Quantification of thermodynamic effects of carbohydrate multivalency on avidity using synthetic discrete glycooligomers.

A quantitative understanding of thermodynamic effects of avidity in biomolecular interactions is important. Herein, we synthesized discrete glycooligomers and evaluated their interactions with a model protein using isothermal titration calorimetry. The dimeric glycooligomer exhibited higher binding constants compared to the glycomonomer, attributed to the reduced conformational entropy loss through local presentation of multiple carbohydrate units. Conversely, divalent glycoligands with polyethylene glycol linkers, aiming for multivalent binding, showed enhanced interactions through increased enthalpy. These findings emphasize the importance of distinguishing between the "local avidity" and the "multipoint avidity".

Optical Property Control by the Interligand Charge Transfer Excited State in Brominated Homoleptic and Heteroleptic Aluminum Dinuclear Triple-Stranded Helicates.

The utilization of aluminum, an abundant and inexpensive element, for the synthesis of novel functional complexes is extremely important, but the design and control of photofunctionality are still unexplored. In this study, we focused on our previously developed dinuclear triple-stranded helicates incorporating two aluminum ions (ALPHY) to synthesize both homoleptic and heteroleptic complexes with bromine atoms at the 3-position of the pyrrole moiety in the Schiff base ligands. The brominated Schiff base ligands were reacted with AlCl3 to synthesize homoleptic complexes, while different ligands were mixed to prepare heteroleptic complexes. Single-crystal X-ray structural analysis revealed the structures of these novel complexes. We found that increasing the degree of bromination resulted in a tunable emission color, shifting progressively from 550 (yellow) to 566 nm (orange). Optical resolution of the complexes facilitated the observation of mirror-image circular dichroism and circularly polarized luminescence. Furthermore, employing ultrafast spectroscopy techniques, we have elucidated that the optical properties are governed by the interligand charge transfer (ILCT) among the three ligands. The formation of heteroleptic complexes induces the ILCT state even in nonpolar environments, thereby accelerating nonradiative decay and intersystem crossing. These findings mark significant advancements in photofunctional materials based on multinuclear complexes.

Laser Patterning of Porous Support Membranes to Enhance the Effective Surface Area of Thin-Film Composite-Facilitated Transport Membranes for CO2 Separation.

Although thin-film composite membranes have achieved great success in CO2 separation, further improvements in the CO2 permeance are required to reduce the size and cost of the CO2 separation process. Herein, we report the fabrication of composite membranes with high CO2 permeability using a laser-patterned porous membrane as the support membrane. High-aspect-ratio micropatterns with well-defined micropores on their surface were carved on microporous polymer supports by a direct laser writing process using a short-pulsed laser. By using a Galvano scanner and optimizing the laser conditions and target materials, in-plane micropatterns, such as microhole arrays, microline grating, microlattices, and out-of-plane hierarchical micropatterns, were created on porous membranes. An aqueous suspension of hydrogel microparticles doped with an amine-based mobile carrier was sprayed onto the patterned surface to form a defect-free thin separation layer. The surface area of the separation layer on the patterned support is up to 80% larger than that of flat pristine membranes, resulting in a 52% higher CO2 permeance (1106 GPU) with a CO2/N2 selectivity of 172. The laser-patterned porous membranes allow the development of inexpensive and high-performance functional membranes not only for CO2 separation but also for other applications, such as water treatment, cell culture, micro-TAS, and membrane reactors.

Simultaneous discovery of chiral and achiral dyes: elucidating the optical functions of helical and flag-hinged boron tetradentate complexes.

The construction of novel complexes can lead to the manifestation of unexpected structures and properties, thereby making chemical exploration in experiments a potential source for novel discoveries. In this study, by reacting 6,6'-dihydrazineyl-2,2'-bipyridine with acyl chlorides and subsequently coordinating with boron trifluoride, two different boron-tetradentate ligand complexes were simultaneously generated. One of these complexes exhibited a unique structure in which tetra-BF2 moieties coordinated to all four coordination sites of the ligand molecule, forming a flag-hinged structure around the bipyridine part. The second complex featured a helical structure formed by the hybridization of two BF2 and one B-O-B moieties, representing a highly unusual form of the complex. The structures of these two boron complexes were consistently observed when various substituted acyl chlorides were employed. Furthermore, it was found that enhancing electron-donor properties could induce a redshift in emissions. Utilizing the dimethylamino group as the proton receptor promoted a yellow-to-blue fluorescence switch in the tetra-BF2 complex and an OFF/ON fluorescence in the B-O-B bridged complex upon protonation. The helical chirality observed in the latter complex resulted in stable (P)/(M)-enantiomers after optical resolution. This complex exhibited circular dichroism with a |gabs| of up to 1.2 × 10-2 and circularly polarized luminescence with a |glum| on the order of 10-3 in solution and polymer film.

Effects of Cyclic Glycopolymers Molecular Mobility on their Interactions with Lectins.

Cyclic polymers, which are found in the field of biopolymers, exhibit unique physical properties such as suppressed molecular mobility. Considering thermodynamics, the suppressed molecular mobility of cyclic polymers is expected to prevent unfavorable entropy loss in molecular interactions. In this study, we synthesized cyclic glycopolymers carrying galactose units and investigated the effects of their molecular mobility on the interactions with a lectin (peanut agglutinin). The synthesized cyclic glycopolymers exhibited delayed elution time on size exclusion chromatography and a short spin-spin relaxation time, indicating typical characteristics of cyclic polymers, including smaller hydrodynamic size and suppressed molecular mobility. The hemagglutination inhibition assay revealed that the cyclic glycopolymers exhibited weakened interactions with PNA compared to the linear counterparts, attributable to the suppressed molecular mobility. Although the results are contrary to our expectations, the impact of polymer topology on molecular recognition remains intriguing, particularly in the context of protein repellent activity in the biomedical field.

Unraveling the Remarkable Influence of Substituents on the Emission Variation and Circularly Polarized Luminescence of Dinuclear Aluminum Triple-Stranded Helicates.

This study explored the development of functional dyes using aluminum, focusing on aluminum-based dinuclear triple-stranded helicates, and examined the effects of substituent variations on their structural and optical properties. Key findings revealed that the modification of methyl groups to the pyrrole positions significantly extended the conjugation system, resulting in a red shift in the absorption and emission spectra. Conversely, the modification of methyl groups at the methine positions due to steric hindrances increased the torsion angle of the ligands, leading to a blue shift in the absorption and emission spectra. A common feature across all complexes was that in the excited state, one of the three ligands underwent significant structural relaxation. This led to a pronounced Stokes shift and minimal spectra overlap with high photoluminescence behaviors. Moreover, our research extended to the optical resolution of the newly synthesized complexes by analyzing the chiroptical properties of the resulting enantiomers, including their circular dichroism and circularly polarized luminescence. These insights offer valuable contributions to the design and application of novel aluminum-based functional dyes, potentially influencing a range of fields, from materials science to optoelectronics.

Design Rationale for CO2 Separation Membranes with Micropatterned Surface Structures.

Here, we report the design rationale of CO2 separation membranes with micropatterned surface structures. Thin film composite (TFC) membranes with micropatterned surface structures were fabricated by spray coating amine-containing hydrogel particles on the top of micropatterned porous support membranes, which were synthesized by a polymerization-induced phase separation process in a micromold (PIPsµM). The pore size of the support membranes was optimized by tuning the proportion of good and poor solvents for the polymerization process so that the microgels would be assembled as a defect-free separation layer. The relationship between the size of the micropatterned structures on the surface of the support membrane and the thickness of the separation layer was optimized to maximize the surface area of the separation layer. The rationally designed micropatterned TFC membrane showed a CO2 permeability (835.8 GPU) proportional to the increase in surface area relative to the flat membrane with a high CO2/N2 selectivity of 58.7. The rational design for micropatterned TFC membranes will enable the development of inexpensive and high-performance functional membranes not only for CO2 separation but also for other applications such as water treatment and membrane reactors.

Role of Halobenzene Guest Molecules in Modulating Room Temperature Phosphorescence of Benzophenone-Naphthalene Diimide Inclusion Crystals.

Materials exhibiting room temperature phosphorescence (RTP) have recently emerged as a subject of significant interest. In this study, we successfully created inclusion crystals by introducing halobenzenes as guests into a host molecule combining benzophenone with naphthalene diimide. This approach led to the creation of fascinating fluorescence and RTP properties dependent on the guest molecules. Notably, crystals containing chlorobenzene showed cyan fluorescence, while those with iodobenzene displayed red RTP. This difference highlights the impact of the guest molecule on the luminescent properties, with the significant external heavy-atom effect of iodobenzene playing a key role in promoting efficient intersystem crossing between the excited singlet and triplet states. Crystals with bromobenzene exhibited a unique blend of fluorescence and RTP, both from benzophenone and naphthalene diimide, highlighting the moderate heavy-atom effect. These findings reveal composite materials with remarkably diverse and interesting optical characteristics.

Design of an Anti-HMGB1 Synthetic Antibody for In Vivo Ischemic/Reperfusion Injury Therapy.

High-mobility group box 1 (HMGB1) is a multifunctional protein. Upon injury or infection, HMGB1 is passively released from necrotic and activated dendritic cells and macrophages, where it functions as a cytokine, acting as a ligand for RAGE, a major receptor of innate immunity stimulating inflammation responses including the pathogenesis of cerebral ischemia/reperfusion (I/R) injury. Blocking the HMGB1/RAGE axis offers a therapeutic approach to treating these inflammatory conditions. Here, we describe a synthetic antibody (SA), a copolymer nanoparticle (NP) that binds HMGB1. A lightly cross-linked N-isopropylacrylamide (NIPAm) hydrogel copolymer with nanomolar affinity for HMGB1 was selected from a small library containing trisulfated 3,4,6S-GlcNAc and hydrophobic N-tert-butylacrylamide (TBAm) monomers. Competition binding experiments with heparin established that the dominant interaction between SA and HMGB1 occurs at the heparin-binding domain. In vitro studies established that anti-HMGB1-SA inhibits HMGB1-dependent ICAM-1 expression and ERK phosphorylation of HUVECs, confirming that SA binding to HMGB1 inhibits the proteins' interaction with the RAGE receptor. Using temporary middle cerebral artery occlusion (t-MCAO) model rats, anti-HMGB1-SA was found to accumulate in the ischemic brain by crossing the blood-brain barrier. Significantly, administration of anti-HMGB1-SA to t-MCAO rats dramatically reduced brain damage caused by cerebral ischemia/reperfusion. These results establish that a statistical copolymer, selected from a small library of candidates synthesized using an "informed" selection of functional monomers, can yield a functional synthetic antibody. The knowledge gained from these experiments can facilitate the discovery, design, and development of a new category of drug.

Sheltering Mono-P-Ligated Metal Complexes in Porous Polystyrene Monolith: Effect of Aryl Pendant Stabilizers on Catalytic Durability.

Metal centers that can generate coordinatively unsaturated metals in accessible and stable states have been developed using synthetic polymers with sophisticated ligand and scaffold designs, which required synthetic efforts. Herein, we report a simple and direct strategy for producing polymer-supported phosphine-metal complexes, which stabilizes mono-P-ligated metals by modulating the electronic properties of the aryl pendant groups in the polymer platform. A three-fold vinylated PPh3 was copolymerized with a styrene derivative and a cross-linker to produce a porous polystyrene-phosphine hybrid monolith. Based on the Hammett substituent constants, the electronic properties of styrene derivatives were modulated and incorporated into the polystyrene backbone to stabilize the mono-P-ligated Pd complex via Pd-arene interactions. Through NMR, TEM, and comparative catalytic studies, the polystyrene-phosphine hybrid, which induces selective mono-P-ligation and moderate Pd-arene interactions, demonstrated high catalytic durability for the cross-coupling of chloroarenes under continuous-flow conditions.

Cooling-induced, localized release of cytotoxic peptides from engineered polymer nanoparticles in living mice for cancer therapy.

Temperature-responsive polymers are often characterized by an abrupt change in the degree of swelling brought about by small changes in temperature. Polymers with a lower critical solution temperature (LCST) in particular, are important as drug and gene delivery vehicles. Drug molecules are taken up by the polymer in their solvent swollen state below their LCST. Increasing the temperature above the LCST, typically physiological temperatures, results in desolvation of polymer chains and microstructure collapse. The trapped drug is released slowly by passive diffusion through the collapsed polymer network. Since diffusion is dependent on many variables, localizing and control of the drug delivery rate can be challenging. Here, we report a fundamentally different approach for the rapid (seconds) tumor-specific delivery of a biomacromolecular drug. A copolymer nanoparticle (NP) was engineered with affinity for melittin, a peptide with potent anti-cancer activity, at physiological temperature. Intravenous injection of the NP-melittin complex results in its accumulation in organs and at the tumor. We demonstrate that by local cooling of the tumor the melittin is rapidly released from the NP-melittin complex. The release occurs only at the cooled tumor site. Importantly, tumor growth was significantly suppressed using this technique demonstrating therapeutically useful quantities of the drug can be delivered. This work reports the first example of an in vivo site-specific release of a macromolecular drug by local cooling for cancer therapy. In view of the increasing number of cryotherapeutic devices for in vivo applications, this work has the potential to stimulate cryotherapy for in vivo drug delivery.

4-Amino-TEMPO-Immobilized Polymer Monolith: Preparations, and Recycling Performance of Catalyst for Alcohol Oxidation.

Continuous flow reactors with immobilized catalysts are in great demand in various industries, to achieve easy separation, regeneration, and recycling of catalysts from products. Oxidation of alcohols with 4-amino-TEMPO-immobilized monolith catalyst was investigated in batch and continuous flow systems. The polymer monoliths were prepared by polymerization-induced phase separation using styrene derivatives, and 4-amino-TEMPO was immobilized on the polymer monolith with a flow reaction. The prepared 4-amino-TEMPO-immobilized monoliths showed high permeability, due to their high porosity. In batch oxidation, the reaction rate of 4-amino-TEMPO-immobilized monolith varied with stirring. In flow oxidation, the eluent permeated without clogging, and efficient flow oxidation was possible with residence times of 2-8 min. In the recycling test of the flow oxidation reaction, the catalyst could be used at least six times without catalyst deactivation.

[A CHILD CASE OF DIFFUSE CUTANEOUS MASTOCYTOSIS].

Cutaneous mastocytosis (CM) usually appears in childhood and improves substantially before adolescence. The c-KIT mutation of D816V is present in 36% and 20% of patients with childhood-onset CM and diffuse cutaneous mastocytosis (DCM), respectively. In some cases of childhood-onset DCM, the disease can progress to systemic mastocytosis; in others, it resolves spontaneously. Thus, assessing the prognosis is difficult. Herein, we described a case of DCM in an 11-month-old, male patient without a c-KIT mutation. The patient presented with dark brown macules and sporadic erythema topped by bullous lesions. A skin biopsy of the macule on the abdomen revealed accumulation of mast cells which were round to oval-shaped with amphophilic cytoplasm within the upper dermis. The patient had received H1 inhibitor until age 3 years and continued to experience blisters on the trunk. However, no severe symptoms, such as anaphylaxis, occurred. Included in this manuscript is a review of previous reports of childhood-onset DCM in Japan and cases specifically seen at our dermatology clinic.

Polymer Nanoparticles with Uniform Monomer Sequences for Sequence-Specific Peptide Recognition.

Synthetic polymer nanoparticles (NPs) that recognize and neutralize target biomacromolecules are of considerable interest as "plastic antibodies", synthetic mimics of antibodies. However, monomer sequences in the synthetic NPs are heterogeneous. The heterogeneity limits the target specificity and safety of the NPs. Herein, we report the synthesis of NPs with uniform monomer sequences for recognition and neutralization of target peptides. A multifunctional oligomer with a precise monomer sequence that recognizes the target peptide was prepared via cycles of reversible addition-fragmentation chain transfer (RAFT) polymerization and flash chromatography. The oligomer or blend of oligomers was used as a chain transfer agent and introduced into poly(N-isopropyl acrylamide) hydrogel NPs by radical polymerization. Evaluation of the interaction with the peptides revealed that multiple oligomers in NPs cooperatively recognized the sequence of the target peptide and neutralized its toxicity. Effect of sequence, combination, density and molecular weight distribution of precision oligomers on the affinity to the peptides was also investigated.

Facile Preparation of a Glycopolymer Library by PET-RAFT Polymerization for Screening the Polymer Structures of GM1 Mimics.

Commercialized oligosaccharides such as GM1 are useful for biological applications but generally expensive. Thus, facile access to an effective alternative is desired. Glycopolymers displaying both carbohydrate and hydrophobic units are promising materials as alternatives to oligosaccharides. Prediction of the appropriate polymer structure as an oligosaccharide mimic is difficult, and screening of the many candidates (glycopolymer library) is required. However, repeating polymerization manipulation for each polymer sample to prepare the glycopolymer library is time-consuming. Herein, we report a facile preparation of the glycopolymer library of GM1 mimics by photoinduced electron/energy transfer-reversible addition-fragmentation chain-transfer (PET-RAFT) polymerization. Glycopolymers displaying galactose units were synthesized in various ratios of hydrophobic acrylamide derivatives. The synthesized glycopolymers were immobilized on a gold surface, and the interactions with cholera toxin B subunits (CTB) were analyzed using surface plasmon resonance imaging (SPRI). The screening by SPRI revealed the correlation between the log P values of the hydrophobic monomers and the interactions of the glycopolymers with CTB, and the appropriate polymer structure as a GM1 mimic was determined. The combination of the one-time preparation and the fast screening of the glycopolymer library provides a new strategy to access the synthetic materials for critical biomolecular recognition.

A QCM study of strong carbohydrate-carbohydrate interactions of glycopolymers carrying mannosides on substrates.

Carbohydrates on cell surfaces are known to interact not only with lectins but also with other carbohydrates; the latter process is known as a carbohydrate-carbohydrate interaction. Such interactions are observed in complex oligosaccharides. It would be surprising if these interactions were observed in simple monosaccharides of mannose. In this study, the interaction between glycopolymers carrying monosaccharides of mannose was quantitatively investigated by quartz crystal microbalance measurements. We measured the interactions with glycopolymers carrying mannose, galactose and glucose. Surprisingly, the interaction between the glycopolymers and mannose was much stronger than that between other saccharides.

De Novo Design of Star-Shaped Glycoligands with Synthetic Polymer Structures toward an Influenza Hemagglutinin Inhibitor.

Synthetic polymers with well-defined structures allow the development of nanomaterials with additional functions beyond biopolymers. Herein, we demonstrate de novo design of star-shaped glycoligands to interact with hemagglutinin (HA) using well-defined synthetic polymers with the aim of developing an effective inhibitor for the influenza virus. Prior to the synthesis, the length of the star polymer chains was predicted using the Gaussian model of synthetic polymers, and the degree of polymerization required to achieve multivalent binding to three carbohydrate recognition domains (CRDs) of HA was estimated. The star polymer with the predicted degree of polymerization was synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization, and 6'-sialyllactose was conjugated as the glycoepitope for HA. The designed glycoligand exhibited the strongest interaction with HA as a result of multivalent binding. This finding demonstrated that the biological function of the synthetic polymer could be controlled by precisely defining the polymer structures.

Probing the Biogenesis of Polysaccharide Granules in Algal Cells at Sub-Organellar Resolution via Raman Microscopy with Stable Isotope Labeling.

Phototrophs assimilate CO2 into organic compounds that accumulate in storage organelles. Elucidation of the carbon dynamics of storage organelles could enhance the production efficiency of valuable compounds and facilitate the screening of strains with high photosynthetic activity. To comprehensively elucidate the carbon dynamics of these organelles, the intraorganellar distribution of the carbon atoms that accumulate at specific time periods should be probed. In this study, the biosynthesis of polysaccharides in storage organelles was spatiotemporally probed via stimulated Raman scattering (SRS) microscopy using a stable isotope (13C) as the tracking probe. Paramylon granules (a storage organelle of ß-1,3-glucan) accumulated in a unicellular photosynthetic alga, Euglena gracilis, were investigated as a model organelle. The carbon source of the culture medium was switched from NaH12CO3 to NaH13CO3 during the production of the paramylon granules; this resulted in the distribution of the 12C and 13C constituents in the granules, so that the biosynthetic process could be tracked. Taking advantage of high-resolution SRS imaging and label switching, the localization of the 12C and 13C constituents inside a single paramylon granule could be visualized in three dimensions, thus revealing the growth process of paramylon granules. We propose that this method can be used for comprehensive elucidation of the dynamic activities of storage organelles.

Screening of a glycopolymer library for GM1 mimetics synthesized by the "carbohydrate module method".

The "carbohydrate module method" is a promising approach for oligosaccharide mimetics using polymeric materials. However, it is difficult to predict the optimal structure for a particular oligosaccharide mimetic, and an efficient strategy for the synthesis and evaluation of glycopolymers is desirable. In this study, a screening of glycopolymers for the "carbohydrate module method" by a combination of photoinduced electron/energy transfer-reversible addition-fragmentation chain-transfer (PET-RAFT) polymerization and surface plasmon resonance imaging (SPRI) is demonstrated. The facile and fast screening of synthetic glycomimetics was achieved, and the glycopolymer with the optimal structure as a GM1 mimetic strongly interacted with the cholera toxin B subunit.

Synthetic hydrogel nanoparticles for sepsis therapy.

Sepsis is a life-threatening condition caused by the extreme release of inflammatory mediators into the blood in response to infection (e.g., bacterial infection, COVID-19), resulting in the dysfunction of multiple organs. Currently, there is no direct treatment for sepsis. Here we report an abiotic hydrogel nanoparticle (HNP) as a potential therapeutic agent for late-stage sepsis. The HNP captures and neutralizes all variants of histones, a major inflammatory mediator released during sepsis. The highly optimized HNP has high capacity and long-term circulation capability for the selective sequestration and neutralization of histones. Intravenous injection of the HNP protects mice against a lethal dose of histones through the inhibition of platelet aggregation and migration into the lungs. In vivo administration in murine sepsis model mice results in near complete survival. These results establish the potential for synthetic, nonbiological polymer hydrogel sequestrants as a new intervention strategy for sepsis therapy and adds to our understanding of the importance of histones to this condition.