Flexible covalent organic frameworks (COFs) are intriguing for their dynamic properties distinctive from rigid counterparts but still suffer from limited accessibility. Especially, controlling ...flexibility of COFs is challenging and the impact of different flexibility on properties of COFs has rarely been unveiled. This article reports stepwise adjustment on flexibility of two-dimensional COFs, which is realized by the designed synthesis of rigid COF (R-COF), semi-flexible COF (SF-COF), and flexible COF (F-COF) through polymerization, linker exchange, and linkage conversion with a newly developed method for reduction of hydrazone, respectively. Significant difference in breathing behavior and self-adaptive capability of the three COFs are uncovered through vapor response and iodine capture experiments. Gas sorption experiments indicate that the porosity of F-COF could switch from "close" state in nitrogen to "open" state in carbon dioxide, which are not observed for R-COF and SF-COF. This study not only develops a strategy to adjust the flexibility of COFs by tuning their linkers and linkages, but also provides a deep insight into the impact of different flexibility on properties of COFs, which lays a foundation for the development of this new class of dynamic porous materials.
There is an urgent need for vaccines against coronavirus disease 2019 (COVID-19) because of the ongoing SARS-CoV-2 pandemic. Among all approaches, a messenger RNA (mRNA)-based vaccine has emerged as ...a rapid and versatile platform to quickly respond to this challenge. Here, we developed a lipid nanoparticle-encapsulated mRNA (mRNA-LNP) encoding the receptor binding domain (RBD) of SARS-CoV-2 as a vaccine candidate (called ARCoV). Intramuscular immunization of ARCoV mRNA-LNP elicited robust neutralizing antibodies against SARS-CoV-2 as well as a Th1-biased cellular response in mice and non-human primates. Two doses of ARCoV immunization in mice conferred complete protection against the challenge of a SARS-CoV-2 mouse-adapted strain. Additionally, ARCoV is manufactured as a liquid formulation and can be stored at room temperature for at least 1 week. ARCoV is currently being evaluated in phase 1 clinical trials.
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•Development of LNP-encapsulated mRNA vaccine (ARCoV) targeting the RBD of SARS-CoV-2•ARCoV induces neutralizing antibodies and T cell immunity in mice and NHPs•ARCoV vaccination confers full protection against SARS-CoV-2 challenge in mice•ARCoV is a thermostable vaccine candidate for phase I studies
ARCoV is an LNP-encapsulated mRNA vaccine platform that is highly immunogenic and safe in mice and non-human primates, conferring protection against challenge with a SARS-CoV-2 mouse-adapted strain.
Recently, we reported that some dairy cows could produce high amounts of milk with high amounts of protein (defined as milk protein yield MPY) when a population was raised under the same nutritional ...and management condition, a potential new trait that can be used to increase high-quality milk production. It is unknown to what extent the rumen microbiome and its metabolites, as well as the host metabolism, contribute to MPY. Here, analysis of rumen metagenomics and metabolomics, together with serum metabolomics was performed to identify potential regulatory mechanisms of MPY at both the rumen microbiome and host levels.
Metagenomics analysis revealed that several Prevotella species were significantly more abundant in the rumen of high-MPY cows, contributing to improved functions related to branched-chain amino acid biosynthesis. In addition, the rumen microbiome of high-MPY cows had lower relative abundances of organisms with methanogen and methanogenesis functions, suggesting that these cows may produce less methane. Metabolomics analysis revealed that the relative concentrations of rumen microbial metabolites (mainly amino acids, carboxylic acids, and fatty acids) and the absolute concentrations of volatile fatty acids were higher in the high-MPY cows. By associating the rumen microbiome with the rumen metabolome, we found that specific microbial taxa (mainly Prevotella species) were positively correlated with ruminal microbial metabolites, including the amino acids and carbohydrates involved in glutathione, phenylalanine, starch, sucrose, and galactose metabolism. To detect the interactions between the rumen microbiome and host metabolism, we associated the rumen microbiome with the host serum metabolome and found that Prevotella species may affect the host's metabolism of amino acids (including glycine, serine, threonine, alanine, aspartate, glutamate, cysteine, and methionine). Further analysis using the linear mixed effect model estimated contributions to the variation in MPY based on different omics and revealed that the rumen microbial composition, functions, and metabolites, and the serum metabolites contributed 17.81, 21.56, 29.76, and 26.78%, respectively, to the host MPY.
These findings provide a fundamental understanding of how the microbiome-dependent and host-dependent mechanisms contribute to varied individualized performance in the milk production quality of dairy cows under the same management condition. This fundamental information is vital for the development of potential manipulation strategies to improve milk quality and production through precision feeding. Video Abstract.
Short-chain fatty acids in diseases Zhang, Dan; Jian, Yong-Ping; Zhang, Yu-Ning ...
Cell communication and signaling,
08/2023, Volume:
21, Issue:
1
Journal Article
Peer reviewed
Open access
Abstract
Short-chain fatty acids (SCFAs) are the main metabolites produced by bacterial fermentation of dietary fibre in the gastrointestinal tract. The absorption of SCFAs is mediated by substrate ...transporters, such as monocarboxylate transporter 1 and sodium-coupled monocarboxylate transporter 1, which promote cellular metabolism. An increasing number of studies have implicated metabolites produced by microorganisms as crucial executors of diet-based microbial influence on the host. SCFAs are important fuels for intestinal epithelial cells (IECs) and represent a major carbon flux from the diet, that is decomposed by the gut microbiota. SCFAs play a vital role in multiple molecular biological processes, such as promoting the secretion of glucagon-like peptide-1 by IECs to inhibit the elevation of blood glucose, increasing the expression of G protein-coupled receptors such as GPR41 and GPR43, and inhibiting histone deacetylases, which participate in the regulation of the proliferation, differentiation, and function of IECs. SCFAs affect intestinal motility, barrier function, and host metabolism. Furthermore, SCFAs play important regulatory roles in local, intermediate, and peripheral metabolisms. Acetate, propionate, and butyrate are the major SCFAs, they are involved in the regulation of immunity, apoptosis, inflammation, and lipid metabolism. Herein, we review the diverse functional roles of this major class of bacterial metabolites and reflect on their ability to affect intestine, metabolic, and other diseases.
Abstract
Fatty acids (FAs) are essential nutrients, but how they are transported into cells remains unclear. Here, we show that FAs trigger caveolae-dependent CD36 internalization, which in turn ...delivers FAs into adipocytes. During the process, binding of FAs to CD36 activates its downstream kinase LYN, which phosphorylates DHHC5, the palmitoyl acyltransferase of CD36, at Tyr91 and inactivates it. CD36 then gets depalmitoylated by APT1 and recruits another tyrosine kinase SYK to phosphorylate JNK and VAVs to initiate endocytic uptake of FAs. Blocking CD36 internalization by inhibiting APT1, LYN or SYK abolishes CD36-dependent FA uptake. Restricting CD36 at either palmitoylated or depalmitoylated state eliminates its FA uptake activity, indicating an essential role of dynamic palmitoylation of CD36. Furthermore, blocking endocytosis by targeting LYN or SYK inhibits CD36-dependent lipid droplet growth in adipocytes and high-fat-diet induced weight gain in mice. Our study has uncovered a dynamic palmitoylation-regulated endocytic pathway to take up FAs.
Joint tissues are exquisitely sensitive to their mechanical environment, and mechanical loading may be the most important external factor regulating the development and long‐term maintenance of joint ...tissues. Moderate mechanical loading maintains the integrity of articular cartilage; however, both disuse and overuse can result in cartilage degradation. The irreversible destruction of cartilage is the hallmark of osteoarthritis and rheumatoid arthritis. In these instances of cartilage breakdown, inflammatory cytokines such as interleukin‐1 beta and tumor necrosis factor‐alpha stimulate the production of matrix metalloproteinases (MMPs) and aggrecanases (ADAMTSs), enzymes that can degrade components of the cartilage extracellular matrix. In order to prevent cartilage destruction, tremendous effort has been expended to design inhibitors of MMP/ADAMTS activity and/or synthesis. To date, however, no effective clinical inhibitors exist. Accumulating evidence suggests that physiologic joint loading helps maintain cartilage integrity; however, the mechanisms by which these mechanical stimuli regulate joint homeostasis are still being elucidated. Identifying mechanosensitive chondroprotective pathways may reveal novel targets or therapeutic strategies in preventing cartilage destruction in joint disease.
Summary
Fungi, as eukaryotic organisms, contain two genomes, the mitochondrial genome and the nuclear genome, in their cells. How the two genomes evolve and correlate to each other is debated. ...Herein, taking the gourmet pine mushroom Tricholoma matsutake as an example, we performed comparative mitogenomic analysis using samples collected from diverse locations and compared the evolution of the two genomes. The T. matsutake mitogenome encodes 49 genes and is rich of repetitive and non‐coding DNAs. Six genes were invaded by up to 11 group I introns, with one cox1 intron cox1P372 showing presence/absence dynamics among different samples. Bioinformatic analyses suggested limited or no evidence of mitochondrial heteroplasmy. Interestingly, hundreds of mitochondrial DNA fragments were found in the nuclear genome, with several larger than 500 nt confirmed by PCR assays and read count comparisons, indicating clear evidence of transfer of mitochondrial DNA into the nuclear genome. Nuclear DNA of T. matsutake showed a higher mutation rate than mitochondrial DNA. Furthermore, we found evidence of incongruence between phylogenetic trees derived from mitogenome and nuclear DNA sequences. Together, our results reveal the dynamic genome evolution of the gourmet pine mushroom.
Hierarchical zeolites combine the intrinsic catalytic properties of microporous zeolites and the enhanced access and transport of the additional meso- and/or macroporous system. These materials are ...the most desirable catalysts and sorbents for industry and become a highly evolving field of important current interests. In addition to the enhanced mass transfer leading to high activity, selectivity, and cycle time, another essential merit of the hierarchical structure in zeolite materials is that it can significantly improve the utilization effectiveness of zeolite materials resulting in the minimum energy, time, and raw materials consumption. Substantial progress has been made in the synthesis, characterization, and application of hierarchical zeolites. Herein, we provide an overview of recent achievements in the field, highlighting the significant progress in the past decade on the development of novel and remarkable strategies to create an additional pore system in zeolites. The most innovative synthesis approaches are reviewed according to the principle, versatility, effectiveness, and degree of reality while establishing a firm link between the preparation route and the resultant hierarchical pore quality in zeolites. Zeolites with different hierarchically porous structures, i.e., micro-mesoporous structure, micro-macroporous structure, and micro-meso-macroporous structure, are then analyzed in detail with concrete examples to illustrate their benefits and their fabrications. The significantly improved performances in catalytic, environmental, and biological applications resulting from enhanced mass transport properties are discussed through a series of representative cases. In the concluding part, we envision the emergence of “material-properties-by-quantitative and real rational design” based on the “generalized Murray’s Law” that enables the predictable and controlled productions of bioinspired hierarchically structured zeolites. This Review is expected to attract important interests from catalysis, separation, environment, advanced materials, and chemical engineering fields as well as biomedicine for artificial organ and drug delivery systems.
Diabetes mellitus is a chronic, life-threatening illness that affects people of every age and ethnicity. It is a long-term pain for those who are affected and must regulate their blood glucose level ...by frequent subcutaneous injection of insulin every day. Herein, we propose a noninsulin and antidiabetic drug-free strategy for regulating blood glucose level by a nanosized “sugar sponge” which is a lectin-bound glycopolymersome capable of regulating glucose due to the dynamic recognition between the lectin and different carbohydrates. The glycopolymersome is self-assembled from poly(ethylene oxide)-block-poly(7-(2-methacryloyloxyethoxy)-4-methylcoumarin)-stat-2-(diethylamino)ethyl methacrylate-stat-(α-d-glucopyranosyl)ethyl methacrylate PEO-b-P(CMA-stat-DEA-stat-GEMA). The lectin bound in the glycopolymersome has different affinity for the glucose in the blood and the glucosyl group in the glycopolymersome. Therefore, this sugar sponge functions as a glucose storage unit by dynamic sugar replacement: The lectin in the sugar sponge will bind and store the glucose from its surrounding solution when the glucose concentration is too high and will release the glucose when the glucose concentration is too low. In vitro, this sugar-breathing behavior is characterized by a remarkable size change of the sugar sponge due to the swelling/shrinkage at high/low glucose levels, which can be used for blood sugar monitoring. In vivo, this sugar sponge showed an excellent antidiabetic effect for type I diabetic mice within 2 days upon one dose, which is much longer than traditional long-acting insulin. Overall, this concept of “controlling sugar levels with sugar” opens new avenues for regulating the blood glucose level without the involvement of insulin or other antidiabetic drugs.
Collagen-producing cells maintain the complex architecture of the lung and drive pathologic scarring in pulmonary fibrosis. Here we perform single-cell RNA-sequencing to identify all ...collagen-producing cells in normal and fibrotic lungs. We characterize multiple collagen-producing subpopulations with distinct anatomical localizations in different compartments of murine lungs. One subpopulation, characterized by expression of Cthrc1 (collagen triple helix repeat containing 1), emerges in fibrotic lungs and expresses the highest levels of collagens. Single-cell RNA-sequencing of human lungs, including those from idiopathic pulmonary fibrosis and scleroderma patients, demonstrate similar heterogeneity and CTHRC1-expressing fibroblasts present uniquely in fibrotic lungs. Immunostaining and in situ hybridization show that these cells are concentrated within fibroblastic foci. We purify collagen-producing subpopulations and find disease-relevant phenotypes of Cthrc1-expressing fibroblasts in in vitro and adoptive transfer experiments. Our atlas of collagen-producing cells provides a roadmap for studying the roles of these unique populations in homeostasis and pathologic fibrosis.
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