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Commit d1a4b85a authored by Carlos GO's avatar Carlos GO
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......@@ -93,10 +93,14 @@
\begin{frame}
\frametitle{RNA}
\begin{itemize}
\item RNA can fulfill virtually all needs of life (information carrying, catalytic activity). All organisms have RNA.
\item Folds hierarchically from a sequence to a 2D scaffold, to a full 3D structure.
\end{itemize}
\begin{figure}[h!]
\centering
\includegraphics[width=0.6\textwidth]{struc.jpeg}
\caption{This is RNA. ~\cite{reinharz2016algorithmic}}
\includegraphics[width=0.5\textwidth]{struc.jpeg}~\cite{reinharz2016algorithmic}
\label{fig:rna}
\end{figure}
......@@ -138,7 +142,7 @@
\frametitle{{\bf Project I:} \maternal, How do complex structures evolve?}
\begin{itemize}
\item \problemtag How can energetically unfavorable structures appear?
\item \problemtag How can populations reach energetically unfavorable structures?
\item \ideatag Model the distribution of mutants.
\end{itemize}
......@@ -159,6 +163,13 @@
\begin{frame}
\frametitle{Sampling methods.}
\begin{itemize}
\item Model probability of $k$ mutant sequence-structure $(\omega, s)\in \mathbb{S}_{\omega_0}^k$ with Boltzmann distribution:
\begin{equation}
\mathbb{P}(\omega, s) = \frac{e^{\frac{-E(\omega, s)}{RT}}}{\mathcal Z},\qquad \mathcal Z = \sum_{(\omega', s')\in \mathbb{S}_{\omega_0}^k}e^{\frac{-E(\omega', s')}{RT}}.
\end{equation}
\end{itemize}
\begin{figure}
\includegraphics[width=\textwidth]{maternal.pdf}
\end{figure}
......@@ -180,7 +191,7 @@
\begin{itemize}
\item Thermodynamic ensembles could have shaped the discovery of complex structures.
\item More complex evolutionary explorations needed to explain full distribution.
\item Manuscript accepted at RNA journal. \cite{oliver2019necessary}
\item Manuscript accepted at RNA journal. \cite{oliver2017necessary}
\end{itemize}
\item Next Steps
\begin{itemize}
......@@ -233,7 +244,7 @@
\item The majority of RNA ligands are discovered through phenotypic screens and later attributed to RNA binding. (e.g. ribocil)
\item Computational approaches focus on direct docking.
\begin{itemize}
\item DOCK 6.0 (2015)
\item DOCK 6.0 (2015) \cite{lang2009dock}
\item Molecular Forecaster (2006) (Moitessier, \textcolor{red}{Collaborators})
\item LigandRNA (Bujnicki)
\end{itemize}
......@@ -269,6 +280,10 @@
\begin{frame}
\frametitle{Results}
\begin{itemize}
\item For each input pocket, how much does \rnamigos increase the probability of finding the true ligand?
\end{itemize}
\begin{figure}[htb!]
\begin{subfigure}{0.45\textwidth}
\includegraphics[width=\textwidth]{violins.pdf}
......@@ -289,6 +304,10 @@
\begin{frame}
\frametitle{Results}
\begin{itemize}
\item Using the 3D structure graph we can increase the probability of retrieving the true ligand.
\end{itemize}
\begin{figure}
\centering
\includegraphics[width=\textwidth]{tree_ligs.pdf}
......@@ -305,11 +324,12 @@
\item Conclusions
\begin{itemize}
\item Binding pocket graphs contain signal that can be exploited for RNA drug discovery.
\item Preparing for resubmission (Preprint ~\cite{oliver2019extended})
\end{itemize}
\item Next Steps
\begin{itemize}
\item \begin{quote} ... holds promise, and the method introduced did seem innovative. Without more detailed retrospective studies for ligand enrichment,..., and without prospective prediction and testing for new, non-trivial ligands, the manuscript will not command the attention of the broad audience that PNAS attracts. In its current form, the manuscript may be better suited to a more specialized journal, such as JCIM. \end{quote}
\item Validate signal with {\bf computational docking}.
\item Validate signal with {\bf computational docking} ~\cite{lang2009dock}.
\end{itemize}
\end{itemize}
......@@ -343,19 +363,19 @@
\frametitle{Related work}
\begin{itemize}
\item We want a motif finding tool that works on graphs and is inductive.
\item We want a fuzzy motif finding tool that works on graphs.
\end{itemize}
\begin{table}[]
\resizebox{\textwidth}{!}{%
\begin{tabular}{lllll}
\hline
& flexible motifs & all ss & graph-based & inductive \\ \hline
rna3dmotif & \xmark & \xmark & \cmark & \xmark \\ \hline
3d motif atlas & $\sim$ & \xmark & $\sim$ & \xmark \\ \hline
carnaval & \xmark & \xmark & \cmark & \xmark \\ \hline
RNAMSC \cite{ge2018novo} & \cmark & \xmark & \xmark & \xmark \\ \hline
{\bf \vernal} & \cmark & \cmark & \cmark & \cmark
& flexible motifs & all ss & graph-based \\ \hline
rna3dmotif ~\cite{djelloul2009algorithmes} & \xmark & \xmark & \cmark \\ \hline
RNA 3D Motif Atlas ~\cite{petrov2013automated} & $\sim$ & \xmark & $\sim$ \\ \hline
CaRNAval ~\cite{reinharz2018mining} & \xmark & \xmark & \cmark \\ \hline
RNAMSC \cite{ge2018novo} & \cmark & \xmark & \xmark \\ \hline
{\bf \vernal} & \cmark & \cmark & \cmark
\end{tabular}%
}
\end{table}
......@@ -376,9 +396,10 @@
\end{figure}
\end{frame}
\begin{frame}{Picking $d$: Edge histogram distance}
Idea: similar rings will have similar distributions of edge types.
\begin{frame}{Node similarity function}
\begin{itemize}
\item \ideatag Similar rings will have similar distributions of edge types.
\end{itemize}
\begin{equation}
k_L(u,v) := \sum_{l=0}^{L-1} \lambda^{l} d(R_u^l, R_v^l)
......@@ -392,7 +413,7 @@
\begin{figure}
\centering
\includegraphics[width=0.4\textwidth]{k.pdf}
\includegraphics[width=0.3\textwidth]{k.pdf}
\end{figure}
\end{frame}
......@@ -437,7 +458,7 @@
\begin{frame}
\frametitle{Full}
\frametitle{Full Framework}
\begin{figure}
......@@ -471,6 +492,7 @@
\frametitle{First Look At Motif Learning}
\begin{itemize}
\item \problemtag Always assigning the same motif
\item Might need extra reconstruction term, or loss function weights need adjusting.
\end{itemize}
\begin{figure}
......@@ -495,8 +517,8 @@
\item Once we've identified related structures we need to align them to build:
\begin{itemize}
\item Analysis of conserved (functional) interactions.
\item Statistical models from consensus (\texttt{BayesPairing})
\item Predictive models from distances (\rnamigos)
\item Statistical models from consensus (\texttt{BayesPairing} ~\cite{sarrazin2019automated})
\item Predictive models from distances (\rnamigos ~\cite{oliver2019extended})
\end{itemize}
\item Graph alignment $\sim$ sequential graph editing or node matching.
\end{itemize}
......@@ -521,6 +543,7 @@
\begin{itemize}
\item Existing methods focus on strict edge conservation.
\item Mostly applied to aligning protein-protein interaction networks.
\item Major tools rely on {\it a priori} node and edge conservation heuristics
\end{itemize}
......@@ -528,12 +551,12 @@
\resizebox{\textwidth}{!}{%
\begin{tabular}{lllll}
\hline
& Node cost & Edge Cost & Custom Cost & Inductive \\ \hline
IsoRank & \cmark & $\sim$ & \cmark & \xmark \\ \hline
GRALL & \cmark & \xmark & $\sim$ & \xmark \\ \hline
WAVE & \xmark & $\sim$ & \xmark & \xmark \\ \hline
Gromov-Wasserstein \cite{ge2018novo} & \cmark & \xmark & \xmark & \xmark \\ \hline
{\bf \garl} & \cmark & \cmark & \cmark & \cmark
& Custom Node Cost & Edge Info & Node Order \\ \hline
IsoRank ~\cite{singh2007pairwise} & \xmark & \xmark & \xmark & \\ \hline
GRALL ~\cite{malod2015graal} & \cmark & \xmark & \xmark & \\ \hline
WAVE ~\cite{sun2015simultaneous} & \cmark & $\sim$ & \xmark & \\ \hline
Gromov-Wasserstein ~\cite{xu2019gromov} & \xmark & \xmark & \xmark & \\ \hline
{\bf \garl} & \cmark & \cmark & \cmark
\end{tabular}%
}
\end{table}
......@@ -543,18 +566,40 @@
\begin{frame}
\frametitle{RL-based graph alignment}
\begin{itemize}
\item Actions: pair of nodes to align
\item State: Graph embedding (GCNs)
\item Reward: user-defined cost function.
\item \problemtag Accomodating arbitrary cost functions without specialized heuristics
\item \ideatag Abstract the cost as an environment factor in RL.
\begin{itemize}
\item {\bf Actions}: pair of nodes to align
\item {\bf State/Value:} Graph embedding (GCNs)
\item {\bf Reward}: user-defined cost function.
\end{itemize}
\end{itemize}
\begin{figure}
\includegraphics[width=0.6\textwidth]{garl.pdf}
\includegraphics[width=0.5\textwidth]{garl.pdf}
\end{figure}
\end{frame}
\begin{frame}
\frametitle{Current Status \& Next Steps}
Current Status
\begin{itemize}
\item Implementation functional
\end{itemize}
Next Steps
\begin{itemize}
\item Initial validation
\end{itemize}
\begin{figure}
\centering
\includegraphics[width=0.65\textwidth]{action_value.pdf}
\end{figure}
\end{frame}
\section{Conclusion}
......@@ -670,6 +715,22 @@
\bibliography{biblio}
\end{frame}
\begin{frame}
\frametitle{We can use \rnamigos to find binding sites}
\includegraphics[width=0.3\textwidth]{3d0x_find.png}
\includegraphics[width=0.3\textwidth]{3ox0_find.png}
\includegraphics[width=0.3\textwidth]{3suy_find.png}
\end{frame}
\begin{frame}
\frametitle{Distribution of RNA ligands}
\begin{figure}
\includegraphics[width=0.9\textwidth]{all_ligs_tsne_wide_labels.pdf}
\end{figure}
\end{frame}
\begin{frame}{Picking $d$: Graphlet Distance}
Idea: Compare structure of nodes in each ring with alignments.
\begin{equation}
......
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