27 research outputs found
Mean first passage time analysis reveals rate-limiting steps, parallel pathways and dead ends in a simple model of protein folding
We have analyzed dynamics on the complex free energy landscape of protein
folding in the FOLD-X model, by calculating for each state of the system the
mean first passage time to the folded state. The resulting kinetic map of the
folding process shows that it proceeds in jumps between well-defined, local
free energy minima. Closer analysis of the different local minima allows us to
reveal secondary, parallel pathways as well as dead ends.Comment: 7 page
The role of multiple marks in epigenetic silencing and the emergence of a stable bivalent chromatin state
We introduce and analyze a minimal model of epigenetic silencing in budding
yeast, built upon known biomolecular interactions in the system. Doing so, we
identify the epigenetic marks essential for the bistability of epigenetic
states. The model explicitly incorporates two key chromatin marks, namely H4K16
acetylation and H3K79 methylation, and explores whether the presence of
multiple marks lead to a qualitatively different systems behavior. We find that
having both modifications is important for the robustness of epigenetic
silencing. Besides the silenced and transcriptionally active fate of chromatin,
our model leads to a novel state with bivalent (i.e., both active and
silencing) marks under certain perturbations (knock-out mutations, inhibition
or enhancement of enzymatic activity). The bivalent state appears under several
perturbations and is shown to result in patchy silencing. We also show that the
titration effect, owing to a limited supply of silencing proteins, can result
in counter-intuitive responses. The design principles of the silencing system
is systematically investigated and disparate experimental observations are
assessed within a single theoretical framework. Specifically, we discuss the
behavior of Sir protein recruitment, spreading and stability of silenced
regions in commonly-studied mutants (e.g., sas2, dot1) illuminating the
controversial role of Dot1 in the systems biology of yeast silencing.Comment: Supplementary Material, 14 page
Goal setting and goal attainment in patients with major depressive disorder: a narrative review on shared decision making in clinical practice
Objective: Narrative review of the processes of goal setting and goal attainment scaling, as practical approaches to operationalizing and implementing the principles of shared decision making (SDM) in the routine care of people living with major depressive disorder (MDD). Methods: We searched electronic databases for clinical studies published in English using key terms related to MDD and goal setting or goal attainment scaling. Two clinical studies of goal setting in MDD are considered in detail to exemplify the practicalities of the goal setting approach. Results: While SDM is widely recommended for people living with mental health problems, there is general agreement that it has thus far been implemented variably. In other areas of medicine, the process of goal setting is an established way to engage the patient, facilitate motivation, and assist the recovery process. For people living with MDD, the concept of goal setting is in its infancy, and only few studies have evaluated its clinical utility. Two clinical studies of vortioxetine for MDD demonstrate the utility of goal attainment scaling as an appropriate outcome for assessing functional improvement in ways that matter to the patient. Conclusions: Goal setting is a pragmatic approach to turning the principles of SDM into realities of clinical practice and aligns with the principles of recovery that encompasses the notions of self-determination, self-management, personal growth, empowerment, and choice. Accumulating evidence supports the use of goal attainment scaling as an appropriate personalized outcome measure for use in clinical trials.</p