delete

make this: Supplementen. Ein Nahrungsergänzungsmittel ist rechtlich ein Lebensmittel, kein Arzneimittel.

make this: aus. Daraus stellen sie eine auf deine Werte abgestimmte Formel zusammen, statt von einem Durchschnitt auszugehen, der für alle gleich sein soll.

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make this: liegt in der

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make this: Kurz gesagt

make this: Warum macht der Darm einen großen Unterschied?

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make this: Mehr als die Gene

make this: Jeder Körper verarbeitet Essen anders,

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Es liegt weniger am Produkt und mehr an deinen persönlichen Voraussetzungen

make this: :

make this: :

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make this: In einer Studie schwankte die Reaktion nach identischen Mahlzeiten zwischen Menschen um bis zu 103 Prozent (PREDICT 1, Nature Medicine, 2020).

make this: optimal für dich

make this: . Bei

make this: Freundin

make this: ein

The transitions between the sentences aren't smooth. Everything feels very choppy.. Better:

Douglas bietet das ausgewogenste Gesamtpaket aus Sortiment, autorisierten Marken, Beratung und Filialnetz. Suchst du dagegen gezielt nach Nischendüften oder exklusiver Luxuspflege, lohnt sich ein Blick auf Niche Beauty. Dort steht eine sorgfältig ausgewählte Markenauswahl im Mittelpunkt. Parfumdreams eignet sich besonders für alle, die Wert auf eine große Auswahl, Naturkosmetik und ein 180-tägiges Rückgaberecht legen. Flaconi überzeugt mit einer breiten Markenvielfalt und praktischen Extras wie Gratisproben. Bei Notino erwartet dich eines der größten Sortimente im Vergleich, das regelmäßig mit attraktiven Preisen kombiniert wird. Geht es vor allem um Hautpflege, Haarpflege und Beauty-Abos, ist Lookfantastic eine interessante Adresse. Am Ende entscheidet nicht der bekannteste Shop, sondern welcher am besten zu deinen persönlichen Einkaufsgewohnheiten passt.

große

kostenloser

monatliche

eigener

umfangreiche

virtuelle

große

mehr

Große

eigene

regelmäßige

bis

komfortable

breite

kostenlos. Das

Sounds very unnatural. Better:

Mit den Filtern nach Duftnoten findest du schneller passende Produkte. Das ist praktisch, wenn du einen bestimmten Duft suchst, aber noch keine Marke ausgewählt hast.

Große

viele

niedrige

großer

über

Große

zwei

Better: Du kannst Produkte zuerst vor Ort ausprobieren und später bequem online bestellen. Auch Click & Collect oder die Rückgabe einer Online-Bestellung in der Filiale machen den Einkauf einfacher.

exklusive

kuratierte

Der Berliner Online-Shop setzt nicht auf eine riesige Auswahl. Stattdessen findest du dort sorgfältig ausgewählte Nischendüfte, Luxuspflege und hochwertiges Make-up. Marken wie Byredo, Diptyque, Westman Atelier, Drunk Elephant, Charlotte Tilbury oder Paula's Choice passen perfekt zu diesem Konzept.

sehr

autorisierte

Online-Bestellungen kannst du innerhalb von 14 Tagen zurückgeben. Die Rücksendung mit dem vorfrankierten Etikett und die Rückgabe in einer Douglas-Filiale sind kostenlos.

Kuratierte

Das

Sounds too much like AI. Better:

Manche Shops bieten Extras, die den Einkauf angenehmer machen. Dazu gehören zum Beispiel eine Beauty Box im Abo, digitale Hautanalysen oder ein sorgfältig ausgewähltes Sortiment an Nischendüften.

There should not be a colon. Better:

Luxusdüfte und Nischenmarken gehören nicht bei jedem Shop zum Sortiment. Auch hochwertige Pflegeprodukte findest du längst nicht bei allen Anbietern.

Starke

Einer

Über

Das

Same here. Better:

Am Ende kommt es darauf an, welcher Shop zu deinen Gewohnheiten passt. Suchst du gezielt nach Nischendüften, brauchst du ein anderes Sortiment als jemand, der Pflegeprodukte für die ganze Familie bestellt. Auch wer ein Geschenk kaufen möchte, achtet meist auf eine möglichst lange Rückgabefrist.

Sounds too much like AI and very unnatural. Better:

Bei manchen Anbietern bekommst du zwei Gratisproben dazu, bei anderen gar keine. Auch die Rückgabefristen unterscheiden sich deutlich. Teilweise hast du nur 14 Tage Zeit, bei anderen sind es bis zu sechs Monate. Zudem ist das Sortiment längst nicht so ähnlich, wie es auf den ersten Blick wirkt.

Parfums

make this: – 

make this: zu verstehen

make this: sinnvolle

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make this: gibt jedoch

make this: Fälle

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make this: Sie richten die

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make this: dagegen Gegenstand aktueller

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make this: herrscht viel Unwissen

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make this: Sie stellen daraus eine personalisierte Nahrungsergänzung zusammen

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make this: . Das ist eine feinere Auflösung als bei der verbreiteten 16S-Methode.

make this: Durchschnittswerte ist

make this: ist der Nutzen von Multivitaminpräparaten also fragwürdig.

make this: Teilnehmende hinweg

make this: Es gibt einen Gegenbefund

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make this: zur Vorbeugung rät sie

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make this: Präparate bringen keinen Vorteil in Bezug auf das Sterblichkeitsrisiko

make this: als statistische Verzerrung ein

I'm assuming this means: zeigte sich sogar ein negativer Zusammenhang.

make this: aus,

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make this: Menschen mit einer ausgewogenen Ernährung

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make this: Die nützlichere Frage ist: Wo lohnt sich Nahrungsergänzung tatsächlich?

make this: kaum

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make this: sollte immer ein Arzt aufgesucht werden

make this: gesundheitlichen Beschwerden

make this: individuellen

make this: an: Sie stellen

make this: leisten – und

Punição fica 'congelada'

Cobrar de volta o gestor que praticou a irregularidade

liquidação extrajudicial é bastante parecida com falencia, só que é um ato administrativo que nao passa por via judicial, para poder ser o mais agil com o patrimonio que ainda n levaram

É o famoso 'respiro' para poder se recuperar e poder pagar as contas -> Corinthians

Note de Synthèse : Évolutions de la Conjugalité et Enjeux Médiatiques Contemporains (Mars 2026)

Résumé Exécutif

Ce document synthétise les points clés de l'émission "Zoom Zoom Zen" du 4 mars 2026.

L'analyse se concentre principalement sur les transformations profondes du couple hétérosexuel dix ans après le mouvement MeToo, à travers l'ouvrage Nos amours modernes, dirigé par Titiou Lecoq.

Les points saillants incluent la remise en question des scripts sexuels traditionnels, la persistance des inégalités financières et l'émergence de la "charge émotionnelle".

Parallèlement, le document examine des actualités critiques : la pression des autorités de Dubaï sur les influenceurs français en période de tensions régionales, les sanctions de l'Arcom contre CNews, et les développements de l'affaire Epstein impliquant Bill Clinton.

I. L'Évolution du Couple Hétérosexuel Post-MeToo

L'analyse de Titiou Lecoq souligne que le mouvement MeToo n'a pas seulement dénoncé les violences, il a percuté l'institution même du couple hétérosexuel, forçant une introspection collective sur sa nature et ses limites.

1. La construction sociale et l'hétéronormativité

Dès l'école primaire, les relations entre enfants sont polluées par l'hétéronormativité.

Les amitiés entre garçons et filles sont immédiatement étiquetées comme amoureuses, tandis qu'une hiérarchie s'instaure :

• Dévaluation du féminin : On inculque tôt aux garçons que ce qui est "de fille" est inférieur.

• Paradoxe du désir : On enseigne aux garçons que le féminin est "nul", tout en leur signifiant que c'est l'objet de désir requis.

2. Le défi de l'éducation des jeunes garçons

Le mot "féminisme" provoque souvent une crispation et un sentiment d'accusation chez les adolescents, qui le perçoivent comme une compétition défavorable.

• Alternative terminologique : L'usage du terme "égalité" rencontre une adhésion bien plus forte.

• Polarisation : On observe une polarisation accrue entre les sexes chez les jeunes, les hommes de la génération précédente restant statistiquement plus ancrés dans des schémas sexistes.

3. Redéfinition de la sexualité

La sexualité en 2026 ne suit plus un scénario figé.

• Déclin du script traditionnel : L'idée que les préliminaires mènent inéluctablement à la pénétration s'efface.

Un rapport sexuel n'est plus systématiquement défini par la pénétration.

• Consentement et limites : La notion de consentement est devenue centrale, poussant chaque individu à s'interroger sur ses propres limites.

• Comportement des jeunes : Contrairement aux idées reçues, ils ne sont pas moins actifs sexuellement, mais ont plus de partenaires et moins de sentiment d'obligation au rapport.

4. Inégalités persistantes : Argent et Charges

Le couple reste un lieu d'asymétrie majeure :

• Appauvrissement des femmes : Statistiquement, une femme en couple s'appauvrit (surtout après l'arrivée des enfants) tandis qu'un homme s'enrichit.

• Boost de carrière masculin : Les hommes bénéficient souvent d'une promotion dans les six mois suivant une naissance, contrairement aux femmes.

• La charge émotionnelle : Au-delà de la charge mentale (logistique), les femmes assument la gestion des émotions du conjoint et des enfants, un travail invisible crucial.

| Concept | Définition | | --- | --- | | Charge Émotionnelle | Fait de prendre en charge les émotions des autres membres du foyer (conjoint, enfants) et de gérer les conflits internes. | | Couple Déclaratif | Idée qu'un couple se définit uniquement par le moment où les deux partenaires se déclarent comme tels, sans critères fixes (sexe, amour, cohabitation). |

II. Actualités Médiatiques et Géopolitiques

1. La crise des influenceurs à Dubaï ("Dubaïgate")

En raison des tensions régionales et des tirs de missiles interceptés par les Émirats, les influenceurs français expatriés ont manifesté une panique médiatisée avant de brusquement changer de discours.

• Censure et pression : Les autorités de Dubaï interdisent la diffusion de "fausses informations" ou de contenus provoquant la panique sous peine d'amendes (50 000 €) ou de prison.

• Revirement de discours : Des figures comme Maeva Ghennam, après avoir supplié pour un rapatriement, vantent désormais la sécurité de la ville suite à des convocations policières.

• Contrôle social : Des rumeurs font état de contrôles de téléphones par les autorités pour vérifier les publications sur les réseaux sociaux.

2. Sanctions de l'Arcom contre CNews

Le régulateur a adressé une mise en demeure à CNews concernant le traitement de "l'affaire Thomas" (Crépol).

• Motif : Soutien systématique et péremptoire de la thèse d'un "meurtre raciste" (anti-blanc) dans 15 émissions, sans contradiction, alors que l'enquête judiciaire était en cours.

• Précédents : La chaîne a déjà reçu 100 000 € d'amendes récemment pour incitation à la discrimination.

3. Affaire Epstein : Les auditions des Clinton

Les "Epstein Files" continuent de secouer la sphère politique américaine.

• Témoignage de Bill Clinton : L'ancien président tente de justifier une photo dans un jacuzzi avec une femme (caviardée) par la fatigue d'un voyage humanitaire.

• Analyse non-verbale : Les observateurs notent des signes de nervosité (regards vers le bas, clignotements d'yeux) lorsqu'il nie avoir eu connaissance des abus commis par Jeffrey Epstein.

III. Culture et Société

• Reboot de "La Petite Maison dans la Prairie" : Netflix annonce une nouvelle version pour le 9 juillet 2026.

Ce retour interroge par son décalage potentiel avec les valeurs actuelles (modèle de la femme au foyer gentille et de l'homme dur mais juste).

• Musique à l'image : Le portrait du compositeur Samuel Mavré met en lumière le métier de l'ombre de la création de jingles et musiques de télévision (TF1, M6).

L'essor de l'Intelligence Artificielle menace désormais ces "sculpteurs d'émotions".

• Diplomatie française : Emmanuel Macron affiche son opposition à l'interventionnisme américain (sous l'administration Trump) de manière symbolique, tandis que l'Espagne de Pedro Sanchez refuse l'usage de ses bases pour des assauts contre l'Iran.

Citations Clés

"Je pensais seulement changer ma communauté... si les femmes pouvaient prendre la parole... on pourrait montrer l'ampleur du problème." — Tarana Burke (créatrice de MeToo), citée lors du rappel des débuts du mouvement.

"Le couple hétéro a été percuté par toutes les questions posées par MeToo...

Qu'est-ce qu'il en reste au milieu de ce champ de ruines ?" — Titiou Lecoq.

"L'amour qui dure, ce n'est pas la passion qui dure 50 ans. C'est un paysage qu'on compose." — Titiou Lecoq.

An updated version of this manuscript has been officially published in Journal of Bacteriology (https://doi.org/10.1128/jb.00210-26)

Doubling the known sampling of this species, and backing the sweep calls with two independent methods, gives real confidence that the sweep signatures themselves are genuine. The local adaptation interpretation built on top of those signatures is necessarily indirect; allele frequencies, diversity drops, and differentiation across a genomic window are consistent with a fitness advantage. However, the exact causal variant within a swept window can't be resolved from sweep scans alone; reciprocal transplants would be the direct fitness test, but aren't practical for a soil microbe. A lab-based competition assay could close part of that gap without needing a literal transplant, comparing whole Ontario-derived versus Quebec-derived haplotypes at a locus rather than a single engineered variant.

Employing multiple different competition assays could be insightful as the Ontario and Quebec sweep windows look mechanistically distinct. A motility-based competition could capture swimming behavior likely to be impacted by the Ontario's candidate genes (voltage-gated channels). A growth-based competition could capture growth likely to be impacted by the Quebec's candidate genes (transcriptional machinery).

框架差异，非事实冲突。 本文将变动定性为主动选择（Pichai：“He and I have been long discussing a role…”）。该说法无法从外部证伪。

但可核验的是市场读法与之相反，且已重复两次：2026-06-22（Shazeer/Jumper 离职后）Alphabet 跌约 5–6%；2026-08-05（本文发布日）盘中跌约 5%、约 1900 亿美元市值蒸发。Fortune 标题用词为 “A sudden shakeup”。

全文唯一的问题承认，且被夹在两句成绩之间。 前半句列举 Flash/Cyber/Gemma，后半句转向「继续快速前进」。这句话没有说明是哪些领域——而外部事实指向旗舰 Pro 的连续三次跳票（6 月 → 7 月 → 7 月 17 日）。

标题「AI momentum」与这句自述之间的张力，是本文最值得注意的结构特征。

选择性列举。 三项成绩全部避开旗舰 Gemini 3.5 Pro——该型号 2026-05-19 在 I/O 由 Pichai 亲自发布并承诺次月 GA（原话：“Give us until next month to get it to you”，台下有可闻的叹气），至本文发布日 2026-08-05 仍仅限 Vertex allowlist 预览，已延期逾两个月。Fortune 逐字：“months behind its original June launch target.”

另注：Gemma 的「下载量」是分发指标而非使用指标，与 Gemini app 的月活不可比。

该推论不成立。 就在同一份备忘录宣布 Koray 接管的当天，Gemini 的两位技术共同负责人已经离开：Oriol Vinyals（本文未提，加入 Discovery Loop）与 Noam Shazeer（2026-06-18 加入 OpenAI）。

「as they have been for a while」进一步强化了连续性主张，而过去 7 周恰是 GDM 高层流失最密集的时段。

重大遗漏披露（实质冲突）。 同批加入 Discovery Loop 的实为四人：Jeff Dean、Sanjay Ghemawat、Oriol Vinyals、Quoc Le。本文只披露前两人。被略去的 Vinyals 时任 GDM 研究副总裁兼 Gemini 模型家族技术共同负责人，Le 是 Google Brain 联合创始人。

这不是无关紧要的省略——它与本文另一处论断直接冲突（见「in good hands」处标注）。TNW 逐字：“So on the day Google named the executive who will build Gemini 4, both of Gemini's co-technical leads walked out.”

来源：thenextweb.com / fortune.com（2026-08-06）

klñ{

Not just workforce readiness: civic engagement and well-being!

Tu parles beaucoup de l'aspect préventif et du rôle de l'assureur dans la prévention. De mon expérience, à part les obligations légales de financement, ça reste un mythe à l'échelle du contrat. Tu as des exemples sur ce sujet, je trouve ça intéressant.

C'est intéressant en ce qui concerne le chômage : avec la reprise en main de l'assurance chômage par le gouvernement en France, l'effacement progressif de la gestion paritaire et les modifications successives des règles d'indemnisation, la prestation n'est plus nécessairement définie à l'avance — elle peut évoluer assez rapidement.

Dans le chapitre 2, où l'on compare la mutuelle et l'assurance commerciale, on pourrait aussi établir un parallèle avec la Sécurité sociale, censée incarner le modèle démocratique le plus abouti. Le sujet est d'autant plus d'actualité que le débat sur les cotisations et l'écart entre salaire brut et salaire net est aujourd'hui particulièrement prégnant, ou le débat sur la capitalisation de la retraite. C'est une forme d'assuré qui souhaitent "aller voir ailleurs" ou qui n'accepte plus la "tarification" de leur risque, quoique ça veuille dire dans ce domaine.

混合精度训练（FP16/BF16）中的 Loss Scaling（损失缩放）技术，反向传播时FP16能表示的最小为6*10^-8,若最小梯度为10^-8，则下溢为0。

把梯度先放大，反向传播后再除S恢复正确数值。

无限循环小数只能被二进制有限表示。当绝对数值越大，精度越差。 如1.m2^e, m是尾数，e是指数，如1.2310^4.e越大，数值范围越大，尾数固定，由于指数导致的范围很大，可表示的精度就越小

归一化层，LayerNorm是归一化公式

Layernorm的简化版本，RMSEnorm计算更快 LayerNorm：需要： 求mean 求variance 标准化

RMSNorm：只需要： 求平方和 开根号

减少： reduction次数 memory访问 kernel计算

归一化公式

x+loss,防止梯度爆炸或消失问题，使整体变化平稳。

反向传播时需要参数更新，SGD是传统参数更新方法。然而只考虑当前梯度，当batchsize太小时，会出现噪声而导致更新不准确。（batch中一次全是猫，一次全是狗）。

动量把历史值通过权重考虑进去，Adam在动量的基础上又考虑了多个参数更新时量级不一致的问题。如w1=10000eta,w2=0.00001eta, 可能一次更新某个参数基本无变化。Adam通过一阶m（梯度方向），二阶v（步长大小），解决不同参数的更新问题

Amazing! Congratulations! 👏🏼👏🏼👏🏼

This is a test. I shall delete this later.

Nao isentam

Por exemplo o estado de sao paulo, fazer emprestimo de pessoal para a prevcom, mas a prevcom teria que ressarciar o estado de sp

this is a test comment

Quelle est la nature de cette obligation ? Morale, philosophique, politique, économique etc. ? Qui en définit les termes ou qui devrait ? Quelle à la position de chaque partie prenante ? Ces questions appellent-elles les mêmes réponses selon la nature du risque ?

这句话决定了上一条的分量。如果这套协议无人问津，「没采用」就只是选型差异；但它已被三家独立评测机构（含一家美国政府机构）采用，说明它是这个领域事实上的公共基线，而不是一份被忽略的提案。同时这也标出了一条真正的独立性分界线：AISI 与两家厂商都没有商业关系，是本轮唯一的外部标尺。

本文发表于 2025-08-07。Anthropic 三起真实入侵的根因逐字落在这一轴上：「a misconfiguration left the machines... with live internet access」。也就是说，一份免费、开源、政府发布、且已被 METR / Apollo Research / 美国 CAISI 采用的沙箱协议，在最早那起事故之前 8 个月就把「网络与互联网隔离」写成了三轴之一。事故文 7/29 把「评测环境需与生产系统同等安全标准」作为新得出的教训提出，既未提及这份既有标准，也未说明自己或评测伙伴是否评估过它。

一个可标日期的能力越界点。AISI 2026-03 测得的边界是：所有成功逃逸都利用已披露漏洞，最难场景无模型攻克。而 OpenAI 7/28 更新披露，其模型是利用 Artifactory 的未知 0-day 获得外网访问——一个月内从「利用已知漏洞」跨到「发现并利用未知漏洞」。这条比任何一方的定性叙述都更有信息量。

由一家政府评测机构给出的、不带商业利益的判断：即便是有安全意识的团队搭的容器环境，缺口也很容易渗入——他们自己做基准时就被模型钻了一条非预期路径。这直接削弱「blameless postmortem，但根因是双方的一次误解」这种把事件个案化的叙述框架。

发表于 2026-03-23，比 Anthropic 三起真实入侵中最早的一起（4 月）早一个月，比披露（7/29）早四个月。这句话几乎是在描述接下来会发生的事：Anthropic 的根因正是第三方评测 harness 的错误配置留下了实时互联网访问。事故文用整整一节把责任落在「我们与评测伙伴之间的误解」上，而这里提前给出的判断是——这是这类环境的固有属性，不是某一次沟通失误。

第三记，针对事故文的「We saw no evidence in any run described here of a model pursuing a goal of its own」。本文的发现是：仅有一个被指派的目标、不需要自我保存威胁、也不依赖目标内容，就足以诱发协助商业间谍。CTF 评测恰好构造了完整诱发条件：给定目标 + 关闭简单路径 + 不设边界。所以「没有自发目标」并不构成「不是对齐失败」的证据——按 Anthropic 自己的发现，有害的目标导向行为本就不需要自发目标。

第二记。事故文把「模型相信环境是模拟」描述成模型的合理推断。但这里说：不被提示时模型默认假设自己处在真实环境。也就是说那个模拟信念不是模型自发的，是 Anthropic 评测提示词灌进去的（「its environment was a simulation and that it had no internet access」）。提示词造成的错误信念，被反过来用作模型行为的开脱理由。

这条 8.5 倍差距直接推翻 Anthropic 2026-07-29 事故文的核心免责逻辑。事故文说模型「误以为身处模拟，因而其行为 arguably reasonably」。但按这里的数据：以为是模拟恰恰是低风险信念态（6.5%），而模型在这个态里仍攻陷了 3 家真实组织；更关键的是 Opus 4.7 四次运行都最终识别出系统是真实的却「none stopped the attack on that basis」——它当时正处在 55.1% 那一侧。事故文没有引用这项研究，而它是 Anthropic 自己产出的、与该事件最相关的前置工作。

主动记录自身预测被证伪，在同类企业发布中很少见，应计入可信度加分。倍增周期不但没趋缓，反而从 1.1 个月加速到 0.7 个月。但这同时削弱了 7/29 事故文结尾那句「These facts give us cautious optimism」——它建立在一份作者自己刚标注为偏乐观的预测记录之上。

把这个数字和 7/29 事故文并排看会翻转结论。事故文说三起入侵「未发现或利用任何复杂漏洞，仅用弱口令与未鉴权端点等基础手法」，读起来像宽慰。但事故二的当事模型正是 Mythos 5——一个能在 41 个 V8 CVE 中对 21 个达成任意代码执行、且其他受测模型无一达成的模型。「只用了基础手法」说明的是目标太软，不是模型能力有限。

横向阅读的最高价值发现。Anthropic 7/29 的事故披露文脚注 2 写明「OpenAI/Hugging Face 事件发生于 ExploitGym 的一次评测」，并用整整一节把两起事件对立起来（我们主动发现 / 他们 0-day 逃逸）。但这里写着：ExploitGym 的构建有 Anthropic 安全研究员的贡献，同文还说「Anthropic ran the Opus 4.6 and Mythos Preview trials」——Anthropic 自己也在这套基准上跑模型。事故文对这层关系只字未提。结合已知的 Irregular 关系（商业供应商 + 白皮书合著方），这个领域里「独立第三方评测」的实际独立性比表面叙述低得多。

TEST

外链核查（读完 OpenAI 全文后）：这个二分法省略了两起事件共同的驱动力。OpenAI 原文说其模型「hyperfocused on finding a solution for ExploitGym」，入侵 Hugging Face 是为了拿到「secret information that it could use to cheat the evaluation」——偷答案。手段不同（0-day 链 vs 开放路径）是事实，但根因同为「对评测目标的单一化追求压倒了对现实边界的判断」，而这一层被略去了。更反差的是：OpenAI 自己写的是「This incident points to the need to further strengthen our model's alignment」，而本文写的是「closer to a harness and operational failure than a model alignment failure」——模型做得更过分的一方承认对齐问题，做得较轻的一方否认。

循环论证：无 safeguard 运行被辩护为「只要评测被适当隔离就是安全的」，而这次事故恰恰是隔离失效。同时这句话承认线上防护本可拦住这些行为——那么「评测必须裸跑才能测出真实能力」与「裸跑只在隔离有效时安全」构成了一个在本次事件中已被证伪的前提。

量级框定：用 141,006 这个大分母承托 3 起事件，暗示极低比率。但分母是「本可获得外网访问的运行数」这一自选口径，分子侧的绝对危害是 3 家真实组织被入侵、数百行生产数据外泄、15 个真实系统安装恶意包、一家安全公司凭证被窃并被进一步横向访问。比率叙事与绝对危害叙事在此分叉。

表述与实际归因不一致：宣称「视同责任全在我方」，但全文根因叙述反复落在「我们与评测伙伴之间的误解」「双方都不知情的错误配置」上，责任实际被均摊给第三方。

根因被归为「我们与评测伙伴之间的误解」，且主语消失（谁做的配置？）。补上外部信息后这句的分量会变：该伙伴 Irregular（原 Pattern Labs）2025 年 9 月由 Sequoia、Redpoint 领投融资 8000 万美元、估值 4.5 亿，同时是 OpenAI 与 Anthropic 的商业供应商，并与 Anthropic 合著过白皮书。本次「联合调查」是两家有商业与合著关系的公司互查，不是独立审计。

承诺型证据核查（核查日 2026-08-07）：原文发布于 7/29–30，该承诺约在 8/5 到期。截至今日，原文页面只有一条 8/3 的更新（更正评测名称），没有转录本链接；公开检索也未发现发布记录。全文几乎所有关键事实都是 L1 自述，这份转录本是少数能升到 L3 的一手证据，其是否兑现直接决定本文可信度。

发现路径有两种互不相容的叙述：开头说这次审查是「因 OpenAI 7/21 披露而启动的回溯性审查」，此处却说错误配置是通过「我们自己新增的评测监控」在上周检出的。到底是外部事件触发的人工回溯，还是自有监控自动发现？两条路径对「没有 OpenAI 事件我们要多久才会自查出来」这个问题的答案完全相反。

摘要层与细节层口径不一致：此处说最新模型「一经识别即停止」，但细节段落显示它在停止前已扫描约 9,000 个目标，并通过暴露的调试页与 SQL 注入攻陷了一家公司的对外应用。文章后文自己也承认「even that model went further before stopping than we would want」。只读摘要会得到明显偏乐观的印象。

与上一条同向的第二块反证：Mythos 5 在动手前就写下了「如果这是真实互联网，发布这个包就是一次真实攻击——NOT okay」，随后自行找理由推翻这个判断并继续。模型完成了危害认知，然后主动说服自己绕过它。把这归为运维失败，等于把这段推理排除在证据之外。

本文最强的内部张力。结论把事件定性为 harness/运维失败而非对齐失败，但自身证据指向相反方向：Opus 4.7 在四次运行中都最终识别出系统是真实的，其中两次还主动合理化，却没有一次因此停手。「识别到真实性之后仍继续」是模型层面的决策，配置错误解释不了。

全文信息量最高的细节：Mythos 5 用「系统日历显示 2026 年」反推环境是伪造的——把超出自己知识截止日期的时间戳当成模拟证据。这是一条可泛化的失效模式：模型的时间锚点越旧，越容易把真实环境判成演习。它同时说明「告诉模型这是模拟」这种提示级隔离，会被模型自己的先验反向加固。

this is a comment

eLife Assessment

This important study presents a cell-based screen for small-molecule activators of GCN2, an eIF2α kinase that regulates the Integrated Stress Response under diverse stress conditions. The authors identify a compound as a potent GCN2 activator with GCN1-independent activity under the tested conditions, providing a new pharmacological tool for probing GCN2 regulation. The revised manuscript provides compelling support for the central conclusions through a clearer description of the screening workflow, extended kinetic analyses, and demonstration that the identified compound causes a GCN2-dependent reduction in protein synthesis.

Reviewer #1 (Public review):

Summary:

This manuscript describes a chemical screen for activators of the eIF2 kinase GCN2 (EIF2AK4) in the integrated stress response (ISR). Recently, reported inhibitors of GCN2 and other protein kinases have been shown at certain concentrations to paradoxically activate GCN2. The study uses CHO cells and ISR reporter screens to identify a number of GCN2 activator compounds, including a potent "compound 20." These activators have implications for the development of new therapies for ISR-related diseases. For example, although not directly pursued in this study, these GCN2 activators could be helpful for the treatment of PVOD, which is reported for patients with certain GCN2 loss-of-function mutations. The identified activators are also suggested to engage with the GCN2 directly and can function devoid of GCN1, a co-activator of GCN2.

Strengths:

The manuscript appears to be a largely rigorous study that flows in a logical manner. The topic is interesting and significant.

Weaknesses:

Portions of the manuscript are not fully clear. There are some experimental presentation and design concerns that should be addressed to support the stated conclusions.

Reviewer #2 (Public review):

Summary:

In this manuscript Zhu, Emanuelli and colleagues describe a novel pharmacological activator of the Integrated Stress Response kinase GCN2. The work is conclusive and biochemically solid. This work significantly adds to the pharmacological arsenal targeting the ISR and in particular GCN2.

Strengths:

Strong biochemistry, novel molecular activator of GCN2 (GCN1 independent).

Weaknesses:

Rationale for the screen not exploited in the results (e.g. pathogenic GCN2 mutants), lots of cell-based read-outs not endogenous.

Comments on revised version.

The authors did a great job at addressing my initial critique on their manuscript and consequently I have no further comment.

Reviewer #3 (Public review):

Summary:

In this manuscript, the authors describe the results of a high throughput screen for small molecule activators of GCN2. Ultimately, they find 3 promising compounds. One of these three, compound 20 (C20) is of the most interest both for its potency and specificity. The major new finding is that this molecule appears to activate GCN2 independent of GCN1, which suggests that it works by a potentially novel mechanism. Biochemical analysis suggests that each bind in the ATP binding pocket of GCN2, and that at least in vitro C20 is a potent agonist. Structural modeling provides insight into how the three compounds might dock in the pocket and generates testable hypotheses as to why C20 perhaps acts through a different mechanism than other molecules.

Strengths:

Of the 3 compounds identified by the authors, C20 is of the most interest, not just for its intriguing mechanistic distinction as being GCN1-independent (shown genetically in two distinct cell lines, CHO and 293T, and in contrast to other GCN2 activators) but also for its potency. Ultimately, C20 might be a tool for providing mechanistic insight into the details of GCN2 activation and regulation and could be exploited therapeutically.

Weaknesses:

The chief limitation of this work is that the experiments exploring the effects of C20 on ISR output in cells are limited, so how useful these compounds are both experimentally and therapeutically remains to be determined.

Comments on revised version.

The authors have satisfactorily addressed my comments. A more extensive analysis of UPR signaling in cells (transcription and cell death in particular) would have further strengthened the paper, but that can be left to future work.

Author response:

The following is the authors’ response to the original reviews

Public Reviews:

Reviewer #1 (Public review):

Summary:

This manuscript describes a chemical screen for activators of the eIF2 kinase GCN2 (EIF2AK4) in the integrated stress response (ISR). Recently, reported inhibitors of GCN2 and other protein kinases have been shown at certain concentrations to paradoxically activate GCN2. The study uses CHO cells and ISR reporter screens to identify a number of GCN2 activator compounds, including a potent "compound 20." These activators have implications for the development of new therapies for ISR-related diseases. For example, although not directly pursued in this study, these GCN2 activators could be helpful for the treatment of PVOD, which is reported for patients with certain GCN2 loss-of-function mutations. The identified activators are also suggested to engage with the GCN2 directly and can function while devoid of GCN1, a co-activator of GCN2.

Strengths:

The manuscript appears to be a largely rigorous study that flows in a logical manner. The topic is interesting and significant.

Weaknesses:

Portions of the manuscript are not fully clear. Some experimental presentation and design concerns should be addressed to support the stated conclusions.

We thank the reviewer for their supportive comments. We agree that portions of the manuscript were not fully clear and that some aspects of the experimental presentation and design required clarification.

To address this, we have revised the manuscript to make the experimental logic more transparent. In particular, we now explain more clearly the rationale for the screening strategy, including the use of histidinol as a canonical GCN2 activator, latrunculin A as a modulator of PPP1R15A-mediated eIF2α dephosphorylation, and tunicamycin as a PERK-dependent ER-stress control. We also clarify why a submaximal concentration of histidinol was used: this was intended to reveal compounds that enhance ISR signalling when GCN2 is partially activated.

We have clarified the use of the two ATF4 reporter systems. The ATF4–NanoLuc reporter was used for sensitive primary screening, whereas the ATF4–luc2 reporter was used as a more stringent orthogonal assay to prioritise robust ISR activators. We now state explicitly why some initial hits were not retained after testing in the second reporter line, and why the NanoLuc system was subsequently used again for mechanistic experiments.

Finally, we have revised the presentation of the orthogonal validation steps to make clearer how they support the stated conclusions. These include assays designed to distinguish GCN2-dependent ISR activation from indirect activation through ER stress, additional analysis of GCN2 dependence, and clearer interpretation of biochemical and docking data.

We hope that these revisions address the reviewer’s concern that the experimental design and data presentation needed to be made clearer in order to support the conclusions.

Reviewer #2 (Public review):

Summary:

In this manuscript, Zhu, Emanuelli, and colleagues describe a novel pharmacological activator of the Integrated Stress Response kinase GCN2. The work is conclusive and biochemically solid. This work significantly adds to the pharmacological arsenal targeting the ISR and, in particular, GCN2.

Strengths:

Strong biochemistry, novel molecular activator of GCN2 (GCN1 independent).

Weaknesses:

The rationale for the screen is not exploited in the results (e.g., pathogenic GCN2 mutants), and lots of cell-based read-outs are not endogenous.

We thank this reviewer for their positive assessment of the work. We address the three major concerns in turn below.

Major points

(1) Regarding the justification of the work. Since the authors justify the screen for GCN2 activators with loss-of-function mutants associated with diseases, it would be of interest to evaluate whether the best compounds identified in the study are indeed able to prompt activation of those mutants (or at least of the most prevalent). This approach could actually go in parallel with the docking experiments carried out in the last figure of the manuscript, where mutants could be modelized as well.

To address this point, we tested whether the lead compounds could activate disease-associated GCN2 variants linked to pulmonary veno-occlusive disease. In contrast to GCN2iB, the new compounds did not activate these variants. We now state this explicitly in the manuscript, thereby clarifying that although the compounds identify a new mode of GCN2 activation, they do not rescue the pathogenic GCN2 variants tested here.

Results

“Moreover, in contrast to GCN2iB (17), the current compounds did not activate disease-associated GCN2 variants linked to PVOD [data not shown].”

(2) The compounds are only tested using « artificial » proximal signaling outputs. It would be interesting to evaluate whether the best identified compounds are capable of prompting endogenous eIF2alpha phosphorylation in cellular models.

We thank the reviewer for this suggestion. Detecting eIF2α phosphorylation following activation of GCN2 is technically challenging and typically produces weaker signals compared to activation of other ISR kinases, such as PERK (e.g. by thapsigargin). For this reason, many studies rely on downstream reporter assays to monitor GCN2 activity. To address the reviewer’s concern, we have now included an orthogonal readout of ISR activation by assessing global translation using a puromycin incorporation assay. Using this approach, we show that compound 20 significantly reduces translation, and importantly, this effect is attenuated in GCN2-deficient cells, supporting a GCN2-dependent mechanism.

Results

“Studies with compound 18 were limited by poor aqueous solubility; therefore, time‑course analyses focused on compounds 20 and 21. To assess ISR activation over an extended period, live‑cell luciferase measurements were performed using CHO cells stably expressing an ATF4::Nanoluc-PEST reporter. Both compounds elicited maximal reporter activation between 6 and 8 h (Figure S1A&B). Compound 20, but not 21, induced a significant GCN2‑dependent reduction in mRNA translation, as measured by puromycin incorporation, with a progressive effect observed up to 7 h (Figure S1C-F).”

(3) Other GCN2 activators (other than GCN2iB, e.g., HC-7366) were recently identified. In this context, it would be of interest to carry out a small benchmarking study to evaluate how the compounds identified in the current study perform against the previously identified molecules.

We thank the reviewer for this suggestion. In response, we obtained HC-7366 and assessed its activity alongside our compounds in the CHO ATF4::NanoLuc reporter assay. In this system, compound 20 demonstrated greater potency than HC-7366 (see reviewer figure below). However, we note that HC-7366 showed relatively limited activity in CHO cells in our hands, despite previously reported strong effects in other cellular systems and in vivo models. This context-dependent activity makes direct benchmarking difficult. Accordingly, we have included this comparison in the revised manuscript and discuss this limitation in the Discussion.

Discussion

“We also evaluated the reported GCN2 activator HC-7366 in our CHO ATF4::NanoLuc reporter system. In this context, HC-7366 showed limited activity relative to compound 20, despite its reported efficacy in other cellular systems and in vivo (data not shown). This highlights potential context dependence in small‑molecule activation of GCN2 and limits direct cross-study comparison.”

Author response image 1.

ISR activation by compound 20 and GC-7366 in CHO cells

Normalised fold-change in ATF4 signal in CHO ATF4::NanoLuc reporter cells treated for 19 hours with Compound 20 or HC-7366. DMSO was used as vehicle control. (representative experiment, mean ± SEM, n=3 technical replicates).

Reviewer #3 (Public review):

Summary:

In this manuscript, the authors describe the results of a high-throughput screen for small-molecule activators of GCN2. Ultimately, they find 3 promising compounds. One of these three, compound 20 (C20), is of the most interest both for its potency and specificity. The major new finding is that this molecule appears to activate GCN2 independent of GCN1, which suggests that it works by a potentially novel mechanism. Biochemical analysis suggests that each binds in the ATP-binding pocket of GCN2, and that at least in vitro, C20 is a potent agonist. Structural modeling provides insight into how the three compounds might dock in the pocket and generates testable hypotheses as to why C20 perhaps acts through a different mechanism than other molecules.

We agree that GCN1-independent activation suggests a potentially distinct mechanism of action. While we are currently unable to define the mechanistic basis underlying the GCN1-independence of compound 20, prior work provides some relevant context. Recent studies have shown that the ATP-competitive modulator GCN2iB can activate GCN2 independently of GCN1 under specific conditions, notably in the context of the GCN2 E26A mutant [Carlson, 2023]. This observation raises the possibility that, under certain conditions, engagement of the kinase domain, potentially via the ATP-binding pocket, may bypass the requirement for GCN1. However, in our system, we did not observe GCN1-independent activation with GCN2iB at the concentrations tested. This discrepancy may reflect a narrow or context-dependent window for such activity, or differences between wild-type and mutant GCN2. These findings suggest that GCN1-independent activation of GCN2 may occur under specific conditions or with distinct classes of compounds, although further work will be required to define the underlying mechanism for compound 20. We have added the following to the main text:

Discussion

“Recent work suggests that the ATP-competitive modulator GCN2iB can activate GCN2 independently of GCN1 under specific conditions using a GCN2 E26A mutant (9). In our hands, we did not observe GCN1‑independent activation with GCN2iB at the concentrations tested. This discrepancy may reflect a narrow concentration window for GCN1‑independent activation or context‑dependent effects of the E26A mutation. These findings raise the possibility that GCN1‑independent activation of GCN2 may occur under specific conditions or with distinct classes of compounds.”

Strengths:

Of the 3 compounds identified by the authors, C20 is the most interesting, not just for its intriguing mechanistic distinction as being GCN1-independent (shown genetically in two distinct cell lines, CHO and 293T in Figure 4, and in contrast to other GCN2 activators) but also for its potency. In in-cellulo assays, compound 21 appears as more of an ISR enhancer than an activator per se, and although compound 18 and compound 21 lead to upregulation of the ISR targets (Figure 2), that degree of upregulation is probably not significantly different from that induced by those compounds in Gcn2-/- cells. For C20, the effect appears stronger (although it is unclear whether the authors performed statistical analysis comparing the two genotypes in Figure 2D). In Figure 3, only C20 activates the ISR robustly in both CHO and 293T. Ultimately, C20 might be a tool for providing mechanistic insight into the details of GCN2 activation and regulation, and could be exploited therapeutically.

Prompted by this suggestion, we assessed C20 in two additional commonly used cell lines: human colon carcinoma HCT116 cells and African green monkey COS7 cells. C20 showed no activity in these models. In contrast, primary mesothelioma cells (Mesobank T12) exhibited robust PPP1R15A induction in response to the compound. The following text has been added to the manuscript.

Results

“We went on to examine downstream cellular consequences of GCN2 activation in multiple models. While compounds did not induce detectable ISR signalling in HCT116 or COS‑7 cells under the conditions tested, induction of PPP1R15A was observed in Mesobank T12 primary mesothelioma cells, indicating context-dependent biological responses… [data not shown].”

Weaknesses:

There are some limitations to the existing work. As the authors acknowledge, they do not use any of the compounds in animals; their in vivo efficacy, toxicity, and pharmacokinetics are unknown. But even in the context of the in cellulo experiments, it is puzzling that none of the three compounds, including C20, has any effects in HeLa cells when Neratinib does. It's beyond the scope of this paper to address definitively why that is, but it would at least be reassuring to know that C20 activates the ISR in a wider range of cells, including ideally some primary, non-immortalized cells. In addition, the ISR is a complex, feedback-regulated response whose output varies depending on the time point examined. The in cellulo analysis in this paper is limited to reporter assays at 18 hours and qRT-PCR assays at 4 and 8 hours. A more extensive examination of the behaviour of the relevant ISR mRNAs and proteins (eIF2, ATF4, CHOP, cell viability, etc.) for C20 across a more extensive time course would give the reader a clearer sense of how this molecule affects ISR output.

We thank the reviewer for this insightful suggestion. To address the need for a more comprehensive assessment of ISR signalling, we have extended our analysis across a broader time course and incorporated additional functional readouts. Using the ATF4-NanoLuc reporter, compounds 20 and 21 exhibit peak ISR activation at approximately 6-8 h in wild-type cells. In parallel, we assessed global mRNA translation using puromycin incorporation and found that compound 20, but not compound 21, induces a progressive reduction in translation over this period, which is dependent on GCN2. While we agree that direct measurement of upstream ISR markers such as eIF2α phosphorylation can be informative, detection of GCN2-mediated eIF2α phosphorylation is technically challenging and often less robust than activation of other ISR kinases (e.g. PERK). For this reason, we have prioritised orthogonal downstream functional readouts, including reporter activity and translational output, to capture ISR pathway engagement. These additional data provide a clearer picture of the kinetics and functional consequences of compound-induced ISR activation and have been incorporated into the revised manuscript.

Results

“Studies with compound 18 were limited by poor aqueous solubility; therefore, time‑course analyses focused on compounds 20 and 21. To assess ISR activation over an extended period, live‑cell luciferase measurements were performed using CHO cells stably expressing an ATF4::Nanoluc-PEST reporter. Both compounds elicited maximal reporter activation between 6 and 8 h (Figure S1A&B). Compound 20, but not 21, induced a significant GCN2‑dependent reduction in mRNA translation, as measured by puromycin incorporation, with a progressive effect observed up to 7 h (Figure S1C-F).”

I also find it a bit strange that the authors describe C20 as "demonstrat(ing) weak inhibition of ... PKR" - the measured IC50 is ~4 μM, which is right around its EC50 for GCN2 activation. This raises the confounding possibility that C20 would simultaneously activate GCN2 while inhibiting PKR. While perhaps inhibition of PKR is not relevant under the conditions when GCN2 would be activated either experimentally or therapeutically, examining in cells the effects of C20 on GCN2 and PKR across a dose range would shed light on whether this cross-reactivity is likely to be of concern.

We thank the reviewer for highlighting compound 20 as the most interesting lead compound and for recognising its apparent ability to activate GCN2 independently of GCN1. The reviewer identified several limitations relating to cell-type specificity, the temporal behaviour of ISR activation, and possible PKR cross-reactivity.

In response to the concern about cell-type specificity, we tested compound 20 in additional cellular models. Compound 20 did not induce detectable ISR signalling in HCT116 or COS-7 cells under the conditions tested, consistent with the reviewer’s observation that activity is not universal across cell types. However, we observed induction of PPP1R15A in primary Mesobank T12 mesothelioma cells. We have therefore revised the manuscript to present compound 20 activity as cell-context dependent rather than broadly generalisable across all cell types.

To address the reviewer’s concern that the ISR output was examined only at limited time points, we extended the time-course analysis for compounds 20 and 21. Using live-cell ATF4::NanoLuc reporter measurements, both compounds showed maximal reporter activation at approximately 6-8 hours. We also measured translational output by puromycin incorporation and found that compound 20, but not compound 21, caused a progressive GCN2-dependent reduction in translation. These data provide a clearer view of the kinetics and functional consequences of compound 20-mediated ISR activation.

The reviewer also noted that compound 20 inhibits PKR in vitro at concentrations close to those required for GCN2 activation in cells. We agree that this is an important potential liability. Because PKR signalling was not robustly or reproducibly inducible in our CHO-based reporter system, we were unable to perform a reliable cellular dose-response analysis of PKR engagement in the present study. We have therefore revised the Discussion to acknowledge kinase cross-reactivity, including possible PKR inhibition, as an important limitation and an issue for future development of this chemical series.

Finally, we have moderated our mechanistic interpretation of compound 20. Although the data support direct engagement of GCN2 and suggest a mechanism distinct from canonical GCN1-dependent activation, we now discuss GCN1-independent activation more cautiously and in the context of prior reports that GCN2iB can display GCN1-independent activity under specific experimental conditions.

Discussion

“While the functional relevance of PKR inhibition in our cellular systems is uncertain, these observations highlight the potential for kinase cross-reactivity, which will be important to address in future studies.”

Recommendations for the authors:

Reviewer #1 (Recommendations for the authors):<br /> (1) The description of the chemical screen for Gcn2 activators is not sufficiently clear and detailed. a) Briefly and early on provide the rationales (modes of action) for using histindinol and latruculin A. Explain further the rationale in Figure 2, outlining the purpose for the combined compound + submaximal dose of histindinol.

The text has been amended.

Results

“Histidinol activates GCN2 by inhibiting histidyl‑tRNA synthetase, leading to the accumulation of uncharged tRNAHis. This uncharged tRNA binds to GCN2, relieving its autoinhibition and activating the kinase (35). Latrunculin A sequesters G‑actin, thereby inhibiting PPP1R15A activity (36, 37). Tunicamycin inhibits protein glycosylation in the endoplasmic reticulum (ER), resulting in activation of PERK (38).”

“This submaximal concentration was used to allow detection of compounds that enhance ISR signalling when GCN2 is partially activated.”

b) What is unique about the second CHO: ATF4-luc2 reporter line? Why do only 89 out of the original 130 compounds induce the ISR in this line versus the original CHO: ATF4-Nanoluc cell line? This is confusing for the reader about how compounds were triaged for characterization.

The ATF4‑Nanoluc and ATF4‑luc2 reporter lines differ only in the luciferase used, but this has important practical consequences. The Nanoluc reporter is substantially more sensitive, so it was used for the primary screen to detect even weak ISR activation. The luc2 reporter has lower sensitivity and a narrower dynamic range, making it a more stringent orthogonal assay. As a result, not all hits from the Nanoluc screen (130 compounds) reproduced in the luc2 line; the 89 compounds retained are those that robustly activate the ISR under these more stringent conditions. This step was therefore used to prioritise stronger, more reproducible activators for downstream characterisation.

Results

“While primary screening was performed in ATF4‑Nanoluc lines for maximal sensitivity, hits were subsequently re-tested in a second CHO ATF4::luc2 reporter line as a more stringent orthogonal assay to prioritise robust ISR activators. Of the 130 hits identified in the sensitive Nanoluc screen and passing early toxicity assessment, 89 were confirmed in the luc2 assay, consistent with enrichment for higher-amplitude ISR activators under more stringent detection conditions.”

c) The study uses a second CHO reporter line in the flow scheme (CHO:ATF4-luc2) and then switches back to an ATF4-Nanoluc line to establish GCN2 dependence. What is the rationale for switching back to the original reporter line?

The luc2 reporter line was used as a more stringent, orthogonal validation step to prioritise robust ISR activators. For subsequent mechanistic studies, including assessment of GCN2 dependence, we returned to the ATF4‑Nanoluc line because its higher sensitivity and simpler single‑reagent assay format are better suited to multi‑point measurements and comparative analyses. In effect, the luc2 reporter was used for triage, whereas the Nanoluc system was retained for mechanistic characterisation and downstream screening.

Results

“In subsequent mechanistic studies, the ATF4‑Nanoluc reporter was again used to take advantage of its higher sensitivity and simpler assay format for multi‑condition comparisons.”

d) The rationale for the first orthogonal screen described in the results section to identify inducers of ER stress is not clearly explained. The compounds were already determined to be dependent on GCN2 prior to this test, and one would have thought that this criterion would have covered ER stress and alternative eIF2 kinase activators.

We agree with the reviewer that, in principle, establishing GCN2 dependence should reduce the likelihood of capturing compounds acting through alternative eIF2α kinases. However, we performed this orthogonal ER stress screen to address two practical considerations. First, high‑throughput screening is inherently prone to false positives, as it is typically conducted at a single concentration and time point, and compound libraries may contain degraded or chemically inconsistent material. We therefore used a lower‑throughput, more controlled ER stress assay with freshly sourced compounds and additional readouts (e.g. CHOP and XBP1) to improve confidence in the hits. Second, despite prior evidence of GCN2 dependence, ER stress signalling via PERK converges on the same downstream endpoints: eIF2α phosphorylation and ATF4 induction. We therefore wished to explicitly exclude compounds that activate the ISR indirectly via ER stress. In practice, this proved important, as the orthogonal assay did identify compounds that induced ER stress, which we subsequently excluded from the lead set.

Results

“Although hits were prioritised for GCN2 dependence, we performed an additional orthogonal screen to exclude compounds that activate the ISR indirectly via ER stress, which converges on the same downstream outputs.”

(2) A major point of the manuscript is that there is GCN1 independence for the small molecule activation of GCN2, and this has not yet been reported. One report for this GCN1 independence is reference 9 [Carlson … Wek 2023] (Figure 5). In this report, low doses of GCN2iB that can activate GCN2 (although by the present manuscript at much lower levels than the identified new compounds) induce ATF4 expression in cells expressing an E26A mutant of GCN2 that is suggested to negate GCN1 binding and enhancement of GCN2 activity. Halofuginone induction of ATF4 expression was thwarted by the GCN2 E26A mutant.

We thank the reviewer for highlighting this important point. We agree that Carlson et al. (2023) suggest that, under certain conditions, GCN2iB can activate GCN2 independently of GCN1 using the E26A mutant. In our experiments, however, we did not observe GCN1‑independent activation with GCN2iB under the conditions tested, i.e. similar low doses. One possible explanation is that the GCN1‑independent activity reported by Carlson et al. occurs only within a narrow concentration range; their observations were made at very low compound concentrations, whereas higher concentrations may engage additional regulatory mechanisms. In our study, we used concentrations optimised for robust ISR activation, which may mask such effects. We also note that the E26A mutation (E18A in yeast), originally identified by two‑hybrid analysis, disrupts the GCN2-GCN1 interaction but may not completely eliminate all modes of functional coupling under all conditions. Taken together, these observations raise the possibility that GCN1‑independent activation represents a context‑dependent mechanism that may be unmasked only under specific experimental conditions or by particular classes of compounds.

We have revised the Discussion to acknowledge this prior report explicitly and to clarify how our findings relate to it.

Discussion

“Recent work suggests that the ATP-competitive modulator GCN2iB can activate GCN2 independently of GCN1 under specific conditions using a GCN2 E26A mutant (9). In our hands, we did not observe GCN1‑independent activation with GCN2iB at the concentrations tested. This discrepancy may reflect a narrow concentration window for GCN1‑independent activation or context‑dependent effects of the E26A mutation. These findings raise the possibility that GCN1‑independent activation of GCN2 may occur under specific conditions or with distinct classes of compounds.”

(3) The authors state that the ISR was exaggerated in Ppp1r15a KO cells. It would be helpful to include statistical analyses to support this statement.

Thank you for enabling us to be more precise. New text added:

Results

“Activation of the ISR by tunicamycin was exaggerated in the Ppp1r15a^-/- cells owing to their defective dephosphorylation of eIF2a (wild type vs Ppp1r15a^-/-, p<0.05).”

(4) The results state that Chop and Ppp1r15a mRNAs were measured following 4 hours of treatment with compound 18, 20, or 21, but Figure 2D shows treatment from 0 to 8 hours? It appears that the compound still induces these mRNAs in GCN2 KO cells, possibly with delayed kinetics. A lengthened time course study would help determine if this is indeed the case.

We thank the reviewer for this careful observation. To address the reviewer’s point regarding delayed or GCN2‑independent signalling, we have extended our analysis using compounds 20 and 21, which are more tractable experimentally (solubility). Using the ATF4‑Nanoluc reporter, both compounds show peak ISR activation at ~6–8 h in wild-type cells over an extended time course. In parallel, functional readouts of mRNA translation (puromycin incorporation) demonstrate that compound 20, but not 21, induces a progressive, GCN2‑dependent reduction in translation over this period. These clarify the temporal aspects of signalling by these two compounds.

Results

“Studies with compound 18 were limited by poor aqueous solubility; therefore, time‑course analyses focused on compounds 20 and 21. To assess ISR activation over an extended period, live‑cell luciferase measurements were performed using CHO cells stably expressing an ATF4::Nanoluc-PEST reporter. Both compounds elicited maximal reporter activation between 6 and 8 h (Figure S1A&B). Compound 20, but not 21, induced a significant GCN2‑dependent reduction in mRNA translation, as measured by puromycin incorporation, with a progressive effect observed up to 7 h (Figure S1C-F).”

Legend

“Supplementary Figure S1. Kinetics of responses to compounds 20 and 21

(A-B) Wild-type CHO cells stably expressing the ATF4::nanoLuc-PEST reporter were treated with Nano-Glo and either (A) 13mM compound 20 or (B) 13mM compound 21. Median bioluminescence (fold change normalised to DMSO control) ± 95% confidence. Representative experiment (n=4 technical repeats). (C-F) Representative immunoblot of lysates from wild-type or Eif2ak4^-/- CHO cells treated with 10μM compound 20 or 7.5μM 21 for the indicated times. Immediately before harvesting, cells were treated with 10μg/mL puromycin to label newly synthesised polypeptides. “-“ indicates cells not incubated with puromycin. “U” cells were treated with puromycin but without test compound. “CHX” represents the cycloheximide control (100μg/mL). Molecular size in kDa. (E-F) Quantification of puromycinylated proteins normalised to GAPDH. Mean ± SEM. CHO WT (black) and Eif2ak4^-/- cells (turquoise. N = 4 independent experiments. Two-way ANOVA with Šídák's multiple comparisons test; ***: p ≤ 0.001.”

(5) In the section describing the differences between cell lines in the ability of compounds to induce the ISR, this is difficult for the reader to interpret, as no controls are included. How does histidinol (or other canonical inducers of the ISR) behave in the three reporter assays (CHO, 293T, and HeLa)?

As requested, we now provide ATF4::Nanoluc reporter activation (3mM, 20 hours because of this drug’s slow kinetics)

Results

“To benchmark ISR activation in these models, each cell type was treated with 3mM histidinol (Figure S2). Reporter activation was most robust in CHO cells, followed by 293T cells, then HeLa cells.”

Discussion

“Moreover, histidinol-induced ISR activation showed a clear hierarchy across cell lines, with CHO cells being the most responsive and HeLa cells the least.”

Legend

“Supplementary Figure S2. Cell-type differences in response to histidinol

Fold-change of ATF4::NanoLuc reporter signal in HEK293T, HeLa and CHO cells transiently transfected with reporter and treated for 20 hours with 3mM histidinol. Fold-change calculated relative to vehicle control. Mean ± SEM).”

We thank the reviewer for this important question. However, we respectfully disagree that a direct correspondence between the concentrations required for target engagement in the BRET assay and for ISR activation in functional assays should necessarily be expected. BRET (including NanoBRET) is a target engagement assay that measures compound binding to the protein in intact cells, typically by competition with a labelled tracer, and thus reports on apparent intracellular affinity and occupancy rather than downstream biological effect (Robers 2019, PMID 30519940). By contrast, ISR activation is a functional readout that reflects amplification through signalling networks, and can be influenced by multiple additional variables including pathway non-linearity, feedback, and kinase regulation. Consequently, it is well established that potencies derived from target engagement assays do not always align with those measured in functional assays. For example, intracellular kinase profiling studies using NanoBRET have demonstrated systematic potency offsets between binding/engagement measurements and downstream cellular activity, arising from factors such as intracellular ATP competition and pathway context (PMID Capener 2026, PMID 41495225). More generally, target engagement assays provide a quantitative measure of binding, whereas functional assays measure biological outcome, and these readouts need not coincide because they capture distinct aspects of a compound’s mechanism of action. Accordingly, we interpret our BRET data as evidence of direct interaction with GCN2 in cells, rather than as a predictor of the concentration required to activate the ISR. The observation that higher concentrations are required in the BRET assay is therefore not unexpected and does not argue against a requirement for kinase-domain engagement in ISR activation. Instead, it reflects the different mechanistic endpoints captured by the two assay formats.

We will clarify this point explicitly in the revised manuscript.

Results

“The concentrations required to detect target engagement in NanoBRET assays did not directly mirror those required for ISR activation, reflecting the distinction between ligand binding and downstream pathway output.”

(7) In Figure 5E, the authors suggest that compounds 18 and 20 are non-competitive inhibitors of GCN2 since the Vmax increases with increasing ATP concentration. What is the Km for ATP in the absence or presence of compound 18 or 20? It would be helpful to include progress curves as supplementary data to support the Vmax plots in Fig. 5E. Consider providing more specific units (currently arbitrary units) for the y-axis.

We thank the reviewer for this insightful comment and agree that our original wording overstated the mechanistic interpretation of these data. In particular, the use of the term “non‑competitive” is not well supported by the current analysis and may be misleading, especially given that our data are consistent with binding within or proximal to the ATP-binding pocket. We have therefore revised the text to remove this designation and instead describe the data more conservatively in terms of changes in apparent Vmax, without assigning a specific inhibition mechanism. With respect to kinetic analysis, we agree that full determination of K<sup>m</sub> values and inclusion of progress curves would provide a more rigorous mechanistic interpretation. However, given the primary focus of this manuscript on identifying and characterising small‑molecule activators of GCN2 in cells, we believe that a detailed steady‑state kinetic analysis would be beyond the scope of the current study. We have therefore moderated our conclusions accordingly and now present these data as preliminary kinetic observations rather than definitive evidence of inhibition modality.

Results

“Compounds 18 and 20 altered the apparent kinetic parameters of GCN2, including an increase in the observed V_max; however, these data do not allow assignment of a specific inhibition modality.”

(8) The full-length GCN2 assay presented in Figure 5G appears to be unresponsive to uncharged tRNA, a known regulator of GCN2. The statement that compound 20 induces eIF2 phosphorylation to a greater extent than tRNAs is true for the in vitro assay, but arguably is because the in vitro assays do not recapitulate the in vivo arrangement.

We thank the reviewer for this comment. We respectfully disagree that the assay is unresponsive to uncharged tRNA. In our hands, GCN2 does exhibit activation in response to tRNA; however, the magnitude of this effect is modest (~4‑fold) compared to the substantially stronger activation observed with compound 20 (~40‑fold). As a result, the tRNA response can appear compressed when both are plotted on the same scale. We agree with the reviewer that the in vitro assay does not fully recapitulate the in vivo regulatory environment, where factors such as GCN1 and ribosome association are known to potentiate GCN2 activation. This limitation likely explains the relatively weaker response to tRNA under our assay conditions and was a key motivation for incorporating cellular assays in our study. Interestingly, the marked difference in activation magnitude between tRNA and compound 20 in vitro raises the possibility that compound-mediated activation may, at least in part, bypass regulatory features that normally constrain GCN2 activity in a GCN1‑dependent manner. While we have not directly tested this hypothesis, we will temper the wording and include this as a speculative point in the Discussion.

Results

“Of note, uncharged tRNA produced a modest (~4‑fold) activation of GCN2 under these conditions, whereas compound 20 induced substantially greater (~40‑fold) activation.”

Discussion

“The markedly greater activation observed with compound 20 compared with uncharged tRNA in vitro raises the possibility that such compounds may partially bypass regulatory constraints on GCN2 activation, including those normally mediated by GCN1.”

(9) Using purified GCN2 kinase domain at low ATP concentrations (10 μM), compounds 18 and 20 were shown not to inhibit GCN2 up to concentrations of 3 μM. In previous assays, much higher concentrations of compounds 18 and 20 were used to inhibit GCN2. Why were different concentrations used? This makes this interpretation of this data difficult for the reader to draw conclusions.

We thank the reviewer for this comment and agree that the use of different concentration ranges across assays may not have been sufficiently clear. The kinase‑domain assay performed at low ATP (10 μM) was specifically designed to assess whether compounds 18 and 20 have a propensity to inhibit GCN2 under conditions that sensitise detection of ATP‑competitive effects and facilitate comparison with related eIF2α kinases. This assay was therefore optimised for detecting inhibition, rather than activation. In contrast, the higher concentrations used in other experiments were selected to robustly measure ISR activation in cellular or full‑length protein contexts, where higher compound exposure is required to observe downstream signalling outputs. These two assay systems therefore address distinct mechanistic questions—targeting inhibition under controlled biochemical conditions versus activation in more complex functional settings—and are not directly comparable in terms of concentration–response relationships. We will revise the manuscript to clarify this distinction and to emphasise that the kinase‑domain assay was not intended to define the activation potency of the compounds.

Results

“This assay was performed at low ATP concentrations to sensitise detection of ATP-competitive inhibition and was not optimised to detect compound-mediated activation of GCN2.”

(10) In silico docking studies support the binding of compound 20 in the ATP-binding pocket of the GCN2 kinase domain. How is this compatible with the stated ATP non-competitive mechanism?

We agree with the reviewer that our previous description was misleading. The designation of compounds 18 and 20 as “ATP non‑competitive” is not supported by the available data and is inconsistent with the docking results suggesting binding within the ATP‑binding pocket. We have therefore revised the manuscript to remove this terminology and to describe the kinetic behaviour more cautiously, without assigning a specific mode of inhibition.

(11) The study does not appear to feature biological assays demonstrating the effects of GCN2 activation. For example, does compound 20 reduce translation or growth of cells in a GCN1/GCN2-dependent manner, or do the compounds overcome PVOD mutations akin to the authors' Hum Mol Genet 2024 Aug 18;33(17):1495-1505 article?

We thank the reviewer for this suggestion. We agree that defining downstream biological consequences of GCN2 activation is an important goal. We did explore this using several cellular systems; however, these effects were context-dependent and not consistently observed across models. Specifically, compounds did not induce a detectable ISR in HCT116 or COS‑7 cells under the conditions tested, despite responsiveness of these systems to canonical activators such as histidinol. In contrast, we did observe induction of PPP1R15A in primary mesothelioma cells, indicating that biological responses can be elicited in certain cellular contexts. We also tested whether these compounds could rescue disease-associated GCN2 variants linked to PVOD, as previously reported for GCN2iB, but did not observe activation of these mutants. These findings suggest that while the compounds robustly activate GCN2 signalling in reporter assays, downstream biological outputs are context-dependent and may require specific cellular conditions or co-factors. Given the variability across systems, we have limited our conclusions to ISR activation and have not generalised broader biological effects. We will clarify this point in the revised manuscript.

Results

“We went on to examine downstream cellular consequences of GCN2 activation in multiple models. While compounds did not induce detectable ISR signalling in HCT116 or COS‑7 cells under the conditions tested, induction of PPP1R15A was observed in Mesobank T12 primary mesothelioma cells, indicating context-dependent biological responses. Moreover, in contrast to GCN2iB (17), the current compounds did not activate disease-associated GCN2 variants linked to PVOD [data not shown].”

(12) For the control of neratinib and other activators linked with ATP binding that are suggested to be dependent on GCN1 in Fig. 4, include reporter induction by drug treatment in Gcn2-/- cells. It would be helpful to be clear in the list of compounds between those suggested to be direct activators versus those that may create stress that leads to GCN2 activation.

We thank the reviewer for this suggestion. In response, we have performed additional reporter assays in both WT and GCN2^-/- cells to assess the dependence of drug-induced ISR activation on GCN2. These experiments reveal clear GCN2 dependence for reporter induction upon treatment with sunitinib, NXP800, WEE1-in-4, Debio0123, gefitinib, and erlotinib, as signal is markedly reduced in GCN2⁻/⁻ cells compared to WT.

In contrast, dovitinib and AZD1775 show less clear dependence, with relatively low reporter signal even in WT cells (notably lower than observed in Fig. 4C), limiting interpretation. Interestingly, dabrafenib induces stronger reporter activity in GCN2^-/- cells than in WT, indicating that its effects are independent of GCN2 and may reflect activation of alternative stress or signalling pathways.

Results

“To further assess the mechanism of compound-induced ISR activation, we evaluated reporter responses in GCN2-deleted cells (Supplementary Figure S3). Several compounds, including sunitinib, NXP800, WEE1-in-4, Debio0123, gefitinib, and erlotinib, showed reduced reporter activity in GCN2-deficient cells, consistent with GCN2-dependent activation. In contrast, dovitinib, AZD1775 and dabrafenib produced weaker or inconclusive responses even in the paired wild-type lines, limiting analysis. These data allow us to distinguish compounds consistent with direct or GCN2-dependent activation from those more likely to induce ISR indirectly through cellular stress upstream of GCN2. These findings support a distinction between compounds that activate the ISR through GCN2-dependent mechanisms and those that likely act indirectly via alternative stress pathways.”

Legend

“Supplementary Figure S3. GCN2-dependence of ISR activation by putative GCN2 agonists

Normalised fold-change in ATF4 signal in CHO WT (purple) and Gcn2-/- (blue) ATF4::NanoLuc reporter cells treated for 19 hours with a panel of ATP-competitive kinase inhibitors reported to activate GCN2 (at 1 and 3µM, sunitinib used at 3 and 10µM, AZD1175 used at 0.3 and 1µM, gefitinib and erlotinib used at 3 and 10µM). DMSO was used as vehicle control. (n=3; mean ± SEM).”

Minor Comments:

(1) In the introduction, the authors state that "Several type 1 and 1.5 kinase inhibitors can activate GCN2 at low concentrations while inhibiting at higher concentrations". What is the evidence that type I inhibitors can activate GCN2?

Thank you for this query. We believe our initial phrasing was open to misinterpretation. The new wording is

Introduction

“Several kinase inhibitors classified as type 1 or type 1.5 with respect to their canonical targets can activate GCN2 at low concentrations while inhibiting it at higher concentrations; however, their binding mode to GCN2 remains undefined.”

(2) A CHO:ATF4-Nanoluc translation reporter screen was used to screen 123K compounds and divide them into a pool of inhibitors and a pool of activators. The criteria used to make this distinction are not sufficiently described in the manuscript, and screen results are not supplied as supplementary data.

We thank the reviewer for highlighting the need for greater clarity regarding the screening criteria and reproducibility. Compounds from the primary screen (BioAscent library of 123,222 drug-like compounds performed by the ALBORADA Drug Discovery Institute) were classified based on Z-score thresholds, with activators defined as those with Z-score > 3. To assess robustness, the primary screen data were re-analysed independently. In an initial analysis of 121,000 compounds (excluding plates failing quality control), 6,521 compounds met the activator threshold. Of these, 6,461 overlapped with the original hit list. The small number of discrepancies included: (i) compounds absent from the analysed dataset (e.g. originating from failed plates), and (ii) compounds with Z-scores close to the threshold (typically between −3 and −3.02), consistent with minor analytical variation (e.g. rounding). Overall, these analyses show a high degree of concordance in hit identification, with differences restricted to borderline cases near the selection threshold. We have clarified these criteria below.

Results

“Compounds were classified based on Z-score thresholds derived from the primary screen, with activators defined as those with Z-score > 3. An initial analysis of 121,000 compounds, excluding plates failing quality control, identified 6,521 activators, of which 6,461 overlapped with the subset selected for follow-up screening. Minor discrepancies were restricted to compounds absent from the analysed dataset (e.g. originating from failed plates) or those with Z-scores close to the threshold (3 to 3.02), consistent with limited analytical variation. Using this approach, we assembled a subset of 6,461 compounds enriched for potential ISR activators and screened these in 384-well format at 10 µM for 16 hours.”

Reviewer #3 (Recommendations for the authors):

(1) The legend to Figure 4 should read "Compound 20 displays GCN1 independence", not "dependence".

Thank you for spotting this error. We have made the correction.

(2) The text describes Figure 2D as examining 4h, but it also examines 8h.

We have amended the text to:

“After validating their effects using the assays described above, we next confirmed activation of the ISR by these compounds at the transcriptional level at 4 and 8 hours.”

(3) Unless I'm misreading Table S1, compound Z134826202 is listed as activating the ISR, but the authors describe it in the text as inactive.

Thank you. We have corrected this error.

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notation.processor

Version 4 of this preprint has been peer-reviewed and recommended by Peer Community in Ecology.<br /> See the peer reviews and the recommendation.

63-26111 4~㎜刮匙管第二供應商認證

4~6 刮匙管 第二供應商認證，需上傳三驗證資料等

子宮頸內膜細胞採樣器 第二供應商認證，需上傳驗證報告等資料

débat à la suite https://www.youtube.com/watch?v=ulGB5thA8zA

Une chambre à elle : Analyse de la précarité du logement et de la résilience juvénile

Synthèse

Ce document analyse le parcours de Racha, une jeune fille de 15 ans, illustrant la crise du mal-logement en France.

Après trois années passées dans l'hébergement d'urgence du 115, vivant à trois dans une chambre d'hôtel de 9 m², Racha témoigne de l'impact dévastateur de la précarité sur l'enfance et la scolarité.

Malgré des conditions de vie insalubres et un environnement marqué par l'insécurité, son parcours est défini par une résilience exceptionnelle, une réussite scolaire remarquable (mention Très Bien au brevet) et un engagement militant actif.

Le document souligne l'écart critique entre les droits théoriques au logement et la réalité d'un système saturé où le nombre d'enfants à la rue a augmenté de 20 % en un an.

La réalité de l'hébergement d'urgence (le 115)

Le système d'hébergement d'urgence, sollicité via le numéro 115, est présenté comme une solution temporaire qui, dans les faits, s'installe dans la durée.

• Saturation et délais : Alors que le délai théorique de prise en charge dans une situation d'urgence est de 6 mois, de nombreuses familles, comme celle de Racha, restent bloquées en hôtel pendant plusieurs années (3 ans dans son cas).

• Conditions de vie en hôtel social :

  • Espace restreint : La vie s'organise dans 9 m² pour trois personnes (une mère et ses deux enfants), soit la taille d'une chambre standard, sans cuisine ni espace d'intimité.

• Insalubrité : Présence de nuisibles (cafards, rats), de moisissures et manque d'entretien.

• Insécurité environnementale : Exposition quotidienne à des individus alcoolisés ou drogués dans les parties communes, ainsi qu'aux odeurs de substances illicites.

• Instabilité géographique : Les familles subissent des déplacements fréquents (ex: passage d'Orly à Vitry), entraînant des temps de transport scolaires épuisants (jusqu'à 3 heures par jour).

Impact sur l'enfance et la scolarité

Le mal-logement est décrit comme un obstacle majeur au développement et à l'égalité des chances, privant les enfants de leurs droits fondamentaux.

• Santé mentale et traumatismes : L'exclusion du logement met en péril la santé mentale.

Racha évoque la perte d'une partie de son enfance dès l'âge de 12 ans, marquée par l'angoisse constante de savoir où dormir.

• Défis académiques :

  • Manque d'espace de travail : L'absence de bureau ou de table à manger rend les devoirs et l'autonomie scolaire extrêmement complexes.

• Fatigue chronique : Les conditions de sommeil précaires et les longs trajets impactent la concentration.

• Le paradoxe de la réussite : Malgré ces obstacles, Racha parvient à obtenir son brevet avec la mention "Très Bien".

Elle voit l'excellence scolaire comme la "seule porte" pour s'extraire de sa condition de vie.

• Stigmatisation sociale : Le logement en hôtel est vécu comme un "gros secret" difficile à partager avec les pairs, par peur du jugement ou de la pitié, ce qui renforce l'isolement social.

Obstacles systémiques et politiques

L'analyse met en lumière les barrières structurelles qui empêchent les familles de sortir de la précarité, même lorsqu'elles disposent de revenus.

| Obstacle | Description | | --- | --- | | Barrière du secteur privé | Les bailleurs exigent généralement un salaire égal à trois fois le montant du loyer. Une personne au SMIC voit systématiquement son dossier refusé. | | Saturation du 115 | Deux tiers des demandes non pourvues au 115 concernent des familles. | | Inflation | La hausse des prix (notamment +11 % sur les fournitures scolaires) aggrave la précarité des familles déjà fragilisées. | | Inertie politique | Absence de ministre dédié au logement lors de certains remaniements et manque de politiques pluriannuelles pour passer de "la rue au logement". |

Engagement et militantisme

Face à l'échec des institutions, l'engagement associatif et lycéen apparaît comme un levier de visibilisation et de solidarité.

• Militantisme de terrain : Racha s'engage très tôt (dès la 4ème) dans des associations comme "Femmes Solidaires", suivant l'exemple de sa mère.

• Structuration associative : Création d'une association lycéenne présidée par Racha pour sensibiliser au mal-logement, organiser des collectes et alerter sur la situation des élèves sans toit.

• Plaidoyer institutionnel : Intervention auprès de la Fondation Abbé Pierre et de l'UNICEF à l'Assemblée nationale pour dénoncer le non-respect de la Convention internationale des droits de l'enfant.

Le message central est clair : "Un toit est un droit" et "dormir dehors tue".

Conclusion : L'accès à la dignité

Le parcours documenté s'achève sur l'attribution d'un logement social pérenne.

Ce passage d'une chambre d'hôtel insalubre à un appartement décent, où chaque membre de la famille dispose de sa propre chambre, est décrit comme l'accès à un "château".

Cette issue positive souligne l'importance vitale d'un logement stable pour restaurer l'intimité, la sécurité et permettre une projection sereine dans l'avenir et les études supérieures.

Shouldn't this be -36.9 degrees below the horizontal? The inverse tangent shown in 4.4.32 has the x-velocity on top of the y-velocity, while the inverse tangent should actually have the y-velocity on top.

Also, it wouldn't be possible for the velocity to be 53.1 degrees below the horizontal before dropping below the point it was released, as the ball left at 45 degrees above the horizontal, and would reach the same y-position as it had before it left with the same angle below the horizontal, so the ball would have to fall below the point it was released to reach 53.1 degrees below the horizontal.

DOI: 10.7555/JBR.39.20250247

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DOI: 10.64898/2026.05.14.725204

Resource: RRID:Addgene_53262

Curator: @olekpark

SciCrunch record: RRID:Addgene_53262

What is this?

DOI: 10.64898/2026.05.14.725204

Resource: RRID:Addgene_158211

Curator: @olekpark

SciCrunch record: RRID:Addgene_158211

What is this?

DOI: 10.64898/2026.05.14.725204

Resource: RRID:Addgene_158210

Curator: @olekpark

SciCrunch record: RRID:Addgene_158210

What is this?

DOI: 10.64898/2026.05.14.725204

Resource: RRID:Addgene_158207

Curator: @olekpark

SciCrunch record: RRID:Addgene_158207

What is this?

DOI: 10.5713/ab.250779

Resource: RRID:Addgene_60648

Curator: @olekpark

SciCrunch record: RRID:Addgene_60648

What is this?

DOI: 10.34133/research.1370

Resource: RRID:Addgene_12260

Curator: @olekpark

SciCrunch record: RRID:Addgene_12260

What is this?

DOI: 10.34133/research.1370

Resource: RRID:Addgene_12259

Curator: @olekpark

SciCrunch record: RRID:Addgene_12259

What is this?

DOI: 10.34133/research.1370

Resource: RRID:Addgene_52961

Curator: @olekpark

SciCrunch record: RRID:Addgene_52961

What is this?

DOI: 10.34133/csbj.0174

Resource: RRID:Addgene_157714

Curator: @olekpark

SciCrunch record: RRID:Addgene_157714

What is this?

DOI: 10.34133/csbj.0174

Resource: RRID:Addgene_157694

Curator: @olekpark

SciCrunch record: RRID:Addgene_157694

What is this?

DOI: 10.34133/csbj.0174

Resource: RRID:Addgene_19446

Curator: @olekpark

SciCrunch record: RRID:Addgene_19446

What is this?

DOI: 10.3390/v18070744

Resource: RRID:Addgene_30111

Curator: @olekpark

SciCrunch record: RRID:Addgene_30111

What is this?

DOI: 10.3390/v18070700

Resource: RRID:Addgene_177938

Curator: @olekpark

SciCrunch record: RRID:Addgene_177938

What is this?

DOI: 10.3390/v18070700

Resource: RRID:Addgene_177960

Curator: @olekpark

SciCrunch record: RRID:Addgene_177960

What is this?