Metal-Free Ring-Opening Metathesis Polymerization: From Concept to Creation.

Ring-opening metathesis polymerization (ROMP), which is derived from transition-metal-based olefin metathesis, has evolved into one of the most prevalent technologies for making functional polymeric materials in academia and in industry. The initial discovery of and advances in ROMP used ill-defined mixtures of metal salts to initiate polymerization. The initiators most commonly used today, developed with tremendous efforts, are well-defined metal-alkylidene complexes that have enabled a good mechanistic understanding of the polymerization as well as improvement of the initiators' activity, stability, and functional group tolerance.The evolution of ROMP has been decidedly metal-centric, with the path to accolades being paved primarily in ruthenium-, molybdenum-, and tungsten-based systems. Our departure from the ROMP trailhead was inspired in part by recent breakthroughs in radical-mediated polymerizations, whereby their mechanisms were leveraged to develop metal-free reaction conditions. Inventing a metal-free complement to traditional ROMP would essentially involve stepping away from decades of inorganic and organometallic developments, but with the promise of crossing new synthetic capabilities and curiosities.Driven by this motivation, as well as a community-inspired desire to develop "greener" controlled polymerizations, our team pioneered the search for, and discovery of, a wholly organic alternative to traditional metal-mediated ROMP. In this Account, we review our recent efforts to develop metal-free ring-opening metathesis polymerization (MF-ROMP), which is inspired by previous reports in electro- and photo-mediated organic transformations.This work began with an exploration of the direct oxidation of enol ethers and the propensity of the ensuing radical cations to initiate ROMP. To overcome limitations of the electrochemical conditions, a photoredox-mediated method was investigated next, using photoexcited pyrylium salts to oxidize the enol ethers. With this system, we demonstrated the ability to produce ROMP products and temporally control the polymerization.Further investigations into different aspects of the reaction included monomer scope, functional group tolerance, the impact of changing photocatalyst properties, and the ability to control molecular weight. The unique mechanism of MF-ROMP, along with the relative ease of synthesizing enol ether initiators, enabled the preparation of numerous polymeric materials that are hard to access through traditional metal-mediated pathways. At the end of this Account, we provide a perspective on future opportunities in this emerging area.

Self-assembly of fullerene-based janus particles in solution: effects of molecular architecture and solvent.

Two molecular Janus particles based on amphiphilic [60]fullerene (C60 ) derivatives were designed and synthesized by using the regioselective Bingel-Hirsh reaction and the click reaction. These particles contain carboxylic acid functional groups, a hydrophilic fullerene (AC60 ), and a hydrophobic C60 in different ratios and have distinct molecular architectures: 1:1 (AC60 -C60 ) and 1:2 (AC60 -2C60 ). These molecular Janus particles can self-assemble in solution to form aggregates with various types of micellar morphology. Whereas vesicular morphology was observed for both AC60 -C60 and AC60 -2C60 in tetrahydrofuran, in a mixture of N,N-dimethylformamide (DMF)/water, spherical micelles and cylindrical micelles were observed for AC60 -C60 and AC60 -2C60 , respectively. A mechanism of formation was tentatively proposed based on the effects of molecular architecture and solvent polarity on self-assembly.

Case report: A rare homozygous variation in the ENPP1 gene, presenting with generalized arterial calcification of infancy in a Chinese infant.

Generalized arterial calcification of infancy (GACI) is a rare genetic disease characterized by arterial calcifications or stenoses and hypertension. GACI is caused by mutations in the ENPP1 or ABCC6 genes, and it often causes intrauterine or early infancy death. Here, we report a case of rare GACI caused by a homozygous variation in ENPP1, in a Chinese infant initially presenting with hypertension. The proband was an 8-month-old boy with in utero tricuspid valve calcification, presenting with hypertension at birth. Enhanced computed tomography revealed extensive arterial calcification. Genetic testing identified a homozygous variation in ENPP1 (c.783C > G p.Y261X), which led to the diagnosis of GACI. This mutation has been reported in only three Chinese patients, which all initially presented with hypophosphatemic rickets rather than GACI. This case enriches the clinical and genetic spectrum of ENPP1 mutations and reminds us that GACI should be considered in an infant presenting with hypertension and extensive arterial calcification, and that genetic testing should be performed.

Rapid hydrogel formation via tandem visible light photouncaging and bioorthogonal ligation.

The formation of benign polymer scaffolds in water using green-light-reactive photocages is described. These efforts pave an avenue toward the fabrication of synthetic scaffolds that can facilitate the study of cellular events for disease diagnosis and treatment. First, a series of boron dipyrromethene (BODIPY) photocages with nitrogen-containing nucleophiles were examined to determine structure-reactivity relationships, which resulted in a >1,000× increase in uncaging yield. Subsequently, photoinduced hydrogel formation in 90 wt % water was accomplished via biorthogonal carbonyl condensation using hydrophilic polymer scaffolds separately containing BODIPY photocages and ortho-phthalaldehyde (OPA) moieties. Spatiotemporal control is demonstrated with light on/off experiments to modulate gel stiffness and masking to provide <100 µm features. Biocompatability of the method was shown through pre-/post-crosslinking cell viability studies. Short term, these studies are anticipated to guide translation to emergent additive manufacturing technology, which, longer term, will enable the development of 3D cell cultures for tissue engineering applications.

Case report: Rare novel MIPEP compound heterozygous variants presenting with hypertrophic cardiomyopathy, severe lactic acidosis and hypotonia in a Chinese infant.

Background: Mitochondrial intermediate peptidase, encoded by the MIPEP gene, is involved in the processing of precursor mitochondrial proteins related to oxidative phosphorylation. Only a few studies have shown that mutations in MIPEP can cause combined oxidative phosphorylation deficiency-31 (COXPD31), an autosomal recessive multisystem disorder associated with mitochondrial dysfunction. We report herein a rare case of an 8-month-old boy in China with hypertrophic cardiomyopathy (HCM), severe lactic acidosis, and hypotonia caused by novel MIPEP compound heterozygous variants. Methods: Trio-whole-exome sequencing and copy number variation sequencing were performed to identify mutated genetic loci. Sanger sequencing and quantitative real-time PCR were used to validate the candidate single nucleotide variants and copy number variants, respectively. Results: The proband was an 8-month-old boy with HCM, severe lactic acidosis, and hypotonia who died 2 months after his first admission. Two novel compound heterozygous variants, c.1081T > A (p. Tyr361Asn) and a whole deletion (Ex1-19 del), were found in the MIPEP gene, which were inherited from his healthy parents respectively. Additionally, his mitochondria DNA copy number was significantly reduced. Conclusion: We are the first to report a patient with rare MIPEP variants in China. Our findings expand the mutation spectrum of MIPEP, and provide insights into the genotype-phenotype relationship in COXPD31.

Clinical characteristics and survival of children with hypertrophic cardiomyopathy in China: A multicentre retrospective cohort study.

Background: Few data on paediatric hypertrophic cardiomyopathy (HCM) are available in developing countries. A multicentre, retrospective, cohort study was conducted to profile the clinical characteristics and survival of children with HCM in China. Methods: We collected longitudinal data on children with HCM aged 0-18 years at three participating institutions between January 1, 2010 and December 31, 2019. Patients were identified by searching for the diagnosis using ICD-10 codes from the electronic medical records database. HCM was diagnosed morphologically with echocardiography or cardiovascular magnetic resonance imaging. The exclusion criteria were secondary aetiologies of myocardial hypertrophy. The primary outcomes were all-cause death or heart transplantation. The Kaplan-Meier method was used to estimate the survival rate of different groups. Findings: A total of 564 children were recruited, with a median age at diagnosis of 1.0 year (interquartile range, IQR: 0.4-8.0 years), followed for a median of 2.6 years (1977 patient-years, IQR:0.5, 5.9 years). The underlying aetiology was sarcomeric (382, 67.7%), inborn errors of metabolism (IEMs) (108, 19.2%), and RASopathies (74, 13.1%). A total of 149 patients (26.4%) died and no patients underwent heart transplantation during follow-up. The survival probability was 71.1% (95% confidence interval [CI], 66.3%-75.3%) at 5 years. Patients with IEMs or those diagnosed during infancy had the poorest outcomes, with an estimated 5-year survival rate of 16.9% (95% CI, 7.7%-29.1%) and 56.0% (95% CI, 48.8%-62.5%), respectively. Heart failure was the leading cause of death in the cohort (90/149, 60.4%), while sudden cardiac death was the leading cause in patients with sarcomeric HCM (32/66, 48.5%). Interpretation: There is a high proportion of patients with IEM and a low proportion of patients with neuromuscular disease in children with HCM in China. Overall, mortality remains high in China, especially in patients with IEMs and those diagnosed during infancy. Funding: National Natural Science Fund of China (81770380, 81974029), China Project of Shanghai Municipal Science and Technology Commission (20MC1920400, 21Y31900301).

Tunable Affinity and Molecular Architecture Lead to Diverse Self-Assembled Supramolecular Structures in Thin Films.

The self-assembly behavior of specifically designed giant surfactants is systematically studied in thin films using grazing incidence X-ray scattering and transmission electron microscopy, focusing on the effects of molecular nanoparticle (MNP) functionalities and molecular architectures on nanostructure formation. Two MNPs with different surface functionalities, i.e., hydrophilic carboxylic acid functionalized [60]fullerene (AC60) and omniphobic fluorinated polyhedral oligomeric silsesquioxane (FPOSS), are utilized as the head portions of the giant surfactants. By covalently tethering these functional MNPs onto the end point or junction point of polystyrene-block-poly(ethylene oxide) (PS-b-PEO) diblock copolymer, linear and star-like giant surfactants with different molecular architectures are constructed. With fixed length of the PEO block, changing the molecular weight of the PS block leads to the formation of various ordered phases and phase transitions. Due to the distinct affinity, the AC60-based and FPOSS-based giant surfactants form two- or three-component morphologies, respectively. A stretching parameter for the PS block is introduced to characterize the PS chain conformation in the different morphologies. The highly diverse self-assembled nanostructures with high etch resistance between components in small dimensions obtained from the giant surfactant thin films suggest that these macromolecules could provide a promising and robust platform for nanolithography applications.