- Oct 2024
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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ntrepreneur's eudaimonic well-being (thriving and activatedaffect) than from their hedonic well-being (life satisfaction and contentment)
the distinction, crystallized again...
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impact of entrepreneurs on the eudaimonic well-being of others (employees, families, communities). The
5th theme...
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a) the degree to which entrepreneurs feel purposefully engaged in what they do; (b) whether they seethemselves as growing and making best use of their talents and potential over time; (c) the quality of their ties to others, includingemployees and collaborators; (d) the sense that they are effective in managing their surrounding environments; (e) the degree towhich they show knowledge and acceptance of their own strengths and weaknesses; and, of course, (f) the degree to which they viewthemselves as self-determined and independent. T
5 key concerns...
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eudaimonic well-being of different types of entrepreneurs, focused on the distinction between necessity versus opportunity entrepreneurs. Th
2nd theme
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how and where eudaimonia might matter at different points in the entrepreneurial process, from initial pursuits to longer-term endeavors.
3rd theme
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he first examines the link between entrepreneurship and autonomy, w
Autonomy = BOTHJ motive and an aspect of well-being. Interesting!
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eudaimonic well-being is modifiable can be promoted
like EQ ... and a growth mindset...
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eudaimonic well-being and health.
if you're happier, and functioning well, you're likely to be healthier too...
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amily roles and experiences to well-being
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n interesting and unexplored question is whether entrepreneurial activities inmid- and later-life might help offset these declines –that is, contribute to maintenance of purposeful engagement and continuingpersonal growth in later adulthood.
food for thought...
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ull understanding of the well-beingof entrepreneurs demands knowledge of their family lives.
...
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he big five model of traits have been linked to the abovedimensions with numerous findings (openness is linked with personal growth, agreeableness with positive relations with others, andextraversion, conscientiousness, and neuroticism with environmental mastery, purpose in life, and self-acceptance) (Sc
wow - awesome link to previous weeks' material...
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se who are married have a well-beingadvantage compared to the divorced, widowed, or never married, but single women score higher on autonomy and personal growthcompared to married women. Parenting seems to enhance well-being, particularly when children are flourishing
ok...
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Self-acceptance brings a potentially neglected aspect of entrepreneurial well-being. It encompasses having positive attitudestoward oneself, but drawing on the Jungian idea of the shadow, also includes the capacity to see one's bad qualities. Thi
self-acceptance!
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How eudaimonic well-being changes with age
??
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work life and eudaimonic well-being
...
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capacityto find meaning in the face of adversity,
So many good Frankl quotes!
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plied to the entrepreneurial context, self-acceptance may be a critical asset, such that effective problem-solving and negotiating through unfolding challenges would seem todemand honest reckoning with one's self. A
honesty is the best policy (especially with oneself!) As it can prevent you from getting in over your head...
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without goals, purposes, and meaning, including during periods ofchallenge and difficulty, it is difficult to fathom an entrepreneur who is experiencing genuine well-being. In
(this is related to the question I asked at the end of our last class -- do you envy people who lead an easy life? Where do they find meaning?)
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Purpose in life is the existential core of eudaimonic well-being, with its emphasis on viewing one's life has having meaning,direction, and goals. These qualities comprise a kind of intentionality that involves having aims and objectives for living. Life
Purpose in life!
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Positive relations with others is the most universally endorsed aspect of what it means to be well. This dimension encompasseshaving warm, trusting ties to others, being concerned about the welfare of others, understanding the give and take of social re-lationships, and having the capacity for empathy and affection.
positive relations!
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Personal growth is concerned with self-realization and achievement of personal potential and thus is closest in content toAristotle's ideas about eudaimonia.
Personal growth!
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Autonomy, emphasizes thatone is self-determining and independent as well as able to evaluate oneself by personal standards, and if need be, to resist socialpressures to think or act in certain ways. T
AUTONOMY
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What relevance, if any, do these eudaimonic components of well-being have for studies of entrepreneurship? Pr
a most useful question...
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an fulfillment
human fulfillment doesn't mean one is a fully functioning human...
(Makes me think of teleology and acorns...)
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Environmental mastery emphasizes the sense that one can manage the surrounding environment, including making effective useof available opportunities, while also creating contexts suitable to one's personal needs and values. Th
Environmental mastery (tied to social settings and social skills in emotional intelligence...)
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igning views of subjective well-being at the time that revolved around assessmentsof happiness, life satisfaction, and positive and negative affect
(mostly) the focus of the other article this week...
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The answer for him was eudaimonia, which he described as activity of the soul in accord with virtue. The key task in lifeis to know and live in truth with one's daimon, a kind of spirit given to all persons at birth. Eu
getting very philosophical here (but context is good)
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two great imperatives of self-truth (knowthyself) and striving toward excellence consistent with one's given potentialities (become what you are). These ideas deepened thephilosophical significance of eudaimonic well-being
which one is more important? Can you say this? Can one become what one is and live up to one's true potential without knowing oneself? Hmmmmm......
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of personalexcellence built on striving to realize one's true and best nature. It
I love how this definition is prefaced with "kind of"
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The second venue addresses varieties of entrepreneurship, with a focus on the distinction between opportunity and ne-cessity entrepreneurs.
all righty then...
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The first section thus examines the conceptual and philo-sophical foundations of a widely-used model of eudaimonic well-being built on the integration of perspectives from clinical, de-velopmental, existential and humanistic psychology, along with distant observations from Aristotle. These differing views convergedin their emphasis on six distinct aspects of what it means to be fully functioning and well.
telling us what is to follow...
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he fifth topic attends to how entrepreneurs impact theeudaimonic well-being of others (employees, families, communities). T
!!
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Eudaimonicformulations, in contrast, emphasize multiple facets of well-being such as purposeful engagement, realization of personal potential,autonomy, mastery, quality ties to others, and self-acceptance.
Completely different focus! Well, not "completely" distinct, but shifting focus away from happiness that comes from achieving things to happiness from achieving purpose ...
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Hedonic formulations emphasizepositive life evaluations, such as life satisfaction and positive feeling states, such as happiness and positive affect
hedonism - often associated with the pursuit of pleasure.
This article doesn't focus on it a lot (since it emphasizes the other main aspect of well-being), but I'd like to just highlight the connection between hedonism and happiness a little bit here by emphasizing the concept of the "hedonic treadmill".
The hedonic treadmill is a metaphor for the human tendency to pursue one pleasure after another. That's because the surge of happiness that's felt after a positive event is likely to return to a steady personal baseline over time.
So, it looks like this:
This is why I was so interested in the discussion we had at the end of the last class (which we'll continue this week) about money and happiness. Mo money, mo problems. We desire more riches, but we're never satisfied ...
Which is one of the reasons we need to look beyond hedonic well-being and explore eudaimonic well-being!
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ive key venues for theentrepreneurial field are then considered: (1) entrepreneurship and autonomy, viewed both as amotive (self-determination theory) and as an aspect of well-being (eudaimonic well-beingtheory); (2) varieties of entrepreneurship (opportunity versus necessity) and eudaimonic well-being; (3) eudaimonia in the entrepreneurial journey (beginning, middle, end); (4) en-trepreneurship, well-being and health; and (5) entrepreneurs and the eudaimonia of others –contrasting virtuous and vicious types.
so, this is going to cover a lot of ground!
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urposeful striving and personal growth are demanding, if not stressfulapproaches to living that may not always be conducive to feelings of happiness and contentment.
as we know, trying to find our purpose or constantly "develop"/optimize/life-hack/actualize/etc, isn't always a recipe for happiness (or even "success")
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Approaches to well-being tend to be partitioned into hedonic and eudaimonicformulations.
ok - we were already introduced to this distinction in the last article - we're going to get into it more here!
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Most entrepreneurial studies have focused on hedonic indicators (life satisfaction,happiness, positive affect).
ok - so we're not going to do that here...
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Researchers in entrepreneurial studies are increasingly interested in the psychological well-beingof entrepreneurs.
ok - we are familiar with this rhetorical contextextualizing... (it's the last half of our whole course)
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e “dark side”of prosocial moti-vation, which may be good for society, but bad for the well-being of the entrepreneur. Im
oof
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orking from a holistic conception of human flourishing that includes social aswell as economic benefits, they distilled three overarching virtues of the excellent/virtuous entrepreneur. These include creativity,beneficence, and integrity.
!
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he well-being literature, new findingslinking subjectively reported hedonia and eudaimonia to objectively measured biomarkers (Bo
huh
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A first observation is that well-being in extant studies is studied primarily as anoutcome (consequent) of the business venture,
curious - given the next statement...
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Entrepreneurial activity, by definition, is self-initiated and hence is fundamentally tied to ideas of autonomy and independence.
makes sense - entrepreneurs value independent thinking...
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Fig. 1. Key dimensions of well-being and underlying theo
a fabulously evocative image.
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at it means to be mentally healthy,psychosocially developed, purposefully engaged, self-actualized, fully functioning, and mature. No
background...
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e vicious entrepreneur is also considered. B
love it -- one can't ignore self-interest!
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ey distinction is made between ofautonomy postulated as a core need or motive i
interesting...
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key aspects of eudaimonic well-being (e.g., realization of personal potential, purposeful life en-gagement, effective management of complex environments) have received little attention eventhough they may be particularly relevant to entrepreneurial pursuits.
narrowing the focus...
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The third venue focuses the unfolding of the entrepreneurial process in time –how it progresses from early stages to longer-term enterprises, at least for some.
ok
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e fourth venue calls for greater research on thehealth, broadly defined, of entrepreneurs via their experiences of well-being.
!
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tuous entrepreneurship. H
aha - morality again (but distinct from that of social entrepreneurs) ...
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The central objective of this essay is to examine the relevance ofeudaimonic well-being for understanding entrepreneurial experience. T
let's take the road less travelled!
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doc-10-1g-prod-01-apps-viewer.googleusercontent.com doc-10-1g-prod-01-apps-viewer.googleusercontent.com
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probability
in certain contexts we can expect behavior but can never count on it in all instances
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a variety of causal chains
follow many different "causal chains" to reach conclusions as opposed to one single cause and affect
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his recognition of the extreme difficulties in making entirely ex-haustive causal imputations.
probability of human behavior doesn't come from notions of free will as much as it comes from the variety of situations and possibilities that can't always be accounted for in strict categories
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Weber argued, for example, that human action was truly unpredict-able only in the case of the insane,
maybe Durkheim would differ
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www.derstandard.at www.derstandard.at
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www.csfd.cz www.csfd.cz
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Drátěnou košili v pračce nevypereš, aneb současná doba si nedokáže vážit statečných rytířů.Stačilo se jen omylem napít lektvaru namíchaného nepřátelským kouzelníkem a rázem se rytíř Godefroy a jeho sluha Jacquouille (již podle tohoto jména poznají Francouzi, že se jedná o zcela neurozeného člověka) ocitli ve 20. století. Samozřejmě, jak už to ve Francii bývá, našli své potomky, i když zrovna ne na takové úrovni, jakou by si představovali. Šlechta, potomci statečných rytířů, zchudla a v jejím zámku se naopak usídlil potomek vykutálených sluhů, který si jen změnil jméno z posměšného Jacquouille na důstojnějšího Jacquarta. Samozřejmě, že se pán i jeho sluha nejdříve ocitnou v blázinci, ale šlechtická krev se nezapře a Beatrice, jako přímý potomek rytíře Godefroy de Montmirail, se o svého předka postará... Režiséra Jean-Marie Poirého známe především díky jeho vynikající komedii Operace Corned Beef, kde se také objevila trojice komiků, kteří ve Francii patří ke špičce v tomto žánru: Jean Reno, Christian Clavier a herečka s neobyčejným komediálním talentem Valérie Lemercier. V Návštěvnících si je navíc užijeme v dvojrolích předků a potomků.
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Tenhle oceněný animovaný film vypráví o dobrodružství, mladé lásce a vzpomínkách z dětství. Paříží se zatím pohybuje ruka oddělená od těla a hledá svého majitele.
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16letý Yuuta je zatížen monstrózním prokletím. Jeho situace přitahuje pozornost kouzelníka Goja Satoru. Ten v Yuutovi vidí obrovský potenciál a doufá, že mu pomůže přeměnit jeho smrtící břemeno v prospěšnou sílu. Ovšem Yuuta upoutal i pozornost kouzelníka Geta Suguru, jenž v jeho síle vidí možnost genocidy.
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Báje o princezně Kaguje představuje jednu z nejzásadnějších literárních klasik japonské kultury. Pojednává o nebeské princezně, kterou v podobě maličké holčičky najde starý sběrač bambusu uvnitř zářícího stonku. Spolu se svou ženou ji vychová jako vlastní dceru. Rychle rostoucí dívka dospěje do krásy, ale z bezstarostných radostí dětství ji vytrhne otcova ambice zajistit jí dokonalý život a udělat z ní dvorní dámu. Její srdce, spoutané povinnostmi a snahou dostát očekáváním, ale touží po něčem zcela jiném. Spoluzakladatel studia Ghibli Isao Takahata vytvořil srdcebolnou oslavu nádhery i stesku života.
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www.csfd.cz www.csfd.cz
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Film sleduje cestu hlavní postavy Bilbo Pytlíka, který se ocitne na dobrodružné výpravě. Cílem cesty je si znovu nárokovat ztracené trpasličí království Erebor. Bilba nečekaně osloví čaroděj Gandalf Šedý, díky kterému se ocitne ve společnosti třinácti trpaslíků v čele s legendárním bojovníkem Thorinem. Cesta do divočiny vede přes tajemné země, kde se to hemží zlobry, skřety a kouzelníky. Ačkoliv cíl jejich výpravy - Osamělá hora, leží na Východě, musí projít nejdříve jeskynním systémem, kde Bilbo potká někoho, kdo mu navždy změní život…Gluma. Skromný Bilbo Pytlík pak sám s Glumem na břehu podzemního jezera objeví nejen hloubku lstivosti a odvahy, která překvapí i jeho samotného, ale také získá do svého vlastnictví Glumův prsten „miláška“, který má nečekané a užitečné možnosti... Jednoduchý zlatý prsten je spojen s osudem celé Středozemě takovým způsobem, jaký Bilbo nemůže zatím ani tušit. (oficiální text distributora)
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Již od pradávných časů si lidé vypráví legendy o strašlivých démonech, kteří se ukrývají v lesích a v noci napadají lidská obydlí, zabíjejí jejich obyvatele a živí se jejich krví a masem. Démoni běžné lidi děsí, protože běžné rány se démonovi hned zacelí a jsou schopni nechat si v mžiku narůst třeba i useknutou končetinu. V těchto legendách se však objevují i zabijáci démonů - zkušení válečníci, kteří znají způsoby, jak démony efektivně zabít. Pro mladého chlapce jménem Tanjirou se tyto legendy velice brzy stanou trpkou skutečností...Již od smrti svého otce se mladý Tanjirou zaměřil vší silou na pomoc své početné rodině. Přestože jejich životy byly poznamenány touto tragédií, společně dokázali najít Tanjirou a jeho rodina trochu toho štěstí. Tento klidný domov je však roztříštěn jednoho dne, když Tanjirou najde většinu své rodiny povražděnou a jediná, kdo přežila, jeho sestra Nezuko, je proměněná v démona. Je však s podivem, že Nezuko i přes svůj stav stále projevuje známky příčetnosti a lidských emocí...Díky těmto událostem a jednomu nečekanému setkání si Tanjiro stanovil velmi těžký cíl - stát se zabijákem démonů a zjistit od nich, jak přeměnit svoji sestru zpět na člověka.
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kumu.brocku.ca kumu.brocku.ca
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meaning was not just about satisfy-ing human appetites, but about doing virtuous things such that we “achieve thebest that is within us”
certainly linked to Csikszentmihalyi's view on happiness!
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Stretching entrepreneurs’skills and abilities through flow experiences enhance their resilience andtenacity
ooh! I really like this link to the previous week on perseverance and grit...
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In addition to creat-ing a life in which they are happy and feel successful, it appears that it isimportant for them to find work that is also meaningful and purposeful whichfulfills their inner life.
meaningful and purposeful work can also help constitute a happy and successful life (!)
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rincipal axis factors(PAF) analysis
unless you're into stats and quantitative measurement, you can skip over these details ... but the social significance rather than the statistical significance of their findings is still trenchant!
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Entrepreneurs need internal psycho-logical resources such as intrinsic definition of success and a spiritual practiceto weather the myriad of external storms
like the lingo!
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rom this eudaimonicperspective, people are looking for what makes life fulfilling and meaningful.
all right -- leading us into the next article!
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The fact that the business provides a source of flow experiences isimportant for entrepreneurs’well-being. Flow is a central construct withinpositive psychology that entrepreneurs can borrow and use to their advantage.
generally accepted as entrepreneurs are assumed to get more meaning and purpose from their work than folk who work for someone/thing else other than themselves...
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ubjective well-being was significantlyand positively linked to intrinsic definitions of success while the more extrin-sic/material-driven definitions of success were significantly but negativelylinked to subjective well-being.
yep
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intrinsic and extrinsic definitions of success such as: money,social recognition, financial security, power, buying power, engagement, doingwhat they love to do, meaning in my life, and purpose in my life
9 factors to measure what matters ...
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entrepreneurs who based their definition ofsuccess on intrinsic factors did experience more well-being than entrepreneurswho based their definition of success on extrinsic-driven factors. In fact, theirwell-being was reduced or declined as their extrinsically driven factorsincreased.
double yep
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hepopular media can often portray entrepreneurs to be motivated by more extrin-sic factors such as money or power. However, recent research has found thatentrepreneurs who find meaning in their work are often intrinsically motivated
interesting
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Entrepreneurs who work in productive organizations,who get intrinsic spiritual fulfillment from having a job that gives meaning andpurpose to their life, and those who experience flow have a greater sense ofwell-being. Entrepreneurs who have these same factors but define their measureof success in terms of extrinsic factors such as making money and achievingsocial recognition for their achievements exhibited less well-being
operationalizing flow, or success, or productivity is difficult enough -- but operationalizing subjective well-being ... sheesh! I think, for our purposes, it's best to interrogate all of these things and not pinpoint them or measure them but assess how they function within a mix of variables to try and reflect on our own intersection with these concepts. We're not trying to "hack" happiness here, but a bit more accurately map its coordinates so that we can find ourselves there when our internal GPS might be going a little funky...
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Subjective well-being questions were asked using the Satisfaction with LifeScale
- check it out in the quiz section this week...
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he original nineflow factors: challenge-skill balance, action-awareness merging, clear goals,unambiguous feedback, concentration, sense of control, loss of self-conscious-ness, time transformation, and autotelic experience
ok! -- there are a number of different tests to capture your capacity for "flow" states...
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“In my business everyone gives his/her best efforts”; “In my business workquality is a high priority for all workers”; “I am able to apply my full capabil-ity in my business”, and “My business is very efficient in getting maximumoutput from the resources we have available (e.g. money, people, equipment,etc.)”
wow! When listed in this way, it seems as though most workplaces or types of work might not encourage group productivity. How many of these apply to your work?
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The ability for finding meaning at work has been found to be a dominantfactor in the conceptualization and measure of intrinsic success and spiritualityresearch
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ntrepreneurshipmotivation appears to link to the basis of rewards, which are either driven byextrinsic measures of success (money, social recognition, financial security,power, or buying power) or on intrinsic measures (such as personal fulfillment,doing something I love, finding meaning and purpose in their lives).
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Entrepreneurs who have an elevated intrinsic definition of success will havegreater subjective well-being than those with elevated extrinsic definition ofsuccess
so, meaning matters more than money when it comes to motivation...
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ersonal causesand callings are examples of intrinsic or meaningful objectives. The respon-dents’definition of success included making a difference, creating lastingimpact, and being engaged in a life of personal fulfillment
making a difference (for others...) or making a difference for oneself (being personally fulfilled)...
summing up perceptions of success
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“spiritual goals that energize
ooh - a link to next week...
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ntrepreneurs whoare doing work they love and who see their work as giving meaning and pur-pose to their lives, and helping others, were more likely to experience personalgrowth and joy
makes sense!
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The job of leadership today is not just to make money, it’s to make meaning
not as far as the marketplace is concerned...
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“entrepreneurs who practice religious andspiritual values regularly see a significant influence on their happiness, health,joy, productivity, and coping skills”
meaning matters, wherever you find it...
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r when they have sufficientresources in their work such as support from colleagues and adequate funds ormaterial
ok...
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employees have been found to experience flow when job demands match theirskills
ok
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wealth, fame, and power were notthe goals or accomplishments that respondents felt were important for success.Money and recognition were only byproducts of work; they are incidental“outcomes of passionately working often on an entirely different objective thatis often a personal cause or calling”
profits and power are important, but are byproducts of passion (!)
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An individual’s well-being is considered a potential source of productivity.On the other hand, an individual’s personal life can be a source of reducedfunctioning.
hmmm
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Flow is interesting in a work context because findings indicate that themore individuals experience flow, the more they report control and greatersense of enjoyment in the activity
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Since uncertainty is central to the entrepreneurialenvironment, it is unclear if the well-being and flow linkage found in otherwork situations extends to entrepreneurial environments.
the testable proposition...
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orkers experienced moreflow at work than in leisure.
yowza!
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Descriptions of flow commonly include three elements: absorption orimmersion in an activity, enjoyment, and intrinsic motivation
ok!
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nce flow isachieved, the attributes are (1) intense focus on the activity at hand and (2)time is perceived to move differently, either more slowly or quickly. The per-son experiences (3) a sense of control and (4) a loss of self-consciousness.There is (5) a merging of action and awareness, that is, the next move is evi-dent. Flow is experienced when (6) challenges and skills are balanced and theperceived challenges of the activity are at or very slightly above the person’sskill level. Usually (7) the experience is rewarding
can you relate this to your own experiences?
remember what I said in my note about happiness and flow in the seminar prompt in week 7 (creative/cultural entrepreneurs)
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real happiness lay in the prospect of finding work thatprovided close social relationships, meaning and purpose, pursuit of personalgoals, and being involved in flow activities
sounds sensible enough (even if slightly utopian, moreso than ever in situations of precocity and neoliberal capitalist accumulation)
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none of theseare assured in an entrepreneurial environment.
leading to the key insight...
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the processof creating art consumed his research subjects and compelled them to losetrack of time, forget to eat, and focus completely on the work. Artistsdescribed being consumed in the process as in the “flow”of it.
!!
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These same factors are related to the intrinsic motivators oftenemployed in entrepreneurial perspectives
ooh! a key answer for one of the questions I asked as a seminar prompt in week 7 (about the propensity for people to feel intrinsically motivated to act/achieve goals....)
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Since work is a major factor inpeople’s lives –it takes up as much as a half of an adult’s waking life –whatgoes on at work is a major factor in understanding what gives individuals asense of meaning and fulfillment
sad but true (and one of the reasons why entrepreneurial ventures are filled with such hope (because of all those times that one's mundane work life isn't...)
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happiness is associated with behaviors that create success, and thathappiness also precedes successful outcomes.
doesn't seem that controversial ... miserable people might be successful, but one doesn't expect it to be sustainable in the face of success (the misery...)
on the other hand, if you're happy (or satisfied), do you strive to achieve greater success?
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happiness precedes successful outcomes by creating positive affect, the charac-teristics of which include confidence, optimism, and self-efficacy; likability andpositive construals of others; sociability, activity, and energy; prosocial behavior;immunity, and physical well-being; effective coping with challenge and stress;and originality and flexibility. Positive affect, in turn, encourages activeinvolvement with the environment, and with the pursuit of goals
this is quite the list -- kind of like success breeds more success, the happier you are, the more spillover there is likely to be in other related fields of achievement.
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When focusing on psychological well-being, there are generally two perspec-tives: the hedonic/subjective well-being perspective and the eudaimonic/mean-ing perspective.
and we're going to focus on the latter... or at least the other reading does!
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Thereare three types of well-being: (1) physical well-being; (2) psychological well-being; and (3) relationship/social well-being
while entrepreneurial activities certainly relate to the well-being of one's physical body and one's relationships, we're going to focus on the psychological...
Feel free to ruminate on the others, though...
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the termeudaimonia, or a state of meaningfulness and fulfillment,
eudaemonia is quite distinct!
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ristotlebelieved that meaning was not about satisfying human appetites, but aboutdoing virtuous things such that we “achieve the best that is within us
so, eudaemonia relates to self-improvement and self-actualization...
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Entrepreneurs who suffer a decline inwell-being may burn out and close their businesses.
D'uh
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Extrinsic fac-tors can include financial and social rewards, while intrinsic personal successis often researched using meaning, happiness, and spirituality within the workcontext.
this should resonate with one of the questions I asked you to answer before the first class...
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what makes life pleasant and unpleasant (Ryan and Deci2001). Research in this area looks at life satisfaction, positive affect, and nega-tive affect
hedonism is focused on the pursuit of pleasure. What feels good...
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Productivity, the second factor examined, can lead to well-being from anextrinsic perspective, since greater productivity would most likely lead togreater success of the organization
whereas flow connects with a sense of intrinsic well-being, productivity relates to extrinsic forces too
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Although many factors could lead to increased entrepre-neurial well-being, the present study examines how flow, productivity, andentrepreneurs’own definition of personal success (intrinsic vs. extrinsic)impacts the entrepreneur’s subjective well-being
focal points...
because there's a difference between being entrepreneurial and happy and being entrepreneurial to be happy (down the road...)
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Continued engagement is a predictorof entrepreneurial business
we're more likely to continue acting entrepreneurially if it satisfies us (if it gives us a sense of pleasure, or well-being) as a result of pursuing the dream, seeking and creating new opportunities... being bold and innovative and creative... (even though there are risks and great costs associated with these too)
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The third factor examined in this study is how an entrepreneur’s de finitionof personal success impacts their subjective well-being.
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The first factor considered in this study was flow, which describes a state ofcomplete attentional energy focused on the task at hand
already introduced 4 weeks ago...
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Yet the directionality is not clear. Are happy workers more productive, orare more productive workers happier?
where do you stand?
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Of interest in this paper are the psychological factors that contribute toentrepreneurs’well-being
focusing on one's sense of subjective well-being (otherwise known as happiness).
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an entrepreneur must attend to their own individual psy-chological factors of development, such as maintaining a strong sense of confi-dence, optimism, and self-efficacy to cope with uncertainty
link to week 8 (and Baron's article...)
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flow has been found to increase work engage-ment (Larson and von Eye 2006, Salanova et al. 2006), to lead to excellencein performance (Demerouti 2006, Bakker 2008), and to make life more inter-esting
adding to (all-around) well-being
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Entrepreneurs, like leaders in other organizations, seek organizational produc-tivity for their businesses to prosper.
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Narodený z obesenej ženy sa sirota Guts dostáva do výchovy žoldniera. Napriek neľahkému detstvu vyrastie z tohto dieťaťa silný mladík a veľmi schopný bojovník. Jeho sila mu dovoľuje používať aj masívny meč, ktorý presahuje dĺžku dospelého človeka.Pri jednom z mnohých vojnových ťažení spoznáva Cascu a charizmatického Griffitha, vodcu žoldnierskej Skupiny Jastraba a držiteľa záhadného prívesku - Behelit. Guts mu očividne padne do oka a stane sa jedným z nich. Medzi členmi družiny nájde skutočných priateľov a postupom času získa pozíciu ako Griffithova pravá ruka.Toto je iba jedna kapitola príbehu z rozsiahlej manga ságy od autora menom Kentaro Miura. Veľmi temný fantasy príbeh láka stále nových fanúšikov, pretože dej nie je ani po vyše dvadsiatich rokoch od jeho uvedenia v roku 1990 stále uzavretý. V roku 1997 sa Berserk dočkal aj svojho 25 dielneho anime prevedenia, ktoré slávilo tiež veľký úspech. Po približne ďalších pätnástich rokoch sa dostávame opäť k anime, ktoré bude ale na rozdiel od svojho seriálového predchodcu rozdelené do niekoľkých dlhších filmov. Prvý z radu filmov, ktoré majú pokryť dej celej manga predlohy, bude uvedený v roku 2012. Nesie názov Berserk Golden Age Arc I: Egg of the Supreme Ruler a ako jeden z troch filmov nám zachytí časť príbehu „zlatého obdobia“.
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Malá dívenka Hotaru se ztratí v lese, o němž se vypráví, že se v něm vyskytují zvláštní bytosti. Jedna taková bytost se před ní objeví a z lesa ji vyvede. Laskavý zachránce se jmenuje Gin a kromě masky na něm nic zvláštního není. Nebo vlastně je: dotkne-li se ho nějaký člověk, tak nadobro zmizí. I přes tento nedostatek se mezi Hotaru a Ginem vytvoří pouto, které časem sílí i bez fyzického kontaktu.
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www.csfd.cz www.csfd.cz
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Třpytivé vody Karibiku jsou pro mazaného kapitána Jacka Sparrowa nevyčerpatelným zdrojem tajemných a vzrušujících dobrodružství. Jeho idylický život se razantně změní ve chvíli, kdy se lstivý kapitán Barbossa zmocní jeho lodi Černá perla a napadne město Port Royal. Nelítostná bitva má jediný cíl: únos guvernérovy krásné dcery Elizabeth. Na její záchranu se vydává přítel z dětství Will Turner, ale sám na to nestačí. Proto se spojí s Jackem, který touží získat zpět svou loď. Nikdo z nich netuší, že prokletý poklad změnil jejich největší rivaly, lstivého kapitána Barbarossu a jeho posádku, v nesmrtelná stvoření. Kletbu může zlomit pouze vrácení pokladu na jeho původní místo a vše musí být zpečetěno Elizabethinou krví. Myslí si totiž, že je dcerou Willa Turnera - otce mladého Willa.
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Benjamin Button se narodil v New Orleans té noci, kdy skončila první světová válka. Rodiče místo radosti čeká šok. Zjistí, že jejich syn vypadá jako stařec. Matka umírá krátce po porodu a vystrašený otec ho položí na schodech starobince v černošské čtvrti, kde ho najde černá kuchařka Queenie a rozhodne se jej přijmout za svého. Lékaři mu nedávají moc dlouhé šance na život - jeho tělo je opotřebované, jako by opravdu žilo už osmdesát let. Zatímco všichni očekávají, že chlapec zemře, on celý život mládne. Časem se vydává do světa, aby zjistil, že nejlépe mu bylo doma. Po svém návratu se setkává se svou přítelkyní z dětství, z které je nádherná žena. Vznikne mezi nimi silné pouto podporované vzájemnými sympatiemi, které postupně přerůstá v hlubší cit. Jak ale jejich vztah vydrží, když Daisy je předurčeno stárnout a Benjaminovi mládnout?
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www.csfd.cz www.csfd.cz
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Edward Bloom (Albert Finney) byl odjakživa vášnivým vypravěčem neuvěřitelných historek ze svého mládí (Ewan McGregor), kdy jej jeho záliba v cestování zavedla na úžasnou výpravu okolo světa. V jeho mýtických dobrodružstvích nechybí obři, vlkodlaci, zpívající siamská dvojčata ani čarodějnice se skleněným okem, která dokáže nahlédnout do budoucnosti. Se svými fantastickými historkami se Bloomovi daří okouzlit každého kromě jeho syna Willa (Billy Crudup). Když pak Edward onemocní, jeho žena Sandra (Jessica Lange) se pokusí Willa přimět, aby ke svému otci znovu našel cestu. Will se musí pokusit oddělit pravdu od fikce a naučit se s heroickými činy i velkými prohrami svého otce žít. (oficiální text distributora)
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www.csfd.cz www.csfd.cz
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The Animatrix
Vítejte do světa Animatrixu, vizionářské fúze počítačové animace a japonské školy animace, od světově nejuznávanějších tvůrců animovanch filmů. Vychutnejte si snímek, který vznikl před filmem Matrix a dozvíte se o posledních městech lidské rasy, válce mezi stroji a lidmi a o závěrečném úpadku lidstva. Staňte se svědky posledního letu Osirise, který připravil půdu pro film Matrix Reloaded a videohru Enter The Matrix. Doplňte si své povědomí o Matrixu a získejte informace, které jinde nenajdete. Je čas zapojit se... (oficiální text distributora)
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pressbooks.pub pressbooks.pub
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Ask nothing of men
Ask only of yourself
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So use all that is called Fortune. Most men gamble with her, and gain all, and lose all
Is this because gambling is frowned upon from a religious perspective or is this because you can't rely on luck. (because it's not yourself lmao)
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As our Religion, our Education, our Art look abroad, so does our spirit of society. All men plume themselves on the improvement of society, and no man improves.
It's almost like he's telling you to spend so much time "looking within" that you forget to look around and you become closed off to the world. He's advocating exceptionalism if you think about it.
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And so the reliance on Property, including the reliance on governments which protect it, is the want of self-reliance.
According to Emerson The secret to a fulfilled life is to just do everything yourself no matter how daunting.
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kumu.brocku.ca kumu.brocku.ca
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successful entrepreneurship is not really just a story about intelligence inthe traditional sense but more fully a story about successful intelligence—the strategic mergerof analytical, creative, and practical intelligence. All three kinds of intelligence can bedeveloped and are developed through good use of experience.
**
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When entrepreneurs and others shape the environment, they are basically applyingsuccessful intelligence to idea generating
!!
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A major barrier is convincing people
rhetoric!
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In sum, successful entrepreneurship requires one to not only to come up with product andservice ideas but also to know what kind of product or service one has.
underwhelming...
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They may end up on used-carlots
that's quite the burn, for an academic article!
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People who are high in creative intelligence but not in the otherkinds may be good at coming up with ideas but often are not good either at knowingwhether their ideas are good ones (analytical intelligence) or at selling their ideas toothers (practical intelligence
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the tests of practical intelligence I mentioned above measure adaptive skills
ok
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Successful intelligence is applied in order to balance adapting to, selecting, and shapingenvironments. When one adapts to the environment, one changes oneself in order to fit intothe environment.
how do you demonstrate this?
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When oneselects an environment, one decides that adaptation is not worth it.
hmm...
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People who are high in analytical intelligence but not the other kinds often aregood memorizers and analyzers, but they need other people’s ideas to remember andanalyze. They make poor entrepreneurs, because entrepreneurs simply must be ideagenerators to succeed
interesting!
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This is the option in which entrepreneurs mustspecialize.
this gets into persuasion & rhetoric. In essence, also "selling" but not selling things, but ideas, selling people on your version of reality...
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people who are high in practical intelligencebut not in analytical or creative intelligence may be effective salespeople, but they willsell anything.
ouch!
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The third option is shaping
!
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The most important kind of intelligence for an entrepreneur, or really anyone else, issuccessful intelligence, which involves a balance of analytical (IQ-based), creative, andpractical intelligence
connecting the 3 types of intelligence...
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One needs the creative intelligence to come upwith new ideas, the analytical intelligence to evaluate whether the ideas are good ones,and the practical intelligence to figure out a way to sell these ideas to people who maynot want to hear about them
synergy! For success ...
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Significant correlations with job-related criteria
hmm
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What matters is not the amountof experience one has but how much one has learned from that experience
you probably have experience with this ...
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In sum, tests of practical intelligence are useful predictors of job-related skills, independ-ently of IQ-based tests.
underwhelming. This really drives home the fact that this article is good mostly as a shell -- kind-of boring and potentially difficult to see (at least in an immediate fashion) how it can relate in a real sense to students' lives (beyond the idea of multiple intelligences). Still, the lens is really useful for helping us focus on social competence and tacit knowledge (practical intelligence) for moving us forward... and considering what might be necessary in order to achieve success in a given field...
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one starts by interviewing successful people in agiven job and asking them for how they performed in the critical incidents that distinguishthose who are highly successful in a field from those who are not. We then try to extract thetacit knowledge underlying the successful actions.
the method...
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Route planning
* (who has an internal GPS? Who is lost without a smart phone?)
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Tacit knowledge for the workplace. Test-takers are presented with situations typical ofthose encountered in low-level jobs in workplace
classic job interview question...
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Trivial correlations with measures of personality and cognitive styles as well. Tests ofpractical intelligence also do not correlate with measures of personal attributes
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Trivial correlations with IQ-based measures.
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Tacit knowledge for sales
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Movies. Individuals are presented with brief fragments of movies showing people their ageconfronting everyday problem
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ome entrepreneurs leave conventional businesssettings because they are not interested in playing the game of figuring out what the tacitknowledge of the organizational environment is. They would rather play by their own rulesthan learn other people’s.
link to independent spirit and counterfactual knowledge...
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Practical mathematics
*
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Tacit knowledge for managers
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Practical everyday inference
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tacit knowledge is the knowledge that often is most important for success in theworkplace, but it is the knowledge that people must pick up on their own
yowza! School can't teach tacit knowledge!
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Of course, people who are high in practical intelligence may also be high in academicintelligence. The two are not necessarily negatively related
hah
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Tacit knowledge for school
so tacit knowledge isn't completely absent from school - it's just not testable in school ...
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there is actually a negative relation between academic and practical intelligence
interesting
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What matters for growth of practical intelligence is not experience but ratherlearning from experience.
(link to the growth mindset)
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Modifiability of practical intelligence. Practical intelligence can be developed. Indeed, itmust be developed. People are not born with the kinds of common sense they show in theireveryday lives
crucial insight
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tacit knowledge is what one needs to know in order to negotiate an environmenteffectively that typically is not directly taught and that often is not even verbalized
(link to cultural capital) (but also just sensitivity to one's environment and a contextual awareness...)
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IQ-based tests, like practical-intelligence tests, predict job success.Both kinds of tests seem to measure intellectual skills necessary for job success
analytical intelligence IS important to fulfill certain job criteria...
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The entrepreneurial children, like theentrepreneur in the forest, seemed to have a kind of intelligence not well measuredby conventional tests
Their "street math" was not replicated in the classroom... They exhibited "street smarts" (not book smarts)
Have you ever been in a situation where your book smarts failed you in the "real" world? Contrarily, how often has "street" knowledge helped you in school?
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intelligence is not asingle entity.
crucial insight - we have access to multiple intelligences!
Please note - this is definitely related to the "theory of multiple intelligences" (which was the basis for the reality TV series "Canada's Smartest Person"):
https://en.wikipedia.org/wiki/Theory_of_multiple_intelligences
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Clearly, more is involved in entrepreneurial success than just the academic side ofintelligence
Think about how often your ability to act in a "socially competent" manner came off as intelligent (a way of adapting to, shaping, and sometimes selecting your environment).
Knowing the right thing to say or how to act (cultural capital) comes off as "smart"
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There is obviously more to intelligence than what conventional tests of intelligence
the moral of the story
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Successful entrepreneurs appearto be higher in social competence than are unsuccessful ones. In particular, four factors seemto underlie this social competence: social perception (which involves accuracy in perceivingothers), (b) impression management (which involves techniques for inducing positivereactions in others), (c) persuasiveness (which involves the ability to change others’ viewsor behavior in desired directions), and (d) social adaptability (which involves feelingcomfortable in a wide range of situations). These variables, especially social perception,seem to be key to entrepreneurial success.
** remember these 4 factors of social competence! (they will be very helpful next week!)
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Successful entrepreneurship requires a blend of analytical, creative, and practical aspects ofintelligence, which, in combination, constitute successful intelligence.
ok - getting right to the heart of it. Introduces the key concepts and emphasizes its 3 parts.
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success is defined in terms of personal goals. People succeed byidentifying their strengths and capitalizing on them and by identifying their weaknesses andeither correcting or compensating for them. They do so by adapting to, shaping, and selectingenvironments.
clarifying "success"
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Perhaps you know the story of the college professor and the entrepreneur who arewalking in a forest.
funny story - the punchline is at the end of the next paragraph!
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sometimes they change themselves to fit the environment; other times,they change the environment to fit them; still other times, they find a different environment
what I was talking about at the end of last Thursday's class...
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Successful intelligenceis the ability to succeed in life, according to one’s own conception of success, within one’senvironmental context.
key concept, defined
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Creative intelligence is needed in order to think flexiblyand to be ahead of the pack rather than merely with it.
link to divergent thinking...
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here are eight basic kinds of new ideas, entrepreneurial orotherwise
**
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reative thinkers defy the crowd,seeing alternative ways of defining and solving problems that others often do not see
link to opportunity discovery/creation
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Creative intelligence is used to generate ideas that are novel, high in quality, andappropriate to the task one faces.
ok - definition by contextualization (and very similar to last week's material...)
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Tobe effective on the job, however, requires a third kind of skill beyond the analytical (IQ-based) and the practical.
completing the picture...
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People (such as my own son!)who wish to be entrepreneurs and form their own business may find school a distraction fromwhat interests and matters most to them.
...
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Practicalskills are necessary to apply these analytical tools correctly to the problems really facing oneon the job
but practical intelligence guides the application of intellectual intelligence...
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there is some kind of construct of practical intelligencethat is distinct from the kind of academic intelligence
yep
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successful intelligence, not just a subset ofits components (analytical, practical, and creative abilities), is needed for entrepreneurialsuccess
ok!
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www.youtube.com www.youtube.com
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rustworthy. I
VISUAL ANNOTATIONS
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(3:55) Code Carbon helps to provide a visual for the emissions produced in a certain time period. Much like the nutrition information on the outside of a cereal box, though it is helpful to know how many calories or grams of sugar are contained in one serving, that information would be useless without knowing what a serving size is. Even more so if we are unaware of how many calories we should consume in a given time frame. This information allows us to make informed decisions about what we should consume.
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(5:04) This visual of the photos that are generated when she inputs her own information provides a bit of shock factor to the audience. Not only are most of those images of someone who is not her, but they are quite illicit photos of someone who is not her. Taken out of context and unknown to be AI generated, photos such as these could be detrimental to someone's career or personal life.
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rustworthy. I
REACTION ANOTAION:
I never paused to consider that AI models are not contained within the digital world and exist boldly in our physical world. I figured that, since AI is so easily available on a cell phone, it couldn't possibly require so much to sustain it.
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Local file Local file
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This is a story we need to know. Industrial transformation turned out tobe a bubble of promise followed by lost livelihoods and damaged landscapes.And yet: such documents are not enough. If we end the story with decay, weabandon all hope—or turn our attention to other sites of promise and ruin,promise and ruin.
Important concept: details the cycle of extracting natural (and finite) resources.
Style elements: speaks directly to the reader, repeats important phrases.
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www.sciencespo.fr www.sciencespo.fr
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La grande hétérogénéité des preuves empiriques est apparente lorsque l'on observe les analyses plus récentes au niveau de l'entreprise, qui ne confirment pas que l'automatisation a un effet négatif sur l'emploi et les salaires globaux lorsque l'on tient compte d'une période d'adaptation (Lane et Saint-Martin, 2021). Toutefois, une grande partie de la recherche empirique reste axée sur la robotisation et l'automatisation, de sorte qu'il est encore nécessaire de procéder à une analyse plus spécifique de l'impact de l'IA générative sur les résultats en matière d'emploi.
Il est ici question des biais liés aux données collectées, aux biais des statistiques et du manque de neutralité de certaines études
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a réduction initiale de la demande de main-d'œuvre dans les domaines hautement automatisés pourrait potentiellement conduire à une résurgence des normes traditionnelles en matière de genre,
Référence à notre réflexion plus haut concernant les biais préexistants, avant l'IA et Nouvelles Technologies
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L'IA a également le potentiel d'accroître les barrières à l'entrée pour les nouvelles générations de main-d'œuvre en raison de l'inégalité d'accès à l'éducation
Un souci primordial à expliciter lorsqu'on parle de l'IA sur le marché du travail est celui de l'accéssiblité numérique, une accessiblité qui n'est pas encore étendue au monde entier et donc le sujet de l'IA dans le monde du travail ne concerne pour l'instant que les pays et les sociétés dit.e.s "développés" (pour la plupart en Occident) et donc opérer un shift majeur en faveur de technologies inacessibles pour beaucoup ne fera qu'alourdir le gap entre eux
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learn.cantrill.io learn.cantrill.io
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Welcome back and by now you should understand the difference between stateless and stateful security protection.
In this lesson I want to talk about one security feature of AWS VPCs and a little bit more depth and that's network access control lists known as knuckles.
Now we do have a lot to cover so let's jump in and get started.
A network access control list we thought of as a traditional firewall available within AWS VPCs so let's look at a visual example.
A subnet within an AWS VPC which has two EC2 instances A and B.
The first thing to understand and this is core to how knuckles work within AWS is that they are associated with subnets.
Every subnet has an associated network ACL and this filters data as it crosses the boundary of that subnet.
In practice this means any data coming into the subnet is affected and data leaving the subnet is affected.
But and this is super important to remember connections between things within that subnet such as between instance A and instance B in this example are not affected by network ACLs.
Each network ACL contains a number of rules, two sets of rules to be precise.
We have inbound rules and outbound rules.
Now inbound rules only affect data entering the subnet and outbound rules affect data leaving the subnet.
Remember from the previous lesson this isn't always matching directly to request and response.
A request can be either inbound or outbound as can a response.
These inbound and outbound rules are focused only on the direction of traffic not whether it's request or response.
In fact and I'll cover this very soon knuckles are stateless which means they don't know if traffic is request or response.
It's all about direction.
Now rules match the destination IP or IP range, destination port or port range together with the protocol and they can explicitly allow or explicitly deny traffic.
Remember this one network ACLs offer both explicit allows and explicit denies.
Now rules are processed in order.
First a network ACL determines if the inbound or outbound rules apply.
Then it starts from the lowest rule number.
It evaluates traffic against each individual rule until it finds a match.
Then that traffic is either allowed or denied based on that rule and then processing stops.
Now this is critical to understand because it means that if you have a deny rule and an allow rule which match the same traffic but if the deny rule comes first then the allow rule might never be processed.
Lastly there's a catch all showed by the asterisk in the rule number and this is an implicit deny.
If nothing else matches then traffic will be denied.
So those are the basics.
Next let's move on to some more complex elements of network ACLs.
Now I just mentioned that network ACLs are stateless and this means that rules are required for both the request and the response part of every communication.
You need individual rules for those so one inbound and one outbound.
Take this example a multi-tiered application running in a VPC.
We've got a web server in the middle and an application server on the left.
On the right we have a user Bob using a laptop and he's accessing the website.
So he makes a connection using HTTPS which is TCP port 443 and this is the request as you know by now and this is also going to mean that a response is required using the ephemeral port range.
This ephemeral port is chosen at random from the available range decided by the operating system on Bob's laptop.
Now to allow for this initial communication if we're using network ACLs then we'll need to have one associated with the web subnet and it will need rules in the inbound and outbound sections of that network ACL.
Notice how on the inbound rule set we have rule number 110 which allows connections from anywhere and this is signified by 0.0.0.0 through this network ACL and this is allowed as long as it's using TCP port 443.
So this is what allows the request from Bob into the web server.
We also have on the outbound rule set rule number 120 and this allows outbound traffic to anywhere again 0.0.0.0 as long as the protocol is TCP using the port range of 1.0.2.4 to 65.5.3.5 and this is the ephemeral port range which I mentioned in the previous lesson.
Now this is not amazingly secure but with stateless firewalls this is the only way.
Now we also have the implicit denies and this is denoted by the rules with the star in the rule number and this means that anything which doesn't match rule 110 or 120 is denied.
Now it's also worth mentioning while I do have rule 110 and 120 number differently the rule numbers are unique on inbound and outbound so we could have the single rule number 110 on both rule sets and that would be okay.
It's just easier to illustrate this if I use unique rule numbers for each of the different rule sets.
Now let's move on and increase the complexity little.
So we have the same architecture we have Bob on the right, the web subnet in the middle and the application subnet on the left.
You know now that because network ACLs are stateless each communication requires one request rule and one response rule.
This becomes more complex when you have a multi-tiered architecture which operates across multiple subnets and let's step through this to illustrate why.
Let's say the pop initiates a connection to the web server we know about this already because I just covered it.
If we have a network ACL around the web subnet we'll need an inbound rule on the web network ACL.
There's also going to be response traffic so this is going to use the ephemeral port range and this is going to need an outbound rule on that same web network ACL so this should make sense so far.
But also the web server might need to communicate with the app server using some application TCP port.
Now this is actually crossing two subnet boundaries the web at subnet boundary and the application subnet boundary so it's going to need an outbound rule on the web at subnet knuckle and also an inbound rule on the application subnet knuckle.
Then we have the response for that as well from the app server through to the web server and this is going to be using ephemeral ports but this also crosses two subnet boundaries it leaves the application subnet which will need an outbound rule on that knuckle and it enters the web subnet which will also need an inbound rule on that network ACL and what if each of those servers need software updates it will get even more complex really quickly.
You always have to be aware of these rule pairs the application port request and the ephemeral response for every single communication in some cases you're going to have multi-tier architecture and this might mean the communications go through different subnets.
If you need software updates this will need more if you use network address translation or NAT you might need more rules still.
You'll need to worry about this if you use network ACLs within a vpc for traffic to a vpc or traffic from a vpc or traffic between subnets inside that vpc.
When a vpc is created it's created with a default network ACL and this contains inbound and outbound rule sets which have the default implicit deny but also a capsule allow and this means that the net effect is that all traffic is allowed so the default within a vpc is that knuckles have no effect they aren't used this is designed [Music] I need to be beginner friendly and reduce admin overhead.
AWS prefer using security groups which I'll be covering soon.
If you create your own custom network ACLs though that's a different story.
Custom knuckles are created for a specific vpc and initially they're associated with no subnets.
They only have one rule on both the inbound and outbound rule sets which is the default deny and the result is that if you associate this custom network ACL with any subnets all traffic will be denied so be careful with this it's radically different behavior than the default network ACL created with a vpc.
Now this point I just want to cover some finishing key points which you need to be aware of for any real-world usage and when you're answering exam questions.
So network access controlists remember they're known as knuckles they are stateless so they view request and response as different things so you need to add rules both for the request and for the response.
A knuckle only affects data which is crossing the subnet boundary so communications between instances in the same subnet is not affected by a network ACL on that subnet.
Now this can mean that if you do have data crossing between subnets then you need to make sure that each knuckle on both of those subnets has the appropriate inbound and outbound rules so you end up with a situation where one connection can in theory need two rules on each knuckle if that connection is crossing two different subnet boundaries.
Now knuckles are able to explicitly allow traffic and explicitly deny and the deny is important because as you'll see when I talk about security groups this is a capability that you need to network ACLs.
So network ACLs allow you to block specific IPs or specific IP ranges which are associated with bad actors so they're a really good security feature when you need to block any traffic attempting to exploit your systems.
Now network ACLs are not aware of any logical resources they only allow you to use IPs and cyber ranges ports and protocols you cannot reference logical resources within AWS and knuckles can also not be assigned two logical resources they're only assigned to subnets within VPCs within AWS.
Now knuckles are very often used together with security groups such as mentioned to add the capability to explicitly deny bad IPs or bad networks so generally you would use security groups to allow traffic and you use knuckles to deny traffic and I'll talk about exactly how this works in the next lesson.
Now each subnet within a VPC has one knuckle associated with it it's either going to be the default network ACL for that VPC or a custom one which you create and associate.
A single knuckle though can be associated with many different subnets so while a subnet can only have one network ACL one network ACL can be associated with many different subnets.
Now this point that is everything that I wanted to cover about network ACLs for this lesson so go ahead complete the video and when you're ready I'll look forward to you joining me in the next lesson.
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openreview.net openreview.net
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nd optimization step extracts the point’s feature embed-ding. Memory networks also share some connections with our work, in particular, if we interpretthe neighborhood of a node as the memory, which is
此处提出了一个新方法
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www.biorxiv.org www.biorxiv.org
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eLife Assessment
This important study provides proof of principle that C. elegans models can be used to accelerate the discovery of candidate treatments for human Mendelian diseases by detailed high-throughput phenotyping of strains harboring mutations in orthologs of human disease genes. The data are compelling and support an approach that enables the potential rapid repurposing of FDA-approved drugs to treat rare diseases for which there are currently no effective treatments. The authors should provide a clearer explanation of how the statistical analyses were performed, as well as a link to a GitHub repository to clarify how figures and tables in the manuscript were generated from the phenotypic data.
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Reviewer #1 (Public review):
Summary:
As the scientific community identifies increasing numbers of genes and genetic variants that cause rare human diseases, a challenge in the field quickly identify pharmacological interventions to address known deficits. The authors point out that defining phenotypic outcomes required for drug screen assays is often a bottleneck, and emphasize how invertebrate models can be used for quick ID of compounds that may address genetic deficits. A major contribution of this work is to establish a framework for potential intervention drug screening based on quantitative imaging of morphology and mobility behavior, using methods that the authors show can define subtle phenotypes in a high proportion of disease gene knockout mutants. Overall, the work constitutes an elegant combination of previously developed high-volume imaging with highly detailed quantitative phenotyping (and some paring down to specific phenotypes) to establish proof of principle on how the combined applications can contribute to screens for compounds that may address specific genetic deficits, which can, in turn, suggest both mechanism and therapy.
In brief, the authors selected 25 genes for which loss of function is implicated in human neuro-muscular disease and engineered deletions in the corresponding C. elegans homologs. The authors then imaged morphological features and behaviors prior to, during, and after blue light stimuli, quantitating features, and clustering outcomes as they elegantly developed previously (PMID 35322206; 30171234; 30201839). In doing so, phenotypes in 23/25 tested mutants could be separated enough to distinguish WT from mutant and half of those with adequate robustness to permit high-throughput screens, an outcome that supports the utility of related general efforts to ID phenotypes in C. elegans disease orthologs. A detailed discussion of 4 ciliopathy gene defects, and NACLN-related channelopathy mutants reveals both expected and novel phenotypes, validating the basic approach to modeling vetted targets and underscoring that quantitative imaging approaches reiterate known biology.
The authors then screened a library of nearly 750 FDA-approved drugs for the capacity to shift the unc-80 NACLN channel-disrupted phenotype closer to the wild type. Top "mover" compounds shift outcome in the experimental outcome space; and also reveal how "side effects" can be evaluated to prioritize compounds that confer the fewest changes of other parameters away from the center.
Strengths:
Although the imaging and data analysis approaches have been reported and the screen is restricted in scope and intervention exposure, it is impressive, encouraging and important that the authors strongly combine tools to demonstrate how quantitative imaging phenotypes can be integrated with C. elegans genetics to accelerate the identification of potential modulators of disease (easily extendable to other goals). Generation of deletion alleles and documentation of their associated phenotypes (available in supplemental data) provide potentially useful reagents/data to the field. The capacity to identify "over-shooting" of compound applications with suggestions for scale back and to sort efficacious interventions to minimize other changes to behavioral and physical profiles is a strong contribution.
Weaknesses:
The work does not have major weaknesses, and in revision, the authors have expanded the discussion to potential utility and application in the field.
The authors have also taken into account minor modifications in writing.
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Reviewer #2 (Public review):
Summary and strengths:
O'Brien et al. present a compelling strategy to both understand rare disease that could have a neuronal focus and discover drugs for repurposing that can affect rare disease phenotypes. Using C. elegans, they optimize the Brown lab worm tracker and Tierpsy analysis platform to look at movement behaviors of 25 knockout strains. These gene knockouts were chosen based on a process to identify human orthologs that could underlie rare diseases. I found the manuscript interesting and a powerful approach to make genotype-phenotype connections using C. elegans. Given the rate that rare Mendelian diseases are found and candidate genes suggested, human geneticists need to consider orthologous approaches to understand the disease and seek treatments on a rapid time scale. This approach is one such way. Overall, I have a few minor suggestions and some specific edits.
Weaknesses:
(1) Throughout the text on figures, labels are nearly impossible to read. I had to zoom into the PDF to determine what the figure was showing. Please make text in all figures a minimum of 10 point font. Similarly, Figure 2D point type is impossible to read. Points should be larger in all figures. Gene names should be in italics in all figures, following C. elegans convention.
(2) I have a strong bias against the second point in Figure 1A. Sequencing of trios, cohorts, or individuals NEVER identifies causal genes in the disease. This technique proposes a candidate gene. Future experiments (oftentimes in model organisms) are required to make those connections to causality. Please edit this figure and parts of the text.
(3) How were the high-confidence orthologs filtered from 767 to 543 (lines 128-131)? Also, the choice of the final list of 25 genes is not well justified. Please expand more about how these choices were made.
(4) Figures 3 and 4, why show all 8289 features? It might be easier to understand and read if only the 256 Tierpsy features were plotted in the heat maps.
(5) The unc-80 mutant screen is clever. In the feature space, it is likely better to focus on the 256 less-redundant Tierpsy features instead of just a number of features. It is unclear to me how many of these features are correlated and not providing more information. In other words, the "worsening" of less-redundant features is far more of a concern than "worsening" of 1000 correlated features.Reviewer #2 (Public review):
Summary and strengths:
O'Brien et al. present a compelling strategy to both understand rare disease that could have a neuronal focus and discover drugs for repurposing that can affect rare disease phenotypes. Using C. elegans, they optimize the Brown lab worm tracker and Tierpsy analysis platform to look at movement behaviors of 25 knockout strains. These gene knockouts were chosen based on a process to identify human orthologs that could underlie rare diseases. I found the manuscript interesting and a powerful approach to make genotype-phenotype connections using C. elegans. Given the rate that rare Mendelian diseases are found and candidate genes suggested, human geneticists need to consider orthologous approaches to understand the disease and seek treatments on a rapid time scale. This approach is one such way. Overall, I have a few minor suggestions and some specific edits.
Weaknesses:
(1) Throughout the text on figures, labels are nearly impossible to read. I had to zoom into the PDF to determine what the figure was showing. Please make text in all figures a minimum of 10 point font. Similarly, Figure 2D point type is impossible to read. Points should be larger in all figures. Gene names should be in italics in all figures, following C. elegans convention.
(2) I have a strong bias against the second point in Figure 1A. Sequencing of trios, cohorts, or individuals NEVER identifies causal genes in the disease. This technique proposes a candidate gene. Future experiments (oftentimes in model organisms) are required to make those connections to causality. Please edit this figure and parts of the text.
(3) How were the high-confidence orthologs filtered from 767 to 543 (lines 128-131)? Also, the choice of the final list of 25 genes is not well justified. Please expand more about how these choices were made.
(4) Figures 3 and 4, why show all 8289 features? It might be easier to understand and read if only the 256 Tierpsy features were plotted in the heat maps.
(5) The unc-80 mutant screen is clever. In the feature space, it is likely better to focus on the 256 less-redundant Tierpsy features instead of just a number of features. It is unclear to me how many of these features are correlated and not providing more information. In other words, the "worsening" of less-redundant features is far more of a concern than "worsening" of 1000 correlated features.
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Reviewer #3 (Public review):
In this study, O'Brien et al. address the need for scalable and cost-effective approaches to finding lead compounds for the treatment of the growing number of Mendelian diseases. They used state-of-the-art phenotypic screening based on an established high-dimensional phenotypic analysis pipeline in the nematode C. elegans.
First, a panel of 25 C. elegans models was created by generating CRISPR/Cas9 knock-out lines for conserved human disease genes. These mutant strains underwent behavioral analysis using the group's published methodology. Clustering analysis revealed common features for genes likely operating in similar genetic pathways or biological functions. The study also presents results from a more focused examination of ciliopathy disease models.
Subsequently, the study focuses on the NALCN channel gene family, comparing the phenotypes of mutants of nca-1, unc-77, and unc-80. This initial characterization identifies three behavioral parameters that exhibit significant differences from the wild type and could serve as indicators for pharmacological modulation.
As a proof-of-concept, O'Brien et al. present a drug repurposing screen using an FDA-approved compound library, identifying two compounds capable of rescuing the behavioral phenotype in a model with UNC80 deficiency. The relatively short time and low cost associated with creating and phenotyping these strains suggest that high-throughput worm tracking could serve as a scalable approach for drug repurposing, addressing the multitude of Mendelian diseases. Interestingly, by measuring a wide range of behavioural parameters, this strategy also simultaneously reveals deleterious side effects of tested drugs that may confound the analysis.
Considering the wealth of data generated in this study regarding important human disease genes, it is regrettable that the data is not made accessible to researchers less versed in data analysis methods. This diminishes the study's utility. It would have a far greater impact if an accessible and user-friendly online interface were established to facilitate data querying and feature extraction for specific mutants. This would empower researchers to compare their findings with the extensive dataset created here.
Another technical limitation of the study is the use of single alleles. Large deletion alleles were generated by CRISPR/Cas9 gene editing. At first glance, this seems like a good idea because it limits the risk that background mutations, present in chemically-generated alleles, will affect behavioral parameters. However, these large deletions can also remove non-coding RNAs or other regulatory genetic elements, as found, for example, in introns. Therefore, it would be prudent to validate the behavioral effects by testing additional loss-of-function alleles produced through early stop codons or targeted deletion of key functional domains.
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Author response:
The following is the authors’ response to the original reviews.
Public Reviews:
Reviewer #1 (Public Review):
Summary:
As the scientific community identifies increasing numbers of genetic variants that cause rare human diseases, a challenge is how the field can most quickly identify pharmacological interventions to address known deficits. The authors point out that defining phenotypic outcomes required for drug screen assays is often challenging, and emphasize how invertebrate models can be used for quick ID of compounds that may address genetic deficits. A major contribution of this work is to establish a framework for potential intervention drug screening based on quantitative imaging of morphology and mobility behavior, using methods that the authors show can define subtle phenotypes in a high proportion of disease gene knockout mutants.
Overall, the work constitutes an elegant combination of previously developed high-volume imaging with highly detailed quantitative phenotyping (and some paring down to specific phenotypes) to establish proof of principle on how the combined applications can contribute to screens for compounds that may address specific genetic deficits, which can suggest both mechanism and therapy.
In brief, the authors selected 25 genes for which loss of function is implicated in human neuro-muscular disease and engineered deletions in the corresponding C. elegans homologs. The authors then imaged morphological features and behaviors prior to, during, and after blue light stimuli, quantitating features, and clustering outcomes as they elegantly developed previously (PMID 35322206; 30171234; 30201839). In doing so, phenotypes in 23/25 tested mutants could be separated enough to distinguish WT from mutant and half of those with adequate robustness to permit high-throughput screens, an outcome that supports the utility of general efforts to ID phenotypes in C. elegans disease orthologs using this approach. A detailed discussion of 4 ciliopathy gene defects, and NACLN-related channelopathy mutants reveals both expected and novel phenotypes, validating the basic approach to modeling vetted targets and underscoring that quantitative imaging approaches reiterate known biology. The authors then screened a library of nearly 750 FDA-approved drugs for the capacity to shift the unc-80 NACLN channel-disrupted phenotype closer to the wild type. Top "mover" compound move outcome in the experimental outcome space; and also reveal how "side effects" can be evaluated to prioritize compounds that confer the fewest changes of other parameters away from the center.
Strengths:
Although the imaging and data analysis approaches have been reported and the screen is limited in scope and intervention exposure, it is important that the authors strongly combine individual approach elements to demonstrate how quantitative imaging phenotypes can be integrated with C. elegans genetics to accelerate the identification of potential modulators of disease (easily extendable to other goals). Generation of deletion alleles and documentation of their associated phenotypes (available in supplemental data) provide potentially useful reagents/data to the field. The capacity to identify "over-shooting" of compound applications with suggestions for scale back and to sort efficacious interventions to minimize other changes to behavioral and physical profiles is a strong contribution.
Weaknesses:
The work does not have major weaknesses, although it may be possible to expand the discussion to increase utility in the field:
(1) Increased discussion of the challenges and limitations of the approach may enhance successful adaptation application in the field.
It is quite possible that morphological and behavioral phenotypes have nothing to do with disease mechanisms and rather reflect secondary outcomes, such that positive hits will address "off-target" consequences.
This is possible and can only be determined with human data. We now discuss the possibility in the discussion.
The deletion approach is adequately justified in the text, but the authors may make the point somewhere that screening target outcomes might be enhanced by the inclusion of engineered alleles that match the human disease condition. Their work on sod-1 alleles (PMID 35322206) might be noted in this discussion.
We agree and now mention this work in the discussion. We are currently working on a collection of strains with patient-specific mutations.
Drug testing here involved a strikingly brief exposure to a compound, which holds implications for how a given drug might engage in adult animals. The authors might comment more extensively on extended treatments that include earlier life or more extended targeting. The assumption is that administering different exposure periods and durations, but if the authors are aware as to whether there are challenges associated with more prolonged applications, larger scale etc. it would be useful to note them.
More prolonged applications are definitely possible. We chose short treatments for this screen to model the potential for changing neural phenotypes once developmental effects of the mutation have already occurred. We now briefly discuss this choice and the potential of longer treatments in the discussion.
(2) More justification of the shift to only a few target parameters for judging compound effectiveness.
- In the screen in Figure 4D and text around 313, 3 selected core features of the unc-80 mutant (fraction that blue-light pause, speed, and curvature) were used to avoid the high replicate requirements to identify subtle phenotypes. Although this strategy was successful as reported in Figure 5, the pared-down approach seems a bit at odds with the emphasis on the range of features that can be compared mutant/wt with the author's powerful image analysis. Adding details about the reduced statistical power upon multiple comparisons, with a concrete example calculated, might help interested scientists better assess how to apply this tool in experimental design.
To empirically test the effect of including more features on the subsequent screen, we have repeated the analysis using increasing numbers of features. In a new supplementary figure we find increasing the number of features reduces our power to detect rescue. At 256 features, we would not be able to detect any compounds that rescued the disease model phenotype.
(3) More development of the side-effect concept. The side effects analysis is interesting and potentially powerful. Prioritization of an intervention because of minimal perturbation of other phenotypes might be better documented and discussed a bit further; how reliably does the metric of low side effects correlate with drug effectiveness?
Ultimately this can only be determined with clinical trial data on multiple drugs, but there are currently no therapeutic options for UNC80 deficiency in humans. We have included some extra discussion of the side effect concept.
Reviewer #2 (Public Review):
Summary and strengths:
O'Brien et al. present a compelling strategy to both understand rare disease that could have a neuronal focus and discover drugs for repurposing that can affect rare disease phenotypes. Using C. elegans, they optimize the Brown lab worm tracker and Tierpsy analysis platform to look at the movement behaviors of 25 knockout strains. These gene knockouts were chosen based on a process to identify human orthologs that could underlie rare diseases. I found the manuscript interesting and a powerful approach to making genotype-phenotype connections using C. elegans. Given the rate at which rare Mendelian diseases are found and candidate genes suggested, human geneticists need to consider orthologous approaches to understand the disease and seek treatments on a rapid time scale. This approach is one such way. Overall, I have a few minor suggestions and some specific edits.
Weaknesses:
(1) Throughout the text on figures, labels are nearly impossible to read. I had to zoom into the PDF to determine what the figure was showing. Please make text in all figures a minimum of 10-point font. Similarly, the Figure 2D point type is impossible to read. Points should be larger in all figures. Gene names should be in italics in all figures, following C. elegans convention.
We have updated all figures with larger labels and, where necessary, split figures to allow for better readability. We’ve also corrected italicisation.
(2) I have a strong bias against the second point in Figure 1A. Sequencing of trios, cohorts, or individuals NEVER identifies causal genes in the disease. This technique proposes a candidate gene. Future experiments (oftentimes in model organisms) are required to make those connections to causality. Please edit this figure and parts of the text.
We have removed references to causation. We were thinking of cases where a known variant is found in a patient where causality has already been established rather than cases of new variant discovery.
(3) How were the high-confidence orthologs filtered from 767 to 543 (lines 128-131)? Also, the choice of the final list of 25 genes is not well justified. Please expand more about how these choices were made.
We now explain the extra keyword filtering step. For the final filtering step, we simply examined the list and chose 25. There is therefore little justification to provide and we acknowledge these cannot be seen as representative of the larger set according to well-defined rules. The choice was based on which genes we thought would be interesting using their descriptions or our prior knowledge (“subjective interestingness” in the main text).
(4) Figures 3 and 4, why show all 8289 features? It might be easier to understand and read if only the 256 Tierpsy features were plotted in the heat maps.
In this case, we included all features because they were all tested for differences between mutants and controls. By consistently using all features for each fingerprint we can be sure that the features that are different that we want to highlight in box plots can be referred to in the fingerprint.
(5) The unc-80 mutant screen is clever. In the feature space, it is likely better to focus on the 256 less-redundant Tierpsy features instead of just a number of features. It is unclear to me how many of these features are correlated and not providing more information. In other words, the "worsening" of less-redundant features is far more of a concern than the "worsening" of 1000 correlated features.
This is a good point. We’ve redone the analysis using the Tierpsy 256 feature set and included this as a supplementary figure. We find that the same trend exists when looking at this reduced feature set.
Reviewer #3 (Public Review):
In this study, O'Brien et al. address the need for scalable and cost-effective approaches to finding lead compounds for the treatment of the growing number of Mendelian diseases. They used state-of-the-art phenotypic screening based on an established high-dimensional phenotypic analysis pipeline in the nematode C. elegans.
First, a panel of 25 C. elegans models was created by generating CRISPR/Cas9 knock-out lines for conserved human disease genes. These mutant strains underwent behavioral analysis using the group's published methodology. Clustering analysis revealed common features for genes likely operating in similar genetic pathways or biological functions. The study also presents results from a more focused examination of ciliopathy disease models.
Subsequently, the study focuses on the NALCN channel gene family, comparing the phenotypes of mutants of nca-1, unc-77, and unc-80. This initial characterization identifies three behavioral parameters that exhibit significant differences from the wild type and could serve as indicators for pharmacological modulation.
As a proof-of-concept, O'Brien et al. present a drug repurposing screen using an FDA-approved compound library, identifying two compounds capable of rescuing the behavioral phenotype in a model with UNC80 deficiency. The relatively short time and low cost associated with creating and phenotyping these strains suggest that high-throughput worm tracking could serve as a scalable approach for drug repurposing, addressing the multitude of Mendelian diseases. Interestingly, by measuring a wide range of behavioural parameters, this strategy also simultaneously reveals deleterious side effects of tested drugs that may confound the analysis.
Considering the wealth of data generated in this study regarding important human disease genes, it is regrettable that the data is not actually made accessible. This diminishes the study's utility. It would have a far greater impact if an accessible and user-friendly online interface were established to facilitate data querying and feature extraction for specific mutants. This would empower researchers to compare their findings with the extensive dataset created here. Otherwise, one is left with a very limited set of exploitable data.
We have now made the feature data available on Zenodo (https://doi.org/10.5281/zenodo.12684118) as a matrix of feature summaries and individual skeleton timeseries data (the feature matrix makes it more straightforward to extract the data from particular mutants for reanalysis). We have also created a static html version of the heatmap in Figure 2 containing the entire behavioural feature set extracted by Tierpsy. This can be opened in a browser and zoomed for detailed inspection. Mousing over the heatmap shows the names of features at each position making it easier to arrive at intuitive conclusions like ‘strain A is slow’ or ‘strain B is more curved’.
Another technical limitation of the study is the use of single alleles. Large deletion alleles were generated by CRISPR/Cas9 gene editing. At first glance, this seems like a good idea because it limits the risk that background mutations, present in chemically-generated alleles, will affect behavioral parameters. However, these large deletions can also remove non-coding RNAs or other regulatory genetic elements, as found, for example, in introns. Therefore, it would be prudent to validate the behavioral effects by testing additional loss-of-function alleles produced through early stop codons or targeted deletion of key functional domains.
We have added a note in the main text on limitations of deletion alleles. We like the idea of making multiple alleles in future studies, especially in cases where a project is focussed on just one or a few genes.
Recommendations for the authors
Reviewer #1 (Recommendations For The Authors):
Note that none of the above suggestions or the one immediately below are considered mandatory.
One additional minor point: The dual implication of mevalonate perturbations for NACLM deficiencies is striking. At the same time, the mevalonate pathway is critical for embryo viability among other things, which prompts questions about how reproductive physiology is integrated in this screen approach. It appears that sterilization protocols are not used to prepare screen target animals, but it would be useful to know if there were a signature associated with drug-induced sterility that might help identify one potential common non-interesting outcome of compound treatments in general. In this work, the screen treatment is only 4 hours, which is probably too short to compromise reproduction, but as noted above, it is likely users would intend to expose test subjects for much longer than 4-hour periods.
This is an interesting point. In its current form our screen doesn’t assess reproductive physiology. This is something that we will consider in ongoing projects.
Figures
Figure 1D might be omitted or moved to supplement.
We have removed 1D and moved figure 1E as a standalone table (Table 1) to improve readability.
Figure 2D "key" is hard to make out size differences for prestim, bluelight, and poststim -more distinctive symbols should be used.
We have increased the size of the symbols so that the key is easier to read.
Line 412 unc-25 should be in italics
Corrected
Reviewer #2 (Recommendations For The Authors):
Specific edits:
All of the errors below have been corrected.
Line 47, "loss of function" should be hyphenated because it is a compound adjective that modifies mutations.
Line 50, "genetically-tractable" should not be hyphenated because it is not a compound adjective. It is an adverb-adjective pair. Line 102 has the same grammatical issue.
Line 85, "rare genetic diseases" do not "affect nervous system function". The disease might have deficits in this function, but the disease does not do anything to function.
Line 86, it should be mutations not mutants. Mutations are changes to DNA. Mutants are individuals with mutations.
Throughout, wild-type should be hyphenated when it is used as a compound adjective.
Figure 4, asterisks is spelled incorrectly.
Reviewer #3 (Recommendations For The Authors):
- As stated in the public review, the utility of the study is limited by the lack of access to the complete dataset. The wealth of data produced by the study is one of its major outputs.
We have made the data publicly available on Zenodo. We appreciate the request.
- Describe the exact break-points of the different alleles, because it was not readily feasible to derive them from the gene fact sheets provided in the supplementary materials.
We have now provided the start position and total length of deletion for each gene in the gene fact sheets.
- Figure 1C: what does "Genetic homology"/"sequence identity" refer to? How were these values calculated?
UNC-49 is clearly not 95% identical to vertebrate GABAR subunits at the protein level.
We have changed the axis label to “BLAST % Sequence Identity” to clarify that these values are calculated from BLAST sequence alignments on WormBase and the Alliance Genom Resources webpages.
- Figure 1E : The data presented in Figure 1E appears somewhat unreliable. For example, a cursory check showed:
(1) Wrong human ortholog: unc-49 is a Gaba receptor, not a Glycine receptor as indicated in the second column.
(2) Wrong disease association: dys-1 is not associated with Bardet-Biedl syndrome; overall the data indicated in the table does not seem to fully match the HPO database.
(3) Inconsistent disease association: why don't the avr-14 and glc-2 (and even unc-49) profiles overlap/coincide given that they present overlapping sets of human orthologs.
Thank you for catching this! We have corrected gene names which were mistakenly pasted. We have also made this a standalone table (Table 1) for improved readability.
- Error in legend to figure 4I : "with ciliopathies and N2" > ciliopathies should be "NALCN disease".
- Error at line 301: "Figures 2E-H" should be "Figures 4E-H".
Corrected.
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