DOI: 10.1038/s44400-025-00004-4

Resource: R Project for Statistical Computing (RRID:SCR_001905)

Curator: @dhovakimyan1

SciCrunch record: RRID:SCR_001905

What is this?

for - from Global Regeneration CoLab - Wasabi Network - Regneration pollination zoom speed dating - April 4, 2025

for - program event selection - 2025 - April 4 - 10:30am-12pm GMT - Skoll World Forum - The Future of AI & Digital Innovation - Stop Reset Go - Indyweb -- relevant to

for - program event selection - 2025 - April 4 - 10:30am-12pm GMT - Skoll World Forum - Partnership for the Planet - Stop Reset Go - TPF - LCE - relevant to

"Different soil compositions help identify which geographic areas the suspect traveled through"

that it shall be lawful for the president of the United States to cause so much of any territory belonging to the United States, west of the Mississippi river, not included in any state or organized territory, and to which the Indian title has been extinguished

for - leverage point - activate 4 different levels - behavior change - cultural change - system change - mindset

Reviewer #4 (Public review):

Summary

Pinho et al use in vivo calcium imaging and chemogenetic approaches to examine the involvement of hippocampal sub-regions across the different stages of a sensory preconditioning task in mice. They find clear evidence for sensory preconditioning in male but not female mice. They also find that, in the male mice, CaMKII-positive neurons in the dorsal hippocampus: (1) encode the audio-visual association that forms in stage 1 of the task, and (2) retrieve/express sensory preconditioned fear to the auditory stimulus at test. These findings are supported by evidence that ranges from incomplete to convincing. They will be valuable to researchers in the field of learning and memory.

Abstract

Please note that sensory preconditioning doesn't require the stage 1 stimuli to be presented repeatedly or simultaneously.

"Finally, we combined our sensory preconditioning task with chemogenetic approaches to assess the role of these two hippocampal subregions in mediated learning."<br /> This implies some form of inhibition of hippocampal neurons in stage 2 of the protocol, as this is the only stage of the protocol that permits one to make statements about mediated learning. However, it is clear from what follows that the authors interrogate the involvement of hippocampal sub-regions in stages 1 and 3 of the protocol - not stage 2. As such, most statements about mediated learning throughout the paper are potentially misleading (see below for a further elaboration of this point). If the authors persist in using the term mediated learning to describe the response to a sensory preconditioned stimulus, they should clarify what they mean by mediated learning at some point in the introduction. Alternatively, they might consider using a different phrase such as "sensory preconditioned responding".

Introduction

"Low-salience" is used to describe stimuli such as tone, light, or odour that do not typically elicit responses that are of interest to experimenters. However, a tone, light, or odour can be very salient even though they don't elicit these particular responses. As such, it would be worth redescribing the "low-salience" stimuli in some other terms.

"These higher-order conditioning processes, also known as mediated learning, can be captured in laboratory settings through sensory preconditioning procedures2,6-11."<br /> Higher-order conditioning and mediated learning are not interchangeable terms: e.g., some forms of second-order conditioning are not due to mediated learning. More generally, the use of mediated learning is not necessary for the story that the authors develop in the paper and could be replaced for accuracy and clarity. E.g., "These higher-order conditioning processes can be studied in the laboratory using sensory preconditioning procedures2,6-11."

In reference to Experiment 2, it is stated that: "However, when light and tone were separated on time (Unpaired group), male mice were not able to exhibit mediated learning response (Figure 2B) whereas their response to the light (direct learning) was not affected (Figure 2D). On the other hand, female mice still present a lower but significant mediated learning response (Figure 2C) and normal direct learning (Figure 2E). Finally, in the No-Shock group, both male (Figure 2B and 2D) and female mice (Figure 2C and 2E) did not present either mediated or direct learning, which also confirmed that the exposure to the tone or light during Probe Tests do not elicit any behavioral change by themselves as the presence of the electric footshock is required to obtain a reliable mediated and direct learning responses."<br /> The absence of a difference between the paired and unpaired female mice should not be described as "significant mediated learning" in the latter. It should be taken to indicate that performance in the females is due to generalization between the tone and light. That is, there is no sensory preconditioning in the female mice. The description of performance in the No-shock group really shouldn't be in terms of mediated or direct learning: that is, this group is another control for assessing the presence of sensory preconditioning in the group of interest. As a control, there is no potential for them to exhibit sensory preconditioning, so their performance should not be described in a way that suggests this potential.

Methods - Behavior

I appreciate the reasons for testing the animals in a new context. This does, however, raise other issues that complicate the interpretation of any hippocampal engagement: e.g., exposure to a novel context may engage the hippocampus for exploration/encoding of its features - hence, it is engaged for retrieving/expressing sensory preconditioned fear to the tone. This should be noted somewhere in the paper given that one of its aims is to shed light on the broader functioning of the hippocampus in associative processes.

This general issue - that the conditions of testing were such as to force engagement of the hippocampus - is amplified by two further features of testing with the tone. The first is the presence of background noise in the training context and its absence in the test context. The second is the fact that the tone was presented for 30 s in stage 1 and then continuously for 180s at test. Both changes could have contributed to the engagement of the hippocampus as they introduce the potential for discrimination between the tone that was trained and tested.

Results - Behavior

The suggestion of sex differences based on differences in the parameters needed to generate sensory preconditioning is interesting. Perhaps it could be supported through some set of formal analyses. That is, the data in supplementary materials may well show that the parameters needed to generate sensory preconditioning in males and females are not the same. However, there needs to be some form of statistical comparison to support this point. As part of this comparison, it would be neat if the authors included body weight as a covariate to determine whether any interactions with sex are moderated by body weight.

What is the value of the data shown in Figure 1 given that there are no controls for unpaired presentations of the sound and light? In the absence of these controls, the experiment cannot have shown that "Female and male mice show mediated learning using an auditory-visual sensory preconditioning task" as implied by its title. Minimally, this experiment should be relabelled.

"Altogether, this data confirmed that we successfully set up an LTSPC protocol in mice and that this behavioral paradigm can be used to further study the brain circuits involved in higher-order conditioning."<br /> Please insert the qualifier that LTSPC was successfully established in male mice. There is no evidence of LTSPC in female mice.

Results - Brain

"Notably, the inhibition of CaMKII-positive neurons in the dHPC (i.e. J60 administration in DREADD-Gi mice) during preconditioning (Figure 4B), but not before the Probe Test 1 (Figure 4B), fully blocked mediated, but not direct learning (Figure 4D)."<br /> The right panel of Figure 4B indicates no difference between the controls and Group DPC in the percent change in freezing from OFF to ON periods of the tone. How does this fit with the claim that CaMKII-positive neurons in the dorsal hippocampus regulate associative formation during the session of tone-light exposures in stage 1 of sensory preconditioning?

Discussion

"When low salience stimuli were presented separated on time or when the electric footshock was absent, mediated and direct learning were abolished in male mice. In female mice, although light and tone were presented separately during the preconditioning phase, mediated learning was reduced but still present, which implies that female mice are still able to associate the two low-salience stimuli."<br /> This doesn't quite follow from the results. The failure of the female unpaired mice to withhold their freezing to the tone should not be taken to indicate the formation of a light-tone association across the very long interval that was interpolated between these stimulus presentations. It could and should be taken to indicate that, in female mice, freezing conditioned to the light simply generalized to the tone (i.e., these mice could not discriminate well between the tone and light).

"Indeed, our data suggests that when hippocampal activity is modulated by the specific manipulation of hippocampal subregions, this brain region is not involved during retrieval."<br /> Does this relate to the results that are shown in the right panel of Figure 4B, where there is no significant difference between the different groups? If so, how does it fit with the results shown in the left panel of this figure, where differences between the groups are observed?

"In line with this, the inhibition of CaMKII-positive neurons from the dorsal hippocampus, which has been shown to project to the restrosplenial cortex56, blocked the formation of mediated learning."<br /> Is this a reference to the findings shown in Figure 4B and, if so, which of the panels exactly? That is, one panel appears to support the claim made here while the other doesn't. In general, what should the reader make of data showing the percent change in freezing from stimulus OFF to stimulus ON periods?

so, normally 315 of Reunification Treaty prevents acts commited on East German soil prior to reunification from being punished, if they were not punishable under East German Law (kinda like our warunek podwójnej karalaności)

BUT, here: - immunity does not apply where there was already West German Law (west german law applied to crimes on foreign soil if): 1. the acts are commited against German 2. the person that committed them becomes a resident of WG or comes to WG

prof. Samson argues that EG became part of WG, so their law is applicable 7(2) (similarly, the people who were shot, were Germans, so 7(1))

BUT it's a stretch, because EGs were considered foreigners by WG

DOI: 10.1186/s13578-025-01355-4

Resource: RRID:Addgene_78534

Curator: @olekpark

SciCrunch record: RRID:Addgene_78534

What is this?

DOI: 10.1186/s12885-025-13762-4

Resource: RRID:Addgene_72263

Curator: @olekpark

SciCrunch record: RRID:Addgene_72263

What is this?

DOI: 10.1038/s42255-024-01196-4

Resource: None

Curator: @olekpark

SciCrunch record: RRID:Addgene_14946

What is this?

DOI: 10.1038/s42003-025-07815-4

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

Curator: @dhovakimyan1

SciCrunch record: RRID:CVCL_0045

What is this?

And in this flea our two bloods mingled be;

The act of sharing blood in intimate and due to that, the speaker tells the listener that a "physical barrier" is, at this point, unnecessary.

DOI: 10.1038/s41593-025-01888-4

Resource: (IMSR Cat# JAX_013044,RRID:IMSR_JAX:013044)

Curator: @dhovakimyan1

SciCrunch record: RRID:IMSR_JAX:013044

What is this?

> for - stats - addiction - cocaine - average duration - 4 years

Reviewer #4 (Public review):

Summary:

The structural mechanism of anion permeation through the open CFTR pore has remained unresolved and is subject to ongoing debate. That is because even in CFTR structures obtained under conditions that normally maximally activate the channel (phosphorylation + ATP + non-hydrolytic mutations + potentiator drugs) a bottleneck region in the pore, too narrow to allow passage of hydrated chloride ions, is observed.

The present study uses molecular dynamics (MD) simulations initiated from such "quasi-open" states to address local conformational dynamics of the pore. The authors conclude that the quasi-open structure stably relaxes to a fully open conformation on the sub-microsecond time scale. They provide a detailed analysis of this fully open structure and of the mechanism of chloride permeation. They conclude that two major exit pathways (a central and a peripheral) exist for chloride ions, and that the ions remain near-fully hydrated throughout the pore: chloride-protein interactions displace only 1-2 waters from the first solvation shell. Furthermore, the simulations provide some hints for conformational changes involved in gating.

Strengths:

The findings are interpreted in the context of the large body of published functional studies on CFTR permeation properties, and caveats are adequately discussed.

Weaknesses:

The conclusions on gating would benefit from further discussions. In particular, a fair comparison of the timescale at which channel gating happens, and that of the MD simulations would strengthen the manuscript.

for - book - Pedagogies of Collapse - Ginie Servant-Miklos - Chapter 4 - Experimental Pedagogics - 2024

Reviewer #5 (Public review):

Summary:

The researchers examined selection across multiple levels, including gene expression, biological processes, and regulatory mechanisms, with a particular focus on comparing selection between different environmental conditions. They further explored potential evolutionary mechanisms. This is made possible with a comprehensive dataset comprising gene expression data from 130 accessions with three replicates collected in two environments in the field, genomic data from 125 genotypes, and associated physiological traits. The findings have significant implications for understanding the evolution of stress adaptation, and the identified possible genes and pathways for further investigation.

The researchers began by focusing on the selection of gene expression across two environments, comparing the number of genes under selection and the effect sizes, as well as examining how selection in each environment acts on the same individual genes. They then expanded their analysis to consider selection in biological processes, investigating the relationships between selection acting on individual genes within processes and selection acting among different processes.<br /> Additionally, they explored selection at the organismal level by examining traits.

The study further transitioned from analyzing individual gene expression to investigating gene-gene interactions. They briefly examined correlation variation among gene pairs between the two conditions, identifying pairs with rewired interactions that suggest potential selection on gene regulation or the effect of rewiring on tolerance. The researchers then delved into the genetic architecture underlying these patterns by mapping eQTLs. Their comparison of cis- and trans-eQTLs revealed that trans-eQTLs were more variable across conditions. Notably, they identified hotspots representing master regulators that possibly underlie the greater variability of trans-eQTLs across environments. They further discovered that trans-eQTLs are generally under purifying selection (particularly in salt conditions), while cis-eQTLs are under balancing selection, exhibiting higher nucleotide diversity. As for how cis- and trans-eQTL effects combine at the level of individual genes, more are found to be reinforced and the hypothesis of genetic fixation on cis- and trans-eQTL effects combination is further tested.

Strengths:

A key strength of this study is its comprehensive approach, extending beyond the analysis of gene expression to include gene-gene interactions, genetic architectures, and selections of genetic regulation factors. The exploration of gene expression selection through its connection with fitness, as introduced in the researchers' previous work, provides valuable insights into the role of gene expression in adaptation. The study investigates selection across multiple levels of biological responses, including individual gene expression, genes associated with biological processes, gene-gene interactions, and the underlying genetic architecture. The experimental design enables a direct comparison of selection between control and salinity conditions, which sheds light on the effects of stress on selection and the dynamics of adaptation to stress. Additionally, the manuscript is well-written, with a clear connection to current literature. The discussion effectively integrates findings with broader implications, making it a satisfying read.

Weaknesses:

The lack of formal testing for environment-specific selections (e.g., selection of gene expression specifically in salinity stress, PCs, or traits) is a major limitation, as previous reviewers have flagged. Explicit tests of eQTLs variation between conditions are introduced, so similar formal tests should also be introduced in selection sections. For example, a formal test of selections of gene expression might be helpful to solve variance/mean- standardization concerns between two environments.

Additionally, some aspects of the analysis appear somewhat arbitrary and could benefit from further sensitivity testing. Line 203: The concern about bias in detecting more CN than AP, as mentioned by the authors and previously flagged by reviewers, does not seem fully resolved with the current methods given the arbitrary cut-off. Incorporating additional tests suggesting the conclusion is insensitive to the cutoff would be very helpful. Similar is the classification of genes into compensatory and reinforcing categories based on 60% of individuals as a cutoff.

While this study focuses on gene regulation, its connection with the selection of gene expression and biological pathways is not well integrated. In particular, the discovery of eQTLs is not explicitly linked to gene expression selection or biological pathways, leaving this relationship underexplored. Suggestive comments: Currently the summarization of selection is based on eQTLs. It would be interesting to also summarize the selection patterns identified from previous sections based on genes being cis/trans-regulated. Moreover, it might be interesting to see if there is more loss or gain of eQTLs under salt stress and their functions. The current results mentioned variations of eQTLs but not clear if they are loss or gain. E.g., one way is to identify genes related to cis and trans-eQTLs and see their correlation changes with genes being regulated using CILP (also as a way to informatively narrow down gene pairs for CILP).

Similarly, the section on selection at the organismal trait level appears disconnected from the rest of the analysis (e.g., if it is not tested to be related to other features, mentioning why it might not be related would be helpful). Admittedly, the discussion of how biological processes discovered at different levels integrate together is helpful.

Other comments: given there is no comparison between loss of coherence (correlations) and gain of coherence under salinity stress to show the dominant role of decoherence, maybe need to also discuss the genes and processes related to the gain of coherence? This is because the understanding of activation (gain of coherence) of some regulations/processes under stress conditions could also be interesting. It is not clear if decoherence (e.g., lines 293-296) refers to significant correlation changes or just loss of the correlation in salinity stress.

DOI: 10.1016/j.celrep.2024.115195

Resource: RRID:ZFIN_ZDB-ALT-150916-4

Curator: @sjvitug

SciCrunch record: RRID:ZFIN_ZDB-ALT-150916-4

What is this?

DOI: 10.1016/j.celrep.2024.115195

Resource: None

Curator: @sjvitug

SciCrunch record: RRID:ZFIN_ZDB-ALT-170615-4

What is this?

for - key insight / quote - source - article - Le Monde - Musk, Trump and the Broligarch's novel hyper-weapon - Yanis Varoufakis - 2025, Jan 4

key insight / quote - (see below) - Returning to Bevan’s brilliant question, today it is easier to see how - wealth persuades poverty to give up its freedom and, instead, - to serve the broligarchs-in-charge: via their cloud capital - that has a capacity, - unlike any hitherto form of capital or government department, - to shape our behaviour - automatically and - directly. - Nothing short of a revolution can restore any hope of personal agency, - let alone of democracy.

for - five roles of cloud capital - source - article - Le Monde - Musk, Trump and the Broligarch's novel hyper-weapon - Yanis Varoufakis - 2025, Jan 4 - monopolizes the attention economy - manufactures desire - sells directly to us that which it has made us desire - controls labor - creates a system of free voluntary behavior to sustain the behavioral modification system, turning us into cloud serfs

for - progress trap - cloud capital - behavioral modification - source - article - Le Monde - Musk, Trump and the Broligarch's novel hyper-weapon - Yanis Varoufakis - 2025, Jan 4

for - comparison: robber barons of the past and today's broligarchs - cloud capital / technofeudalism - source - article - Le Monde - Musk, Trump and the Broligarch's novel hyper-weapon - Yanis Varoufakis - 2025, Jan 4

for - relevant quote - the more things change, the more they remain the same - seems to apply to this statement - source - article - Le Monde - Musk, Trump and the Broligarch's novel hyper-weapon - Yanis Varoufakis - 2025, Jan 4

for - further research - Oligarch's favorite book - The Sovereign Individual - Author - James Dale Davidson and William Rees-Mogg - source - article - Le Monde - Musk, Trump and the Broligarch's novel hyper-weapon - Yanis Varoufakis - 2025, Jan 4

for - Trumps three gifts to lobbyists - article - Le Monde - Musk, Trump and the Broligarch's novel hyper-weapon - Yanis Varoufakis - 2025, Jan 4 - 1. Huge government contracts - 2. Deregulation will enable a free-for-all - 3. State-sanctioned power over labor

for - further research - Aneurin Bevan - 1952 - liberal democracy's greatest paradox - How does wealth manage to persuade poverty to use its political freedom to keep wealth in power? - source - article - Le Monde - Musk, Trump and the Broligarch's novel hyper-weapon - Yanis Varoufakis - 2025, Jan 4 - inequality - elites - source - article - Le Monde - Musk, Trump and the Broligarch's novel hyper-weapon - Yanis Varoufakis - 2025, Jan 4

for - key insight - inequality - elites - How does wealth manage to persuade poverty to use its political freedom to keep wealth in power? - source - article - Le Monde - Musk, Trump and the Broligarch's novel hyper-weapon - Yanis Varoufakis - 2025, Jan 4

for - article - Le Monde - Musk, Trump and the Broligarch's novel hyper-weapon - Yanis Varoufakis - 2025, Jan 4

for - from - article - Le Monde - Musk, Trump and the Broligarch's novel hyper-weapon - Yanis Varoufakis - 2025, Jan 4 - https://hyp.is/n7kI1M2wEe-jUutC8gY3WQ/www.yanisvaroufakis.eu/2025/01/06/musk-trump-and-the-broligarchs-novel-hyper-weapon-le-monde-4-1-2025-full-original-english-version/

for - Substack article - The Cosmo-Local Plan for our Next Civilization - Michel Bauwens - 2024, Dec 20 - adjacency - web 3 and Blockchain / crypto technology - communities engaged in regeneration and relocalization - tinkering at the edge - missed opportunity - cosmolocal strategy as leverage point - safe and just cross scale translation of earth system boundaries - Tipping Point Festival - Web 4 - Indyweb

Summary adjacency between - web 3 and crypto / Blockchain technology - communities engaged in regeneration and relocalization - tinkering at the edge - missed opportunity - cosmolocal lens and framework as a leverage point for synthesis - cosmolocal projects as leverage points - cross scale translated safe and just earth system boundaries as necessary cosmolocal accounting system - meme: sync global, act local - new relationship - This article explores the untapped potential and leverage point offered by recognising a new adjacency and concomitant synthesis of - globalising Web 3 and crypto/Blockchain technology - communities engaged in regenerative and relocation interventions - The fragmentation between these areas keeps activists working in each respective one - tinkering at the edge - severely constraining their potential impact - This is a case of the whole Berlin car greater than the sun of its parts - By joining forces in a global, strategic and systemic way, each can achieve fast more through their mutual support - A cosmolocal lens offers a perspective and framework that makes joining forces make sense<br /> - Projects that recognize that the adjacency between - the globalizing technologies of web 3 and Blockchains and - interventions at the local community level - offer a significant leverage point to bottom up efforts to drive a rapid transition are themselves a leverage point - In this regard, incorporation of an equitable accounting system such as safe and just earth system boundaries that can be cross scale translated to - bioregional, - city and - community, district and ward scale - are an important cosmolocal component of a system designed for rapid transition - Global bottom up community scale events such as the Tipping Point Festival can help rapidly advocate for a cosmolocal lens, framework and strategy - At the same time, Web 4 technology that's goes beyond decentralising into people-centered can contribute another dimension to humanizing technology

Addendum - 2024, Dec 26 - added a comment to the actual substack page - My substack comment makes commenters of the article aware that we have a public hypothes.is discussion going on in parallel. - This makes the hitherto invisible discussion visible to them

for - mindfulness meditation research - 4 pillars of wellbeing - Youtube - Tukdam talk - An Overview Of CHM’s Work On “Well-Being And Tukdam” - Prof. Richard J. Davidson

summary - four pillars of wellbeing - 1 awareness - 2 connection - 3 insight (of the nature of self) - 4 purpose (intention)

for - climate crisis - Medium article - climate communication - how climate change is framed to disempower you - Joe Brewer - 2024, Dec 4 - from - post - LinkedIn - climate crisis - climate communication - climate change discourse has been framed to disempower us - changing the story - so that grassroots, bottom-up initiatives can restore health to ecosystems - Joe Brewer, 2024, Dec 4 - from - Resilience article - A 'Transcender Manifesto" for a world beyond capitalism. A seed.

summary - A good article that offers an explanation of how language has potentially led the public to rely on top down actors to provide solutions to the climate crisis - Joe Brewer draws on his background as a frame analyst to analyse the role language and cognitive linguistics has played in framing the discourse on the climate crisis - He claims that this has led the public to look to elite top down actors to provide the solutions - This had led to a disempowerment of the public in actively participating in contributing too solutions - Indeed it could be why we have a sleeping giant - Reframing the story could have the opposite effect of inspiring people's to wake up and take action to regenerate nature within and surrounding the communities where people live.

from - post - LinkedIn - climate crisis - climate communication - climate change discourse has been framed to disempower us - changing the story - so that grassroots, bottom-up initiatives can restore health to ecosystems - Joe Brewer, 2024, Dec 4 - https://hyp.is/yvHstLfVEe-cyRN4sq09Ow/www.linkedin.com/posts/joe-brewer-4957925_earlier-this-week-i-lived-into-an-important-activity-7270035170328494080-E7Cq/ - from - Resilience article - A 'Transcender Manifesto" for a world beyond capitalism. A seed. - https://hyp.is/0NOdtLiREe--pwPfB1SmdA/www.resilience.org/stories/2024-04-18/a-transcender-manifesto-for-a-world-beyond-capitalism-a-seed/

for - post - LinkedIn - climate crisis - climate communication - climate change discourse has been framed to disempower us - changing the story - so that grassroots, bottom-up initiatives can restore health to ecosystems - Joe Brewer, 2024, Dec 4 - to - Medium article - How Climate Change is framed to Disempower you - Joe Brewer - 2024, Dec 4

to - Medium article - How Climate Change is framed to Disempower you - Joe Brewer - 2024, Dec 4 - https://hyp.is/XoQoRLfVEe-ZMIMjZheLLA/medium.com/@joe_brewer/how-climate-change-is-framed-to-disempower-you-01d871413487

Fortalecer la responsabilidad contextual para la no discriminación en los sistemas de IA

Empoderar a los organismos de igualdad para que inicien acciones

Aliviar la carga de la prueba para los demandantes

Categorías:

1. Diseño inclusivo e innovación democrática

2. Participación significativa en la gobernanza de la IA

3. Transparencia y rendición de cuentas para la prevención de daños

4. Acceso efectivo a la justicia

Puntos de acción

Asignar un presupuesto para los costos de participación. Incluir líneas presupuestarias específicas para cubrir los costos de participación de representantes de grupos marginados, como compensación por su tiempo y experiencia, y adaptaciones razonables para garantizar la accesibilidad (por ejemplo, intérpretes de lengua de señas, intérpretes guía para personas sordociegas, intérpretes de lenguas indígenas).

Al facilitar la participación, considera las dinámicas de poder específicas del contexto, incluyendo género, expresión de género, edad, raza, clase, cultura, identidad, habilidades y lenguaje, para garantizar una inclusión efectiva. Además, crea incentivos que motiven a los actores privados a involucrarse activamente en el diseño, desarrollo y gobernanza de sistemas de IA inclusivos.

for - paper - Assessing the size and uncertainty of Remaining Carbon Budget (RCB) - Lamboll et al, 2023 - from - youtube - Climate scientist Kevin Anderson warns: Only 4 years left to stay below 1.5°C without urgent action

from - youtube - Climate scientist Kevin Anderson warns: Only 4 years left to stay below 1.5°C without urgent action - https://hyp.is/u-rKxK-6Ee-TT7OpdMUOTw/www.youtube.com/watch?v=kFDRp-JMf9Q

Reviewer #4 (Public Review):

Summary:

In their revised manuscript "Conformational dynamics of a nicotinic receptor neurotransmitter binding site," Singh and colleagues present molecular docking and dynamics simulations to explore the initial conformational changes associated with agonist binding in the muscle nicotinic acetylcholine receptor, in context with the extensive experimental literature on this system. Their central findings are of a consistently preferred pose for agonists upon initial association with a resting channel, followed by a dramatic rotation of the ligand and contraction of a critical loop over the binding site. Principal component analysis also suggests the formation of an intermediate complex, not yet captured in structural studies. Binding free energy estimates are consistent with the evolution of a higher-affinity complex following agonist binding, with a ligand efficiency notably similar to experimental values. Snapshot comparisons provide a structural rationale for these changes on the basis of pocket volume, hydration, and rearrangement of key residues at the subunit interface.

Strengths:

Docking results are clearly presented and remarkably consistent. Simulations are produced in triplicate with each of four different agonists, providing an informative basis for internal validation. They identify an intriguing transition in ligand pose, not well documented in experimental structures, and potentially applicable to mechanistic or even pharmacological modeling of this and related receptor systems. The paper seems a notable example of integrating quantitative structure-function analysis with systematic computational modeling and simulations, likely applicable to the wider journal audience.

Weaknesses:

The response to the initial review is somewhat disappointing, declining in some places to implement suggested clarifications, and propagating apparent errors in at least one table (Fig 2-source data 1). Some legends (e.g. Fig 2-supplement 4, Fig 3, Fig 4) and figure shadings (e.g. Fig 2-supplement 2, Fig 6-supplement 2) remain unclear. Apparent convergence of agonist-docked simulations towards a desensitized state (l 184) is difficult to interpret in absence of comparative values with other states, systems, etc. In more general concerns, aside from the limited timescales (200 ns) that do not capture global rearrangements, it is not obvious that landscapes constructed on two principal components to identify endpoint and intermediate states (Fig 3) are highly robust or reproducible, nor whether they relate consistently to experimental structures.

Reviewer #3 (Public review):

Summary:

This study investigated motor system adaptation to new environments through modifications in redundant body movements. Utilizing a novel bimanual stick-manipulation task, participants controlled a virtual stick to reach targets, focusing on how tip-movement direction perturbations affected tip movement and stick-tilt adaptation. The findings revealed a consistent strategy among participants who flexibly adjusted the tilt angle of the stick in response to errors. The adaptation patterns were influenced by physical space relationships, which guided the motor system's selection of movement patterns. This study underscores the motor system's adaptability through changes in redundant body movement patterns.

Strengths:

This study introduces an innovative bimanual stick manipulation task to explore motor system adaptation to novel environments through alterations in redundant body movement patterns. It also expands the use of endpoint robots in motor control studies.

Weaknesses:

The generalizability of the findings is limited. Future work may strengthen the present study's findings by examining whether the observed relationships hold for different stick lengths (i.e., varying hand positions along the virtual stick) or when reaching targets to the left and right of the starting position, not just at varying angles along one side. Additionally, a more comprehensive review of the existing literature on redundant systems, rather than primarily focusing on the lack of redundancy in endpoint-reaching tasks, would have strengthened this study. While the novel task expands the use of endpoint robots in motor control studies, its utility in exploring broader aspects of motor control and learning may be constrained.

for - wisdom stages - 4 middle school stages and - 4 high school stages - John Churchill

for - paraphrase - Buddhist framework - 4 turnings - 4 stages of initiation - John Churchill

paraphrase - Buddhist framework - 4 turnings - 4 stages of initiation - John Churchill - The fourth stage of "soul" - interdependent origination - systems thinking - can make use the knowledge of the third stage "mind" - which in turn uses the knowledge of the second stage "emotional body" - which uses the knowledge of the first stage "body"

1. 定义和作用： 一个证明就像正确运行的代码，必须在逻辑上严谨且能被他人理解。

2. 证明的标准： 一个好的数学证明应该做到两点：

3. 正确性：每一步推理都必须符合逻辑，因为如果证明不正确，就不能称为“证明”。

4. 易于理解：在确保正确的前提下，证明应该尽可能容易理解。 证明的结构：

5. 人类阅读的特殊性： 证明是写给人类阅读的，所以允许一定的常识性和简单的推测。比如，数学家可能会使用“显然”之类的词汇，但在初学证明时，建议避免这类词，以免产生错误的假设。

6. 符号和文字的平衡： 证明既可以用符号也可以用文字表达，甚至可以两者结合。重要的是逻辑清晰，而不一定要用大量符号来显得“专业”。

Reviewer #4 (Public review):

The authors apply what I gather is a novel methodology titled "Multi-gradient Permutation Survival Analysis" to identify genes that are robustly associated with prognosis ("GEARs") using tumour expression data from 15 cancer types available in the TCGA. The resulting lists of GEARs are then interrogated for biological insights using a range of techniques including connectivity and gene enrichment analysis.

I reviewed this paper primarily from a statistical perspective. Evidently, an impressive amount of work has been conducted, and concisely summarised, and great effort has been undertaken to add layers of insight to the findings. I am no stranger to what an undertaking this would have been. My primary concern, however, is that the novel statistical procedure proposed, and applied to identify the gene lists, as far as I can tell offers no statistical error control or quantification. Consequently, we have no sense of what proportion of the highlighted GEAR genes and networks are likely to just be noise.

Major comments:

(1) The main methodology used to identify the GEAR genes, "Multi-gradient Permutation Survival Analysis" does not formally account for multiple testing and offers no formal error control. Meaning we are left with no understanding of what the family-wise (aka type 1) error rate is among the GEAR lists, nor the false discovery rate. I would generally recommend against the use of any feature selection methodology that does not provide some form of error quantification and/or control because otherwise we do not know if we are encouraging our colleagues and/or readers to put resources into lists of genes that contain more noise than not. There are numerous statistical techniques available these days that offer error control, including for lists of p-values from arbitrary sets of tests (see expansion on this and some review references below).

(2) Similarly, no formal significance measure was used to determine which of the strongest "SAS" connections to include as edges in the "Core Survival Network".

(3) There is, as far as I could tell, no validation of any identified gene lists using an independent dataset external to the presently analysed TCGA data.

(4) There are quite a few places in the methods section where descriptions were not clear (e.g. elements of matrices referred to without defining what the columns and rows are), and I think it would be quite challenging to re-produce some aspects of the procedures as currently described (more detailed notes below).

(5) There is a general lack of statistical inference offered. For example, throughout the gene enrichment section of the results, I never saw it stated whether the pathways highlighted are enriched to a significant degree or not.

Smith Corona Typewriters 1935 - 1980 Type Alignment / Shift Motion Upper Lower Case Adjustment by [[Phoenix Typewriter]]

Duane starts out by showing the two adjustment screws for the upper and lower case motion adjustment on a 5 Series Smith-Corona portable. (This should be the same across several decades of machines and include the 4 and 6 series as well.)

Reviewer #4 (Public review):

Summary:

The authors have performed endoscopic calcium recordings of individual CeA neuron responses to food and shock, as well as to cues predicting food and shock. They claim that a majority of neurons encode valence, with a substantial minority encoding salience.

Strengths:

The use of endoscopic imaging is valuable, as it provides the ability to resolve signals from single cells, while also being able to track these cells across time. The recordings appear well-executed, and employ a sophisticated circular shifting analysis to avoid statistical errors caused by correlations between neighboring image pixels.

Weaknesses:

My main critique is that the authors didn't fully test whether neurons encode valence. While it is true that they found CeA neurons responding to stimuli that have positive or negative value, this by itself doesn't indicate that valence is the primary driver of neural activity. For example, they report that a majority of CeA neurons respond selectively to either the positive or negative US, and that this is evidence for "type I" valence encoding. However, it could also be the case that these neurons simply discriminate between motivationally relevant stimuli in a manner unrelated to valence per se. A simple test of this would be to check if neural responses generalize across more than one type of appetitive or aversive stimulus, but this was not done. The closest the authors came was to note that a small number of neurons respond to CS cues, of which some respond to the corresponding US in the same direction. This is relegated to the supplemental figures (3 and 4), and it is not noted whether the the same-direction CS-US neurons are also valence-encoding with respect to different USs. For example, are the neurons excited by CS-food and US-food also inhibited by shock? If so, that would go a long way toward classifying at least a few neurons as truly encoding valence in a generalizable way.

A second and related critique is that, although the authors correctly point out that definitions of salience and valence are sometimes confused in the existing literature, they then go on themselves to use the terms very loosely. For example, the authors define these terms in such a way that every neuron that responds to at least one stimulus is either salience or valence-encoding. This seems far too broad, as it makes essentially unfalsifiable their assertion that the CeA encodes some mixture of salience and valence. I already noted above that simply having different responses to food and shock does not qualify as valence-encoding. It also seems to me that having same-direction responses to these two stimuli similarly does not quality a neuron as encoding salience. Many authors define salience as being related to the ability of a stimulus to attract attention (which is itself a complex topic). However, the current paper does not acknowledge whether they are using this, or any other definition of salience, nor is this explicitly tested, e.g. by comparing neural response magnitudes to any measure of attention.

The impression I get from the authors' data is that CeA neurons respond to motivationally relevant stimuli, but in a way that is possibly more complex than what the authors currently imply. At the same time, they appear to have collected a large and high-quality dataset that could profitably be made available for additional analyses by themselves and/or others.

Lastly, the use of 10 daily sessions of training with 20 trials each seems rather low to me. In our hands, Pavlovian training in mice requires considerably more trials in order to effectively elicit responses to the CS. I wonder if the relatively sparse training might explain the relative lack of CS responses?

How many electoral votes does Illinois have? Cite yourr source(s).

Describe how and when industriallization took place in each country, Russia and the US.

Cite your sources.

https://www.liberatingstructures.com/1-1-2-4-all/

https://app.thebrain.com/brain/3d80058c-14d8-5361-0b61-a061f89baf87/fee4a5d8-6d7d-417a-8be2-2b2cc0e97966

DOI: 10.1038/s41467-024-51680-4

Resource: RRID:Addgene_34831

Curator: @olekpark

SciCrunch record: RRID:Addgene_34831

What is this?

DOI: 10.1038/s41467-024-50498-4

Resource: RRID:Addgene_52961

Curator: @olekpark

SciCrunch record: RRID:Addgene_52961

What is this?

DOI: 10.1038/s41467-024-51664-4

Resource: RRID:Addgene_12456

Curator: @olekpark

SciCrunch record: RRID:Addgene_12456

What is this?

DOI: 10.1038/s41586-024-07706-4

Resource: RRID:Addgene_132778

Curator: @olekpark

SciCrunch record: RRID:Addgene_132778

What is this?

DOI: 10.1038/s41467-024-50765-4

Resource: RRID:Addgene_71237

Curator: @olekpark

SciCrunch record: RRID:Addgene_71237

What is this?

DOI: 10.1186/s13578-024-01288-4

Resource: RRID:Addgene_8453

Curator: @olekpark

SciCrunch record: RRID:Addgene_8453

What is this?

DOI: 10.1038/s41593-023-01557-4

Resource: RRID:Addgene_114472

Curator: @olekpark

SciCrunch record: RRID:Addgene_114472

What is this?

DOI: 10.1038/s41467-024-51424-4

Resource: RRID:Addgene_63800

Curator: @olekpark

SciCrunch record: RRID:Addgene_63800

What is this?

DOI: 10.1186/s12964-024-01795-4

Resource: RRID:Addgene_17360

Curator: @olekpark

SciCrunch record: RRID:Addgene_17360

What is this?

DOI: 10.1186/s12967-024-05627-4

Resource: RRID:Addgene_40973

Curator: @olekpark

SciCrunch record: RRID:Addgene_40973

What is this?

DOI: 10.1038/s41598-017-19065-4

Resource: Bloomington Drosophila Stock Center (RRID:SCR_006457)

Curator: @maulamb

SciCrunch record: RRID:SCR_006457

What is this?

https://reddit.com/r/Zettelkasten/comments/1fjfl1g/highest_quality_archival_4x6_index_cards_lined/

მიუხედავად ოფიციალური ორგანოებისა და პასუხისმგებელი პირების მხრიდან ამ პრობლემის უგუვებელყოფის,აუცილებელია ქალებმა კვლავ განაგრძონ ბრძოლა საკუთარი უფლებების დასაცავად და მყარად მოიკიდონ ფეხი პლიტიკურ სფეროში,მიუცედავად არსებული წინააღმდეგობებისა,რადგან დანებება წახალისებაა იმ საზოგადოების,რომელიც შრომას ყოფს გენდერულად და არაფასებს ქალის შესაძლებლობას.

for - safe and just earth system boundaries - translations and transformations - 4 parts

earth system boundaries - translations and transformations - 4 parts - part 1 - theoretical framework - part 2 - quantification of - safe and just ESB, - which ones are transgressed - who are the victims - safe and just corridor - base - ceiling - for timeframe - present - 2050 - part 3 - translating - safe and just ESB - approaches - challenges - enabling conditions - to - cities - businesses

Your brain cannot tell whether it is real or imaginary, so imagine and think in "crazy" creative ways to get your brain to start creating something you might not have without thinking in an almost unrealistic way.

Reviewer #4 (Public Review):

Summary:

With their 'CMR-replay' model, Zhou et al. demonstrate that the use of spontaneous neural cascades in a context-maintenance and retrieval (CMR) model significantly expands the range of captured memory phenomena.

Strengths:

The proposed model compellingly outperforms its CMR predecessor and, thus, makes important strides towards understanding the empirical memory literature, as well as highlighting a cognitive function of replay.

Weaknesses:

Competing accounts of replay are acknowledged but there are no formal comparisons and only CMR-replay predictions are visualized. Indeed, other than the CMR model, only one alternative account is given serious consideration: A variant of the 'Dyna-replay' architecture, originally developed in the machine learning literature (Sutton, 1990; Moore & Atkeson, 1993) and modified by Mattar et al (2018) such that previously experienced event-sequences get replayed based on their relevance to future gain. Mattar et al acknowledged that a realistic Dyna-replay mechanism would require a learned representation of transitions between perceptual and motor events, i.e., a 'cognitive map'. While Zhou et al. note that the CMR-replay model might provide such a complementary mechanism, they emphasize that their account captures replay characteristics that Dyna-replay does not (though it is unclear to what extent the reverse is also true).

Another important consideration, however, is how CMR replay compares to alternative mechanistic accounts of cognitive maps. For example, Recurrent Neural Networks are adept at detecting spatial and temporal dependencies in sequential input; these networks are being increasingly used to capture psychological and neuroscientific data (e.g., Zhang et al, 2020; Spoerer et al, 2020), including hippocampal replay specifically (Haga & Fukai, 2018). Another relevant framework is provided by Associative Learning Theory, in which bidirectional associations between static and transient stimulus elements are commonly used to explain contextual and cue-based phenomena, including associative retrieval of absent events (McLaren et al, 1989; Harris, 2006; Kokkola et al, 2019). Without proper integration with these modeling approaches, it is difficult to gauge the innovation and significance of CMR-replay, particularly since the model is applied post hoc to the relatively narrow domain of rodent maze navigation.

Der südkoreanische Verfassungsgerichtshof hat die Regierung des Landes dazu verurteilt ein Klimschutzgesetz vorzulegen, das auch für 2031-2049 verpflichtende Ziele für die Reduktion der Emissionen vorgibt. Andernfalls würden die verfassungsmäßigen Rechte der jüngeren Generation beeinträchtigt. Das Verfahren hatte 2020 mit einer Klage der Gruppe Youth 4 Climate Action begonnen. https://www.theguardian.com/world/article/2024/aug/29/south-korea-court-climate-law-violates-rights-future-generations

Reviewer #4 (Public Review):

The authors report the role of the Piruvate Kinase M2 (PKM2) enzyme nuclear translocation as fundamental in the activation of astrocytes in a model of autoimmune encephalitis (EAE). They show that astrocytes, activated through culturing in EAE splenocytes medium, increase their nuclear PKM2 with a consequent activation of NFkB and STAT3 pathways. Prevention of PKM2 nuclear translocation decreases astrocyte counteracts this activation. The authors found that the E3 ubiquitin ligase TRIM21 interacts with PKM2 and promotes its nuclear translocation. In vivo, either silencing of TRIM21 or inhibition of PKM2 nuclear translocation ameliorates the severity of the disease in the EAE model.

Strengths

This work contributes to the knowledge of the complex action of the PKM2 enzyme in the context of an autoimmune-neurological disease, highlighting its nuclear role and a novel partner, TRIM21, promoting its nuclear translocation. In vivo amelioration of the pathological signs through inhibition of either of the two, PKM2 and TRIM21, provides a novel rationale for therapeutic targeting.

Weaknesses

I believe that the major weakness is the fact that TRIM21 is known to have per se many roles in autoimmune and immune pathways and some of the effects observed might be due to a PKM2-independent action. Some of the experiments to link the two proteins, besides their interaction, are not completely clarifying the issue. On top of that, the in vivo experiments address the role of TRIM21 and the nuclear localisation of PKM2 independently, thus leaving the matter unsolved.

In general, the conclusions of the manuscript are supported by the reported results. The points to be addressed in future are the assessment of PKM2 as substrate of TRIM21 ubiquitin ligase activity and the proof of the epistatic relationship of TRIM21 and PKM2 in astrocyte activation. However, the data surely open novel directions to follow for the understanding of multiple sclerosis and related pathologies.

Reviewer #4 (Public Review):

The manuscript examines how patterns of selection on gene expression differ between a normal field environment and a field environment with elevated salinity based on transcript abundances obtained from leaves of a diverse panel of rice germplasm. In addition, the manuscript also maps expression QTL (eQTL) that explains variation in each environment. One highlight from the mapping is that a small group of trans-mapping regulators explains some gene expression variation for large sets of transcripts in each environment. The overall scope of the datasets is impressive, combining large field studies that capture information about fecundity, gene expression, and trait variation at multiple sites. The finding related to patterns indicating increased LD among eQTLs that have cis-trans compensatory or reinforcing effects is interesting in the context of other recent work finding patterns of epistatic selection. However, other analyses in the manuscript are less compelling or do not make the most of the value of collected data. Revisions are also warranted to improve the precision with which field-specific terminology is applied and the language chosen when interpreting analytical findings.

Selection of gene expression:<br /> One strength of the dataset is that gene expression and fecundity were measured for the same genotypes in multiple environments. However, the selection analyses are largely conducted within environments. The addition of phenotypic selection analyses that jointly analyze gene expression across environments and or selection on reaction norms would be worthwhile.

Gene expression trade-offs:<br /> The terminology and possibly methods involved in the section on gene expression trade-offs need amendment. I specifically recommend discontinuing reference to the analysis presented as an analysis of antagonistic pleiotropy (rather than more general trade-offs) because pleiotropy is defined as a property of a genotype, not a phenotype. Gene expression levels are a molecular phenotype, influenced by both genotype and the environment. By conducting analyses of selection within environments as reported, the analysis does not account for the fact that the distribution of phenotypic values, the fitness surface, or both may differ across environments. Thus, this presents a very different situation than asking whether the genotypic effect of a QTL on fitness differs across environments, which is the context in which the contrasting terms antagonistic pleiotropy and conditional neutrality have been traditionally applied. A more interesting analysis would be to examine whether the covariance of phenotype with fitness has truly changed between environments or whether the phenotypic distribution has just shifted to a different area of a static fitness surface.

Biological processes under selection / Decoherence: PCs are likely not the most ideal way to cluster genes to generate consolidated metrics for a selection gradient analysis. Because individual genes will contribute to multiple PCs, the current fractional majority-rule method applied to determine whether a PC is under direct or indirect selection for increased or decreased expression comes across as arbitrary and with the potential for double-counting genes. A gene co-expression network analysis could be more appropriate, as genes only belong to one module and one can examine how selection is acting on the eigengene of a co-expression module. Building gene co-expression modules would also provide a complementary and more concrete framework for evaluating whether salinity stress induces "decoherence" and which functional groups of genes are most impacted.

Selection of traits:<br /> Having paired organismal and molecular trait data is a strength of the manuscript, but the organismal trait data are underutilized. The manuscript as written only makes weak indirect inferences based on GO categories or assumed gene functions to connect selection at the organismal and molecular levels. Stronger connections could be made for instance by showing a selection of co-expression module eigengene values that are also correlated with traits that show similar patterns of selection, or by demonstrating that GWAS hits for trait variation co-localize to cis-mapping eQTL.

Genetic architecture of gene expression variation:<br /> The descriptive statistics of the eQTL analysis summarize counts of eQTLs observed in each environment, but these numbers are not broken down to the molecular trait level (e.g., what are the median and range of cis- and trans-eQTLs per gene). In addition, genetic architecture is a combination of the numbers and relative effect sizes of the QTLs. It would be useful to provide information about the relative distributions of phenotypic variance explained by the cis- vs. trans- eQTLs and whether those distributions vary by environment. The motivation for examining patterns of cis-trans compensation specifically for the results obtained under high salinity conditions is unclear to me. If the lines sampled have predominantly evolved under low salinity conditions and the hypothesis being evaluated relates to historical experience of stabilizing selection, then my intuition is that evaluating the eQTL patterns under normal conditions provides the more relevant test of the hypothesis.

DOI: 10.1038/s44321-024-00068-4

Resource: (Thermo Fisher Scientific Cat# 45-0621-82, RRID:AB_996667)

Curator: @AniH

SciCrunch record: RRID:AB_996667

What is this?

DOI: 10.1038/s44321-024-00068-4

Resource: (Thermo Fisher Scientific Cat# 25-0441-82, RRID:AB_469623)

Curator: @AniH

SciCrunch record: RRID:AB_469623

What is this?

DOI: 10.1038/s44321-024-00068-4

Resource: (Thermo Fisher Scientific Cat# 17-0801-82, RRID:AB_469417)

Curator: @AniH

SciCrunch record: RRID:AB_469417

What is this?

DOI: 10.1038/s44321-024-00068-4

Resource: (Thermo Fisher Scientific Cat# 17-0451-82, RRID:AB_469392)

Curator: @AniH

SciCrunch record: RRID:AB_469392

What is this?

DOI: 10.1038/s44321-024-00068-4

Resource: (Thermo Fisher Scientific Cat# 17-0451-82, RRID:AB_469392)

Curator: @AniH

SciCrunch record: RRID:AB_469392

What is this?

DOI: 10.1038/s44321-024-00068-4

Resource: (Thermo Fisher Scientific Cat# 17-0451-82, RRID:AB_469392)

Curator: @AniH

SciCrunch record: RRID:AB_469392

What is this?

DOI: 10.1038/s44321-024-00068-4

Resource: (Thermo Fisher Scientific Cat# 12-0311-82, RRID:AB_465632)

Curator: @AniH

SciCrunch record: RRID:AB_465632

What is this?

DOI: 10.1038/s44321-024-00068-4

Resource: (Thermo Fisher Scientific Cat# 12-0114-82, RRID:AB_465552)

Curator: @AniH

SciCrunch record: RRID:AB_465552

What is this?

DOI: 10.1038/s44321-024-00068-4

Resource: (Thermo Fisher Scientific Cat# 11-0081-82, RRID:AB_464915)

Curator: @AniH

SciCrunch record: RRID:AB_464915

What is this?

DOI: 10.1038/s44321-024-00068-4

Resource: (Thermo Fisher Scientific Cat# 11-0081-82, RRID:AB_464915)

Curator: @AniH

SciCrunch record: RRID:AB_464915

What is this?

DOI: 10.1038/s44321-024-00068-4

Resource: (Abcam Cat# ab10558, RRID:AB_442810)

Curator: @AniH

SciCrunch record: RRID:AB_442810

What is this?

DOI: 10.1038/s44321-024-00068-4

Resource: (Abcam Cat# ab217344, RRID:AB_2890649)

Curator: @AniH

SciCrunch record: RRID:AB_2890649

What is this?

DOI: 10.1038/s44321-024-00068-4

Resource: (BioLegend Cat# 861001, RRID:AB_2814585)

Curator: @AniH

SciCrunch record: RRID:AB_2814585

What is this?

DOI: 10.1038/s44321-024-00068-4

Resource: (Cell Signaling Technology Cat# 97585, RRID:AB_2800282)

Curator: @AniH

SciCrunch record: RRID:AB_2800282

What is this?

DOI: 10.1038/s44321-024-00068-4

Resource: (Cell Signaling Technology Cat# 46890, RRID:AB_2799313)

Curator: @AniH

SciCrunch record: RRID:AB_2799313

What is this?

DOI: 10.1038/s44321-024-00068-4

Resource: (Cell Signaling Technology Cat# 46890, RRID:AB_2799313)

Curator: @AniH

SciCrunch record: RRID:AB_2799313

What is this?

DOI: 10.1038/s44321-024-00068-4

Resource: AB2573372

Curator: @AniH

SciCrunch record: RRID:AB2573372

What is this?

DOI: 10.1038/s44321-024-00068-4

Resource: AB_25724331

Curator: @AniH

SciCrunch record: RRID:AB_25724331

What is this?

DOI: 10.1038/s44321-024-00068-4

Resource: (Bioss Cat# bs-1444R, RRID:AB_10855240)

Curator: @AniH

SciCrunch record: RRID:AB_10855240

What is this?

DOI: 10.7554/eLife.82249

Resource: ZFIN_ZDB-ALT-230316-4

Curator: @olekpark

SciCrunch record: RRID:ZFIN_ZDB-ALT-230316-4

What is this?

DOI: 10.7554/eLife.91429

Resource: (ZFIN Cat# ZDB-ALT-051223-4,RRID:ZFIN_ZDB-ALT-051223-4)

Curator: @olekpark

SciCrunch record: RRID:ZFIN_ZDB-ALT-051223-4

What is this?

DOI: 10.1038/s41467-023-36644-4

Resource: RRID:BDSC_48306

Curator: @anisehay

SciCrunch record: RRID:BDSC_48306

What is this?

DOI: 10.1038/s41420-023-01642-4

Resource: RRID:BDSC_37721

Curator: @anisehay

SciCrunch record: RRID:BDSC_37721

What is this?

Reviewer #4 (Public Review):

Summary:

The authors report a novel isomorphism in which the folds of the elephant trunk are recognizably mapped onto the principal sensory trigeminal nucleus in the brainstem. Further, they identify the enlarged nucleus as being situated in this species in an unusual ventral midline position.

Strengths:

The identity of the purported trigeminal nucleus and the isomorphic mapping with the trunk folds is supported by multiple lines of evidence: enhanced staining for cytochrome oxidase, an enzyme associated with high metabolic activity; dense vascularization, consistent with high metabolic activity; prominent myelinated bundles that partition the nucleus in a 1:1 mapping of the cutaneous folds in the trunk periphery; near absence of labeling for the anti-peripherin antibody, specific for climbing fibers, which can be seen as expected in the inferior olive; and a high density of glia.

Weaknesses:

Despite the supporting evidence listed above, the identification of the gross anatomical bumps, conspicuous in the ventral midline, is problematic. This would be the standard location of the inferior olive, with the principal trigeminal nucleus occupying a more dorsal position. This presents an apparent contradiction which at a minimum needs further discussion. Major species-specific specializations and positional shifts are well-documented for cortical areas, but nuclear layouts in the brainstem have been considered as less malleable.

DOI: 10.1002/cne.23733

Resource: RRID:ZFIN_ZDB-GENO-100308-4

Curator: @chewbeccax

SciCrunch record: RRID:ZFIN_ZDB-GENO-100308-4

What is this?

DOI: 10.1038/s41556-023-01227-4

Resource: SCR_006457

Curator: @anisehay

SciCrunch record: RRID:SCR_006457

What is this?

DOI: 10.1038/s41598-021-82944-4

Resource: RRID:BDSC_7011

Curator: @olekpark

SciCrunch record: RRID:BDSC_7011

What is this?

DOI: 10.1038/s41419-021-03742-4

Resource: Bloomington Drosophila Stock Center (RRID:SCR_006457)

Curator: @olekpark

SciCrunch record: RRID:SCR_006457

What is this?

DOI: 10.1038/s41598-020-74448-4

Resource: RRID:BDSC_32078

Curator: @anisehay

SciCrunch record: RRID:BDSC_32078

What is this?

DOI: 10.1038/s41598-021-84413-4

Resource: SCR_00645

Curator: @anisehay

SciCrunch record: RRID:SCR_00645

What is this?

DOI: 10.1038/s41598-021-88910-4

Resource: Bloomington Drosophila Stock Center (RRID:SCR_006457)

Curator: @mpairish

SciCrunch record: RRID:SCR_006457

What is this?

DOI: 10.1038/s41559-021-01482-4

Resource: RRID:BDSC_51307

Curator: @anisehay

SciCrunch record: RRID:BDSC_51307

What is this?

DOI: 10.1038/s41598-022-09869-4

Resource: RRID:BDSC_5138

Curator: @mpairish

SciCrunch record: RRID:BDSC_5138

What is this?

DOI: 10.1038/s41467-022-30975-4

Resource: BDSC_25125

Curator: @anisehay

SciCrunch record: RRID:BDSC_25125

What is this?

DOI: 10.1186/s13064-022-00166-4

Resource: (BDSC Cat# 2376,RRID:BDSC_2376)

Curator: @anisehay

SciCrunch record: RRID:BDSC_2376

What is this?

DOI: 10.1038/s41586-022-04578-4

Resource: BDSC_50746

Curator: @mpairish

SciCrunch record: RRID:BDSC_50746

What is this?

DOI: 10.1186/s13578-021-00595-4

Resource: RRID:BDSC_67608

Curator: @bandrow

SciCrunch record: RRID:BDSC_67608

What is this?

DOI: 10.1038/s41588-020-0615-4

Resource: Bloomington Drosophila Stock Center (RRID:SCR_006457)

Curator: @anisehay

SciCrunch record: RRID:SCR_006457

What is this?

DOI: 10.1007/s12192-020-01171-4

Resource: Bloomington Drosophila Stock Center (RRID:SCR_006457)

Curator: @bpowell22

SciCrunch record: RRID:SCR_006457

What is this?

DOI: 10.1038/s41593-024-01678-4

Resource: (MMRRC Cat# 031796-UCD,RRID:MMRRC_031796-UCD)

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DOI: 10.1186/s12964-024-01733-4

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DOI: 10.1038/s41422-020-0388-4

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DOI: 10.1038/s41467-023-36474-4

Resource: RRID:BDSC_34347

Curator: @mpairish

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DOI: 10.1007/s12192-020-01074-4

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Curator: @PeterEckmann

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DOI: 10.1038/s41467-020-14781-4

Resource: Bloomington Drosophila Stock Center (RRID:SCR_006457)

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DOI: 10.1007/s00359-019-01396-4

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Curator: @bandrow

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DOI: 10.1038/s41598-019-48860-4

Resource: RRID:BDSC_30910

Curator: @bandrow

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DOI: 10.1038/s41420-023-01769-4

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Curator: @olekpark

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DOI: 10.1038/s41467-023-38755-4

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DOI: 10.1007/s12195-024-00811-4

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DOI: 10.1038/s41559-023-02127-4

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Curator: @mpairish

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Reviewer #4 (Public Review):

In this manuscript by Sha et al. the authors test the role of TNFa in modulating tumor regression/recurrence under therapeutic pressure from castration (or enzalutamide) in both in vitro and in vivo models of prostate cancer. Using the PTEN-null genetic mouse model, they compare the effect of a TNFα ligand trap, etanercept, at various points pre- and post-castration. Their most interesting findings from this experiment were that etanercept given 3 days prior to castration prevented tumor regression, which is a common phenotype seen in these models after castration, but etanercept given 1 day prior to castration prevented prostate cancer recurrence after castration. They go on to perform RNA sequencing on tumors isolated from either sham or castrate mice from two time points post-castration to study acute and delayed transcriptional responses to androgen deprivation. They found enrichment of gene sets containing TNF-targets which initially decrease post-castration but are elevated by 35 days, the time at which tumors recur. The authors conduct a similar set of experiments using human prostate cancer cell lines treated with the androgen receptor inhibitor enzalutamide and observe that drug treatment leads to cells with basal stem-like features that express high levels of TNF. They noticed that CCL2 levels correlate with changes in TNF levels raising the possibility that CCL2 might be a critical downstream effector for disease recurrence. To this end, they treated PTEN-null and hi-MYC castrated mice with a CCR2-antagonist (CCR2a) because CCR2 is one receptor of CCL2 and monitors tumor growth dynamics. Interestingly, upon treatment with CCR2a, tumors did not recur according to their measurements. They go on to demonstrate that the tumors pre-treated with CCR2a had reduced levels of putative TAMs and increased CTLs in the context of TNF or CCR2 inhibition providing a cellular context associated with disease regression. Lastly, they perform single-cell RNA sequencing to further characterize the tumor microenvironment post-castration and report that the ratio of CTLs to TAMs is lower in a recurrent tumor.

While the concepts behind the study have merit, the data are incomplete and do not fully support the authors' conclusions. The author's definition of recurrence is subjective given that the amount of disease regression after castration is both variable (Figure 8) and relatively limited, particularly in the PTEN loss model. Critical controls are missing. For example, both drug experiments were completed without treating non-castrate plus drug controls which raises the question of how specific these findings are to castration resistance. No validation was performed to ensure that either the TNF ligand trap or the CCR2 agonist was acting on target. The single-cell sequencing experiments were done without replicates which raises concern about its interpretation. At a conceptual level, the authors say that a major cause of disease recurrence in the immunosuppressive TME, but provide little functional data that macrophages and T cells are directly responsible for this phenotype. Statistical analyses were performed on only select experiments. In summary, further work is recommended to support the conclusions of this story.

DOI: 10.1038/s41467-024-47465-4

Resource: RRID:BDSC_93857

Curator: @bandrow

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