Discovery of Novel Ortho-Aminophenol Derivatives Targeting Lipid Peroxidation with Potent Antiferroptotic Activities.

The concept of ferroptosis inhibition has gained growing recognition as a promising therapeutic strategy for addressing a wide range of diseases. Here, we present the discovery of four series of ortho-aminophenol derivatives as potential ferroptosis inhibitors beginning with the endogenous substance 3-hydroxyanthranilic acid (3-HA) by employing quantum chemistry techniques, in vitro and in vivo assays. Our findings reveal that these ortho-aminophenol derivatives exhibit unique intra-H bond interactions, compelling ortho-amines to achieve enhanced alignment with the aromatic π-system, thereby expanding their activity. Notably, compounds from all four series display remarkable activity against RSL3-induced ferroptosis, showcasing an activity 100 times more than that of 3-HA. Furthermore, these compounds also demonstrate robust in vivo efficacy in protecting mice from kidney ischemia-reperfusion injury and acetaminophen-induced hepatotoxicity. In summary, we provide four distinct series of active scaffolds that significantly expand the chemical space of ferroptosis inhibitors, serving as valuable insights for future structural modifications.

Exploring the immunological landscape of osteomyelitis through mendelian randomization analysis.

Background: Osteomyelitis is a severe bone marrow infection, whose pathogenesis is not yet fully understood. This study aims to explore the causal relationship between immune cell characteristics and osteomyelitis, hoping to provide new insights for the prevention and treatment of osteomyelitis. Methods: Based on two independent samples, this study employed a two-sample Mendelian randomization (MR) analysis to assess the causal relationship between 731 immune cell characteristics (divided into seven groups) and osteomyelitis. Genetic variants were used as proxies for risk factors to ensure that the selected instrumental variables meet the three key assumptions of MR analysis. Genome-Wide Association Studies (GWAS) data for immune characteristics were obtained from the public GWAS catalog, while data for osteomyelitis was sourced from the FinnGen. Results: At a significance level of 0.05, 21 immune phenotypes were identified as having a causal relationship with osteomyelitis development. In the B cell group, phenotypes such as Memory B cell % B cell (percentage of memory B cells within the total B cell population, % finger cell ratio), CD20- %B cell (percentage of B cells that do not express the CD20 marker on their surface), and Memory B cell % lymphocyte showed a positive causal relationship with osteomyelitis, while Naive-mature B cell %B cell and IgD-CD38-absolute cell counts (AC) phenotypes showed a negative causal relationship. In addition, specific immune phenotypes in the conventional dendritic cells (cDCs) group, Myeloid cell group, TBNK (T cells, B cells, natural killer cells) cell group, T cell maturation stage, and Treg cell group also showed significant associations with osteomyelitis. Through reverse MR analysis, it was found that osteomyelitis had no significant causal impact on these immune phenotypes, suggesting that the occurrence of osteomyelitis may not affect these immune cell phenotypes. Conclusion: To our knowledge, this is the first study to shed light on the causal relationship between specific immune cell characteristics and the development of osteomyelitis, thereby providing a new perspective to understand the immune mechanism of osteomyelitis. These findings are significant for formulating targeted prevention and treatment strategies, and hold promise to improve the treatment outcomes for patients with osteomyelitis.

Fast Human Motion reconstruction from sparse inertial measurement units considering the human shape.

Inertial Measurement Unit-based methods have great potential in capturing motion in large-scale and complex environments with many people. Sparse Inertial Measurement Unit-based methods have more research value due to their simplicity and flexibility. However, improving the computational efficiency and reducing latency in such methods are challenging. In this paper, we propose Fast Inertial Poser, which is a full body motion estimation deep neural network based on 6 inertial measurement units considering body parameters. We design a network architecture based on recurrent neural networks according to the kinematics tree. This method introduces human body shape information by the causality of observations and eliminates the dependence on future frames. During the estimation of joint positions, the upper body and lower body are estimated using separate network modules independently. Then the joint rotation is obtained through a well-designed single-frame kinematics inverse solver. Experiments show that the method can greatly improve the inference speed and reduce the latency while ensuring the reconstruction accuracy compared with previous methods. Fast Inertial Poser runs at 65 fps with 15 ms latency on an embedded computer, demonstrating the efficiency of the model.

Sustained Phosphorus Removal and Enrichment through Off-Flow Desorption in a Reservoir of Membrane Capacitive Deionization.

In this study, we used a membrane capacitive deionization device with a reservoir (R-MCDI) to enrich phosphorus (P) from synthetic wastewater. This R-MCDI had two small-volume electrode chambers, and most of the electrolyte was contained in the reservoir, which was circulated along the electrode chambers. Compared with conventional MCDI, R-MCDI exhibited a phosphate removal rate of 0.052 µmol/(cm2·min), approximately double that of MCDI. This was attributed to R-MCDI's utilization of OH- alternative adsorption to remove phosphate from the influent. Noticing that around 73.9% of the removed phosphate was stored in the electrolyte in R-MCDI, we proposed a novel off-flow desorption operation to enrich the removed phosphate in the reservoir. Exciting results from the multicycle experiment (∼8 h) of R-MCDI showed that the PO43--P concentration in the reservoir increased all the way from the initial 152 mg/L to the final 361 mg/L, with the increase in the P charge efficiency from 5.5 to 22.9% and the decrease in the energy consumption from 28.2 to 6.8 kW h/kg P. The P recovery performance of R-MCDI was evaluated by viewing other similar studies, which revealed that R-MCDI in this study achieved superior P enrichment with low energy consumption and that the off-flow desorption proposed here considerably simplified the operation and enabled continuous P enrichment.

Design, synthesis, and biological evaluation of 2-amino-6-methyl-phenol derivatives targeting lipid peroxidation with potent anti-ferroptotic activities.

The suppression of ferroptosis is emerging as a promising therapeutic strategy for effectively treating a wide range of diseases, including neurodegenerative disorders, organ ischemia-reperfusion injury, and inflammatory conditions. However, the clinical utility of ferroptosis inhibitors is significantly impeded by the limited availability of rational drug designs. In our previous study, we successfully unraveled the efficacy of ferrostatin-1 (Fer-1) attributed to the synergistic effect of its ortho-diamine (-NH) moiety. In this study, we present the discovery of the ortho-hydroxyl-amino moiety as a novel scaffold for ferroptosis inhibitors, employing quantum chemistry as well as in vitro and in vivo assays. 2-amino-6-methylphenol derivatives demonstrated remarkable inhibition of RSL3-induced ferroptosis, exhibiting EC50 values ranging from 25 nM to 207 nM. These compounds do not appear to modulate iron homeostasis or lipid reactive oxygen species (ROS) generation pathways. Nevertheless, they effectively prevent the accumulation of lipid peroxides in living cells. Furthermore, compound 13 exhibits good in vivo activities as it effectively protect mice from kidney ischemia-reperfusion injury. In summary, compound 13 has been identified as a potent ferroptosis inhibitor, warranting further investigation as a promising lead compound.

Emerging electro-driven technologies for phosphorus enrichment and recovery from wastewater: A review.

The recovery of phosphorus from wastewater is a critical step in addressing the scarcity of phosphorus resources. Electro-driven technologies for phosphorus enrichment have gathered significant attention due to their inherent advantages, such as mild operating conditions, absence of secondary pollution, and potential integration with other technologies. This study presents a comprehensive review of recent advancements in the field of phosphorus enrichment, with a specific focus on capacitive deionization and electrodialysis technologies. It highlights the underlying principles and effectiveness of electro-driven techniques for phosphorus enrichment while systematically comparing energy consumption, enrichment rate, and concentration factor among different technologies. Furthermore, the study provides a thorough analysis of the capacity of various technologies to selectively enrich phosphorus and proposes several methods and strategies to enhance selectivity. These insights offer valuable guidance for advancing the future development of electrochemical techniques with enhanced efficiency and effectiveness in phosphorus enrichment from wastewater.

Biosynthesis of uniform fluorescent-stable telluride quantum dots in Escherichia coli and its detection of Fe3+ in water.

Quantum dots (QDs) containing zinc (Zn) and tellurium (Te) have low toxicity and excellent optoelectronic properties, which make them ideal fluorescent probes for use in environmental monitoring. However, their size/shape distribution synthesized by existing methods is not as good as that of other nanoparticles, thus limiting their application. Exploring whether this kind of QD can be biosynthesized and whether it can act as a nanoprobe are favorable attempts to expand the synthesis method and the application of QDs. Telluride QDs were biosynthesized in Escherichia coli cells. The nanoparticles were characterized by transmission electron microscopy (TEM), high-resolution transmission electron microscopy (HRTEM), energy dispersive X-ray spectroscopy (EDX), and inductively coupled plasma-atomic emission spectrometry (ICP‒AES), indicating that they were Zn3STe2 QDs. The QDs were monodispersed, spherical and fluorescently stable, with a uniform particle size of 3.05 ± 0.48 nm. The biosynthesis conditions of the QDs, including substrate concentrations and their process time, were optimized respectively. It was verified that the cysE and cysK genes were involved in the biosynthesis of telluride QDs. The biosynthesis ability of the QDs was improved by knocking out the tehB gene and overexpressing the pckA gene. Escherichia coli BW25113 cells that synthesized Zn3STe2 QDs were used as environmentally friendly fluorescent bioprobes to specifically select and quantitatively detect Fe3+ in water with a low limit of detection (2.62 µM). The fluorescent cells were also photobleach resistant and had good fluorescence stability. This study expands on the synthesis method of telluride QDs and the application of fluorescent probes.

miR171-targeted SCARECROW-LIKE genes CsSCL2 and CsSCL3 regulate somatic embryogenesis in citrus.

Somatic embryogenesis (SE) is a key regeneration pathway in various biotechnology approaches to crop improvement, especially for economically important perennial woody crops like citrus. However, maintenance of SE capability has long been a challenge and becomes a bottleneck in biotechnology-facilitated plant improvement. In the embryogenic callus (EC) of citrus, we identified 2 csi-miR171c-targeted SCARECROW-LIKE genes CsSCL2 and CsSCL3 (CsSCL2/3), which exert positive feedback regulation on csi-miR171c expression. Suppression of CsSCL2 expression by RNA interference (RNAi) enhanced SE in citrus callus. A thioredoxin superfamily protein CsClot was identified as an interactive protein of CsSCL2/3. Overexpression of CsClot disturbed reactive oxygen species (ROS) homeostasis in EC and enhanced SE. Chromatin immunoprecipitation sequencing (ChIP-Seq) and RNA-Seq identified 660 genes directly suppressed by CsSCL2 that were enriched in biological processes including development-related processes, auxin signaling pathway, and cell wall organization. CsSCL2/3 bound to the promoters of regeneration-related genes, such as WUSCHEL-RELATED HOMEOBOX 2 (CsWOX2), CsWOX13, and Lateral Organ Boundaries Domain 40 (LBD40), and repressed their expression. Overall, CsSCL2/3 modulate ROS homeostasis through the interactive protein CsClot and directly suppress the expression of regeneration-related genes, thus regulating SE in citrus. We uncovered a regulatory pathway of miR171c-targeted CsSCL2/3 in SE, which shed light on the mechanism of SE and regeneration capability maintenance in citrus.

Adaptive Laboratory Evolution Reveals the Selenium Efflux Process To Improve Selenium Tolerance Mediated by the Membrane Sulfite Pump in Saccharomyces cerevisiae.

Selenium (Se) is a micronutrient in most eukaryotes, and Se-enriched yeast is the most common selenium supplement. However, selenium metabolism and transport in yeast have remained unclear, greatly hindering the application of this element. To explore the latent selenium transport and metabolism mechanisms, we performed adaptive laboratory evolution under the selective pressure of sodium selenite and successfully obtained selenium-tolerant yeast strains. Mutations in the sulfite transporter gene ssu1 and its transcription factor gene fzf1 were found to be responsible for the tolerance generated in the evolved strains, and the selenium efflux process mediated by ssu1 was identified in this study. Moreover, we found that selenite is a competitive substrate for sulfite during the efflux process mediated by ssu1, and the expression of ssu1 is induced by selenite rather than sulfite. Based on the deletion of ssu1, we increased the intracellular selenomethionine content in Se-enriched yeast. This work confirms the existence of the selenium efflux process, and our findings may benefit the optimization of Se-enriched yeast production in the future. IMPORTANCE Selenium is an essential micronutrient for mammals, and its deficiency severely threatens human health. Yeast is the model organism for studying the biological role of selenium, and Se-enriched yeast is the most popular selenium supplement to solve Se deficiency. The cognition of selenium accumulation in yeast always focuses on the reduction process. Little is known about selenium transport, especially selenium efflux, which may play a crucial part in selenium metabolism. The significance of our research is in determining the selenium efflux process in Saccharomyces cerevisiae, which will greatly enhance our knowledge of selenium tolerance and transport, facilitating the production of Se-enriched yeast. Moreover, our research further advances the understanding of the relationship between selenium and sulfur in transport.

Hypoxia-Inducible Factor-1α Protects Against Intervertebral Disc Degeneration Through Antagonizing Mitochondrial Oxidative Stress.

Intervertebral disc degeneration (IVDD) demonstrates a gradually increased incidence and has developed into a major health problem worldwide. The nucleus pulposus is characterized by the hypoxic and avascular environment, in which hypoxia-inducible factor-1α (HIF-1α) has an important role through its participation in extracellular matrix synthesis, energy metabolism, cellular adaptation to stresses and genesis. In this study, the effects of HIF-1α on mouse primary nucleus pulposus cells (MNPCs) exposed to TNF-α were observed, the potential mechanism was explored and a rabbit IVDD model was established to verify the protective role of HIF-1α on IVDD. In vitro results demonstrated that HIF-1α could attenuate the inflammation, apoptosis and mitochondrial dysfunction induced by TNF-α in MNPCs; promote cellular anabolism; and inhibit cellular catabolism. In vivo results demonstrated that after establishment of IVDD model in rabbit, disc height and IVD extracellular matrix were decreased in a time-dependent manner, MRI analysis showed a tendency for decreased T2 values in a time-dependent manner and supplementation of HIF-1α improved histological and imaginative IVDD while downregulation of HIF-1α exacerbated this degeneration. In summary, HIF-1α protected against IVDD, possibly through reducing ROS production in the mitochondria and consequent inhibition of inflammation, metabolism disorders and apoptosis of MNPCs, which provided a potential therapeutic instrument for the treatment of IVDD diseases.

Cortistatin attenuates titanium particle-induced osteolysis through regulation of TNFR1-ROS-caspase-3 signaling in osteoblasts.

Aseptic loosening is a major complication of prosthetic joint surgery and is associated with impaired osteoblast homeostasis. Cortistatin (CST) is a neuropeptide that protects against inflammatory conditions. In this study, we found that expression of CST was diminished in patients with prosthetic joint loosening and in titanium (Ti) particle-induced animal models. A Ti particle-induced calvarial osteolysis model was established in wild-type and CST gene knockout mice; CST deficiency enhanced, while exogenously added CST attenuated, the severity of Ti particle-mediated osteolysis. CST protected against inflammation as well as apoptosis and maintained the osteogenic function of MC3T3-E1 osteoblasts upon stimulation with Ti particles. Furthermore, CST antagonized reactive oxygen species production and suppressed caspase-3-associated apoptosis mediated by Ti particles in osteoblasts. Additionally, CST protects against Ti particle-induced osteolysis through tumor necrosis factor receptor 1. Taken together, CST might provide a therapeutic strategy for wear debris-induced inflammatory osteolysis.

High-Performance Ferroelectric Electromagnetic Attenuation Materials with Multiple Polar Units Based on Nanodomain Engineering.

The multirelaxation behavior is promising for high-performance dielectric materials based on polarization-controllable high-efficiency electromagnetic attenuation. However, a single polar unit is the main problem that restricts the development of dielectric materials in the field. Herein, by constructing multiple polar units based on nanodomain engineering, enhanced electromagnetic attenuation properties are achieved in La doping BiFeO3 ferroelectric ceramics. A dual-band attenuation with a maximum reflection loss of -43.4 dB together with a wide effective bandwidth (<-10 dB) of 3.3 GHz in X-band, is acquired in Bi0.85 La0.15 FeO3 which just has a thickness of 1.54 mm. A systematic experimental analysis coupled with potential well modeling suggests that the miniaturization of the ferroelectric domain, from micron to nanoscale, induces an additional interface polarization that is capable of responding to microwave frequency, leading to the formation of dual dielectric relaxation. The way that intrinsic polar unit induces another polar unit through size effect to obtain multiple contributions of electromagnetic loss provides a feasible and universal strategy to design high-performance electromagnetic attenuation materials based on the ferroelectric family.

Stepwise hollow Prussian blue/carbon nanotubes composite as a novel electrode material for high-performance desalination.

As a promising intercalation material for capacitive deionization (CDI), Prussian blue (PB) and its analogues (PBAs) have the superiority of high theoretical capacity and easy synthesis. But they often suffer from low conductivity and severe crystal phase transition, resulting in inferior desalination capacity and poor cycling stability. Herein, the dual strategy of structural optimization and carbon-based materials introduction is proposed to enhance the desalination performance of PBAs. Stepwise hollow structure formed by surface etching has been proved to be more outstanding than cubic structure. Enlarged the specific surface area, the contact area with the electrolyte increases, therefore, more active sites are exposed. Besides, the etching of external surfaces provides more buffer space, improves the tolerance to crystal phase transition, and enhances the cycling stability. The introduction of carbon nanotubes brings high conductivity. Specifically, the desalination test shows that stepwise hollow Prussian blue/carbon nanotubes composite delivers a high desalination capacity of 103.4 mg g-1 with outstanding cycling stability. Moreover, the low energy consumption of 0.23 Wh g-1 is also suitable for practical application. The dual strategy opens a window to design advanced electrode materials for CDI.

Damage to the blood­brain barrier and activation of neuroinflammation by focal cerebral ischemia under hyperglycemic condition.

Hyperglycemia aggravates brain damage caused by cerebral ischemia/reperfusion (I/R) and increases the permeability of the blood­brain barrier (BBB). However, there are relatively few studies on morphological changes of the BBB. The present study aimed to investigate the effect of hyperglycemia on BBB morphological changes following cerebral I/R injury. Streptozotocin­induced hyperglycemic and citrate­buffered saline­injected normoglycemic rats were subjected to 30 min middle cerebral artery occlusion. Neurological deficits were evaluated. Brain infarct volume was assessed by 2,3,5­triphenyltetrazolium chloride staining and BBB integrity was evaluated by Evans blue and IgG extravasation following 24 h reperfusion. Changes in tight junctions (TJ) and basement membrane (BM) proteins (claudin, occludin and zonula occludens­1) were examined using immunohistochemistry and western blotting. Astrocytes, microglial cells and neutrophils were labeled with specific antibodies for immunohistochemistry after 1, 3 and 7 days of reperfusion. Hyperglycemia increased extravasations of Evan's blue and IgG and aggravated damage to TJ and BM proteins following I/R injury. Furthermore, hyperglycemia suppressed astrocyte activation and damaged astrocytic endfeet surrounding cerebral blood vessels following I/R. Hyperglycemia inhibited microglia activation and proliferation and increased neutrophil infiltration in the brain. It was concluded that hyperglycemia­induced BBB leakage following I/R might be caused by damage to TJ and BM proteins and astrocytic endfeet. Furthermore, suppression of microglial cells and increased neutrophil infiltration to the brain may contribute to the detrimental effects of pre­ischemic hyperglycemia on the outcome of cerebral ischemic stroke.

Biosynthesis of biocompatibility Ag2Se quantum dots in Saccharomyces cerevisiae and its application.

As fluorescence in the second near-infrared window (NIR-II, 1000-1400 nm) could image deep tissue with high signal-to-noise ratios compared with that in NIR-I (750-900 nm), Ag2Se quantum dots (QDs) with fluorescence in the NIR-II could be ideal fluorophores. Here, we described a biosynthesis method to prepare the Ag2Se QDs by using temporally coupling the irrelated biochemical reactions, whose photoluminescence (PL) emission can reach NIR-II. The nanoparticles were characterized by transmission electron microscopy (TEM), high-resolution transmission electron microscopy (HRTEM), energy-dispersive X-ray spectroscopy (EDX) and X-ray diffraction (XRD). The results showed that the nanoparticles obtained by extracellular purification were Ag2Se QDs with a uniform size of 3.9 ± 0.6 nm. In addition, the fluorescence intensity of Saccharomyces cerevisiae was improved successfully by nearly 4-fold by constructed engineering strain. In particular, the biosynthesis of Ag2Se QDs had good biocompatibility because it was capped by protein. Furthermore, investigating the toxicity of Ag2Se on cells and NIR images of nude mice showed that the Ag2Se synthesized using S. cerevisiae had low toxicity and could be used for in vivo imaging. In this work, the synthesis pathway of biocompatible Ag2Se was broadened and laid a foundation for the enlarged applicability of bioimaging in the biosynthesis of NIR-II QDs.

Remote activation of nanoparticulate biomimetic activity by light triggered pH-jump.

Herein, we report a facile, efficient and versatile method for the photo-regulation of pH-dependent activities of artificial enzymes by incorporating flash photolysis reagents. Under light excitation, a persistent pH shift is achieved by proton release from photosensitive 2-nitrobenzaldehyde. Following such change, the controlled activation of oxidase-like activity of nanoceria is successfully demonstrated.