Designing a circular carbon and plastics economy for a sustainable future.

The linear production and consumption of plastics today is unsustainable. It creates large amounts of unnecessary and mismanaged waste, pollution and carbon dioxide emissions, undermining global climate targets and the Sustainable Development Goals. This Perspective provides an integrated technological, economic and legal view on how to deliver a circular carbon and plastics economy that minimizes carbon dioxide emissions. Different pathways that maximize recirculation of carbon (dioxide) between plastics waste and feedstocks are outlined, including mechanical, chemical and biological recycling, and those involving the use of biomass and carbon dioxide. Four future scenarios are described, only one of which achieves sufficient greenhouse gas savings in line with global climate targets. Such a bold system change requires 50% reduction in future plastic demand, complete phase-out of fossil-derived plastics, 95% recycling rates of retrievable plastics and use of renewable energy. It is hard to overstate the challenge of achieving this goal. We therefore present a roadmap outlining the scale and timing of the economic and legal interventions that could possibly support this. Assessing the service lifespan and recoverability of plastic products, along with considerations of sufficiency and smart design, can moreover provide design principles to guide future manufacturing, use and disposal of plastics.

Genomic investigations of unexplained acute hepatitis in children.

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children.

The technological and economic prospects for CO2 utilization and removal.

The capture and use of carbon dioxide to create valuable products might lower the net costs of reducing emissions or removing carbon dioxide from the atmosphere. Here we review ten pathways for the utilization of carbon dioxide. Pathways that involve chemicals, fuels and microalgae might reduce emissions of carbon dioxide but have limited potential for its removal, whereas pathways that involve construction materials can both utilize and remove carbon dioxide. Land-based pathways can increase agricultural output and remove carbon dioxide. Our assessment suggests that each pathway could scale to over 0.5 gigatonnes of carbon dioxide utilization annually. However, barriers to implementation remain substantial and resource constraints prevent the simultaneous deployment of all pathways.

Persistent Low-Level Variants in a Subset of Viral Genes Are Highly Predictive of Poor Outcome in Immunocompromised Patients With Cytomegalovirus Infection.

BACKGROUND: Human cytomegalovirus (HCMV) is the most common and serious opportunistic infection after solid organ and hematopoietic stem cell transplantation. In this study, we used whole-genome HCMV data to investigate viral factors associated with the clinical outcome. METHODS: We sequenced HCMV samples from 16 immunocompromised pediatric patients with persistent viremia. Eight of the 16 patients died of complications due to HCMV infection. We also sequenced samples from 35 infected solid organ adult recipients, of whom 1 died with HCMV infection. RESULTS: We showed that samples from both groups have fixed variants at resistance sites and mixed infections. Next-generation sequencing also revealed nonfixed variants at resistance sites in most of the patients who died (6/9). A machine learning approach identified 10 genes with nonfixed variants in these patients. These genes formed a viral signature that discriminated patients with HCMV infection who died from those who survived with high accuracy (area under the curve = 0.96). Lymphocyte numbers for a subset of patients showed no recovery posttransplant in the patients who died. CONCLUSIONS: We hypothesize that the viral signature identified in this study may be a useful biomarker for poor response to antiviral drug treatment and indirectly for poor T-cell function, potentially identifying early those patients requiring nonpharmacological interventions.

High Molar Mass Polycarbonates as Closed-Loop Recyclable Thermoplastics.

Using carbon dioxide (CO2) to make recyclable thermoplastics could reduce greenhouse gas emissions associated with polymer manufacturing. CO2/cyclic epoxide ring-opening copolymerization (ROCOP) allows for >30 wt % of the polycarbonate to derive from CO2; so far, the field has largely focused on oligocarbonates. In contrast, efficient catalysts for high molar mass polycarbonates are underinvestigated, and the resulting thermoplastic structure-property relationships, processing, and recycling need to be elucidated. This work describes a new organometallic Mg(II)Co(II) catalyst that combines high productivity, low loading tolerance, and the highest polymerization control to yield polycarbonates with number average molecular weight (Mn) values from 4 to 130 kg mol-1, with narrow, monomodal distributions. It is used in the ROCOP of CO2 with bicyclic epoxides to produce a series of samples, each with Mn > 100 kg mol-1, of poly(cyclohexene carbonate) (PCHC), poly(vinyl-cyclohexene carbonate) (PvCHC), poly(ethyl-cyclohexene carbonate) (PeCHC, by hydrogenation of PvCHC), and poly(cyclopentene carbonate) (PCPC). All these materials are amorphous thermoplastics, with high glass transition temperatures (85 < Tg < 126 °C, by differential scanning calorimetry) and high thermal stability (Td > 260 °C). The cyclic ring substituents mediate the materials' chain entanglements, viscosity, and glass transition temperatures. Specifically, PCPC was found to have 10× lower entanglement molecular weight (Me)n and 100× lower zero-shear viscosity compared to those of PCHC, showing potential as a future thermoplastic. All these high molecular weight polymers are fully recyclable, either by reprocessing or by using the Mg(II)Co(II) catalyst for highly selective depolymerizations to epoxides and CO2. PCPC shows the fastest depolymerization rates, achieving an activity of 2500 h-1 and >99% selectivity for cyclopentene oxide and CO2.

Quantifying CO2 Insertion Equilibria for Low-Pressure Propene Oxide and Carbon Dioxide Ring Opening Copolymerization Catalysts.

While outstanding catalysts are known for the ring-opening copolymerization (ROCOP) of CO2 and propene oxide (PO), few are reported at low CO2 pressure. Here, a new series of Co(III)M(I) heterodinuclear catalysts are compared. The Co(III)K(I) complex shows the best activity (TOF = 1728 h-1) and selectivity (>90% polymer, >99% CO2) and is highly effective at low pressures (<10 bar). CO2 insertion is a prerate determining chemical equilibrium step. At low pressures, the concentration of the active catalyst depends on CO2 pressure; above 12 bar, its concentration is saturated, and rates are independent of pressure, allowing the equilibrium constant to be quantified for the first time (Keq = 1.27 M-1). A unified rate law, applicable under all operating conditions, is presented. As proof of potential, published data for leading literature catalysts are reinterpreted and the CO2 equilibrium constants estimated, showing that this unified rate law applies to other systems.

Synergic Catalysis: the Importance of Intermetallic Separation in Co(III)K(I) Catalysts for Ring Opening Copolymerizations.

Dinuclear polymerization catalysts can show high activity and control. Understanding how to design for synergy between the metals is important to improving catalytic performances. Three heterodinuclear Co(III)K(I) catalysts, featuring very similar coordination chemistries, are prepared with different intermetallic separations. The catalysts are compared for the ring-opening copolymerization (ROCOP) of propene oxide (PO) with CO2 or with phthalic anhydride (PA). The catalyst with a fixed, wide intermetallic separation, LwideCoK(OAc)2 (Co-K = 8.06 Å), shows very high activity for PO/PA ROCOP, but is inactive for PO/CO2 ROCOP. On the other hand, the catalyst with a fixed, narrow intermetallic separation, LshortCoK(OAc)2 (Co-K, 3.59 Å), shows high activity for PO/CO2 ROCOP, but is much less active for PO/PA ROCOP. A bicomponent catalyst system, comprising a monometallic complex LmonoCoOAc used with an equivalent of KOAc[18-crown-6], shows high activity for both PO/CO2 and PO/PA ROCOP, provided the catalyst concentration is sufficiently high, but underperforms at low catalyst loadings. It is proposed that the two lead catalysts, LwideCoK(OAc)2 and LshortCoK(OAc)2, operate by different mechanisms for PO/PA and PO/CO2 ROCOP. The new wide separation catalyst, LwideCoK(OAc)2, shows some of the best performances yet reported for PO/PA ROCOP, and suggests other catalysts featuring larger intermetallic separations should be targeted for epoxide/anhydride copolymerizations.

Exploiting Organometallic Chemistry to Functionalize Small Cuprous Oxide Colloidal Nanocrystals.

The ligand chemistry of colloidal semiconductor nanocrystals mediates their solubility, band gap, and surface facets. Here, selective organometallic chemistry is used to prepare small, colloidal cuprous oxide nanocrystals and to control their surface chemistry by decorating them with metal complexes. The strategy is demonstrated using small (3-6 nm) cuprous oxide (Cu2O) colloidal nanocrystals (NC), soluble in organic solvents. Organometallic complexes are coordinated by reacting the surface Cu-OH bonds with organometallic reagents, M(C6F5)2, M = Zn(II) and Co(II), at room temperature. These reactions do not disrupt the Cu2O crystallinity or nanoparticle size; rather, they allow for the selective coordination of a specific metal complex at the surface. Subsequently, the surface-coordinated organometallic complex is reacted with three different carboxylic acids to deliver Cu-O-Zn(O2CR') complexes. Selective nanocrystal surface functionalization is established using spectroscopy (IR, 19F NMR), thermal gravimetric analyses (TGA), transmission electron microscopy (TEM, EELS), and X-ray photoelectron spectroscopy (XPS). Photoluminescence efficiency increases dramatically upon organometallic surface functionalization relative to that of the parent Cu2O NC, with the effect being most pronounced for Zn(II) decoration. The nanocrystal surfaces are selectively functionalized by both organic ligands and well-defined organometallic complexes; this synthetic strategy may be applicable to many other metal oxides, hydroxides, and semiconductors. In the future, it should allow NC properties to be designed for applications including catalysis, sensing, electronics, and quantum technologies.

Kinetic Model for the Heterogeneous Biocatalytic Reactions Using Tethered Cofactors.

Understanding the mechanism of interfacial enzyme kinetics is critical to the development of synthetic biological systems for the production of value-added chemicals. Here, the interfacial kinetics of the catalysis of ß-nicotinamide adenine dinucleotide (NAD+)-dependent enzymes acting on NAD+ tethered to the surface of silica nanoparticles (SiNPs) has been investigated using two complementary and supporting kinetic approaches: enzyme excess and reactant (NAD+) excess. Kinetic models developed for these two approaches characterize several critical reaction steps including reversible enzyme adsorption, complexation, decomplexation, and catalysis of the surface-bound enzyme/NAD+ complex. The analysis reveals a concentrating effect resulting in a very high local concentration of enzyme and cofactor on the particle surface, in which the enzyme is saturated by surface-bound NAD, facilitating a rate enhancement of enzyme/NAD+ complexation and catalysis. This resulted in high enzyme efficiency within the tethered NAD+ system compared to that of the free enzyme/NAD+ system, which increases with decreasing enzyme concentration. The role of enzyme adsorption onto solid substrates with a tethered catalyst (such as NAD+) has potential for creating highly efficient flow biocatalytic systems.

Using a picture-based book to support epilepsy care in clinical consultations for people with intellectual disabilities.

BACKGROUND AND AIMS: People with intellectual disabilities are more likely to have epilepsy than the general population. A picture-based book, Getting on with Epilepsy, may help to improve their epilepsy management and quality of life. The present study aimed to explore how the book could be best used in routine clinical care. METHODS: Twenty people with epilepsy and intellectual disabilities were video-recorded using the Getting on with Epilepsy book with a nurse or doctor. This was analysed using conversation analytic methods. Eighteen patients and five clinicians took part in interviews to explore their views on book use, which were thematically analysed. All data were then synthesised to form themes. RESULTS: Three themes were identified which demonstrated the importance of (1) understanding the book depicted seizures (2) relating the book to the participants' experiences (3) using the book as an education and information tool. The themes highlighted the techniques and approaches that clinicians used to facilitate understanding. Some tensions and differences were noted between training and implementation in routine practice, particularly around prompts in themes 1 and 3 intended to correct or change participants' interpretation of the book. CONCLUSIONS: The Getting on with Epilepsy book can be used in routine clinical practice to support people with intellectual disabilities and epilepsy. There was a balance between exploring patients' narratives and understanding with the need to convey clinical information, and this may also apply to the use of other accessible resources.

Clinical application of whole-genome sequencing in the management of extensively drug-resistant tuberculosis: a case report.

BACKGROUND: Whole-genome sequencing (WGS)-based prediction of drug resistance in Mycobacterium tuberculosis has the potential to guide clinical decisions in the design of optimal treatment regimens. METHODS: We utilized WGS to investigate drug resistance mutations in a 32-year-old Tanzanian male admitted to Kibong'oto Infectious Diseases Hospital with a history of interrupted multidrug-resistant tuberculosis treatment for more than three years. Before admission, he received various all-oral bedaquiline-based multidrug-resistant tuberculosis treatment regimens with unfavourable outcomes. RESULTS: Drug susceptibility testing of serial M. tuberculosis isolates using Mycobacterium Growth Incubator Tubes culture and WGS revealed resistance to first-line anti-TB drugs, bedaquiline, and fluoroquinolones but susceptibility to linezolid, clofazimine, and delamanid. WGS of serial cultured isolates revealed that the Beijing (Lineage 2.2.2) strain was resistant to bedaquiline, with mutations in the mmpR5 gene (Rv0678. This study also revealed the emergence of two distinct subpopulations of bedaquiline-resistant tuberculosis strains with Asp47f and Glu49fs frameshift mutations in the mmpR5 gene, which might be the underlying cause of prolonged resistance. An individualized regimen comprising bedaquiline, delamanid, pyrazinamide, ethionamide, and para-aminosalicylic acid was designed. The patient was discharged home at month 8 and is currently in the ninth month of treatment. He reported no cough, chest pain, fever, or chest tightness but still experienced numbness in his lower limbs. CONCLUSION: We propose the incorporation of WGS in the diagnostic framework for the optimal management of patients with drug-resistant and extensively drug-resistant tuberculosis.

Digital Light Processing to Afford High Resolution and Degradable CO2-Derived Copolymer Elastomers.

Vat photopolymerization 3D printing has proven very successful for the rapid additive manufacturing (AM) of polymeric parts at high resolution. However, the range of materials that can be printed and their resulting properties remains narrow. Herein, we report the successful AM of a series of poly(carbonate-b-ester-b-carbonate) elastomers, derived from carbon dioxide and bio-derived ϵ-decalactone. By employing a highly active and selective Co(II)Mg(II) polymerization catalyst, an ABA triblock copolymer (Mn=6.3 kg mol-1, ÐM=1.26) was synthesized, formulated into resins which were 3D printed using digital light processing (DLP) and a thiol-ene-based crosslinking system. A series of elastomeric and degradable thermosets were produced, with varying thiol cross-linker length and poly(ethylene glycol) content, to produce complex triply periodic geometries at high resolution. Thermomechanical characterization of the materials reveals printing-induced microphase separation and tunable hydrophilicity. These findings highlight how utilizing DLP can produce sustainable materials from low molar mass polyols quickly and at high resolution. The 3D printing of these functional materials may help to expedite the production of sustainable plastics and elastomers with potential to replace conventional petrochemical-based options.

Lithium Borate Polycarbonates for High-Capacity Solid-State Composite Cathodes.

Improving composite cathode function is key to the success of the solid-state battery. Maximizing attainable cathode capacity and retention requires integrating suitable polymeric binders that retain a sufficiently high ionic conductivity and long-term chemo-mechanical stability of the cathode active material-solid-electrolyte-carbon mixture. Herein, we report block copolymer networks composed of lithium borate polycarbonates and poly(ethylene oxide) that improved the capacity (200 mAh g-1 at 1.75 mA cm-2) and capacity retention (94 % over 300 cycles) of all-solid-state composite cathodes with nickel-rich LiNi0.8Co0.1Mn0.1O2 cathode active material, Li6PS5Cl solid electrolyte, and carbon. Tetrahedral B(OR)2(OH)2 - anions immobilized on the polycarbonate segments provide hydrogen-bonding chain crosslinking and selective Li-counterion conductivity, parameterized by Li-ion transference numbers close to unity (tLi+~0.94). With 90 wt % polycarbonate content and a flexible low glass transition temperature backbone, the single-ion conductors achieved high Li-ion conductivities of 0.2 mS cm-1 at 30 °C. The work should inform future binder design for improving the processability of cathode composites towards commercializing solid-state batteries, and allow use in other cell configurations, such as lithium-sulphur cathode designs.

Ring Opening Copolymerization of Boron-Containing Anhydride with Epoxides as a Controlled Platform to Functional Polyesters.

Boron-functionalized polymers are used in opto-electronics, biology, and medicine. Methods to produce boron-functionalized and degradable polyesters remain exceedingly rare but relevant where (bio)dissipation is required, for example, in self-assembled nanostructures, dynamic polymer networks, and bio-imaging. Here, a boronic ester-phthalic anhydride and various epoxides (cyclohexene oxide, vinyl-cyclohexene oxide, propene oxide, allyl glycidyl ether) undergo controlled ring-opening copolymerization (ROCOP), catalyzed by organometallic complexes [Zn(II)Mg(II) or Al(III)K(I)] or a phosphazene organobase. The polymerizations are well controlled allowing for the modulation of the polyester structures (e.g., by epoxide selection, AB, or ABA blocks), molar masses (9.4 < Mn < 40 kg/mol), and uptake of boron functionalities (esters, acids, "ates", boroxines, and fluorescent groups) in the polymer. The boronic ester-functionalized polymers are amorphous, with high glass transition temperatures (81 < Tg < 224 °C) and good thermal stability (285 < Td < 322 °C). The boronic ester-polyesters are deprotected to yield boronic acid- and borate-polyesters; the ionic polymers are water soluble and degradable under alkaline conditions. Using a hydrophilic macro-initiator in alternating epoxide/anhydride ROCOP, and lactone ring opening polymerization, produces amphiphilic AB and ABC copolyesters. Alternatively, the boron-functionalities are subjected to Pd(II)-catalyzed cross-couplings to install fluorescent groups (BODIPY). The utility of this new monomer as a platform to construct specialized polyesters materials is exemplified here in the synthesis of fluorescent spherical nanoparticles that self-assemble in water (Dh = 40 nm). The selective copolymerization, variable structural composition, and adjustable boron loading represent a versatile technology for future explorations of degradable, well-defined, and functional polymers.

Chemical Recycling of Commercial Poly(l-lactic acid) to l-Lactide Using a High-Performance Sn(II)/Alcohol Catalyst System.

Poly(l-lactic acid) (PLLA) is a leading commercial polymer produced from biomass, showing useful properties for plastics and fiber applications; after use, it is compostable. One area for improvement is postconsumer waste PLLA chemical recycling to monomer (CRM), i.e., the formation of l-lactide (l-LA) from waste plastic. This process is currently feasible at high reaction temperatures and shows low catalytic activity accompanied, in some cases, by side reactions, including epimerization. Here, a commercial Sn(II) catalyst, applied with nonvolatile commercial alcohol, enables highly efficient CRM of PLLA to yield l-LA in excellent yield and purity (92% yield, >99% l-LA from theoretical max.). The depolymerization is performed using neat polymer films at low temperatures (160 °C) under a nitrogen flow or vacuum. The chemical recycling operates with outstanding activity, achieving turnover frequencies which are up to 3000× higher than previously excellent catalysts and applied at loadings up to 6000× lower than previously leading catalysts. The catalyst system achieves a TOF = 3000 h-1 at 0.01 mol % or 1:10,000 catalyst:PLLA loading. The depolymerization of waste PLLA plastic packaging (coffee cup lids) produces pure l-LA in excellent yield and selectivity. The new catalyst system (Sn + alcohol) can itself be recycled four times in different PLLA "batch degradations" and maintains its high catalytic productivity, activity, and selectivity.

Coordinated assembly and release of adhesions builds apical junctional belts during de novo polarisation of an epithelial tube.

Using the zebrafish neural tube as a model, we uncover the in vivo mechanisms allowing the generation of two opposing apical epithelial surfaces within the centre of an initially unpolarised, solid organ. We show that Mpp5a and Rab11a play a dual role in coordinating the generation of ipsilateral junctional belts whilst simultaneously releasing contralateral adhesions across the centre of the tissue. We show that Mpp5a- and Rab11a-mediated resolution of cell-cell adhesions are both necessary for midline lumen opening and contribute to later maintenance of epithelial organisation. We propose that these roles for both Mpp5a and Rab11a operate through the transmembrane protein Crumbs. In light of a recent conflicting publication, we also clarify that the junction-remodelling role of Mpp5a is not specific to dividing cells.

Synergic Heterodinuclear Catalysts for the Ring-Opening Copolymerization (ROCOP) of Epoxides, Carbon Dioxide, and Anhydrides.

The development of sustainable plastic materials is an essential target of chemistry in the 21st century. Key objectives toward this goal include utilizing sustainable monomers and the development of polymers that can be chemically recycled/degraded. Polycarbonates synthesized from the ring-opening copolymerization (ROCOP) of epoxides and CO2, and polyesters synthesized from the ROCOP of epoxides and anhydrides, meet these criteria. Despite this, designing efficient catalysts for these processes remains challenging. Typical issues include the requirement for high catalyst loading; low catalytic activities in comparison with other commercialized polymerizations; and the requirement of costly, toxic cocatalysts. The development of efficient catalysts for both types of ROCOP is highly desirable. This Account details our work on the development of catalysts for these two related polymerizations and, in particular, focuses on dinuclear complexes, which are typically applied without any cocatalyst. We have developed mechanistic hypotheses in tandem with our catalysts, and throughout the Account, we describe the kinetic, computational, and structure-activity studies that underpin the performance of these catalysts. Our initial research on homodinuclear M(II)M(II) complexes for cyclohexene oxide (CHO)/CO2 ROCOP provided data to support a chain shuttling catalytic mechanism, which implied different roles for the two metals in the catalysis. This mechanistic hypothesis inspired the development of mixed-metal, heterodinuclear catalysts. The first of this class of catalysts was a heterodinuclear Zn(II)Mg(II) complex, which showed higher rates than either of the homodinuclear [Zn(II)Zn(II) and Mg(II)Mg(II)] analogues for CHO/CO2 ROCOP. Expanding on this finding, we subsequently developed a Co(II)Mg(II) complex that showed field leading rates for CHO/CO2 ROCOP and allowed for unique insight into the role of the two metals in this complex, where it was established that the Mg(II) center reduced transition state entropy and the Co(II) center reduced transition state enthalpy. Following these discoveries, we subsequently developed a range of heterodinuclear M(III)M(I) catalysts that were capable of catalyzing a broad range of copolymerizations, including the ring-opening copolymerization of CHO/CO2, propylene oxide (PO)/CO2, and CHO/phthalic anhydride (PA). Catalysts featuring Co(III)K(I) and Al(III)K(I) were found to be exceptionally effective for PO/CO2 and CHO/PA ROCOP, respectively. Such M(III)M(I) complexes operate through a dinuclear metalate mechanism, where the M(III) binds and activates monomers while the M(I) species binds the polymer change in close proximity to allow for insertion into the activated monomer. Our research illustrates how careful catalyst design can yield highly efficient systems and how the development of mechanistic understanding aids this process. Avenues of future research are also discussed, including the applicability of these heterodinuclear catalysts in the synthesis of sustainable materials.

Dynamic Metalloporphyrin-Based [2]Rotaxane Molecular Shuttles Stimulated by Neutral Lewis Base and Anion Coordination.

A series of dynamic metalloporphyrin [2]rotaxane molecular shuttles comprising of bis-functionalised Zn(II) porphyrin axle and pyridyl functionalised macrocycle components are prepared in high yield via active metal template synthetic methodology. Extensive variable temperature 1 H NMR and quantitative UV-Vis spectroscopic titration studies demonstrate dynamic macrocycle translocation is governed by an inter-component co-ordination interaction between the macrocycle pyridyl and axle Zn(II) metalloporphyrin, which serves to bias a 'resting state' co-conformation. The dynamic shuttling behaviour of the interlocked structures is dramatically inhibited by the addition of a neutral Lewis base such as pyridine, but can also be tuned via post-synthetic rotaxane demetallation of the porphyrin axle core to give free-base, or upon subsequent metallation, Ni(II) [2]rotaxane analogues. Importantly, the Lewis acidic Zn(II) porphyrin axle component is also capable of coordinating anions which induces mechanical bond shuttling behaviour resulting in a novel optical sensing response.

Matched Ligands for Small, Stable Colloidal Nanoparticles of Copper, Cuprous Oxide and Cuprous Sulfide.

This work applies organometallic routes to copper(0/I) nanoparticles and describes how to match ligand chemistries with different material compositions. The syntheses involve reacting an organo-copper precursor, mesitylcopper(I) [CuMes]z (z=4, 5), at low temperatures and in organic solvents, with hydrogen, air or hydrogen sulfide to deliver Cu, Cu2 O or Cu2 S nanoparticles. Use of sub-stoichiometric quantities of protonated ligand (pro-ligand; 0.1-0.2 equivalents vs. [CuMes]z ) allows saturation of surface coordination sites but avoids excess pro-ligand contaminating the nanoparticle solutions. The pro-ligands are nonanoic acid (HO2 CR1 ), 2-[2-(2-methoxyethoxy)ethoxy]acetic acid (HO2 CR2 ) or di(thio)nonanoic acid, (HS2 CR1 ), and are matched to the metallic, oxide or sulfide nanoparticles. Ligand exchange reactions reveal that copper(0) nanoparticles may be coordinated by carboxylate or di(thio)carboxylate ligands, but Cu2 O is preferentially coordinated by carboxylate ligands and Cu2 S by di(thio)carboxylate ligands. This work highlights the opportunities for organometallic routes to well-defined nanoparticles and the need for appropriate ligand selection.

RAFT Polymer-Antibody Conjugation: Squaramide Ester Chemistry Leads to Conjugates with a Therapeutic Anti-EGFR Antibody with Full Retention of Activity and Increased Tumor Uptake In Vivo.

Covalent conjugation of a biologically stable polymer to a therapeutic protein, e.g., an antibody, holds many benefits such as prolonged plasma exposure of the protein and improved tumor uptake. Generation of defined conjugates is advantageous in many applications, and a range of site-selective conjugation methods have been reported. Many current coupling methods lead to dispersity in coupling efficiencies with subsequent conjugates of less-well-defined structure, which impacts reproducibility of manufacture and ultimately may impact successful translation to treat or image diseases. We explored designing stable, reactive groups for polymer conjugation reactions that would lead to conjugates through the simplest and most abundant residue on most proteins, the lysine residue, yielding conjugates in high purity and demonstrating retention of mAb efficacy through surface plasmon resonance (SPR), cell targeting, and in vivo tumor targeting. We utilized squaric acid diesters as coupling agents for selective amidation of lysine residues and were able to selectively conjugate one, or two, high-molecular-weight polymers to a therapeutically relevant antibody, 528mAb, that subsequently retained full binding specificity. Water-soluble copolymers of N-(2-hydroxypropyl) methacrylamide (HPMA) and N-isopropylacrylamide (NIPAM) were prepared by Reversible Addition-Fragmentation chain-Transfer (RAFT) polymerization and we demonstrated that a dual-dye-labeled antibody-RAFT conjugate (528mAb-RAFT) exhibited effective tumor targeting in model breast cancer xenografts in mice. The combination of the precise and selective squaric acid ester conjugation method, with the use of RAFT polymers, leads to a promising strategic partnership for improved therapeutic protein-polymer conjugates having a very-well-defined structure.