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Renal fibrosis, a detrimental feature of irreversible kidney damage, remains a sinister consequence of long-term calcineurin inhibitor (CNI) immunosuppressive therapy. Our study not only incorporates renal fibroblasts into the growing list of cell types negatively impacted by CNIs but also identifies renal fibroblast-to-myofibroblast transition as a process mediated via a TGF-β-dependent mechanism. This insight will direct future studies investigating the feasibility of inhibiting TGF-β signaling to maintain CNI-mediated immunosuppression while ultimately preserving kidney health.

This roundtable takes up old themes and new perspectives in the field of political history. Scholars engage with six questions across three main categories: the scope of the field, current debates, and teaching. The first two questions ask how we should think about political power and the boundaries of what constitute political history. The section on current debates interrogates the relationship between governing and social movements during the GAPE, and how to situate the political violence of the January 6, 2021, Capitol Hill riot in historical perspective. The final section on teaching takes up two very different challenges. One question is a perennial concern about connecting with students in the classroom about political history. The other dilemma is how to respond to the growing cascade of censorship laws passed by state legislatures that prohibit the teaching of so-called “divisive concepts.”

We report the synthesis of alternating poly(lactic-co-glycolic acid) via a regioselective ring-opening polymerization of (S)-methyl glycolide. An enantiopure aluminum salen catalyst with binaphthyl backbone facilitates the regioselective ring-opening of this unsymmetrical cyclic diester exclusively at the glycolide acyl-oxygen bond site. This living, chain-growth polymerization is able to reach low dispersities with tailored molecular weights. Quantitative regioselectivity calculations and sequence error analysis have been established for this sequence-controlled polymer.

A new general synthetic approach to sequenced macromolecules was developed and applied to the synthesis of polymers comprising lactic acid (L), glycolic acid (G), and e-caprolactone (C)-derived monomer units. The new method employs entropy-driven ring-opening metathesis polymerization (ED-ROMP) to prepare copolymers with embedded sequences and controlled molecular weights. Cyclic macromonomer precursors were prepared by ring-closing metathesis of ethylene glycol (Eg)-linked sequenced oligomers bearing terminal olefins. ED-ROMP of the resulting macrocycles using Grubbs’ second generation catalyst yielded poly(CL-Eg-LC-Oed), poly(CLL-Eg-LLC-Oed), poly(LGL-Eg-LGL-Oed), and poly(LGL-Eg-LGL-Hed) (Oed = octenedioc acid; Hed = hexenedioc acid). Hydrogenation produced the saturated sequenced copolymers. Molecular weight was well-controlled and could be adjusted by varying the monomer-to-catalyst ratio. Mns of 26–60 kDa were obtained (dispersities = 1.1–1.3). The methodology proved general for three different sequ...

The dawn of the 21st century has brought with it an increasing interest in emulating the adaptive finesse of natural systems by designing materials with on-demand, tunable properties. The creation of such responsive systems could be expected, based on historical precedent, to lead to completely new engineering design paradigms. Using a bioinspired approach of coupling multiple equilibria that operate on different length scales, a material whose bulk mechanical properties can be manipulated by electrical input has been developed. The new macroscale electroplastic elastomer hydrogels can be reversibly cycled through soft and hard states while maintaining a three-dimensional shape by sequential application of oxidative and reductive potentials. This input changes the cross-linking capacity of iron ions within the gel matrix, between a poorly coordinating +2 and a more strongly binding +3 oxidation state. Inclusion of carbon nanotubes in the hydrogel preparation increases conductivity and decreases transition time.

Process oriented guided inquiry learning (POGIL) is a specific type of active learning centered on a learning cycle where students first explore a concept through scientific models, followed by a c...

Functional precision polymers based on monodisperse oligo(N-substituted acrylamide)s and oligo(2-substituted-α-hydroxy acid)s have been synthesized. The discrete sequences originate from a direct translation of side-chain functionality sequences of a peptide with well-studied properties. The peptide was previously selected to solubilize the photosensitizer meta-tetra(hydroxyphenyl)chlorin. The resulting peptidomimetic formulation additives preserve the drug solubilization and release characteristics of the parent peptide. In some cases, superior properties are obtained, reaching up to 40 % higher payloads and 27-times faster initial drug release.

The extent to which small changes in monomer sequence affect the behaviors of biological macromolecules is studied regularly, yet the dependence of bulk properties on small sequence alterations is underexplored for synthetic copolymers. Investigations of this type are limited by the arduous syntheses required, lack of scalability, and scarcity of examples of polymer systems that are known to exhibit sensitive sequence/property dependencies. Our group has previously explored the hydrolysis behaviors of a library of sequenced poly(lactic-co-glycolic acid)s and found a strong correlation with the L–G sequence. To investigate the degree to which properties are dominated in this system by relatively short-range sequence changes, we have incorporated precisely sequenced and mildly “scrambled” L–G oligomers into cyclic macromonomers and subjected them to entropy-driven ring-opening metathesis polymerization, a method that we have recently shown produces polymers with molecular weight control and sequence preserv...

Despite the known sensitivity to sequence mutations of biological polymers, little is known about the effects of errors in sequenced synthetic copolymers. The degradation behaviors of copolyesters, for example, are known to depend on monomer-by-monomer order, yet the contribution of isolated monomer substitutions on hydrolysis behaviors has not been studied. We have developed a synthetic method in which precise quantities of a critical sequence error are doped into a sequenced polyester and studied how hydrolysis behaviors are affected by this distinct and potent sequence-error. The degradation rate proved tolerant to substitutions up to 1% of the monomers but accelerated significantly when the error population was larger.

Heterogeneous “linkers” are incorporated into polymers for a number of reasons, most commonly to facilitate the coupling of the targeted backbone segments. Due to their inclusion in the backbone, these linkers have the potential to affect the overall properties of the copolymer, even when present in relatively low weight percentages. To characterize the degree of impact of some common linkers, a set of polymers that incorporate both degradable sequenced segments and linkers were synthesized and systematically examined. Seven sequence-controlled olefin containing ester macrocycles were prepared, each with a unique central moiety, including a five-carbon alkyl chain, diethylene glycol, a urea, a thioether, a triazole, a bioaromatic, and an extension of the ester sequence. The macrocycles were polymerized via ED-ROMP to yield seven polymers that vary only in the the linker segment. The properties of all polymers were compared to determine the relative dominance of the different linker types. The properties tested in the study included thermal behavior, mechanical characteristics, hydrolytic degradation and film qualities. The thermal and mechanical properties proved to be dependent primarily on the ability of the linker to promote interchain interactions, as well as the weight fraction of the linker, whereas the hydrolytic degradation was dominated by the relative hydrophobicity of the linker groups. In all cases, the linker identity was a significant contributer to the behavior.

The hydrolytic behavior and physical properties of a polymer are directly related to its constituent monomer sequence, yet the scalable and controllable synthesis of sequenced copolymers remains scarcely realized. To address this need, an enhanced version of entropy-driven ring-opening metathesis polymerization (ED-ROMP) has been developed. An unprecedented level of control is obtained by exploiting the kinetic and thermodynamic differences in the metathesis activity of cis- and trans-olefins embedded in large, unstrained macrocycles. First-order rate kinetics were observed, and polymer molecular weights were found to be proportional to catalyst loading. Computational analysis suggests that incorporation of a cis-olefin into the monomer backbone both introduces a thermodynamic driving force and increases the population of metathesis-active conformers. This approach offers a generally applicable method for enhancing living character in ED-ROMP.

Controlling the backbone architecture of poly(lactic-co-glycolic acid)s (PLGAs) is demonstrated to have a strong influence on the production and release of acidic degradation by-products in microparticle matrices. Previous efforts for controlling the internal and external accumulation of acidity for PLGA microparticles have focused on the addition of excipients including neutralization and anti-inflammatory agents. In this report, we utilize a sequence-control strategy to tailor the microstructure of PLGA. The internal acidic microclimate distributions within sequence-defined and random PLGA microparticles were monitored in vitro using a non-invasive ratiometric two-photon microscopy (TPM) methodology. Sequence-defined PLGAs were found to have minimal changes in pH distribution and lower amounts of percolating acidic by-products. A parallel scanning electron microscopy study further linked external morphological events to internal degradation-induced structural changes. The properties of the sequenced and random copolymers characterized in vitro translated to differences in in vivo behavior. The sequence alternating copolymer, poly LG, had lower granulomatous foreign-body reactions compared to random racemic PLGA with a 50:50 ratio of lactic to glycolic acid. Statement of Significance This paper demonstrates that changing the monomer sequence in poly(lactic-co-glycolic acid)s (PLGAs) leads to dramatic differences in the rate of degradation and the internal acidic microclimate of microparticles degrading in vitro. We note that the acidic microclimates within these particles were imaged for the first time with two-photon microscopy, which gives an extremely clear and detailed picture of the degradation process. Importantly, we also document that the observed sequence-controlled in vitro processes translate into differences in the in vivo behavior of polymers which have the same L to G composition but differing microstructures. These data, placed in the context of our prior studies on swelling, erosion, and MW loss (Biomaterials 2017, 117, 66 and other references cited within the manuscript), provide significant insight not only about sequence effects in PLGAs but into the underlying mechanisms of PLGA degradation in general.

The synthesis and characterization of sequenced copolymers is a relatively underdeveloped field despite the fact that biological polymer properties are known to depend directly on sequence. The concept of sequence fidelity is introduced and defined for repeating sequence copolymers as the ratio of repeat units of the target sequence to the total number of repeat units. 1H NMR spectroscopy and matrix-assisted laser desorption/ionization time-of- flight mass spectrometry (MALDI–ToF MS) are used to characterize the sequence fidelity of repeating sequenced copolymers comprising poly(lactic-co-glycolic acid)s. Both characterization methods are found to have both advantages and weaknesses with regard to identifying and quantifying error in these copolymers. A method for using routine MALDI–ToF MS data to quantify sequence fidelity is proposed and applied to a series of copolymers with synthetically defined error rates. The MS-determined sequence fidelities are comparable to those obtained by NMR analysis.

To understand the influence of monomer sequence on the properties and performance of conjugated oligomers, a series of dimers, trimers, and tetramers were prepared from phenylene (P) and benzothiadiazole (B) monomers linked by vinylene groups. Optical and electrochemical studies established the influence of sequence on both the λmax and redox potentials of this series of structurally related oligomers. For tetramers with bromo end groups (PBBP, BPPB, PBPB, PPBB), the λmax ranged from 493 to 512 nm (Δ = 19 nm), the electrochemical oxidation potential from 0.65 to 0.82 (Δ = 0.17 V) and the reduction potential from −1.45 to −1.31 (Δ = 0.14 V), all of which are sequence-dependent. The effect of end groups (cyano, bromo, and alkyl) was also demonstrated to be important for the properties of these oligomers. DFT calculations of the tetramers were performed and the energy levels were correlated well with the experimentally determined spectroscopic data. Bulk heterojunction (BHJ) solar cells fabricated with selec...

The bulk properties of a copolymer are directly affected by monomer sequence, yet efficient, scalable, and controllable syntheses of sequenced copolymers remain a defining challenge in polymer science. We have previously demonstrated, using polymers prepared by a step-growth synthesis, that hydrolytic degradation of poly(lactic- co-glycolic acid)s is dramatically affected by sequence. While much was learned, the step-growth mechanism gave no molecular weight control, unpredictable yields, and meager scalability. Herein, we describe the synthesis of closely related sequenced polyesters prepared by entropy-driven ring-opening metathesis polymerization (ED-ROMP) of strainless macromonomers with imbedded monomer sequences of lactic, glycolic, 6-hydroxy hexanoic, and syringic acids. The incorporation of ethylene glycol and metathesis linkers facilitated synthesis and provided the olefin functionality needed for ED-ROMP. Ring-closing to prepare the cyclic macromonomers was demonstrated using both ring-closing metathesis and macrolactonization reactions. Polymerization produced macromolecules with controlled molecular weights on a multigram scale. To further enhance molecular weight control, the macromonomers were prepared with cis-olefins in the metathesis-active segment. Under these selectivity-enhanced (SEED-ROMP) conditions, first-order kinetics and narrow dispersities were observed and the effect of catalyst initiation rate on the polymerization was investigated. Enhanced living character was further demonstrated through the preparation of block copolymers. Computational analysis suggested that the enhanced polymerization kinetics were due to the cis-macrocyclic olefin being less flexible and having a larger population of metathesis-reactive conformers. Although used for polyesters in this investigation, SEED-ROMP represents a general method for incorporation of sequenced segments into molecular weight-controlled polymers.

To investigate the sequence effect on donor-acceptor conjugated oligomers and polymers, the trimeric isomers PBP and BPP, comprising dialkoxy phenylene vinylene (P), benzothiadiazole vinylene (B), and alkyl endgroups with terminal olefins, are synthesized. Sequence effects are evident in the optical/electrochemical properties and thermal properties. Absorption maxima for PBP and BPP differ by 41 nm and the electrochemical band gaps by 0.1 V. The molar emission intensity is five times greater in PBP than BPP. Both trimers are crystalline and the melting points differ by 17 °C. The PBP and BPP trimers are used as macromonomers in an acyclic diene metathesis polymerization to give PolyPBP and PolyBPP. The optical and electrochemical properties are similar to those of their trimer precursors-sequence effects are still evident. These results suggest that sequence is a tunable variable for electronic materials and that the polymerization of oligomeric sequences is a useful approach to introducing sequence into polymers.

A unique class of stimuli-responsive hydrogels, termed electroplastic elastomers (EPEs), whose mechanical properties can be reversibly tuned between hard and soft states with the application of an electric potential, is described. Electrochemically reversible cross-links formed within a permanent, covalently cross-linked polymeric hydrogel network are switched between strongly binding Fe3+ and weak to nonbinding Fe2+, as determined by potentiometric titration. With the incorporation of graphene oxide (GO) into the EPE, a significant enhancement in modulus and toughness was observed, allowing for the preparation of thinner EPE samples, 80–100 μm in thickness, which could be reversibly cycled between soft (Young’s modulus: ∼0.38 MPa) and hard (∼2.3 MPa) states over 30 min. Further characterization of EPE samples by magnetic susceptibility measurements suggests the formation of multinuclear iron clusters within the gel.

The effect of the bridging ligand on electronic delocalization was examined in a series p-bis(alkoxy)benzene dimers relevant to conducting polymers used for organic devices. Using spectroscopic methods, the degree of delocalization for an ethylene-bridged p-bis(alkoxy)benzene dimer was determined and compared to the electronic coupling for directly coupled and phenylene-bridged p-bis(alkoxy)benzene dimers reported previously. Despite a significant increase in distance (53%) between the redox-active sites, the ethylene-bridged compound exhibited a higher electronic coupling than either of the others previously reported. The increased coupling can be attributed to the lower rotational barrier to planarization for the ethylene-bridged dimer. This result highlights the need to minimize both sterics and distance between redox active sites in molecular systems designed for promoting electron mobility and provides quantitative evidence that an optimal balance between these parameters can be achieved.