Multifunctional Constructs Research Articles

Accessing Therapeutically-Relevant Multifunctional Antisense Oligonucleotide Conjugates Using Native Chemical Ligation.

Antisense oligonucleotide (ASO) therapies hold significant promise in the realm of molecular medicine. By precisely targeting RNA molecules, ASOs offer an approach to modulate gene expression and protein production, making them valuable tools for treating a wide range of genetic and acquired diseases. As the precise intracellular targeting and delivery of ASOs is challenging, strategies for preparing ASO-ligand conjugates are in exceedingly high demand. This work leverages the utility of native chemical ligation to conjugate ASOs with therapeutically relevant chemical modifications including locked nucleic acids and phosphorothioate backbone modifications to peptides and sugars via a stable amide linkage. A suite of post-ligation functionalizations through modification of the cysteine ligation handle are highlighted, including chemoselective radical desulfurization, lipidation, and alkylation with a range of valuable handles (e.g. alkyne, biotin, and radionuclide chelating ligands), affording multifunctional constructs for further applications in biology and medicine. Application of the methodology to a clinically-relevant triantennary-GalNAc ASO conjugate and validation of its binding and functional activity underpins the applicability of the technique to oligonucleotide-based therapeutics.

Nitric Oxide-Photodelivering Materials with Multiple Functionalities: From Rational Design to Therapeutic Applications.

The achievement of materials that are able to release therapeutic agents under the control of light stimuli to improve therapeutic efficacy is a significant challenge in health care. Nitric oxide (NO) is one of the most studied molecules in the fascinating realm of biomedical sciences, not only for its crucial role as a gaseous signaling molecule in the human body but also for its great potential as an unconventional therapeutic in a variety of diseases including cancer, bacterial and viral infections, and neurodegeneration. Handling difficulties due to its gaseous nature, reduced region of action due to its short half-life, and strict dependence of the biological effects on its concentration and generation site are critical questions to be solved for appropriate therapeutic uses of NO. Light-activatable NO precursors, namely, NO photodonors (NOPDs), address the above issues since they are stable in the dark and permit in a noninvasive fashion the remote-controlled delivery of NO on demand with great spatiotemporal precision. Engineering biocompatible materials with NOPDs and their combination with additional imaging, therapeutic, and phototherapeutic components leads to intriguing light-responsive multifunctional constructs exhibiting promising potential for biomedical applications. This contribution illustrates the most significant progress made over the last five years in achieving engineered materials including nanoparticles, gels, and thin films, sharing the common feature to deliver NO under the exclusive control of the biocompatible visible/near infrared light inputs. We will highlight the logical design behind the fabrication of these systems, illustrating the potential therapeutic applications with particular emphasis on cancer and bacterial infections.

Synergetic construction of color and multifunction for sustainable lyocell fabric by Coptis chinensis and BTCA

In the context of escalating standards of living, the demand for healthy and multifunctional textiles is increasing. As a kind of cellulose macromolecular-based material, lyocell fiber has low carbon, is environmentally friendly, and demonstrates superb performance. The utilization of some Chinese herb dyes solves the pollution problem in the color and functionality construction of lyocell fabric by synthetic dyes and finishing agents. However, problems such as low dye utilization rate, light apparent color, and weak functionality of dyed fabrics remain, thus limiting the further application of the powerful combination of lyocell fabric and Chinese herb dyes. Here, a color and multifunction construction method of lyocell fabric with Coptis chinensis and 1,2,3,4-butanetetracarboxylic acid was proposed. Under the optimal color construction condition, the color depth increased remarkably, and the dye exhaustion rate of the modified fabric enhanced by 332.3 % compared with the unmodified one. The multifunction construction imparted outstanding fuzz and pilling inhibition, fibrillation resistance, and antiwrinkle performance for lyocell fabrics. Moreover, the dyed lyocell fabric exhibited considerable UV protective activity and antibacterial property against Staphylococcus aureus. This work provided an efficient color and multifunction construction technology for lyocell fabric with high value added.

Mechanical properties and electromagnetic wave absorption characteristics of solid waste low-carbon cementitious materials

A low-carbon multi-functional cement substitute material has been developed to reduce electromagnetic pollution in building spaces and protect human health. The solid waste electromagnetic absorption cementitious material (SWEACM) is produced by combining steel slag (SS), blast furnace slag (BFS), and phosphogypsum (PG). In this study, the properties of SWEACM were analyzed, including flow, electromagnetic wave absorption, strength, and environmental properties. Additionally, the hydration and electromagnetic wave absorption mechanisms were examined. The results indicate that SS, BFS, and PG content significantly affect the strength and electromagnetic wave absorption properties of SWEACM. S-6 exhibits the best overall performance (SS: BFS: PG = 3:6:1), with the highest strength (28 days compressive strength = 33.5 MPa) and fluidity (19.1 cm). Furthermore, it has excellent electromagnetic absorption performance (RLmin = −45.4 dB), with an adequate absorption bandwidth of up to 10 GHz in the 2–18 GHz range. The excellent electromagnetic wave absorption capability of SWEACM is mainly due to the resonance, polarization relaxation loss, and conduction loss of the magnetic and conductive components in the material. The results show that SWEACM can be used as a multi-functional construction engineering material for electromagnetic protection, combining high levels of high electromagnetic wave absorption, strength performance, and environmental benefits.

Synchronized path planning and tracking for front and rear axles in articulated wheel loaders

Wheel loaders are multi-function construction equipment, yet their complex kinematics and coupled front-rear axle relationships pose significant challenges in path planning and tracking control. This paper presents a synchronous path planning method and a reinforcement learning-based tracking controller for these axles. Initially, a kinematic model and tracking error model are developed based on steering radius analysis and verified through simulations. The Reeds-Shepp curve is used to plan the V-shaped path for the front axle, with the rear axle path derived from the kinematic model. Using reinforcement learning, a path tracking controller is developed with a preview model of tracking error. Performance is validated through simulations and field tests, showing a position error reduction of 25% and 37.5% for two paths, and heading error reductions of 27.8% and 27.3%. The results also indicate improved stability in heading and articulation angles during tracking.

Multifunctional MXene-Based Platforms for Soft and Bone Tissue Regeneration and Engineering.

MXenes and their composites hold great promise in the field of soft and bone tissue regeneration and engineering (TRE). However, there are challenges that need to be overcome, such as ensuring biocompatibility and controlling the morphologies of MXene-based scaffolds. The future prospects of MXenes in TRE include enhancing biocompatibility through surface modifications, developing multifunctional constructs, and conducting in vivo studies for clinical translation. The purpose of this perspective about MXenes and their composites in soft and bone TRE is to critically evaluate their potential applications and contributions in this field. This perspective aims to provide a comprehensive analysis of the challenges, advantages, limitations, and future prospects associated with the use of MXenes and their composites for soft and bone TRE. By examining the existing literature and research, the review seeks to consolidate the current knowledge and highlight the key findings and advancements in MXene-based TRE. It aims to contribute to the understanding of MXenes' role in promoting soft and bone TRE, addressing the challenges faced in terms of biocompatibility, morphology control, and tissue interactions.

Hybrid micromechanical modelling and experiments on temperature-dependent thermal conductivity of graphene reinforced porous cement composites

Dispersing graphene and its derivatives into traditional cement matrix to develop high-performance and multifunctional construction materials has attracted great attention. Pores and temperature are evidenced to have significant effects on the thermal properties of graphene nanoplatelets (GNPs) reinforced cement composites (GNPRCCs). Accurate prediction of the thermal property of the GNPRCCs with considering pores and temperature is crucial for their engineering application. In this work, the GNPRCCs samples with different GNPs volume fractions are prepared, characterized, and tested for their thermal conductivity. A hybrid micromechanical model (HMM), employing effective medium theory (EMT) with Mori-Tanaka (MT) approach is developed for the thermal conductivity of the porous GNPRCCs. Particularly, a phonon physical model is incorporated into the model to capture the temperature-dependency of the thermal conductivity. The model is validated by comparing present results with experimental data. The obtained results show that the thermal conductivity of the GNPRCCs with 1 wt% GNPs decreases by 19.79% as the temperature increases from 300 K to 350 K. The increase in porosity results in the blockage of phonon heat transport and the decrease in the thermal conductivity of the GNPRCCs. It is observed that the thermal conductivity of GNPRCCs with 1 wt% GNPs decreases by 14.78% as the porosity increases by 10%. Spherical pores are found to be more favorable for heat flow transport and enhancement of the thermal conductivity. In contrast, the needle-like GNPs with larger size promote the formation of heat transport network and enhance the thermal conductivity of the samples more effectively. For example, the thermal conductivity of the GNPRCCs with 1 wt% GNPs increases by 20.75% as the size of the GNPs increases from 15 μm to 30 μm. The developed model for the thermal conductivity of the cement composites is envisaged to provide useful guidelines for their potential engineering applications in snow melting, de-icing and geothermal structures.

Synergetic construction of color and multifunction for sustainable lyocell fabric by microbial nano pigment

As a kind of low-carbon, environmentally friendly and high-quality regenerated cellulose fiber derived from nature plant, the promotion and application of lyocell fiber is attracting much attention. In this paper, for the first time, microbial pigment was applied for color and multifunction construction of lyocell fabric. The size change of the pigment nano-particles during the color construction process was explored to verify the dyeing mechanism of nano-suspension system, and the optimal dyeing condition was obtained. In order to improve the dyeing effect and functionality of fabric, 1,2,3,4-butanetetracarboxylic acid (BTCA) was used to realize the anionic modification of lyocell fabric with high strength retention rate. Under optimal color construction condition, the color depth of the modified fabric was 298.5% higher than that of the unmodified one, and the dyed fabric possessed excellent dyeing uniformity and permeability. Moreover, the crosslinking reaction between BTCA and cellulose macromolecules, as well as the pigment deposition inside the fibers were helpful to the fibrillation prevention function of lyocell fibers. Dyed fabrics inherited the antibacterial and ultraviolet absorption properties of prodigiosins. The bacteriostatic rate against Staphylococcus aureus was above than 98.5%, and the UV protection performance was obviously improved. This technology successfully realized the color and multi-functional construction of the lyocell fabric in one step by natural pigment from microorganism.

Multiwalled carbon nanotubes as hard templates to yield advanced geopolymer-based self-assembled nanostructured ceramics

Novel multifunctional construction materials are needed to promote resilient infrastructure in the face of climate change and extreme weather. Nanostructured materials such as geopolymer reinforced with carbon-based nanomaterials are a promising way to reach that goal. In recent years, several studies have investigated the influence of nanomaterials on the physical properties of geopolymer composites such as compressive strength and fracture toughness. Yet, a fundamental understanding of the influence of nanomaterials on the nanoscale and micron-scale structure has been elusive so far. Our research objective is to understand how multiwalled carbon nanotubes (MWCNT) can help tailor the microstructure of geopolymers to yield architected multifunctional nanocomposites. We synthesized geopolymer nanocomposites reinforced with 50-nm thick multiwalled carbon nanotubes with mass fractions in the range of 0.1 wt%, 0.2 wt%, and 0.5 wt%. Our major finding is that MWCNTs act as hard templates that promote geopolymer formation via self-assembly. Geopolymer nanoparticle growth is observed along the walls of MWCNTs. A refinement in grain size is observed: increasing the fraction of MWCNTs by 0.5 wt% leads to a reduction in grain size by 54%. Similarly, increasing the mass fraction of MWCNTs leads to a densification of the geopolymer matrix as demonstrated by the Fourier transform infrared spectroscopy results and the statistical deconvolution analysis. Mercury intrusion porosimetry shows a nanoscale tailoring of the pore size distribution: a 26% decrease in porosity is observed as the fraction of MWCNTs is increased to 0.5 wt%. As a result of these nanoscale structural changes, a greater resistance to long-term deformation is observed for MWCNT-reinforced geopolymers, as the creep modulus increases both locally and macroscopically. At the macroscopic level, a 42% increase in the macroscopic logarithmic creep modulus is observed as the fraction of MWCNTs is increased to 0.5 wt%. These findings and the supporting methodology are important to understand how to manipulate matter below 100 nm. This research also paves the way for the design of resilient infrastructure materials with tailored microstructure and mechanical properties.

Determinants of Developability and Evolvability of Synthetic Miniproteins as Ligand Scaffolds

Binding ligands empower molecular therapeutics and diagnostics. Despite an array of protein scaffolds engineered for binding, the biophysical elements that drive developability and evolvability are not fully understood. In particular, engineering novel function while maintaining biophysical integrity within the context of small, single-domain proteins is challenged by integration of the structural framework and the evolved binding site. Miniproteins present a challenge to our limits of protein engineering capability and provide advantages in physiological targeting, modularity for multi-functional constructs, and unique binding modes. Herein, we evaluate the ability of hyperstable synthetic miniproteins, originally designed for foldedness, to function as binding scaffolds. We synthesized 45 combinatorial libraries, with 109 variants, systematically varied across two topologies, each with five starting frameworks and four or five diverse, structurally distinct paratopes, to elucidate their impact on evolvability and developability. We evaluated evolvability with yeast display binding selections against four targets. High-throughput assays –stability via yeast display and soluble expression via split-GFP in E. coli – measured developability. The comprehensive, robust dataset demonstrates how protein topology, parental framework, and paratope structure and location all impact scaffold performance. A hyperstable framework and localized diversity are not sufficient for an effective scaffold, but several designs of these elements within synthetic miniproteins designed solely for stability result in scaffold libraries with effective evolvability and developability. Engineered variants were well-folded, thermally stable, and bound target with single-digit nanomolar affinity. Thus, hyperstable synthetic miniproteins can serve as precursors to developable, evolvable mini-scaffolds with unique potential for physiological transport, modularity, and binding modes.

A new smart sustainable earth-cement composite doped by carbon microfibers with self-sensing properties

Civil constructions need to be monitored during their lifespan to assess any changes in structural performance following critical events. Among the various available monitoring solutions, this paper contributes to the literature on multifunctional construction materials that have the ability to provide an electrical output that can be correlated with materials’ damage. The novelty of the work consists of achieving self-sensing properties in a sustainable concrete, where cement is substituted with natural earth in the ratio of 7/2 in volume. Self-sensing properties are provided through the addition of a small amount of carbon microfibers enabling a piezoresistive behavior. Experimental tests were carried out using samples with different shapes to investigate their electrical and sensing properties. The results showed that the best carbon microfiber doping level of 0.05% relative to the binder exhibited clear and repeatable signals, an average gauge factor of 46, and high linearity. Moreover, the smart multifunctional earth-concrete showed good electrical, diagnostic, and sensing properties during failure tests.

Designed Multifunctional Peptides for Intracellular Targets.

Nature’s way for bioactive peptides is to provide them with several related functions and the ability to cooperate in performing their job. Natural cell-penetrating peptides (CPP), such as penetratins, inspired the design of multifunctional constructs with CPP ability. This review focuses on known and novel peptides that can easily reach intracellular targets with little or no toxicity to mammalian cells. All peptide candidates were evaluated and ranked according to the predictions of low toxicity to mammalian cells and broad-spectrum activity. The final set of the 20 best peptide candidates contains the peptides optimized for cell-penetrating, antimicrobial, anticancer, antiviral, antifungal, and anti-inflammatory activity. Their predicted features are intrinsic disorder and the ability to acquire an amphipathic structure upon contact with membranes or nucleic acids. In conclusion, the review argues for exploring wide-spectrum multifunctionality for novel nontoxic hybrids with cell-penetrating peptides.

Effect of Austenite Grain Size on the Bainitic Transformation in a 690 MPa Grade High-Strength Multi-Functional Construction Steel

A high-strength low-carbon construction structural steel was investigated in the laboratory. The various austenite grain sizes were obtained by austenitizing the steel at different temperatures. The effect of austenite grain size on bainite transformation was studied by the dilatometer. The results show that the microstructure of high-strength low-carbon structural steels mainly includes granular bainite, lath-like bainite and martensite-austenite (M-A). The microstructure changes from granular bainite to lath-like bainite with the increase in austenitizing temperature or austenite grain size. When the samples were heated at the lower temperature of 860 °C, the bainite starting temperature was relatively high, which was mainly attributed to the promotion of the granular bainitic nucleation and the formation of the solute-depleted regions in the austenite. Compared to 860 and 1260 °C, the bainite transformation rate in the specimen austenitized at 1000 °C is the highest because of the small prior austenite grain size and larger transformation driving force.

Effect of tempering on the microstructure and properties of a new multi-functional 460 MPa Grade construction structural steel

A new generation of multi-functional construction structural steel with high yield strength of ∼545 MPa, excellent toughness of ∼170 J/cm2 at −20 °C, lower yield ratio smaller than 0.83, good fire resistance, and good corrosion resistance was successfully developed by thermo-mechanical controlled processing plus tempering. The effects of tempering on the microstructure and mechanical properties were investigated. The results show that although the bainite lath slightly coarsens and the dislocation density slightly decreases as the tempering temperature increases, the yield strength of the steel increases mainly due to the precipitation strengthening. The samples tempered at 300 °C show the best combination of strength, toughness, and yield ratio. In addition, the high-temperature strength of the newly developed Q460 steel is obviously higher than the conventional one, which is mainly attributed to the bainitic strengthening and precipitation strengthening. Moreover, a denser rust layer forms on the surface of new Q460 steel during corrosion because of the addition of Cr and Cu, which increases the corrosion resistance of the steel.

Cover Picture: DNA‐Damage‐Response‐Targeting Mitochondria‐Activated Multifunctional Prodrug Strategy for Self‐Defensive Tumor Therapy (Angew. Chem. Int. Ed. 16/2022)

The DNA damage response , which includes DNA repair and cell cycle checkpoint pathways in cancer cells, has been considered one of the main impediments to traditional chemotherapy. In their Research Article (e202117075), Na Kong, Xingcai Zhang, Wei Tao, Jong Seung Kim, and co-workers developed a multifunctional construct, M1, to target the DNA damage response of cancer cells. The findings identified a critical role of DNA damage repair pathways during 5-FU/FUDR therapy and underscore the role of inhibition of these pathways in sensitizing cancer cells to chemotherapeutics.

DNA-Damage-Response-Targeting Mitochondria-Activated Multifunctional Prodrug Strategy for Self-Defensive Tumor Therapy.

We report a novel multifunctional construct, M1, designed explicitly to target the DNA damage response in cancer cells. M1 contains both a floxuridine (FUDR) and protein phosphatase 2A (PP2A) inhibitor combined with a GSH-sensitive linker. Further conjugation of the triphenylphosphonium moiety allows M1 to undergo specific activation in the mitochondria, where mitochondria-mediated apoptosis is observed. Moreover, M1 has enormous effects on genomic DNA ascribed to FUDR's primary function of impeding DNA/RNA synthesis combined with diminishing PP2A-activated DNA repair pathways. Importantly, mechanistic studies highlight the PP2A obtrusion in FUDR/5-fluorouracil (5-FU) therapy and underscore the importance of its inhibition to harbor therapeutic potential. HCT116 cell xenograft-bearing mice that have a low response rate to 5-FU show a prominent effect with M1, emphasizing the importance of DNA damage response targeting strategies using tumor-specific microenvironment-activatable systems.

DNA‐Damage‐Response‐Targeting Mitochondria‐Activated Multifunctional Prodrug Strategy for Self‐Defensive Tumor Therapy

AbstractWe report a novel multifunctional construct, M1, designed explicitly to target the DNA damage response in cancer cells. M1 contains both a floxuridine (FUDR) and protein phosphatase 2A (PP2A) inhibitor combined with a GSH‐sensitive linker. Further conjugation of the triphenylphosphonium moiety allows M1 to undergo specific activation in the mitochondria, where mitochondria‐mediated apoptosis is observed. Moreover, M1 has enormous effects on genomic DNA ascribed to FUDR's primary function of impeding DNA/RNA synthesis combined with diminishing PP2A‐activated DNA repair pathways. Importantly, mechanistic studies highlight the PP2A obtrusion in FUDR/5‐fluorouracil (5‐FU) therapy and underscore the importance of its inhibition to harbor therapeutic potential. HCT116 cell xenograft‐bearing mice that have a low response rate to 5‐FU show a prominent effect with M1, emphasizing the importance of DNA damage response targeting strategies using tumor‐specific microenvironment‐activatable systems.

Hydrophobic and antimicrobial polyimide based composite phase change materials with thermal energy storage capacity, applied as multifunctional construction material

Hydrophobic and antimicrobial polyimide based composite phase change materials with thermal energy storage capacity, applied as multifunctional construction material

Self-sensing performance of cementitious composites with functional fillers at macro, micro and nano scales

Self-sensing cementitious composites have attracted substantial attention as a multifunctional construction material for structural health monitoring (SHM). This study aimed to develop self-sensing cementitious composites using a combination of macro, micro and nanoscale conductive fillers, as the hybrid fillers can take advantage of different types of conductive fillers and create a synergistic effect. Magnetite aggregate (MA), carbon fibre (CF) and carbon nanotube (CNT) were combined and used as the conductive fillers for the fabrication of self-sensing cementitious composites, where the mechanical properties, electrical properties and piezoresistive performance were studied. The MA at 100 wt% achieve the optimal mechanical properties, leading to a 5% increment in compressive and a 25% increment flexural strength with a value of 37.3 and 5.7 MPa. Additionally, multiple reinforcing effects were achieved when combining different types of functional fillers, which a single filler cannot achieve. The best conductive filler combination is MA, CF and CNT hybridisation, each at 100, 0.3 and 0.05 wt%, respectively. A 17% improvement in terms of compressive strength can be observed. And the piezoresistive response can achieve a maximum fractional change in resistivity of 44.7% and demonstrates enhanced linearity, repeatability, signal to noise ratio and stability.

Genetic fusion of P450 BM3 and formate dehydrogenase towards self-sufficient biocatalysts with enhanced activity

Fusion of multiple enzymes to multifunctional constructs has been recognized as a viable strategy to improve enzymatic properties at various levels such as stability, activity and handling. In this study, the genes coding for cytochrome P450 BM3 from B. megaterium and formate dehydrogenase from Pseudomonas sp. were fused to enable both substrate oxidation catalyzed by P450 BM3 and continuous cofactor regeneration by formate dehydrogenase within one construct. The order of the genes in the fusion as well as the linkers that bridge the enzymes were varied. The resulting constructs were compared to individual enzymes regarding substrate conversion, stability and kinetic parameters to examine whether fusion led to any substantial improvements of enzymatic properties. Most noticeably, an activity increase of up to threefold was observed for the fusion constructs with various substrates which were partly attributed to the increased diflavin reductase activity of the P450 BM3. We suggest that P450 BM3 undergoes conformational changes upon fusion which resulted in altered properties, however, no NADPH channeling was detected for the fusion constructs.