Human retinal ganglion cell neurons generated by synchronous BMP inhibition and transcription factor mediated reprogramming.

In optic neuropathies, including glaucoma, retinal ganglion cells (RGCs) die. Cell transplantation and endogenous regeneration offer strategies for retinal repair, however, developmental programs required for this to succeed are incompletely understood. To address this, we explored cellular reprogramming with transcription factor (TF) regulators of RGC development which were integrated into human pluripotent stem cells (PSCs) as inducible gene cassettes.

Restoring vision and rebuilding the retina by Müller glial cell reprogramming.

Müller glia are non-neuronal support cells that play a vital role in the homeostasis of the eye. Their radial-oriented processes span the width of the retina and respond to injury through a cellular response that can be detrimental or protective depending on the context. In some species, protective responses include the expression of stem cell-like genes which help to fuel new neuron formation and even restoration of vision.

Chromatin Accessibility and Transcriptional Differences in Human Stem Cell-Derived Early-Stage Retinal Organoids.

Retinogenesis involves the specification of retinal cell types during early vertebrate development. While model organisms have been critical for determining the role of dynamic chromatin and cell-type specific transcriptional networks during this process, an enhanced understanding of the developing human retina has been more elusive due to the requirement for human fetal tissue. Pluripotent stem cell (PSC) derived retinal organoids offer an experimentally accessible solution for investigating the developing human retina.

Density of states-based molecular simulations.

One of the central problems in statistical mechanics is that of finding the density of states of a system. Knowledge of the density of states of a system is equivalent to knowledge of its fundamental equation, from which all thermodynamic quantities can be obtained. Over the past several years molecular simulations have made considerable strides in their ability to determine the density of states of complex fluids and materials.

GNNQQNY--investigation of early steps during amyloid formation.

Protein aggregation has been implicated in the pathology of several neurodegenerative diseases, and a better understanding of how it proceeds is essential for the development of therapeutic strategies. Recently, the amyloidogenic heptapeptide GNNQQNY has emerged as a molecule of choice for fundamental studies of protein aggregation. A number of experimental and computational studies have examined the structure of the GNNQQNY aggregate.

Solution structures of rat amylin peptide: simulation, theory, and experiment.

Amyloid deposits of amylin in the pancreas are an important characteristic feature found in patients with Type-2 diabetes. The aggregate has been considered important in the disease pathology and has been studied extensively. However, the secondary structures of the individual peptide have not been clearly identified.

Hydrodynamic effects on the translocation rate of a polymer through a pore.

The translocation of large DNA molecules through narrow pores has been examined in the context of multiscale simulations that include a full coupling of fluctuating hydrodynamic interactions, boundary effects, and molecular conformation. The actual rate constants for this process are determined for the first time, and it is shown that hydrodynamic interactions can lead to translocation rates that vary by multiple orders of magnitude when molecular weights are only changed by a factor of 10, in stark contrast to predictions from widely used free draining calculations.

Folding of polyglutamine chains.

Long polyglutamine chains have been associated with a number of neurodegenerative diseases. These include Huntington's disease, where expanded polyglutamine (PolyQ) sequences longer than 36 residues are correlated with the onset of symptoms. In this paper we study the folding pathway of a 54-residue PolyQ chain into a beta-helical structure.

Improved transition path sampling methods for simulation of rare events.

The free energy surfaces of a wide variety of systems encountered in physics, chemistry, and biology are characterized by the existence of deep minima separated by numerous barriers. One of the central aims of recent research in computational chemistry and physics has been to determine how transitions occur between deep local minima on rugged free energy landscapes, and transition path sampling (TPS) Monte-Carlo methods have emerged as an effective means for numerical investigation of such transitions. Many of the shortcomings of TPS-like approaches generally stem from their high computational demands.

Order-parameter-based Monte Carlo simulation of crystallization.

A Monte Carlo simulation method is presented for simulation of phase transitions, with emphasis on the study of crystallization. The method relies on a random walk in order parameter Phi(q(N)) space to calculate a free energy profile between the two coexisting phases. The energy and volume data generated over the course of the simulation are subsequently reweighed to identify the precise conditions for phase coexistence.

Improved density of states Monte Carlo method based on recycling of rejected states.

In this paper a new algorithm is presented that improves the efficiency of Wang and Landau algorithm or density of states (DOS) Monte Carlo simulations by employing rejected states. The algorithm is shown to have a performance superior to that of the original Wang-Landau [F. Wang and D.

Interactions of liquid crystal-forming molecules with phospholipid bilayers studied by molecular dynamics simulations.

Recent experiments have shown that liquid crystals can be used to image mammalian cell membranes and to amplify structural reorganization in phospholipid-laden liquid crystal-aqueous interfaces. In this work, molecular dynamics simulations were employed to explore the interactions between commonly used liquid crystal-forming molecules and phospholipid bilayers. In particular, umbrella sampling was used to obtain the potential of mean force of 4-cyano-4'-pentylbiphenyl (5CB) and 4'-(3,4-difluor-phenyl)-4-pentyl-bicylohexyl (5CF) molecules partitioning into a dipalmitoylphosphatidylcholine bilayer.

Optimal allocation of replicas in parallel tempering simulations.

We have studied the efficiency of parallel tempering simulations for a variety of systems including a coarse-grained protein, an atomistic model polypeptide, and the Lennard-Jones fluid. A scheme is proposed for the optimal allocation of temperatures in these simulations. The method is compared to the existing empirical approaches used for this purpose.