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hi everyone i'm a third year phd student

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in earth sciences at the university of

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cambridge

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i'm really looking forward to appgradcon

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the lineup seems extremely diverse

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which is perfect given that the whole

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point of my talk is to argue in favor of

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interdisciplinary science

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specifically the key questions i'm

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asking today are

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how can we describe and integrate the

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complexity of naturally occurring

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geochemical environments into probiotic

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chemistry and can

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doing this help us to quantify prebiotic

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plausibility

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prebiotic chemistry as a field is

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largely concerned with discovering

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synthesis

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of those molecules that could have given

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rise to life for example

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holy grails in the field including

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nucleic acids lipid membranes and

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proteins which i'm sure you're all aware

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i would summarize probiotic chemists as

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building and testing probiotic pathways

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a series of steps reactions usually

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needed to synthesize a given molecule or

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set of molecules

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over time these lab assembled pathways

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have become more complex

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at first we had merely single step

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reactions then linear change of

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reactions

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and nowadays there are fully fledged

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systems of chemical reactions that lead

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to numerous desired products

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a plausible probiotic system must make

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use of reagents which co-occurred

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in early earth environments

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but it's our knowledge of the early

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earth where many problems arise

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because prebiotic chemists are largely

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reliant upon geologists for these

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constraints

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yet we geologists have a pretty poor

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understanding of the early earth

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this isn't really our fault the first

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half the billion years simply have no

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rocks left for us to study

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we do think that there was an anoxic

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atmosphere with surface oceans

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and probably some land but we don't

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ultimately know how reducing the

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atmosphere would have been

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which is very important for many types

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of proposed prebiotic organic chemistry

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we don't know if there were continents

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we don't know what the surface

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temperature was and many other things

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within that global view we have more

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detailed picture of specific

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environments

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an environment being proposed to host a

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particular prebiotic system

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is called a scenario a testable union of

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chemical and geological ideas

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whilst we often talk pretty broadly

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about plausible environments on the

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early earth

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probiotic pathways for the origin of

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life will have had to contend with what

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was actually there

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specifically an environment is not just

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defined by its most interesting

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or useful characteristics for prebiotic

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chemistry it is in reality

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a hugely diverse and dynamic system

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which may pose many more challenges to

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the periodic system

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than any simplified lab analog so the

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challenge facing us is twofold

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how to incorporate environmental

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complexity into the lab and how to

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constrain earlier conditions

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sufficiently to properly evaluate

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prebiotic plausibility

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inter-interference chemistry this is our

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proposed term

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for describing the response of a

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probiotic system to interferences that

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are present in the proposed host

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environment

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defined by many species

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and variables external to what is

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strictly necessary to execute the

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probiotic pathway at hand

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these extra species among many other

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environmental parameters

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may get in the way or indeed assist with

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the desired reaction steps

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i.e destructively or constructively

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interfere with the pathway

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therefore by thinking about interference

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chemistry we can reformulate the entire

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problem in a way that calls upon both

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chemists and geologists

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to explore a wide reach of parameter

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space not only the best conditions for

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given synthesis

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at the paper at hand that is to say

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rather than asking if the chemicals used

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in our proposed probiotic pathway

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have occurred anywhere on early earth

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together we can ask

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if a proposed probiotic system would

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have survived anywhere on the early

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earth

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in order to demonstrate our approach we

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require a toy chemical scenario

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that is complex enough to illustrate

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both the utility

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and present some limitations of

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interference chemistry

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but it's simple enough to explore

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reasonably comprehensively

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here we explore interference chemistry

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for a simple series of reactions

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ribose and nucleobased formation ribose

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phosphorylation

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ribonucleotide formation and

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ribonucleotide polymerization to make

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rna

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our selected system of reactions is very

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close to the traditional retrosynthetic

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disconnection of rna

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in general search reaction pathways are

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not considered to be probiotically

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plausible at the present time

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we do not consider our minor variation

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on the traditional

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retrosynthetic disconnection of rna to

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be a novel or especially prematurely

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plausible approach

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however we do choose this example

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because the relevant environmental

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dependencies have already been widely

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explored

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which provides a perfect opportunity to

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illustrate how combining systems and

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interference chemistry

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may be able to formalize constraints on

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probiotic plausibility so step one

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you take some glycoaldehyde and

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glyceraldehyde and react them to form

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ribose during simultaneous heating and

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base catalysis

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in general ribose is highly unstable in

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aqueous solution

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this would be rather restrictive for any

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probiotic pathway requiring ribose

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and indeed the issue has plagued

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probiotic chemists for some time

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the presence of a borate ring moiety

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does improve resistance of ribose to

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nucleophilic attack significantly

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bore it can also encourage ribose

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selective forward reactions

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acting as a desirable constructive

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interference in the reaction scheme

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however boric acid only speciates mainly

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as borate in aqueous solution under

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highly alkaline conditions

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this requirement is compatible with the

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base catalysis we need to drive rivals

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formation itself

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via the reaction step we describe here

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however

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we already have some stringent

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requirements here on the environmental

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ph

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for this step we begin to have

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sufficiently quantitative constraints in

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place to begin formulating

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a model with experimental knowledge of

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the reaction constant k

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and some calculations we did to describe

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its dependence on water activity

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because the forward reaction and

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phosphorylation involves condensation

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we can plot the parameter space for

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expected equilibrium yield of ribose

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phosphate under varying conditions

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on the y-axis we have our yield of

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robust phosphate on the x-axis we have

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water activity

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map to a range of various environments

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if we lose water

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and maintain reactant concentrations we

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move along either the top or the bottom

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pink lane

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for the bottom condition which is micro

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molar initial ribose and phosphate

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if we residually concentrate those

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reactants as we lose water

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we will move more steeply along the

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central pink line

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if we account for the fact that the

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equilibrium constant itself

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actually depends on the activity of

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water to some extent then equilibrium

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ribose phosphate increases slightly more

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steeply

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that's the top pink line overall in

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order to obtain greater than one

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millimolar concentrations of ribose

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phosphate

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we are looking at some combination of

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reasonably high reactant concentrations

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and low water activity which has more

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environmental implications from nature

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various combinations of equilibrium

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reacting concentrations are also

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indicated on the right hand side

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next step in the constellation the

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reaction

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of nuclear base and ribose phosphate to

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form a nucleotide

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now in order to stop things becoming

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prohibitively complex at this stage

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we arbitrarily restricted sources of

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nuclear bases in this scenario to

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delivery by meteorites

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this imposition means we are

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environmentally restricted to shallow

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surface

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environments we followed on with our

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work from a model for this delivery

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mechanism

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formulated previously by piercetal in

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their 2017

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pns paper but we made a few so

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our results here show adenine

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concentration

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and pawn volume on the y-axis and time

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on the x-axis

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in plot a we have totally uv shielded

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scenarios for the evaporative

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concentration of adenine

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in a one meter radius pond solid lines

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have no outflow

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dashed lines have an estimated rate of

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outflow which will remove nuclear bases

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from the pond

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in plot b we have only partial uv

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shielding

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the orange line in plot b has only uv

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shielding in the white phase

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whereas the blue line shows uv shielding

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only in the dry phase

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we find that only uv shielded systems

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can accumulate useful concentrations of

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nuclear bases

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peaking during the final evaporation of

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the pond uv

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radiation in the white phase will

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destroy too many nuclear bases

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whereas uv irradiation in the dry phase

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will destroy all nuclear bases

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with respect to the glaciation reaction

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itself

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the reactant concentrations and water

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activity conditions required

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for reaction between nuclear base and

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ribosomal phosphate are similar to the

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previous phosphorylation step

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but less favorable however the

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experimental constraints on this step

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also indicate a requirement for acidic

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conditions from suarez merino towel in

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chemical communications this is not a

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terribly compatible

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environmental scenario with previous

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steps which required base catalysis

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this is the point i'll come back to near

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the end of the talk

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finally we have the polymerization of

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nucleic acids

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we use the experimentally informed

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parameterization of nucleic acid

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polymerization

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by mastital in their 2013 pnes paper

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to explore the effect of water activity

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on this process

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we assume that monomer monomer addition

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rates depend linearly

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on water activity we can only place an

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upper limit on polymerization efficiency

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because previous work used enzyme

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propagated polymerization

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we therefore have to assume that this

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would be similar to pre-activated

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nucleotide behavior which is certainly a

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big assumption

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either way given these assumptions the

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results place constraints on the

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concentration convergence profile

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of various rna polymer lengths as you

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can see

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it is a struggle to achieve long lengths

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under most environmentally plausible

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conditions

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using all this information we created a

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simple chemical network and solved for

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the equilibrium concentration of rna

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that we would expect at different

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imposed initial water activities

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the system is closed which means the

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forward reaction will produce water

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due to condensation reactions creating

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an inherent limit on the minimum water

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activity that could be achieved

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even if we adjust the plausible

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equilibrium constants to the most

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optimum values

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we cannot achieve very long terms of rna

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these are far too short to cook to code

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for any sorts of useful information

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implying the need for some sort of open

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system water loss without diffusing our

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other reactants

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to access longer strands

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okay so in my final few slides i will

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try to crystallize for you

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all of that information into a

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relatively simple outcome by running

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quickly through an overall interference

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chemistry analysis

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of this particular system we impose an

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initial restriction

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that all of our nuclear bases should

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come from meteoritic deposition

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which means we need to look at

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restricted basins with uv

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within saturation we universally need

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some way to access low water activity

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in order to drive all of those

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condensation reactions this can involve

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bulk wet dry cycles or local scale

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cycling in bubbles

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aerosols or protocol membranes etc

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the key is to be able to maintain

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reactants in one place and continuously

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exclude water

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fully closed systems will be incapable

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of producing useful results

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zooming in on these basins we have

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constraints from the ribose

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phosphorylation step

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for phosphorus rich borate rich ribose

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rich alkaline restricted basins

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the raw types that can host such

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environments are different depending on

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the atmospheric conditions

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specifically under low pco2 alkaline

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conditions will be possible in any given

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solar lake

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but under high pco2 we will need to

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drive alkaline conditions

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through serpentinizing hydrothermal

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systems glycosylation

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is only favored in acidic variants of

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these restricted basins

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which provides a disconnect in the ph of

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these environmental scenarios

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this is a fairly fundamental challenge

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00:11:50,710 --> 00:11:49,040
to the scenario from the perspective of

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interference chemistry

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because in an acidic scenario ribose

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accumulation and phosphorylation will be

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looking at the overall path analysis we

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00:12:01,990 --> 00:12:01,440
can see that our interference chemistry

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00:12:04,069 --> 00:12:02,000
approach

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helps to identify favorite scenarios as

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well as places

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where the scenario breaks down the most

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00:12:11,350 --> 00:12:09,600
ideal is alkaline closed basins

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linked to mechanisms of open system

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00:12:15,750 --> 00:12:13,920
water loss but overall there is no clear

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00:12:18,069 --> 00:12:15,760
prebiotically plausible scenario

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00:12:21,030 --> 00:12:18,079
because even this struggles when you

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00:12:22,629 --> 00:12:21,040
need acidic conditions for glycosylation

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00:12:24,069 --> 00:12:22,639
i started the talk by saying that was

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00:12:25,829 --> 00:12:24,079
our expected outcome

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00:12:27,269 --> 00:12:25,839
for the probiotic system not to be

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00:12:28,949 --> 00:12:27,279
plausible however

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00:12:30,629 --> 00:12:28,959
i hope i have convinced you that putting

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00:12:32,710 --> 00:12:30,639
the environmental interferences

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00:12:33,910 --> 00:12:32,720
responsible for rendering the system

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00:12:36,069 --> 00:12:33,920
implausible

401
00:12:38,150 --> 00:12:36,079
at the front and center is a helpful way

402
00:12:39,670 --> 00:12:38,160
to think about the challenges we face

403
00:12:40,870 --> 00:12:39,680
when i think the limitations that i

404
00:12:42,470 --> 00:12:40,880
faced in mapping out with the

405
00:12:43,990 --> 00:12:42,480
environmental parameter space

406
00:12:45,670 --> 00:12:44,000
for this very well-studied and simple

407
00:12:47,590 --> 00:12:45,680
system it seems clear to me

408
00:12:49,190 --> 00:12:47,600
that we need to pay closer attention to

409
00:12:50,470 --> 00:12:49,200
both probiotic systems

410
00:12:52,790 --> 00:12:50,480
and their response to interference

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00:12:55,269 --> 00:12:52,800
chemistry in the coming years

412
00:12:57,110 --> 00:12:55,279
many many more variables than i

413
00:12:58,629 --> 00:12:57,120
considered in this talk for sure

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00:13:00,310 --> 00:12:58,639
i'm happy to take questions in the time

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00:13:02,150 --> 00:13:00,320
i have left and i'm very responsive to

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email if anybody has any other