Exosomal long non-coding RNA AU020206 alleviates macrophage pyroptosis in atherosclerosis by suppressing CEBPB-mediated NLRP3 transcription.

Recent studies have suggested exosomes (EXO) as potential therapeutic tools for cardiovascular diseases, including atherosclerosis (AS). This study investigates the function of bone marrow stem cell (BMSC)-derived exosomes (EXO) on macrophage pyroptosis in AS and explores the associated mechanism. BMSC-EXO were isolated from healthy mice and identified. RAW264.7 cells (mouse macrophages) were exposed to oxLDL to simulate an AS condition. BMSC-EXO treatment enhanced viability and reduced lactate dehydrogenase release of macrophages. An animal model of AS was established using ApoE-/- mice. BMSC-EXO treatment suppressed plaque formation as well as macrophage and lipid infiltration in mouse aortic tissues. Moreover, BMSC-EXO decreased concentrations of pyroptosis-related markers interleukin (IL)-1ß, IL-18, cleaved-caspase-1 and gasdermin D in vitro and in vivo. Long non-coding RNA AU020206 was carried by the BMSC-EXO, and it bound to CCAAT enhancer binding protein beta (CEBPB) to block CEBPB-mediated transcriptional activation of NLR family pyrin domain containing 3 (NLRP3). Functional assays revealed that silencing of AU020206 aggravated macrophage pyroptosis and exacerbated AS symptoms in mice. These exacerbations were blocked upon CEBPB silencing but then restored after NLRP3 overexpression. In conclusion, this study demonstrates that AU020206 delivered by BMSC-EXO alleviates macrophage pyroptosis in AS by blocking CEBPB-mediated transcriptional activation of NLRP3.

A strong and tough supramolecular assembled ß-cyclodextrin and chitin nanocrystals protein adhesive: Synthesis, characterization, bonding performance on three-layer plywood.

The development of a biomass adhesive as a substitute for petroleum-derived adhesives has been considered a viable option. However, achieving both superior bonding strength and toughness in biomass adhesives remains a significant challenge. Inspired by the human skeletal muscles structure, this study reveals a promising supramolecular structure using tannin acid (TA) functionalized poly-ß-cyclodextrin (PCD) (TA@PCD) as elastic tissues and chitin nanocrystals (ChNCs) as green reinforcements to strengthen the soybean meal (SM) adhesive crosslinking network. TA@PCD acts as a dynamic crosslinker that facilitates reversible host-guest interactions, hydrogen bonds, and electrostatic interactions between adjacent stiff ChNCs and SM matrix, resulting in satisfactory strength and toughness. The resulting SM/TA@PCD/ChNCs-2 adhesive has demonstrated satisfactory wet and dry shear strength (1.25 MPa and 2.57 MPa, respectively), toughness (0.69 J), and long-term solvents resistance (80 d). Furthermore, the adhesive can exhibit desirable antimildew characteristics owing to the phenol hydroxyl groups of TA and amino groups of ChNCs. This work showcases an effective supramolecular chemistry strategy for fabricating high-performance biomass adhesives with great potential for practical applications.

Engineered poly(A)-surrogates for translational regulation and therapeutic biocomputation in mammalian cells.

Here, we present a gene regulation strategy enabling programmable control over eukaryotic translational initiation. By excising the natural poly-adenylation (poly-A) signal of target genes and replacing it with a synthetic control region harboring RNA-binding protein (RBP)-specific aptamers, cap-dependent translation is rendered exclusively dependent on synthetic translation initiation factors (STIFs) containing different RBPs engineered to conditionally associate with different eIF4F-binding proteins (eIFBPs). This modular design framework facilitates the engineering of various gene switches and intracellular sensors responding to many user-defined trigger signals of interest, demonstrating tightly controlled, rapid and reversible regulation of transgene expression in mammalian cells as well as compatibility with various clinically applicable delivery routes of in vivo gene therapy. Therapeutic efficacy was demonstrated in two animal models. To exemplify disease treatments that require on-demand drug secretion, we show that a custom-designed gene switch triggered by the FDA-approved drug grazoprevir can effectively control insulin expression and restore glucose homeostasis in diabetic mice. For diseases that require instantaneous sense-and-response treatment programs, we create highly specific sensors for various subcellularly (mis)localized protein markers (such as cancer-related fusion proteins) and show that translation-based protein sensors can be used either alone or in combination with other cell-state classification strategies to create therapeutic biocomputers driving self-sufficient elimination of tumor cells in mice. This design strategy demonstrates unprecedented flexibility for translational regulation and could form the basis for a novel class of programmable gene therapies in vivo.

Selective knowledge sharing for privacy-preserving federated distillation without a good teacher.

While federated learning (FL) is promising for efficient collaborative learning without revealing local data, it remains vulnerable to white-box privacy attacks, suffers from high communication overhead, and struggles to adapt to heterogeneous models. Federated distillation (FD) emerges as an alternative paradigm to tackle these challenges, which transfers knowledge among clients instead of model parameters. Nevertheless, challenges arise due to variations in local data distributions and the absence of a well-trained teacher model, which leads to misleading and ambiguous knowledge sharing that significantly degrades model performance. To address these issues, this paper proposes a selective knowledge sharing mechanism for FD, termed Selective-FD, to identify accurate and precise knowledge from local and ensemble predictions, respectively. Empirical studies, backed by theoretical insights, demonstrate that our approach enhances the generalization capabilities of the FD framework and consistently outperforms baseline methods. We anticipate our study to enable a privacy-preserving, communication-efficient, and heterogeneity-adaptive federated training framework.

Hydrogen Sulfide Enhances Browning Repression and Quality Maintenance in Fresh-Cut Peaches via Modulating Phenolic and Amino Acids Metabolisms.

Effects of hydrogen sulfide (H2S) on the browning and quality maintenance of fresh-cut peach fruit were studied. The results showed that H2S treatment repressed the development of surface browning, suppressed the increase in respiration rate and weight loss, and delayed the decline of firmness while soluble solids content (SSC) and microbial growth were unaffected during storage. H2S treatment maintained higher contents of phenolic compounds, especially neo-chlorogenic acid, catechin, and quercetin, and delayed the degradation of phenolic compounds by enhancing the activities of phenolic biosynthesis-related enzymes and inhibiting the oxidative activities of polyphenol oxidase (PPO) in comparison with control. Moreover, H2S stimulated the accumulation of amino acids and their derivatives including proline, γ-aminobutyric acid (GABA), and polyamines (PAs) via enhancing biosynthesis and repressing degradation compared to control. These results suggested that H2S treatment enhanced the accumulation of phenolic, amino acids, and their derivatives by modulating phenolic and amino acids metabolisms, which contributed to the higher antioxidant activity and membrane integrity maintenance, ultimately repressing browning development and maintaining the quality. Therefore, the current study speculated that H2S might be a promising approach for browning inhibition and quality maintenance in fresh-cut peach fruit.

Circumcoronenes.

Circumcoronene, a hexagonal graphene fragment with six zigzag edges, has been the focus of theoretical studies for many years, but its synthesis in solution has remained a challenge. In this study, we present a facile method for synthesizing three derivatives of circumcoronene using Brønsted/Lewis acid-mediated cyclization of vinyl ether or alkyne. Their structures were confirmed through X-ray crystallographic analysis. Bond length analysis, NMR measurement, and theoretical calculations showed that circumcoronene mostly follows Clar's bonding model and exhibits dominant local aromaticity. Its absorption and emission spectra are similar to those of the smaller hexagonal coronene due to its six-fold symmetry.

Predicting the acute-phase response fever risk in bisphosphonate-naive osteoporotic patients receiving their first dose of zoledronate.

INTRODUCTION: To devise a precise and efficient tool for predicting the individualized risk of acute-phase response (APR) in bisphosphonate (BP)-naive osteoporotic (OP) patients, receiving their first intravenous dose of zoledronate (ZOL). METHODS: The baseline clinical and laboratory data of 475 consecutive BP-naive OP patients, who received their first intravenous dose of ZOL between March 2016 and March 2021 in the Affiliated Kunshan Hospital of Jiangsu University, were chosen for analysis. Univariate and multivariable logistic regression models were generated to establish candidate predictors of APR fever risk, using three distinct fever thresholds, namely, 37.3 °C (model A), 38.0 °C (model B), and 38.5 °C (model C). Next, using predictor regression coefficients, three fever-threshold nomograms were developed. Discrimination, calibration, and clinical usefulness of each predicting models were then assessed using the area under the curve (AUC), calibration curve (CC), and decision curve analysis (DCA). The internal and external model validations were then performed. RESULTS: The stable predictors were age, serum 25-hydroxy vitamin D, serum total calcium, and peripheral blood erythrocytes count. These were negatively associated with the APR fever risk. The AUCs of models A, B, and C were 0.828 (95% confidence intervals [CI], 0.782 to 0.874), 0.825 (95% CI, 0.767 to 0.883), and 0.879 (95% CI, 0.824 to 0.934), respectively. Good agreement was observed between the predictions and observations in the CCs of all three nomograms. CONCLUSIONS: This study developed and validated nomogram prediction models that can predict APR fever risk in BP-naive OP patients receiving their first infusion of ZOL.

A Self-Powered Optogenetic System for Implantable Blood Glucose Control.

Diabetes treatment and rehabilitation are usually a lifetime process. Optogenetic engineered designer cell-therapy holds great promise in regulating blood glucose homeostasis. However, portable, sustainable, and long-term energy supplementation has previously presented a challenge for the use of optogenetic stimulation in vivo. Herein, we purpose a self-powered optogenetic system (SOS) for implantable blood glucose control. The SOS consists of a biocompatible far-red light (FRL) source, FRL-triggered transgene-expressing cells, a power management unit, and a flexible implantable piezoelectric nanogenerator (i-PENG) to supply long-term energy by converting biomechanical energy into electricity. Our results show that this system can harvest energy from body movement and power the FRL source, which then significantly enhanced production of a short variant of human glucagon-like peptide 1 (shGLP-1) in vitro and in vivo. Indeed, diabetic mice equipped with the SOS showed rapid restoration of blood glucose homeostasis, improved glucose, and insulin tolerance. Our results suggest that the SOS is sufficiently effective in self-powering the modulation of therapeutic outputs to control glucose homeostasis and, furthermore, present a new strategy for providing energy in optogenetic-based cell therapy.

Hydrogen sulfide alleviates chilling injury in peach fruit by maintaining cell structure integrity via regulating endogenous H2S, antioxidant and cell wall metabolisms.

Effects of hydrogen sulfide (H2S) on chilling injury (CI), H2S, antioxidant and cell-wall metabolisms of refrigerated peaches treated with H2S and hypotaurine (HT, H2S scavenger) were investigated in present study. Results revealed that H2S treatment enhanced endogenous H2S content, which was associated with increased related H2S synthase enzymes activities, while HT showed the opposite results. Moreover, H2S treatment induced the accumulation of ascorbic acid, glutathione and the enhancement of antioxidant enzymes activities compared to control and HT, contributing to lower hydrogen peroxide content and superoxide radical production. Furthermore, H2S suppressed the increase of cell-wall degradation enzymes accompanied by higher levels of water-insoluble pectin, 24% KOH-soluble hemicellulose and cellulose, while HT accelerated these components degradation. Therefore, results indicated that H2S mitigated CI of refrigerated peaches by regulating H2S, antioxidant and cell-wall metabolisms, maintaining higher H2S and antioxidants contents, suppressing cell-wall degradation, thereby contributing to redox homeostasis maintenance and cell structure integrity.

Exosomes Derived from Mesenchymal Stem Cells Ameliorate the Progression of Atherosclerosis in ApoE-/- Mice via FENDRR.

Exosomes (EXO) are extracellular vesicles with lipid bilayer membrane structure containing noncoding RNA, DNA, and other molecules which mediate biological functions. The importance of EXO derived from mesenchymal stem cells (MSCs) has been underlined in cardiovascular diseases. However, the functional role of long non-coding RNA (lncRNA) released by MSCs-EXO on atherosclerosis (AS) was unknown. We aimed to investigate the effects of lncRNA fetal-lethal non-coding developmental regulatory RNA (FENDRR) released from MSC-derived EXO on AS. The accumulation of oxidized low-density lipoprotein (oxLDL) caused AS in mice and damage to human vascular endothelial cells (HUV-EC-C). MSC-EXO restored HUV-EC-C activity and alleviated arterial injury. LncRNA microarrays revealed that FENDRR was delivered to cells and tissues by MSC-EXO. FENDRR bound to microRNA (miR)-28 to regulate TEA domain transcription factor 1 (TEAD1) expression. Moreover, FENDRR knockdown exacerbated cell injury and arterial injury in mice. miR-28 inhibitor reversed the effects of FENDRR silencing and reduced atherosclerotic plaque formation. While loss of TEAD1 mitigated the effect of miR-28 inhibitor and accentuated HUV-EC-C injury in vitro and AS symptoms in vivo. Our results demonstrated that MSC-EXO secreted FENDRR to treat AS. FENDRR competed with TEAD1 to bind to miR-28, thereby reducing HUV-EC-C injury and atherosclerotic plaque formation.

Engineering Mammalian Cells to Control Glucose Homeostasis.

Diabetes mellitus is a complex metabolic disease characterized by chronically deregulated blood-glucose levels. To restore glucose homeostasis, therapeutic strategies allowing well-controlled production and release of insulinogenic hormones into the blood circulation are required. In this chapter, we describe how mammalian cells can be engineered for applications in diabetes treatment. While closed-loop control systems provide automated and self-sufficient synchronization of glucose sensing and drug production, drug production in open-loop control systems is engineered to depend on exogenous user-defined trigger signals. Rational, robust, and reliable manufacture practices for mammalian cell engineering are essential for industrial-scale mass-production in view of clinical and commercial applications.

Efficient nitrogen doped porous carbonaceous CO2 adsorbents based on lotus leaf.

In this work, the waste biomass lotus leaf was converted into N-doped porous carbonaceous CO2 adsorbents. The synthesis process includes carbonization of lotus leaf, melamine post-treatment and KOH activation. For the resultant sorbents, high nitrogen content can be contained due to the melamine modification and advanced porous structure were formed by KOH etching. These samples were carefully characterized by different techniques and their CO2 adsorption properties were investigated in detail. These sorbents hold good CO2 adsorption abilities, up to 3.87 and 5.89 mmol/g at 25 and 0°C under 1 bar, respectively. By thorough investigation, the combined interplay of N content and narrow microporous volume was found to be responsible for the CO2 uptake for this series of sorbents. Together with the high CO2 adsorption abilities, these carbons also display excellent reversibility, high CO2/N2 selectivity, applicable heat of adsorption, fast CO2 adsorption kinetics and good dynamic CO2 adsorption capacity. This study reveals a universal method of obtaining N-doped porous carbonaceous sorbents from leaves. The low cost of raw materials accompanied by easy synthesis procedure disclose the enormous potential of leaves-based carbons in CO2 capture as well as many other applications.

A synthetic BRET-based optogenetic device for pulsatile transgene expression enabling glucose homeostasis in mice.

Pulsing cellular dynamics in genetic circuits have been shown to provide critical capabilities to cells in stress response, signaling and development. Despite the fascinating discoveries made in the past few years, the mechanisms and functional capabilities of most pulsing systems remain unclear, and one of the critical challenges is the lack of a technology that allows pulsatile regulation of transgene expression both in vitro and in vivo. Here, we describe the development of a synthetic BRET-based transgene expression (LuminON) system based on a luminescent transcription factor, termed luminGAVPO, by fusing NanoLuc luciferase to the light-switchable transcription factor GAVPO. luminGAVPO allows pulsatile and quantitative activation of transgene expression via both chemogenetic and optogenetic approaches in mammalian cells and mice. Both the pulse amplitude and duration of transgene expression are highly tunable via adjustment of the amount of furimazine. We further demonstrated LuminON-mediated blood-glucose homeostasis in type 1 diabetic mice. We believe that the BRET-based LuminON system with the pulsatile dynamics of transgene expression provides a highly sensitive tool for precise manipulation in biological systems that has strong potential for application in diverse basic biological studies and gene- and cell-based precision therapies in the future.

Synthesis of a Sidewall Fragment of a (12,0) Carbon Nanotube.

Synthesis of a carbon nanobelt (CNB) is a very challenging task in organic chemistry. Herein, we report the successful synthesis of an octabenzo[12]cyclacene based CNB (6), which can be regarded as a sidewall fragment of a (12,0) carbon nanotube. The key intermediate compound, a tetraepoxy nanobelt (5), was first synthesized by Diels-Alder reaction, and subsequent reductive aromatization gave the fully conjugated CNB 6. X-ray crystallographic analysis unambiguously confirmed the belt-shaped structure of 6. 1 H NMR spectrum and theoretical calculations (ACID, NICS, and 2D/3D ICSS) revealed localized aromaticity and stronger shielding chemical environment in the inner region of the belt. The optical properties (absorption and emission) of 6 were studied and correlated to its electronic structure. Strain analysis indicates that the phenyl substituents at the zigzag edges are crucial to the successful synthesis of 6. This report presents a new strategy towards highly strained CNBs.

Engineering a far-red light-activated split-Cas9 system for remote-controlled genome editing of internal organs and tumors.

It is widely understood that CRISPR-Cas9 technology is revolutionary, with well-recognized issues including the potential for off-target edits and the attendant need for spatiotemporal control of editing. Here, we describe a far-red light (FRL)-activated split-Cas9 (FAST) system that can robustly induce gene editing in both mammalian cells and mice. Through light-emitting diode-based FRL illumination, the FAST system can efficiently edit genes, including nonhomologous end joining and homology-directed repair, for multiple loci in human cells. Further, we show that FAST readily achieves FRL-induced editing of internal organs in tdTomato reporter mice. Finally, FAST was demonstrated to achieve FRL-triggered editing of the PLK1 oncogene in a mouse xenograft tumor model. Beyond extending the spectrum of light energies in optogenetic toolbox for CRISPR-Cas9 technologies, this study demonstrates how FAST system can be deployed for programmable deep tissue gene editing in both biological and biomedical contexts toward high precision and spatial specificity.

Electrogenetic cellular insulin release for real-time glycemic control in type 1 diabetic mice.

Sophisticated devices for remote-controlled medical interventions require an electrogenetic interface that uses digital electronic input to directly program cellular behavior. We present a cofactor-free bioelectronic interface that directly links wireless-powered electrical stimulation of human cells to either synthetic promoter-driven transgene expression or rapid secretion of constitutively expressed protein therapeutics from vesicular stores. Electrogenetic control was achieved by coupling ectopic expression of the L-type voltage-gated channel CaV1.2 and the inwardly rectifying potassium channel Kir2.1 to the desired output through endogenous calcium signaling. Focusing on type 1 diabetes, we engineered electrosensitive human ß cells (Electroß cells). Wireless electrical stimulation of Electroß cells inside a custom-built bioelectronic device provided real-time control of vesicular insulin release; insulin levels peaked within 10 minutes. When subcutaneously implanted, this electrotriggered vesicular release system restored normoglycemia in type 1 diabetic mice.

Notoginseng Saponin Rg1 Prevents Cognitive Impairment through Modulating APP Processing in Aß1-42-injected Rats.

With the intensification of the aging process of the world, Alzheimer's disease (AD), which is the main type of senile dementia, has become a primary problem in the present society. Lots of strategies have been used to prevent and treat AD in animal models and clinical trials, but most of them ended in failure. Panax notoginseng saponins (PNS) contain a variety of monomer compositions which have been separated and identified. Among of the monomer compositions, notoginseng saponin Rg1 (Rg1) accounts for 20% of the cultivation of panax notoginseng roots. And now PNS have been reported to be widely used to treat cardio-cerebrovascular diseases and have neuroprotective effects to restrain the ß-amyloid peptide (Aß)25-35-mediated apoptosis. Moreover, it is reported that PNS could accelerate the growth of nerve cells, increase the length of axons and promote synaptic plasticity. Whether Rg1 can ameliorate the cognitive impairment and the underlying mechanism has not been elucidated. To study the preventive effect of Rg1 on cognitive impairment and the possible mechanism, we established the cognitive impairment model in rats through Aß1-42 (2.6 µg/µL, 5 µL) injection and then treated the rats with Rg1 (25, 50 and 100 mg/kg) administered intragastrically for 4 weeks. We observed that Aß1-42 could induce spatial learning and memory deficits in rats. Simultaneously, Aß1-42 injection also resulted in the reduced neuron number in cornuammonis 1 (CA1) and dentate gyrus (DG) of hippocampus, as well as the increased level of hyperphosphorylated ß-amyloid precursor protein (APP) at Thr668 site with up-regulation of ß-APP cleaving enzyme 1 (BACE1) and presenilin 1 (PS1) and down-regulation of a disintegrin and metalloprotease domain-containing protein 10 (ADAM10) and insulin-degrading enzyme (IDE). Administration of Rg1 effectively rescued the cognitive impairment and neuronal loss, and inhibited the ß-secretase processing of APP through reducing APP-Thr668 phosphorylation and BACE1/PS1 expression, and increasing the expression of ADAM10 and IDE. We concluded that Rg1 might have neuroprotective effects and could promote learning and memory ability, which might be a viable candidate in AD therapy probably through reducing the generation of Aß and increasing the degradation of Aß.

Thieno[3,2-b]thiophene-DPP based near-infrared nanotheranostic agent for dual imaging-guided photothermal/photodynamic synergistic therapy.

Diketopyrrolopyrrole (DPP) based organic molecules have drawn significant research attention as phototheranostic agents. Herein, based on thieno[3,2-b]thienyl-DPP (TT-DPP), a near-infrared small molecule photosensitizer diethyl 3,3'-((((2,5-bis(2-decyltetradecyl)-3,6-dioxo-2,3,5,6-tetrahydropyrrolo[3,4-c]pyrrole-1,4-diyl)bis(thieno[3,2-b]thiophene-5,2-diyl))bis-(4,1-phenylene))bis(7-bromo-10H-phenothiazine-10,3-diyl))(2E,2'E)-diacrylate (PDBr), with a high singlet oxygen (1O2) quantum yield of 67%, was developed. After nano-precipitation, the hydrophilic PDBr NPs present an encouraging photothermal conversion efficiency of 35.7% and excellent fluorescence/infrared-thermal imaging performance. In vitro studies disclosed the high phototoxicity but low dark cytotoxicity of PDBr NPs to tumor cells. Furthermore, PDBr NPs can effectively impede the tumor growth without noticeable side effects in living mice through imaging-guided synergistic photothermal/photodynamic therapy. Therefore, PDBr NPs could be a promising nanotheranostic agent for imaging-guided synergistic photothermal and photodynamic therapy in the clinic.

Synthetic far-red light-mediated CRISPR-dCas9 device for inducing functional neuronal differentiation.

The ability to control the activity of CRISPR-dCas9 with precise spatiotemporal resolution will enable tight genome regulation of user-defined endogenous genes for studying the dynamics of transcriptional regulation. Optogenetic devices with minimal phototoxicity and the capacity for deep tissue penetration are extremely useful for precise spatiotemporal control of cellular behavior and for future clinic translational research. Therefore, capitalizing on synthetic biology and optogenetic design principles, we engineered a far-red light (FRL)-activated CRISPR-dCas9 effector (FACE) device that induces transcription of exogenous or endogenous genes in the presence of FRL stimulation. This versatile system provides a robust and convenient method for precise spatiotemporal control of endogenous gene expression and also has been demonstrated to mediate targeted epigenetic modulation, which can be utilized to efficiently promote differentiation of induced pluripotent stem cells into functional neurons by up-regulating a single neural transcription factor, NEUROG2 This FACE system might facilitate genetic/epigenetic reprogramming in basic biological research and regenerative medicine for future biomedical applications.

Smartphone-controlled optogenetically engineered cells enable semiautomatic glucose homeostasis in diabetic mice.

With the increasingly dominant role of smartphones in our lives, mobile health care systems integrating advanced point-of-care technologies to manage chronic diseases are gaining attention. Using a multidisciplinary design principle coupling electrical engineering, software development, and synthetic biology, we have engineered a technological infrastructure enabling the smartphone-assisted semiautomatic treatment of diabetes in mice. A custom-designed home server SmartController was programmed to process wireless signals, enabling a smartphone to regulate hormone production by optically engineered cells implanted in diabetic mice via a far-red light (FRL)-responsive optogenetic interface. To develop this wireless controller network, we designed and implanted hydrogel capsules carrying both engineered cells and wirelessly powered FRL LEDs (light-emitting diodes). In vivo production of a short variant of human glucagon-like peptide 1 (shGLP-1) or mouse insulin by the engineered cells in the hydrogel could be remotely controlled by smartphone programs or a custom-engineered Bluetooth-active glucometer in a semiautomatic, glucose-dependent manner. By combining electronic device-generated digital signals with optogenetically engineered cells, this study provides a step toward translating cell-based therapies into the clinic.