Pretubulysin: From Hypothetical Biosynthetic Intermediate to Potential Lead in Tumor Therapy

Pretubulysin is a natural product that is found in strains of myxobacteria in only minute amounts. It represents the first enzyme-free intermediate in the biosynthesis of tubulysins and undergoes post-assembly acylation and oxidation reactions. Pretubulysin inhibits the growth of cultured mammalian cells, as do tubulysins, which are already in advanced preclinical development as anticancer and antiangiogenic agents. The mechanism of action of this highly potent compound class involves the depolymerization of microtubules, thereby inducing mitotic arrest. Supply issues with naturally occurring derivatives can now be circumvented by the total synthesis of pretubulysin, which, in contrast to tubulysin, is synthetically accessible in gram-scale quantities. We show that the simplified precursor is nearly equally potent to the parent compound. Pretubulysin induces apoptosis and inhibits cancer cell migration and tubulin assembly in vitro. Consequently, pretubulysin appears to be an ideal candidate for future development in preclinical trials and is a very promising early lead structure in cancer therapy

Electromechanical analysis of an adaptive piezoelectric energy harvester controlled by two segmented electrodes with shunt circuit networks

This paper presents an adaptive power harvester using a shunted piezoelectric control system with segmented electrodes. This technique has spurred new capability for widening the three simultaneous resonance frequency peaks using only a single piezoelectric laminated beam where normally previous works only provide a single peak for the resonance at the first mode. The benefit of the proposed techniques is that it provides effective and robust broadband power generation for application in self-powered wireless sensor devices. The smart structure beam with proof mass offset is considered to have simultaneous combination between vibration-based power harvesting and shunt circuit control-based electrode segments. As a result, the system spurs new development of the two mathematical methods using electromechanical closed-boundary value techniques and Ritz method-based weak-form analytical approach. The two methods have been used for comparison giving accurate results. For different electrode lengths using certain parametric tuning and harvesting circuit systems, the technique enables the prediction of the power harvesting that can be further proved to identify the performance of the system using the effect of varying circuit parameters so as to visualize the frequency and time waveform responses

A smart pipe energy harvester excited by fluid flow and base excitation

This paper presents an electromechanical dynamic modelling of the partially smart pipe structure subject to the vibration responses from fluid flow and input base excitation for generating the electrical energy. We believe that this work shows the first attempt to formulate a unified analytical approach of flow-induced vibrational smart pipe energy harvester in application to the smart sensor-based structural health monitoring systems including those to detect flutter instability. The arbitrary topology of the thin electrode segments located at the surface of the circumference region of the smart pipe has been used so that the electric charge cancellation can be avoided. The analytical techniques of the smart pipe conveying fluid with discontinuous piezoelectric segments and proof mass offset, connected with the standard AC–DC circuit interface, have been developed using the extended charge-type Hamiltonian mechanics. The coupled field equations reduced from the Ritz method-based weak form analytical approach have been further developed to formulate the orthonormalised dynamic equations. The reduced equations show combinations of the mechanical system of the elastic pipe and fluid flow, electromechanical system of the piezoelectric component, and electrical system of the circuit interface. The electromechanical multi-mode frequency and time signal waveform response equations have also been formulated to demonstrate the power harvesting behaviours. Initially, the optimal power output due to optimal load resistance without the fluid effect is discussed to compare with previous studies. For potential application, further parametric analytical studies of varying partially piezoelectric pipe segments have been explored to analyse the dynamic stability/instability of the smart pipe energy harvester due to the effect of fluid and input base excitation. Further proof between case studies also includes the effect of variable flow velocity for optimal power output, 3-D frequency response, the dynamic evolution of the smart pipe system based on the absolute velocity-time waveform signals, and DC power output-time waveform signals

A conserved motif flags acyl carrier proteins for β-branching in polyketide synthesis

Type I PKSs often utilise programmed β-branching, via enzymes of an “HMG-CoA synthase (HCS) cassette”, to incorporate various side chains at the second carbon from the terminal carboxylic acid of growing polyketide backbones. We identified a strong sequence motif in Acyl Carrier Proteins (ACPs) where β-branching is known. Substituting ACPs confirmed a correlation of ACP type with β-branching specificity. While these ACPs often occur in tandem, NMR analysis of tandem β-branching ACPs indicated no ACP-ACP synergistic effects and revealed that the conserved sequence motif forms an internal core rather than an exposed patch. Modelling and mutagenesis identified ACP Helix III as a probable anchor point of the ACP-HCS complex whose position is determined by the core. Mutating the core affects ACP functionality while ACP-HCS interface substitutions modulate system specificity. Our method for predicting β-carbon branching expands the potential for engineering novel polyketides and lays a basis for determining specificity rules

Morphing in nature and beyond: a review of natural and synthetic shape-changing materials and mechanisms

Shape-changing materials open an entirely new solution space for a wide range of disciplines: from architecture that responds to the environment and medical devices that unpack inside the body, to passive sensors and novel robotic actuators. While synthetic shape-changing materials are still in their infancy, studies of biological morphing materials have revealed key paradigms and features which underlie efficient natural shape-change. Here, we review some of these insights and how they have been, or may be, translated to artificial solutions. We focus on soft matter due to its prevalence in nature, compatibility with users and potential for novel design. Initially, we review examples of natural shape-changing materials—skeletal muscle, tendons and plant tissues—and compare with synthetic examples with similar methods of operation. Stimuli to motion are outlined in general principle, with examples of their use and potential in manufactured systems. Anisotropy is identified as a crucial element in directing shape-change to fulfil designed tasks, and some manufacturing routes to its achievement are highlighted. We conclude with potential directions for future work, including the simultaneous development of materials and manufacturing techniques and the hierarchical combination of effects at multiple length scales.</p