scholarly journals Next-Generation Drugs and Probes for Chromatin Biology: From Targeted Protein Degradation to Phase Separation

Molecules ◽  
2018 ◽  
Vol 23 (8) ◽  
pp. 1958 ◽  
Author(s):  
Katerina Cermakova ◽  
H. Hodges
Keyword(s):  
Small Molecules ◽  
Three Dimensional ◽  
Synthetic Control ◽  
Chromatin Regulation ◽  
Next Generation ◽  
Nuclear Function ◽  
Polycomb Repression ◽  
Chromatin Biology ◽  
Fast Acting ◽  
Insight Into

Chromatin regulation is a critical aspect of nuclear function. Recent advances have provided detailed information about dynamic three-dimensional organization of chromatin and its regulatory factors. Mechanisms crucial for normal nuclear function and epigenetic control include compartmentalization of biochemical reactions by liquid-phase separated condensates and signal-dependent regulation of protein stability. Synthetic control of these phenomena by small molecules provides deep insight into essential activities such as histone modification, BAF (SWI/SNF) and PBAF remodeling, Polycomb repression, enhancer looping by cohesin and CTCF, as well as many other processes that contribute to transcription. As a result, a complete understanding of the spatiotemporal mechanisms that underlie chromatin regulation increasingly requires the use of fast-acting drugs and chemical probes. Here, we provide a comprehensive review of next-generation chemical biology tools to interrogate the chromatin regulatory landscape, including selective PROTAC E3 ubiquitin ligase degraders, degrons, fluorescent ligands, dimerizers, inhibitors, and other drugs. These small molecules provide important insights into the mechanisms that govern gene regulation, DNA repair, development, and diseases like cancer.

Structure and function of neural networks in the retina

1988 ◽  
Vol 46 ◽  
pp. 26-27
Author(s):  
Peter Sterling
Keyword(s):  
Ganglion Cells ◽  
Three Dimensional ◽  
Structure And Function ◽  
Synaptic Connections ◽  
Visual Axis ◽  
One Dimensional ◽  
Cat Retina ◽  
Ultrathin Sections ◽  
And Function ◽  
Insight Into

The synaptic connections in cat retina that link photoreceptors to ganglion cells have been analyzed quantitatively. Our approach has been to prepare serial, ultrathin sections and photograph en montage at low magnification (˜2000X) in the electron microscope. Six series, 100-300 sections long, have been prepared over the last decade. They derive from different cats but always from the same region of retina, about one degree from the center of the visual axis. The material has been analyzed by reconstructing adjacent neurons in each array and then identifying systematically the synaptic connections between arrays. Most reconstructions were done manually by tracing the outlines of processes in successive sections onto acetate sheets aligned on a cartoonist's jig. The tracings were then digitized, stacked by computer, and printed with the hidden lines removed. The results have provided rather than the usual one-dimensional account of pathways, a three-dimensional account of circuits. From this has emerged insight into the functional architecture.

A Free Energy Perturbation Approach to Estimate the Intrinsic Solubilities of Drug-like Small Molecules

2019 ◽  
Author(s):  
Sayan Mondal ◽  
Gary Tresadern ◽  
Jeremy Greenwood ◽  
Byungchan Kim ◽  
Joe Kaus ◽  
...  
Keyword(s):  
Solid State ◽  
Small Molecules ◽  
Three Dimensional ◽  
Aqueous Solubility ◽  
Computational Approach ◽  
Free Energy Perturbation ◽  
Perturbation Approach ◽  
Energy Perturbation ◽  
State Form ◽  
Good Agreement

<p>Optimizing the solubility of small molecules is important in a wide variety of contexts, including in drug discovery where the optimization of aqueous solubility is often crucial to achieve oral bioavailability. In such a context, solubility optimization cannot be successfully pursued by indiscriminate increases in polarity, which would likely reduce permeability and potency. Moreover, increasing polarity may not even improve solubility itself in many cases, if it stabilizes the solid-state form. Here we present a novel physics-based approach to predict the solubility of small molecules, that takes into account three-dimensional solid-state characteristics in addition to polarity. The calculated solubilities are in good agreement with experimental solubilities taken both from the literature as well as from several active pharmaceutical discovery projects. This computational approach enables strategies to optimize solubility by disrupting the three-dimensional solid-state packing of novel chemical matter, illustrated here for an active medicinal chemistry campaign.</p>

scholarly journals Completely non-fused electron acceptor with 3D-interpenetrated crystalline structure enables efficient and stable organic solar cell

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lijiao Ma ◽  
Shaoqing Zhang ◽  
Jincheng Zhu ◽  
Jingwen Wang ◽  
Junzhen Ren ◽  
...  
Keyword(s):  
Organic Solar Cell ◽  
Low Cost ◽  
Three Dimensional ◽  
Molecular Geometry ◽  
Interpenetrating Network ◽  
Fused Ring ◽  
Molecule Design ◽  
End Capping ◽  
Conversion Efficiencies ◽  
Insight Into

AbstractNon-fullerene acceptors (NFAs) based on non-fused conjugated structures have more potential to realize low-cost organic photovoltaic (OPV) cells. However, their power conversion efficiencies (PCEs) are much lower than those of the fused-ring NFAs. Herein, a new bithiophene-based non-fused core (TT-Pi) featuring good planarity as well as large steric hindrance was designed, based on which a completely non-fused NFA, A4T-16, was developed. The single-crystal result of A4T-16 reveals that a three-dimensional interpenetrating network can be formed due to the compact π–π stacking between the adjacent end-capping groups. A high PCE of 15.2% is achieved based on PBDB-TF:A4T-16, which is the highest value for the cells based on the non-fused NFAs. Notably, the device retains ~84% of its initial PCE after 1300 h under the simulated AM 1.5 G illumination (100 mW cm−2). Overall, this work provides insight into molecule design of the non-fused NFAs from the aspect of molecular geometry control.

scholarly journals The distribution of myosin II in Dictyostelium discoideum slug cells.

1991 ◽  
Vol 115 (5) ◽  
pp. 1267-1274 ◽  
Author(s):  
S Eliott ◽  
P H Vardy ◽  
K L Williams
Keyword(s):  
Cell Motility ◽  
Dictyostelium Discoideum ◽  
Immunofluorescence Microscopy ◽  
Molecular Genetic ◽  
Myosin Ii ◽  
Three Dimensional ◽  
Homogeneous Distribution ◽  
Multicellular Development ◽  
Insight Into

While the role of myosin II in muscle contraction has been well characterized, less is known about the role of myosin II in non-muscle cells. Recent molecular genetic experiments on Dictyostelium discoideum show that myosin II is necessary for cytokinesis and multicellular development. Here we use immunofluorescence microscopy with monoclonal and polyclonal antimyosin antibodies to visualize myosin II in cells of the multicellular D. discoideum slug. A subpopulation of peripheral and anterior cells label brightly with antimyosin II antibodies, and many of these cells display a polarized intracellular distribution of myosin II. Other cells in the slug label less brightly and their cytoplasm displays a more homogeneous distribution of myosin II. These results provide insight into cell motility within a three-dimensional tissue and they are discussed in relation to the possible roles of myosin II in multicellular development.

Analysis of SiC CVD Growth in a Horizontal Hot-Wall Reactor by Experiment and 3D Modelling

2007 ◽  
Vol 556-557 ◽  
pp. 61-64
Author(s):  
Y. Shishkin ◽  
Rachael L. Myers-Ward ◽  
Stephen E. Saddow ◽  
Alexander Galyukov ◽  
A.N. Vorob'ev ◽  
...  
Keyword(s):  
Growth Rate ◽  
Growth Process ◽  
Three Dimensional ◽  
Chemical Species ◽  
3D Modelling ◽  
Complete Model ◽  
Cvd Growth ◽  
Dimensional Simulation ◽  
Insight Into ◽  
Hot Zone

A fully-comprehensive three-dimensional simulation of a CVD epitaxial growth process has been undertaken and is reported here. Based on a previously developed simulation platform, which connects fluid dynamics and thermal temperature profiling with chemical species kinetics, a complete model of the reaction process in a low pressure hot-wall CVD reactor has been developed. Close agreement between the growth rate observed experimentally and simulated theoretically has been achieved. Such an approach should provide the researcher with sufficient insight into the expected growth rate in the reactor as well as any variations in growth across the hot zone.

The Three-Dimensional Surface Topographic Characterisation of Diamond Grinding Wheels

2010 ◽  
Vol 126-128 ◽  
pp. 690-695
Author(s):  
David Lee Butler
Keyword(s):  
Measurement Techniques ◽  
Three Dimensional ◽  
Surface Measurement ◽  
Grinding Wheel ◽  
Profile Measurement ◽  
Detailed Knowledge ◽  
Grinding Wheels ◽  
Diamond Grinding ◽  
Insight Into ◽  
Dimensional Surface

Surface measurement using three-dimensional stylus instruments is a relatively new technique that offers numerous advantages over more traditional profilometry methods. The information generated is, unlike profile measurement, less subjective and more statistical providing additional insight into the surface structure. One application of surface measurement that has encountered problems when using the profilometry method is that of grinding wheel characterisation. The wheel surface texture (topography) and the conditions under which it is generated have a profound effect upon the grinding performance as characterised by the grinding forces, power consumption, temperature, and surface integrity of components. A detailed knowledge of the nature of the topography of the grinding wheel would provide further insight into surface interactions between the wheel and workpiece as well as enabling improved control of the grinding process in general. In this paper four diamond grinding wheels of 91 and 181 micron grit size were subjected to differing dressing conditions to produce varying final wheel topographies. Three-dimensional surface measurement techniques were employed to quantitatively characterise the topographic change and provide an aerial estimation of the number of cutting grains. The results demonstrate that the techniques can distinguish between a worn and dressed wheel. In addition, the parametric values generated from the various surfaces can aid the user in determining when re-dressing is required.

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