to me during tonight’s reading. In the narrative of the poem, we are presented with the lines “Then spoke the thunder/DA,” suggesting that this is, finally, “What the Thunder Said.” Interestingly, Ira’s reading of this line splits the term “DA” into the prefix for the three proceeding words, “datta,” “dayahadvam,” and “damyata.” All of which were meant to represent the interpretations of the thunder’s words to the different groups – gods, humans, and demons. What interested me the most about her annotation, however, was the question that she indirectly asks in the second paragraph, do we care more about the interpretations of the thunder’s words than the true words themselves? She further asks “what if “da” were intended to encompass all three meanings?”

      With this in mind, it makes me wonder: To what degree do the Thunder’s words matter at all? Clearly, they acted as a stem, a savoir for the datta,” “dayahadvam,” and “damyatal;” however, the meanings and suffixes of these words were all human creations. Perhaps what Eliot is suggesting is that we don’t need to look for guidance or a savoir from our action-induced reality, perhaps we have the answers within ourselves, though they may seem to be too divine or grand for human creation and understanding. Do we need to look outward to find the solution to The Waste Land?

    2. ellagoldsmith 17 Oct 2025
      There is the empty chapel, only the wind’s home.

      This line with an “empty chapel” is a direct reference back to Weston’s chapter on the Perilous Chapel. In some of the Grail legends, Gawain (or Perceval) stumble upon the empty chapel on their way to the Grail Castle. In Gawain’s legend, he finds himself stuck at a crossroads, deciding to take shelter in the chapel. Once inside, he sees a large hand and hears a voice from underneath the building. When he leaves, the night is clear. Perceval’s story is largely similar, however, in his version, there is a dead knight on the altar, slain by a Black Hand, which is actually the Devil, whom he fights to save the enchantment upon the chapel. This line, from Eliot’s poem, makes reference to these wandering knights, looking for shelter amid the storm, only to find further chaos inside.

      This chapel, in the narrative of “What the Thunder Said,” acts as a supposed refuge for the wasted land outside – a world of rock and no water, unfit for human habitation. This chapel (an obvious religious reference) acts as one's connection to divinity and religion in the harsh environment. As a result of this connection, the wording of an “empty chapel” denies the existence of an omnipresent god among us (perhaps contradicting the “other one” who walks on the other side of the speaker’s partner). As a reference to the Grail Legend as well, this empty, God-less chapel also aligns well with the Devil’s presence in the Perilous Chapel. In both tales, the narrative follows a protagonist seeking refuge from their environment, only to face the wrath of divinity (or lack thereof). This contrast, between the natural forces and divine, begs the question of which is stronger? In the Grail legend, the two are at odds, with the knight forced to choose between the storm or death at the hand of the Black Hand. In the Waste Land, though, the force or presence of God is completely diminished, with “only wind’s home.” This suggests that the natural world, in all of its rocky and thunderous glory, holds power over the divine.

      Furthermore, the second part of the phrase “only the wind’s home” provides two contrasting perceptions of the “empty chapel.” As it is written, Eliot marks the word “wind” with a possessive “‘s,” noting that the “empty chapel” is the home of the wind. While this reading suggests ownership of the chapel by the wind, another reading could be a conjunction between the “wind” and perhaps the word “is,” with the apostrophe used as a placeholder for the “i,” leading to a “wind’s home” that means the “wind is home.” While I am unsure what this could be suggesting, I think that it is cool to think about, especially given my contribution to the website on punctuation.

      Conversely, Scholar Anthony Hu took this notion of an empty chapel as a continuation of the “collapse of towers – and of the ‘Unreal City.’” He said that “since churches only survive as witnesses of the replacement of divinity with human industrial progress, their destruction is reminiscent of the ruination of the gargantuan Tower of Babel, where the collective hubris of humans is met with devastating consequences.” I think these two opposing views of the Chapel – one rooted in civilization and industrialization, while the other harks back to tales from the 12th century – showcase the multiplicity and repetition of civilization, a cycle continually touched on by Eliot throughout The Waste Land. In his reading, the chapel stays as a religious figure, standing the test of time through its connection with God. In the Weston reference, though, the chapel is stripped of its religious significance–aligning more closely with the wind and surrounding forest than the “unreal cities.”

    3. sofiarasic 17 Oct 2025
      Datta: what have we given? My friend, blood shaking my heart The awful daring of a moment’s surrender Which an age of prudence can never retract By this, and this only, we have existed Which is not to be found in our obituaries Or in memories draped by the beneficent spider

      This is quite a confusing section. Upon reading it, I was both captivated and extremely perplexed, however, I will try my best to unpack the significance of these lines. 1. Datta. A Hindu custom, "Datta" most nearly translates to "give", an act performed without the intention of receiving transactional reward. In TWL, the narrator asks, "what have we given?" (402). The question is rhetorical, for both the reader and the speaker know the answer: nothing at all. Humanity, as the narrator suggests, has grown incapable of generosity or surrendering selfishness. In doing so, they have strayed way from the ideals of religion or morality (in this case, Hindu customs), and have become estranged from both divine grace and one another. 2. However, the narrator also introduces a sort of hope for humanity's redemption. While acknowledging the depth of human selfishness, he exhibits a brief instance of grace: "The awful daring of a moment's surrender / Which an age of prudence can never retract" (405-6). In the selfless act of "a moment's surrender", human life finally achieves meaning, as existence, for Eliot, is not defined by the literal act of living, meaningless achievement, or worldly possessions, but in the moments in which people choose to open their hearts to others and offer genuine love and compassion Of course, this essential element of humanity remains invisible to history: it cannot be expressed in obituaries or in other physical elements of our legacy that we leave behind. However, what transcends history, what endures silently and often unnoticed, is what is actually the true essence of human existence: the act of giving and/or surrender. That is where the narrator locates the opportunity for redemption for a morally corrupt and disjunct mankind.

    4. LucaswRuiz 16 Oct 2025
      Damyata: The boat responded

      Datta means "give," dayadhvam means "be compassionate," and damyata means "be self-controlling." Eliot's footnote cites these three Sanskrit words from the Brihadaranyaka Upanishad, where the thunder speaks "DA DA DA" to gods, humans, and demon. The reference to a boat in the damyata section (lines 418-422) deliberately contrasts with earlier water imagery. As Scholar Marisin observes, “Earlier references to 'death by water' and 'drowned sailors' immediately fills the mind with dread at the mere implication of the liquid, yet here the ‘sea was calm” and the hand is an “expert with sail and oar.” This shift from threatening to tranquil water happens because a prophetic voice can finally appear in the Wasteland. When the thunder speaks, it represents authentic divine revelation rather than Madame Sosostris's fraudulent fortune-telling. The spiritual chaos that has defined the poem momentarily stills, just like the sea. The fortune of the sailor takes on new meaning here. Madame Sosostris warned "Fear death by water" (line 55), and we saw Phlebas the Phoenician drowned in Part IV. But the damyata section reframes water entirely. The boat "responded / Gaily" to "controlling hands" (lines 418, 422). This isn't about technological mastery over nature but rather the heart "beating obedient" (line 421) to spiritual discipline. Damyata as self-control leads to harmony rather than drowning.

    5. williambecker 16 Oct 2025
      Ganga was sunken, and the limp leaves Waited for rain, while the black clouds Gathered far distant, over Himavant. The jungle crouched, humped in silence.

      The first lines of the stanza stuck out to me, as a contrast from the final lines of the previous stanza where there is “a damp gust bringing rain.” Imagery of water abounds here, a break from the water/rock section found earlier, where the word “water” is hyper-present, but water itself is missing, creating a desert, or a waste land. In this passage the wind is “damp” and brings “rain,” water seeping into the imagery of the poem in reality. The imagery appears to continue in this passage, with the language of “sunken” and the mention of “Ganga,” another word for the river Ganges. However, upon closer inspection, the images here evoke the barren land of before, with rain clouds “distant,” leaves still “limp,” a landscape “waiting for rain.” The storm is on the horizon, anticipation plaguing the landscape, “the jungle crouched” waiting to pounce, to soak up the water that has not appeared yet, but is closer than ever. In her annotation on this section, specifically the line “bringing rain,” Jeannie argues “The irony of waiting (p)ages for something so abrupt simulates the imbalanced power dynamic between gods and men.” The gods, in her interpretation, are in control of the rain, refusing that the water be distributed in the hands of the men, until finally they break the dam and the rain flows. The gods toy with the humans to an even greater degree, explaining the discontinuous nature of the timeline. They give rain, then take it away, leaving a landscape “sunken” and “limp,” still in the state of anticipation. I find an interesting connection between this and the Anniversary Papers, where Kittredge writes “the Brahmans are never wear of inculcating the duty of free-handedness, and deem it more blessed to give than to receive.” In TWL, that attitude remains, the people and the land giving all they have, waiting to receive water. The gods don’t give rain, allowing the land to wait, anticipation building, blessing them, as they are giving and not receiving. This implies a double standard, where the land and the people must follow the rules of the gods, but the gods are not held to those same standards, a potential reflection of the elitism that destroyed the waste land as a public space.

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    thewasteland.info/2025-2/
  42. aiarchives.org aiarchives.org
    A.I. Archives | Save, Share, and Cite Generative A.I.
    1
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    aiarchives.org/id/tZgykyDEJrdlnO0ZVvt7
  43. structseeker.github.io structseeker.github.io
    An introduction to Topological Data Analysis: fundamental and practical aspects for data scientists
    1
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    structseeker.github.io/hypothes.is.pdf.mobile/viewer/web/未知 - An introduction to Topological Data Analysis_ fundamental and practical aspects for data scientists.pdf
  44. social-media-ethics-automation.github.io social-media-ethics-automation.github.io
    9.1. Privacy
    1
    1. gfong07 17 Oct 2025
      We might want a conversation or action that happens in one context not to be shared in another (context collapse)

      This is an interesting case of wanting to keep privacy. It depends on how dire the situation goes in order for a site to have to step in. Imagine if two people were planning a crime using the direct messaging system, would it be ethical for the site to step in? Discussing sensitive content should be private but it depends if the conversation can cause direct harm to others. But this brings up another issue in bullying and harassment which is frankly commonplace in sites like these.

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    social-media-ethics-automation.github.io/book/bsky/ch09_privacy/01_privacy_concerns.html
  45. social-media-ethics-automation.github.io social-media-ethics-automation.github.io
    9.7. Bibliography — Social Media, Ethics, and Automation
    1
    1. gfong07 17 Oct 2025
      Rosie Hopegood. The perils of ‘sharenting’: The parents who share too much. Al Jazeera, October 2020. URL: https://www.aljazeera.com/features/2020/10/11/facing-the-music-the-parents-who-share-too-much (visited on 2023-12-06).

      This is a really interesting debate. When it comes to parents sharing photos of their kids, it could be seen as sensitive information. It’s a question on if social media can be seen as a trusted way to communicate with friends and family rather than people who might want to use your information for themselves. I’ve seen certain internet personalities share photos of their children which seems strange since with their large followings, it will attract unwanted attention to the kid who doesn’t even know they are being posted to the internet.

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    social-media-ethics-automation.github.io/book/bsky/ch09_privacy/07_bibliography.html
  46. human.libretexts.org human.libretexts.org
    14: Assignment Resources for Instructors
    1
    1. kayla_67 16 Oct 2025
      The goal of this assignment is to get you to think more deeply about how we are consuming information.

      I think that this sentence means that however your brain understands how to remember information really connects more deeply to yourself.

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    human.libretexts.org/Bookshelves/Literature_and_Literacy/Literacy_and_Critical_Thinking/Critical_Thinking_and_Information_Literacy_(Pogue)/14:_Assignment_Resources_for_Instructors
  47. social-media-ethics-automation.github.io social-media-ethics-automation.github.io
    8.5. Activity: What platforms think of you — Social Media, Ethics, and Automation
    1
    1. gfong07 16 Oct 2025
      How comfortable are you with Google knowing (whether correctly or not) those things about you?

      I think that overall it’s not great that they know so much about me considering they sell it for profits, but it also personalizes my experience on their platforms. It makes sense that I am not getting recommended videos in other languages or for certain interests that I don’t pay attention to. Overall, it is scary of how much information and control sites like Google have on everyone but it’s not that big of a deal at this point since it is meant for recommendations and interaction more than anything.

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    social-media-ethics-automation.github.io/book/bsky/ch08_data_mining/05_what_platforms_think_of_you.html
  48. human.libretexts.org human.libretexts.org
    13: Professional Conversations
    1
    1. kayla_67 16 Oct 2025
      Presenting a well researched and reasoned argument in your writing can be pivotal to achieving goals.

      I think this sentence means that how you write your story or sentence can really do you good and help others really understand your point.

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    human.libretexts.org/Bookshelves/Literature_and_Literacy/Literacy_and_Critical_Thinking/Critical_Thinking_and_Information_Literacy_(Pogue)/13:_Professional_Conversations
  49. onlinelibrary.wiley.com onlinelibrary.wiley.com
    Individualization of Extended Family Bonds? An Analysis of Youth Narratives from Three Dutch Generations
    15
    1. Murp2096 16 Oct 2025
      emotional family functions did not holdthe greatest significance for the youngest generation, and the analysis did not reveal an increasein the instability of extended family bonds across generations

      The study proved that while it's true family roles are shifting and individual choice is increasing, it's not causing instability in extended family bonds. (the case is against intergenerational change associated w individualization)

    2. Murp2096 16 Oct 2025
      Characteristics of individuals (both of the participants and theirextended family members), their (nuclear) families, the living environment, and the specificsociohistorical context were perceived by participants as highly influential, sometimes evendetermining their extended family bonds.

      Thye study showed that characteristics, nuclear family, living environment, and social and historical context influenced their extended family bonds

    3. Murp2096 16 Oct 2025
      intergenerational transmission of kinship norms could actas a counterbalance to changes in extended family bonds associated with individualization

      The reason that there isnt the change associated with individualization that theorists expected, is because there are factors being passed through generations are working against it.

    4. Murp2096 16 Oct 2025
      Moreover, the continuing impor-tance of traditional family contact, the shared intergenerational experience of declining familycontact in youth, and the transmission of kinship norms across generations, argue for inter-generational continuity rather than change associated with individualization.

      continuing importance of traditional family contact. Shared experience of declining family contact at a certain age over generations and passing down norms/ideas about family argue that there isn't change associated with individualization. rather the family dynamic stays the same throughout generations

    5. Murp2096 16 Oct 2025
      intergenerational transmission of family normsmay inhibit intergenerational changes in extended family bonds, such as those associated withindividualization, thereby acting as a counterbalance to the individualization of these bonds.

      family norms being passed through generations may prevent changes in extended family bonds. counterbalancing the idea that people will choose their extended family bonds

    6. Murp2096 16 Oct 2025
      A few participants explicitlyattributed this difference to the nature of youth as a life phase, during which they grew moreindependent from their families in general.

      Instability wasn't found by generations over time, but by the age when children grew more independent

    7. Murp2096 16 Oct 2025
      In general, individual choice with whom to have a family bond seemed to play a moreimportant role in the extended family narratives of the youngest generation. This could bederived from the finding that the youngest participants more often explained their family con-tacts in a more detailed and elaborate manner compared to participants from the two oldestgenerations.

      Younger generations where more detailed and elaborate than older generations when describing the bonds of extended family. (Because younger generations chose which bonds where important to them and wanted to keep.)

    8. Murp2096 16 Oct 2025
      intergenerational transmission

      intergenerational transmission- the process of values, beliefs, behaviors, and characteristics being passed down through generations

    9. Murp2096 16 Oct 2025
      The three generations were similar regarding gender distribution, religion, andliving environment during their youth

      not a very diverse group of people, could be missing factors in the results

    10. Murp2096 16 Oct 2025
      However, the iterative process of cod-ing, refining codes names and relationships, and theory development continued until no newtheoretical insights emerged, indicating theoretical saturation (Charmaz, 2014; Flick, 2019)

      This entire process is how they ended up with 14 families that explored most or all possible info and theories

    11. Murp2096 16 Oct 2025
      he use of sensitiz-ing concepts in the initial coding phase

      being aware and sensitive to nuances and complexities in data. They started this way so that other themes could still be revealed

    12. Murp2096 16 Oct 2025
      This approach allowed emerging questions and provi-sional theories—such as the impact of specific personal characteristics—to guide the selectionof the next family to be analyzed.

      They had a software program perform coding to pick which interviews would be analyzed based off the amount of info given related to the topic, emerging questions from people analyzing data, and provisional theories

    13. Murp2096 16 Oct 2025
      All of the participants were interviewed in per-son, most of them in their own home. B

      probably to make them feel more comfortable, since this subject can be sensitive

    15. Murp2096 16 Oct 2025
      The use of preexisting datameant that the data had to be sorted and special consideration had to be given to the selectionof the interviews, as the scope of the primary study for which the data were collected extendedbeyond the focus of the present study (Heaton, 2004: Long-Sutehall et al., 2011).

      The interviews had to be carefully picked and studies because the original study at the time of the interviews had a wider focus than this study

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    onlinelibrary.wiley.com/doi/pdfdirect/10.1111/fare.13183
  50. human.libretexts.org human.libretexts.org
    12: Misinformation and Fake News
    1
    1. kayla_67 16 Oct 2025
      Fake News: Sources that entirely fabricate information, disseminate deceptive content, or grossly distort actual news reports.

      I think this sentence shows that anyone can make a false report or say something that is untrue about anything.

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    human.libretexts.org/Bookshelves/Literature_and_Literacy/Literacy_and_Critical_Thinking/Critical_Thinking_and_Information_Literacy_(Pogue)/12:_Misinformation_and_Fake_News
  51. human.libretexts.org human.libretexts.org
    11: Confirmation Bias and Filter Bubbles
    1
    1. kayla_67 16 Oct 2025
      Filter bubbles are outside forces that affect the information we take in. But, there's also a lot of stuff going on in our own brains that influences the way we take in and interpret information. This is called confirmation bias.

      Our brains filter things and information that we want to hear if it doesn't interest our brains then we just ignore whatever is going on.

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    human.libretexts.org/Bookshelves/Literature_and_Literacy/Literacy_and_Critical_Thinking/Critical_Thinking_and_Information_Literacy_(Pogue)/11:_Confirmation_Bias_and_Filter_Bubbles
  52. www.insidehighered.com www.insidehighered.com
    Are AI skills a key part of career preparation in college?
    5
    1. riaramos07 16 Oct 2025
      If, as some experts believe, AI skills are critical for the future of work, the question becomes how to deliver these skills equitably across academic programs

      Heavy reliance on AI can negatively impact important critical thinking skills and stunt intellectual betterment. Although experts think AI skills are important for future jobs, it should be highlighted that there should be a blend of knowledge of AI use and genuine intelligence that will be valued.

    2. riaramos07 16 Oct 2025
      Some of DiLellio’s M.B.A. students use ChatGPT to run analytical calculations, similarly to how they would in Excel, for a faster and more efficient computation.

      Many are against use of AI in classrooms but it is important to recognize that AI's like chatgpt can be used as learning tools.

    3. thumbsup 16 Oct 2025
      “I am afraid to be flagged, so I refrain from utilizing it at all,” a junior from Florida Gulf Coast University wrote in the Student Voice survey.

      Ai makes it difficult even for those who don't use it to pass their classes.

    4. thumbsup 16 Oct 2025
      A majority of U.S. students believe use of generative AI tools should be limited in assessed work (53 percent), and 10 percent believe it should be banned.

      Most agree that generative ai prevents an actual education.

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    insidehighered.com/news/student-success/life-after-college/2024/10/03/are-ai-skills-key-part-career-preparation
  53. human.libretexts.org human.libretexts.org
    10.4: Text Description Profits by Industry Graphic
    1
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    human.libretexts.org/Bookshelves/Literature_and_Literacy/Literacy_and_Critical_Thinking/Critical_Thinking_and_Information_Literacy_(Pogue)/10:_Information_Value_and_Privilege/10.04:_Text_Description_Profits_by_Industry_Graphic
  54. www.smogon.com www.smogon.com
    Incineroar | SV | Smogon Strategy Pokedex
    1
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    smogon.com/dex/sv/pokemon/incineroar/vgc/
  55. human.libretexts.org human.libretexts.org
    10.3: Text Description - Digital Divide Information Graphic
    1
    1. kayla_67 16 Oct 2025
      60% of the world's population is offline

      I think this sentence means that not everyone gets the same life and not everything is handed down to them. Although some poeple don't have phones and electronics that is actually a bonus for their mental health.

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    human.libretexts.org/Bookshelves/Literature_and_Literacy/Literacy_and_Critical_Thinking/Critical_Thinking_and_Information_Literacy_(Pogue)/10:_Information_Value_and_Privilege/10.03:_Text_Description_-_Digital_Divide_Information_Graphic
  56. inst-fs-iad-prod.inscloudgate.net inst-fs-iad-prod.inscloudgate.net
    untitled
    9
    1. emj73 16 Oct 2025
      dentify protein ‘cocktails’essential for developing normal immune function

      This ending feels like we’re still guessing at nature’s perfect recipe or secret formula for balance. Maybe it’s not about finding the perfect “cocktail” but about preserving natural variety so we never have to recreate it in a lab...

    2. emj73 16 Oct 2025
      polyfloral diets enhanced someimmune functions

      The polyfloral effect might reveal a deeper evolutionary truth. And that is that specialization (monoculture feeding) is efficient but fragile while diversity creates resilience. That principle applies to ecosystems and even social systems sometimes

    3. emj73 16 Oct 2025
      bees would invest more resources insocial rather than individual immunity

      This is such an interesting trade off. It makes me think of public health.. where limited resources go to community wide defenses like vaccines rather than personal treatments

    4. emj73 16 Oct 2025
      polyfloral diets induced ahigher GOX activity

      This data point could be the quiet headline of the whole paper in my opinion. Its that diversity literally scales up collective protection. It’s almost evolutionary logic: diversity strengthens the hive’s social fabric

    5. emj73 16 Oct 2025
      Control beeshad a higher haemocyte concentration comparedwith bees fed with pollen

      This result flips expectations, bees without protein having more haemocytes seems counterintuitive. Maybe their bodies are over producing defense cells out of stress like short term gain, long term exhaustion

    6. emj73 16 Oct 2025
      polyfloral diets that had the same amount of protein as monofloraldiets (table 1).

      Controlling for total protein was clever. It isolates diversity as its own variable. But it also exposes how easily research on nutrition can oversimplify. equal protein doesn’t mean equal nutrition if amino acid profiles differ. Bees like us, probably need balance not bulk.

    7. emj73 16 Oct 2025
      So, we also analysed glucose oxidase (GOX)activity as a parameter of social immunity

      The idea of “social immunity” is so underrated. Instead of focusing only on the individual bee’s health the study treats the colony like a single organism with shared defenses. That could reshape how we think about disease prevention in other social species.. even humans

    8. emj73 16 Oct 2025
      honeybee populations have been decliningover the last year

      The authors subtly connect diet to colony collapse but it makes me think... are we looking at nutrition as a cause or as a symptom?? Maybe poor floral diversity reflects an already imbalanced ecosystem that’s failing on multiple levels.

    9. emj73 16 Oct 2025
      diet diversity increasedIC levels

      It’s fascinating that diversity, not just quantity drives immune strength. This almost parallels human nutrition. And suggests that health might rely more on variety than abundance. I wonder if monoculture farming could indirectly weaken pollinator immunity by limiting their like “immune menu" I guess

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    inst-fs-iad-prod.inscloudgate.net/files/86e51cd3-f7ec-4504-b258-7e0a46e33983/Alaux et al. 2010_diet effects on honeybee immunocompetence(1).pdf
  57. human.libretexts.org human.libretexts.org
    10.1: Information Value and Privilege Details
    1
    1. kayla_67 16 Oct 2025
      I mentioned that academics have been pushing for more open access.

      I think this sentence means that there are many different teachers and professors want research to be free to everyone instead of having to pay for subscriptions.

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    URL

    human.libretexts.org/Bookshelves/Literature_and_Literacy/Literacy_and_Critical_Thinking/Critical_Thinking_and_Information_Literacy_(Pogue)/10:_Information_Value_and_Privilege/10.01:_Information_Value_and_Privilege_Details
  58. www.creativedelightstudio.com www.creativedelightstudio.com
    Personal Portraits Workshop
    11
    1. candocontent 16 Oct 2025
      THIS IS IT!

      Can you add a short section above this final invite to join that touches on the promise on the course? 'This course will take you from x to y/ This program will help you.../ Imagine being having all the resources and guicance to confidenctly ...

    2. candocontent 16 Oct 2025
      what will this workshop be like? If you've never tried a Zoom workshop before, you're in for a treat! how it works: When the course begins, you’ll have instant access to all the Mixed Media Art tutorials.

      This is really hard to read, and I'm actually not sure it adds anything. So possibly remove it?

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    URL

    creativedelightstudio.com/personalportraits-new
  59. beautifulangle.com beautifulangle.com
    Repent - Beautiful Angle Letterpess Poster Tacoma WA
    1
    1. lailahypothesis 16 Oct 2025
      Repent$500.003 in stock

      Repent:

      TEXT: The poster Repent references belief that America has failed Jesus through it's language. While the text references Jesus many times, to me it seems available to many different audiences because of how broad the religious language is. Whether it be Christianity, a major religion in the US and Tacoma, or people who don't view themselves as religious or people of other religions involving the figure of Jesus such as Islam, I would argue that most people can interpret the posters text as long as they're familiar with the figure of Jesus and the US current/past social and political standings.

      COLOR: The colors of the poster Repent contribute to the religious messages. The poster uses orange, yellow, and blue as the colors of the print with a white background. The use of yellow and orange, both warm colors which represent humanity, color the image's sun and heart, which can be interpreted as symbols of Jesus. The blue is used as the color of the text, language which speak about a need to repent for wrong doings. Blue, a color associated with sorrow and cleanliness, represents the texts message.

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    beautifulangle.com/product/repent-is-a-beautiful-angle-poster-from-2007/
  60. docdrop.org docdrop.org
    view
    3
    1. aliyah.duarte 16 Oct 2025
      Despite supportive parents who expressed concern about her situa-tion, Terri said she was a "very depressed child." Her father would have conversations with her "about being Black and beautiful" and about "the union of people of color that had always existed that I needed to find. And the pride." However, her parents did not have a network of Black friends to help support her.

      This is extremely worrisome to me. As someone who aspires to work with children in emotional and behavioral contexts, hearing that there are children who become depressed because of societal circumstances and not personal events makes me wonder what protections and reforms should happen in education in order to keep vulnerable populations from being exposed to hate at school.

    2. aliyah.duarte 16 Oct 2025
      As has been rhe case historically, these parents of color see college education as the ticket to their children's life chances, yet too often their children's aca-demic performance lags behind that of their White counterparts.

      This is a statement that resonates with me. As a Hispanic student myself, the message that in order to succeed in life, you must obtain a college degree is encouraged and repeated to us as motivation. The fact that White parents don't push this onto their children makes me wonder if it is because academically, their schools have always been better in terms of opportunity, and has given them the option to see college as "just another option" and not their ticket to success.

    3. aliyah.duarte 16 Oct 2025
      In the context of predominantly White schools, however, Black boys may enjoy a degree of social success, particularly if they are athletically talented. The culture has embraced the Black athlete, and the young man who can fulfill that role is often pursued by Black girls and White girls alike.

      I think even this is a stereotype that can be harmful to Black students. Why should we only celebrate a Black student if they are bringing their high school football team to state championships? It creates an expectation or pressure on Black students to be good at something for the approval of their white peers.

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    docdrop.org/download_annotation_doc/Tatum-Ch-4-Identity-Development-Why-are-all-the-Black-kids-s-n8pnx.pdf
  61. Local file Local file
    Untitled document
    2
    2. majenm 16 Oct 2025

      moral education of patriotism

      to be a patriot is to be in favor of the country even when the country is unjust, at least when its taught in many cases

      moral education of loyalty--but to what?

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  62. nmoer.pressbooks.pub nmoer.pressbooks.pub
    Chapter 39: Informative Research Reports
    5
    2. gpaquin1 16 Oct 2025
      Thus, Tier Two sources can provide quality information that is more accessible to non-academics. There are three main categories. First, official reports from government agencies or major international institutions like the World Bank or the United Nations; these institutions generally have research departments staffed with qualified experts who seek to provide rigorous, even-handed information to decision-makers. Second, feature articles from major newspapers and magazines like the New York Times, Wall Street Journal, London Times, or The Economist are based on original reporting by experienced journalists (not press releases) and are typically 1500+ words in length. Third, there are some great books from non-academic presses that cite their sources; they’re often written by journalists. All three of these sources are generally well researched descriptions of an event or state of the world, undertaken by credentialed experts who generally seek to be even-handed.

      Teir Two Sources: official reports from government agencies or major institutions; studies that submit statistics within communities? Magazines, books from non-academic presses that cite their sources written bb y journalists

    3. gpaquin1 16 Oct 2025
      Scholarly articles appear in academic journals, which are published multiple times a year in order to share the latest research findings with scholars in the field

      similar to state legislative updates that are published annually for the courts/attorney's (reference to my own paper)

    4. gpaquin1 16 Oct 2025
      highlight specific information about your topic. In this project, you may be asking “after researching general aspects about my topic, what do I want others to understand about it?”

      keep audience in mind when writing essay as well

    5. gpaquin1 16 Oct 2025
      The Informative Research Report is a report that relays the results of a central research question in an organized manner through more formal sources. These resources could include Google Scholar, library catalogs and academic article databases, websites of relevant agencies, and Google searches using

      based off research question through formal resources

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    nmoer.pressbooks.pub/english1101/chapter/chapter-30-1-exploratory-essays-and-informative-research-papers-mytext-cnm/
  63. jardin.cc jardin.cc
    Des-programar en clítoris, por LaGuerraRuda
    2
    1. Nina_rojkind 16 Oct 2025
      La parte más grande del clítoris está oculta; apenas podemos ver una pequeña punta

      El cuerpo femenino casi siempre se ha entendido a través de un esquema visual patriarcal (solo existe para fines reproductivos, estéticos y / o médicos) y lp que queda fuera de esta mirada se vuelve inexistente. Esto no es casual es totalmente político ya que hay una relación entre lo que no se representa y lo que no se puede experimentar. El que haya sido invisibilizado durante tanto tiempo es una forma de controlar el placer y de negar la anatomía propia del cuerpo. Esto igual funciona como una metáfora para los sistemas de poder en general en donde todo lo que sale de la norma se tapa, se borra o se vuelve una amenaza. Desprogramar entonces sería una forma de reconfigurar nuestro conocimiento a través de lo que se nos ha negado o escondido.

    2. Nina_rojkind 16 Oct 2025
      Aprender haciendo, repitiendo para el disfrute, construyendo de la experiencia, explorando siempre sin otro fin más que seguir disfrutando.

      En una sociedad que mide todo en términos de productividad el hacer algo simplemente por placer es un acto de resistencia. Desprogramar el clímax también sería una forma de desarmar la manera en la que el capitalismo entiende el cuerpo humano (como una máquina funcional). Así se podría habitar un cuerpo que existe sin objetivos externos.

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    jardin.cc/material/des-programar-en-clitoris-por-laguerraruda/