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Scalable Approach to Molecular Motor-Polymer Conjugates for Light-Driven Artificial Muscles
No full textThe integration of molecular machines and motors into materials represents a promising avenue for creating dynamic and functional molecular systems, with potential applications in soft robotics or reconfigurable biomaterials. However, the development of truly scalable and controllable approaches for incorporating molecular motors into polymeric matrices has remained a challenge. Here, we show that light-driven molecular motors with sensitive photo-isomerizable double bonds can be converted into initiators for Cu-mediated controlled/living radical polymerization enabling the synthesis of star-shaped motor-polymer conjugates. This approach enables scalability, precise control over molecular structure, block copolymer structures, and high end group fidelity. Moreover, we demonstrate that these materials can be crosslinked to form gels with quasi-ideal network topology, exhibiting light-triggered contraction. We investigate the influence of arm length and polymer structure, and develop the first molecular dynamics simulation framework to gain deeper insights into the contraction processes. Leveraging this scalable methodology, we showcase the creation of bilayer soft robotic devices and cargo-lifting artificial muscles, highlighting the versatility and potential applications of this advanced polymer chemistry approach. We anticipate that our integrated experimental and simulation framework will accelerate scalable approaches for active polymer materials based on molecular machines, opening up new horizons in materials science and bioscience
Main methods and tools for peptide development based on protein-protein interactions (PPIs)
No full textProtein-protein interactions (PPIs) regulate crucial physiological and pathological processes. PPIs are considered a class of biological targets almost infeasible for small molecules because the binding surfaces are usually large and shallow. Peptides are molecules able to bind to these drug targets; they can be used as modulators and mimic one of the interaction partners. This review details the advances in in silico peptide design and experimental approaches for the evaluation of PPI-based peptides
Assessment of Risk and Processing Effects on Banned Pesticide Residue Levels in Nigerian Staple Foods
No full textThe use of pesticides has overwhelming advantage to food security but not so much to the environmentalists and toxicologists. Governments of nations or regions have over the years restricted or banned the use of certain pesticides. This work examined the incidence, dietary exposure and risk characterization of some Nigerian-banned organochlorine and organophosphate pesticides in rice, cassava, maize and beans marketed in Kogi state, Nigeria. The extraction of pesticide residues was performed using the Quick, Effective, Cheap, Easy, Rugged and Safe (QuEChERS) technique, and gas chromatography tandem mass spectrometry was used for quantification of the pesticide residues in the samples. The residues detected in order of decreasing incidence were methoxychlor, α-chlordane, γ-chlordane, endosulfan II, dieldrin, aldrin, p,p\u27-DDE, Δ-BHC (hexachlorobenzene), endrin aldehyde, p,p\u27-DDD, lindane, p,p\u27-DDT, and endosulfan sulfate. No assayed organophosphate residue was detected. Methoxychlor and α-chlordane had the highest incidences of 46.88% and 31.25% respectively, while lindane, p,p\u27-DDT and endosulfan sulfate had the lowest incidence (3.13% in each case). The processing steps applied including cold water washing, warm water washing, soaking and fermentation had various effects on the level of residues ranging from -149% to 100% reduction in level of pesticide, and are recommended. Risk characterization by percentage tolerable daily intake estimation showed that aldrin and dieldrin were detected at concentrations that far exceeds the safety threshold, the hazard index also revealed that Δ-BHC (hexachlorobenzene), lindane, aldrin, dieldrin and methoxychlor were present in staples at levels with potentials to induce chronic toxicity. None detection, low incidence, low concentrations and low hazard index and risk posed by most pesticides in this study is indicative that the ban on these pesticides has been impactful in reducing their use within Nigeria and consequently in averting health challenges associated with their use. Finding them at any level should alert the regulatory agencies to further strategize towards risk mitigation and elimination
Photodynamic treatment of Staphylococcus aureus with non-iron hemin analogs in the presence of hydrogen peroxide
No full textPhotodynamic treatment of Staphylococcus aureus with non-iron hemin analogs in the presence of hydrogen peroxide acteria subjected to antiseptic or antibiotic stress often develop tolerance, a trait that can lead to permanent resistance. To determine whether photodynamic agents could be used to counter tolerance, we evaluated three non-iron hemin analogs (M-PpIX; M = Al, Ga, In) as targeted photosensitizers for antimicrobial photodynamic inactivation (aPDI) following exposure to sublethal H2O2. Al-PpIX is an active producer of ROS whereas Ga- and In-PpIX are more efficient at generating singlet oxygen. Al- and Ga-PpIX are highly potent aPDI agents against S. aureus and methicillin-resistant strains (MRSA) with antimicrobial activity (3-log reduction in colony-forming units) at nanomolar concentrations. The aPDI activities of Al- and Ga-PpIX against S. aureus were tested in the presence of 1 mM H2O2 added at different stages of growth. Bacteria exposed to H2O2 during log-phase growth were less susceptible to aPDI but bacteria treated with H2O2 in their postgrowth phase exhibited aPDI hypersensitivity, with 6-log reduction (eradication) using only 15 nM Ga-PpIX
AJICAP-M: Traceless Affinity Peptide Mediated Conjugation Technology for Site-Specific Antibody-Drug Conjugate Synthesis
No full textA traceless site-selective conjugation method, “AJICAP-M,” was developed for native antibodies at specific sites using Fc-affinity peptides, focusing on Lys248 or Lys288. It produces antibody-drug conjugates (ADCs) with consistent drug-to-antibody ratios, enhanced stability, and simplified manufacturing. Comparative in vivo assessment demonstrated AJICAP-M\u27s superior stability over traditional ADCs. This technology has been successfully applied to continuous-flow manufacturing, marking the first achievement in site-specific ADC production. This manuscript outlines AJICAP-M\u27s methodology and its effectiveness in ADC production
Flavin-Mediated Reductive Deiodination: Conformational Events and Reactivity Pattern in the Active Site of Human Iodotyrosine Deiodinase
No full textHuman iodotyrosine deiodinase (hIYD) catalyzes the reductive deiodination of iodotyrosine using a flavin mononucleotide cofactor to maintain iodine concentration in the body. Mutations in the hIYD gene are linked to human hypothyroidism, emphasizing its role in thyroid function regulation. The present work employs microsecond-scale molecular dynamics simulations and quantum chemical calculations to elucidate the conformational dynamics and reactivity in the active site at various stages of hIYD catalysis. The flavin is found to employ a unique butterfly motion of its isoalloxazine ring accompanied by a novel active-and-resting state of its ribose 2′-OH group during the catalytic cycle. The flavin dynamics is found to control substrate binding affinity, the active site lid closure, and NADPH recognition. The enzyme uses a group of basic residues (R100, R101, R104, K182, and R279) to stabilize flavin at different stages of catalysis, suggesting potential mutations to control enzyme activity. The reactivity descriptor analysis and stereo-electronic analysis predict the N5 nitrogen of flavin as a proton source during the reductive deiodination. The present findings provide key insights into the molecular basis of hIYD activity and lay the groundwork for future research aimed at therapeutic interventions and industrial applications
Self-Replicating DNA-Based Nanoassemblies
No full textThe properties of DNA that make it an effective genetic material also allow it to be ideal for programmed self-assembly. Accordingly, DNA-programmed assembly has been utilized to construct responsive DNA origami and wireframe nanoassemblies, yet the replication of these hybrid nanomaterials remains a challenge. Here we report a strategy for replicating DNA wireframe nanoassemblies using the isothermal ligase chain reaction lesion-induced DNA amplification (LIDA). In this first generation, we designed a triangle wireframe structure that can be formed in one step by ring-closing its linear analog. Introducing a small amount of the wireframe triangle to an excess of the linear analog and complementary Fragments, one of which contained a destabilizing abasic lesion, led to rapid sigmoidal self-replication of the wireframe triangle via cross-catalysis. Using the same cross-catalytic strategy we also demonstrated rapid self-replication of a hybrid wireframe triangle containing synthetic vertices as well as the self-replication of circular DNA. This work reveals the suitability of isothermal ligase chain reactions such as LIDA to self-replicate complex DNA architectures, opening the door to incorporating self-replication, a hallmark of life, into biomimetic DNA nanotechnology
Intramolecular Cyclization and a Retro-Ene Reaction Enable the Rapid Fragmentation of a Vitamin B1-derived Breslow Intermediate
No full textIn solution, analogues of the Breslow intermediate formed during catalysis by benzoylformate decarboxylase (BFDC) undergo rapid, irreversible fragmentation. The ability of BFDC to prevent this reaction and preserve its’ cofactor is a striking example of an enzyme ‘steering’ a reactive intermediate towards a productive pathway. To understand how BFDC suppresses the off-pathway reactivity of this Breslow intermediate, a clear mechanistic understanding of the fragmentation reaction is required. Here, DFT calculations reveal an unexpected mechanism for the solution-phase fragmentation that involves an intramolecular cyclization and a subsequent retro-ene reaction to release the final products. Free energy profiles demonstrate that this pathway is significantly more facile than the previously proposed mechanism that invoked Breslow intermediate enolates as intermediates. Additional computations have been performed to understand why related Breslow intermediates do not undergo analogous fragmentation reactions. Calculations performed with two closely related Breslow intermediates suggest that subtle differences in the relative values of ∆G‡ for protonation and fragmentation dictate whether a given intermediate will fragment or not. These differences and the fragmentation mechanism unveiled in this work have ramifications for the catalytic mechanism of BFDC and other thiamin-dependent enzymes and will provide general lessons related to the control of reactive intermediates by enzymes
Harnessing ultrasound-derived hydroxyl radicals for the selective oxidation of aldehyde functions
No full textUltrasonic irradiation holds potential for the selective oxidation of non-volatile organic substrates in the aqueous phase by harnessing hydroxyl radicals as chemical initiators. Here, a mechanistic description of hydroxyl radical-initiated glyoxal oxidation is constructed by gleaning insights from photolysis and radiation chemistry to explain the yields and kinetic trends for oxidation products. The mechanistic description and kinetic measurements reported herein reveal that increasing the formation rate of hydroxyl radicals by changing the ultrasound frequency increases both the rates of glyoxal consumption and the selectivity towards C2 acid products over those from C-C cleavage. Glyoxal consumption also occurs more rapidly and with greater selectivity towards C2 acids under acidic conditions, which favor the protonation of carboxylate intermediates into their less reactive acidic forms. Leveraging such pH and frequency effects is crucial to mitigating product degradation by secondary reactions with hydroxyl radicals and oxidation products (specifically H2O2 and •O2–). These findings demonstrate the potential of ultrasound as a driver for the selective oxidation of aldehyde functions to carboxylic acids, offering a sustainable route for converting biomass-derived platform molecules into valuable products
Localized nanopore fabrication in silicon nitride membranes by femtosecond laser exposure and subsequent controlled breakdown.
No full textControlled breakdown (CBD) has emerged as an effective method for fabricating solid-state nanopores in thin suspended dielectric membranes for various biomolecular sensing applications. On an unpatterned membrane, the site of nanopore formation by controlled breakdown is random. Nanopore formation on a specific site on the membrane has previously been realized using local thinning of the membrane by lithographic processes or laser-assisted photothermal etching under immersion in an aqueous salt solution. However, these approaches require elaborate and expensive cleanroom-based lithography processes or involve intricate procedures using custom-made equipment. Here, we present a rapid cleanroom-free approach using single pulse femtosecond laser exposures of 50 nm thick silicon nitride membranes in air to localize the site of nanopore formation by subsequent controlled breakdown to an area less than 500 nm in diameter on the membrane. The precise positioning of the nanopores on the membrane could be produced both using laser exposure powers which caused significant thinning of the silicon nitride membrane (up to 60 % of the original thickness locally), as well as at laser powers which caused no visible modification of the membrane at all. We show that nanopores made using our approach can work as single-molecule sensors by performing dsDNA translocation experiments. Due to the applicability of femtosecond laser processing to a wide range of membrane materials, we expect our approach to simplify the fabrication of localized nanopores by controlled breakdown in a variety of thin film material stacks, thereby enabling more sophisticated nanopore sensors