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正在设定更高的

碳边境调节机制（CBAM)核查

Learn key Indian remote call center compliance steps, data privacy rules, and real lessons that keep your remote team legally safe and audit-ready.

PMID: 24713488

Gene: ABCA4

Disease: ABCA4-Associated Retinopathies

This variant is included in a table that lists all ABCA4 variants

Case#: Male, Family#3, Proband M1, M2: II,1 on pedigree

DiseaseAssertion: STGD

FamilyInfo: mother of proband has p.N18681 and p.P1380L mutations and is asymptomatic with no changes to NIR-AF and SD-OCT. Treated with 400mg of hydroxychloroquine for lupus prior to imaging. Non-affected father.

CasePresentingHPOs:HP:0007663, HP:0000493

CaseHPOFreeText: Proband has reduced visual acuity and issues reading with BCVA 20/200 in R.E and 20/50-2 in L.E. Oval foveal lesions with stage 2 flecks. Visual acuity reducing starting at age 10.

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

Genotyping Method: Genotyping performed at Columbia University, sequencing technology used is not disclosed.

PreviouslyPublished: n/a

Variant: M1:p.P1380L, complex allele: M2: p.N18681 and IVS38:c.5461-10T>C. M3: c.4139C>T(p.P1380L)

ClinVar: M1) 99390 M2) 99067 M3) Variation ID: 7904

CAID: n/a

SupplementalData: Fig 1: Pedigree illustrating ABCA4 variants and the associated Stargardt phenotype for 5 families. Proband Labeled w/ white arrow for each family. Fig 2: retinal scan measuring melanin in 4 patients of family 2. Panel shows bull's-eye ring of RPE atropy. Fig 3: Macular SD-OCT line profile from b-scans. Reflectivity plotted against function of retinal depth. Table 1: table shows patients with p.N18681 variant, type of mutation, and pathogenicity class. Table 2: Patients, age on-set and first symptom

Case#: Case1, Sex:Female, Age:35

DiseaseAssertion: STGD

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Clinical Notes: the patient reported an ocular trauma in the right eye, which required hospitalization and caused sudden loss of vision at the age of 9 years. In 1998, at our first observation, visual acuity was 20/1,000 in the right eye and 20/600 in the left eye.

CaseNotHPOs:n/a

CaseNotHPOFreeText: n/a

Genotyping Method: genetic analysis

PreviouslyPublished: n/a

Variant: Variant is a heterozygous mutation given as (N965S/G1961E); NM_000350.3(ABCA4):c.2894A>G (p.Asn965Ser) /NM_000350.3(ABCA4):c.5882G>A (p.Gly1961Glu)

ClinVar: Variation ID: 236096 / Variation ID: 7888

SupplementalData: n/a

PMID: 28050124

Gene: ABCA4

HGNC ID: 34

Case#: Cideciyan Case #86, male, 20.5yo at report

DiseaseAssertion: "clinical diagnosis within the spectrum of Stargardt disease or cone–rod dystrophy caused by ABCA4 mutations."

FamilyInfo: Parental segregation of the reported alleles confirmed. P87 is the proband's sibling, affected, same genotype

CasePresentingHPOs:

CaseHPOFreeText: LDF eccentricity along principal meridians [deg]: superior=16.9, inferior=11.7, temporal=18.9, inner nasal=9.6, outer nasal=18.9

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: NGS

PreviouslyPublished: PMID: 24550365

Variant: c.203 C>T p.Pro68Leuc.5882 G>A p.(Gly1961Glu); c.5882 G>A p.(Gly1961Glu). Phase confirmed.

ClinVar: 99113

CAID: CA226972

SupplementalData: table s1

PMID:35973334

Gene: ABCA4

HGNC ID: 34

Case#: eldest sister II.2 aged 22 year

Variant splice-site variant NC_000003.11(NM_016247.3):c.1239 + 1G > T [Chr3:100972539C > A

FammilyInfo two-generation north Indian family with three members affected with Stargardt-like macular dys trophy

CasePresentingHPOs:ow vision and difficulty in night vision, with symptoms starting in the early second decade of life, which progressed slowly over time

PedrigreeIn the results section is mentioned

CaseHPOFreeText:NA

CaseNotHPOs:Na

CaseNotHPOFreeText:NA

Genotyping Method:2.3. Validation of identified variant by Sanger sequencing

PreviouslyPublished:NA

PMID: 40948369

Gene: ABCA4

HGNC ID: 34

Case#:3, 34–year-old woman

DiseaseAssertion:NR

FamilyInfo: no family history of an ocular disease

CasePresentingHPOs: HP:0007663, HP:0030506, HP:0030528, HP:0000603

CaseHPOFreeText:bilateral markedly decreased vision (logMar BCVA OD:0.93, OS:0.95), bilateral atrophic lesions of the macula accompanied by yellow-white stellate flecks at the level of the retinal pigment epithelium, Atrophic lesions and flecks were also extending to the mid-periphery of both retinae, bilateral absolute central scotoma and relative paracentral scotomas as well in both eyes, PERG was significantly reduced, while scotopic and photopic amplitudes were also lower than normal.

CaseNotHPOs:

CaseNotHPOFreeText:NR

Genotyping Method: “Analysis of the ABCA4 gene”

PreviouslyPublished: No

Variant: NM_000350.3:c.5882G>A, NM_000350.3:c.6709dup

ClinVar: ​​7888, 99485

CAID: CA119132, CA227437

SupplementalData:

PMID: 35112029

Gene: ABCA4

HGNCID: HGNC:34

Case#: Family MD-0247/ARDM-247 Proband, 12yo at onset

DiseaseAssertion: AR cone rod dystrophy

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText: STGD diagnosed based on "bilateral central vision loss; fundus presenting with a beaten-bronze appearance and/or the presence of orange-yellow flecks in the retina from the posterior pole to the mid-periphery; fluorescein angiography showing typical dark choroid; and normal to subnormal electroretinogram (ERGs)." VA loss, VF loss, BCVA=0.05/0.1, cone-pattern on ERG

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

Variant: c.6410G>A (p.Cys2137Tyr); c.3386G>T (p.Arg1129Leu) found by ABCR400 + dHPLC + HRM

ClinVar: 2202779

CAID: CA341277358

SupplementalData: n/a

PMID: 18024811

Gene: ABCA4

Disease: bull's-eye maculopathy

Case#: Maia-Lopes Family 18 Proband 5709, Portuguese, 9yo at onset

DiseaseAssertion: STGD

FamilyInfo: Family 18

CasePresentingHPOs:

CaseHPOFreeText: mild central fundus changes, vision: 2/10 / 2/10

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: ABCR400 microarray, dHPLC

PreviouslyPublished: n/a

Variant: c.1804C<T/ c.32T>C(1); p.Arg602Thr/p.Leu11Pro

ClinVar: 99217

CAID: CA227106

SupplementalData: n/a

In supplemental table S2, Case LL291 is a female listed as "likely solved" with a clinical diagnosis of CRD. Proband is compound heterozygous for c.32T>C p.(Leu11Pro) and c.5196+1137G>A.

In Supplemental table S1, this proband is a female, 54yo at report, 50yo at onset. Nyctalopia, visual acuity=0.05/0.6, OD: extremely high myopia OS: high myopia, no family information

Eight families that are not labelled all have this variant and pedigrees to show family information in supplemental figure s2.

This variant is found in table S2A to have an OR of infinity with a CI (10.92-infinity).

This variant is found in table S2A to have an OR of infinity with a CI (25.35-infinity), so PS4 is applicable

PMID: 33261146

Gene: ABCA4

Disease: ABCA4-Associated Retinal Dystrophies

Case#: Somali origin, 11 years of age, onset age 8

DiseaseAssertion: STGD

FamilyInfo: Parents were heterozygous for Arg212Cys, asymptoamtic 32 year old father was found to be homozygous for Gly1961Glu

CasePresentingHPOs: HP:0011504, ORPHA:827, HP:0000608

CaseHPOFreeText: BCVA 20/70 and 20/80, atrophic zone of outer retinal and RPE atrophy, Bull's Eye Maculopathy, Macular atrophy

CaseNotHPOs: N/a

CaseNotHPOFreeText: N/a

Genotyping Method: Whole genome sequencing

PreviouslyPublished: N/a

Variant: NM_000350.3:c.5882G>A p.(Gly1961Glu) ; NM_000350.3:c.634C>T p.(Arg212Cys)

ClinVar: 7888; 7898

CAID: CA119132, CA203216

SupplementalData: N/a

PMID: 26527198

Gene: ABCA4

HGNCID: HGNC:34

CRM or marketing automation which drives better sales results? Compare features, benefits, and use cases to choose the right solution for business growth.

Know More: https://www.apsense.com/article/887190-crm-or-marketing-automation-which-drives-better-sales-results.html

can all thee section not have a sub container with beig background and jsut show two columns of info? side bby side make it take less space?

Legacy Inbox 451 emails some will be to suppress case they can'T recive emails but some of these will just be to monitor right?

Unverifiable Inbox 1,783 emails Verification could not complete (legacy ISPs, strict servers). Unknown is not bad, it is unknown.

doe sthis mean we couldn't check and give a reponsse? so we give 1783 credits back?

lets add in bold in description this label is in to monitr. so if it is the ony label for the meail the email will be marked as to monitor in the csv file.

are we using the right terminology? for saturated inbox or compromised addressetc?

also why are they one label instead of three? do we have three labels or we have merged ones as engagement risk signals?

For the accept all some of them can be checked with deep checks etc, so we need to explain what it is, but without losing its meaning or useflnness? what do you think we shoudl write?

what are the 91 domains? shoudl i check if the wbseit actually is parked?

we can'T tell people the typo fixed would allow them to email them. this is part of the typos, not a different kind of typo

https://share.google/M40trzTTcrsmwrym5

a logical form of deductive reasoning where a specific conclusion is derived from two stated or assumed premises

uhm I'm type one diabetic and my mom raise my siblings and I on a vegan diet.

the process of estimating an unknown value or future event by extending a known trend or pattern past the limits of your current data

the act of naming or listing things one by one

hypothesis

Management

：麻像青菜只能“冷”水洗，毛像头发要用“温”水洗，棉像毛巾可以“热”水烫！

活活被牛轧糖卡麻了，鼠（属）实难受！”

人每天都要多 “Bǔ C hōng”（补充）水分！ 其他都是脂溶性

生儿er育女

干肉 = 蛋白质（常识：牛肉干、鸡胸肉干，全都是纯纯的高蛋白）

吃饭叫“狼吞虎咽”（消化），呼吸叫“咽下最后一口气”（呼吸）。

eLife Assessment

This study offers a large-scale resource that maps the transcriptional landscape following combinatorial transcription factor overexpression. The authors propose a modular framework for understanding gene regulatory networks and identify transcription factor cocktails for cellular reprogramming. While the dataset and proposed principles are valuable, the strength of the evidence is incomplete, in part due to the complexity of the computational analyses and limited orthogonal experimental validation. The study will be of interest to the fields of gene regulation and developmental biology.

Reviewer #1 (Public review):

Summary:

Duan, Li, Kulkarni et al. apply a multiplexed single-cell overexpression screen (Reprogram-Seq) to combinatorially perturb 105 transcription factors across 7 target cell types in mouse embryonic fibroblasts, generating a resource of ~200,000 single-cell transcriptomes spanning over 1,300 TF combinations. They develop a framework for classifying pairwise TF-TF interactions, identify a modular, shared architecture of gene regulatory programs across diverse TF combinations, and use these tools to nominate and partially validate new reprogramming cocktails.

Strengths:

The scale of the combinatorial screen is substantial, and the resulting dataset is a genuine resource for the field. The TF-TF interaction typing framework is a useful conceptual extension of prior genetic-interaction approaches to an overexpression/reprogramming context, and the modularity finding that diverse TF combinations converge on shared gene programs is a compelling organizing principle. The authors are, for the most part, careful and appropriately hedged in their claims; the overclaiming we flag below is the exception, not the rule. We also note that the core Reprogram-Seq assay itself builds directly on the authors' own prior work; the novelty here rests on scale, the interaction framework, and the modularity analysis.

Weaknesses:

Most of the concerns raised below relate to how existing data are quantified, cited, and reconciled with the text, rather than to the underlying experiments themselves. Several quantitative and comparative claims in the Results are not fully supported by the figures cited, and some conclusions are in tension with the authors' own data. Key methodological details relevant to interpreting the central TF-TF interaction framework, including TF expression dosage and within-combination transcriptional variability, are not reported or controlled for, which limits confidence in the resulting interaction classifications. The relationship between TF number and reprogramming efficiency is not clearly distinguished from a simple combinatorial coverage effect and does not consistently generalize across batches. Experimental validation of predicted cocktails is limited to a single target cell type. The manuscript would also benefit from addressing whether TF overexpression in fibroblasts can fully capture a factor's endogenous regulatory network, given that pioneer activity and chromatin accessibility are not addressed.

Reviewer #2 (Public review):

Summary:

This manuscript presents a large-scale combinatorial transcription factor overexpression screen in mouse embryonic fibroblasts coupled with single-cell RNA-seq to systematically map the relationship between TF combinations, gene regulatory networks, and transcriptional reprogramming. Using approximately 100 transcription factors, the authors identify TF combinations that shift cells toward diverse transcriptional states, organize TF combinations into "perturbation clusters" with shared transcriptional outputs, infer modular gene regulatory networks, model pairwise TF interactions, and use pseudotime analyses to nominate candidate reprogramming TF combinations. The resulting dataset represents a potentially valuable resource for studying combinatorial TF activity and transcriptional reprogramming.

Strengths:

The primary strength of the study is its experimental scale and the breadth of the generated dataset. The Reprogram-Seq platform enables systematic interrogation of thousands of TF combinations that would be difficult to test individually, and the authors develop several computational frameworks to organize these data and generate biological hypotheses. The epicardial reprogramming analyses, including independent qPCR and protein localization experiments, provide proof-of-principle that the platform can recover biologically relevant TF combinations.

Weaknesses:

Many of the manuscript's central conclusions rely on a complex computational pipeline that is not sufficiently justified or independently validated. Identification of transcriptionally reprogrammed cells depends on co-embedding with reference atlases, yet the robustness of this analysis and the interpretation of cells occupying primary-cell clusters are not explored in depth. Similarly, the conclusions regarding modular gene regulatory networks depend critically on the perturbation clusters defined by MDE embedding and HDBSCAN clustering. These perturbation clusters form the basis for nearly all downstream analyses, including differential expression, gene module identification, gene specificity, and TF modularity, yet little evidence is provided that the clusters are robust to alternative embedding strategies, clustering parameters, or resampling approaches.

The manuscript also provides relatively limited orthogonal validation of its computational predictions. Although the epicardial analyses are validated experimentally, comparable validation is not performed for most other predicted cell fates, TF interaction classes, or perturbation modules. Consequently, many conclusions regarding the generality of modular TF activity, TF cooperativity, and the predicted reprogramming cocktails remain supported primarily by computational inference.

In addition, several aspects of the analytical workflow-including the quality filtering of TF combinations, interpretation of unclustered perturbations, selection of genes for downstream visualization, and robustness of pseudotime analyses across lineages-would benefit from greater methodological transparency.

Overall, this work provides a valuable dataset and introduces analytical approaches that will likely be useful to the community. However, in its current form, I believe the strongest biological conclusions are insufficiently validated. Additional analyses demonstrating the robustness of the computational framework, together with broader orthogonal validation of representative predictions, would substantially strengthen confidence in the proposed principles governing combinatorial transcription factor activity and transcriptional reprogramming.

Reviewer #3 (Public review):

Summary:

In this manuscript, Duan et al perform a combinatorial TF overexpression screen combined with single-cell RNA-seq (Reprogram-Seq) to extract general principles of how combinatorial TF interactions drive distinct gene regulatory networks in reprogrammed cells. Using a library of 105 TFs, they induce different cell fates, many of which resemble in vivo cell identities. They observe that combinations of TFs have better reprogramming results than inductions driven by a single TF. By looking at gene expression enrichment/depletion in different reprogrammed cell clusters, they infer functional GRNs induced by specific TF combinations and identify GRNs specific for certain cell types. They also identify TFs that could improve known TF cocktails for the induction of certain cell fates. They observe that TFs with cooperative interactions regarding the regulation of gene expression may lead to better reprogramming results, and finally, they build a bottom-up approach that utilizes the single-cell transcriptomes to predict TFs driving certain reprogrammed fates.

Strengths:

Reprogram-Seq is not new, but the strength of the study lies in the fact that the authors assess the induction outcome from a large number of different TF combinations. The authors are thus able to make broad observations, such as the modularity of GRNs and TF cooperativity, as well as propose new TFs and TF interactions to be tested for the induction of certain cell fates. The manuscript is well written, and the conclusions are, in general, supported well by the authors' analyses and data.

Weaknesses:

The study would benefit from some further analysis and discussion to better tighten the conclusions:

While both expression enrichment and depletion were used to define perturbation clusters, the authors then focused on analyzing functional gene groups only for the enriched genes. Are there any functional relations between the repressed genes within a perturbation cluster? Do the authors observe the same modularity (in terms of regulation by TFs) for repressed genes as they do for induced genes?

Can the authors give a description of how neomorphic TF interactions work? How would gene expression be affected in single vs double perturbation in those cases?

What does it mean functionally when a TF pair shows more than one type of interaction (as shown in Supplementary Table 6), and how do such interactions correlate with successful transcriptional reprogramming?

In the last Results section, the authors are able to use the transcriptome to predict the TF that was used for the induction. Could the authors discuss some plausible applications of this TF prediction method? For example, could they use it on in vivo single-cell RNA-seq of a certain cell type to predict candidate TFs for the induction of that cell type?

It would help the reader if, at the end of each Results section, the authors add a concluding paragraph, highlighting the most important conclusions and findings (same as they have done in the section titled "Combinatorial TF over-expression reprograms MEFs to diverse states").

The repo is more than 600 GB, can use this command to download only what you need.

epidural hematoma

reye syndrome

delirium

cerebral contusion

huntington's disease

transient ischemic attack (tia)

spina bifida

cerebral vascular accident (cva)

bell palsy

epilepsy

trigeminal neuralgia

cerebral vascular accident

traumatic brain injury

obsessive compulsive disorder

attention deficit hyperactivity disorder

spinal cord injury

level/loss of consciousness

computed tomography

inter-cranial pressure

cerebral spinal fluid

hyperphasia (?)

spinogenesis (?)

cephalalgia

一大根又红又甜的胡萝卜

老祖宗造字时就说了，“鲸”就是水里“最大（京）”的动物！

“早”上“抬”头，发“觉”自己“裸”着，赶紧盖上“被”子！

医用酒精的“气味”（75）太冲了！

在“纸张”上画画，一定要懂得“硫（留）白”。

“人”躺在“海”边的“地”上，“仰”（氧）望天空。

点燃“火药”，虫子全吓“溜”（硫）了

爆米花 ➡️ 老板鞠躬说抱歉（爆铅）。 松花蛋 ➡️ 谈恋爱送花要花钱（松花铅）。 油条 ➡️ 早餐和豆浆是绝佳伴侣（油条铝）。

事情“黄”了，真的很“痛心”（铜、锌）

年“轻”的“女太美”（铝、钛、镁）！

llegada de colon a america

dedse los años 1500 y 1900 fueron un periodo de constante cambio e hibridación. ¿400 años de colonización europea?

This marked the beginning of viewing education as a universal investment in the formation of the United States. Similar to democracy, the system could only succeed if the public placed faith in it and supported its purpose, believing that education had the power to improve both individuals and society.

This relates well to the discussion on Tuesday about how the purpose of education can be to help certain groups of people, particularly disadvantaged students. While I believe education is an important tool for empowerment and equity, I also wonder if there is truth to the idea that social differences will continue to be an issue in our society as there may be limitations to how much education can do when inequity must be addressed systematically through multiple institutions rather than just education.

This strict regulation of times and routines within the education system remains prevalent today, even in higher education where students are expected to meet for the same intervals. While this routine has practical effectiveness and prepares students for the workforce and teaches skills like accountability and time management, the strict confinement may take away from the process and enjoyment of learning, as everyone learns at their own pace and having too short or long intervals for different learners may be detrimental.

It is difficult to fathom this more individualized form of grading now that age-based grading has become so intuitive to the educational system. There are many benefits as I don’t think standards-based grading would be possible without separating students based on age, but it makes me wonder if there may be drawbacks to this as well.

This is an important distinction since it may help families who feel embarrassed about sending their children to free school feel more comfortable and maintain their family dignity and pride. The analogy to air is a good reminder of how education is not just a want but a right and a necessity for young people’s development and functioning in society.

In some ways, this divide is still seen in today’s society, as high-income families choose expensive private schools to distinguish their children’s opportunities, and the quality of education generally can be higher in privileged communities. Southerners’ fear of educating slaves also revealed how they recognized its ability to empower groups of people. It reminds me of the lecture where we discussed how education can have the power to help or aid certain groups.

I wonder what drove this transition from religious to secular education?

一个标签可以有多个属性，每个属性是一个key-value对 ，多个属性之间没有先后顺序

a conclusion you reach by combining clues from evidence with your own background knowledge

defined as singing quietly with intimacy.

at the summit.

your long-term, relationship-led

I would recommend having a 2-column table here where you clearly stack up the inclusions for the extended access and the Bundle against each other.

Same here... I would give more context around each of the bonuses including individual price for each.

Seeing that you've broken these off from the list above, I assume they're significant. I would definitely add an explainer for each here so people understand why they're critical to their ongoing momentum.

Can you answer the 'so what' in this section somehow? I would also add a visual element here, even if it's just one graphic per category.

beyond this summit.

I would turn this into a question. What if you could finally stop starting over every quarter?

The contracst and font size of the inclusions make them easy to miss.

I would make these 2 lines pop more by breaking them up. Sub-heading: Your free summit ticket shows you what's working now. Main heading: The Booked Out Bundle gives you everything to turn those ideas into action.

I would definitely add a vidual mockup of the inclusions up here

beyond this summit

long-term, relationship-led

6口可以使用

Do amendments to the bill require resubmission?

third in order, rank, or stage

These results are intriguing but largely observational and/or rely on pre-determined cutoffs. Given your tree and your set of features, shouldn't more quantitative resulsts be available? e.g., are there detectable signals of feature covariation across evolutionary time? hierarchical/directional relationships between directons and genomic features?

1 = 23s + 25t for \(s,t \in \mathbb{Z}\) can be solved using Euclid's algorithm. Is there another method?

Each element in A can only have one element in B assigned to it. If an equivalence class corresponds to a single element of A, the entire class must be assigned only one element in B. We should be able to define the function \(\phi\) if each element of the equivalence class [a/b] were an element of A, but then the domain would not be the rational numbers. It would be a larger set \({\frac{a}{b} | a,b \in \mathbb{N}, b \neq 0}\).

This theorem doesn't say that you can't use two negative integers to give a positive integer. The product is unique only when you consider other prime combinations. However, it is not unique if you include the negative numbers. Of course, a combination of negative integers that gives a positive product will be equivalent to the same combination of positive integers times negative one.

Materia viva y materia inerte

a type of antibiotic

to free from the dominating influence of a colonizing power

developing from a single common ancestral form

assumed to exist, commonly accepted

finely detailed

occurring in a hospital

characterized by widespread growth

blood poisonings

the sum of the factors controlling the presence or absence of a disease or pathogen

we need to understand why SA is effective in order to control its spread.

great number

native to a region

capacity to cause disease or damage

synthetic form of penicillin

Esta descripción me resulta bastante alineada con la definición de Peirce sobre el símbolo, y al igual que la categoría de representación icónica, establece una relación directa con los postulados de la lingüística y los procesos educativos.

Este articulo reúne de manera elocuente el una parte de la teoría del desarrollo cognitivo y es importante para la implementación en un entorno educativo.

Esta reflexión me parece interesante porque nos permite entender como las vivencias personales impactan las decisiones que tomamos y nuestra actitud o perspectiva frente a ellas nos puede brindar posibilidades de exploración y aprendizaje.

Considero que este postulado del constructivismo de Bruner es muy valioso y pertinente para nuestro presente, porque nos recuerda a los estudiantes la responsabilidad que tenemos con nosotros mismos en nuestros procesos de aprendizaje y nos invita a tomar una actitud crítica, tomando distancia de un rol meramente pasivo y receptivo en el que los resultados dependen enteramente de un docente o instructor que guía mentes como a un rebaño.

El uso de incentivos y correctivos resulta un tema de gran interés. Desde mi perspectiva, promover la participación es fundamental, y este mecanismo ha demostrado ser eficaz para lograrlo.

El currículo en espiral es un modelo educativo creado por Jerome Bruner en 1960. Consiste en enseñar los mismos temas de forma repetida a lo largo del tiempo, pero con mayor dificultad y profundidad cada vez. Este enfoque conecta los nuevos datos con los conocimientos previos para evitar el olvido.

https://eng-sci.udmercy.edu/academics/engineering/electrical-computer/spiral-curriculum.php

Creo que la representación icónica es el lenguaje más antiguo, ya que por medio de dibujos y formas nos hemos podido comunicar.

https://www.revistaesfinge.com/2023/02/el-lenguaje-de-las-pinturas-rupestres/

Creo que es relevante el entorno en el que convivimos y permanecemos, a parte de las experiencias vividas ya que esto influye bastante en nuestro desarrollo cognitivo.

https://www.bbc.com/mundo/articles/cp39ndzkq74o

primera fase del desarrollo cognitivo según Jean Piaget, abarcando desde el nacimiento hasta los dos años de edad. Durante este período, el bebé aprende sobre el mundo usando sus sentidos y sus movimientos

Extraído Universidad VIU

Enactivo (derivado del inglés enactive) describe aquello que se adquiere, comprende o surge mediante la acción y la interacción corporal con el entorno, en lugar de ser una simple recepción pasiva de información o una representación mental abstracta.

https://www.cienciascognitivascorporizadas.com/4ea/cognici%C3%B3n-enactiva

CMN

Aplicações compulsórias - Investimento forçado Limites minimos de aplicação - gastar uma quantia em algum setor ou produto

gsthgsetgergerg

August 2026 Top-Ranked Stocks Summary

Macro & Market Context

• S&P 500 total return sits at ~9.5% YTD, with maximum drawdowns under 12% despite underlying stock volatility and macroeconomic shifts.
• Market drivers include escalating regional conflict involving the U.S. and Iraq, high oil prices, and shifting central bank policies.

Ranked Stock Recommendations & Valuations

1. Amazon (AMZN) [00:01:35]
   • Market Price / Fair Value: ~$271 / $313
   • Bullish: AWS growth accelerated to >35% across 5 consecutive quarters; operating margins expanding to record levels.
   • Bearish: High AI capex leading to negative projected FCF (-$15B); revenue heavy on unprofitable AI players (OpenAI, Anthropic).
2. Meta Platforms (META) [00:03:48]
   • Market Price / Fair Value: ~$556 / $849
   • Bullish: Strong user growth and engagement; unmatched AI spending budget enhances platform monetization over rivals.
   • Bearish: Significant FCF contraction down to ~$1.27B; increasing global regulatory scrutiny over platform addictiveness.
3. Netflix (NFLX) [00:05:53]
   • Market Price / Fair Value: <$72 / $126
   • Bullish: Broad convenience tailwinds for streaming; proven proprietary data engine for creating viral internal content.
   • Bearish: Shifting consumer preference toward short-form mobile video; negative sentiment around potential Warner Bros. acquisition rumors.
4. Nvidia (NVDA) [00:08:28]
   • Market Price / Fair Value: ~$200 / $300
   • Bullish: Massive hyperscaler spending on AI data centers (> $800B target); competitive moat built via CUDA software ecosystem.
   • Bearish: Major hyperscalers developing in-house custom chips; financial fragility among core AI model end-users.
5. Uber Technologies (UBER) [00:10:41]
   • Market Price / Fair Value: ~$70 / $124
   • Bullish: Scaled asset-light platform model; vehicle ownership cost increases make ridesharing attractive for non-family demographics.
   • Bearish: Long-term displacement threats from autonomous vehicles, with players like Tesla and Waymo scaling independent fleets.
6. Microsoft (MSFT) [00:12:44]
   • Market Price / Fair Value: ~$464 / $490
   • Bullish: Re-acceleration in Azure cloud revenue driven by AI enterprise demand.
   • Bearish: High counterparty risk due to massive backlog commitments tied directly to OpenAI; lacks a breakout proprietary LLM.
7. Pinterest (PINS) [00:14:05]
   • Market Price / Fair Value: ~$24 / $56
   • Bullish: Strong monetization potential from North American users; improved AI recommendation algorithms.
   • Bearish: Meta’s massive AI spending risks widening the competitive gap; macroeconomic headwinds cause ad spend cutbacks.
8. The Trade Desk (TTD) [00:16:06]
   • Market Price / Fair Value: ~$18 / $49
   • Bullish: Pioneer in digital ad expansion; buy-side focus builds trust with advertisers over ad-selling competitors.
   • Bearish: Amazon's entry into the space with aggressively low fee structures (1-5% vs. TTD's 15-20%) has hammered sentiment.
9. Visa (V) [00:18:10]
   • Market Price / Fair Value: ~$366 / $394
   • Bullish: Massive two-way network effect with >4 billion cards issued creates a defensible merchant acceptance mandate.
   • Bearish: Regulatory pushback favoring local payment rails; emerging competition from stablecoins, crypto, and direct transfers.
10. Adobe (ADBE) [00:20:13]
    • Market Price / Fair Value: ~$215 / $367
    • Bullish: Extremely high switching costs for creative professionals embedded in the software ecosystem.
    • Bearish: Generative AI startups disrupting lower-cost creation; uncertainty from a prolonged CEO transition search.
11. McDonald's (MCD) [00:21:42]
    • Market Price / Fair Value: ~$270 / $315
    • Bullish: Expanded delivery reach via third-party apps; margin expansion from kiosks and automated drive-thrus; unmatched value tier.
    • Bearish: GLP-1 weight loss adoption reducing fast-food appetite; pressure on lower-income consumer disposable income.
12. Lululemon (LULU) [00:24:01]
    • Market Price / Fair Value: <$119 / $165
    • Bullish: High brand equity allows for premium pricing and industry-leading operating margins.
    • Bearish: Higher import tariffs and de minimis exemption changes impacting profits; weaker consumer discretionary spending.

Portfolio Performance Update

• YTD Return: 8.02% (up from 3.62% in July), narrowing the performance gap against the S&P 500 (9.55%).
• Past Exits: Previously locked in massive gains on Micron (+125%), Qualcomm (+97%), and Broadcom (+52%) prior to valuation extensions.

WRITING ALERT! "Classical" is used as a proper noun that defines a set of styles and cultures. Thus, it should be capitalized.

FACT CHECK: Though we do have inscriptions of the Etruscan written language and can read some of it. It is not fully deciphered.

Fascinating study! Have you looked at whether the position of the deoxycytidine substitutions matters? For example, do substitutions near the 5′ end have a different effect than those near the 3′ end, or is it mainly the total amount of dCTP incorporation that drives the phenotype? The differences between the luciferase and eGFP reporters in Figure 2 also made me wonder whether the effect depends on the transcript's underlying sequence composition.

• Diagnoza polskiego sektora IT i potencjału AI:
  • Polscy inżynierowie i naukowcy odnoszą sukcesy na świecie (np. współtworząc OpenAI czy wygrywając międzynarodowe konkursy), lecz krajowy ekosystem nie potrafi ich zjednoczyć do budowy globalnych potęg.
  • Polska przez lata pełniła rolę "Bangladeszu programowania" – skupiała się na taniej sprzedaży roboczogodzin (software house'y, centra usług wspólnych) zamiast na budowaniu własnych skalowalnych produktów technologicznych.
• Bariery systemowe i postulaty zmian:
  • W Europie wciąż brakuje przyzwolenia na porażkę biznesową, co hamuje innowacyjność i odwagę młodych twórców w porównaniu do realiów USA.
  • Skomplikowane regulacje, utrudnienia w realizacji ESOP-ów (akcji pracowniczych) oraz biurokracja przy przyznawaniu grantów blokują komercjalizację badań naukowych.
  • Kluczowe postulaty to: powołanie dedykowanego Uniwersytetu AI / Ministerstwa AI, budowa narodowej infrastruktury obliczeniowej (GPU) oraz stworzenie atrakcyjnej polityki migracyjnej dla wybitnych talentów.
• Natura rewolucji AI i przyszłość społeczeństwa:
  • Rewolucja AI to multiplikacja rewolucji przemysłowej, prowadząca do powstania autonomicznych systemów oraz firm wartych miliardy dolarów tworzonych przez pojedyncze osoby ("one-man unicorn").
  • Zamiast ścigać się na wielkość zbiorów danych czy sprzęt, Polska powinna postawić na teoretyczną sztukę AI i algorytmiczną optymalizację.
  • W obliczu powszechnego dostępu do wiedzy, rola człowieka przesunie się w stronę filozofii, logiki i myślenia koncepcyjnego, a ruch Open Source pozostanie kluczową przeciwwagą dla wielkich korporacji.
• Strategia Synerise i innowacje w Wiśle Kraków:
  • Synerise: Powstało w oparciu o autorskie silniki bazodanowe i modele decyzyjne stworzone z braku środków na kosztowne licencje; obecnie obsługuje miliardy autonomicznych decyzji dziennie.
  • Wisła Kraków: Działa jako laboratorium technologiczne (Sport-Tech Hub / Living Lab), łączące dane kibicowskie i sportowe (czego przykładem jest nagrodzony na Cannes Lions "Indeks Szczęścia"), tworząc nowy model biznesowy dla klubu sportowego.

very important

important

important

Je m'arrête là pour ce soir, mais je peux déjà dire que c'est super agréable à lire !

Un exemple intéressant, ca peut être les politiques différentes qu'on eu les mutuelles et les assureurs lors du COVID, certaines ont rétrocédé des cotisations, d'autres non.

Si l'ouvrage s'adresse aussi aux profanes, je choisirai de dire "assurance décès", vu la connotation qu'a le terme d'assurance vie en France :o)

Disordered regions typically mediate protein-protein interactions, half-life, and post-translational modification sites, in addition to driving phase separation. Deleting the whole region, or mutating every residue of one type, perturbs all of that at once, so you can't cleanly attribute what changed to phase separation specifically. Disease alleles offer a more targeted way to probe these effects, but relying only on the ones nature happens to produce caps what we can learn. Here, inverting the physics models circumvents that: you're optimizing directly for the physical property you want, since χ, ε, and the RPA parameters carry real physical meaning. This is valuable for building sensors but also for understanding the biology and evolution of disordered proteins.

The living-cell client/excluder assay nicely validates the approach. The asymmetry in Figure 4 stood out: client enrichment is consistently stronger than excluder depletion, in both de novo and natural sequences. This could be a thermodynamic feature: favorable contacts are just easier to design for than exclusion is. It doesn't look like an optimization shortfall to me, but I'd be curious how far the cross-interaction parameter was pushed for excluders, and whether a titration series of excluder strengths was tried.

Natural selective pressure on hydrophobic residues in Pab1 has previously been used to design point mutations that disrupt phase separation (https://doi.org/10.1016/j.cell.2017.02.027). Has a similar evolutionary signal been considered here? One way to check would be comparing physics-model parameters across orthologous gene families (beyond the human genome) to see whether they're conserved even where residue identity has diverged, then checking whether de novo designs fall inside or outside that natural distribution. That would help clarify whether these designs occupy genuinely novel sequence space or land somewhere a real cell wouldn't tolerate.

C'est d'ailleurs un cercle vicieux, une résiliation à l'initiative de l'assureur (y compris sans sinistre) peut très bien être un facteur aggravant pour les autres assureurs.

Le capital culturel (comprendre un modèle, décoder un dossier) et le capital social (savoir à qui s'adresser, avoir un réseau pour activer ces leviers) sont déjà en partie présents, mais pourraient être nommés explicitement selon moi :o)

Je ne sais pas si ce point sera traité plus loin dans l'ouvrage, mais à mon sens, la position par rapport au marché constitue également une composante de la réflexion de l'assureur — certes secondaire, mais bien réelle. Par exemple, un profil peut être correctement tarifé en théorie, mais si son tarif se situe en dessous de celui du marché, l'assureur va sur-performer commercialement sur ce segment, au détriment de son équilibre technique. Au contraire, pour des raisons business un assureur pourrait être agressif sur un segment et détériorer les resultats techniques de tout le marché.

En Europe, pour renforcer cette confiance et l'asymétrie de la connaissance sur ces sujets complexes, le IPID (Document d'Information sur le Produit d'Assurance) permet au futur assuré de comparer plus facilement les garanties entre assureurs avec un document normalement standardisé (mais ca peut rester assez obscur dans les faits).

En revanche, il n'existe aucune information facilement accessible qui lui permette d'évaluer la qualité de la gestion des sinistres, en particulier les délais de traitement et la qualité du suivi administratif.

I am the corresponding author for this paper (https://doi.org/10.1101/2025.03.24.645145), which has now been published in the journal Laboratories, here: https://doi.org/10.3390/laboratories3030016 as “Tracking CCI Alumni: Community College STEM Pathways 5 to 12 Years After a National Laboratory Internship”

Thank you, bioRxiv team!

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THis is an annotation.