New Advances in Covalent Network Polymers via Dynamic Covalent Chemistry.

Covalent network polymers, as materials composed of atoms interconnected by covalent bonds in a continuous network, are known for their thermal and chemical stability. Over the past two decades, these materials have undergone significant transformations, gaining properties such as malleability, environmental responsiveness, recyclability, crystallinity, and customizable porosity, enabled by the development and integration of dynamic covalent chemistry (DCvC). In this review, we explore the innovative realm of covalent network polymers by focusing on the recent advances achieved through the application of DCvC. We start by examining the history and fundamental principles of DCvC, detailing its inception and core concepts and noting its key role in reversible covalent bond formation. Then the reprocessability of covalent network polymers enabled by DCvC is thoroughly discussed, starting from the significant milestones that marked the evolution of these polymers and progressing to their current trends and applications. The influence of DCvC on the crystallinity of covalent network polymers is then reviewed, covering their bond diversity, synthesis techniques, and functionalities. In the concluding section, we address the current challenges faced in the field of covalent network polymers and speculates on potential future directions.

Systematic calibration of epitranscriptomic maps using a synthetic modification-free RNA library.

Recent years have witnessed rapid progress in the field of epitranscriptomics. Functional interpretation of the epitranscriptome relies on sequencing technologies that determine the location and stoichiometry of various RNA modifications. However, contradictory results have been reported among studies, bringing the biological impacts of certain RNA modifications into doubt. Here, we develop a synthetic RNA library resembling the endogenous transcriptome but without any RNA modification. By incorporating this modification-free RNA library into established mapping techniques as a negative control, we reveal abundant false positives resulting from sequence bias or RNA structure. After calibration, precise and quantitative mapping expands the understanding of two representative modification types, N6-methyladenosine (m6A) and 5-methylcytosine (m5C). We propose that this approach provides a systematic solution for the calibration of various RNA-modification mappings and holds great promise in epitranscriptomic studies.

Dynamic Entwined Topology in Helical Covalent Polymers Dictated by Competing Supramolecular Interactions.

Naturally occurring polymeric structures often consist of 1D polymer chains intricately folded and entwined through non-covalent bonds, adopting precise topologies crucial for their functionality. The exploration of crystalline 1D polymers through dynamic covalent chemistry (DCvC) and supramolecular interactions represents a novel approach for developing crystalline polymers. This study shows that sub-angstrom differences in the counter-ion size can lead to various helical covalent polymer (HCP) topologies, including a novel metal-coordination HCP (m-HCP) motif. Single-crystal X-ray diffraction (SCXRD) analysis of HCP-Na revealed that double helical pairs are formed by sodium ions coordinating to spiroborate linkages to form rectangular pores. The double helices are interpenetrated by the unreacted diols coordinating sodium ions. The reticulation of the m-HCP structure was demonstrated by the successful synthesis of HCP-K. Finally, ion-exchange studies were conducted to show the interconversion between HCP structures. This research illustrates how seemingly simple modifications, such as changes in counter-ion size, can significantly influence the polymer topology and determine which supramolecular interactions dominate the crystal lattice.

Single-Crystal Cage Framework with High Selectivity and Reversibility in Fullerene Binding.

Host-guest chemistry, a pivotal branch of supramolecular chemistry, plays an essential role in understanding and constructing complex structures through non-covalent interactions. Organic molecular cages, characterized by their intrinsic confined cavities, can selectively bind a variety of guest molecules. Their host-guest chemistry has been well studied in the solution phase, and several attempts have been made to encode well-defined molecular architectures into solid-state polymeric materials. However, only limited studies have explored their potential in the solid state, where their lack of robustness and less ordered networks significantly hinder practical applications. Herein, we report the synthesis of a single-crystal cage framework and a systematic study of its host-guest chemistry, spanning from the solution state to the solid state. Our studies reveal that the host-guest interactions inherent to the cage are successfully maintained in the solid-state polymeric material. Furthermore, the framework's robustness allows for the guest molecules (fullerene) to be released triggered by an organic acid (trifluoracetic acid), with subsequent regeneration of the framework through an organic base (triethylamine) treatment. Our findings represent the first synthesis of a robust, single-crystal cage framework exhibiting highly selective and reversible host-guest chemistry, thus showing great potential towards molecular separation application.

Spiroborate-Linked Ionic Covalent Adaptable Networks with Rapid Reprocessability and Closed-Loop Recyclability.

Covalent adaptable networks (CANs) represent a novel class of polymeric materials crosslinked by dynamic covalent bonds. Since their first discovery, CANs have attracted great attention due to their high mechanical strength and stability like conventional thermosets under service conditions and easy reprocessability like thermoplastics under certain external stimuli. Here, we report the first example of ionic covalent adaptable networks (ICANs), a type of crosslinked ionomers, consisting of negatively charged backbone structures. More specifically, two ICANs with different backbone compositions were prepared through spiroborate chemistry. Given the dynamic nature of the spiroborate linkages, the resulting ionomer thermosets display rapid reprocessability and closed-loop recyclability under mild conditions. The materials mechanically broken into smaller pieces can be reprocessed into coherent solids at 120 °C within only 1 min with nearly 100% recovery of the mechanical properties. Upon treating the ICANs with dilute hydrochloric acid at room temperature, the valuable monomers can be easily chemically recycled in almost quantitative yield. This work demonstrates the great potential of spiroborate bonds as a novel dynamic ionic linkage for development of new reprocessable and recyclable ionomer thermosets.

3D Covalent Organic Framework as a Metastable Intermediate in the Formation of a Double-Stranded Helical Covalent Polymer.

The design and development of intricate artificial architectures have been pursued for decades. Helical covalent polymer (HCP) was recently reported as an unexpected topology that consists of chiral 1D polymers assembled through weak hydrogen bonds from achiral building blocks. However, many questions remained about the formation, driving force, and the single-handedness observed in each crystal. In this work, we reveal a metastable, racemic, fully covalently cross-linked, 3D covalent organic framework (COF) as an intermediate in the early stage of polymerization, which slowly converts into single-handed HCP double helices through partial fragmentation and self-sorting with the aid of a series of hydrogen bonding. Our work provides an intriguing example where weak noncovalent bonds serve as the determining factor of the overall product structure and facilitate the formation of a sophisticated polymeric architecture.

Double-Walled Covalent Organic Frameworks with High Stability.

Double-walled covalent organic frameworks, consisting of two same building blocks parallel to each other forming ladder-shape linkers, could enhance the stability of the frameworks and increase the density of functional sites, thus making them suitable for various applications. In this study, two double-walled covalent organic frameworks, namely DW-COF-1 and DW-COF-2, were successfully synthesized via imine condensation. The resulting DW-COFs exhibited a honeycomb topology, high crystallinity and stability. Particularly, DW-COF-2 showed excellent resistance toward boiling water, strong acid, and strong base, due to its double-walled structure, which limits the exposure of labile imine bonds to external chemical environments. The DW-COFs showed high porosity near 900 m2 /g, making them suitable for gas storage/separation. The selective gas adsorption experiments showed that at 273 K and 1 atm pressure, DW-COF-1 and DW-COF-2 exhibited a good IAST selectivity towards CO2 /N2 (15/85) adsorption, with selectivity values of 121.3 and 56.4 for CO2 over N2 , respectively.

Mapping single-nucleotide m6A by m6A-REF-seq.

The past few years have witnessed rapid progress in the field of RNA modifications. As the most prevailing modification on eukaryotic mRNA, m6A is characterized to play a vital role in various cellular activities. However, limitations of the detection method impede functional studies of m6A. Here we introduce m6A-REF-seq, a powerful and straightforward method to identify m6A at single-nucleotide resolution. m6A-REF-seq relies on the recognition of RNA endonuclease MazF towards m6A at the ACA motif, providing an orthogonal method independent of the m6A antibody being adopted by most of current methods. We describe a detailed protocol to perform m6A-REF-seq, including NGS library construction and sequencing data analysis. In particular, we describe an optimized assay to validate individual m6A sites identified by m6A-REF-seq, which can also be applied to detect any candidate m6A sites.

Dynamic Covalent Self-sorting in Molecular and Polymeric Architectures Enabled by Spiroborate Bond Exchange.

Self-sorting is commonly observed in complex reaction systems, which has been utilized to guide the formation of single major by-design molecules. However, most studies have been focused on non-covalent systems, and using self-sorting to achieve covalently bonded architectures is still relatively less explored. Herein, we first demonstrated the dynamic nature of spiroborate linkage and systematically studied the self-sorting behavior observed in the transformation between spiroborate-linked well-defined polymeric and molecular architectures, which is enabled by spiroborate bond exchange. The scrambling between a macrocycle and a 1D helical covalent polymer led to the formation of a molecular cage, whose structures are all unambiguously elucidated by single-crystal X-ray diffraction. The results indicate that the molecular cage is the thermodynamically favored product in this multi-component reaction system. This work represents the first example of a 1D polymeric architecture transforming into a shape-persistent molecular cage, driven by dynamic covalent self-sorting. This study will further guide the design of spiroborate-based materials and open the possibilities for the development of novel complex yet responsive dynamic covalent molecular or polymeric systems.

Cyanurate-Linked Covalent Organic Frameworks Enabled by Dynamic Nucleophilic Aromatic Substitution.

We report, for the first time, highly crystalline cyanurate-linked covalent organic frameworks synthesized via dynamic nucleophilic aromatic substitution. The high crystallinity is enabled by the bond exchange reaction (self-correction) between 2,4,6-triphenoxy-1,3,5-triazine and diphenols via reversible SNAr catalyzed by triazabicyclodecene. The CN-COFs contain flexible backbones that exhibit a unique AA'-stacking due to interlayer hydrogen bonding interactions. The isoreticular expansion study demonstrates the general applicability of this synthetic method. The resulting CN-COFs exhibited good stability, as well as high CO2/N2 selectivity.

Treatment of symptomatic hip dysplasia by posterolateral small incision assisted Bernese periacetabular osteotomy.

BACKGROUND: For periacetabular osteotomy, traditional approaches usually have a long learning curve. We aimed to evaluate the postoperative results and complications of periacetabular osteotomy under a new double-incision approach. METHODS: The records of 58 consecutive patients (65 hips) who underwent periacetabular osteotomy using the new approach were retrospectively reviewed and evaluated. There were 52 women and 6 men with a mean age of 28.1 years at the time of surgery. RESULTS: The average follow-up period was 35.2 months, during which no patients were converted to total hip arthroplasty. Complications included 6 hips (9.2%) with nerve dysesthesias and 1 hip (1.5%) with delayed wound healing. The mean operative time and intraoperative blood loss were 88.6 min and 402.8 ml, respectively. The mean modified Harris hip score had improved from 72.2 points preoperatively to 91.3 points at the last follow-up. Fifty-five patients (62 hips, 95.4%) were satisfied to their outcomes, and good preoperative functional score was associated with a satisfactory outcome. Furthermore, the average lateral center-edge angle, anterior center-edge angle and acetabular index angle were corrected well after surgery. CONCLUSION: Periacetabular osteotomy using modified Smith-Petersen or Bikini approach with posterolateral assisted small incision can be performed safely and with satisfactory results. In addition, this technique shortens the learning curve, and reduces the operating complexity, especially for beginner.

Is COPD associated with increased mortality and morbidity in hospitalized pneumonia? A systematic review and meta-analysis.

This review aimed to investigate whether chronic obstructive pulmonary disease (COPD) is associated with increased mortality and morbidity in patients hospitalized with community-acquired pneumonia (CAP). EMBASE, PubMed and Web of Science were searched for cohort studies and case-control studies investigating the impact of COPD on CAP. The primary outcome was all-cause mortality, and secondary outcomes included length of hospital stay, intensive care unit (ICU) admission and need for mechanical ventilation. Methodological quality was assessed using the Newcastle-Ottawa Scale. The Mantel-Haenszel method and inverse variance method were used to calculate pooled relative risks (RRs) and mean differences (MD), respectively. Eleven studies (nine cohort studies and two case-control studies), involving 257 958 patients, were included. The overall methodological quality was high. COPD was not associated with increased mortality in hospitalized CAP patients (RR, 1.20; 95% confidence interval (CI): 0.92-1.56; P = 0.19; I(2) = 55%) in cohort studies, and was associated with reduced mortality in case-control studies (RR, 0.82; 95% CI: 0.74-0.90; P < 0.0001; I(2) = 80%). COPD was not associated with longer hospital stay (MD, 0.11; 95% CI: -0.42 to 0.64; P = 0.68; I(2) = 21%), more frequent ICU admission (RR, 0.97; 95% CI: 0.70-1.35; P = 0.87; I(2) = 65%), and more need for mechanical ventilation (RR 0.91, 95% CI: 0.71-1.16; P = 0.44; I(2) = 4%).The current available evidence indicates that COPD may not be associated with increased mortality and morbidity in patients hospitalized with CAP. This conclusion should be re-evaluated by prospective population-based cohort studies.

Molecular recognition with resolution below 0.2 angstroms through thermoregulatory oscillations in covalent organic frameworks.

Crystalline materials with uniform molecular-sized pores are desirable for a broad range of applications, such as sensors, catalysis, and separations. However, it is challenging to tune the pore size of a single material continuously and to reversibly distinguish small molecules (below 4 angstroms). We synthesized a series of ionic covalent organic frameworks using a tetraphenoxyborate linkage that maintains meticulous synergy between structural rigidity and local flexibility to achieve continuous and reversible (100 thermal cycles) tunability of "dynamic pores" between 2.9 and 4.0 angstroms, with resolution below 0.2 angstroms. This results from temperature-regulated, gradual amplitude change of high-frequency linker oscillations. These thermoelastic apertures selectively block larger molecules over marginally smaller ones, demonstrating size-based molecular recognition and the potential for separating challenging gas mixtures such as oxygen/nitrogen and nitrogen/methane.

Pogostone attenuates osteolysis in breast cancer by inhibiting the NF-kB and JNK signaling pathways of osteoclast.

AIMS: Breast cancer is the most prevalent cancer in females, and approximately 70 % of all patients have evidence of metastatic bone disease, which substantially affects the quality of life and survival rate of breast cancer patients. Osteoporosis has become a global public health problem, and the abnormal activation of osteoclasts is the key to the progression of osteoporosis and the key to both diseases lies in the osteoclasts. Effective drug treatments are lacking and there is an urgent need to explore new drugs. MATERIALS AND METHODS: We observed the effects of pogostone (PO) on osteoclast differentiation, bone resorption function and other indicators, and F-actin ring formation by using Trap staining, SEM and immunofluorescence, and further explored the targets of pogostone in regulating osteoclast differentiation and function using qPCR and Western Blot. In addition, we used CCK 8, Transwell, and flow cytometry to study the effects of pogostone on proliferation, invasion, migration, and apoptosis of MDA-MB-231 cells. Animal models were also constructed for in vivo validation. KEY FINDINGS: Pogostone inhibits osteoclast differentiation, bone resorption, formation of F-actin ring, and the expression of specific genes by attenuated NF-kB degradation and phosphorylation of JNK. In vitro, pogostone suppresses invasion of breast cancer cells, migration, and promotes their apoptosis. In mouse models, pogostone attenuated osteoclast formation and bone resorption, blocked breast cancer cells migration, and supprsed breast cancer-induced osteolysis and ovariectomized (OVX)-mediated osteoporosis. SIGNIFICANCE: These biological functions of pogostone make it a potential drug for treatment of breast cancer-associated bone metastasis in the future.

Co-effects of m6A and chromatin accessibility dynamics in the regulation of cardiomyocyte differentiation.

BACKGROUND: Cardiomyocyte growth and differentiation rely on precise gene expression regulation, with epigenetic modifications emerging as key players in this intricate process. Among these modifications, N6-methyladenosine (m6A) stands out as one of the most prevalent modifications on mRNA, exerting influence over mRNA metabolism and gene expression. However, the specific function of m6A in cardiomyocyte differentiation remains poorly understood. RESULTS: We investigated the relationship between m6A modification and cardiomyocyte differentiation by conducting a comprehensive profiling of m6A dynamics during the transition from pluripotent stem cells to cardiomyocytes. Our findings reveal that while the overall m6A modification level remains relatively stable, the m6A levels of individual genes undergo significant changes throughout cardiomyocyte differentiation. We discovered the correlation between alterations in chromatin accessibility and the binding capabilities of m6A writers, erasers, and readers. The changes in chromatin accessibility influence the recruitment and activity of m6A regulatory proteins, thereby impacting the levels of m6A modification on specific mRNA transcripts. CONCLUSION: Our data demonstrate that the coordinated dynamics of m6A modification and chromatin accessibility are prominent during the cardiomyocyte differentiation.

Systematic comparison of tools used for m6A mapping from nanopore direct RNA sequencing.

N6-methyladenosine (m6A) has been increasingly recognized as a new and important regulator of gene expression. To date, transcriptome-wide m6A detection primarily relies on well-established methods using next-generation sequencing (NGS) platform. However, direct RNA sequencing (DRS) using the Oxford Nanopore Technologies (ONT) platform has recently emerged as a promising alternative method to study m6A. While multiple computational tools are being developed to facilitate the direct detection of nucleotide modifications, little is known about the capabilities and limitations of these tools. Here, we systematically compare ten tools used for mapping m6A from ONT DRS data. We find that most tools present a trade-off between precision and recall, and integrating results from multiple tools greatly improve performance. Using a negative control could improve precision by subtracting certain intrinsic bias. We also observed variation in detection capabilities and quantitative information among motifs, and identified sequencing depth and m6A stoichiometry as potential factors affecting performance. Our study provides insight into the computational tools currently used for mapping m6A based on ONT DRS data and highlights the potential for further improving these tools, which may serve as the basis for future research.

[Brucine chitosan thermosensitive hydrogel for intra-articular injection].

The aim of this study was to develop a sustained release converse thermosensitive hydrogel for intra-articular injection using chitosan-glycerol-borax as matrix, its physical properties and biocompatibility were investigated. Taking gelation time and gelation condition as index, the influence of concentration of chitosan, ratio of chitosan to glycerol, pH on physical properties of hydrogel were investigated. And then the in vitro drug release, rheological properties and biocompatibility were studied. The thermosensitive hydrogel flows easily at room temperature and turns to gelation at body temperature, which can certainly prolong the release of drug and has good biocompatibility.

Recyclable and malleable thermosets enabled by activating dormant dynamic linkages.

Chemical recycling of polymers is critical for improving the circular economy of plastics and environmental sustainability. Traditional thermoset polymers have generally been considered permanently crosslinked materials that are difficult or impossible to recycle. Herein, we demonstrate that by activating 'dormant' covalent bonds, traditional polycyanurate thermosets can be recycled into the original monomers, which can be circularly reused for their original purpose. Through retrosynthetic analysis, we redirected the synthetic route from forming conventional C-N bonds via irreversible cyanate trimerization to forming the C-O bonds through reversible nucleophilic aromatic substitution of alkoxy-substituted triazine derivatives by alcohol nucleophiles. The new reversible synthetic route enabled the synthesis of previously inaccessible alkyl-polycyanurate thermosets, which exhibit excellent film properties with high chemical resistance, closed-loop recyclability and reprocessing capability. These results show that 'apparently dormant' dynamic linkages can be activated and utilized to construct fully recyclable thermoset polymers with a broader monomer scope and increased sustainability.

Pan-cancer analysis of CREB3L1 as biomarker in the prediction of prognosis and immunotherapeutic efficacy.

Background: CAMP response element binding protein 3-like 1 (CREB3L1) has been indicated as a critical biomarker and can modulate multifaced behaviors of tumor cells in diverse cancers. However, a systematic assessment of CREB3L1 in pan-cancer is of absence, and the predictive value of CREB3L1 in cancer prognosis, the tumor immune microenvironment and the efficacy of immunotherapy remains unexplored. Methods: CREB3L1 expression in 33 different cancer types was investigated using RNAseq data from The Cancer Genome Atlas (TCGA) database. The characteristics of CREB3L1 alternations were illustrated in cBioPortal database. The prognostic and clinicopathological value of CREB3L1 was analyzed through clinical data downloaded from the TCGA database. The potential role of CREB3L1 in the tumor immune microenvironment was illustrated by utilizing CIBERSORT and ESTIMATE algorithms, and TISIDB online database. The associations between CREB3L1 expression and tumor mutation burden (TMB), and microsatellite instability (MSI) were assessed by spearman's rank correlation coefficient. Furthermore, Gene Set Enrichment Analysis (GSEA) was conducted to explore the potential biological functions and downstream pathways of CREB3L1 in different human cancers. The correlations of CREB3L1 expression with PD-1/PD-L1 inhibitors efficacy and drug sensitivity were also investigated. Results: The expression of CREB3L1 was abnormally high or low in several different cancer types, and was also strictly associated with the prognosis of cancer patients. CREB3L1 expression levels have a strong relationship with infiltrating immune cells, including regulatory T cells, CD8+ T cells, macrophages, B naïve cells, dendritic cells and mast cells. CREB3L1 expression was also correlated with the expression of multiple immune-related biomolecules, TMB, and MSI in several cancers. Moreover, CREB3L1 had promising applications in predicting the immunotherapeutic benefits and drug sensitivity in cancer management. Conclusions: Our results highlight the value of CREB3L1 as a predictive biomarker for the prognosis and immunotherapy efficacy in multiple cancers, and CREB3L1 seems to play key roles in the tumor immune microenvironment, suggesting the role of CREB3L1 as a promising biomarker for predicting the prognosis and immune-related signatures in diverse cancers.

High-precision mapping reveals rare N6-deoxyadenosine methylation in the mammalian genome.

N6-deoxyadenosine methylation (6mA) is the most widespread type of DNA modification in prokaryotes and is also abundantly distributed in some unicellular eukaryotes. However, 6mA levels are remarkably low in mammals. The lack of a precise and comprehensive mapping method has hindered more advanced investigations of 6mA. Here, we report a new method MM-seq (modification-induced mismatch sequencing) for genome-wide 6mA mapping based on a novel detection principle. We found that modified DNA bases are prone to form a local open region that allows capture by antibody, for example, via a DNA breathing or base-flipping mechanism. Specified endonuclease or exonuclease can recognize the antibody-stabilized mismatch-like structure and mark the exact modified sites for sequencing readout. Using this method, we examined the genomic positions of 6mA in bacteria (E. coli), green algae (C. reinhardtii), and mammalian cells (HEK239T, Huh7, and HeLa cells). In contrast to bacteria and green algae, human cells possess a very limited number of 6mA sites which are sporadically distributed across the genome of different cell types. After knocking out the RNA m6A methyltransferase METTL3 in mouse ES cells, 6mA becomes mostly diminished. Our results imply that rare 6mA in the mammalian genome is introduced by RNA m6A machinery via a non-targeted mechanism.