Loss of PPARγ activity characterizes early protumorigenic stromal reprogramming and dictates the therapeutic window of opportunity.

Although robustly expressed in the disease-free (DF) breast stroma, CD36 is consistently absent from the stroma surrounding invasive breast cancers (IBCs). In this study, we primarily observed CD36 expression in adipocytes and intralobular capillaries within the DF breast. Larger vessels concentrated in interlobular regions lacked CD36 and were instead marked by the expression of CD31. When evaluated in perilesional capillaries surrounding ductal carcinoma in situ, a nonobligate IBC precursor, CD36 loss was more commonly observed in lesions associated with subsequent IBC. Peroxisome proliferator-activated receptor γ (PPARγ) governs the expression of CD36 and genes involved in differentiation, metabolism, angiogenesis, and inflammation. Coincident with CD36 loss, we observed a dramatic suppression of PPARγ and its target genes in capillary endothelial cells (ECs) and pericytes, which typically surround and support the stability of the capillary endothelium. Factors present in conditioned media from malignant cells repressed PPARγ and its target genes not only in cultured ECs and pericytes but also in adipocytes, which require PPARγ for proper differentiation. In addition, we identified a role for PPARγ in opposing the transition of pericytes toward a tumor-supportive myofibroblast phenotype. In mouse xenograft models, early intervention with rosiglitazone, a PPARγ agonist, demonstrated significant antitumor effects; however, following the development of a palpable tumor, the antitumor effects of rosiglitazone were negated by the repression of PPARγ in the mouse stroma. In summary, PPARγ activity in healthy tissues places several stromal cell types in an antitumorigenic state, directly inhibiting EC proliferation, maintaining adipocyte differentiation, and suppressing the transition of pericytes into tumor-supportive myofibroblasts.

Data-independent acquisition and quantification of extracellular matrix from human lung in chronic inflammation-associated carcinomas.

Early events associated with chronic inflammation and cancer involve significant remodeling of the extracellular matrix (ECM), which greatly affects its composition and functional properties. Using lung squamous cell carcinoma (LSCC), a chronic inflammation-associated cancer (CIAC), we optimized a robust proteomic pipeline to discover potential biomarker signatures and protein changes specifically in the stroma. We combined ECM enrichment from fresh human tissues, data-independent acquisition (DIA) strategies, and stringent statistical processing to analyze "Tumor" and matched adjacent histologically normal ("Matched Normal") tissues from patients with LSCC. Overall, 1802 protein groups were quantified with at least two unique peptides, and 56% of those proteins were annotated as "extracellular." Confirming dramatic ECM remodeling during CIAC progression, 529 proteins were significantly altered in the "Tumor" compared to "Matched Normal" tissues. The signature was typified by a coordinated loss of basement membrane proteins and small leucine-rich proteins. The dramatic increase in the stromal levels of SERPINH1/heat shock protein 47, that was discovered using our ECM proteomic pipeline, was validated by immunohistochemistry (IHC) of "Tumor" and "Matched Normal" tissues, obtained from an independent cohort of LSCC patients. This integrated workflow provided novel insights into ECM remodeling during CIAC progression, and identified potential biomarker signatures and future therapeutic targets.

Tough while Recyclable Plastics Enabled by Monothiodilactone Monomers.

The current scale of plastics production and the attendant waste disposal issues represent an underexplored opportunity for chemically recyclable polymers. Typical recyclable polymers are subject to the trade-off between the monomer's polymerizability and the polymer's depolymerizability as well as insufficient performance for practical applications. Herein, we demonstrate that a single atom oxygen-by-sulfur substitution of relatively highly strained dilactone is an effective and robust strategy for converting the "non-recyclable" polyester into a chemically recyclable polymer by lowering the ring strain energy in the monomer (from 16.0 kcal mol-1 in dilactone to 9.1 kcal mol-1 in monothiodilactone). These monothio-modification monomers enable both high/selective polymerizability and recyclability, otherwise conflicting features in a typical monomer, as evidenced by regioselective ring-opening, minimal transthioesterifications, and quantitative recovery of the pristine monomer. Computational and experimental studies demonstrate that an n→π* interaction between the adjacent ester and thioester in the polymer backbone has been implicated in the high selectivity for propagation over transthioesterification. The resulting polymer demonstrates high performance with its mechanical properties being comparable to some commodity polyolefins. Thio-modification is a powerful strategy for enabling conversion of six-membered dilactones into chemically recyclable and tough thermoplastics that exhibit promise as next-generation sustainable polymers.

Genome-Wide Identification, Evolution, and Expression Analyses of AP2/ERF Family Transcription Factors in Erianthus fulvus.

The AP2/ERF transcription factor family is one of the most important gene families in plants and plays a vital role in plant abiotic stress responses. Although Erianthus fulvus is very important in the genetic improvement of sugarcane, there are few studies concerning AP2/ERF genes in E. fulvus. Here, we identified 145 AP2/ERF genes in the E. fulvus genome. Phylogenetic analysis classified them into five subfamilies. Evolutionary analysis showed that tandem and segmental duplication contributed to the expansion of the EfAP2/ERF family. Protein interaction analysis showed that twenty-eight EfAP2/ERF proteins and five other proteins had potential interaction relationships. Multiple cis-acting elements present in the EfAP2/ERF promoter were related to abiotic stress response, suggesting that EfAP2/ERF may contribute to adaptation to environmental changes. Transcriptomic and RT-qPCR analyses revealed that EfDREB10, EfDREB11, EfDREB39, EfDREB42, EfDREB44, EfERF43, and EfAP2-13 responded to cold stress, EfDREB5 and EfDREB42 responded to drought stress, and EfDREB5, EfDREB11, EfDREB39, EfERF43, and EfAP2-13 responded to ABA treatment. These results will be helpful for better understanding the molecular features and biological role of the E. fulvus AP2/ERF genes and lay a foundation for further research on the function of EfAP2/ERF genes and the regulatory mechanism of the abiotic stress response.

Mechanistic Insight into Anion-Binding Catalytic Living Cationic Polymerization.

Exploiting non-covalent interactions to catalyze challenging ionic polymerizations is an ambitious goal but is in its infancy. We recently demonstrated non-covalent anion-binding catalysis as an effective methodology to enable living cationic polymerization (LCP) of vinyl ethers in an environmentally benign manner. Here, we further elucidate the structure-reactivity relationships of the elaborately designed seleno-cyclodiphosph(V)azanes catalysts and the roles of anion-binding interactions by a combined theoretical DFT study and experimental study. The investigation suggests that the distinct cis-cyclodiphosph(V)azane framework combined with "selenium effect" and electron-withdrawing 3,5-(CF3 )2 -Phenyl substitution pattern in catalyst enables a critical contribution to accessing excellent stability, anion affinity and solubility under polymerization conditions. Thus, the catalyst could leverage anion-binding interactions to precisely control reversible and transient dormant-active species equilibrium, allowing it to dynamically bind, recognize and pre-organize propagating ionic species and monomer, thereby facilitating efficient chain propagation and minimizing irreversible chain transfer events under mild conditions. The more in-depth understanding of the mechanism for anion-binding catalytic LCP reported herein should help to guide future catalyst design and to extend this concept to broader polymerization systems where ionic species serve as crucial intermediates.

Performance-Advantaged Stereoregular Recyclable Plastics Enabled by Aluminum-Catalytic Ring-Opening Polymerization of Dithiolactone.

Chemically recyclable polymers that can depolymerize into their constituent monomers are attractive candidates to replace non-recyclable petroleum-derived plastics. However, the physical properties and mechanical strengths of depolymerizable polymers are commonly insufficient for practical applications. Here we demonstrate that by proper ligand design and modification, aluminum complexes can catalyse stereoretentive ring-opening polymerization of dithiolactone, yielding highly isotactic polythioesters with molar masses up to 45.5 kDa. This material can form crystalline stereocomplex with a Tm of 94.5 °C, and exhibits mechanical performances comparable to petroleum-based low density polyethylene. Exposure of the polythioester to aluminum precatalyst used to synthesized it resulted in depolymerization to pristine chiral dithiolactone. Experimental and computational studies suggest that aluminum complexes have appropriate binding affinity with sulfide propagating species, thereby avoiding catalyst poisoning and minimizing epimerization reactions, which has not been accessible using other metal catalysts. Overall, aluminum catalysis provides access to performance-advantaged stereoregular recyclable plastics as a promising alternative to petrochemical plastics, thus incentivizing improved plastic sustainability.

A Supported Catalyst that Enables the Synthesis of Colorless CO2 -Polyols with Ultra-Low Molecular Weight.

Ultra-low molecular weight (ULMW) CO2 -polyols with well-defined hydroxyl end groups represent useful soft segments for the preparation of high-performance polyurethane foams. However, owing to the poor proton tolerance of catalysts towards CO2 /epoxide telomerization, it remains challenging to synthesize ULMW yet colorless CO2 -polyols. Herein, we propose an immobilization strategy of constructing supported catalysts by chemical anchoring of aluminum porphyrin on Merrifield resin. The resulting supported catalyst displays both extremely high proton tolerance (≈8000 times the equivalents of metal centers) and independence of cocatalyst, affording CO2 -polyols with ULMW (580 g mol-1 ) and high polymer selectivity (>99 %). Moreover, the ULMW CO2 -polyols with various architectures (tri-, quadra-, and hexa-arm) can be obtained, suggesting the wide proton universality of supported catalysts. Notably, benefiting from the heterogeneous nature of the supported catalyst, colorless products can be facilely achieved by simple filtration. The present strategy provides a platform for the synthesis of colorless ULMW polyols derived from not only CO2 /epoxides, but also lactone, anhydrides etc. or their combinations.

Precision Synthesis of Polypeptides via Living Anionic Ring-Opening Polymerization of N-Carboxyanhydrides by Tri-thiourea Catalysts.

The chemistry of α-amino acid N-carboxyanhydrides (NCAs) has a history of over 100 years, but precise and efficient ring-opening polymerization methods for NCAs remain highly needed to facilitate the studies of polypeptides─that is, mimics of natural proteins─in various disciplines. Moreover, the universally accepted NCA polymerization mechanisms are largely limited to the "amine" and the "activated monomer" mechanisms, and the anionic ring-opening polymerization of NCAs has so far not been invoked. Herein, we show an unprecedented anion-binding catalytic system combining tripodal tri-thiourea with sodium thiophenolate that enables the fast and selective anionic ring-opening polymerization of NCAs. This method leads to the precision construction of various polypeptides with living polymerization behavior and is evidenced by narrow molecular weight distributions (Mw/Mn < 1.2), chain extension experiments, and minimal "activated monomer" pathway. Calculations and experimental results elucidate a living anionic polymerization mechanism, and high selectivities for monomer propagation relative to other deleterious side reactions, such as the "activated monomer" pathway, are attributed to the enhanced stabilization of the propagating carbamate anion, which is enforced by an intramolecular hydrogen bond within the tri-thiourea structure.

Chromosome-specific painting unveils chromosomal fusions and distinct allopolyploid species in the Saccharum complex.

Karyotypes provide key cytogenetic information on the phylogenetic relationships and evolutionary origins in related eukaryotic species. Despite our knowledge of the chromosome numbers of sugarcane and its wild relatives, the chromosome composition and evolution among the species in the Saccharum complex have been elusive owing to the complex polyploidy and the large numbers of chromosomes of these species. Oligonucleotide-based chromosome painting has become a powerful tool of cytogenetic studies especially for plant species with large numbers of chromosomes. We developed oligo-based chromosome painting probes for all 10 chromosomes in Saccharum officinarum (2n = 8x = 80). The 10 painting probes generated robust fluorescence in situ hybridization signals in all plant species within the Saccharum complex, including species in the genera Saccharum, Miscanthus, Narenga and Erianthus. We conducted comparative chromosome analysis using the same set of probes among species from four different genera within the Saccharum complex. Excitingly, we discovered several novel cytotypes and chromosome rearrangements in these species. We discovered that fusion from two different chromosomes is a common type of chromosome rearrangement associated with the species in the Saccharum complex. Such fusion events changed the basic chromosome number and resulted in distinct allopolyploids in the Saccharum complex.

Switchable Polymerization Organocatalysis: From Monomer Mixtures to Block Copolymers.

One-pot production of sequence-controlled block copolymer from mixed monomers is a crucial but rarely reached goal. Using a switchable Lewis-pair organocatalyst, we have accomplished sequence-selective polymerization from a mixture of O-carboxyanhydride (OCA) and epoxide. Polymerization of the OCA monomer occurs first and exclusively because of its exceedingly high polymerizability. When OCA is fully consumed, alternating copolymerization of epoxide and CO2 liberated in OCA polymerization is triggered from the termini of the first block. The two polymerizations thus occur in tandem, both in chemoselective fashion, so that a sequence-controlled block polymer with up to 99 % CO2 conversion is furnished in this one-pot protocol. Calculations and experimental results demonstrate a chemoselective and cooperative mechanism, where the high polymerizability of the OCA monomers guarantees exquisite sequence selectivity and the cooperative decarboxylation partly arose from the stabilization effect by triethylborane, which facilitates the smooth transformation of the chain end from carbonate to alkoxide.

Tug-of-War between Two Distinct Catalytic Sites Enables Fast and Selective Ring-Opening Copolymerizations.

Ring-opening copolymerizations have emerged as a powerful approach towards the creation of sustainable polymers. Typical H-bonding catalysts for ring-opening are subject to a single catalytic site. Here we describe a H-bond-donor/Lewis-acidic-boron organocatalyst featuring two distinct catalytic sites in one molecule. The ring-opening copolymerization of epoxides with anhydride mediated by these modular, and tunable catalysts achieves high selectivity (>99 % polyester selectivity) and markedly higher activity compared to either of the di-thiourea analogues or any combinations of them. Calculations and experimental studies reveal that the superior catalytic performance arises from tug-of-war between two differentiated catalytic sites: thiourea pulls off the propagating chain-end from boron center, simultaneously enhancing the role of monomer activation and also nucleophilicity of the propagation intermediates.

Iterative Synthesis of Stereo- and Sequence-Defined Polymers via Acid-Orthogonal Deprotection Chemistry.

Absolute control over polymer stereo- and sequence structure is highly challenging in polymer chemistry. Here, an acid-orthogonal deprotection strategy is proposed for the iterative synthesis of a family of unimolecular polymers starting with enantiopure serines, featuring precise sequence, stereoconfiguration and side-chain functionalities that cannot be achieved using traditional polymerization techniques. Acid-orthogonal deprotections proceed independently of one another by the selection of protecting groups that feature the respective acid-lability. Under p-toluenesulfonic acid, acidolysis of tert-butyloxycarbonyl can proceed exclusively, while low-dosage trifluoroacetic acid and low temperature only trigger the selective and quantitative cleavage of trityl. The pioneering use of this acid-orthogonal deprotection chemistry increases the compatibility with otherwise sensitive groups and opens up pathways to facilely introduce structural and functional diversity into stereo- and sequence-defined polymers, thus imparting their unique properties beyond natural biopolymers.

From Impossible to Possible: Atom-Economic Polymerization of Low Strain Five-Membered Carbonates.

The direct ring-opening polymerization (ROP) of propylene carbonate (PC) only affords oligomers with substantial unidentified by-products, which hinders the efficient utilization of PC. Through detailed studies, for the first time, a careful mechanism involving the in situ release of propylene oxide (PO) from PC decarboxylation is proposed. Further, we report a novel strategy of copolymerization of PC/cyclic anhydrides via in situ capture of the formed intermediates. Results show that PC is successfully transformed into polyesters. Especially for the ring-opening alternating copolymerization (ROAC) of PC/phthalic anhydride (PA), a variety of advantages are manifold: i) slow-release of PO ensuring a perfectly alternating structure; ii) quantitative and fast transformation of PC; iii) visualization of polymerization process by a CO2 pressure gauge. Of importance, through tandem polymerizations, PC is fully transformed into polyesters and polycarbonates concurrently, thus achieving PC utilization with a high atom-economy.

S-Carboxyanhydrides: Ultrafast and Selective Ring-Opening Polymerizations Towards Well-defined Functionalized Polythioesters.

Aliphatic polythioesters are popular polymers because of their appealing performance such as metal coordination ability, high refractive indices, and biodegradability. One of the most powerful approaches for generating these polymers is the ring-opening polymerization (ROP) of cyclic monomers. However, the synthesis of precisely controlled polythioesters via ROP of thiolactones still faces formidable challenges, including the minimal functional diversity of available thiolactone monomers, as well as inevitable transthioesterification side reactions. Here we introduce a hyperactive class of S-carboxyanhydride (SCA) monomers derived from amino acids that are significantly more reactive than thiolactones for ultrafast and selective ROP. Inclusion of the initiator PPNOBz ([PPN]=bis(triphenylphosphine)-iminium) with chain transfer agent benzoic acid, the polymerizations that can be operated in open vessels reach complete conversion within minutes (1-2 min) at room temperature, yielding polythioesters with predictable molecular weight, low dispersities, retained stereoregularity and chemical recyclability. Most fascinating are the functionalized SCAs that allow the incorporating of functional groups along the polythioester chain and thus finely tune their physicochemical performance. Computational studies were carried out to explore the origins of the distinctive rapidity and exquisite selectivity of the polymerizations, offering mechanistic insight and explaining why high polymerizability of SCA monomer is able to facilitate exquisitely selective ring-opening for enchainment over competing transthioesterification and backbiting reactions.

O-to-S Substitution Enables Dovetailing Conflicting Cyclizability, Polymerizability, and Recyclability: Dithiolactone vs. Dilactone.

Developing chemically recyclable polymers represents a greener alternative to landfill and incineration and offers a closed-loop strategy toward a circular materials economy. However, the synthesis of chemically recyclable polymers is still plagued with certain fundamental limitations, including trade-offs between the monomer's cyclizability and polymerizability, as well as between polymer's depolymerizability and properties. Here we describe the subtle O-to-S substitution, dithiolactone monomers derived from abundant feedstock α-amino acids can demonstrate appealing chemical properties different from those of dilactone, including accelerated ring closure, augmented kinetics polymerizability, high depolymerizability and selectivity, and thus constitute a unique class of polythioester materials exhibiting controlled molecular weight (up to 100.5 kDa), atactic yet high crystallinity, structurally diversity, and chemical recyclability. These polythioesters well addresses the formidable challenges of developing chemically recyclable polymers by having an unusual set of desired properties, including easy-to-make monomer from ubiquitous feedstock, and high polymerizability, crystallinity and precise tunability of physicochemical performance, as well as high depolymerizability and selectivity. Computational studies explain why O-to-S modification of polymer backbone enables dovetailing desirable, but conflicting, performance into one polymer structure.

Cobalt-Mediated Switchable Catalysis for the One-Pot Synthesis of Cyclic Polymers.

A cobalt salen pentenoate complex [salen=(R,R)-N,N'-bis(3,5-di-tertbutylsalicylidene)-1,2-cyclohexanediamine] is rationally designed as the catalyst for the ring-opening copolymerization (ROCOP) of epoxides/anhydrides/CO2 . Via migratory insertion of carbon monoxide (CO) into the Co-O bonds, the ROCOP-active species α-alkene-ω-O-CoIII (salen) can be rapidly and quantitatively transformed into α-alkene-ω-O2 C-CoIII (salen) telechelic linear precursors. Upon dilution of reaction mixtures, the homolytic cleavage of Co-C bonds induced by visible light generates α-alkene acyl radicals that spontaneously undergo intramolecular radical addition to afford organocobalt-functionalized cyclic polyesters and CO2 -based polycarbonates with excellent regioselectivity. The cyclic products can either react with radical scavengers to generate metal-free cyclic polymers or serve as photo-initiators for organometallic-mediated radical polymerization (OMRP) to produce tadpole-shaped copolymers.

Enhanced sugar accumulation and regulated plant hormone signalling genes contribute to cold tolerance in hypoploid Saccharum spontaneum.

BACKGROUND: Wild sugarcane Saccharum spontaneum plants vary in ploidy, which complicates the utilization of its germplasm in sugarcane breeding. Investigations on cold tolerance in relation to different ploidies in S. spontaneum may promote the exploitation of its germplasm and accelerate the improvement of sugarcane varieties. RESULTS: A hypoploid clone 12-23 (2n = 54) and hyperploid clone 15-28 (2n = 92) of S. spontaneum were analysed under cold stress from morphological, physiological, and transcriptomic perspectives. Compared with clone 15-28, clone 12-23 plants had lower plant height, leaf length, internode length, stem diameter, and leaf width; depressed stomata and prominent bristles and papillae; and thick leaves with higher bulliform cell groups and thicker adaxial epidermis. Compared with clone 15-28, clone 12-23 showed significantly lower electrical conductivity, significantly higher water content, soluble protein content, and superoxide dismutase activity, and significantly higher soluble sugar content and peroxidase activity. Under cold stress, the number of upregulated genes and downregulated genes of clone 12-23 was higher than clone 15-28, and many stress response genes and pathways were affected and enriched to varying degrees, particularly sugar and starch metabolic pathways and plant hormone signalling pathways. Under cold stress, the activity of 6-phosphate glucose trehalose synthase, trehalose phosphate phosphatase, and brassinosteroid-signalling kinase and the content of trehalose and brassinosteroids of clone 12-23 increased. CONCLUSIONS: Compared with hyperploid clone 15-28, hypoploid clone 12-23 maintained a more robust osmotic adjustment system through sugar accumulation and hormonal regulation, which resulted in stronger cold tolerance.

Synergetic Organocatalysis for Eliminating Epimerization in Ring-Opening Polymerizations Enables Synthesis of Stereoregular Isotactic Polyester.

Ring-opening polymerization of O-carboxyanhydrides (OCAs) can furnish polyesters with a diversity of functional groups that are traditionally hard to harvest by polymerization of lactones. Typical ring-opening catalysts are subject to unavoidable racemization of most OCA monomers, which hampers the synthesis of highly isotactic crystalline polymers. Here, we describe an effective bifunctional single-molecule organocatalysis for selective ring-opening polymerization of OCAs without epimerization. The close vicinity of both activating groups in the same molecule engenders an amplified synergetic effect and thus allows for the use of mild bases, thereby leading to minimal epimerization for polymerization. Ring-opening polymerization of manOCA monomer (OCA from mandelic acid) mediated by the bifunctional single-molecule organocatalyst yields highly isotactic poly(mandelic acid) (PMA) with controlled molecular weights (up to 19.8 kg mol-1). Mixing of the two enantiomers of PMA generates the first example of a crystalline stereocomplex in this area, which displayed distinct Tm values around 150 °C. Remarkably, the bifunctional catalysts are moisture-stable, recyclable, and easy to use, allowing sustainable and scalable synthesis of a stereoregular functional polyester.

Synthesis of Y-Shaped OEGylated Poly(amino acid)s: The Impact of OEG Architecture.

OEGylation is an attractive approach to modifying poly(amino acid)s. OEG conjugation improves water-solubility of poly(amino acid)s, and confers possible thermal-responsive functionality for the conjugated poly(amino acid)s. Nevertheless, the impact of OEG architecture and the manner in which the OEG moiety interferes with the performances of poly(amino acid)s remain a work in progress. In this study, a series of new linear and Y-shaped OEG-substituted poly(glutamic acid)s were designed and synthesized. It is found that the thermoresponsive behavior of OEGylated poly(glutamic acid)s experiences steric repulsion effect, the strengths of which are architecture and length-dependent, and grows pronounced only when the number of the OEG units is ≥6. Notably, the Y-shaped architecture is able to stabilize the helicity of poly(glutamic acid) backbones, while maintaining higher α-helical conformation than its linear counterparts. In sum, our result indicate that Y-shaped architecture is more appropriate toward OEGylating poly(amino acid)s for biomedical applications.

Oxygen-Triggered Switchable Polymerization for the One-Pot Synthesis of CO2 -Based Block Copolymers from Monomer Mixtures.

Switchable polymerization provides the opportunity to regulate polymer sequence and structure in a one-pot process from mixtures of monomers. Herein we report the use of O2 as an external stimulus to switch the polymerization mechanism from the radical polymerization of vinyl monomers mediated by (Salen)CoIII -R [Salen=N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine; R=alkyl] to the ring-opening copolymerization (ROCOP) of CO2 /epoxides. Critical to this process is unprecedented monooxygen insertion into the Co-C bond, as rationalized by DFT calculations, leading to the formation of (Salen)CoIII -O-R as an active species to initiate ROCOP. Diblock poly(vinyl acetate)-b-polycarbonate could be obtained by ROCOP of CO2 /epoxides with preactivation of (Salen)Co end-capped poly(vinyl acetate). Furthermore, a poly(vinyl acetate)-b-poly(methyl acrylate)-b-polycarbonate triblock copolymer was successfully synthesized by a (Salen)cobalt-mediated sequential polymerization with an O2 -triggered switch in a one-pot process.