small changes to text and references

gating_table.tex

@@ -22,7 +22,7 @@ RS pyramidal,		        & \(\textrm{I}_{\textrm{Na}}\) inactivation
     
 
     \end{tabular}}
-      \caption[Gating Properties]{ For comparability to typical electrophysiological data fitting reported and for ease of further gating curve manipulations, a sigmoid function (eqn.\ref{eqn:Boltz}) %Boltzmann \(x_\infty = {\left(\frac{1-a}{1+{exp[{\frac{V-V_{1/2}}{k}}]}} +a\right)^j}\) 
+      \caption[Gating Properties]{ For comparability to typical electrophysiological data fitting reported and for ease of further gating curve manipulations, a sigmoid function (Eqn.\ref{eqn:Boltz}) %Boltzmann \(x_\infty = {\left(\frac{1-a}{1+{exp[{\frac{V-V_{1/2}}{k}}]}} +a\right)^j}\) 
        with slope \(k\), voltage for half-maximal activation or inactivation (\(V_{1/2}\)), exponent \(j\), and persistent current \(0 \leq a \leq 1\) were fitted for the \citet{pospischil_minimal_2008} models where \(\alpha_x\) and \(\beta_x\) are used. Gating parameters for  \(\textrm{I}_{\textrm{K}_{\textrm{V}}\textrm{1.1}}\ \) are taken from \citet{ranjan_kinetic_2019} and fit to mean wild type parameters in \citet{lauxmann_therapeutic_2021}. Model gating parameters not listed are taken directly from source publication.}
     \label{tab:gating}
 \end{table}

manuscript.tex

@@ -163,13 +163,13 @@ Ion channels determine neuronal excitability and mutations that alter ion channe
 
 \notejb{LOF or LoF? GOF or GoF?} \notels{LOF and GoF!!! (I think it is usually all big letters, not 100\% sure though)}
 
-\section*{Introduction (750 Words Maximum  - Currently 592)} 
+\section*{Introduction (750 Words Maximum  - Currently 675)} 
 %\textit{The Introduction should briefly indicate the objectives of the study and provide enough background information to clarify why the study was undertaken and what hypotheses were tested.}
 
 Voltage-gated ion channels are vital in determining neuronal excitability, action potential generation and firing patterns \citep{bernard_channelopathies_2008, carbone_ion_2020}. In particular, the properties and combinations of ion channels and their resulting currents determine the firing properties of the neuron \citep{rutecki_neuronal_1992, pospischil_minimal_2008}. However, ion channel function can be disturbed, resulting in altered ionic current properties and altered neuronal firing behaviour \citep{carbone_ion_2020}. Ion channel mutations are a common cause of such channelopathies and are often associated with hereditary clinical disorders including ataxias, epilepsies, pain disorders, dyskinesias, intellectual disabilities, myotonias, and periodic paralyses among others  \citep{bernard_channelopathies_2008, carbone_ion_2020}.
 
 \notenk{Are there any obvious citations missing from the following section?}
-The effects of channelopathies on ionic current kinetics are frequently assessed by transfection of heterologous expression systems without endogenous currents  \citep{Balestrini1044, Noebels2017, Dunlop2008}, and are frequently classified as either a loss of function (LOF) or a gain of function (GOF) with respect to changes in the amount of ionic current \citep{Musto2020, Kullmann2002, Waxman2011, Kim2021}. \notenk{Do you think we need to discuss LOF and GOF more than this?} \notels{LOF and GOF are usually not explained in detail, I would think it's fine}  This classification can be used to make rough estimates of the effects on neuronal firing \textcolor{red}{(papers?\citep{Niday2018, Wei2017}?)}, which in turn is important for understanding the pathophysiology of these disorders and for identification of potential therapeutic targets \citep{Orsini2018, Yang2018}. Experimentally, the effects of channelopathies on neuronal firing can be assessed using primary neuronal cultures  \citep{Scalmani2006, Smith2018, Liu2019}  or \textit{in vitro} recordings from transgenic mouse lines \citep{Mantegazza2019, Xie2010,Lory2020, Habib2015,  Hedrich2019}.
+The effects of channelopathies on ionic current kinetics are frequently assessed by transfection of heterologous expression systems without endogenous currents  \citep{Balestrini1044, Noebels2017, Dunlop2008}, and are frequently classified as either a loss of function (LOF) or a gain of function (GOF) with respect to changes in the amount of ionic current \citep{Musto2020, Kullmann2002, Waxman2011, Kim2021}. \notenk{Do you think we need to discuss LOF and GOF more than this?} \notels{LOF and GOF are usually not explained in detail, I would think it's fine}  This classification can be used to make rough estimates of the effects on neuronal firing \textcolor{red}{(papers?\citep{Niday2018, Wei2017, Wolff2017}?)}, which in turn is important for understanding the pathophysiology of these disorders and for identification of potential therapeutic targets \citep{Orsini2018, Yang2018}. Genotype-phenotype relationships are complex and the understanding of the relationships between these is still evolving \citep{Wolff2017, johannesen_genotype-phenotype_2021}. Experimentally, the effects of channelopathies on neuronal firing can be assessed using primary neuronal cultures  \citep{Scalmani2006, Smith2018, Liu2019}  or \textit{in vitro} recordings from transgenic mouse lines \citep{Mantegazza2019, Xie2010,Lory2020, Habib2015,  Hedrich2019}.
 
 
 %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.
@@ -335,7 +335,7 @@ Mutations in \Kv are associated with episodic ataxia type~1 (EA1) and have been
 \end{figure}
 
 
-\section*{Discussion (3000 Words Maximum - Currently 2139)}
+\section*{Discussion (3000 Words Maximum - Currently 2145)}
 % \textit{The discussion section should include a brief statement of the principal findings, a discussion of the validity of the observations, a discussion of the findings in light of other published work dealing with the same or closely related subjects, and a statement of the possible significance of the work. Extensive discussion of the literature is discouraged.}\\
 Using a set of diverse conductance-based neuronal models, the effects of changes to properties of ionic currents and conductances on firing were determined to be heterogenous for the AUC of the steady state fI curve but more homogenous for rheobase. For a known channelopathy, episodic ataxia type~1 associated \Kv mutations, the effects on rheobase is consistent across model cell types, whereas the effect on AUC depends on cell type. Our results demonstrate that LoF and GoF on the biophysical level cannot be uniquely transfered to the level of neuronal firing.
 

ref.bib

@@ -1,4 +1,22 @@
  
+@Article{Wolff2017,
+  author   = {Wolff, Markus and Johannesen, Katrine M. and Hedrich, Ulrike B. S. and Masnada, Silvia and Rubboli, Guido and Gardella, Elena and Lesca, Gaetan and Ville, Dorothée and Milh, Mathieu and Villard, Laurent and Afenjar, Alexandra and Chantot-Bastaraud, Sandra and Mignot, Cyril and Lardennois, Caroline and Nava, Caroline and Schwarz, Niklas and Gérard, Marion and Perrin, Laurence and Doummar, Diane and Auvin, Stéphane and Miranda, Maria J. and Hempel, Maja and Brilstra, Eva and Knoers, Nine and Verbeek, Nienke and van Kempen, Marjan and Braun, Kees P. and Mancini, Grazia and Biskup, Saskia and Hörtnagel, Konstanze and Döcker, Miriam and Bast, Thomas and Loddenkemper, Tobias and Wong-Kisiel, Lily and Baumeister, Friedrich M. and Fazeli, Walid and Striano, Pasquale and Dilena, Robertino and Fontana, Elena and Zara, Federico and Kurlemann, Gerhard and Klepper, Joerg and Thoene, Jess G. and Arndt, Daniel H. and Deconinck, Nicolas and Schmitt-Mechelke, Thomas and Maier, Oliver and Muhle, Hiltrud and Wical, Beverly and Finetti, Claudio and Brückner, Reinhard and Pietz, Joachim and Golla, Günther and Jillella, Dinesh and Linnet, Karen M. and Charles, Perrine and Moog, Ute and Õiglane-Shlik, Eve and Mantovani, John F. and Park, Kristen and Deprez, Marie and Lederer, Damien and Mary, Sandrine and Scalais, Emmanuel and Selim, Laila and Van Coster, Rudy and Lagae, Lieven and Nikanorova, Marina and Hjalgrim, Helle and Korenke, G. Christoph and Trivisano, Marina and Specchio, Nicola and Ceulemans, Berten and Dorn, Thomas and Helbig, Katherine L. and Hardies, Katia and Stamberger, Hannah and de Jonghe, Peter and Weckhuysen, Sarah and Lemke, Johannes R. and Krägeloh-Mann, Ingeborg and Helbig, Ingo and Kluger, Gerhard and Lerche, Holger and Møller, Rikke S},
+  journal  = {Brain},
+  title    = {Genetic and phenotypic heterogeneity suggest therapeutic implications in {SCN2A}-related disorders},
+  year     = {2017},
+  issn     = {0006-8950},
+  month    = may,
+  number   = {5},
+  pages    = {1316--1336},
+  volume   = {140},
+  abstract = {Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (\<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatment regimen and the course of the epilepsy in 66 patients for which well-documented medical information was available. We find that the use of sodium channel blockers was often associated with clinically relevant seizure reduction or seizure freedom in children with early infantile epilepsies (\<3 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (≥3 months) and sometimes induced seizure worsening. Regarding the genetic findings, truncating mutations were exclusively seen in patients with late onset epilepsies and lack of response to sodium channel blockers. Functional characterization of four selected missense mutations using whole cell patch-clamping in tsA201 cells—together with data from the literature—suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function, characterized by slowing of fast inactivation, acceleration of its recovery or increased persistent sodium current. Further, a good response to sodium channel blockers clinically was found to be associated with a relatively small gain-of-function. In contrast, mutations in patients with late-onset forms and an insufficient response to sodium channel blockers were associated with loss-of-function effects, including a depolarizing shift of voltage-dependent activation or a hyperpolarizing shift of channel availability (steady-state inactivation). Our clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy.},
+  doi      = {10.1093/brain/awx054},
+  file     = {:wolff_genetic_2017 - Genetic and Phenotypic Heterogeneity Suggest Therapeutic Implications in SCN2A Related Disorders.pdf:PDF},
+  url      = {https://doi.org/10.1093/brain/awx054},
+  urldate  = {2022-05-17},
+}
+
+ 
 @Article{Wei2017,
   author     = {Wei, Feng and Yan, Li-Min and Su, Tao and He, Na and Lin, Zhi-Jian and Wang, Jie and Shi, Yi-Wu and Yi, Yong-Hong and Liao, Wei-Ping},
   journal    = {Neuroscience Bulletin},