Enhancing Electrical Conductivity of Stretchable Liquid Metal-Silver Composites through Direct Ink Writing.

Structure-property-process relationships are a controlling factor in the performance of materials. This offers opportunities in emerging areas, such as stretchable conductors, to control process conditions during printing to enhance performance. Herein, by systematically tuning direct ink write (DIW) process parameters, the electrical conductivity of multiphase liquid metal (LM)-silver stretchable conductors is increased by a maximum of 400% to over 1.06 × 106 S·m-1. This is achieved by modulating the DIW print velocity, which enables the in situ elongation, coalescence, and percolation of these multiphase inclusions during printing. These DIW printed filaments are conductive as fabricated and are soft (modulus as low as 1.1 MPa), stretchable (strain limit >800%), and show strain invariant conductivity up to 80% strain. These capabilities are demonstrated through a set of electromagnetic induction coils that can transfer power wirelessly through air and water, even under deformation. This work provides a methodology to program properties in stretchable conductors, where the combination of material composition and process parameters leads to greatly enhanced performance. This approach can find use in applications such as soft robots, soft electronics, and printed materials for deformable, yet highly functional devices.

Kuttsukigami: sticky sheet design.

Shaping 3D objects from 2D sheets enables form and function in diverse areas from art to engineering. Here we introduce kuttsukigami, which exploits sheet-sheet adhesion to create structure. The technique allows thin sheets to be sculpted without requiring sharp folds, enabling structure in a broad range of materials for a versatile and reconfigurable thin-sheet engineering design scheme. Simple closed structures from cylindrical loops to complex shapes like the Möbius loop are constructed and modeled through the balance between deformation and adhesion. Importantly, the balance can be used to create experimental measurements of elasticity in complex morphologies. More practically, kuttsukigami is demonstrated to encapsulate objects from the kitchen to micro scales and to build on-demand logic gates through sticky electronic sheets for truly reusable, reconfigurable devices.

Probing the Mechanisms Underlying the Transport of the Vinca Alkaloids by P-glycoprotein.

The efficacy of many cancer drugs is hindered by P-glycoprotein (Pgp), a cellular pump that removes drugs from cells. To improve chemotherapy, drugs capable of evading Pgp must be developed. Despite similarities in structure, vinca alkaloids (VAs) show disparate Pgp-mediated efflux ratios. ATPase activity and binding affinity studies show at least two binding sites for the VAs: high- and low-affinity sites that stimulate and inhibit the ATPase activity rate, respectively. The affinity for ATP from the ATPase kinetics curve for vinblastine (VBL) at the high-affinity site was 2- and 9-fold higher than vinorelbine (VRL) and vincristine (VCR), respectively. Conversely, VBL had the highest Km (ATP) for the low-affinity site. The dissociation constants (KDs) determined by protein fluorescence quenching were in the order VBL < VRL< VCR. The order of the KDs was reversed at higher substrate concentrations. Acrylamide quenching of protein fluorescence indicate that the VAs, either at 10 µM or 150 µM, predominantly maintain Pgp in an open-outward conformation. When 3.2 mM AMPPNP was present, 10 µM of either VBL, VRL, or VCR cause Pgp to shift to an open-outward conformation, while 150 µM of the VAs shifted the conformation of Pgp to an intermediate orientation, between opened inward and open-outward. However, the conformational shift induced by saturating AMPPNP and VCR condition was less than either VBL or VRL in the presence of AMPPNP. At 150 µM, atomic force microscopy (AFM) revealed that the VAs shift Pgp population to a predominantly open-inward conformation. Additionally, STDD NMR studies revealed comparable groups in VBL, VRL, and VCR are in contact with the protein during binding. Our results, when coupled with VAs-microtubule structure-activity relationship studies, could lay the foundation for developing next-generation VAs that are effective as anti-tumor agents. A model that illustrates the intricate process of Pgp-mediated transport of the VAs is presented.

Drug-Induced Conformational Dynamics of P-Glycoprotein Underlies the Transport of Camptothecin Analogs.

P-glycoprotein (Pgp) plays a pivotal role in drug bioavailability and multi-drug resistance development. Understanding the protein's activity and designing effective drugs require insight into the mechanisms underlying Pgp-mediated transport of xenobiotics. In this study, we investigated the drug-induced conformational changes in Pgp and adopted a conformationally-gated model to elucidate the Pgp-mediated transport of camptothecin analogs (CPTs). While Pgp displays a wide range of conformations, we simplified it into three model states: 'open-inward', 'open-outward', and 'intermediate'. Utilizing acrylamide quenching of Pgp fluorescence as a tool to examine the protein's tertiary structure, we observed that topotecan (TPT), SN-38, and irinotecan (IRT) induced distinct conformational shifts in the protein. TPT caused a substantial shift akin to AMPPNP, suggesting ATP-independent 'open-outward' conformation. IRT and SN-38 had relatively moderate effects on the conformation of Pgp. Experimental atomic force microscopy (AFM) imaging supports these findings. Further, the rate of ATPase hydrolysis was correlated with ligand-induced Pgp conformational changes. We hypothesize that the separation between the nucleotide-binding domains (NBDs) creates a conformational barrier for substrate transport. Substrates that reduce the conformational barrier, like TPT, are better transported. The affinity for ATP extracted from Pgp-mediated ATP hydrolysis kinetics curves for TPT was about 2-fold and 3-fold higher than SN-38 and IRT, respectively. On the contrary, the dissociation constants (KD) determined by fluorescence quenching for these drugs were not significantly different. Saturation transfer double difference (STDD) NMR of TPT and IRT with Pgp revealed that similar functional groups of the CPTs are accountable for Pgp-CPTs interactions. Efforts aimed at modifying these functional groups, guided by available structure-activity relationship data for CPTs and DNA-Topoisomerase-I complexes, could pave the way for the development of more potent next-generation CPTs.

Mobile Phase Aging and Its Impact on Electrospray Ionization of Oligonucleotides.

The implementation of fluoroalcohol/alkylamine mobile phase systems in oligonucleotide LC-MS provides a good balance between chromatographic separations and MS sensitivity. Since its introduction, several parameters including mobile phase composition, additive concentration, alkylamine hydrophobicity, and different fluoroalcohols have been carefully evaluated and optimized. While our understanding of this mobile phase system has increased over the years, there are challenges that continue to hinder method performance and remain poorly understood. One of these challenges is the constant loss of MS sensitivity over time, commonly termed mobile phase aging. This study investigates two aging mechanisms associated with loss of MS sensitivity: alkylamine oxidation and aggregate formation. The relationship between pH, organic solvent, oxygen, and mobile phase aging is characterized, and mitigation strategies to extend mobile phase lifetime are discussed.

Characterization of mRNA therapeutics.

Therapeutic messenger RNAs (mRNAs) have emerged as powerful tools in the treatment of complex diseases, especially for conditions that lack efficacious treatment. The successful application of this modality can be attributed to its ability to encode entire proteins. While the large nature of these molecules has supported their success as therapeutics, its extended size creates several analytical challenges. To further support therapeutic mRNA development and its deployment in clinical trials, appropriate methods to support their characterization must be developed. In this review, we describe current analytical methods that have been used in the characterization of RNA quality, identity, and integrity. Advantages and limitations from several analytical techniques ranging from gel electrophoresis to liquid chromatography-mass spectrometry and from shotgun sequencing to intact mass measurements are discussed. We comprehensively describe the application of analytical methods in the measurements of capping efficiency, poly A tail analysis, as well as their applicability in stability studies.

Metamaterial adhesives for programmable adhesion through reverse crack propagation.

Adhesives are typically either strong and permanent or reversible with limited strength. However, current strategies to create strong yet reversible adhesives needed for wearable devices, robotics and material disassembly lack independent control of strength and release, require complex fabrication or only work in specific conditions. Here we report metamaterial adhesives that simultaneously achieve strong and releasable adhesion with spatially selectable adhesion strength through programmed cut architectures. Nonlinear cuts uniquely suppress crack propagation by forcing cracks to propagate backwards for 60× enhancement in adhesion, while allowing crack growth in the opposite direction for easy release and reusability. This mechanism functions in numerous adhesives on diverse substrates in wet and dry conditions and enables highly tunable adhesion with independently programmable adhesion strength in two directions simultaneously at any location. We create these multifunctional materials in a maskless, digital fabrication framework to rapidly customize adhesive characteristics with deterministic control for next-generation adhesives.

Prodrug Strategies for the Development of ß-l-5-((E)-2-Bromovinyl)-1-((2S,4S)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl))uracil (l-BHDU) against Varicella Zoster Virus (VZV).

Varicella zoster virus (VZV) establishes lifelong infection after primary disease and can reactivate. Several drugs are approved to treat VZV diseases, but new antivirals with greater potency are needed. Previously, we identified ß-l-5-((E)-2-bromovinyl)-1-((2S,4S)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl))uracil (l-BHDU, 1), which had significant anti-VZV activity. In this communication, we report the synthesis and evaluation of numerous l-BHDU prodrugs: amino acid esters (14-26), phosphoramidates (33-34), long-chain lipids (ODE-l-BHDU-MP, 38, and HDP-l-BHDU-MP, 39), and phosphate ester prodrugs (POM-l-BHDU-MP, 41, and POC-l-BHDU-MP, 47). The amino acid ester l-BHDU prodrugs (l-phenylalanine, 16, and l-valine, 17) had a potent antiviral activity with EC50 values of 0.028 and 0.030 µM, respectively. The phosphate ester prodrugs POM-l-BHDU-MP and POC-l-BHDU-MP had a significant anti-VZV activity with EC50 values of 0.035 and 0.034 µM, respectively, and no cellular toxicity (CC50 > 100 µM) was detected. Out of these prodrugs, ODE-l-BHDU-MP (38) and POM-l-BHDU-MP (41) were selected for further evaluation in future studies.

Previsual and Early Detection of Myrtle Rust on Rose Apple Using Indices Derived from Thermal Imagery and Visible-to-Short-Infrared Spectroscopy.

Myrtle rust, caused by the fungus Austropuccinia psidii, is a serious disease, which affects many Myrtaceae species. Commercial nurseries that propagate Myrtaceae species are prone to myrtle rust and require a reliable method that allows previsual and early detection of the disease. This study uses time-series thermal imagery and visible-to-short-infrared spectroscopy measurements acquired over 10 days from 81 rose apple plants (Syzygium jambos) that were either inoculated with myrtle rust or maintained disease-free. Using these data, the objectives were to (i) quantify the accuracy of models using thermal indices and narrowband hyperspectral indices (NBHI) for previsual and early detection of myrtle rust using data from older resistant green leaves and young susceptible red leaves and (ii) identify the most important NBHI and thermal indices for disease detection. Using predictions made on a validation dataset, models using indices derived from thermal imagery were able to perfectly (F1 score = 1.0; accuracy = 100%) distinguish control from infected plants previsually one day before symptoms appeared (1 DBS) and for all stages after early symptoms appeared. Compared with control plants, plants with myrtle rust had lower and more variable normalized canopy temperature, which was associated with higher stomatal conductance and transpiration. Using NBHI derived from green leaves, excellent previsual classification was achieved 3 DBS, 2 DBS, and 1 DBS (F1 score range = 0.89 to 0.94). The accurate characterization of myrtle rust during previsual and early stages of disease development suggests that a robust detection methodology could be developed within a nursery setting. [Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.

Microflow liquid chromatography - multi-emitter nanoelectrospray mass spectrometry of oligonucleotides.

While the most sensitive LC-MS methods for oligonucleotide analysis contain ion-pairs in the mobile phase, these modifiers have been associated with instrument contamination and ion suppression. Typically, entire LC-MS systems are reserved for oligonucleotide LC-MS when using ion-pairing buffers. To overcome these limitations, numerous HILIC methods, liberated from ion-pairs, have been recently developed. Since ion-pairs play a role in analyte desorption from ESI droplets, their removal from mobile phases tend to impact method sensitivity. An effective way to recover MS sensitivity is to reduce the LC flow rate and therefore reduce ESI droplet size. With a focus on MS sensitivity, this study investigates the applicability of a microflow LC- nanoelectrospray MS platform in oligonucleotide ion-pair RP and HILIC LC-MS methods. The platform is effective and substantially increased the MS sensitivity of HILIC methods. Furthermore, LC method development for both types of separations provide insight into microflow chromatography of oligonucleotides, an under investigated chromatographic scale.

Managing nonspecific adsorption to liquid chromatography hardware: A review.

The choice of alternative materials over stainless steel hardware in the construction of liquid chromatography systems has unveiled the degree to which nonspecific adsorption impacts the reproducibility of LC methods. Some of the major contributors to nonspecific adsorption losses are charged metallic surfaces and leached metallic impurities, that may interact with the analyte and result in analyte loss and overall poor chromatographic performance. In this review, we describe several mitigation strategies available to chromatographers to minimize nonspecific adsorption to chromatographic systems. Alternative surfaces to stainless steel such as titanium, PEEK, and hybrid surface technologies are discussed. Furthermore, mobile phase additives used to prevent metal ion-analyte interactions are reviewed. Nonspecific adsorption of analytes is not reserved to metallic surfaces, as analytes may adsorb to the surfaces of filters, tubes, and pipette tips during sample preparation. Identifying the source of nonspecific interactions is paramount, as mitigation strategies may differ depending on what stage nonspecific losses are taking place. With this in mind, we discuss diagnostic methods that may help the chromatographer to differentiate losses resulting from sample preparation, and losses during LC runs.

X-ray scattering as an effective tool for characterizing liquid metal composite morphology.

Quantitative analysis of particle size and size distribution is crucial in establishing structure-property relationships of composite materials. An emerging soft composite architecture involves dispersing droplets of liquid metal throughout an elastomer, enabling synergistic properties of metals and soft polymers. The structure of these materials is typically characterized through real-space microscopy and image analysis; however, these techniques rely on magnified images that may not represent the global-averaged size and distribution of the droplets. In this study, we utilize ultra-small angle X-ray scattering (USAXS) as a reciprocal-space characterization technique that yields global-averaged dimensions of eutectic gallium indium (EGaIn) alloy soft composites. The Unified fit and Monte Carlo scattering methods are applied to determine the particle size and size distributions of the liquid metal droplets in the composites and are shown to be in excellent agreement with results from real-space image analysis. Additionally, all methods indicate that the droplets are getting larger as they are introduced into composites, suggesting that the droplets are agglomerating or possibly coalescing during dispersion. This work demonstrates the viability of X-ray scattering to elucidate structural information about liquid metal droplets for material development for applications in soft robotics, soft electronics, and multifunctional materials.

Tough Bonding of Liquid Metal-Elastomer Composites for Multifunctional Adhesives.

Liquid metal (LM) composites, which consist of LM droplets dispersed in highly deformable elastomers, have recently gained interest as a multifunctional material for soft robotics and electronics. The incorporation of LM into elastic solids allows for unique combinations of material properties such as high stretchability with thermal and electrical conductivity comparable to metals. However, it is currently a challenge to incorporate LM composites into integrated systems consisting of diverse materials and components due to a lack of adhesion control. Here, a chemical anchoring methodology to increase adhesion of LM composites to diverse substrates is presented. The fracture energy increases up to 100× relative to untreated surfaces, with values reaching up to 7800 J m-2 . Furthermore, the fracture energy, tensile modulus, and thermal conductivity can be tuned together by controlling the microstructure of LM composites. Finally, the bonding technique is used to integrate LM composites with functional electronic components without encapsulation or clamping, allowing for extreme deformations while maintaining exceptional thermal and electrical conductivity. These findings can accelerate the adoption of LM composites into complex soft robotic and electronic systems where strong, reliable bonding between diverse materials and components is required.

Octopus-inspired adhesive skins for intelligent and rapidly switchable underwater adhesion.

The octopus couples controllable adhesives with intricately embedded sensing, processing, and control to manipulate underwater objects. Current synthetic adhesive-based manipulators are typically manually operated without sensing or control and can be slow to activate and release adhesion, which limits system-level manipulation. Here, we couple switchable, octopus-inspired adhesives with embedded sensing, processing, and control for robust underwater manipulation. Adhesion strength is switched over 450× from the ON to OFF state in <50 ms over many cycles with an actively controlled membrane. Systematic design of adhesive geometry enables adherence to nonideal surfaces with low preload and independent control of adhesive strength and adhesive toughness for strong and reliable attachment and easy release. Our bio-inspired nervous system detects objects and autonomously triggers the switchable adhesives. This is implemented into a wearable glove where an array of adhesives and sensors creates a biomimetic adhesive skin to manipulate diverse underwater objects.

Putative biotic drivers of plant phenology: With special reference to pathogens and deciduousness.

Plant phenology is not only manifested in the seasonal timing of vegetative and reproductive processes but also has ontogenetic aspects. The adaptive basis of seasonal phenology has been considered mainly in terms of climatic drivers. However, some biotic factors as likely evolutionary influences on plants' phenology appear to have been under-researched. Several specific cases of putative biotic factors driving plant phenology are outlined, involving both herbivores and pathogens. These illustrate the diversity of likely interactions rather than any systematic coverage or review. Emphasis is on woody perennials, in which phenology is often most multifaceted and complicated by the ontogenetic aspect. The complete seasonal leaf fall that characterizes deciduous plants may be a very important defense against some pathogens. Whether biotic influences drive acquisition or long-term persistence of deciduousness is considered. In one case, of leaf rusts in poplars, countervailing influences of the rusts and climate suggest persistence. Often, however, biotic and environmental influences likely reinforce each other. The timing and duration of shoot flushing may in at least some cases contribute to defenses against herbivores, largely through brief periods of "predator satiation" when plant tissues have highest food value. Wide re-examination of plant phenology, accommodating the roles of biotic factors and their interplays with environments as additional adaptive drivers, is advocated toward developing and applying hypotheses that are observationally or experimentally testable.

On-Demand Programming of Liquid Metal-Composite Microstructures through Direct Ink Write 3D Printing.

Soft, elastically deformable composites with liquid metal (LM) droplets can enable new generations of soft electronics, robotics, and reconfigurable structures. However, techniques to control local composite microstructure, which ultimately governs material properties and performance, is lacking. Here a direct ink writing technique is developed to program the LM microstructure (i.e., shape, orientation, and connectivity) on demand throughout elastomer composites. In contrast to inks with rigid particles that have fixed shape and size, it is shown that emulsion inks with LM fillers enable in situ control of microstructure. This enables filaments, films, and 3D structures with unique LM microstructures that are generated on demand and locked in during printing. This includes smooth and discrete transitions from spherical to needle-like droplets, curvilinear microstructures, geometrically complex embedded inclusion patterns, and connected LM networks. The printed materials are soft (modulus < 200 kPa), highly deformable (>600 % strain), and can be made locally insulating or electrically conductive using a single ink by controlling the process conditions. These capabilities are demonstrated by embedding elongated LM droplets in a soft heat sink, which rapidly dissipates heat from high-power LEDs. These programmable microstructures can enable new composite paradigms for emerging technologies that demand mechanical compliance with multifunctional response.

Shape morphing mechanical metamaterials through reversible plasticity.

Biological organisms such as the octopus can reconfigure their shape and properties to perform diverse tasks. However, soft machines struggle to achieve complex configurations, morph into shape to support loads, and go between multiple states reversibly. Here, we introduce a multifunctional shape-morphing material with reversible and rapid polymorphic reconfigurability. We couple elastomeric kirigami with an unconventional reversible plasticity mechanism in metal alloys to rapidly (<0.1 seconds) morph flat sheets into complex, load-bearing shapes, with reversibility and self-healing through phase change. This kirigami composite overcomes trade-offs in deformability and load-bearing capacity and eliminates power requirements to sustain reconfigured shapes. We demonstrate this material through integration with onboard control, motors, and power to create a soft robotic morphing drone, which autonomously transforms from a ground to air vehicle and an underwater morphing machine, which can be reversibly deployed to collect cargo.

Impact of Nonspecific Adsorption to Metal Surfaces in Ion Pair-RP LC-MS Impurity Analysis of Oligonucleotides.

Nonspecific adsorption has been a consistent challenge in the analysis of oligonucleotides. Nonspecific adsorption is a result of interactions between charged acidic analytes and adsorption sites present in metallic surfaces located in the fluidic path of chromatography systems. Due to their high surface area, adsorption to column frits is especially concerning. Poor peak shape, low recovery and compromised LOQ have been associated with this phenomenon. Alternative methods including substitution of stainless steel for different hardware materials and mobile phase additives have been explored in an attempt to minimize this issue. Chemical modification of metal surfaces using hybrid surface technology (HST) by-passes the limitation of stainless steel construction material by forming a hybrid organic/inorganic layer that acts as a barrier and limits nonspecific interactions. In this study we explore the implications of this new technology in sensitive analysis and determination of relative impurity levels of oligonucleotides. Higher relative impurity levels and better reproducibility were obtained with columns using HST.