POetry at the eisteddfod, while with a medieval flavour, sought to use the past to legitimise themselves

Link to eistedfodd

good quote!

Medieval revival kinda was aided by the growth of nonconformity and scholarly thinking that medieval times saw welsh church og not affilitated with rome

Interesting - did people even accept the pre-raphelite medieval revival? Had close links to catholicism.

The art style was also used to assert dominance - not exactly very nationalist is it

A popular archtectural style that was impressive - was this nationalism

Medieval revival with william bute's castle possibly due to his catholic beliefs? idksome architect said that gothic was the true religious art style?

SLAYYY very important

Quelles sont-elles?

Pathologie de l'usage d'internet en général

Usage du "tout le monde" comme généralité absolu sans fondement scientifique. En fait un simple avis.

eLife Assessment

This study addresses a fundamental question in glycobiology by elucidating how a single-site processive enzyme orchestrates the alternating addition of sugars to synthesize complex polysaccharides such as hyaluronan. The findings are exceptional and compelling, providing a clear mechanistic framework supported by strong experimental validation. Major strengths include the integration of high-resolution structural data with rigorous biochemical analyses, resulting in a well-supported model of hyaluronan assembly.

Reviewer #1 (Public review):

Summary:

This revised manuscript describes critical intermediate reaction steps of a HA synthase at the molecular level; specifically, they examine the 2nd step, polymerization, adding GlcA to GlcNAc to form the initial disaccharide of the repeating HA structure. Unlike the vast majority of known glycosyltransferases, the viral HAS (a convenient proxy extrapolated to resemble the vertebrate forms) uses a single pocket to catalyze both monosaccharide transfer steps. The authors work illustrates the interactions needed to bind & proof-read the UDP-GlcA using direct and '2nd layer' amino acid residues. This step also allows the HAS to distinguish the two UDP-sugars; this is very important as the enzymes are not known or observed to make homopolymers of only GlcA or GlcNAc, but only make the HA disaccharide repeats GlcNAc-GlcA.

Strengths:

Techniques & analysis; overview of HA synthase mechanisms

Weaknesses:

None

Comments on revisions:

Previous clarity issues in the original submission were all resolved. Again, this is a very well done body of work!!

Reviewer #2 (Public review):

Summary:

The paper by Stephens and co-workers provides important mechanistic insight into how hyaluronan synthase (HAS) coordinates alternating GlcNAc and GlcA incorporation using a single Type-I catalytic centre. Through cryo-EM structures capturing both "proofreading" and fully "inserted" binding poses of UDP-GlcA, combined with detailed biochemical analysis, the authors show how the enzyme selectively recognizes the GlcA carboxylate, stabilizes substrates through conformational gating, and requires a priming GlcNAc for productive turnover.

These findings clarify how one active site can manage two chemically distinct donor sugars while simultaneously coupling catalysis to polymer translocation.

The work also reports a DDM-bound, detergent-inhibited conformation that possibly illuminates features of the acceptor pocket, although this appears to be a purification artefact (it is indeed inhibitory) rather than a relevant biological state.

Overall, the study convincingly establishes a unified catalytic mechanism for Type-I HAS enzymes and represents a significant advance in understanding HA biosynthesis at the molecular level.

Strengths:

There are many strengths.

This is a multi-disciplinary study with very high-quality cryo-EM and enzyme kinetics (backed up with orthogonal methods of product analysis) to justify the conclusions discussed above.

Comments on revisions:

The suggestions made in the initial comments have all been responded to very well.

Author response:

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

Public Reviews:

Reviewer #1 (Public review):

Summary:

This manuscript describes critical intermediate reaction steps of a HA synthase at the molecular level; specifically, it examines the 2nd step, polymerization, adding GlcA to GlcNAc to form the initial disaccharide of the repeating HA structure. Unlike the vast majority of known glycosyltransferases, the viral HAS (a convenient proxy extrapolated to resemble the vertebrate forms) uses a single pocket to catalyze both monosaccharide transfer steps. The authors' work illustrates the interactions needed to bind & proof-read the UDP-GlcA using direct and '2nd layer' amino acid residues. This step also allows the HAS to distinguish the two UDP-sugars; this is very important as the enzymes are not known or observed to make homopolymers of only GlcA or GlcNAc, but only make the HA disaccharide repeats GlcNAc-GlcA.

Strengths:

Overall, the strengths of this paper lie in its techniques & analysis.

The authors make significant leaps forward towards understanding this process using a variety of tools and comparisons of wild-type & mutant enzymes. The work is well presented overall with respect to the text and illustrations (especially the 3D representations), and the robustness of the analyses & statistics is also noteworthy.

Furthermore, the authors make some strides towards creating novel sugar polymers using alternative primers & work with detergent binding to the HAS. The authors tested a wide variety of monosaccharides and several disaccharides for primer activity and observed that GlcA could be added to cellobiose and chitobiose, which are moderately close structural analogs to HA disaccharides. Did the authors also test the readily available HA tetramer (HA4, [GlcA-GlcNAc]2) as a primer in their system? This is a highly recommended experiment; if it works, then this molecule may also be useful for cryo-EM studies of CvHAS as well.

The reviewer requested testing whether an HA tetratsaccharide could also serve as an glycosyl transfer acceptor for HAS. The commerically available HA tetrasaccharide (HA4) is terminated at its non-reducing end by GlcA, therein we proceeded to measure its effect on UDP-GlcNAc turnover kientics. Titration of HA4 failed to elicit any detectable change in UDP-GlcNAc turnover rate, indicating no priming. This is now mentioned in the main text and the data is shown in Fig. S9.

Weaknesses:

In the past, another report describing the failed attempt of elongating short primers (HA4 & chitin oligosaccharides larger than the cello- or chitobiose that have activity in this report) with a vertebrate HAS, XlHAS1, an enzyme that seems to behave like the CvHAS ( https://pubmed.ncbi.nlm.nih.gov/10473619/); this work should probably be cited and briefly discussed. It may be that the longer primers in the 1999 paper and/or the different construct or isolation specifics (detergent extract vs crude) were not conducive to the extension reaction, as the authors extracted recombinant enzyme.

We apologize for the oversight. This reference is now cited (ref. 18) together with the description of the failed elongation of HA4 by CvHAS.

There are a few areas that should be addressed for clarity and correctness, especially defining the class of HAS studied here (Class I-NR) as the results may (Class I-R) or may not (Class II) align (see comment (a) below), but overall, a very nicely done body of work that will significantly enhance understanding in the field.

Done as requested

Reviewer #2 (Public review):

Summary:

The paper by Stephens and co-workers provides important mechanistic insight into how hyaluronan synthase (HAS) coordinates alternating GlcNAc and GlcA incorporation using a single Type-I catalytic centre. Through cryo-EM structures capturing both "proofreading" and fully "inserted" binding poses of UDP-GlcA, combined with detailed biochemical analysis, the authors show how the enzyme selectively recognizes the GlcA carboxylate, stabilizes substrates through conformational gating, and requires a priming GlcNAc for productive turnover.

These findings clarify how one active site can manage two chemically distinct donor sugars while simultaneously coupling catalysis to polymer translocation.

The work also reports a DDM-bound, detergent-inhibited conformation that possibly illuminates features of the acceptor pocket, although this appears to be a purification artefact (it is indeed inhibitory) rather than a relevant biological state.

Overall, the study convincingly establishes a unified catalytic mechanism for Type-I HAS enzymes and represents a significant advance in understanding HA biosynthesis at the molecular level.

Strengths:

There are many strengths.

This is a multi-disciplinary study with very high-quality cryo-EM and enzyme kinetics (backed up with orthogonal methods of product analysis) to justify the conclusions discussed above.

Weaknesses:

There are few weaknesses.

The abstract and introduction assume a lot of detailed prior knowledge about hyaluronan synthases, and in doing so, risk lessening the readership pool.

A lot of discussion focuses on detergents (whose presence is totally inhibitory) and transfer to non-biological acceptors (at high concentrations). This risks weakening the manuscript.

The abstract and parts of the introduction have been revised to address the reviewer’s concerns.

Reviewer #1 (Recommendations for the authors):

(1) As noted above, please state in title, abstract & introduction that this work is focused on a "Class I-NR HAS" (as described in Ref. #4), and NOT all HAS families...this is truly essential to note as someone working with the Pasteurella HAS version (Class II) would be totally misled & at this point, no one knows the Streptococcus HAS (Class-IR) mechanistic details which could be different due to its inverse molecular directionality of elongation compared to the CvHAS Class I-NR enzyme.

Done as requested.

(2) Page 6 - for the usefulness of the HAS mutants as being folded correctly, it was stated these mutants are suitable since they all 'purify' similarly...the use of the more proper term should probably be 'chromatograph', similarly suggesting similar hydrodynamic radii without massive folding issues.

This has been revised to state that they all exhibited comparable size exclusion chromatography profiles.

“All mutants share similar size exclusion chromatography profiles with the WT enzyme, suggesting that the substitutions do not cause a folding defect (Fig. S3).”

(3) Page 7 - please check these sentences (& rest of paragraph?) as the meaning is not clear. "First, UDP-GlcNAc was titrated in the presence of excess UDP-GlcA, resulting in a response similar to the acceptor-free condition (Fig. 2C). However, the maximum reaction velocity at 20 mM UDP-GlcNAc was approximately 25% lower than that measured in the presence of UDP-GlcNAc only (Fig. 2C)."

The paragraph has been revised to avoid confusion.

(4) In Methods, please use an italicized 'g' for the centrifugation steps globally.

Changed as requested

(5) Please note the source/vendor for the HA standards on gels.

Done

(6) Page 35 - TLC section.

(a) 'n-butanol' (with italic n) is the most widespread chemical name (not butan-1-ol).

Done

(b) Also, for all of the TLC images, the origin and the solvent front should be marked.

Changed as suggested.

Reviewer #2 (Recommendations for the authors):

A number of minor issues should be addressed.

(1) Abstract

Two comments on the Abstract, which I found surprisingly weak given the quality of the work, and lacking a key detail.

A major conceptual contribution of this work is the demonstration of how a single Type-I catalytic centre discriminates, positions, and transfers two chemically distinct substrates in an alternating pattern. This distinguishes HAS from dual-active-site (Type-II) glycosyltransferases and is important for understanding HA polymerization.

However, this central point is not clearly articulated in the abstract. I suggest explicitly stating that HAS performs both GlcNAc and GlcA transfer reactions within a single catalytic site, and that the proofreading/inserted poses illuminate how this multifunctionality is achieved.

The abstract currently ends with the observation of a DDM-bound, detergent-inhibited state. While this is interesting, it absolutely does not represent the central conceptual advance of the study and gives the abstract an artefactual ending.

I strongly recommend revising the final sentences to emphasize the broader mechanistic insight and not an "artefact" (indeed, the enzyme is inactive in the presence of this detergent; it is thus a very unusual way to conclude an abstract).

That is, finish with the wider implications of how HAS coordinates alternating substrate use, proofreading, and polymer translocation. Ending on the main mechanistic or biological significance would make the abstract considerably stronger and more aligned with the main message of the paper.

The abstract has been revised thoroughly to reflect the important insights gained on CvHAS’ catalytic function and HA biogenesis in general.

(2) Introduction

The distinction between single active-centre enzymes, which transfer both sugars alternately, and twin catalytic domain enzymes that each perform one addition is surely central to the whole paper. But it is not discussed. Surely this has to be covered. There is a lot of work in this space, including, but not limited to:

https://doi.org/10.1093/glycob/cwg085

https://doi.org/10.1093/glycob/10.9.883

https://doi.org/10.1093/glycob/cwad075 (includes this author team)

Originally back to https://doi.org/10.1021/bi990270y

If the authors instead assume such a level of knowledge for the reader, then surely they are writing for a specialist audience, not consistent with the wider readership ambitions of eLife?

The Introduction has been revised as suggested by the reviewer, providing necessary background to frame our description of the Chlorella virus HAS. We made a deliberate effort to put new insights into a broader context.

(3) Results and Discussion

DDM "was observed for >50% of the analysed particles". I struggled with this. I couldn't understand how the authors selected particles that did or did not contain DDM. The main body text states: "To our surprise, careful sorting of the UDP-GlcA supplemented cryo EM dataset revealed a CvHAS subpopulation that was not bound to the substrate, but, instead, a DDM molecule near the active site (Fig 3A and S7). This was observed for >50% of the analyzed particles."

That reads like there is one sample with two populations. But the figures and the methods section suggest differently: they suggest two samples with different data-collection regimes. That does not match the main text. Could this be clarified?

Yes, that wasn’t explained well. We clarified the text to stress that the DDM-bound sample came from a dataset that was intended to resolve an UDP-GlcA-bound state, but instead revealed the inhibition by DDM.

Also in this space, in the modern world, "nominal magnification" has no real meaning, and calibrated pixel size would be more appropriate. Can this be given, please?

The relevant Methods section now states: “imaging of … was performed at a calibrated pixel size of 0.652 Å”.

The discovery of DDM in the active site is surprising. But it is an inhibitory artefact. Is this section pushed a little too hard? Also, "The coordination of DDM's maltoside moiety, an αlinked glucose disaccharide, is consistent with priming by cellobiose and chitobiose." I'm not sure why an α-linked maltose is consistent with the binding of a β-linked cellobiose. That makes no sense. There will be no other enzymes where starch and cellulose oligos are mutually accepted. Consider rewriting.

We like to stress the DDM coordination because it could lead to the development of compounds that can really function as inhibitors, either for HAS or other related enzymes. In the observed DDM binding pose, the alpha-linkage is not recognized. Instead, the reducing end glucosyl unit stacks against Trp342 while the non-reducing unit extends into the catalytic pocket. Hence, a similar binding pose is conceivable for cellobiose and potentially also for chitobiose. The relevant section has been reworded.

web-trail://💻/thinkpad/🧊/me/📓/2026/02/15/translated/ady-endre-magyar-pimodan

TODO

maps to local.link

eLife Assessment

This paper investigates the Achilles' heel of an aggressive pediatric bone cancer known as Ewing sarcoma. The authors aimed to better understand how its previously undruggable drivers mediate oncogenic mechanisms using several omics approaches. Transcriptomic changes aligned with their findings provide convincing evidence for the role of a short alpha helix in the DNA binding domain of FLI1 in modulating binding to GGAA microsatellites and promoting enhancer activity. The study provides valuable new insights into the underlying oncogenic mechanisms in Ewing sarcoma.

Reviewer #1 (Public review):

Summary:

Ewing sarcoma is an aggressive pediatric cancer driven by the EWS-FLI oncogene. Ewing sarcoma cells are addicted to this chimeric transcription factor, which represents a strong therapeutic vulnerability. Unfortunately, targeting EWS-FLI has proven to be very difficult and better understanding how this chimeric transcription factor works is critical to achieving this goal. Towards this perspective, the group had previously identified a DBD-𝛼4 helix (DBD) in FLI that appears to be necessary to mediate EWS-FLI transcriptomic activity. Here, the authors used multi-omic approaches, including CUT&tag, RNAseq, and MicroC to investigate the impact of this DBD domain. Importantly, these experiments were performed in the A673 Ewing sarcoma model where endogenous EWS-FLI was silenced, and EWS-FLI-DBD proficient or deficient isoforms were re-expressed (isogenic context). They found that the DBD domain is key to mediate EWS-FLI cis activity (at msat) and to generate the formation of specific TADs. Furthermore, cells expressing DBD deficient EWS-FLI display very poor colony forming capacity, highlighting that targeting this domain may lead to therapeutic perspectives.

Strengths:

The group has strong expertise in Ewing sarcoma genetics and epigenetics and also in using and analyzing this model (Theisen et al., 2019; Boone et al., 2021; Showpnil et al., 2022).

They aim at better understanding how EWS-FLI mediated its oncogenic activity, which is critical to eventually identifying novel therapies against this aggressive cancer.

They use the most recent state-of-the-art omics methods to investigate transcriptome, epigenetics, and genome conformation methods. In particular, Micro-C enables achieving up to 1kb resolved 3D chromatin structures, making it possible to investigate a large number of TADs and sub-TADs structures where EWS-FLI1 mediates its oncogenic activity.

They performed all their experiments in an Ewing sarcoma genetic background (A673 cells) which circumvents bias from previously reported approaches when working in non-orthologous cell models using similar approaches.

Weaknesses:

The main weakness stems from the poor reproducibility of the Micro-C data. Indeed, the distances and clustering observed between replicates appear to be similar to, or even greater than, those observed between biological conditions. For instance, in Figure 1B, we do not observe any clear clustering among DBD1, DBD2, DBD+1, and DBD+2. Although no further experiments were performed, the authors tempered their claims by rephrasing aspects related to this issue and the reviewer also acknowledged that the transcriptomic data are convincing and support their findings.

Regarding DBD stability and the cycloheximide experiments requested to rule out any half-life bias of DBD (as higher stability of the re-expressed DBD+ could also partially explain the results independently of a 3D conformational change), the reviewer acknowledged that the WB, RNA-seq data and agar assays presented by the authors appear reproducible across experiments.

Author response:

The following is the authors’ response to the previous reviews

Public Review:

Reviewer #1 (Public review):

Ewing sarcoma is an aggressive pediatric cancer driven by the EWS-FLI oncogene. Ewing sarcoma cells are addicted to this chimeric transcription factor, which represents a strong therapeutic vulnerability. Unfortunately, targeting EWS-FLI has proven to be very difficult and better understanding how this chimeric transcription factor works is critical to achieving this goal. Towards this perspective, the group had previously identified a DBD-𝛼4 helix (DBD) in FLI that appears to be necessary to mediate EWS-FLI transcriptomic activity. Here, the authors used multi-omic approaches, including CUT&tag, RNAseq, and MicroC to investigate the impact of this DBD domain. Importantly, these experiments were performed in the A673 Ewing sarcoma model where endogenous EWS-FLI was silenced, and EWS-FLI-DBD proficient or deficient isoforms were re-expressed (isogenic context). They found that the DBD domain is key to mediate EWS-FLI cis activity (at msat) and to generate the formation of specific TADs. Furthermore, cells expressing DBD deficient EWS-FLI display very poor colony forming capacity, highlighting that targeting this domain may lead to therapeutic perspectives.

This new version of the study comprises as requested new data from an additional cell line. The new data has strengthened the manuscript. Nevertheless, some of the arguments of the authors pertaining to the limitations of immunoblots to assess stability of the DBD constructs or the poor reproducibility of the Micro C data remain problematic. While the effort to repeat MicroC in a different cell line is appreciated, the data are as heterogeneous as those in A673 and no real conclusion can be drawn. The authors should tone down their conclusions. If DBD has a strong effect on chromatin organization, it should be reproducible and detectable. The transcriptomic and cut and tag data are more consistent and provide robust evidence for their findings at these levels. 

We agree that the Micro-C data have more apparent heterogeneity within and across cell lines as compared to other analyses such as our included CUT&Tag and RNA-seq. We addressed the possible limitations of the technique as well as inherent biology that might be driving these findings in our previous responses. Despite the poor clustering on the PCA plots, our analysis on differential interacting regions, TADs and loops remain consistent across both cell lines. We are confident that these findings reflect the context of transcriptional regulation by the constructs, therefore the role of the alpha-helix in modulating chromatin organization. To address the concerns raised by the editors and reviewers for the strength of the conclusions we drew from the Micro-C findings we have made changes to the language used to describe them throughout the manuscript. Find these changes outlined below.

• On lines 70-71, "is required to restructure" was changed to "is implicated in restructuring of"

• On line 91, "is required for" was changed to "participates in"

• On line 98, "is required for" changed to "is potentially required for"

• On line 360-361, "is required for restructuring" changed to "participates in restructuring"

Concerning the issue of stability of the DBD and DBD+ constructs, a simple protein half-life assay (e.g. cycloheximide chase assay) could rule out any bias here and satisfactorily address the issue.

While we generally agree that a cycloheximide assay is a relatively simple approach to look at protein half-life, as we discussed last me the assays included in this paper are performed at equilibrium and rely on the concentration of protein at the me of the assay. This is particularly true for assays involving crosslinking, like Micro-C. As discussed in our prior response, western blots are semi quantitative at best, even when normalized to a housekeeping protein. In analyzing the relative protein concentration of DBD vs. DBD+ with relative protein intensities first normalized to tubulin and using the wildtype EWSR1::FLI1 rescue as a reference point, we find that there is no statistical difference in the samples used for micro-C here (Author responseimage 1A) or across all of the samples that we have used for publication (Author response image 1B). This does show that DBD generally has more variable expression levels relative to wildtype EWSR1::FLI1, and this is consistent with our experience in the lab.

Nonetheless, we did attempt to perform the requested cycloheximide chase experiment to determine protein stability. Unfortunately, despite an extensive number of troubleshooting attempts, we have not been able to get good expression of DBD for these experiments. The first author who performed this work has left the lab and we have moved to a new lab space since the benchwork was performed. We continue to try to troubleshoot to get this experimental system for DBD and DBD+ to work again. When we tried to look at stability of DBD+ following cycloheximide treatment, there did appear to be some difference in protein stability (Author response image 2). However, these conditions are not the same conditions as those we published, they do not meet our quality control standards for publication, and we are concerned about being close to the limit of detection for DBD throughout the later timepoints. Additional studies will be needed with more comparable expression levels between DBD and DBD+ to satisfactorily address the reviewer concerns.

Author response image 1.

Expression Levels of DBD and DBD+ Across Experiments. Expression levels of DBD and DBD+ protein based on western blot band intensity normalized by tubulin band intensity. Expression levels are relative to wildtype EWSR1::FLI1 rescue levels and are calculated for (A) A673 samples used for micro-C and (B) all published studies of DBD and DBD+. P-values were calculated with an unpaired t-test.

Author response image 2.

CHX chase assay to determine the stability of DBD and DBD+. (A) Knock-down of endogenous EWSR1::FLI1 detected with FLI1 ab and rescue with DBD and DBD+ detected with FLAG ab. (B) CHX chase assay to determine the stability of DBD and DBD+ in A-673 cells with quantification of the protein levels (n=3). Error bars represent standard deviation. The half-lives (t1/2) of DBD and DBD+ were listed in the table.

Suggestions:

The Reviewing Editor and a referee have considered the revised version and the responses of the referees. While the additional data included in the new version has consolidated many conclusions of the study, the MicroC data in the new cell line are also heterogeneous and as the authors argue, this may be an inherent limitation of the technique. In this situation, the best would be for the authors to avoid drawing robust conclusions from this data and to acknowledge its current limitations.

As discussed above, we have changed the language regarding our conclusions from micro-C data to soften the conclusions we draw per the Editor’s suggestion.

The referee and Reviewing Editor also felt that the arguments of the authors concerning a lack of firm conclusions on the stability of EWS-FLI1 under +/-DBD conditions could be better addressed. We would urge the authors to perform a cycloheximide chase type assay to assess protein half-life. These types of experiments are relatively simple to perform and should address this issue in a satisfactory manner.

As discussed above, we do not feel that differences in protein stability would affect the results here because the assays performed required similar levels of protein at equilibrium. Our additional analyses in this response shows that there are not significant differences between DBD and DBD+ levels in samples that pass quality control and are used in published studies. However, we attempted to address the reviewer and editor comments with a cycloheximide chase assay and were unable to get samples that would have passed our internal quality control standards. These data may suggest differences in protein stability, but it is unclear that these conditions accurately reflect the conditions of the published experiments, or that this would matter with equal protein levels at equilibrium.

The Two Parts of Likelihood: Likelihood isn't just one number. It is calculated by combining two factors:

Likelihood of Initiation/Occurrence: Will the enemy try to attack? (Or will the hurricane happen?)

Likelihood of Resulting in Adverse Impact: If they do attack, will they succeed? (Will our defenses stop them, or will they break through?)

Overall Likelihood: You combine those two factors to get the final score (e.g., if they are likely to try, AND likely to succeed, the Overall Likelihood is High).

to determine whether the strategy is on track

relate to an organization’s purpose and aspirations, and are typically communicated in some form of brief written statements

Overlap in developing strategy

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The Chain of Events (The Diagram)

The diagram flows from left to right, showing the "story" of how a risk happens. You should understand the relationship between these boxes:

Threat Source (The "Who" or "What"):

This is the adversary (e.g., a hacker, a dishonest employee) or a non-adversarial source (e.g., a power failure).

Key factors: They have capability (skill), intent (motivation), and targeting.

Threat Event (The "Action"):

The source initiates an event (e.g., sending a phishing email, launching malware).

Key factor: Likelihood of initiation (how likely are they to try?).

Vulnerability (The "Weakness"):

The threat event exploits a vulnerability (e.g., unpatched software, a weak password).

Predisposing Conditions: Things that make the weakness easier to exploit (e.g., the server is facing the public internet).

Security Controls: Things that block the attack (e.g., a firewall). These reduce the likelihood of success.

Adverse Impact (The "Consequence"):

If the vulnerability is exploited, it causes impact (e.g., data theft, system downtime).

Organizational Risk (The "Result"):

The combination of the likelihood of the attack succeeding and the severity of the impact produces the final risk level.

Step 1: Prepare for Assessment Before you start, you need a plan. You align the assessment with the organization's goals. (Slide 2 explains this in detail).

Step 2: Conduct Assessment (The Core) This is the "Execution" phase. Memorize this sequence inside the gray box, as it is often a quiz question:

• Identify Threats: Who/what wants to attack us?
• Identify Vulnerabilities: Where are we weak?
• Determine Likelihood: What are the odds of this happening?
• Determine Impact: If it happens, how bad will it hurt?
• Determine Risk: Combine Likelihood and Impact to get a Risk score. Formula to remember: Risk = Likelihood × Impact

Step 3: Communicate Results Notice the arrows go both ways. You don't just report at the end; you talk to stakeholders during the process to ensure facts are correct.

Step 4: Maintain Assessment Risk assessment is not a one-time event. You must monitor and update it over time as technology changes.

implementation layer - where hardware and software live

operational layer/middle management - bridge between top-lvl goals n actual tech - focuses on functions the business needs to perform to survive

decisions made here affect the entire company -- laws, budget, high-level policy

Thème central avec l'opacité des processus de régulation

Asins markiert

PMID:31836589

Gene: ABCA4

HGNC ID: 34

Note d'Information : Priorités de la Protection de l’Enfance et Justice des Mineurs

Synthèse de l'Exécutif

Ce document synthétise les orientations stratégiques et les réformes engagées par le ministère de la Justice pour renforcer la protection de l’enfance et moderniser la justice des mineurs.

Les points clés incluent :

• Urgence et Rapidité : Réduction des délais de jugement (passés de 18 mois à 8,7 mois en quatre ans) et création d'une ordonnance de protection provisoire permettant au procureur de statuer en 72 heures.

• Refonte du Placement : Fermeture des Centres Éducatifs Fermés (CEF) publics au profit des Unités de Placement de la Jeunesse et de l'Éducation (UJPE), mettant l'accent sur la continuité pédagogique (52 semaines/an).

• Moyens Humains Massifs : Création de 1 600 postes au ministère de la Justice, dont 50 nouveaux cabinets de juges des enfants en deux ans et 70 postes à la Protection Judiciaire de la Jeunesse (PJJ).

• Évolutions Législatives : Soutien à l'imprescriptibilité des crimes sexuels sur mineurs, à la présence obligatoire de l'avocat pour l'enfant, et volonté de réformer l'« excuse de minorité » pour les crimes les plus graves.

• Protection contre les Fléaux Modernes : Lutte contre la prostitution des mineurs (6 prostituées sur 10 sont mineures), interdiction des téléphones portables en centres de placement, et encadrement du protoxyde d'azote.

--------------------------------------------------------------------------------

1. Renforcement de la Protection des Enfants Victimes

Urgence Judiciaire et Mesures de Sûreté

L'accent est mis sur la nécessité d'une justice qui s'adapte au rythme de l'enfant.

• Ordonnance de protection provisoire : Un nouveau dispositif permet au procureur d'agir en 72 heures pour protéger immédiatement un mineur, avec des interdictions de contact et l'attribution provisoire du logement au parent protecteur.

Le juge dispose ensuite de 8 jours pour être saisi et de 15 jours pour statuer.

• Loi du 18 mars 2024 : Prévoit le retrait automatique de l'autorité parentale pour les parents condamnés pour crime ou violence sexuelle sur leur enfant, ainsi que l'élargissement de la suspension de l'exercice de cette autorité dès la mise en examen.

Accompagnement et Droits des Mineurs

• Avocat pour l'enfant : Soutien à la présence obligatoire d'un avocat en assistance éducative.

Une expérimentation avec les barreaux est envisagée avant une généralisation législative.

• Unités d'Accueil Pédiatrique (UAPED) : Déploiement en cours sur tout le territoire pour améliorer le recueil de la parole et le soin des victimes.

• Chiens d'assistance judiciaire : Passage de 10 à une trentaine de chiens actuellement, avec un objectif de 100 chiens (un par département) d'ici un à deux ans pour apaiser les enfants lors des procédures.

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2. Réforme de la Justice Pénale des Mineurs

Équilibre entre Sanction et Éducation

La doctrine ministérielle refuse l'opposition entre ces deux concepts.

• La sanction comme acte éducatif : « La sanction fait partie de l'éducation. La sanction toute seule n'est pas un but en soi [...] et une éducation sans aucun interdit mène au n'importe quoi. »

• Efficacité du Code de la Justice Pénale des Mineurs (CJPM) : Les délais entre les faits et la sanction ont été divisés par deux en quatre ans (8,7 mois en 2024 contre 18 mois en 2020).

Transformation des Structures de Placement

Le constat sur les Centres Éducatifs Fermés (CEF) est jugé sévère : coût élevé (30 à 50 % de plus), taux de fugue identique aux centres classiques, et déshérence éducative (seulement 5 à 10 heures de cours par semaine).

• Création des UJPE : Ces nouvelles unités fusionnent les anciens foyers et les CEF pour garantir un parcours de reconstruction pédagogique.

• Recrutement de professeurs techniques : Réouverture d'un concours pour 40 professeurs dépendant directement du ministère de la Justice afin d'assurer 26 heures de cours par semaine, 52 semaines sur 52, y compris durant les vacances scolaires.

• Santé et Addictions : Recrutement de 60 infirmiers pour pallier les carences de soins psychiatriques et de prise en charge des addictions dans les centres de placement.

--------------------------------------------------------------------------------

3. Moyens et Organisation de la Justice

Augmentation des Effectifs

Le budget de la Justice permet une hausse inédite des moyens humains :

• Magistrature : Création de 50 cabinets de juges des enfants supplémentaires en deux ans (notamment à Bobigny, Cambrai, Alès).

Actuellement, certains cabinets gèrent entre 400 et 500 dossiers.

• PJJ : Recréation de 70 postes, permettant de renforcer les effectifs là où ils baissaient depuis 20 ans (ex: Marseille, Île-de-France).

• Milieu Ouvert : Réaffectation de 150 éducateurs vers le milieu ouvert pour ramener la charge de travail à environ 23 dossiers par agent (contre 25 auparavant).

Unité de Commandement

Le système actuel est jugé trop fragmenté (plusieurs ministères concernés, compétences partagées avec les départements pour l'ASE).

Une volonté de meilleure coordination, voire d'unité de responsabilité, est exprimée.

--------------------------------------------------------------------------------

4. Enjeux de Société et Nouvelles Menaces

Violences Sexuelles et Imprescriptibilité

• Fin de la prescription : Avis favorable pour l'imprescriptibilité des crimes sexuels sur mineurs, ainsi que pour les crimes de sang (assassinats).

• Prostitution des mineurs : Un constat alarmant montre que 60 % des prostituées en France sont mineures.

Des unités dédiées au sein de la PJJ sont opérationnelles depuis trois mois pour lutter contre ce fléau et les réseaux de proxénétisme.

Sécurité Numérique et Addictions

• Interdiction des téléphones : La nouvelle circulaire de politique éducative et pénale impose l'interdiction des téléphones portables dans les chambres des centres de placement pour protéger les mineurs des prédations numériques (trafiquants, proxénètes).

• Protoxyde d'azote : Soutien à la pénalisation du transport et de l'achat en ligne (en dehors du cadre médical), alors que les intoxications ont triplé entre 2020 et 2023.

Débats sur la Responsabilité Pénale

• Excuse de minorité : Position favorable à la fin de l'automatisme de l'atténuation de peine pour les crimes les plus graves (assassinats, tortures) commis par des mineurs de 13 à 15 ans.

Cela nécessiterait une évolution constitutionnelle tout en préservant la spécialisation du jugement des mineurs.

--------------------------------------------------------------------------------

5. Données Clés et Statistiques

| Indicateur | Donnée Source | | --- | --- | | Délai moyen de jugement (2020) | 18 mois | | Délai moyen de jugement (2024) | 8,7 mois | | Dossiers par cabinet de juge des enfants | 400 à 500 (moyenne) | | Proportion de mineurs parmi les prostitués | 60 % | | Nombre de mineurs à l'ASE | 400 000 (dont 200 000 placés) | | Heures de cours en CEF | < 10h/semaine (contre 26h en milieu classique) | | Placements chez des tiers de confiance | < 9 % (19 000 jeunes) |

--------------------------------------------------------------------------------

Citations Marquantes

« L'enfant ne vit pas au rythme d'un dossier administratif ou d'un dossier judiciaire. [...] 4 mois pour un mineur c'est une vie. »

« Nous devrions pouvoir en grande partie avoir honte de la façon dont on traite une partie de ces enfants notamment à l'aide sociale à l'enfance. »

« Le placement doit protéger et pas rendre encore plus vulnérable. »

« La sanction fait partie de l'éducation. [...] Une éducation sans jamais aucun interdit mène au n'importe quoi. »

Everyone brings something valuable to the community. I love this sentences and I believe it's something to remember not only for language learning but about all aspects of community building in international education.

Case report no known pathogenic variants of ABCA4 found. subject had a diagnosis of stargardt disease

PMID:32043016

Gene: ABCA4

HGNC ID: 34

payment_id will not be available in case of API Payment (non3p)

ABCA4 variant revealed but not target of research and doesn't seem to amount to anything Variantc.3113C>T p.(Ala1038Val)

PMID:31721179

Gene: ABCA4

HGNC ID: 34

on

Should this be formatted as code like elsewhere?

"On Atari," is better. Same with further on "while in the other two", should be "while on the other two"

The links didn't work for me

Deletion on exon 44 resulting in dystrophy of parts of eye

PMID: 32627976

Gene: ABCA4

HGNC ID: 34

go up from 18 to 20. do 20 divided by 4 = 6. 6 - 4 = 2. 2 is the remainder and the answer to 18 % 4.

Nature is not external to humanity and it is certainly not harmonious in the sense that everyone gets along, but ecologies function in a way where threads pulls every which way and affect every lifeform. We can prescribe that life is neutral and ecologies being "harmonious" is neutral, but we have to contend with our accountability ot each other and to the suffering of other humans and other species (read: individuals) that we can reasonably perceive as being harmed unnaturally.

"being left to itself" is too vague. Humans are a part of nature and always will be. There is no separation, therefore it cannot be left to itself. We can identify behaviors that are more or less destructive to individuals and ecosystems thriving, but we can't say nature must just be left to itself.

PMID:328843395

Gene: ABCA4

HGNC ID: 34

I agree with this statement, I am proud of Jourdon for listening to his wife and being smart with his request. Not only is he aiming to get money, but he's doing it in a way that can be a double edge sword for the "master". this puts the master in a situation where he truly has to ponder. Dose he sacrifice his ego and put it to the side giving them their well-deserved money, or dose he reject their offer but lose the chance of them coming back.

This sentence is important to me because it shows the fear of any parent right through is words of worry. The fear of their daughters being dishonored. In this day and age there are still cases such as where a woman is disrespected and or mistreated just because she is a woman, and this is today where society has changed its views and is less misogynistic. I can only imagine the scenarios that play in Jourdon Anderson mind back then. I believe He is a great father.

I figure the reason why this sentence confuses me is because usually after someone as powerful as a slave owner at the time had previously held control over u, one would usually coward. In this case this man was being blunt, why? is there a greater meaning than just wanting to stand grown. I wondered how he felt writing this letter. weather he was scared or worried, perhaps calm, maybe confident?

El conocimiento no se termina, lo que permite ver que Julia siempre estará en constante mejora, pues al ser código abierto tendrá siempre un aporte nuevo, sin embargo también estará abierto a posibles errores. Se podría llegar a pensar también que con el tiempo pueda ser reemplazado o superado por algún otro lenguaje innovador que se base en el lenguaje de Julia como este se inspiró en otros lenguajes para su creación.

La colaboración entre comunidad y desarrolladores es imprescindible ya que estos mismos usuarios al encontrarse con necesidades propias y la adaptabilidad de las herramientas en condición de software libre genera una distribución y una evolución del proyecto de una manera que el equipo original jamás hubiera logrado. Es importante contar con el desarrollo y ayuda de cualquier persona interesada ya que al fin y al cabo de esa misma manera se hace la ciencia, mediante comunicación y aportando a lo ya existente.

Hasta ahora no sabía de lenguajes de programación creados a partir de combinar varios lenguajes existentes y establecidos para transformar algo nuevo, ya ahora se me hace una idea muy interesante que se alinea con el objetivo que se planteó al principio el cual era hacer un lenguaje accesible para todos, cómodo para los principiantes y completo para los veteranos, por lo que este esfuerzo de crear algo nuevo con bases de otros se entiende como tomar los mejor de cada uno y crear algo nuevo mas allá de la suma de sus partes.

Cuando Julia es puesta en código abierto, se convierte en un espacio donde muchas personas pueden contribuir y también proponer una mejora continua. Considero que de esta manera los usuarios dejan de solo consumir información a crear nuevo conocimiento a partir de sus intervenciones.

Lenguaje de programación precursor

Scheme

Creo que el hecho de siempre crear algo para hacer un cambio mayor en el mundo, trae muchos problemas como el hecho de no querer usarlo por ser nuevo, pero por lo que se nos cuenta, realmente era algo diferente a lo que ya habia

Es curioso como en algunas historias tambien se escuchan temas similares, una persona que tiene un trabajo en una empresa haciendo una labor, pero cuando tienen tiempo a solas, y esa libertad de crear, es cuando avanzan en su proyecto personal

Normalmente los proyectos siempre empiezan para un grupo pequeño, pero a medica avanza, el objetivo cambia al darse cuenta del potencial que hay

Me encanta esta frase ya que resalta que lo que realmente une a las personas no es solo la tecnología en sí, sino un propósito compartido y no individual.

Me gusta mucho como inicia la lectura ya que nos muestra que Julia no fue una línea perfecta , si no que fueron trazos no lineales , pero necesarios , vemos que las mejores cosas no salen de la perfección si no de frustraciones o incomodidades .

relate the way the city is handled

I really like this question because it challenges how loosely people use the word “archive.” If everything becomes an archive, then the term loses its power. She is defending the real labor and structure behind institutional archives.

What makes something truly worthy of being preserved and recognized as history?

Putting things online doesn’t automatically fix the problem. It might look like progress, but if there’s no real explanation or context, people still won’t understand what they’re looking at or why it matters. Just uploading images isn’t the same as making history truly accessible.

This part highlights the disconnect between theory and reality. Scholars debate what an archive means, but real Black historical materials are sitting on shelves and not accessible to the communities they belong to. It shows how discussion does not always translate into action.

Although nothing will be perfect, it's important to remember use the resources given!

one of the theories where Nyatri was a strange looking grandson of the Indian king who was cast to the Ganges river and grew up till fleeing to Tibet...

This text states that Nyati was the one of the younger sons of King Skyab seng of the Shakya lineage, who fled to the Himalayas with his platoons up the summut of Lha Ri pol of Yarlung Tibet before descended through god's staircase to the four Tsansgo where he was proclaimed king

When you think about how students are moved through the school system, this makes sense. In elementary school, you spend a year with an entire teacher. It become a bi-directional relationship. Meaning that there is more of a relationship. Moving towards middle school, the teachers have more students, more classes to teach, and less time to get to know the students. The same can be said at a high school level unless students are going to smaller schools.

why? this seems to be like a equity issue, probably the root of the problem?

Why use that ratio? Why not say 16 of 10,000? Why not just give a percentage? Was this done to make it "more digestible" for the reader?

One of the reasons of this must be that funding for STEM/STEAM programs are likely to get cut for schools that are in low-income neighborhoods. It should also be noted that the STEM/STEAM teaching positions are hard to fill.

Who made this a priority?

I would be interested to see the location of this study. Was it for an entire district? a city? a state?

see website at https://www.badgerbalm.com/ Good products, see About and Healthy Business -- can be successful AND do business well! (not an either/or proposition).

the true danger is a societal standstill where human progress altogether grinds to a halt.

Studies show that heavy GPS users have less activity in the mapping center

We're all very sympathetic to Caliban, but he does attempt to use Miranda as a bargaining chip here, specifically selling her out for sexual purposes to Stephano. Its interesting that Miranda is made a sexual object by Caliban and Prospero, who hates Caliban for his attempted rape of her. Ferdinand isn't sexless, but is far less threatening as a white guy and prince. Prosper approves of him for those reasons, as well as the fact that he's in control, ]since he wants Ferdinand to fall in love with Miranda so he can exploit their courtship for power.

paragraph on Tibetan Buddhist theories on Nyatri

Bon theory of where Nyatri came from

last theory says that Nyatri came from a goblin race

these are the three theories made Tibetan scholars

Secret Buddhist tradition attribute the king to Shakya lineage of Indian kings and Mahabharata epic

Bon tradition says he came from the native Bon god Yablha Daldrug

the progression eyes - ears - mind . he is tracing the path of digital consumption. how technology interfaces with humans

Carr uses words like "quick" and "a few" to highlight the speed of the internet. While this sounds positive, the subtext of the entire essay is that this efficiency comes at the cost of deep reading and contemplative thought.

Finger prints according to an algorithm

Defining algorithm

Definition of big data for the article

Never thought of just interaction with the police as introduction into the criminal justice system

Profilinh

Young women and sexual appeal compared to older women.

Reread--confused

A majority of women also felt supported in their workplace, but at lower rates than those reporting feeling comfortable. Women between 18 and 24 felt most supported in their workplace, at 71 percent, which is interesting as they were the age group that felt least comfortable (73 percent).

While women commonly experienced gender bias in the music industry, still over three-quarters felt comfortable in their work environment (77 percent), while almost two-thirds felt supported in their work environment (64 percent).

When looking at the second question regarding gender bias (whether gender affected their employment in the music industry), women in their forties were most likely to feel that their gender had affected their employment (61 percent), while just 34 percent of women between 18 and 24 agreed.

Self-employed/freelancers were the employment type most likely to feel they had been treated differently, at 84 percent.

Women:

78% felt that they were experiencing different treatment in the workplace.

52% felt that their gender has affected their employment in the music industry.

Two questions were asked:

1.) Was the respondent treated differently in the music industry because of their gender?

2.) If the respondent felt that their gender affected their employment in the music industry?

Fewer comments noted discrimination against women with children or stress of working and parenting.

Sixty-one percent of women said that their career was a factor in decisions about having or raising children. Women most commonly cited concerns about work/life balance when asked to explain further. Twenty-two percent of comments noted that career considerations influenced decisions to have fewer children or none at all.

When asked to assess if they were where they should be at this stage of their career, nearly half of respondents (47 percent across all job levels) felt they should be further ahead, while a third (33 percent) felt they were where they should be, and 8 percent were further ahead.

Nearly half of respondents (48 percent) work over 40 hours a week in the music industry, not including any time working in non-music-industry occupations. Weekly time spent working in the industry varies considerably by employment type. A majority of women who work for a company or own a company work over 40 hours a week in the industry, while those who are self-employed or freelancers, or report multiple employment types, report a wider range of hours worked.

Eighty-two percent of respondents said that their primary occupation was in the music industry, and nearly half of them (47 percent) also had a secondary music- related job. overall, 49 percent of respondents had an additional source of income that was music- related, whether or not their primary occupation was in the music industry. one quarter of those with a secondary music-related position had a primary job outside the music industry.

Level of education was related to increased rates of current employment in a related field as shown in figure 4.

Eighty-three percent of respondents had earned a bachelor’s degree or higher.

Nearly 30 percent of women indicated that they were in their thirties, while just over a third were between 18 and 29. The remaining 37 percent were 40 years old and older.

MIRA (2018) found that women musicians spent more time giving lessons and less time performing, traveling, and composing than men.

Very little women work in the production of their music, no real statistics in 2016.

Billboard 2024 2015-2016:

Small percentages of hit songs include women performers, female songwriters, and very few female producers.

From 1997-2007:

Male artists had higher numbers of Top 40 hits--even though female artists' hits were more likely to reach number one on the chart (Billboard).

¿Quién es Krysinski? ¿Qué entiendes por dialogismo? ¿Qué entiendes por dialógico? ¿Qué diferencia encuentras entre los dos?

¿Cuáles son los aportes del concepto de intertextualidad a la teoría literaria? ¿Qué cambia con el viraje del modelo de intertextualidad al del dialogismo para el concepto de autor? Si, según Bajtín, el dialogismo implica la inclusión de la voz del otro, ¿por qué la intertextualidad se considera equivalente al dialogismo?

This needs to be removed

Chapter 1 summary

Chapter 2 summary

discussed in class - it is a key point in history - changed the path of things 1769 - start of Cali missions 1869 - the year the railroad connected Cali to the rest of the country - two events that expeditated the growth of Cali.

Tidbits: - oranges, grapes, horses, cows - all came to Cali. via the Spanish (Cows brought up from Baja.) - there is agriculture before the Spanish but the variety of crops that Cali is now famous for traces back to the Spanish. - student comments on how the water changes may have affected crops (the distribution of water and its movement) -> Gastil disagrees as Spanish did not make any aqueducts or anything. They did make some dams, some aquifers.

Differences between "Indian schools" and Missions: - Observation: missions allowed for expression and preservation of culture (though it blended with European culture)

Cabrillo

• Conquistador
• very different from Vizcaino
• protégé of Cortez
• abusive???
• San Miguel Bay -> Mt. Miguel High

Father Serra - short and bald, very charismatic - 'moved people,' a gifted preacher; had followers and taught other priests - speaking to physicality: walked thousands of miles. a martyr. endurance. - lived here for 15 years. contributed to the building of 9 missions in those years.

• was still a colonizer, did contribute to behavior (abuse and death of NAs). but still wanted to love a life according to God. modeling himself after GOD
• "Most idealistic man" - Gastil There is a need to discuss Serra carefully. He contributed greatly but he was still part of the problem. You have to acknowledge both! Acknowledge the nuance.
• judge actions within the time.

add to other notes later: - Wintu and Shasta not within mission system - tribes outside: were wiped out during gold rush era - mission system helped tribes survive the times (in the long run) - does not excuse mission system but they seem to have helped in some respects

Father Juan Crespi

Miguel Costanso

A jump to the 1760s

What happens in between late 1500s and 1760s - colonization of California; missions in Cali

Jose de Galvez

Discussed in Class:

How the Philippines relate to this story: - they were taken over by the Spanish - were separate islands and cultures prior; Spanish collectivized them - Connection to California: both colonized, part of New Spain (New Spanish Empire) - Trade/interaction between Manila port, Mexico port, and the shores of California

Interesting! connection to Connecting Cali Gastil

After reading the article "What is implicit bias?" I noticed implicit bias in this case, in the assumption that Latino individuals are “foreign” or suspicious. Though for Enrique this was just one of his experiences, like he mentioned, it is well known to many that bias opinion towards others ethnicity can harm one another both physically and mentally. Implicit bias can be harmful and lead many apart.

Enrique's stake is a sense of identity as a Mexican American individual and safety when confronted at a border checkpoint. He was cautious and aware of the reality of his scenario. At the end, he showed greater clarity about his own identity and confidence in his voice to speak up. He had shown great change, and even though this experience wasn't pleasant, the ability to continue and speak up about a hurtful issue he was able to persevere after reflecting.

You can tell this is making a foundation for industrialization; making law shape the economy.

Ivan IV truly made Moscow into a major empire even though it was just a little principality before. This is an excellent example of good leadership playing a key role in the success of place.

The theme I see within this story was self belief that helped motivate her campaign and her self-empowering, resilient mind. There were also challenging expectations, especially with a hard start to trying to speak up in politics as a black woman. Kathi had shown strong virtues of resilience that strengthened her appearance. She grew through risk when she challenged the limits others placed on her, and the ones she placed on herself. Kathi discovered unexpected strength throughout her entire campaign.

The story centers on a moment where Kathi Kinnear is telling herself what she can’t do. She is limiting her capabilities in her own mind, which is a problem she was facing in the beginning of her hardship. The real stakes are whether she will accept those limitations or challenge them. If she fails to surpass her limitations, she reinforces doubt and dwells in that state of despair. If she succeeds in pushing past her own limits, she reshapes her identity. In the end, Kathi was able to see light through these dark times in her memory and persevere past what once restrained her.

Conclusions that have sound judgement allow us to be able to make reliable and accurate analysis of things.

Although this type of quick analysis is good, it's not always accurate. We always need to make sure to dig deeper and to see beneath the surface to find the truth.

Technical writing is audience centric

Technical writing is crucial in an audience sense

Formal formers must be studied is needed to succeed in writing professions

Technical writing is made for the targeted audience in mind

NY Times financial journalist

are there any FAQs you can come up with where the answer is a flat-out "NO"?

this whole section is feeling a little vague for me (it's the only time I felt myself slow down while reading this page) — I would focus more on Venus and Mars as the potential pathfinders to the answers your student seeks, and why you are leaning on them in this immersion a little bit more here. I think grounding this section down with more specifics will help it feel more tangible.

I would make this bigger!

the effect of this theory globally into policy and prevent warfare