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@@ -114,13 +114,13 @@ Voltage-gated ion channels are vital in determining neuronal excitability, actio
 
 Although the effects of channelopathies on ion current kinetics are frequently assessed by transfection of heterologous expression systems without endogenous currents  \citep{Balestrini1044, Noebels2017, Dunlop2008} \textcolor{red}{(cite more stuff?)}, the effect of these changes in current biophysics on neuronal firing is important for understanding the pathophysiology of these disorders and for identification of potential therapeutic targets \textcolor{red}{(cite some stuff)}. Experimentally, the effects of channelopathies on neuronal firing can be assessed using primary neuronal cultures  \citep{Scalmani2006, Smith2018, Liu2019} \textcolor{red}{(cite more stuff?)} or \textit{in vitro} recordings from transgenic mouse lines \textcolor{red}{(cite some stuff)}.
 
-However, experimental resources are limited the effect of a given channelopathy on different neuronal types across the brain is often unclear and not feasible to experimentally obtain. This is especially true when large numbers of distinct mutations are present and personalized medicine approaches are desired.
+%However the effect of a given channelopathy on different neuronal types across the brain is often unclear and not feasible to experimentally obtain. This is especially true when large numbers of distinct mutations are present and personalized medicine approaches are desired.
 
 %Linking the effects of modified currents to neuronal firing is crucial for understanding the disease and finding possible treatments. There are many widely accepted approaches. Transfection of heterologous expression systems without endogenous currents reveals changes in ionic current kinetics \textcolor{red}{(cite some stuff)}. Simulations of these effects can predict their effect on neuronal firing \textcolor{red}{(cite some stuff)}. Or the influence on firing behaviour can be directly measured in transfected primary neuronal cultures \textcolor{red}{(cite some stuff)} or in brain slice recordings of mouse lines \textcolor{red}{(cite some stuff)}. 
 
 
-General understanding of the effects of changes in current properties on neuronal firing may help to fill the need to understand the impacts of ion channel mutations on neuronal firing. Different neuron types have different ion current compositions and therefore likely respond differently to changes in the properties of one current. For instance, altering relative current amplitudes can be dramatically alter the firing behaviour and dynamics of neurons \citep{rutecki_neuronal_1992, pospischil_minimal_2008,Kispersky2012, golowasch_failure_2002, barreiro_-current_2012, Noebels2017, Layer2021}, however other current parameters impact neuronal firing as well.  \textcolor{red}{\citet{Liu2019} reported that a mutation in \(\textrm{Na}_{\textrm{V}}\text{1.6}\) that drastically slowed the inactivation time constant for that channel led to large prolonged depolarization plateaus after an action potential.} Another example is the R1629H SCN1A mutation which increases interneuron but decreases pyramidal neuron excitability \citep{Hedrich14874}\textcolor{red}{(and the other paper?)}. 
-\textcolor{red}{The underlying dynamics of neuronal types may be different and thus may transition between firing states differently \textcolor{red}{(cite some bifurcation stuff?)}. This further increases the possible heterogeneity in firing responses to altered current properties.}
+%General understanding of the effects of changes in current properties on neuronal firing may help to fill the need to understand the impacts of ion channel mutations on neuronal firing. 
+However the effect of a given channelopathy on different neuronal types across the brain is often unclear and not feasible to experimentally obtain. Different neuron types have different ion current compositions \textcolor{red}{(cite Berens and Allan Institute)} and therefore likely respond differently to changes in the properties of one current. In the simplest case, the influence on the firing behaviour should correlate with the expression level of the affected gene \textcolor{red}{(cite Niko, other Papers)}. But if a\textcolor{red}{ kinetic parameter} is changed too much, it can have unforseen consequences. For instance, altering relative current amplitudes can dramatically influence the firing behaviour and dynamics of neurons \citep{rutecki_neuronal_1992, pospischil_minimal_2008,Kispersky2012, golowasch_failure_2002, barreiro_-current_2012, Noebels2017, Layer2021}, however other current parameters impact neuronal firing as well. In extreme cases, a mutation can have opposite effects on different neuron types. For example, the R1629H SCN1A mutation is associated which increased firing in interneurons, but decreases pyramidal neuron excitability \citep{Hedrich14874}\textcolor{red}{(and the other paper?)}. 
 
 %However, the effect on the firing behaviour of different neurons is often unclear \textcolor{red}{(and always incomplete)}. Generally, different neuron types have different ionic current compositions and therefore could react in different ways to changes in one ionic current. In the simpler cases, the respective firing behaviour should mostly correlate with expression level of the affected current and scale with it \textcolor{red}{(cite some stuff, cite NikoPaper)}. \textcolor{red}{If the change in gating kinetics is too strong, the firing behaviour can change qualitatively.} Altering the relative current amplitudes in neuronal models leads to dramtic changes in their firing behaviour and dynamics \citep{rutecki_neuronal_1992, pospischil_minimal_2008,Kispersky2012, golowasch_failure_2002, barreiro_-current_2012, Noebels2017}. \textcolor{red}{The same could happen for other parameters too. \citet{Liu2019} reported a drastically slowed inacitvaiton time constant for a mutation in \textcolor{red}{Na$_V$1.6}, which led to huge depolarization plateaus after an action potential, that lasted several 100 milliseconds.} The most drastic example known to us would be the R1629H mutation in \textcolor{red}{SCN2A}. This mutation increases the excitability of interneurons, but decreases it in pyramidal neurons \textcolor{red}{(cite Hedrich2014 and the other paper)}. \textcolor{red}{Some neuron types may be closer to certain transitions between firing states than other, making these observations even more unpredictable \textcolor{red}{(cite some bifurcation stuff?)}.}