Recent Advances in Combretastatin A-4 Inspired Inhibitors of Tubulin Polymerization-An Update

Cancer is one of the leading causes of fatality and mortality worldwide. Investigations on developing therapeutic strategies for cancer are supported throughout the world. The massive achievements in molecular sciences involving biochemistry, molecular chemistry, medicine, and pharmacy, and high throughput techniques such as genomics and proteomics have helped to create new potential drug targets for cancer treatment. Microtubules are very attractive targets for cancer therapy because of the crucial roles they play in cell division. In recent years, lots of efforts have been put into the identification of new microtubule-targeting agents (MTAs) in anticancer therapy. Combretastatin A-4 (CA-4) is a natural compound that binds to microtubules’ colchicine binding site and inhibits microtubule polymerization. Due to CA-4’s structural simplicity, many analogs have been synthesized. This article summarizes the new molecule development efforts to reach CA-4 analogs by modifications on its pharmacophore groups, published since 2015.

Physical mechanisms of ESCRT-III–driven cell division

Living systems propagate by undergoing rounds of cell growth and division. Cell division is at heart a physical process that requires mechanical forces, usually exerted by assemblies of cytoskeletal polymers. Here we developed a physical model for the ESCRT-III–mediated division of archaeal cells, which despite their structural simplicity share machinery and evolutionary origins with eukaryotes. By comparing the dynamics of simulations with data collected from live cell imaging experiments, we propose that this branch of life uses a previously unidentified division mechanism. Active changes in the curvature of elastic cytoskeletal filaments can lead to filament perversions and supercoiling, to drive ring constriction and deform the overlying membrane. Abscission is then completed following filament disassembly. The model was also used to explore how different adenosine triphosphate (ATP)-driven processes that govern the way the structure of the filament is changed likely impact the robustness and symmetry of the resulting division. Comparisons between midcell constriction dynamics in simulations and experiments reveal a good agreement with the process when changes in curvature are implemented at random positions along the filament, supporting this as a possible mechanism of ESCRT-III–dependent division in this system. Beyond archaea, this study pinpoints a general mechanism of cytokinesis based on dynamic coupling between a coiling filament and the membrane.

Closeness to singularity based on kinematics and dynamics and singularity avoidance of a planar parallel robot with kinematic redundancy

Planar parallel robots are appealing due to their structural simplicity, high stiffness, and large payload capacity. One major problem is that workspace and singularity of non-redundant parallel robots are unchangeable. Hence, when the desired path crossed with singularity or exceeded the workspace’s boundary, the robot is incapable of finishing the task. Another one is closeness to singularity. If one can know the distance between the end manipulator and singularity or workspace’s boundary, the robot will avoid lose control or breakdown. Compared with the traditional planar parallel robot, the planar parallel robot with kinematic redundancy possesses the advantages of avoiding singularity, expanding workspace by adjusting kinematic redundancy parameter. Therefore, the objective of this article is to present an offline action-strategy of a planar robot with kinematic redundancy to measure the closeness to singularity and avoid singularity. It includes two main parts: First, before the robot moves along the desired paths, the closeness to singularity was measured based on the performance of the kinematics and dynamics so that one can know where to pause the robot. Second, an algorithm is designed to previously find the proper kinematic redundancy parameters for changing singularity and workspace. Hence, the robot can smoothly move far from the singularity to finish all paths. The results indicate that the robot can adjust its configuration to well realize the goal by the offline action-strategy.

Docking and ADMET studies for investigating the anticancer potency of Moscatilin on APC10/DOC1 and PKM2 against five clinical drugs

Background Moscatilin is a bibenzyl derivative (stilbenoid), mainly found in Dendrobium species. This plant-derived chemical is a potential cytotoxic anticancer drug that acts against different cancer types. The present study compared the structural interactions of Moscatilin along with five clinically relevant drugs against two target proteins, viz., Anaphase-Promoting Complex subunit 10/Death of Cyclase 1 and Pyruvate Kinase Muscle isozyme M2 in silico. Out of five clinical ligands, four were plant-derived compounds, viz., Resveratrol, Paclitaxel, Shikonin, and Colchicine. The synthetic chemotherapeutic agent, Mitomycin-C, was used as a ligand to compare the mechanistic insights. The objective of the study was to determine the anticancer potency of Moscatilin in silico. Results Moscatilin was found to have an advantage over other drugs of interest due to its structural simplicity and folding bridge connecting the bibenzyl structures. Moscatilin exhibited dual function by exclusively affecting the cancer cells, creating instabilities in biochemical and molecular cascades. Conclusions The study demonstrates that Moscatilin is has a multi-antimetastatic function. Moscatilin interaction with APC10/DOC1 indicated that the drug is involved with post-replicative inhibition, and with PKM2 showed glycolytic pathway inhibition in cancer cells. Moscatilin can function as an effective cell cycle inhibitor. Graphical abstract

An Overview of the Medicinally Important Plant Type III PKS Derived Polyketides

Plants produce interesting secondary metabolites that are a valuable source of both medicines for human use, along with significant advantages for the manufacturer species. The active compounds which lead to these instrumental effects are generally secondary metabolites produced during various plant growth phases, which provide the host survival advantages while affecting human health inadvertently. Different chemical classes of secondary metabolites are biosynthesized by the plant type III polyketide synthases (PKSs). They are simple homodimeric proteins with the unique mechanistic potential to produce a broad array of secondary metabolites by utilizing simpler starter and extender units. These PKS derived products are majorly the precursors of some important secondary metabolite pathways leading to products such as flavonoids, stilbenes, benzalacetones, chromones, acridones, xanthones, cannabinoids, aliphatic waxes, alkaloids, anthrones, and pyrones. These secondary metabolites have various pharmaceutical, medicinal and industrial applications which make biosynthesizing type III PKSs an important tool for bioengineering purposes. Because of their structural simplicity and ease of manipulation, these enzymes have garnered interest in recent years due to their application in the generation of unnatural natural polyketides and modified products in the search for newer drugs for a variety of health problems. The following review covers the biosynthesis of a variety of type III PKS-derived secondary metabolites, their biological relevance, the associated enzymes, and recent research.

Phonetically Grounded Structural Bias in Learning Tonal Alternations

This study investigates the hypothesis that tone alternation directionality becomes a basis of structural bias for tone alternation learning, where “structural bias” refers to a tendency to prefer uni-directional tone deletions to bi-directional ones. Two experiments were conducted. In the first, Mandarin speakers learned three artificial languages, with bi-directional tone deletions, uni-directional, left-dominant deletions, and uni-directional, right-dominant deletions, respectively. The results showed a learning bias toward uni-directional, right-dominant patterns. As Mandarin tone sandhi is right-dominant while Cantonese tone change is lexically restricted and does not have directionality asymmetry, a follow-up experiment trained Cantonese speakers either on left- or right-dominant deletions to see whether the right-dominant preference was due to L1 transfer from Mandarin. The results of the experiment also showed a learning bias toward right-dominant patterns. We argue that structural simplicity affects tone deletion learning but the simplicity should be grounded on phonetics factors, such as syllables’ contour-tone bearing ability. The experimental results are consistent with the findings of a survey on other types of tone alternation’s directionality, i.e., tone sandhi across 17 Chinese varieties. This suggests that the directionality asymmetry found across different tone alternations reflects a phonetically grounded structural learning bias.

Directionality of Disyllabic Tone Sandhi across Chinese Dialects is Conditioned by Phonetically-Grounded Structural Simplicity

Despite various work which aimed to identify the phonetic and structural underpinning of tone sandhi directionality, the underlying mechanism that governs tone sandhi remains unknown. We note that the two widely discussed properties of tone sandhi, their phonetic grounds and directionality, correspond to two types of cognitive biases widely investigated in segmental phonology, namely substantive bias and structural bias respectively. This study examines structural simplicity and phonetic naturalness of tone sandhi patterns across seventeen Chinese varieties. Based on a structure-based analysis, we show that tone sandhi patterns are overwhelmingly uni-directional (i.e. structurally simple) either throughout a sandhi system or within each grammatical category. Crucially, uni-directionality is largely right-dominant, which could be attributed to its phonetic grounding. We argue that structural simplicity grounded on phonetic substance better captures tone sandhi asymmetries and such phonetically-grounded structural simplicity bias is reflected in the asymmetries of Chinese tone sandhi directionality.

A Magneto-Active Elastomer Crawler with Peristaltic and Caterpillar Locomotion Patterns

In this work we present a soft crawler fabricated using a magneto-active elastomer. The crawler is controlled by an external magnetic field to produce two locomotion patterns: peristaltic and caterpillar crawling. Due to its structural simplicity, low mass, wirelessly controlled actuation and compliant body the design of this crawler has the potential to address the key challenges faced by existing crawling robots. Experimental data were gathered to evaluate the performance of the crawler locomotion in a pipe. The results validated the mathematical models proposed to estimate the distance traveled by the crawler. The crawler shows potential for use in exploration of confined spaces.

Integrate-and-Fire Neuron Circuit Without External Bias Voltages

In this study, we propose an integrate-and-fire (I&F) neuron circuit using a p-n-p-n diode that utilizes a latch-up phenomenon and investigate the I&F operation without external bias voltages using mixed-mode technology computer-aided design (TCAD) simulations. The neuron circuit composed of one p-n-p-n diode, three MOSFETs, and a capacitor operates with no external bias lines, and its I&F operation has an energy consumption of 0.59 fJ with an energy efficiency of 96.3% per spike. The presented neuron circuit is superior in terms of structural simplicity, number of external bias lines, and energy efficiency in comparison with that constructed with only MOSFETs. Moreover, the neuron circuit exhibits the features of controlling the firing frequency through the amplitude and time width of the synaptic pulse despite of the reduced number of the components and no external bias lines.

Physical mechanisms of ESCRT-III-driven cell division in archaea

Living systems propagate by undergoing rounds of cell growth and division. Cell division is at heart a physical process that requires mechanical forces, usually exerted by protein assemblies. Here we developed the first physical model for the division of archaeal cells, which despite their structural simplicity share machinery and evolutionary origins with eukaryotes. We show how active geometry changes of elastic ESCRT-III filaments, coupled to filament disassembly, are sufficient to efficiently split the cell. We explore how the non-equilibrium processes that govern the filament behaviour impact the resulting cell division. We show how a quantitative comparison between our simulations and dynamic data for ESCRTIII-mediated division in Sulfolobus acidocaldarius, the closest archaeal relative to eukaryotic cells that can currently be cultured in the lab, and reveal the most likely physical mechanism behind its division.