Steel manufacturing.

Topics to discuss on first 1:1

DOI: 10.1016/j.celrep.2021.109775

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What is this?

DOI: 10.1016/j.celrep.2021.109775

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What is this?

Is this saying that the court must put the Constitution first, over an act of congress? Are the principles, which are being referred to, those in the Constitution? If not, what are they?

DOI: 10.1016/j.isci.2021.103064

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What is this?

Question: Is having a job a legal right? I understand that this case was also trying to figure out that same question.

So where does appellate jurisdiction come in? I only see this statement mention original jurisdiction but in the video Prof explained the Constitutional Article III held the Supreme Court has power to do both. So in what circumstances does appellate court because the jurisdiction for a case/trial?

This assertion is fascinating to me. In my interpretation, Marshall is basically saying that every single clause in the constitution has a deliberate effect. I wonder, are there any clauses that the framers explicitly wrote as transitional sentences between two more important thoughts that have been interpreted to have a huge effect? In other words, was Marshall right to say that every single clause was supposed to have an effect?

In what circumstances is the officer not removable at the will of the President in this context? From my knowledge the house impeaches and the Senate holds the trial

Is this inciting that in order to be given civil liberty, you must obeyed by the laws set in place?

From what I understand about this case. it vaguely reminds me of the case of a baker who refused to bake a cake for a gay couple due to his religious beliefs. I think it made it to the state supreme court and they ruled he was within his constitutional right to refuse service. Since they ruled here that they could not force him to deliver the commissions (even though he did violate the law) did this case have any affect on the ruling of the more current case? I know that it said in a previous module that they have to follow precedent set by previous cases.

This is confusing to me because I don't understand how this is an opinion answered question. If something has gone wrong shouldn't there be a remedy owed?

When this is referring to a man considering himself "injured", does that mean that a remedy can only be given to cases in which someone was injured? Or is this a form of metaphorical speech?

Does this simply suggest our government is laws and doesn't have much to do with the men that are supposed to uphold them? What legal right are they referring to?

If the Court is only bound to issue a mandamus as an exercise or remedy provided the powers granted by its appellate jurisdiction, which it denied given the case was brought directly to the Court, then how did it take the case under original jurisdiction? Did Marshall have a different take on jurisdiction than Justice Chase a few decades later?

Why would he not be if his position is upheld by the law as they mentioned previously? Why would he not be entitled to a remedy of the situation?

DOI: 10.7554/eLife.66483

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What is this?

Economic Action Plan 2015 Act, No. 1, SC 2015, c 36, https://canlii.ca/t/52m2b, s. 172, amends IRPA s. 32(d.5) to say:

(d.5) the requirement for an employer to provide a prescribed person with prescribed information in relation to a foreign national’s authorization to work in Canada for the employer;

Previously it had said:

(d.5) the requirement for an employer to provide a prescribed person with prescribed information in relation to a foreign national’s authorization to work in Canada for the employer, the electronic system by which that information must be provided, the circumstances in which that information may be provided by other means and those other means;

Economic Action Plan 2015 Act, No. 1, SC 2015, c 36, https://canlii.ca/t/52m2b, s. 171(1) repealed IRPA s. 14(3), which had said: "(3) For the purposes of subsection 11(1.01), the regulations may include provisions respecting the circumstances in which an application may be made by other means and respecting those other means."

Economic Action Plan 2015 Act, No. 1, SC 2015, c 36, https://canlii.ca/t/52m2b, s. 171(2) repealed IRPA s. 14(4), which had said:

(4) The regulations may provide for any matter relating to the application of section 11.1, including (a) the circumstances in which a foreign national is exempt from the requirement to follow the procedures prescribed under that section; (b) the circumstances in which a foreign national is not required to provide certain biometric information; and (c) the processing of the collected biometric information, including creating biometric templates or converting the information into digital biometric formats.

Economic Action Plan 2015 Act, No. 1, SC 2015, c 36, https://canlii.ca/t/52m2b, s. 171(3) repealed IRPA s. 14(5), which had said:

(5) The regulations may require foreign nationals who make an application for a visa or other document under subsection 11(1) and foreign nationals who were issued an invitation under Division 0.1 to apply for permanent residence to make those applications by means of an electronic system and may include provisions respecting that system, respecting the circumstances in which those applications may be made by other means and respecting those other means.

Economic Action Plan 2015 Act, No. 1, SC 2015, c 36, https://canlii.ca/t/52m2b, s. 170, repealed s. 11.1, which until that point read:

11.1 A prescribed foreign national who makes an application for a temporary resident visa, study permit or work permit must follow the prescribed procedures for the collection of prescribed biometric information.

Economic Action Plan 2015 Act, No. 1, SC 2015, c 36, https://canlii.ca/t/52m2b, s. 169(1), adds a new s. 11(1.01):

(1.01) Despite subsection (1), a foreign national must, before entering Canada, apply for an electronic travel authorization required by the regulations by means of an electronic system, unless the regulations provide that the application may be made by other means. The application may be examined by an officer and, if the officer determines that the foreign national is not inadmissible and meets the requirements of this Act, the authorization may be issued by the officer.

The section previously read:

(1.01) Despite subsection (1), a foreign national must, before entering Canada, apply for an electronic travel authorization required by the regulations by means of an electronic system, unless the regulations provide that the application may be made by other means. The application may be examined by the system or by an officer and, if the system or officer determines that the foreign national is not inadmissible and meets the requirements of this Act, the authorization may be issued by the system or officer.

Economic Action Plan 2015 Act, No. 1, SC 2015, c 36, https://canlii.ca/t/52m2b, s. 169(2), adds a new subsection: "(1.02) Subject to the regulations, a foreign national who has temporary resident status may apply for a visa or other document during their stay in Canada."

Ut enim ad minim veniam, quis nostrud exercitation ullamco laboris nisi ut aliquip ex ea commodo consequat. Duis aute irure dolor in reprehenderit in voluptate velit esse cillum dolore eu fugiat nulla pariatur. Excepteur sint occaecat cupidatat non proident, sunt in culpa qui officia deserunt mollit anim id est laborum.

Fundamentos pedagógicos. En el PEI de la institución pudimos identificar las tendencias pedagógicas del colegio universitario de socorro como lo son: el aprendizaje significativo- humanista y constructivista, al igual orientan contenidos al estudio del medio ambiente.

DOI: 10.1016/j.devcel.2021.09.005

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What is this?

DOI: 10.1016/j.devcel.2021.09.005

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What is this?

DOI: 10.1016/j.devcel.2021.09.005

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What is this?

combine this with Oxfam's 2020 report on carbon emissions and we have the real driver's of carbon emissions, the wealthy. COP26 addresses nation states, not individuals. We need to focus on individuals as well.

DOI: 10.7554/eLife.68920

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What is this?

DOI: 10.7554/eLife.68920

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What is this?

So how is this measured? How is the court able to tell how "religious" a school is and does how "religious; they are determine the funding amount they receive?

I think the simplicity of this statement demonstrates what side of the argument Cortman is on. Clearly, so far throughout the entire case he has been defending the funding of the playground. While other are challenging his idea, he flat out says this case is not that difficult.

Not sure if it's really a question necessarily, but I find it odd they are being so technical. I realize that they need to set a precedent and be able to justify their decisions and make sure it fits within the laws and everything, but they should be focusing on the merits of the case at hand, not coming up with every possible thing it could be compared to. Again it makes sense that they need to cross reference this type of information and those questions are worth answering but in this setting it somehow seems to me to be off topic.

I believe justice sotomayor is one of the dissenting judges based on these comments. I think she makes a very good point and I don't think Cortman does a good job defending his point here. He tries to argue that it creates a conflict with the establishment clause but it seems to me that following the establishment clause would suggest they not fund the school.

I'm curious, in their attempts to, as Professor Roberts characterized it, "probe the strength of their legal arguments, implications and hypothetical effects," how often do Justices describe hypothetical situations? If there was a statistic on how many times, on average per case, a hypothetical was posed, how high or low do we think it would be?

For those who were unfamiliar with the phrase, as I was, Oxford defines "passé" as "no-longer fashionable; out of date." By asking Cortman whether he believes the precedent set by Everson holds, and subtly confirming that she believes it does, I think Justice Ginsberg is signaling her intention to Dissent, eventually becoming one of the two Justices in the minority of the final decision.

In providing Cortman the opportunity to directly refute Justice Sotomayor's reasoning, I believe Justice Alito is revealing that he is part of the majority that will come to decide in favor of Trinity Lutheran.

I think this is one of the majority justices. It is still very early and his course may change but it seems like he is already convinced and suggesting that spending this money is not about advancing religion, as it would be similar for spending the earthquake proofing money on a church window.

I wish this had been elaborated on more. What do these two cases mean, and how does citing them help?

My first question is a bit more overarching of the argument that is happening so far. Is this argument, that the division of religious versus secular property on the church grounds, a violation of the first amendment? More specifically, if every individual has the freedom of religion, why does it matter that this church playground must be secular? Are they telling Cortman that they can judge what happens on the churches own private property? Why does this affect whether the church can join a fundraiser or not?

DOI: 10.1016/j.cub.2021.08.049

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What is this?

DOI: 10.1016/j.cub.2021.08.049

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What is this?

DOI: 10.1016/j.cub.2021.08.049

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What is this?

DOI: 10.1016/j.cub.2021.08.049

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What is this?

DOI: 10.1016/j.cub.2021.08.049

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What is this?

" We're going to have to control your tongue" I felt like that was an analogy. I took it as "you should watch what come's out of your mouth because words can hurt someone." Kind of like the saying when people say " watch your tongue"

Brighton social services patch teams.

Unsubstantiated claims

Important for Exam 1 need to know what this is.

lien vers l'article

Is it possible to say that COVID -19 sped up what was to come in the future? For example, we all knew that the world was moving into a more digital/ tech/ world. People are so connected to their electronic devices. Social media and the internet has changed the way humans communicated. Is it safe to safe that these organizations and leaders in these positions of power failed us by not thinking ahead.

Task 1. What does the title tell you about the text? The author of this text is going to explain why and how philosophy is so valuable to people. What do the section titles tell you about the text? The section titles show how the author felt they needed to break up his statement to prove their point. What do the footnotes tell you about the text? The footnotes could possibly contain examples or references that has been cited.

Task 1 WHAT DOES THE TITLE TELL YOU ABOUT THE TEXT? The title tells me that the reading will be probably about what philosophy has to value and what it is.

DOI: 10.1016/j.devcel.2021.07.021

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What is this?

DOI: 10.1016/j.devcel.2021.07.021

Resource: (ZFIN Cat# ZDB-ALT-111102-1,RRID:ZFIN_ZDB-ALT-111102-1)

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What is this?

DOI: 10.7554/eLife.61733

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Curator: @evieth

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What is this?

DOI: 10.7554/eLife.61733

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Curator: @evieth

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What is this?

DOI: 10.7554/eLife.42881

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Curator: @scibot

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What is this?

asfvaerv

erwerf

erver

DOI: 10.1016/j.neuron.2018.10.045

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What is this?

I like the differentiation that Jared has made here on his homepage with categories for "fast" and "slow".

It's reminiscent of the system 1 (fast) and system2 (slow) ideas behind Kahneman and Tversky's work in behavioral economics. (See Thinking, Fast and Slow)

It's also interesting in light of this tweet which came up recently:

I very much miss the back and forth with blog posts responding to blog posts, a slow moving argument where we had time to think.

— Rachel Andrew (@rachelandrew) August 22, 2017

Because the Tweet was shared out of context several years later, someone (accidentally?) replied to it as if it were contemporaneous. When called out for not watching the date of the post, their reply was "you do slow web your way…" #

This gets one thinking. Perhaps it would help more people's contextual thinking if more sites specifically labeled their posts as fast and slow (or gave a 1-10 rating?). Sometimes the length of a response is an indicator of the thought put into it, thought not always as there's also the oft-quoted aphorism: "If I Had More Time, I Would Have Written a Shorter Letter".

The ease of use of the UI on Twitter seems to broadly make it a platform for "fast" posting which can often cause ruffled feathers, sour feelings, anger, and poor communication.

What if there were posting UIs (or micropub clients) that would hold onto your responses for a few hours, days, or even a week and then remind you about them after that time had past to see if they were still worth posting? This is a feature based on Abraham Lincoln's idea of a "hot letter" or angry letter, which he advised people to write often, but never send.

Where is the social media service for hot posts that save all your vituperation, but don't show them to anyone? Or which maybe posts them anonymously?

The opposite of some of this are the partially baked or even fully thought out posts that one hears about anecdotally, but which the authors say they felt weren't finish and thus didn't publish them. Wouldn't it be better to hit publish on these than those nasty quick replies? How can we create UI for this?

I saw a sitcom a few years ago where a girl admonished her friend (an oblivious boy) for liking really old Instagram posts of a girl he was interested in. She said that deep-liking old photos was an obvious and overt sign of flirting.

If this is the case then there's obviously a social standard of sorts for this, so why not hold your tongue in the meanwhile, and come up with something more thought out to send your digital love to someone instead of providing a (knee-)jerk reaction?

Of course now I can't help but think of the annotations I've been making in my copy of Lucretius' On the Nature of Things. Do you suppose that Lucretius knows I'm in love?

DOI: 10.7554/eLife.68755

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What is this?

DOI: 10.7554/eLife.68755

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What is this?

Most murders are system 1-based and spur-of-the-moment.

System 2-based murders are even more deplorable because in most ethical systems it means the person actively spent time and planning to carry the murder out. The second category includes pre-meditated murder, murder-for-hire as well as all forms of capital punishment.

DOI: 10.1002/cne.24042

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What is this?

DOI: 10.1016/j.cell.2019.08.001

Resource: (ZFIN Cat# ZDB-ALT-120117-1,RRID:ZFIN_ZDB-ALT-120117-1)

Curator: @ethanbadger

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What is this?

DOI: 10.1016/j.cell.2019.08.001

Resource: (ZFIN Cat# ZDB-ALT-110721-1,RRID:ZFIN_ZDB-ALT-110721-1)

Curator: @ethanbadger

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What is this?

DOI: 10.1016/j.neuron.2018.10.045

Resource: (ZFIN Cat# ZDB-ALT-180201-1,RRID:ZFIN_ZDB-ALT-180201-1)

Curator: @scibot

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What is this?

DOI: 10.1016/j.celrep.2019.07.078

Resource: (IMSR Cat# OBS_1,RRID:IMSR_OBS:1)

Curator: @ethanbadger

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What is this?

DOI: 10.7554/eLife.45303

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Curator: @bandrow

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What is this?

DOI: 10.7554/eLife.35796

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Curator: @evieth

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What is this?

DOI: 10.1016/j.celrep.2019.03.013

Resource: (ZFIN Cat# ZDB-ALT-080321-1,RRID:ZFIN_ZDB-ALT-080321-1)

Curator: @ethanbadger

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What is this?

DOI: 10.1016/j.celrep.2019.03.013

Resource: (ZFIN Cat# ZDB-ALT-110721-1,RRID:ZFIN_ZDB-ALT-110721-1)

Curator: @ethanbadger

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What is this?

DOI: 10.1016/j.cub.2018.05.079

Resource: (ZFIN Cat# ZDB-ALT-100721-1,RRID:ZFIN_ZDB-ALT-100721-1)

Curator: @Naa003

SciCrunch record: RRID:ZFIN_ZDB-ALT-100721-1

What is this?

DOI: 10.1242/dev.105718

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Curator: @mpairish

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What is this?

DOI: 10.1242/dev.105718

Resource: (ZFIN Cat# ZDB-ALT-090116-1,RRID:ZFIN_ZDB-ALT-090116-1)

Curator: @mpairish

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What is this?

DOI: 10.1093/glycob/cwv009

Resource: (ZFIN Cat# ZDB-ALT-130122-1,RRID:ZFIN_ZDB-ALT-130122-1)

Curator: @mpairish

SciCrunch record: RRID:ZFIN_ZDB-ALT-130122-1

What is this?

DOI: 10.1016/j.stemcr.2015.02.006

Resource: (ZFIN Cat# ZDB-ALT-070205-1,RRID:ZFIN_ZDB-ALT-070205-1)

Curator: @mpairish

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What is this?

DOI: 10.1002/dvdy.24260

Resource: (ZFIN Cat# ZDB-ALT-080528-1,RRID:ZFIN_ZDB-ALT-080528-1)

Curator: @mpairish

SciCrunch record: RRID:ZFIN_ZDB-ALT-080528-1

What is this?

DOI: 10.1002/dvdy.24260

Resource: (ZFIN Cat# ZDB-ALT-070314-1,RRID:ZFIN_ZDB-ALT-070314-1)

Curator: @mpairish

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What is this?

DOI: 10.7554/eLife.07288

Resource: (ZFIN Cat# ZDB-ALT-130722-1,RRID:ZFIN_ZDB-ALT-130722-1)

Curator: @mpairish

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What is this?

DOI: 10.1371/journal.pgen.1005437

Resource: (ZFIN Cat# ZDB-ALT-110526-1,RRID:ZFIN_ZDB-ALT-110526-1)

Curator: @mpairish

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What is this?

DOI: 10.1016/j.cub.2017.11.018

Resource: (ZFIN Cat# ZDB-ALT-070316-1,RRID:ZFIN_ZDB-ALT-070316-1)

Curator: @evieth

SciCrunch record: RRID:ZFIN_ZDB-ALT-070316-1

What is this?

DOI: 10.1523/ENEURO.0003-19.2019

Resource: (WB Cat# OP50-1,RRID:WB-STRAIN:OP50-1)

Curator: @Naa003

SciCrunch record: RRID:WB-STRAIN:OP50-1

Curator comments: E. Coli. Escherichia Coli WB Cat# OP50-1

What is this?

DOI: 10.1016/j.cell.2019.07.015

Resource: (ZFIN Cat# ZDB-ALT-190607-1,RRID:ZFIN_ZDB-ALT-190607-1)

Curator: @ethanbadger

SciCrunch record: RRID:ZFIN_ZDB-ALT-190607-1

What is this?

DOI: 10.1016/j.celrep.2019.03.044

Resource: (WB Cat# OP50-1,RRID:WB-STRAIN:OP50-1)

Curator: @bandrow

SciCrunch record: RRID:WB-STRAIN:OP50-1

What is this?

DOI: 10.1016/j.cmet.2019.02.013

Resource: (WB Cat# OP50-1,RRID:WB-STRAIN:OP50-1)

Curator: @bandrow

SciCrunch record: RRID:WB-STRAIN:OP50-1

What is this?

DOI: 10.1016/j.neuron.2017.06.001

Resource: (ZFIN Cat# ZDB-ALT-080514-1,RRID:ZFIN_ZDB-ALT-080514-1)

Curator: @Zeljana_Babic

SciCrunch record: RRID:ZFIN_ZDB-ALT-080514-1

What is this?

DOI: 10.1016/j.neuron.2018.08.038

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Curator: @Jmenke

SciCrunch record: RRID:IMSR_KOMP:VG10108-1-Vlcg

What is this?

DOI: 10.7554/eLife.37001

Resource: (ZFIN Cat# ZDB-ALT-100402-1,RRID:ZFIN_ZDB-ALT-100402-1)

Curator: @evieth

SciCrunch record: RRID:ZFIN_ZDB-ALT-100402-1

What is this?

DOI: 10.7554/eLife.37001

Resource: (ZFIN Cat# ZDB-ALT-090324-1,RRID:ZFIN_ZDB-ALT-090324-1)

Curator: @evieth

SciCrunch record: RRID:ZFIN_ZDB-ALT-090324-1

What is this?

DOI: 10.1016/j.cub.2021.06.036

Resource: (ZFIN Cat# ZDB-ALT-170419-1,RRID:ZFIN_ZDB-ALT-170419-1)

Curator: @Naa003

SciCrunch record: RRID:ZFIN_ZDB-ALT-170419-1

What is this?

DOI: 10.7554/eLife.54894

Resource: (ZFIN Cat# ZDB-ALT-150807-1,RRID:ZFIN_ZDB-ALT-150807-1)

Curator: @scibot

SciCrunch record: RRID:ZFIN_ZDB-ALT-150807-1

What is this?

Much like tparmar's comment, some of the professors I have had were not very willing to use technology. This was either because they did not know how or just did not like to use it. I think with the way things are going people are going to have to start using technology or at least know how to use it in order to do some things. Especially with this last year when everything was online many had no choice. A lot of professors I had learned new things by doing class online and also used different apps and modes of communication. Maybe it was not that they were uninterested in the digital humanities, it was more that they were unfamiliar with it and now that everyone has learned some of the basics it could continue into in-person things. I know that I had no idea what digital humanities could do and now that we have started talking about it I am excited to learn more.

I like the way this was worded. I think that some people view digital media as an end and so there is not much you can do with it. What people are forgetting is that if digital media is a means, then that means there are so many things you could do with it and directions you could take. Digital media is the means to spark inspiration and generate new ideas on different subjects. It is also a different way to deliver things that could be more effective for some audiences.

I agree that the latest frontier is about method. Methods change all the time with new ideas and developments taking place in every field. I think it is important to keep up with the changes and stay relevant because if you refuse to adapt a little bit you could lose some of your audience. Since scholars are using digitized materials that previous humanities scholars did not have they can take things to the next level and keep learning. Their work can be shown off in new and exciting ways.

My mom and dad still have their old tapes but we never use them anymore. I also remember burning cd's but we never use them either. The phone has taken over and we just use aux or bluetooth to connect to speakers. I doubt I would ever use a CD again unless I find an old movie, but the computers barely even have a slot to load them anymore since people use netflix and other websites to watch shows and movies.

I did not think that computers were more expensive back then than they are now. If you look at iMac's and MacBook airs, they are well in the 2000 dollar range if you buy them brand new. Prices of phones, tablets and computers have gone up considerably so I wonder how much they were valued at in the 80s and 90s.

I like the part that says "if any single-word term can be used to describe this period, it would almost certainly be "consolidation"". Computers have not been around for very long but their technology very quickly started advancing. Everything was then consolidated into one place: the computer. It seems like in the 70's and 80's people began to realize what a computer could do for them. I think it is interesting that the "diffusion of knowledge" was not just done through computers, it was still being done at conferences as well. People were using a combination of computers, technology, and conferences to share their knowledge. I think that is a piece of what digital humanities is.

I did not know that the most influential investigation was carried in the 60s because I would have thought that it would be later on when technology was more prevalent. I just google searched the image of the old mechanical calculators and it is interesting to see how that big box became so advanced. Imagine carrying that to a math exam! The dials on it look confusing since you have to turn them. It is fascinating to see how much technology advances and how it becomes faster and faster.

I agree that it will change the way you write. Because you are using a blogging platform you already know someone is going to read it or at least that is the goal. One of the main things I have learned in digital humanities so far is that there are different ways to do things. Writing for a blog or website is one of those different ways. Because you can use hyperlinks, add audio, or add video you need to be very clear in what you want to say in case some readers don't click on these links. They are added tools you can use to enhance your writing that you would not be able to get with a written paper but you have to engage your reader enough to want to click on them.

I completely agree that technology has changed the way we read, write, and learn. You can do all three of those things using a computer nowadays. I am doing it right now to write this post. In any assignment I get in a class I immediately go to online articles for research or start typing up notes on my laptop. I was not always so dependent upon it, when I was younger we used books and notebooks. Kids today are growing up with it almost right away though. I think everything is going to continue to be done digitally because that seems to be where we are heading. Technology links the components of digital humanities together and in the article Brett Bobley describes it as a game changer. I think that it is as well because we are learning new things and are going to be able to use the humanities in different ways.

I love that this referenced digital humanities as a unicorn. Being a unicorn sometimes means that the thing, in this case digital humanities, is desired but difficult to obtain. I could see that being true because everyone uses a computer these days so more and more people are looking for someone who knows how to work one and what they can do with it. I don't think it is super difficult to obtain, more that not everyone really understands what digital humanities is. I had no idea what it was I signed up for the course because I wanted to learn more. I think that everyone can learn how to participate in digital humanities especially since it is becoming more and more prevalent.

This makes sense since there are less resources around for these women and typically more violence in the area.

develops from the first three levels. focuses on the person individually

These 4 levels makes up the ecological model

a model that helps explain the influences that usually leads to violence against women.

a psychoeducational group

Those without prior knowledge tend to ask this question often and even those with background. However, the possibility of mental illness and so much more can derive from this.

This is interesting to learn and this could lead to the decrease in victim reports.

DOI: 10.1016/j.cub.2021.05.042

Resource: (ZFIN Cat# ZDB-ALT-130617-1,RRID:ZFIN_ZDB-ALT-130617-1)

Curator: @Naa003

SciCrunch record: RRID:ZFIN_ZDB-ALT-130617-1

What is this?

DOI: 10.1016/j.cub.2021.05.042

Resource: (ZFIN Cat# ZDB-ALT-090716-1,RRID:ZFIN_ZDB-ALT-090716-1)

Curator: @Naa003

SciCrunch record: RRID:ZFIN_ZDB-ALT-090716-1

What is this?

DOI: 10.1016/j.cub.2021.05.042

Resource: (ZFIN Cat# ZDB-ALT-150324-1,RRID:ZFIN_ZDB-ALT-150324-1)

Curator: @Naa003

SciCrunch record: RRID:ZFIN_ZDB-ALT-150324-1

What is this?

DOI: 10.1126/science.abe7790

Resource: (ZFIN Cat# ZDB-GENO-130306-1,RRID:ZFIN_ZDB-GENO-130306-1)

Curator: @scibot

SciCrunch record: RRID:ZFIN_ZDB-GENO-130306-1

What is this?

cool

Reviewer #1 (Public Review):

Sierra M. Barone developed an automated, quantitative toolkit for immune monitoring that would span a wide range of possible immune changes, identify and phenotype statistically significant cell subsets, and provide an overall vector of change indicating both the direction and magnitude of shifts, either in the immune system as a whole or in a key cell subpopulation. The machine learning workflow Tracking Responders Expanding (T-REX) was a modular data analysis workflow including UMAP, KNN, and MEM. T-REX is designed to capture both very rare and very common cell types and place them into a common context of immune change. T-REX was analyzed data types including a new spectral flow cytometry dataset and three existing mass cytometry datasets.

The conclusions of this paper are mostly well supported by data, but one aspect need to be clarified and extend. Cytometry tools like SPADE, FlowSOM, Phenograph, Citrus, and RAPID generally work best to characterize cell subsets representing >1% of the sample and are less capable of capturing extremely rare cells or subsets distinguished by only a fraction of measured features. Tools like t-SNE, opt-SNE, and UMAP embed cells or learn a manifold and represent these transformations as algorithmically-generated axes. The advantages of T-REX tool were not very clear.

Reviewer #1 (Public Review):

In the early days of the pandemic there was unqualified enthusiasm for convalescent plasma therapy. This enthusiasm shifted dramatically as several trials showed no apparent benefit. Although this manuscript does not show a causal relationship between convalescent plasma therapy and prognosis it is provocative and suggests that further work is needed to assess its utility.

Strengths of the manuscript include the comprehensive review of existing datasets and the use of state-of-the-art statistical methods for examining potential confounders such as patient age, seasonal variation in hospital admissions that might have impacted quality of care, and the emergence of SARS-CoV-2 variants. Weaknesses include lack of data that might have enabled identification of patients who are likely to benefit from convalescent plasma and characteristics of plasma (such as neutralization titers) that may be associated with efficacy. These weaknesses do not indicate a lack of effort on the part of the team; there is simply no way to obtain the data.

Reviewer #1 (Public Review):

In this paper, Alhussein and Smith set out to determine whether motor planning under uncertainty (when the exact goal is unknown before the start of the movement) results in motor averaging (average between the two possible motor plans) or in performance optimization (one movement that maximizes the probability of successfully reaching to one of the two targets). Extending previous work by Haith et al. with two new, cleanly designed experiments, they show that performance optimization provides a better explanation of motor behaviour under uncertainty than the motor averaging hypothesis.

Main comments:

1) The main caveat of experiment 1 is that it rules out one particular extreme version of the movement averaging idea- namely that the motor programs are averaged at the level of muscle commands or dynamics. It is still consistent with the idea that the participant first average the kinematic motor plans - and then retrieve the associated force field for this motor plan. This idea is ruled out in Experiment 2, but nonetheless I think this is worth adding to the discussion.

2) The logic of the correction for variability between the one-target and two-target trials in Formula 2 is not clear to me. It is likely that some of the variability in the two-target trials arises from the uncertainty in the decision - i.e. based on recent history one target may internally be assigned a higher probability than the other. This is variability the optimal controller should know about and therefore discard in the planning of the safety margin. How big was this correction factor? What is the impact when the correction is dropped ?

3) Equation 3 then becomes even more involved and I believe it constitutes somewhat of a distractions from the main story - namely that individual variations in the safety margin in the 1-target obstacle-obstructed movements should lead to opposite correlations under the PO and MA hypotheses with the safety margin observed in the uncertain 2-target movements (see Fig 5e). Given that the logic of the variance-correction factor (pt 2) remains shaky to me, these analyses seem to be quite removed from the main question and of minor interest to the main paper.

Reviewer #1 (Public Review):

The authors first use light sheet microscopy to reconstruct embryonic brain development of O. vulgaris. From these images they note a region adjacent to the eye and the developing brain that initially increases in size and subsequently shrinks. They perform transcriptomics and use phylogenetic analyses to identify 4 classes of genes involved in neurogenesis: those that specify the neuroectoderm, neurogenic genes, and markers for differentiated neurons and mature neurons. They perform spatio-temporal analyses of these genes to demonstrate that the lateral lip is the neurogenic region that harbours neuronal progenitors. This region is distinct from the brain, suggesting that neurons migrate long distances from where they are specified to populate the brain. They perform lineage tracing to provide evidence for this migration and demonstrate that the lateral lip is spatially fated so that regions within it generate neurons specific to parts of the brain.

In summary, this is an elegant study that provides deep insight into embryonic neurogenesis in O. vulgaris.

Reviewer #1 (Public Review):

The manuscript has several merits. Most remarkably, Corbett and colleagues developed an alternative to describing biases in decision making by shifting the starting point of evidence accumulation. Instead, they included a linearly increasing urgency buildup rate that was biased by a value cue presented before task onset. Hence, the subsequent evidence accumulation process (labeled the "cumulative bias plus evidence function", p. 5) was affected by this bias in addition to gradually-accumulated stimulus evidence. To allow the estimation of these new model parameters, starting points and urgency buildup rates were constrained to equal the amplitude and temporal slope of the corresponding beta signal captured in simultaneous EEG recordings.

They tested a set of alternative model implementations and found that the bias in stimulus-evidence accumulation was best represented by a concentrated burst of value-biased activity that mirrored voltage changes in the LRP. In comparison, a model with sustained value-biased activity provided an inferior account of the data. Moreover, the authors found that a model gradually increasing evidence and noise provided a better account of the data than a stationary evidence accumulation function. This systematic comparison of alternative model implementations is a great highlight of the paper, because it allows to narrow down on the neurocognitive processes underlying biased decision making.

What limits the generalizability of the authors' results is the sample size and composition. With only 18 participants (one of which was a co-author of this manuscript), the robustness of the authors' modeling results remains an open question. Although 18 participants may provide sufficient power to test a simple main effect in a within-subject design, this does not speak to the issue of the reliability and generalizability of modeling results. Moreover, it is important to note that a sample of 18 participants gives only a power of about 50 % to detect a medium-sized effect with α = .05. Nevertheless, I believe that the generalizability of modeling results is a larger issue than the statistical power. It would have been interesting to assess if the best-fitting model identified in Table 2 provides the best account of the data for all participants or only for a certain percentage of the sample.

Reviewer #1 (Public Review):

Human and animal work over the last couple of years established that fluctuations in pupil size track the activity of a number of neuromodulatory nuclei, including the noradrenergic locus coeruleus, cholinergic basal forebrain, serotonergic dorsal raphe and perhaps the dopaminergic midbrain. In other words, pupil size fluctuations might track a "cocktail" of neuromodulators. The current paper leverages sophisticated data driven analysis techniques to show that pupil size changes can indeed be modulated by different combinations of subcortical nuclei. Doing so, the paper helps laying a solid and nuanced neurophysiological foundation for the interpretation of results from cognitive pupillometry, an area of neuroscience and psychology that is rapidly expanding over the past years. I do have a couple of concerns.

Major issues:

The BOLD hemodynamic response function is slower than the pupil impulse response function. It seems that the authors did not correct for the "lag" between the two (as in Yellin et al., 2015, for example). How much does this matter for the results?

Baseline pupil size was different between the identified clusters. How was pupil size normalized across rats and scanning runs, so that we can meaningfully interpret such a difference?

A substantial part of the literature focuses on the relationship between task-evoked pupil and neuromodulatory responses. I understand that this paper describes results from a resting state experiment, but even in these conditions one typically observes rapid dilations. Right now, it seems that the analysis is somewhat blind to these. See for example Fig. 2C in which frequencies are plotted only until 0.05Hz. Can we see this on log-log axes, to inspect the higher frequencies? Note that there is some work that indicates that the slower pupil fluctuations more reliably track ACh signaling, and faster fluctuations more reliably track NE signaling (Reimer & McGinley et al., 2016).

The authors write "Cluster 2 had the strongest positive weights in [...], but also in brainstem arousal-regulating locus coeruleus, laterodorsal tegmental and parabrachial nuclei." However, the voxel size is very large with respect to the size subcortical nuclei. Because of this, here and in other places, I think the authors should use locus coeruleus region or area, to indicate that their voxel captures more tissue than just LC proper. A discussion paragraph on the spatial specificity of their effects would also help.

The approach is very data driven and the Results section mostly descriptive. I'm personally not at all unsympathetic to this approach, but I do think the authors could aid the reader better by briefly interpreting their results already in the Results section. Related, the authors end each paragraph with "These results verified [...]" or "These results highlight [...]"; however they don't explicitly inform us how.

Rainbow and jet colormaps are confusing because they are not perceptually uniform (https://colorcet.holoviz.org/). Please consider using something like "coolwarm"?

Minor issues:

"Trial" is not well defined. I take this is a 15 minute run?

How many trials in each cluster (Fig. 2)? It would be nice to see a more zoomed in version of Fig. 5 so that we can actually see the subcortical regions in more detail.

Reviewer #1 (Public Review):

Previous reports have provided evidence identifying infection of cotton bollworm with a densovirus as resulting in increased fitness. In the current manuscript, the relevance of this infection towards field resistance to transgenic Bt corn is evaluated by comparing its incidence between regions in China growing non-Bt versus Bt cotton. A clear correlation emerges with infection rates being higher in Bt versus non-Bt cotton growing areas, although its effect on resistance to Cry1Ac and Bt cotton is not as clear.

Strengths:

The manuscript presents evidence for the spread of densovirus infection in field bollworm populations, and that this spread seems to occur at a faster rate in areas of China where Bt cotton is grown versus non-Bt cotton areas. Life table comparisons clearly show increased fitness in bollworms infected with the virus. The study capitalizes on availability of an impressive collection of samples with distinct geographic and historic origin to address relevant evolutionary questions.

Weaknesses:

The suggested role for densovirus infection in resistance to Cry1Ac and Bt cotton is supported by association and the data presented does not necessarily support causation. In fact, the confidence intervals in all the comparisons from bioassays overlap substantially and the resulting resistance ratio is not a good estimate of any significant differences the infection may have on ability to survive Cry1Ac. Infection by a virus is expected to activate the immune system, so the larvae used in bioassays should be considered as "primed" and the slight reduction in susceptibility should not be considered as an effect of the virus itself. The life table data clearly shows that fertility and fecundity are probably the most relevant aspects affecting fitness of infected insects. These differences in reproduction (even more than differences in larval growth) could explain why infection is rapidly spreading in the wild. However, most of the research and analyses are focused on the possibility that the viral infection may make the insects more able to survive Cry1Ac or Bt cotton. There are no conclusive data supporting this hypothesis in the current version, other than increased infection rates in Bt-cotton growing areas. This could be explained by effects on reproduction rather than enhanced survival. Related to this aspect, there should be a more clear distinction between the densovirus increasing fitness versus increasing resistance, the data supports the former but is not so clear in the later. It would be useful to provide a map detailing regions were moths were collected.

Reviewer #1 (Public Review):

The field of genome dynamics is currently very hot and adaptive transposable elements insertions polymorphisms (TIPS) in wild populations are extensively looked for. Here Oggenfuss et al provide evidence that TE activity within a fungus species can vary drastically (1) in different regions of the world and (2) in the same region within a relatively short timeframe (25 years). The data are properly described and both the figures and text are clear. The authors provide examples of candidate TIPS that could adaptive.

Important findings:

• A repertoire of TIPS is provided for 284 genomes. A PCA analysis show that a small number of TIPS can better differentiate two samplings 25 years apart on the same area than the same number of SNPs.
• Increase in TE content is associated with genome size, between areas and within a single area 25 years apart.
• Interesting candidates for adaptative TIPS are provided and discussed.

Limitations:

• The TIPS (or a subset of them) are not validated using another technique.
• The relative expression of the adaptive TIPS is not investigated in this manuscript.
• For genomicists not familiar with fungal genomes the distinction between core chromosomes and accessories chromosomes might be difficult to appreciate.

Reviewer #1 (Public Review):

Gupta et al. provide a very detailed and in depth analysis of the dimerization / oligomerization behavior of the protein Survival Motor Neuron (SMN). The protein is able to use a modified glycine zipper motif to form tightly packed dimers and additional hydrophobic amino acids for higher oligomeric states. Mutations in SMN cause Spinal Muscular Atrophy and the authors show that mutations leading to this disease affect the oligomerization state of the protein. Overall, this is a very detailed study using several biophysical techniques and extensive mutagenesis. The data are of high importance for researchers working in the field of SMN proteins.

A mechanistic link of how these differences in oligomeric states changes the cellular behavior leading to Spinal Muscular Atrophy is unfortunately missing. The authors stress several times that SMN is part of membraneless organelles. Multivalent interactions are characteristic of such organelles, although they are typically based on "fuzzy" interactions involving low complexity regions (and not all dimerization / oligomerization events can be classified as liquid-liquid phase separation). This limits the impact of this detailed analysis.

While this very detailed analysis is an excellent source for researchers working in this field the interest beyond SMN proteins will be limited. The paper could also be written in a less dense manner, which would make its reading easier. The main weakness is a missing mechanistic model that can explain how differences in the oligomerization behavior relates to the function of the protein and causes Spinal Muscular Atrophy. The impact of oligomerization on the formation of membraneless organelles would be important.

Reviewer #1 (Public Review):

Breska and Ivry tested the role of the cerebellum in temporal expectation, specifically in how temporal expectation affects perception. The question is interesting, as the neural mechanisms mediating the substantial effects of temporal expectation on perception are not well understood. The authors found that in a perceptual discrimination task, individuals with cerebellar degeneration (CD) showed reduced effects of temporal expectation on discriminability with interval timing cues, but intact effects with rhythmic cues. This shows that the role of the cerebellum in temporal expectation (which had been previously demonstrated by the authors) is not merely one of motor preparation. Rather, the cerebellum appears to play a causal role in bringing about the perceptual consequences of temporal expectation for predictable intervals. It also reveals differences between interval timing and rhythmic manipulations in terms of the mechanisms by which they affect perception.

This is a straightforward study with a clean experimental approach and clear presentation of the data. However, I felt the manuscript would benefit from a more thorough analysis of the dataset, especially given the rarity of individuals with CD.

Reviewer #1 (Public Review):

The manuscript aims to identify origins of stochasticity ('noise') in mammalian gene expression focused on the case when a single transcription factor controls the expression of a target gene. It also aims to devise strategies to control mean and variance of gene expression independently.

The experimental approach uses a light-induced transcriptional activator in two stimulation modes, namely amplitude modulation (AM: time-constant light input) and pulse width modulation (PWM: periodic light inputs in the form of a pulse train). Perturbation experiments target histone-modifying enzymes to influence epigenetic states, with corresponding measurements of single-cell epigenetic states and mRNA dynamics to dissect mechanisms of noise control. Beyond this synthetic setting, the study is complemented by endogenous gene expression noise in human and mouse cells under the same perturbations.

Major strengths of the study are:

• The experimental demonstration that, and under which conditions PWM can reduce gene expression noise in mammalian cells; the corresponding data sets could be very valuable for further quantitative analysis.
• Providing strong evidence via perturbation studies that the extent of gene expression noise is linked to chromatin-modifying activities, specifically opposing HDAC4/5 histone deacetylase activities and CBP/p300 histone acetyltransferase activities.
• Proposing a positive-feedback model established by these two opposing activities that is consistent with the reported data from perturbation experiments and on chromatin accessibility / modification states.
• Providing evidence that also in the natural (human and mouse cell) setting, the regulators HDAC4/5 and CBP/p300 contribute to the control of gene expression noise.

Major weaknesses are:

• Limited conceptual novelty because noise-reducing effects of PWM have been demonstrated and analyzed previously in synthetic systems in bacteria (with an engineered positive feedback loop; https://www.nature.com/articles/s41467-017-01498-0) and in yeast (with an engineered single transcription factor as in the present study: https://www.nature.com/articles/s41467-018-05882-2#Sec25).
• Insufficient evidence for the postulated bistability caused by positive feedback on chromatin states in the mammalian system analyzed, which has implications for the mechanistic explanations provided (e.g., if PWM allows rapid cell switching between 'high' and 'low' states as postulated).
• Limited theoretical support for the proposed (not directly observable) mechanisms that uses a mathematical model illustrating the potential consistency, but the model is not directly linked to the experimental data and hence of limited use for their interpretation.

Overall, the authors achieved their aim of elucidating mechanisms for noise control in mammalian gene expression by identifying specific, opposing regulators of chromatin states, with clear support in the synthetic setting, and evidence in endogenous expression control. Conceptual advances regarding strategies for the external control of gene expression noise appear limited because of prior work, which includes more in-depth theoretical analysis in simpler (bacterial, yeast) systems.

Hence, the likely impact of the work will be primarily on the more detailed (in terms of histone regulators, etc.) study of noise control in mammalian cells, while the data sets presented in the study could prove valuable for follow-up quantitative (model-based) analyses because they are unique in combining different readouts such as single-cell protein and mRNA abundances as well as histone and chromatin states.

Pretty amazing statement! Elizabeth Warren is right!

Reviewer #1 (Public Review):

This paper presents evidence that membrane potential excursions called plateau potentials are driven by subthreshold oscillation generated by calcium fluxes in mitochondria. Pharmacological and electrophysiological methods were used to deduce that calcium waves were generated in a bilateral pair of electrically-coupled neurons and spread to additional neurons that were coupled to that pair. The identified neurons in Aplysia allow for the detailed measurements needed to determine this mechanism.

• James did not want anyone to think that God sends trials to break down or destroy our faith; therefore, he will come back to this point in James 1:13-18. -James knew that most people have an evil tendency to blame God when they find themselves in trials. Yet by His very nature, God is unable to either be tempted (in the sense we are tempted, as James will explain), nor does He Himself tempt anyone.

Reviewer #1 (Public Review):

Acyl-homoserine lactone (AHL) based quorum sensing systems are an important form of intercellular communication in bacteria. These systems, minimally comprised of a synthase and a receptor, often involve different types of AHLs. This paper uses covariation analyses to try and tease out the determinants of this AHL specificity. Using the GREMLIN pipeline, they identify a series of coevolving residues in LasR and LasI homologs. This is interesting in its own right, and a strength of the paper, as LasR and LasI don't physically interact, and instead interact and covary indirectly by virtue of sharing the same AHL. Through various reporter and biochemical assays, the authors then demonstrate that the residues identified are important for AHL recognition. In the last part of the manuscript, they attempt to use the covariation analysis to guide the 'rewiring' of LasR-LasI to behave like MupR-MupI. This is mostly successful, although LasR-LasI specificity hasn't been 'rewired' so much as simply broadened. The paper could also be improved by fleshing out the description of the results/data obtained - at times it is difficult to assess how the authors have arrived at certain rather sweeping conclusions.

Reviewer #1 (Public Review):

This study shows that the Shu complex is critical for 3meC damage tolerance in yeast, supporting the existence of a new pathway for the removal of an important DNA lesion that seems essential in yeast but likely contributes in other organisms. At the same time, it contributes to clarify the distinctive role of homologous recombination in double strand break repair and post-replicative repair.

Reviewer #1 (Public Review):

Dravet syndrome is a developmental and epileptic encephalopathy resulting from mutations in a sodium channel subunit that is widely thought to cause disease by affecting synaptic inhibition. Here the authors use a well-established mouse model to show that circuit dysfunction results from excess synaptic excitation in the dentate gyrus, potentially providing new insight into the pathological mechanisms underlying seizure activity.

Strengths of the study include the sophisticated approach of 2P Ca2+ imaging of population activity and whole-cell recording in slices that provide well-supported evidence that circuit dysfunction is independent of GABAergic inhibition. Weaknesses include some oversimplification of the results in the data interpretation such that not all the claims are fully supported and lack of in-depth analysis of the circuit dysfunction with a clear presentation of its developmental time course.

Reviewer #1 (Public Review):

The dark structure of GtACR1 has been almost simultaneously published at the end of 2018 and beginning of 2019 by the Deisseroth and Spudich groups, respectively. Both groups did not manage to solve a structure with an ion bound and there is very limited information on the open conformation of the channel. Both groups identified a central constriction site as being central for the gating mechanism but the Spudich group proposes two additional constrictions (C1 and C3). In this work Li et al are able to solve the structure of a GtACR1 with a bromide bound near C3, which clearly represents a significant step towards understanding the mechanism of light gated anion channels. The structure reveals that Br binds to the intracellular constriction site (C3) resulting in a small opening of C3. The data support the notion that the partial electropositivity of Pro58 together with two tryptophans play a critical role in anion interaction at C3, which was also confirmed by mutagenesis studies. In addition, there was a noteworthy conformational change in the Bromide bound protein in the extracellular constriction (C1), a 180 degree flip of Arg 94 resulting in a salt bridge to Asp 234 and a slight opening of the C1 constriction.

While the data and conclusions are sound, the lack of discussion of their data in the context of the work of others is a bit surprising.

Reviewer #1 (Public Review):

This paper investigates the structural conformation of BtuB, a membrane protein involved in the intracellular transport of vitamin B12 in bacteria, using DEER techniques through the labelling of targeted pairs of amino acids. Using these techniques on whole cells, they detect structural conformations of the transporter upon binding of its substrate vitB12 that were not detected when BtuB is not in a natural environment.

BtuB belongs to a well-known family of transporters found in the outer membrane of Gram-negative bacteria, called TBDTs (TonB Dependent Transporters). The structure of BtuB has been determined by X-ray crystallography in its apo and vitB12 bound states, as well as interacting with a C-terminal domain of the TonB protein, a periplasmic protein linked to the inner membrane that conveys the energy needed for the transport of vitB12 through BtuB. The TBDTs share a conserved architecture comprising a C-terminal 22 ß-barrel ring occluded by a globular N-terminal domain.

Using EPR techniques, the Cafiso's lab has shown previously that the BtuB structural states are somewhat different or more dynamic than the X-ray structures would suggest. In the present paper they show that the Substrate Binding SB3 loop of BtuB, upon vitB12 binding, adopts some structural conformations in whole cells that are different than observed with BtuB reconstituted in liposomes, showing that a non-natural environment might alter its functionality. By using a set of mutants that supposedly mimics the BtuB-TonB state, they find dramatic conformational changes of the SB3 loop, which might represent an intermediate conformation of the open state of BtuB, in which vitB12 is allowed to move toward the periplasm, bypassing the need of an energized Ton complex. The data presented are convincing and show that the natural environment of BtuB, i.e., an intact outer membrane, but also probably some periplasmic components such as peptidoglycan and the Ton complex, influence the structural state of this protein. Most importantly these states are not detected when BtuB is reconstituted into liposomes, stressing the importance of studying these transporters in whole cells. However, some of the conclusions are premature, especially concerning the mechanism of action of the Ton complex in the catalyzed transport of vitB12. While the data show clear differences between the apo and vitB12 bound states of BtuB, the conclusions on the actual transport mechanism of vitB12 into the periplasm are more speculative.

The main concern of this reviewer is the conclusions reached from the data obtained with the R14A and/or D316A mutants. There is a clear dramatic change of conformation for the SB3 loop for these mutants upon substrate binding, and as shown the natural environment of BtuB is important to detect these changes. However, the authors state that "breaking the ionic lock and eliminate the electrostatic interactions of R14, as we have done here, should mimic the TonB bound state" (lines 487-488). The data presented in the manuscript do not support this statement as they do not allow to monitor the structural state of the N-terminal TonB box.

Later it is proposed that "the movement of SB3 may also drive the movement of substrate" (lines 466-467) and that "this structural change may be sufficient to move the substrate into the periplasm" (lines 501-502). This is highly speculative, as in the structural states observed with the broken ionic lock, it cannot be determined if vitB12 is still bound to BtuB, or released in the periplasm. As noted, the "conversion of the transporter to the apo state does not occur under the conditions of the experiment" (lines 398-399). It is possible that this structural state is locked with a vitB12 bound and unable to complete the transport cycle.

Nevertheless, these mutants affecting the ionic lock seem to represent valuable tools to investigate the structural intermediates during transport. It remains to be seen if these mutants still promote transport in vivo.

Reviewer #1 (Public Review):

The study is focused on the role of noncoding RNA (sfRNA) of DENV in mosquito transmission of the virus. The requirement of sfRNA for efficient transmission of flaviviruses by mosquitoes is well-documented, however the exact mechanisms of this effect are not clearly established. In this manuscript, authors demonstrated that DENV sfRNA is secreted into mosquito saliva within the extracellular vesicles (EV) and can facilitate infection of the acceptor human cells when delivered together with infectious virus in mosquito saliva. This is a novel and intriguing finding that has a potential to expand our understanding of flavivirus transmission and functions of sfRNA.

The data provided are mostly compelling and provide answers to posed questions. However, additional evidence for EV-mediated delivery of sfRNA into acceptor human cells and the effect of this sfRNA on viral replication in acceptor cells are required to further our understanding of mechanistic aspects of how sfRNA is delivered by salivary extracellular vesicles and how it facilitates virus replication in acceptor cells. A number of additional experiments and clarifications has been requested to clarify this.

Reviewer #1 (Public Review):

After infection, new HIV-particles assemble at the host cell plasma membrane in a process that requires the viral protein Gag. Here, Inamdar et al. showed that a component of the host cell, the membrane curvature-inducing protein IRSp53, contributes to efficiently promote the formation of viral particles in synergy with the viral Gag protein.

In cells depleted of IRSp53, the formation of HIV-1 Gag viral-like particles (VLPs) was compromised. The authors showed in compelling electron micrographs that the formation of VLPs was arrested at about half stage of particle budding. Biochemical data (co-IPs and analysis of VLPs and HIV particle content), super-resolution nanoscopy (single molecule localization microscopy) data, and in vitro biophysics measurements (in GUVs), all seem to indicate a functional connection between Gag and the iBAR-domain containing protein IRSp53. The combination of the different techniques and approaches is a clear strength of this manuscript. However, to my opinion, the interpretation of some of the experimental data is somehow limited by the lack of some appropriate controls (that are lacking for different reasons, as the authors state in some parts of the text). These are:

1) Specificity of the IRSp53 siRNA. Although the authors showed that the siRNA used can deplete the expression of the protein (both endogenous and ectopic), they did not presented any rescue experiments of the phenotypes (or corroboration with different siRNA oligoes).

2) In the co-IPs (IRSp53 IP + Gag co-IP) there is no assessment of the IRSp53 IP efficiency in the different conditions. The authors argued that IgG signal masking precluded them from doing that.

3) The authors observed an increase in the membrane-bound pool of IRSp53 when Gag is present (Fig. 2c). It is not clear whether this is specific for IRSp53 or other IBAR proteins can also be more membrane-bound as a result of Gag expression.

Reviewer #1 (Public Review):

Gentile A et al show a novel role of Snai1b in growth regulation of zebrafish myocardial wall. Specifically, authors show that zebrafish lacking Snai1b exhibit cardiac looping defects (~50% penetrance), consistent with previously described morpholino mediated Snai1b knockdown phenotype. Extruding cardiomyocytes away from cardiac lumen, mostly in the atrioventricular canal region were observed in remaining 50% of Snai1b knockout zebrafish. Using RNA-seq, authors identified several dysregulated genes, including enrichment of intermediate filament genes in Snai1b knockout zebrafish. Among these dysregulated genes, authors suggest that increased Desmin expression and its aberrant localization promote cardiomyocyte extrusion in Snai1b knockout zebrafish hearts. Overall, present manuscript describes a novel phenomenon during cardiac development, hence, it is of interest to developmental biologists.

Major concerns are:

1) Snai1 is known to affect cushion formation in atrioventricular canal region. It would be helpful to establish cause and effect relationship for Snai1b in this region. Zebrafish lack global Snai1b expression - so it would be helpful to show if defective cushion promotes cardiomyocyte extrusion in atrioventricular canal region. Tnnt2 morpholino experiments provides some insights, however, it does not rule out role of defective atrioventricular cushion (defective EMT).

2) For Figure 2 - additional histology / immunohistology to show extrusion, cohesion, and orientation of cardiomyocytes at a section level (2D) in Snai1b knockout hearts could help to characterize phenotype at a cellular level. It is assumed that all cardiomyocytes lack Snai1b protein (immunostaining would help), however, only few cardiomyocyte show extrusion. Minor point - Cartoon images in figure 2 are somewhat disconnected from immunostaining images.

3) It is unclear whether Snai1b knockout hearts exhibit defective contractile phenotype and whether there is a cardiac phenotype in surviving adult zebrafish. It is also unclear whether RNA-seq and SEM from adult zebrafish heart represent embryonic extrusion and intermediate filament defects.

4) It is unclear why only few cardiomyocytes show extrusion when most of cardiomyocytes, if not all, are overexpressing Desmin gene.

5) Molecular link connecting Snai1b and cardiac filaments genes is not determined.

Reviewer #1 (Public Review):

The authors found a mechanosensitive channel gene in T. cruzi, and aimed to characterize the functions. The strength of this manuscript is that the channel has been examined from various aspects: the modelled molecular structures; expression and localization during development; electrophysiological characteristics; cell motility; responses to osmotic stress; regulation of Ca2+ homeostasis; infectivity to host cells. The weakness of this study is the assessment of motility and the nature of the recombinant protein. To conclude, this study provides data sufficient for reporting the discovery and initial characterization of the novel mechanosensitive in T. cruzi. The most significant finding is the correlation with infection, but the involvement in the response to osmotic stress is also interesting in the field of cell biology.

Joint Public Review:

Strengths & Overall Comments:

This behavioral study aims to provide an account of the spontaneous behavior of mice as they learn to explore a novel maze in search of a water reward. The authors analyze the trajectories of mice as they adapt to the labyrinth with particular focus on decisions taken at nodes and T junctions. They describe extremely rapid route learning to home and discontinuous exploratory learning or 'light bulb' moments as evident by instantaneous improvements in navigation performance. The authors capture most of the variance in their overall data with a predictive Markov models that could account for the much subsequent actions of the mouse as it moves from one node to the next. The study should be important to anyone who spends their time thinking about decision-making in mice. It highlights the importance of considering ethologically relevant tasks for understanding decision making in rodent species.

In this submission, the authors introduce a new experimental paradigm for the study decision making in naturalistic contexts, presenting an opportunity to observe these dynamics away from the standard two-alternative-forced-choice paradigm. The application of modern tracking and posture analysis to maze exploration by rodents generates rich and interesting data, and allows the authors to do their experiments with many animals, and with nearly no human interference or specific instructions. The design of the maze is clever, using an underlying tree-like structure (with the tree folded so it precisely and fully occupies a rectangular area), and relatively deep (6 branching points from main trunk to a leaf node). Mice explore this voluntarily, and water-restricted mice learn to find water rewards at a leaf of the maze. The authors thus study truly voluntary and highly interesting complex behavior, and in a high-throughput way. By studying the dynamics of a mouse in a maze, the authors perform a careful set of analyses, describing discontinuous learning dynamics and the effects of history on decision-making. These results should be of interest to a wide group of behavioral neuroscientists that are attempting to understand the neural basis of how animals make decisions in complicated natural environments.

The data set released with this submission will be of broad use to the community, and we would not be surprised to see dozens of papers using it moving forward.