Self-Assembled Activatable Probes to Monitor Interactive Dynamics of Intracellular Nitric Oxide and Hydrogen Sulfide.

The increasing understanding of the intricate relationship between two crucial gasotransmitters nitric oxide (NO) and hydrogen sulfide (H2S) in biological actions has generated significant interest. However, comprehensive monitoring of the dynamic fluctuations of endogenous NO and H2S remains a challenge. In this study, we have designed an innovative aggregation-induced reporter SAB-NH-SC with enhanced responsiveness to H2S for visualizing the fluctuations of intracellular NO and H2S. This probe leverages the hydrophilic properties of the pyridinium salt derivative, which can rapidly self-assemble into positively charged nanoparticles under physiological conditions, avoiding the introduction of organic solvents or tedious preparations. Notably, the reporter can repeatedly cycle S-nitrosation and SNO-transnitrosation reactions when successively treated with NO and H2S. Consequently, fluorescence alternation at 751 (H2S) and 639 nm (NO) facilitates the dynamic visualization of the alternating presence of H2S and NO within cells. This dynamic and reversible probe holds immense potential for unraveling the intricate interactions between NO and H2S in a complex network of biological applications.

High-Fidelity Spatiotemporal Recognition of Golgi ALP through an Initial-Accumulation and Postactivation Strategy.

Various signal molecules mediate complex physiological processes collectively in the Golgi. However, most currently accessible probes are questionable in illuminating the functions of these reactive species in Golgi because of the inability to irradiate these probes only at the desired Golgi location, which compromises specificity and accuracy. In this study, we rationally designed the first photocontrollable and Golgi-targeted fluorescent probe to in situ visualize the Golgi alkaline phosphatase (ALP). The designed probe with natural yellow fluorescence can provide access into Golgi and monitor the exact timing of accumulation in Golgi. On-demand photoactivation at only the desired Golgi location affords a significant emission response to ALP with illuminating red fluorescence at 710 nm. Through the photocontrollable fluorescence responsiveness to ALP, precise spatiotemporal recognition of Golgi ALP fluctuations is successfully performed. With this probe, for the first time, we revealed the Golgi ALP levels during cisplatin-induced acute kidney injury (AKI), which will further facilitate and complement the comprehensive exploration of ALP kinetics during physiological and pathological processes.

RSS and ROS Sequentially Activated Carbon Monoxide Release for Boosting NIR Imaging-Guided On-Demand Photodynamic Therapy.

Carbon monoxide shows great therapeutic potential in anti-cancer. In particular, the construction of multifunctional CO delivery systems can promote the precise delivery of CO and achieve ideal therapeutic effects, but there are still great challenges in design. In this work, a RSS and ROS sequentially activated CO delivery system is developed for boosting NIR imaging-guided on-demand photodynamic therapy. This designed system is composed of a CO releaser (BOD-CO) and a photosensitizer (BOD-I). BOD-CO can be specifically activated by hydrogen sulfide with simultaneous release of CO donor and NIR fluorescence that can identify H2S-rich tumors and guide light therapy, also depleting H2S in the process. Moreover, BOD-I generates 1O2 under long-wavelength light irradiation, enabling both PDT and precise local release of CO via a photooxidation mechanism. Such sequential activation of CO release by RSS and ROS ensured the safety and controllability of CO delivery, and effectively avoided leakage during delivery. Importantly, cytotoxicity and in vivo studies reveal that the release of CO combined with the depletion of endogenous H2S amplified PDT, achieving ideal anticancer results. It is believed that such theranostic nanoplatform can provide a novel strategy for the precise CO delivery and combined therapy involved in gas therapy and PDT.

Precise Spatiotemporal Identification of Mitochondrial H2S Fluctuations through Exploiting an On-Demand Photoactivated Probe.

Various signal molecules participate in complex biological processes in mitochondria. However, most currently available probes have problems in elucidating the functions of these active species in mitochondria due to the inability to light up these probes exclusively at the desired mitochondrial location, thereby compromising the specificity and accuracy. In this study, we present an on-demand photoactivation approach to the molecular design of optimized probes for precise spatiotemporal identification of mitochondrial H2S fluctuations. The designed probe with native yellow fluorescence can monitor the process into mitochondria but maintains nonfluorescent response to H2S during cellular delivery, providing the accurate timing of accumulation in mitochondria. On-demand photoactivation exclusively at the desired mitochondrial location affords a significant aggregation-enhanced and emissive response to H2S with lighting up red fluorescence at 690 nm, which is the only way to get such an emissive phenomenon and greatly improves the specificity and accuracy of targeting mitochondrial H2S. By using this photocontrolled fluorescence responsiveness to H2S, precise spatiotemporal identification of mitochondrial H2S fluctuations is successfully performed. Our work could facilitate advances toward interrogating the physiological and pathological consequences of mitochondrial H2S in various biological events.

Phase-Segregated Ductile Eutectogels with Ultrahigh Modulus and Toughness for Antidamaging Fabric Perception.

Ionogels are extremely soft ionic materials that can undergo large deformation while maintaining their structural and functional integrity. Ductile ionogels can absorb energy and resist fracture under external load, making them an ideal candidate for wearable electronics, soft robotics, and protective gear. However, developing high-modulus ionogels with extreme toughness remains challenging. Here, a facile one-step photopolymerization approach to construct an acrylic acid (AA)-2-hydroxyethylacrylate (HEA)-choline chloride (ChCl) eutectogel (AHCE) with ultrahigh modulus and toughness is reported. With rich hydrogen bonding crosslinks and phase segregation, this gel has a 99.1 MPa Young's modulus and a 70.6 MJ m-3 toughness along with 511.4% elongation, which can lift 12 000 times its weight. These features provide extreme damage resistance and electrical healing ability, offering it a protective and strain-sensitive coating to innovate anticutting fabric with motion detection for human healthcare. The work provides an effective strategy to construct robust ionogel materials and smart wearable electronics for intelligent life.

Specific imaging of intracellular hydrogen sulfide by a positively charged NIR fluorescent probe.

The poor water solubility of traditional activatable organic molecular probes usually limits their detection ability in physiological environment. In this work, a positively charged H2S probe was designed, which exhibited a significantly enhanced responsiveness to H2S in the aggregated state due to the increased positive charge density on the aggregate surface. Under physiological conditions, the probe could be activated by H2S with specificity and sensitivity to release near-infrared fluorescence signal. Moreover, endogenous H2S levels in living cells were successfully monitored by using this probe. We expect that this probe can provide a new strategy for the design of activatable probes to break the limitation of poor water solubility of conventional organic molecular probes.

An activatable endoplasmic reticulum-targeted probe for NIR imaging-guided photothermal therapy.

An H2O2-activated, endoplasmic reticulum-targeted theranostic probe was developed. This designed probe could be activated by H2O2, resulting in increased NIR fluorescence and photothermal signals, thus achieving specific recognition of H2O2 and further photothermal therapy in the endoplasmic reticulum of H2O2-overexpressing cancer cells.

A Bio-Inspired Molecular Design Strategy toward 2D Organic Semiconductor Crystals with Superior Integrated Optoelectronic Properties.

Inspired by the 2D bilayer lipid membranes in nature, a unique supramolecular "push-pull" synergetic strategy toward self-assembled 2D organic crystals (2DOCs) is proposed in this work, which can effectively suppress the interlayer 3D stacking while maintaining the assembly of the intralayer for 2D growth. For this purpose, a model molecule PF-Py consisting of a planar supramolecular "attractor" and a nonplanar steric "repellor" is designed for the solution self-assembly process. Well-defined 2DOCs including crystal nanosheets and millimeter-sized crystal films with layered amphiphile-like packing are obtained, which is analogical to the cell membranes of living organisms. Thanks to the special packing mode, the 2DOCs have fascinating integrated photoelectric property, with high mobility of 7.8 × 10-2 cm2 V-1 s-1 , high crystalline state photoluminescence quantum yield of 55%, and superior deep-blue laser characteristics with a low threshold of 5.51 µJ cm-2 . This supramolecular synergetic strategy advances the design of 2D organic semiconductor crystals for high performance optoelectronics.

Evaluating the risk of QTc prolongation associated with hydroxychloroquine use with antidepressants in lupus patients with fibromyalgia.

OBJECTIVE: Hydroxychloroquine (HCQ) is widely used in patients with systemic lupus erythematosus (SLE) due to its immunomodulatory properties. Antidepressants are commonly used in patients with fibromyalgia syndrome (FMS). Both HCQ and antidepressants are reported to cause QTc prolongation, which potentially increases the risk for a lethal ventricular arrhythmia that can result in sudden death. The objective of the study is to investigate the risk of QTc prolongation associated with HCQ use concomitantly with antidepressants in lupus patients with FMS. METHODS: Outpatient 12-lead electrocardiograms (ECGs) were extracted from an electronic medical record and QTc intervals were calculated using the Bazett's formula. QTc intervals in 135 lupus patients treated with HCQ with or without antidepressants were analyzed. RESULTS: We found taking HCQ was associated with mild QTc prolongation, and the prolongation was not affected by the length of time of HCQ use or the accumulated dose of HCQ. Concurrent use of HCQ and antidepressants had not further increased QTc intervals in this cohort. However, four patients on HCQ alone and three patients on HCQ and antidepressants were found QTc interval more than 500 milliseconds and most of these patients had underlying cardiological conditions. CONCLUSIONS: It is important to evaluate lupus patient with ECG before and after starting HCQ, though our study suggests that while HCQ use did prolong the QTc in some, but the overall prolongation was subclinical, with or without antidepressants. ECG monitoring therefore is essential to identify new changes potentially related to drug use.

IL-7 receptor alpha defines heterogeneity and signature of human effector memory CD8+ T cells in high dimensional analysis.

The IL-7 receptor alpha chain (IL-7Rα or CD127) can be differentially expressed in memory CD8+ T cells. Here we investigated whether IL-7Rα could serve as a key molecule in defining a comprehensive landscape of heterogeneity in human effector memory (EM) CD8+ T cells using high-dimensional Cytometry by Time-Of-Flight (CyTOF) and single-cell RNA-seq (scRNA-seq). IL-7Rα had diverse, but organized, expressional relationship in EM CD8+ T cells with molecules related to cell function and gene regulation, which rendered an immune landscape defining heterogeneous cell subsets. The differential expression of these molecules likely has biological implications as we found in vivo signatures of transcription factors and homeostasis cytokine receptors, including T-bet and IL-7Rα. Our findings indicate the existence of heterogeneity in human EM CD8+ T cells as defined by distinct but organized expression patterns of multiple molecules in relationship to IL-7Rα and its possible biological significance in modulating downstream events.

LncRNA LINC00899 promotes progression of acute myeloid leukaemia by modulating miR-744-3p/YY1 signalling.

Long non-coding RNA (lncRNA) LINC00899 is one kind cytoplasmic lncRNA, however, there is rarely little information about its function in physiological process. Here, we demonstrated that lncRNA LINC00899 was upregulated in acute myeloid leukaemia (AML) cells and was quite correlated with poor prognosis of AML patients. High expression of LINC00899 in AML cells could promote cell proliferation and inhibit cell apoptosis, and facilitate the progression of AML consequently both in vitro and in vivo. Besides, LINC00899 acted as a molecular sponge of miR-744-3p. Furthermore, we characterized YY1 as the direct target of miR-744-3p, and LINC00899/miR-744-3p interaction modulated YY1 expression in AML cells. Finally, we verified LINC00899 modulated AML cell proliferation and apoptosis via regulating YY1. Our study revealed novel mechanism about how did lncRNA LINC00899 execute function in AML and thus provided potential therapeutic interventions for AML. SIGNIFICANCE OF THE STUDY: LncRNA LINC00899 is upregulated in AML cells and is correlated with poor prognosis of AML patients. LncRNA LINC00899 mediates cell proliferation and apoptosis of acute myeloid leukaemia cells. Knockdown of LINC00899 inhibited the growth of xenograft glioma tumour in vivo. LINC00899 acts as a molecular sponge of miR-744-3p. YY1 is the downstream target of LINC00899/miR-744-3p signalling.

Engineering organelle-specific activatable molecules for ultra-fast and reliable in situ mapping of subcellular nitric oxide.

Nitric oxide (NO), a ubiquitous gaseous transmitter in living systems, is closely associated with physiopathological processes in the endoplasmic reticulum and lysosomes. This free radical gas is very widely but very heterogeneously distributed in the biological microenvironment, which poses a great challenge to specifically detect its localized levels in certain subcellular regions. In this study, we proposed six subcellular targeting probes by rational molecular engineering and selected two probes with optimal performance for the precise spatiotemporal identification of endoplasmic reticulum (ER) and lysosomal NO fluctuations. The probes could rapidly undergo a N-nitrosation reaction with NO at a riveted subcellular location, blocking the initial photoinduced electron transfer (PET) process and generating bright fluorescence for precise mapping of NO in the ER and lysosomes. The screened probes have ultra-sensitive reactivity and ultra-low detection limits for NO, realizing the precise depiction of exogenous and endogenous NO in the corresponding subcellular area. Fluctuations in the subcellular levels of NO during inflammation were also successfully mapped by the probes. Our work will contribute to the accurate study of the physiological and pathological consequences of subcellular NO in various biological events.

Depletion and Downregulation of Hydrogen Sulfide Using an Activatable Probe for Promoting Photothermal Therapy toward Colorectal Cancers.

Since hydrogen sulfide (H2S) is an important endogenous gaseous mediator, therapeutic manipulation of H2S is promising for anticancer treatment. In this work, we develop a novel theranostic nanoplatform with H2S-specific and photocontrolled synergistic activation for imaging-guided H2S depletion and downregulation along with promoted photothermal therapy. Such a nanoplatform is fabricated by integration of a H2S-responsive molecule probe that can generate a cystathionine-ß-synthase (CBS) inhibitor AOAA and a photothermal transducer into an NIR-light-responsive container. Our nanoplatform can turn on NIR fluorescence specifically in H2S-rich cancers, guiding further laser irradiation. Furthermore, prominent conversion of photoenergy into heat guarantees special container melting with controllable AOAA release for H2S-level downregulation. This smart regulation of the endogenous H2S level amplifies the PTT therapeutic effect, successfully suppressing colorectal tumor in living mice under NIR fluorescence imaging guidance. Thus, we believe that this nanoplatform may provide a powerful tool toward H2S-concerned cancer treatment with an optimized diagnostic and therapeutic effect.

Dual-modal imaging-guided agent based on NIR-II aggregation-induced emission luminogens with balanced phototheranostic performance.

Phototherapy has garnered considerable interest for its potential to revolutionize conventional cancer treatment. Organic materials with near-infrared II (NIR-II, 1000-1700 nm) fluorescence and photothermal effects are key for precise tumor diagnosis and treatment, yet optimizing their output for higher resolution and reduced photodamage remains a challenge. Herein, a multifunctional NIR-II photosensitizer (LSC) has been developed using the aggregation-induced emission (AIE) technology. The utilization of thieno[3,2-b]thiophene as an electron-rich and bulky donor/acceptor bridge has allowed for the elongation of conjugation length and distortion of the AIE main chain. This strategic modification effectively enhances the electron push-pull effect, endowing the LSC with a Stokes shift of over 400 nm and AIE characteristics. We have successfully built-up stable nanoparticles called FA-LSC NPs using a nano-precipitation method. These nanoparticles exhibit high NIR-II fluorescent brightness (ε × QY = 1064 M-1 cm-1) and photothermal conversion efficiency (41%). Furthermore, the biocompatible FA-LSC NPs demonstrate effective tumor accumulation and exceptional photothermal therapeutic efficacy both in vitro and in vivo. These nanoparticles were applied to fluorescence-photothermal dual-mode imaging-guided photothermal ablation in a HeLa tumor xenograft mouse model, resulting in favorable photothermal clearance outcomes.

Evaluation of Rice Straw, Corncob, and Soybean Straw as Substrates for the Cultivation of Lepista sordida.

Lepista sordida is a type of high-quality rare edible and medicinal mushroom, and its research boom is just beginning. More than 80 million tons of grain crop residues are produced each year in Heilongjiang Province. To realize the exploration and utilization of wild L. sordida mushrooms and also provide a theoretical support for the high-value utilization of these resources in Heilongjiang Province, we evaluated the cultivation of L. sordida mushrooms using rice straw, corncob, and soybean straw as substrates. L. sordida grew on all three substrates, and the biological efficiency and yield of the mushrooms grown on soybean straw and corncob were 32.33 ± 1.78% and 4.20 ± 0.23 kg m-2, and 30.15 ± 0.93% and 3.92 ± 0.12 kg m-2, respectively, which increased by 9.38% and 2.08% compared with that on the rice straw substrate with 3.84 ± 0.12 kg m-2 and 29.56 ± 0.89%. The time it took for the mycelia to colonize and initiate primordia on the soybean straw substrate was 22.33 ± 0.58 d and 19.67 ± 0.58 d, respectively, which was delayed by 2 d and 3 d compared with that on the rice straw substrate with 20.67 ± 2.08 d and 16.33 ± 0.58 d, respectively. The fruiting bodies grown on corncob and soybean straw substrates were relatively larger than those on the rice straw substrate. The highest amount of crude protein was 57.38 ± 0.08 g 100 g-1, and the lowest amount of crude polysaccharide was 6.03 ± 0.01 g 100 g-1. They were observed on mushrooms collected from the corncob substrate. The contents of the heavy metal mercury, lead, arsenic, and cadmium in the fruiting bodies grown on each substrate were within the national safety range.

A bionic self-driven retinomorphic eye with ionogel photosynaptic retina.

Bioinspired bionic eyes should be self-driving, repairable and conformal to arbitrary geometries. Such eye would enable wide-field detection and efficient visual signal processing without requiring external energy, along with retinal transplantation by replacing dysfunctional photoreceptors with healthy ones for vision restoration. A variety of artificial eyes have been constructed with hemispherical silicon, perovskite and heterostructure photoreceptors, but creating zero-powered retinomorphic system with transplantable conformal features remains elusive. By combining neuromorphic principle with retinal and ionoelastomer engineering, we demonstrate a self-driven hemispherical retinomorphic eye with elastomeric retina made of ionogel heterojunction as photoreceptors. The receptor driven by photothermoelectric effect shows photoperception with broadband light detection (365 to 970 nm), wide field-of-view (180°) and photosynaptic (paired-pulse facilitation index, 153%) behaviors for biosimilar visual learning. The retinal photoreceptors are transplantable and conformal to any complex surface, enabling visual restoration for dynamic optical imaging and motion tracking.

Dual emission N-doped carbon dots as a ratiometric fluorescent and colorimetric dual-signal probe for indigo carmine detection.

Novel dual-emission fluorescent nitrogen-doped carbon dots (N-CDs) were synthesized by a facile one-pot hydrothermal method using ascorbic acid and rhodamine B as precursors and melamine as nitrogen source. The obtained N-CDs exhibited dual-emitting peaks at 435 nm and 578 nm under the single excitation of 350 nm. The fluorescence at 578 nm was more effectively quenched by indigo carmine (IC) based on the internal filtration effect and aggregation-induced emission quenching. Meanwhile, the apparent color change of N-CDs from pink to blue-purple after adding various concentrations of IC could be clearly observed with the naked eye. Therefore, a ratiometric fluorescent and colorimetric dual-signal probe based on N-CDs was developed for IC detection with high selectivity and sensitivity. The addition of IC caused the ratiometric fluorescent value (F435/F578) to increase linearly within the range from 0 to100 µM with a detection limit (LOD) of 0.18 µM and the colorimetric signal presented a linear response in the range of 0-133 µM with a LOD of 57.4 nM. Furthermore, the IC in juice drink, candy, and water was successfully detected. Besides, the N-CDs were also designed as a ratiometric temperature probe, and the ratiometric fluorescence signal (F435/F578) was linearly and reversibly responsive to temperature in the range of 20-75 °C.

Corrigendum: Multi-task learning based on Stochastic Configuration Networks.

[This corrects the article DOI: 10.3389/fbioe.2022.890132.].

Molecular Engineering of Luminogens for High-Integrity Imaging of Hydrogen Polysulfides via Activatable Aggregation-Induced Dual-Color Fluorescence.

Understanding biological events associated with H2Sn rather than mediated by H2S is of great significance but remains to be solved due to a lack of high-integrity imaging tools. In this study, we report a chemoselective probe for H2Sn over H2S through the molecular engineering of luminogens. Based on our search for H2Sn-activatable probes with high selectivity, we fabricate water-soluble and biocompatible nanoprobes. Such a designed nanoprobe shows rare aggregation-induced dual-color fluorescence responses to H2Sn, lighting up bright emissions at 588 and 750 nm, respectively. By use of this activatable dual-color fluorescence, high-integrity identification of intracellular H2Sn was successfully realized. Thus, our approach to H2Sn-activated multicolor fluorescent probes could provide valuable insight into interrogating H2Sn-mediated biological events.